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20 Jul 2024 at 01:55
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Bibliography on: The Denisovans, Another Human Ancestor


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RJR: Recommended Bibliography 20 Jul 2024 at 01:55 Created: 

The Denisovans, Another Human Ancestor

Wikipedia: The Denisovans are an extinct species or subspecies of human in the genus Homo. In March 2010, scientists announced the discovery of a finger bone fragment of a juvenile female who lived about 41,000 years ago, found in the remote Denisova Cave in the Altai Mountains in Siberia, a cave that has also been inhabited by Neanderthals and modern humans. Two teeth belonging to different members of the same population have since been reported. In November 2015, a tooth fossil containing DNA was reported to have been found and studied. A bone needle dated to 50,000 years ago was discovered at the archaeological site in 2016 and is described as the most ancient needle known. Analysis of the mitochondrial DNA (mtDNA) of the finger bone showed it to be genetically distinct from the mtDNAs of Neanderthals and modern humans. Subsequent study of the nuclear genome from this specimen suggests that Denisovans shared a common origin with Neanderthals, that they ranged from Siberia to Southeast Asia, and that they lived among and interbred with the ancestors of some modern humans. A comparison with the genome of a Neanderthal from the same cave revealed significant local interbreeding with local Neanderthal DNA representing 17% of the Denisovan genome, while evidence was also detected of interbreeding with an as yet unidentified ancient human lineage.

Created with PubMed® Query: ( denisovan OR denisova ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2024-07-18
CmpDate: 2024-07-18

Gibbons A (2024)

Oldest human genome comes from a Denisovan.

Science (New York, N.Y.), 385(6706):240-241.

200,000-year-old DNA shows our now-extinct cousins mated with Neanderthals.

RevDate: 2024-07-13

Du S, Chen J, Li J, et al (2024)

A multi-ancestry GWAS meta-analysis of facial features and its application in predicting archaic human features.

Journal of genetics and genomics = Yi chuan xue bao pii:S1673-8527(24)00181-4 [Epub ahead of print].

Facial morphology, a complex trait influenced by genetics, holds great significance in evolutionary research. However, due to limited fossil evidence, the facial characteristics of Neanderthals and Denisovans have remained largely unknown. In this study, we conducted a large-scale multi-ethnic meta-analysis of Genome-Wide Association Study (GWAS), including 9674 East Asians and 10,115 Europeans, quantitatively assessing 78 facial traits using 3D facial images. We identified 71 genomic loci associated with facial features, including 21 novel loci. We developed a facial polygenic score (FPS) that enables the prediction of facial features based on genetic information. Interestingly, the distribution of FPSs among populations from diverse continental groups exhibited significant correlations with observed facial features. Furthermore, we applied the FPS to predict the facial traits of seven Neanderthals and one Denisovan using ancient DNA, and aligned predictions with the fossil records. Our results suggested that Neanderthals and Denisovans likely shared similar facial features, such as a wider but shorter nose and a wider endocanthion distance. The decreased mouth width was characterized specifically in Denisovan. The integration of genomic data and facial trait analysis provides valuable insights into the evolutionary history and adaptive changes in human facial morphology.

RevDate: 2024-07-11

Dengler NF, Ferraresi S, Rochkind S, et al (2024)

In Reply: Thoracic Outlet Syndrome Part I: Systematic Review of the Literature and Consensus on Anatomy, Diagnosis, and Classification of Thoracic Outlet Syndrome, and Thoracic Outlet Syndrome Part II: Consensus on the Management of Thoracic Outlet Syndrome by the European Association of Neurosurgical Societies' Section of Peripheral Nerve Surgery.

Neurosurgery pii:00006123-990000000-01277 [Epub ahead of print].

RevDate: 2024-07-03

Xia H, Zhang D, Wang J, et al (2024)

Middle and Late Pleistocene Denisovan subsistence at Baishiya Karst Cave.

Nature [Epub ahead of print].

Genetic and fragmented palaeoanthropological data suggest that Denisovans were once widely distributed across eastern Eurasia[1-3]. Despite limited archaeological evidence, this indicates that Denisovans were capable of adapting to a highly diverse range of environments. Here we integrate zooarchaeological and proteomic analyses of the late Middle to Late Pleistocene faunal assemblage from Baishiya Karst Cave on the Tibetan Plateau, where a Denisovan mandible and Denisovan sedimentary mitochondrial DNA were found[3,4]. Using zooarchaeology by mass spectrometry, we identify a new hominin rib specimen that dates to approximately 48-32 thousand years ago (layer 3). Shotgun proteomic analysis taxonomically assigns this specimen to the Denisovan lineage, extending their presence at Baishiya Karst Cave well into the Late Pleistocene. Throughout the stratigraphic sequence, the faunal assemblage is dominated by Caprinae, together with megaherbivores, carnivores, small mammals and birds. The high proportion of anthropogenic modifications on the bone surfaces suggests that Denisovans were the primary agent of faunal accumulation. The chaîne opératoire of carcass processing indicates that animal taxa were exploited for their meat, marrow and hides, while bone was also used as raw material for the production of tools. Our results shed light on the behaviour of Denisovans and their adaptations to the diverse and fluctuating environments of the late Middle and Late Pleistocene of eastern Eurasia.

RevDate: 2024-07-03

Callaway E (2024)

How Denisovans thrived on top of the world: mysterious ancient humans' survival secrets revealed.

RevDate: 2024-07-03

Anonymous (2024)

Eating habits of Denisovans on the Tibetan Plateau revealed.

RevDate: 2024-07-02

Denisova EI, EN Makarova (2024)

Influence of leptin administration to pregnant mice on fetal gene expression and adaptation to sweet and fatty food in adult offspring of different sexes.

Vavilovskii zhurnal genetiki i selektsii, 28(3):288-298.

Elevated leptin in pregnant mice improves metabolism in offspring fed high-calorie diet and its influence may be sex-specific. Molecular mechanisms mediating leptin programming action are unknown. We aimed to investigate programming actions of maternal leptin on the signaling function of the placenta and fetal liver and on adaptation to high-calorie diet in male and female offspring. Female C57BL/6J mice received leptin injections in mid-pregnancy. Gene expression was assessed in placentas and in the fetal brain and liver at the end of pregnancy. Metabolic parameters and gene expression in the liver, brown fat and hypothalamus were assessed in adult male and female offspring that had consumed sweet and fatty diet (SFD: chow, lard, sweet biscuits) for 2 weeks. Females had lower blood levels of leptin, glucose, triglycerides and cholesterol than males. Consuming SFD, females had increased Ucp1 expression in brown fat, while males had accumulated fat, decreased blood triglycerides and liver Fasn expression. Leptin administration to mothers increased Igf1 and Dnmt3b expression in fetal liver, decreased post-weaning growth rate, and increased hypothalamic Crh expression in response to SFD in both sexes. Only in male offspring this administration decreased expression of Fasn and Gck in the mature liver, increased fat mass, blood levels of glucose, triglycerides and cholesterol and Dmnt3a expression in the fetal liver. The results suggest that the influence of maternal leptin on the expression of genes encoding growth factors and DNA methyltransferases in the fetal liver may mediate its programming effect on offspring metabolic phenotypes.

RevDate: 2024-06-26

Sobolev V, Muminova M, Zhukova O, et al (2024)

HGF, HNRPD, and sFLT1 Interfere with the Induction of VEGF in Patients with Severe Psoriasis.

Current molecular medicine pii:CMM-EPUB-141246 [Epub ahead of print].

BACKGROUND: Restructuring of dermal microcapillaries is one of the hallmarks of plaque psoriasis. To control the proliferation of vascular endothelial cells, vascular endothelial growth factor (VEGF) promotes the remodeling of the existing blood vessels and angiogenesis.

OBJECTIVE: This study aimed to explain the lowering protein and mRNA levels of VEGF in lesional skin of patients with severe psoriasis (the Psoriasis Area and Severity Index, PASI > 25).

METHODS: Using the method of qPCR, we assessed the expression of VEGF mRNA in lesional and nonlesional psoriatic skin. Using ELISA, we also compared the levels of VEGF in skin homogenates of psoriasis patients and healthy volunteers.

RESULTS: We found that the exacerbation of psoriasis induced VEGF on mRNA and protein levels 12 and 20 times, respectively. We also confirmed a strong correlation between VEGF and PASI score in patients with PASI < 25. In addition, we showed that several factors, namely HGF, HNRPD, and sFLT1 interfere with the biosynthesis of VEGF in skin lesions of patients with PASI > 25%.

CONCLUSION: Thus, using VEGF as a biomarker to monitor the disease shall be done cautiously in patients with severe psoriasis.

RevDate: 2024-06-18
CmpDate: 2024-06-18

Yermakovich D, André M, Brucato N, et al (2024)

Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations.

Proceedings of the National Academy of Sciences of the United States of America, 121(26):e2405889121.

Neandertals and Denisovans, having inhabited distinct regions in Eurasia and possibly Oceania for over 200,000 y, experienced ample time to adapt to diverse environmental challenges these regions presented. Among present-day human populations, Papua New Guineans (PNG) stand out as one of the few carrying substantial amounts of both Neandertal and Denisovan DNA, a result of past admixture events with these archaic human groups. This study investigates the distribution of introgressed Denisovan and Neandertal DNA within two distinct PNG populations, residing in the highlands of Mt Wilhelm and the lowlands of Daru Island. These locations exhibit unique environmental features, some of which may parallel the challenges that archaic humans once confronted and adapted to. Our results show that PNG highlanders carry higher levels of Denisovan DNA compared to PNG lowlanders. Among the Denisovan-like haplotypes with higher frequencies in highlander populations, those exhibiting the greatest frequency difference compared to lowlander populations also demonstrate more pronounced differences in population frequencies than frequency-matched nonarchaic variants. Two of the five most highly differentiated of those haplotypes reside in genomic areas linked to brain development genes. Conversely, Denisovan-like haplotypes more frequent in lowlanders overlap with genes associated with immune response processes. Our findings suggest that Denisovan DNA has provided genetic variation associated with brain biology and immune response to PNG genomes, some of which might have facilitated adaptive processes to environmental challenges.

RevDate: 2024-06-03

Denisova K (2024)

Neurobiology of cognitive abilities in early childhood autism.

JCPP advances, 4(2):e12214.

This perspective considers complexities in the relationship between impaired cognitive abilities and autism from a maturational, developmental perspective, and aims to serve as a helpful guide for the complex and growing investigation of cognitive abilities and Autism Spectrum Disorder (ASD). Low Intelligence Quotient (IQ) and ASD are frequently co-occurring. About 37% of 8-year old children and 48% of 4-year old children diagnosed with ASD also have Intellectual Disability, with IQ below 70. And, low IQ in early infancy, including below 1 year of age, carries a 40% greater chance of receiving ASD diagnosis in early childhood. We consider the evidence that may explain this co-occurrence, including the possibility that high IQ may "rescue" the social communication issues, as well as the possible role of critical periods during growth and development. We consider how early low IQ may subsume a part of a subgroup of individuals with ASD, in particular, those diagnosed with autism in very early childhood, and we provide neurobiological evidence in support of this subtype. Moreover, we distinguish the concept of early low IQ from the delay in speech onset in preschool and school-aged children, based on (i) age and (ii) impairments in both verbal and non-verbal domains. The etiology of these early-diagnosed, early low IQ ASD cases is different from later-diagnosed, average or higher-IQ cases, and from children with speech delay onset. Given recent interest in formulating new subtypes of autism, rather than continuing to conceive of ASD as a spectrum, as well as new subtypes that vary in the degree of severity along the spectrum, we identify gaps in knowledge and directions for future work in this complex and growing area.

RevDate: 2024-05-31

Brázda V, Šislerová L, Cucchiarini A, et al (2024)

G-quadruplex propensity in H. neanderthalensis, H. sapiens and Denisovans mitochondrial genomes.

NAR genomics and bioinformatics, 6(2):lqae060.

Current methods of processing archaeological samples combined with advances in sequencing methods lead to disclosure of a large part of H. neanderthalensis and Denisovans genetic information. It is hardly surprising that the genome variability between modern humans, Denisovans and H. neanderthalensis is relatively limited. Genomic studies may provide insight on the metabolism of extinct human species or lineages. Detailed analysis of G-quadruplex sequences in H. neanderthalensis and Denisovans mitochondrial DNA showed us interesting features. Relatively similar patterns in mitochondrial DNA are found compared to modern humans, with one notable exception for H. neanderthalensis. An interesting difference between H. neanderthalensis and H. sapiens corresponds to a motif found in the D-loop region of mtDNA, which is responsible for mitochondrial DNA replication. This area is directly responsible for the number of mitochondria and consequently for the efficient energy metabolism of cell. H. neanderthalensis harbor a long uninterrupted run of guanines in this region, which may cause problems for replication, in contrast with H. sapiens, for which this run is generally shorter and interrupted. One may propose that the predominant H. sapiens motif provided a selective advantage for modern humans regarding mtDNA replication and function.

RevDate: 2024-05-27

Roca-Ayats N, Maceda I, Bruque CD, et al (2024)

Evolutionary and functional analyses of LRP5 in archaic and extant modern humans.

Human genomics, 18(1):53.

BACKGROUND: The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced.

RESULTS: We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.

CONCLUSIONS: In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.

RevDate: 2024-05-23
CmpDate: 2024-05-23

Yee SW, Ferrández-Peral L, Alentorn-Moron P, et al (2024)

Illuminating the function of the orphan transporter, SLC22A10, in humans and other primates.

Nature communications, 15(1):4380.

SLC22A10 is an orphan transporter with unknown substrates and function. The goal of this study is to elucidate its substrate specificity and functional characteristics. In contrast to orthologs from great apes, human SLC22A10, tagged with green fluorescent protein, is not expressed on the plasma membrane. Cells expressing great ape SLC22A10 orthologs exhibit significant accumulation of estradiol-17β-glucuronide, unlike those expressing human SLC22A10. Sequence alignments reveal a proline at position 220 in humans, which is a leucine in great apes. Replacing proline with leucine in SLC22A10-P220L restores plasma membrane localization and uptake function. Neanderthal and Denisovan genomes show proline at position 220, akin to modern humans, indicating functional loss during hominin evolution. Human SLC22A10 is a unitary pseudogene due to a fixed missense mutation, P220, while in great apes, its orthologs transport sex steroid conjugates. Characterizing SLC22A10 across species sheds light on its biological role, influencing organism development and steroid homeostasis.

RevDate: 2024-05-13
CmpDate: 2024-05-13

Helmbrecht N, Lackner M, Maricic T, et al (2024)

The modern human aryl hydrocarbon receptor is more active when ancestralized by genome editing.

Proceedings of the National Academy of Sciences of the United States of America, 121(22):e2402159121.

The aryl hydrocarbon receptor (AHR) is a transcription factor that has many functions in mammals. Its best known function is that it binds aromatic hydrocarbons and induces the expression of cytochrome P450 genes, which encode enzymes that metabolize aromatic hydrocarbons and other substrates. All present-day humans carry an amino acid substitution at position 381 in the AHR that occurred after the divergence of modern humans from Neandertals and Denisovans. Previous studies that have expressed the ancestral and modern versions of AHR from expression vectors have yielded conflicting results with regard to their activities. Here, we use genome editing to modify the endogenous AHR gene so that it encodes to the ancestral, Neandertal-like AHR protein in human cells. In the absence of exogenous ligands, the expression of AHR target genes is higher in cells expressing the ancestral AHR than in cells expressing the modern AHR, and similar to the expression in chimpanzee cells. Furthermore, the modern human AHR needs higher doses of three ligands than the ancestral AHR to induce the expression of target genes. Thus, the ability of AHR to induce the expression of many of its target genes is reduced in modern humans.

RevDate: 2024-04-17

Liu X, Koyama S, Tomizuka K, et al (2024)

Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing.

Science advances, 10(16):eadi8419.

We generated Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL), a high-depth whole-genome sequencing dataset comprising 3256 individuals from across Japan. Analysis of JEWEL revealed genetic characteristics of the Japanese population that were not discernible using microarray data. First, rare variant-based analysis revealed an unprecedented fine-scale genetic structure. Together with population genetics analysis, the present-day Japanese can be decomposed into three ancestral components. Second, we identified unreported loss-of-function (LoF) variants and observed that for specific genes, LoF variants appeared to be restricted to a more limited set of transcripts than would be expected by chance, with PTPRD as a notable example. Third, we identified 44 archaic segments linked to complex traits, including a Denisovan-derived segment at NKX6-1 associated with type 2 diabetes. Most of these segments are specific to East Asians. Fourth, we identified candidate genetic loci under recent natural selection. Overall, our work provided insights into genetic characteristics of the Japanese population.

RevDate: 2024-04-10

Kuzminykh NA, Shcherbakova LV, Gafarov VV, et al (2024)

Associations of ECG Signs of Ischemic and Non-Specific Signs of Metabolic Changes in the Myocardium With Unfavorable Cardiovascular Prognosis in a 7-Year Prospective Follow-Up of Young People Under 45 Years.

Kardiologiia, 64(3):18-24.

AIM: To study ischemic and/or nonspecific ECG signs of metabolic changes in the myocardium and to determine their relationship with unfavorable cardiovascular prognosis in a 7-year prospective observation of young people under 45 years of age.

MATERIAL AND METHODS: A cross-sectional population survey of a random sample aged 25-44 years (n=1363) was conducted in Novosibirsk. The survey program used the standardized epidemiological Rose questionnaire. Biochemical tests were used to measure blood concentrations of total cholesterol (C), triglycerides (TG), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), and fasting blood plasma glucose. Systolic and diastolic BP (SBP, DBP), the presence of arterial hypertension (AH), body mass index (BMI), waist circumference (WC), and smoking status were assessed. ECG was recorded at rest in 12 standard leads followed by interpretation according to the Minnesota Code. The presence of ischemic and/or nonspecific ECG signs of metabolic changes in the myocardium was determined. Subjects with ECG signs of ischemic changes in the myocardium were selected for long-term follow-up and additional examination by cardiologists. Then the whole cohort was monitored for 7 years, and cardiovascular events were recorded, including using data from the WHO Myocardial Infarction Registry in Novosibirsk. For statistical analysis of the results, cardiovascular events were combined into a composite endpoint.

RESULTS: During 7 years, 40 people (27 men and 13 women) had an unfavorable cardiovascular prognosis. Multivariate regression analysis showed that a 7-year unfavorable cardiovascular prognosis in people younger than 45 years was associated with signs of ischemic myocardial alterations identified on the background ECG (OR 5.319, 95% CI: 1.543-18.342, p=0.008) and nonspecific ECG signs of metabolic changes in the myocardium (OR 2.978, 95% CI: 1.216-7.216, p=0.017) regardless of age, gender, the presence of arterial hypertension (AH) and type 2 diabetes mellitus (DM2).

CONCLUSION: In young people under 45 years of age, not only ECG signs of ischemic changes in the myocardium, but also nonspecific ECG signs of metabolic changes in the myocardium are associated with an unfavorable cardiovascular prognosis, directly and independently on age and gender, in a long-term, 7-year period.

RevDate: 2024-04-01

Aneli S, Ceccatelli Berti C, Gilea AI, et al (2024)

Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.

Human molecular genetics pii:7638486 [Epub ahead of print].

Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.

RevDate: 2024-03-27

Stavchansky VV, Yuzhakov VV, Sevan'kaeva LE, et al (2024)

Melanocortin Derivatives Induced Vascularization and Neuroglial Proliferation in the Rat Brain under Conditions of Cerebral Ischemia.

Current issues in molecular biology, 46(3):2071-2092 pii:cimb46030133.

Stroke remains the second leading cause of death worldwide. The development of new therapeutic agents focused on restoring vascular function and neuroprotection of viable tissues is required. In this study the neuroprotective activity of melanocortin-like ACTH(4-7)PGP and ACTH(6-9)PGP peptides was investigated in rat brain at 24 h after transient middle cerebral artery occlusion (tMCAO). The severity of ischemic damage, changes in the proliferative activity of neuroglial cells and vascularization of rat brain tissue were analyzed. The administration of peptides resulted in a significant increase in the volume density of neurons in the perifocal zone of infarction compared to rats subjected to ischemia and receiving saline. Immunohistochemical analysis of the proliferative activity of neuroglia cells using PCNA antibodies showed a significant increase in the number of proliferating cells in the penumbra and in the intact cerebral cortex of rats receiving peptide treatment. The effect of peptides on vascularization was examined using CD31 antibodies under tMCAO conditions, revealing a significant increase in the volume density of vessels and their sizes in the penumbra after administration of ACTH(4-7)PGP and ACTH(6-9)PGP. These findings confirm the neuroprotective effect of peptides due to the activation of neuroglia proliferation and the enhancement of collateral blood flow.

RevDate: 2024-03-08

Geier A, Trost J, Wang K, et al (2024)

PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans.

Gut pii:gutjnl-2023-331594 [Epub ahead of print].

OBJECTIVE: Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date.

DESIGN: Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed.

RESULTS: We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years.

CONCLUSION: Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.

RevDate: 2024-03-06

Hautavoine H, Arnaud J, Balzeau A, et al (2024)

Quantifying hominin morphological diversity at the end of the middle Pleistocene: Implications for the origin of Homo sapiens.

American journal of biological anthropology [Epub ahead of print].

OBJECTIVES: The Middle Pleistocene (MP) saw the emergence of new species of hominins: Homo sapiens in Africa, H. neanderthalensis, and possibly Denisovans in Eurasia, whose most recent common ancestor is thought to have lived in Africa around 600 ka ago. However, hominin remains from this period present a wide range of morphological variation making it difficult to securely determine their taxonomic attribution and their phylogenetic position within the Homo genus. This study proposes to reconsider the phenetic relationships between MP hominin fossils in order to clarify evolutionary trends and contacts between the populations they represent.

MATERIALS AND METHODS: We used a Geometric Morphometrics approach to quantify the morphological variation of the calvarium of controversial MP specimens from Africa and Eurasia by using a comparative sample that can be divided into 5 groups: H. ergaster, H. erectus, H. neanderthalensis, and H. sapiens, as well as individuals from current modern human populations. We performed a Generalized Procrustes Analysis, a Principal Component Analysis, and Multinomial Principal Component Logistic Regressions to determine the phenetic affinities of the controversial Middle Pleistocene specimens with the other groups.

RESULTS: MP African and Eurasian specimens represent several populations, some of which show strong affinities with H. neanderthalensis in Europe or H. sapiens in Africa, others presenting multiple affinities.

DISCUSSION: These MP populations might have contributed to the emergence of these two species in different proportions. This study proposes a new framework for the human evolutionary history during the MP.

RevDate: 2024-03-04

Tyrinova T, Batorov E, Aristova T, et al (2024)

Decreased circulating myeloid-derived suppressor cell count at the engraftment is one of the risk factors for multiple myeloma relapse after autologous hematopoietic stem cell transplantation.

Heliyon, 10(5):e26362.

Recent studies demonstrated that myeloid-derived suppressor cells (MDSCs) are involved in the pathogenesis and progression of multiple myeloma (MM). Nevertheless, data on the quantitative and functional changes in MDSCs during standard MM treatment remain poorly understood. Here, we determined that monocytic MDSCs (M-MDSC; CD14[+]HLA-DR[low/-]) and granulocytic MDSCs (PMN-MDSC; Lin[-]HLA-DR[-]CD33[+]CD66b[+]) in MM patients in remission following induction therapy (IT) were significantly increased, while early MDSCs (E-MDSCs; Lin[-]HLA-DR[-]CD33[+]CD66b[-]) were decreased compared to the donor group. In progression, MM patients had the most pronounced decrease in E-MDSCs and enhanced levels of PMN-MDSCs. IT was accompanied with a decrease in the expression of arginase-1 (Arg-1). In MM patients with relapse or resistance to IT, Arg-1[+] cell frequency in M-MDSCs and E-MDSCs, as well as PD-L1[+] M-MDSCs, was increased, which may facilitate tumor immunosuppression. G-CSF administration led to a significant increment in the MDSC subsets. At the engraftment, circulating M-MDSC and PMN-MDSCs were temporarily increased, with a gradual decline to the pre-transplant levels in 12 months. The percentage of E-MDSCs was decreased at the leukocyte recovery. Patients with a higher (>Me) M-MDSC count at the engraftment had a shorter post-transplant leukopenia duration (Me 11 vs. 13 days; pU = 0.0086). The advanced MM stage, depth of response, and lower relative count of circulating E-MDSCs at the engraftment were independent risk factors associated with a lower progression-free survival. The obtained data allow us to hypothesize that MDSCs may play a positive role at the stage of leukocyte recovery by ameliorating the long-term anti-tumor response in MM.

RevDate: 2024-02-26

Kerdoncuff E, Skov L, Patterson N, et al (2024)

50,000 years of Evolutionary History of India: Insights from ~2,700 Whole Genome Sequences.

bioRxiv : the preprint server for biology pii:2024.02.15.580575.

India has been underrepresented in whole genome sequencing studies. We generated 2,762 high coverage genomes from India - including individuals from most geographic regions, speakers of all major languages, and tribal and caste groups - providing a comprehensive survey of genetic variation in India. With these data, we reconstruct the evolutionary history of India through space and time at fine scales. We show that most Indians derive ancestry from three ancestral groups related to ancient Iranian farmers, Eurasian Steppe pastoralists and South Asian hunter-gatherers. We uncover a common source of Iranian-related ancestry from early Neolithic cultures of Central Asia into the ancestors of Ancestral South Indians (ASI), Ancestral North Indians (ANI), Austro-asiatic-related and East Asian-related groups in India. Following these admixtures, India experienced a major demographic shift towards endogamy, resulting in extensive homozygosity and identity-by-descent sharing among individuals. At deep time scales, Indians derive around 1-2% of their ancestry from gene flow from archaic hominins, Neanderthals and Denisovans. By assembling the surviving fragments of archaic ancestry in modern Indians, we recover ~1.5 Gb (or 50%) of the introgressing Neanderthal and ~0.6 Gb (or 20%) of the introgressing Denisovan genomes, more than any other previous archaic ancestry study. Moreover, Indians have the largest variation in Neanderthal ancestry, as well as the highest amount of population-specific Neanderthal segments among worldwide groups. Finally, we demonstrate that most of the genetic variation in Indians stems from a single major migration out of Africa that occurred around 50,000 years ago, with minimal contribution from earlier migration waves. Together, these analyses provide a detailed view of the population history of India and underscore the value of expanding genomic surveys to diverse groups outside Europe.

RevDate: 2024-02-17

Zeberg H, Jakobsson M, S Pääbo (2024)

The genetic changes that shaped Neandertals, Denisovans, and modern humans.

Cell pii:S0092-8674(23)01403-4 [Epub ahead of print].

Modern human ancestors diverged from the ancestors of Neandertals and Denisovans about 600,000 years ago. Until about 40,000 years ago, these three groups existed in parallel, occasionally met, and exchanged genes. A critical question is why modern humans, and not the other two groups, survived, became numerous, and developed complex cultures. Here, we discuss genetic differences among the groups and some of their functional consequences. As more present-day genome sequences become available from diverse groups, we predict that very few, if any, differences will distinguish all modern humans from all Neandertals and Denisovans. We propose that the genetic basis of what constitutes a modern human is best thought of as a combination of genetic features, where perhaps none of them is present in each and every present-day individual.

RevDate: 2024-02-16

Denisova SA, Shchenkov SV, VV Lebedenkov (2024)

Microanatomy and ultrastructure of the nervous system of adult Renicola parvicaudatus (Digenea: Renicolidae).

Journal of morphology, 285(2):e21672.

The digenean complex life cycle includes various morphological forms with different locomotory and behavioral activities, and the functional specialization of their nervous system is of importance for the transmission of these parasites. Adult digeneans acquire many adaptive features associated with the final settlement in a vertebrate host. Our study describes the general morphology and ultrastructure of the nervous system of the adult renicolid digenean Renicola parvicaudatus parasitizing the renal tubules of herring gulls. Using immunocytochemical and electron microscopic methods, we identified the distinctive characteristics of ganglia and synapses in the studied species. A comparative analysis of the organization of the nervous system of adult individuals and their continuously-swimming stylet cercariae revealed a number of stage-related differences in the composition of ganglia, the distribution of serotonin- and FMRFamide-immunoreactive neurons, the cytomorphology of neuron somata and free sensory endings. Thus, in adults, the presence of FMRFamide-positive neuron somata, accessory muscle bundles in the ganglionic cortex, and eight types of neuronal vesicles was detected, but no glia-like elements were identified. Their neurons are characterized by a larger volume of cytoplasm and also show greater ultrastructural diversity. Although the sensory papillae of adults do not vary in their external morphology as much as those of larvae, their sensory bulbs are more diverse in cytomorphology. Following our previous data on the "support" cell processes related to various tissues of the larvae and considered as glia-like structures, we also briefly present the identified features of the parenchyma, attachment organs and excretory system of adult individuals. The excretory system of adult R. parvicaudatus is characterized by the presence of unique terminal cells with several flame tufts, which are not typical either for the larvae of this species or for other digeneans studied so far. We also used molecular phylogenetic analysis to clarify species identification.

RevDate: 2024-02-15

Denisová N, Piercey SJ, M Wälle (2024)

Mineralogy and mineral chemistry of the ABM replacement-style volcanogenic massive sulfide deposit, Finlayson Lake district, Yukon, Canada.

Mineralium deposita, 59(3):473-503.

UNLABELLED: The ABM deposit is a bimodal-felsic, replacement-style volcanogenic massive sulfide deposit (VMS) that is hosted by back-arc affinity rocks of the Yukon-Tanana terrane in the Finlayson Lake VMS district, Yukon, Canada. Massive sulfide zones occur as stacked and stratabound lenses subparallel to the volcanic stratigraphy, surrounded by pervasive white mica and/or chlorite alteration. Remnant clasts of volcanic rocks and preserved bedding occur locally within the massive sulfide lenses and indicate that mineralization formed through subseafloor replacement of pre-existing strata. Three mineral assemblages occur at the ABM deposit: (1) a pyrite-chalcopyrite-magnetite-pyrrhotite assemblage that is associated with Cu-Bi-Se-Co-enrichment and occurs at the center of the massive sulfide lenses; (2) a pyrite-sphalerite assemblage, which occurs more commonly towards lens margins and is enriched in Zn-Pb-Ag-Au-Hg-As-Sb-Ba; and (3) a minor assemblage comprising chalcopyrite-pyrrhotite-pyrite stringers associated with pervasive chlorite alteration, which occurs mostly at the sulfide lens margins. Petrographic observations of preserved primary, zone refining, and metamorphic textures in combination with in situ geochemistry show that the pyrite-sphalerite assemblage formed at lower temperatures (< 270 °C) than the other two mineral assemblages (~ 270-350 °C), and that mineral chemistry in all mineral assemblages was affected by greenschist facies metamorphism, although the effects are limited to recrystallization, small-scale remobilization (< 1 m) and trace element redistribution.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00126-023-01217-4.

RevDate: 2024-02-10

Végh EI, K Douka (2024)

SpecieScan: Semi-Automated taxonomic identification of bone collagen peptides from MALDI-ToF MS spectra.

Bioinformatics (Oxford, England) pii:7604576 [Epub ahead of print].

MOTIVATION: Zooarchaeology by Mass Spectrometry (ZooMS) is a palaeoproteomics method for the taxonomic determination of collagen, which traditionally involves challenging manual spectra analysis with limitations in quantitative results. As the ZooMS reference database expands, a faster and reproducible identification tool is necessary. This paper presents SpecieScan, an open-access algorithm for automating taxa identification from raw MALDI-ToF Mass Spectrometry (MS) data.

RESULTS: SpecieScan was developed using R (pre-processing) and Python (automation). The algorithm's output includes identified peptide markers, closest matching taxonomic group (taxon, family, order), correlation scores with the reference databases, and contaminant peaks present in the spectra. Testing on original MS data from bones discovered at several archaeological sites, including Denisova Cave, as well as publicly available externally produced data, achieved >90% accuracy at the genus-level and ∼92% accuracy at the family-level for data of mammalian bone collagen previously analysed using manual methods.

SUPPLEMENTARY INFORMATION: The SpecieScan algorithm, original raw data, results, reference databases, and contamination lists are freely available on the web and can be found on Github (https://github.com/mesve/SpecieScan).

RevDate: 2024-01-26

Larivière D, Abueg L, Brajuka N, et al (2024)

Scalable, accessible and reproducible reference genome assembly and evaluation in Galaxy.

RevDate: 2024-01-12

Borodko DD, Zhenilo SV, FS Sharko (2023)

Search for differentially methylated regions in ancient and modern genomes.

Vavilovskii zhurnal genetiki i selektsii, 27(7):820-828.

Currently, active research is focused on investigating the mechanisms that regulate the development of various pathologies and their evolutionary dynamics. Epigenetic mechanisms, such as DNA methylation, play a significant role in evolutionary processes, as their changes have a faster impact on the phenotype compared to mutagenesis. In this study, we attempted to develop an algorithm for identifying differentially methylated regions associated with metabolic syndrome, which have undergone methylation changes in humans during the transition from a hunter-gatherer to a sedentary lifestyle. The application of existing whole-genome bisulfite sequencing methods is limited for ancient samples due to their low quality and fragmentation, and the approach to obtaining DNA methylation profiles differs significantly between ancient hunter-gatherer samples and modern tissues. In this study, we validated DamMet, an algorithm for reconstructing ancient methylomes. Application of DamMet to Neanderthal and Denisovan genomes showed a moderate level of correlation with previously published methylation profiles and demonstrated an underestimation of methylation levels in the reconstructed profiles by an average of 15-20 %. Additionally, we developed a new Python-based algorithm that allows for the comparison of methylomes in ancient and modern samples, despite the absence of methylation profiles in modern bone tissue within the context of obesity. This analysis involves a two-step data processing approach, where the first step involves the identification and filtration of tissue-specific methylation regions, and the second step focuses on the direct search for differentially methylated regions in specific areas associated with the researcher's target condition. By applying this algorithm to test data, we identified 38 differentially methylated regions associated with obesity, the majority of which were located in promoter regions. The pipeline demonstrated sufficient efficiency in detecting these regions. These results confirm the feasibility of reconstructing DNA methylation profiles in ancient samples and comparing them with modern methylomes. Furthermore, possibilities for further methodological development and the implementation of a new step for studying differentially methylated positions associated with evolutionary processes are discussed.

RevDate: 2024-01-08

Ziv I, Avni I, Dinstein I, et al (2024)

Oculomotor randomness is higher in autistic children and increases with the severity of symptoms.

Autism research : official journal of the International Society for Autism Research [Epub ahead of print].

A variety of studies have suggested that at least some children with autism spectrum disorder (ASD) view the world differently. Differences in gaze patterns as measured by eye tracking have been demonstrated during visual exploration of images and natural viewing of movies with social content. Here we analyzed the temporal randomness of saccades and blinks during natural viewing of movies, inspired by a recent measure of "randomness" applied to micro-movements of the hand and head in ASD (Torres et al., 2013; Torres & Denisova, 2016). We analyzed a large eye-tracking dataset of 189 ASD and 41 typically developing (TD) children (1-11 years old) who watched three movie clips with social content, each repeated twice. We found that oculomotor measures of randomness, obtained from gamma parameters of inter-saccade intervals (ISI) and blink duration distributions, were significantly higher in the ASD group compared with the TD group and were correlated with the ADOS comparison score, reflecting increased "randomness" in more severe cases. Moreover, these measures of randomness decreased with age, as well as with higher cognitive scores in both groups and were consistent across repeated viewing of each movie clip. Highly "random" eye movements in ASD children could be associated with high "neural variability" or noise, poor sensory-motor control, or weak engagement with the movies. These findings could contribute to the future development of oculomotor biomarkers as part of an integrative diagnostic tool for ASD.

RevDate: 2024-01-03

Ojomoko LO, Kryukova EV, Egorova NS, et al (2023)

Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds.

Frontiers in pharmacology, 14:1327603 pii:1327603.

Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed "cyclo"R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), C-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. "Cyclo"R8 showed similar activity to that of R8 against α9α10 nAChR (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.

RevDate: 2024-01-03

Levinstein Hallak K, S Rosset (2024)

Dating ancient splits in phylogenetic trees, with application to the human-Neanderthal split.

BMC genomic data, 25(1):4.

BACKGROUND: We tackle the problem of estimating species TMRCAs (Time to Most Recent Common Ancestor), given a genome sequence from each species and a large known phylogenetic tree with a known structure (typically from one of the species). The number of transitions at each site from the first sequence to the other is assumed to be Poisson distributed, and only the parity of the number of transitions is observed. The detailed phylogenetic tree contains information about the transition rates in each site. We use this formulation to develop and analyze multiple estimators of the species' TMRCA. To test our methods, we use mtDNA substitution statistics from the well-established Phylotree as a baseline for data simulation such that the substitution rate per site mimics the real-world observed rates.

RESULTS: We evaluate our methods using simulated data and compare them to the Bayesian optimizing software BEAST2, showing that our proposed estimators are accurate for a wide range of TMRCAs and significantly outperform BEAST2. We then apply the proposed estimators on Neanderthal, Denisovan, and Chimpanzee mtDNA genomes to better estimate their TMRCA with modern humans and find that their TMRCA is substantially later, compared to values cited recently in the literature.

CONCLUSIONS: Our methods utilize the transition statistics from the entire known human mtDNA phylogenetic tree (Phylotree), eliminating the requirement to reconstruct a tree encompassing the specific sequences of interest. Moreover, they demonstrate notable improvement in both running speed and accuracy compared to BEAST2, particularly for earlier TMRCAs like the human-Chimpanzee split. Our results date the human - Neanderthal TMRCA to be [Formula: see text] years ago, considerably later than values cited in other recent studies.

RevDate: 2023-12-30

Ivchenko GS, Lobzhanidze NN, Rusina DS, et al (2023)

[Mild post-COVID syndrome in young patients].

Terapevticheskii arkhiv, 95(8):674-678.

BACKGROUND: Many COVID-19 survivors suffer from post-COVID syndrome, which significantly worsens the quality of life. Its presentation is quite diverse, with cognitive disorders being of particular importance. Liver injury due to the direct virus action and the treatment of the new coronavirus infection can persist for a long time during the recovery period and lead to hyperammonemia, which can cause cognitive disorders, including minimal hepatic encephalopathy.

AIM: To study cognitive disorders in post-COVID syndrome and the possibility of their treatment with L-ornithine-L-aspartate.

MATERIALS AND METHODS: The study included 30 students from 18 to 24 years old who had COVID-19 and decreased attention, memory impairment, and other cognitive disorders inherent in hepatic encephalopathy of latent (grade 0) or mild (grade 1) severity, without pronounced impairment of intelligence, memory, speech, and learning ability. Hyperammonemia, elevated alanine aminotransferase, aspartate aminotransferase, and ã-glutamyl transpeptidase, signs of hepatic encephalopathy according to psychometric tests, were reported in young people. All patients in the study were treated with L-ornithine-L-aspartate to correct the ammonia blood level and improve signs of hepatic encephalopathy and the general condition.

RESULTS AND CONCLUSION: An improvement in the objective findings, liver enzymes, a decrease in ammonia level, and an improvement in testing results for changes in cognitive functions were reported.

RevDate: 2023-12-19

Zhao H, Liu LL, Sun J, et al (2023)

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression.

Science China. Life sciences [Epub ahead of print].

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution.

RevDate: 2023-12-14

Velazquez-Arcelay K, Colbran LL, McArthur E, et al (2023)

Archaic Introgression Shaped Human Circadian Traits.

Genome biology and evolution, 15(12):.

When the ancestors of modern Eurasians migrated out of Africa and interbred with Eurasian archaic hominins, namely, Neanderthals and Denisovans, DNA of archaic ancestry integrated into the genomes of anatomically modern humans. This process potentially accelerated adaptation to Eurasian environmental factors, including reduced ultraviolet radiation and increased variation in seasonal dynamics. However, whether these groups differed substantially in circadian biology and whether archaic introgression adaptively contributed to human chronotypes remain unknown. Here, we traced the evolution of chronotype based on genomes from archaic hominins and present-day humans. First, we inferred differences in circadian gene sequences, splicing, and regulation between archaic hominins and modern humans. We identified 28 circadian genes containing variants with potential to alter splicing in archaics (e.g., CLOCK, PER2, RORB, and RORC) and 16 circadian genes likely divergently regulated between present-day humans and archaic hominins, including RORA. These differences suggest the potential for introgression to modify circadian gene expression. Testing this hypothesis, we found that introgressed variants are enriched among expression quantitative trait loci for circadian genes. Supporting the functional relevance of these regulatory effects, we found that many introgressed alleles have associations with chronotype. Strikingly, the strongest introgressed effects on chronotype increase morningness, consistent with adaptations to high latitude in other species. Finally, we identified several circadian loci with evidence of adaptive introgression or latitudinal clines in allele frequency. These findings identify differences in circadian gene regulation between modern humans and archaic hominins and support the contribution of introgression via coordinated effects on variation in human chronotype.

RevDate: 2023-12-05

Wroblewski TH, Witt KE, Lee SB, et al (2023)

Pharmacogenetic variation in Neanderthals and Denisovans and implications for human health and response to medications.

Genome biology and evolution pii:7459155 [Epub ahead of print].

Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes - genes responsible for the processing of exogenous substances such as food, pollutants, and medications - as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore eleven key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these eleven CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.

RevDate: 2023-11-29

Agata A, Ohtsuka S, Noji R, et al (2023)

A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice.

Frontiers in cell and developmental biology, 11:1247361.

Changes in genomic structures underlie phenotypic diversification in organisms. Amino acid-changing mutations affect pleiotropic functions of proteins, although little is known about how mutated proteins are adapted in existing developmental programs. Here we investigate the biological effects of a variant of the GLI3 transcription factor (GLI3[R1537C]) carried in Neanderthals and Denisovans, which are extinct hominins close to modern humans. R1537C does not compromise protein stability or GLI3 activator-dependent transcriptional activities. In contrast, R1537C affects the regulation of downstream target genes associated with developmental processes. Furthermore, genome-edited mice carrying the Neanderthal/Denisovan GLI3 mutation exhibited various alterations in skeletal morphology. Our data suggest that an extinct hominin-type GLI3 contributes to species-specific anatomical variations, which were tolerated by relaxed constraint in developmental programs during human evolution.

RevDate: 2023-11-27
CmpDate: 2023-11-27

Mikhailova SV, Ivanoshchuk DE, Orlov PS, et al (2023)

Assessment of the Genetic Characteristics of a Generation Born during a Long-Term Socioeconomic Crisis.

Genes, 14(11):.

BACKGROUND: A socioeconomic crisis in Russia lasted from 1991 to 1998 and was accompanied by a sharp drop in the birth rate. The main factor that influenced the refusal to have children during this period is thought to be prolonged social stress.

METHODS: comparing frequencies of common gene variants associated with stress-induced diseases among generations born before, after, and during this crisis may show which genes may be preferred under the pressure of natural selection during periods of increased social stress in urban populations.

RESULTS: In the "crisis" group, a statistically significant difference from the other two groups was found in rs6557168 frequency (p = 0.001); rs4522666 was not in the Hardy-Weinberg equilibrium in this group, although its frequency did not show a significant difference from the other groups (p = 0.118). Frequencies of VNTRs in SLC6A3 and MAOA as well as common variants rs17689918 in CRHR1, rs1360780 in FKBP5, rs53576 in OXTR, rs12720071 and rs806377 in CNR1, rs4311 in ACE, rs1800497 in ANKK1, and rs7412 and rs429358 in APOE did not differ among the groups.

CONCLUSIONS: a generation born during a period of prolonged destructive events may differ from the rest of the gene pool of the population in some variants associated with personality traits or stress-related disorders.

RevDate: 2023-11-28

Denisova K (2023)

Reply to Silber: on discoveries in science.

RevDate: 2023-11-24

Rzhepakovsky I, Piskov S, Avanesyan S, et al (2023)

Composite of bacterial cellulose and gelatin: A versatile biocompatible scaffold for tissue engineering.

International journal of biological macromolecules pii:S0141-8130(23)05268-6 [Epub ahead of print].

Synthesis of 0.4 ± 0.03 g/L per day of pure and porous bacterial cellulose (BC) scaffolds (scaffBC) and BC scaffolds modified with gelatin (scaffBC/Gel) was carried out using the Medusomyces gisevii Sa-28 bacterial strain. FT-IR spectroscopy and X-ray diffraction analysis showed that the scaffolds largely consist of crystalline cellulose I (Iα, Iß). Heating of BC with gelatin to 60 °C with subsequent lyophilization led to its modification by adsorption and binding of low-molecular fractions of gelatin and the formation of small pores between the fibers, which increased the biocompatibility and solubility of BC. The solubility of scaffBC and scaffBC/Gel was 20.8 % and 44.4 %, respectively, which enhances degradation in vivo. Light microscopy, scanning electron microscopy, and microcomputed tomography showed a uniform distribution of pores with a diameter of 100-500 μm. The chicken chorioallantoic membrane (CAM) model and subcutaneous implantation in rats confirmed low immunogenicity and intense formation of collagen fibers in both scaffolds and active germination of new blood vessels in scaffBC and scaffBC/Gel. The proliferative cellular activity of fibroblasts confirmed the safety of scaffolds. Taken together, the results obtained show that scaffBC/Gel can be used for the engineering of hard and soft tissues, which opens opportunities for further research.

RevDate: 2023-11-28

Marshenya SN, Dembitskiy AD, Fedorov DS, et al (2023)

NaGaPO4F - a KTiOPO4-structured solid sodium-ion conductor.

Dalton transactions (Cambridge, England : 2003), 52(46):17426-17437.

Advanced ionic conductors are crucial for a large variety of contemporary technologies spanning solid state ion batteries, fuel cells, gas sensors, water desalination, etc. In this work, we report on a new member of KTiOPO4-structured materials, NaGaPO4F, with sodium-ion conductivity. NaGaPO4F has been obtained for the first time via a facile two-step synthesis consisting of a hydrothermal preparation of an ammonia-based precursor, NH4GaPO4F, followed by an ion exchange reaction with NaNO3. Its crystal structure was precisely refined using a combination of synchrotron X-ray powder diffraction and electron diffraction tomography. The material is thermally stable upon 450 °C showing no significant structural transformations or degradation but only a ∼1% cell volume expansion. Na-ion mobility in NaGaPO4F was investigated by a joint experimental and computational approach comprising solid-state nuclear magnetic resonance (NMR) and density functional theory (DFT). DFT and bond-valence site energy (BVSE) calculations reveal 3D diffusion of sodium in the [GaPO4F] framework with migration barriers amounting to 0.22 and 0.44 eV, respectively, while NMR yields 0.3-0.5 eV that, being coupled with a calculated bandgap of ∼4.25 eV, makes NaGaPO4F a promising fast Na-ion conductor.

RevDate: 2023-11-10
CmpDate: 2023-11-10

Katargina LA, Chesnokova NB, Denisova EV, et al (2023)

[The role of endothelin-1 in the pathogenesis of familial exudative vitreoretinopathy].

Vestnik oftalmologii, 139(5):14-18.

UNLABELLED: Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disease characterized by pathological retinal vascularization with a progressive and variable course. The mechanisms of disease progression remain unclear. One substance that plays an important role in the pathogenesis of retinal vascular diseases is endothelin (ET). It was found that tissue hypoxia enhances the expression of the gene encoding ET-1, and ET-1 can be locally produced in the eye.

PURPOSE: The study evaluates the possible role of endothelin-1 in the pathogenesis of FEVR.

MATERIAL AND METHODS: The study included 85 patients with FEVR aged from 1 months to 17 years who were examined in Helmholtz National Medical Research Center of Eye Diseases. The concentration of ET-1 was evaluated in 19 patients with FEVR in the blood serum (n=17), lacrimal fluid (n=18) and 16 patients from the control group.

RESULTS: The median of ET-1 in the lacrimal fluid in patients with FEVR was 13.74 pg/mL, respectively, which exceeded the same indicator of the control group 4.66 pg/mL by 2.5 times (p<0.001). The median of ET-1 in the blood serum exceeded the control group by 2.4 times (21.61 pg/mL and 9.21 pg/mL, respectively, p<0.001).

CONCLUSIONS: An increase in the concentration of ET-1 in the lacrimal fluid and blood serum of patients with FEVR in comparison with the control group indicates its involvement in the pathogenesis of the disease.

RevDate: 2023-11-04

Gaggiano C, Gupta V, Agrawal R, et al (2023)

Knowledge and Current Practices in Monogenic Uveitis: An International Survey by IUSG and AIDA Network.

Ophthalmology and therapy [Epub ahead of print].

INTRODUCTION: This study aims to explore awareness, knowledge, and diagnostic/therapeutic practices in monogenic uveitis (mU) among uveitis experts.

METHODS: This is an explorative, cross-sectional survey study. An anonymous, semi-structured, electronic survey was delivered to uveitis experts from the Autoinflammatory Diseases Alliance (AIDA) Network and International Uveitis Study Group (IUSG). We included respondents answering ≥ 50% of the survey.

RESULTS: Seventy-seven participants rated their knowledge of mU as proficient (3.9%), adequate (15.6%), sufficient (16.9%), or poor (63.6%). When asked about the first mU gene they thought of, 60.4% mentioned NOD2, 3.9% mentioned NLRP3 or MEFV, and 49.4% provided incorrect or no answers. Success rates in clinical scenarios varied from 15.6% to 55.8% and were higher for ophthalmologists working in multidisciplinary teams (p < 0.01). Genetic testing was ordered for suspected mU by 41.6% of physicians. The availability of molecular techniques did not significantly differ based on geography (p > 0.05). The public healthcare system ensured a higher percentage of tests prescribed were obtained by patients compared to private insurances (p < 0.00). In terms of disease-modifying anti-rheumatic drugs (DMARDs), tumor necrosis factor-α inhibitors were the most familiar to uveitis experts. The difficulties with off-label therapy procedures were the primary barrier to DMARDs prescription for patients with mU and correlated inversely with the obtained/prescribed drug ratio for interleukin-1 (p < 0.01) and interleukin-6 (p < 0.01) inhibitors.

CONCLUSIONS: This survey identifies proficiency areas, gaps, and opportunities for targeted improvements in patients care. The comprehensive outputs may inform evidence-based guidelines, empowering clinicians with standardized approaches, and drive an AIDA Network-IUSG unified effort to advance scientific knowledge and clinical practice.

RevDate: 2023-11-02
CmpDate: 2023-11-02

Danchenko EA, Ertuzun IA, Bugaeva LI, et al (2023)

Analysis of General Toxicity of Ergoferon.

Bulletin of experimental biology and medicine, 175(5):644-648.

For antibody-based drugs, it is important and relevant to study their toxic effects, which can often become limiting when prescribing this type of therapy. General toxicity of antiviral drug Ergoferon based on technologically processed antibodies was studied on sexually mature animals. Analysis of acute toxicity showed the absence of lethal outcomes when the drug was administered to adult rats at the maximum tolerated doses. In a study of repeated dose toxicity, no adverse effects of the drug were detected.

RevDate: 2023-10-23
CmpDate: 2023-10-23

Sokolov S, Shchenkov S, Frolov E, et al (2023)

Molecular and morphological screening of Podocotyle spp. (Trematoda: Opecoelidae) sheds light on their diversity in Northwest Pacific and eastern European Arctic.

Journal of helminthology, 97:e78 pii:S0022149X23000603.

Podocotyle is a genus of marine opecoelid digeneans that parasitize a wide variety of fish as adults. We present the first phylogenetic analysis of several Podocotyle isolates using nuclear 28S rDNA and mitochondrial cox1 DNA regions. New sequences were obtained for Podocotyle specimens from fish caught in the Sea of Okhotsk and the White Sea. Based on morphological and molecular data, eight Podocotyle lineages of species rank were revealed. However, this diversity is poorly formalized within the current taxonomic model of the genus. As a result, we identified Podocotyle cf. angulata, Podocotyle cf. atomon, Podocotyle cf. reflexa, Podocotyle atomon of Sokolov et al., 2019, Podocotyle sp. of Denisova et al., 2023, Podocotyle sp. 1, Podocotyle sp. 2 and Podocotyle sp. 3. We also highlight the unresolved question of the life cycles of representatives of Podocotyle whose intramolluscan stages parasitize the intertidal snails Littorina spp.

RevDate: 2023-11-03
CmpDate: 2023-11-03

Alenkina IV, Chukin AV, Leitus G, et al (2024)

Analysis of the iron states in iron-containing pharmaceutical products using Mössbauer spectroscopy.

Journal of pharmaceutical and biomedical analysis, 237:115745.

Iron-containing pharmaceuticals, namely: (i) PreNatal with ferrous fumarate, (ii) Tardyferon® with ferrous sulfate, (iii) Fenules with water free ferrous sulfate, (iv) Iron Complex with iron glycinate, citrate, (v) Gentle Iron, (vi) Hema-Plex® and (vii) Iron Bisglycinate with iron (ferrous) bisglycinate chelate (iron compounds are given as declared by the manufactures) were studied by [57]Fe Mössbauer spectroscopy with X-ray diffraction and magnetization measurements for analysis of the iron state. The obtained results demonstrate that the iron compound announced by the manufacturer in each pharmaceutical is not homogeneous and exists as some modifications of this compound or results of its transformation/oxidation probably due to its instability. The presence of ferrous and ferric compounds is observed, and the relative ferric iron fractions are roughly determined for each pharmaceutical product. This analysis clearly shows the differences between the iron compounds proclaimed by the manufacturers and those obtained by Mössbauer spectroscopy. That justifies as to why this technique should be used for the control and analysis of the iron-containing pharmaceuticals.

RevDate: 2023-10-19

Villanea FA, Peede D, Kaufman EJ, et al (2023)

The MUC19 gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection.

bioRxiv : the preprint server for biology.

All humans carry a small fraction of archaic ancestry across the genome, the legacy of gene flow from Neanderthals, Denisovans, and other hominids into the ancestors of modern humans. While the effects of Neanderthal ancestry on human fitness and health have been explored more thoroughly, there are fewer examples of adaptive introgression of Denisovan variants. Here, we study the gene MUC19, for which some modern humans carry a Denisovan-like haplotype. MUC19 is a mucin, a glycoprotein that forms gels with various biological functions, from lubrication to immunity. We find the diagnostic variants for the Denisovan-like MUC19 haplotype at high frequencies in admixed Latin American individuals among global population, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that some Neanderthals--Vindija and Chagyrskaya--carry the Denisovan-like MUC19 haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. Finally, we find that the Denisovan-like MUC19 haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat relative to the Human-like haplotype, and that copy numbers of this repeat are exceedingly high in American populations. Our results suggest that the Denisovan-like MUC19 haplotype served as the raw genetic material for positive selection as American populations adapted to novel environments during their movement from Beringia into North and then South America.

RevDate: 2023-10-26
CmpDate: 2023-10-26

Solovev AS, Denisova EM, Kurbatova EA, et al (2023)

Synthesis of methylphosphorylated oligomannosides structurally related to lipopolysaccharide O-antigens of Klebsiella pneumoniae serotype O3 and their application for detection of specific antibodies in rabbit and human sera.

Organic & biomolecular chemistry, 21(41):8306-8319.

Methylphosphorylated mono-, di- and trimannosides structurally related to the lipopolysaccharide (LPS) O-antigens of Klebsiella pneumoniae of serotype O3 were synthesized and conjugated with a biotin tag. The stereo- and regioselective assembly of target carbohydrate chains was conducted using uniform monosaccharide synthetic blocks. After that, a methylphosphate group was introduced by coupling with a methyl-H-phosphonate reagent followed by oxidation and deprotection to give the target oligosaccharides. The [1]H and [13]C NMR spectra of the obtained compounds showed a good fit with the spectrum of the corresponding natural polysaccharide. The newly prepared biotinylated oligosaccharides along with the previously reported biotinylated glycoconjugates related to galactan I and galactan II of K. pneumoniae LPS were used for the ELISA detection of antibodies in anti-K. pneumoniae rabbit sera. Anti-O3 serum antibodies specifically recognized the synthesized oligosaccharide ligands with terminal methylphosphomannosyl residues, whereas anti-O1 serum antibodies recognized the oligosaccharide related to K. pneumoniae galactan II. The analysis of human sera from patients with confirmed Klebsiella infection also revealed the presence of antibodies against the synthesized oligosaccharides in clinical cases. Thus, the described compounds together with other Klebsiella related antigenic oligosaccharides could be potentially used as molecular probes for K. pneumoniae serological diagnostics development and strain serotyping.

RevDate: 2023-10-20

Yee SW, Ferrández-Peral L, Alentorn P, et al (2023)

Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.

Research square.

SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17β-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.

RevDate: 2023-11-21
CmpDate: 2023-09-29

Bacon AM, Bourgon N, Dufour E, et al (2023)

Palaeoenvironments and hominin evolutionary dynamics in southeast Asia.

Scientific reports, 13(1):16165.

Secure environmental contexts are crucial for hominin interpretation and comparison. The discovery of a Denisovan individual and associated fauna at Tam Ngu Hao 2 (Cobra) Cave, Laos, dating back to 164-131 ka, allows for environmental comparisons between this (sub)tropical site and the Palearctic Denisovan sites of Denisova Cave (Russia) and Baishiya Karst Cave (China). Denisovans from northern latitudes foraged in a mix of forested and open landscapes, including tundra and steppe. Using stable isotope values from the Cobra Cave assemblage, we demonstrate that, despite the presence of nearby canopy forests, the Denisovan individual from Cobra Cave primarily consumed plants and/or animals from open forests and savannah. Using faunal evidence and proxy indicators of climates, results herein highlight a local expansion of rainforest at ~ 130 ka, raising questions about how Denisovans responded to this local climate change. Comparing the diet and habitat of the archaic hominin from Cobra Cave with those of early Homo sapiens from Tam Pà Ling Cave (46-43 ka), Laos, it appears that only our species was able to exploit rainforest resources.

RevDate: 2023-10-12
CmpDate: 2023-10-09

Roca-Umbert A, Garcia-Calleja J, Vogel-González M, et al (2023)

Human genetic adaptation related to cellular zinc homeostasis.

PLoS genetics, 19(9):e1010950.

SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.

RevDate: 2023-09-22

Peyrégne S, Slon V, J Kelso (2023)

More than a decade of genetic research on the Denisovans.

Nature reviews. Genetics [Epub ahead of print].

Denisovans, a group of now extinct humans who lived in Eastern Eurasia in the Middle and Late Pleistocene, were first identified from DNA sequences just over a decade ago. Only ten fragmentary remains from two sites have been attributed to Denisovans based entirely on molecular information. Nevertheless, there has been great interest in using genetic data to understand Denisovans and their place in human history. From the reconstruction of a single high-quality genome, it has been possible to infer their population history, including events of admixture with other human groups. Additionally, the identification of Denisovan DNA in the genomes of present-day individuals has provided insights into the timing and routes of dispersal of ancient modern humans into Asia and Oceania, as well as the contributions of archaic DNA to the physiology of present-day people. In this Review, we synthesize more than a decade of research on Denisovans, reconcile controversies and summarize insights into their population history and phenotype. We also highlight how our growing knowledge about Denisovans has provided insights into our own evolutionary history.

RevDate: 2023-11-02
CmpDate: 2023-11-02

Ge X, Lu Y, Chen S, et al (2023)

Genetic Origins and Adaptive Evolution of the Deng People on the Tibetan Plateau.

Molecular biology and evolution, 40(10):.

The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30-60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700-7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000-14,000 years; TIB-HAN, 7,200-10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

RevDate: 2023-09-30
CmpDate: 2023-09-29

Flegontov P, Işıldak U, Maier R, et al (2023)

Modeling of African population history using f-statistics is biased when applying all previously proposed SNP ascertainment schemes.

PLoS genetics, 19(9):e1010931.

f-statistics have emerged as a first line of analysis for making inferences about demographic history from genome-wide data. Not only are they guaranteed to allow robust tests of the fits of proposed models of population history to data when analyzing full genome sequencing data-that is, all single nucleotide polymorphisms (SNPs) in the individuals being analyzed-but they are also guaranteed to allow robust tests of models for SNPs ascertained as polymorphic in a population that is an outgroup in a phylogenetic sense to all groups being analyzed. True "outgroup ascertainment" is in practice impossible in humans because our species has arisen from a substructured ancestral population that does not descend from a homogeneous ancestral population going back many hundreds of thousands of years into the past. However, initial studies suggested that non-outgroup-ascertainment schemes might produce robust enough results using f-statistics, and that motivated widespread fitting of models to data using non-outgroup-ascertained SNP panels such as the "Affymetrix Human Origins array" which has been genotyped on thousands of modern individuals from hundreds of populations, or the "1240k" in-solution enrichment reagent which has been the source of about 70% of published genome-wide data for ancient humans. In this study, we show that while analyses of population history using such panels work well for studies of relationships among non-African populations and one African outgroup, when co-modeling more than one sub-Saharan African and/or archaic human groups (Neanderthals and Denisovans), fitting of f-statistics to such SNP sets is expected to frequently lead to false rejection of true demographic histories, and failure to reject incorrect models. Analyzing panels of SNPs polymorphic in archaic humans, which has been suggested as a solution for the ascertainment problem, has limited statistical power and retains important biases. However, by carrying out simulations of diverse demographic histories, we show that bias in inferences based on f-statistics can be minimized by ascertaining on variants common in a union of diverse African groups; such ascertainment retains high statistical power while allowing co-analysis of archaic and modern groups.

RevDate: 2023-11-28

Denisova K (2023)

English translation of the first study reporting cyclical periods of increased respiration and eye and body motility during sleep in infants in 1926, with commentary.

Sleep pii:7250121 [Epub ahead of print].

This is the first English translation of the work Periodic phenomena in the sleep in children, published in 1926 in the Journal Novoe v refleksologii i fiziologii nervnoi sistemy (Vol. 2, pp. 338-345) by Maria Denisova and Nicholai Figurin; it is the first study to report data on what is currently termed Rapid Eye Movement (REM) sleep. The authors acquired continuous quantitative respiration data, as well as eye and body movements during sleep in children for up to 6 hours, and discovered several novel features of sleep cycles in healthy infants from birth to about 1 year of age.First, the study reports cyclical periods of increased respiration and eye and body movements, with rapid ocular movements visible under relaxed eyelids (separation:0.5-1 mm). These observations suggest atonia of REM sleep.Second, the length of the complete cycle (alternating active and quiet sleep phases or states) is about 50 minutes, an estimate that is consistent with later work.Third, the study identifies infant-specific ordering of sleep states, with the active phase beginning after sleep onset, followed by the quiescence phase. Importantly, these published data on sleep cycles precede all published studies related to the state now termed REM sleep by about 30 years (i.e.publishing in Science and in the Journal of Applied Physiology in the 1950s by Eugene Aserinski and Nathaniel Kleitman). In the historical commentary accompanying this translation, the findings of those later works are carefully compared to the original data on respiration and ocular and body motility cycles during sleep in infants, first reported and published by Denisova and Figurin(1926).

RevDate: 2023-10-19

Yee SW, Ferrández-Peral L, Alentorn P, et al (2023)

Illuminating the Function of the Orphan Transporter, SLC22A10 in Humans and Other Primates.

bioRxiv : the preprint server for biology.

SLC22A10 is classified as an orphan transporter with unknown substrates and function. Here we describe the discovery of the substrate specificity and functional characteristics of SLC22A10. The human SLC22A10 tagged with green fluorescent protein was found to be absent from the plasma membrane, in contrast to the SLC22A10 orthologs found in great apes. Estradiol-17β-glucuronide accumulated in cells expressing great ape SLC22A10 orthologs (over 4-fold, p<0.001). In contrast, human SLC22A10 displayed no uptake function. Sequence alignments revealed two amino acid differences including a proline at position 220 of the human SLC22A10 and a leucine at the same position of great ape orthologs. Site-directed mutagenesis yielding the human SLC22A10-P220L produced a protein with excellent plasma membrane localization and associated uptake function. Neanderthal and Denisovan genomes show human-like sequences at proline 220 position, corroborating that SLC22A10 were rendered nonfunctional during hominin evolution after the divergence from the pan lineage (chimpanzees and bonobos). These findings demonstrate that human SLC22A10 is a unitary pseudogene and was inactivated by a missense mutation that is fixed in humans, whereas orthologs in great apes transport sex steroid conjugates.

RevDate: 2023-08-24
CmpDate: 2023-08-18

Essel E (2023)

Releasing secrets bound to ancient remains with modern DNA extraction techniques: an interview with Elena Essel.

BioTechniques, 75(2):42-46.

Elena Essel (Msc) spoke to Ebony Torrington, Managing Editor of BioTechniques. Essel is a molecular biologist in Matthias Meyer's Advanced DNA Sequencing Techniques group at the Max Planck Institute for Evolutionary Anthropology in Leipzig (Germany). Essel studied biology at University of Erlangen-Nuremberg (Erlangen, Germany) for her bachelor's and in Martin-Luther-University Halle-Wittenberg (Halle an der Saale, Germany) for her master's. Essel worked in Meyer's group on DNA extraction of very degraded material for her master's thesis. Meyer is an expert in developing new cutting-edge methods for researching ancient DNA, with a focus on skeletal remains, and more recently on sediment remains. Essel now focusses on DNA sampling and extraction aspects of the pipeline at Meyer's lab for the ancient DNA workflow.

RevDate: 2023-08-14

Cherkashina NI, Pavlenko ZV, Pushkarskaya DV, et al (2023)

Synthesis and Properties of Polystyrene Composite Material with Hazelnut Shells.

Polymers, 15(15):.

In this study we evaluated the potential use of hazelnut shell powder in the production of a composite material. Polystyrene was used as a polymer matrix. This work presents the results of modifying hazelnut powder particles to create a polystyrene shell on their surfaces. Modification of the filler increased its contact angle wetted with water from θ=60.16±1.03° to θ=87.02±1.10°. Composite materials containing from 10 to 50 wt.% of modified hazelnut shell powder were prepared and studied. As a result of the experiments, it was found that the composites have optimal physical, mechanical, and operational properties at the following ratio: polystyrene 60-80 wt.%, modified hazelnut shell powder 20-40 wt.%. If the introduction of polystyrene was more than 90 wt.%, the flexural strength and Vickers hardness were quite low at the load of 200 g, and accordingly, the durability of such materials was not satisfactory. These samples are characterized by small percentages of hazelnut shells; therefore, the resulting material will be of pale, unsaturated color. The upper limit of the working temperature range for the composite lies between 265.0-376.0 °C, depending on the percentage of the hazelnut shell powder filling.

RevDate: 2023-09-22
CmpDate: 2023-08-14

Ruan J, Timmermann A, Raia P, et al (2023)

Climate shifts orchestrated hominin interbreeding events across Eurasia.

Science (New York, N.Y.), 381(6658):699-704.

When, where, and how often hominin interbreeding happened is largely unknown. We study the potential for Neanderthal-Denisovan admixture using species distribution models that integrate extensive fossil, archaeological, and genetic data with transient coupled general circulation model simulations of global climate and biomes. Our Pleistocene hindcast of past hominins' habitat suitability reveals pronounced climate-driven zonal shifts in the main overlap region of Denisovans and Neanderthals in central Eurasia. These shifts, which influenced the timing and intensity of potential interbreeding events, can be attributed to the response of climate and vegetation to past variations in atmospheric carbon dioxide and Northern Hemisphere ice-sheet volume. Therefore, glacial-interglacial climate swings likely played an important role in favoring gene flow between archaic humans.

RevDate: 2023-09-27
CmpDate: 2023-08-14

Maasch JRMA, Torres MDT, Melo MCR, et al (2023)

Molecular de-extinction of ancient antimicrobial peptides enabled by machine learning.

Cell host & microbe, 31(8):1260-1274.e6.

Molecular de-extinction could offer avenues for drug discovery by reintroducing bioactive molecules that are no longer encoded by extant organisms. To prospect for antimicrobial peptides encrypted within extinct and extant human proteins, we introduce the panCleave random forest model for proteome-wide cleavage site prediction. Our model outperformed multiple protease-specific cleavage site classifiers for three modern human caspases, despite its pan-protease design. Antimicrobial activity was observed in vitro for modern and archaic protein fragments identified with panCleave. Lead peptides showed resistance to proteolysis and exhibited variable membrane permeabilization. Additionally, representative modern and archaic protein fragments showed anti-infective efficacy against A. baumannii in both a skin abscess infection model and a preclinical murine thigh infection model. These results suggest that machine-learning-based encrypted peptide prospection can identify stable, nontoxic peptide antibiotics. Moreover, we establish molecular de-extinction through paleoproteome mining as a framework for antibacterial drug discovery.

RevDate: 2023-08-01

Tkachenko OV, Evseeva NV, Kargapolova KY, et al (2023)

Rhizobacteria Increase the Adaptation Potential of Potato Microclones under Aeroponic Conditions.

Microorganisms, 11(7):.

Adaptation ex vitro is strongly stressful for microplants. Plant-growth-promoting rhizobacteria (PGPR) help to increase the adaptation potential of microplants transplanted from test tubes into the natural environment. We investigated the mechanisms of antioxidant protection of PGPR-inoculated potato microclones adapting to ex vitro growth in an aeroponic system. Potato (Solanum tuberosum L. cv. Nevsky) microplants were inoculated in vitro with the bacteria Azospirillum baldaniorum Sp245 and Ochrobactrum cytisi IPA7.2. On days 1 and 7 of plant growth ex vitro, catalase and peroxidase activities in the leaves of inoculated plants were 1.5-fold higher than they were in non-inoculated plants. The activity of ascorbate peroxidase was reduced in both in vitro and ex vitro treatments, and this reduction was accompanied by a decrease in the leaf content of hydrogen peroxide and malondialdehyde. As a result, inoculation contributed to the regulation of the plant pro/antioxidant system, lowering the oxidative stress and leading to better plant survival ex vitro. This was evidenced by the higher values of measured morphological and physiological variables of the inoculated plants, as compared with the values in the control treatment. Thus, we have shown some PGPR-mediated mechanisms of potato plant protection from adverse environmental factors under aeroponic conditions.

RevDate: 2023-08-08
CmpDate: 2023-08-08

Shpetko YY, Filippenkov IB, Denisova AE, et al (2023)

Isoflurane Anesthesia's Impact on Gene Expression Patterns of Rat Brains in an Ischemic Stroke Model.

Genes, 14(7):.

BACKGROUND: Ischemic stroke (IS) is one of the most severe brain diseases. Animal models with anesthesia are actively used to study stroke genomics and pathogenesis. However, the anesthesia-related gene expression patterns of ischemic rat brains remain poorly understood. In this study, we sought to elucidate the impact of isoflurane (ISO) anesthesia on the extent of ischemic brain damage and gene expression changes associated with stroke.

METHODS: We used the transient middle cerebral artery occlusion (tMCAO) model under long-term and short-term ISO anesthesia, magnetic resonance imaging (MRI), RNA sequencing, and bioinformatics.

RESULTS: We revealed that the volume of cerebral damage at 24 h after tMCAO was inversely proportional to the duration of ISO anesthesia. Then, we revealed hundreds of overlapping ischemia-related differentially expressed genes (DEGs) with a cutoff of >1.5; Padj < 0.05, and 694 and 1557 DEGs only under long-term and short-term anesthesia, respectively, using sham-operated controls. Concomitantly, unique DEGs identified under short-term anesthesia were mainly associated with neurosignaling systems, whereas unique DEGs identified under long-term anesthesia were predominantly related to the inflammatory response.

CONCLUSIONS: We were able to determine the effects of the duration of anesthesia using isoflurane on the transcriptomes in the brains of rats at 24 h after tMCAO. Thus, specific genome responses may be useful in developing potential approaches to reduce damaged areas after cerebral ischemia and neuroprotection.

RevDate: 2023-08-01
CmpDate: 2023-07-31

Filippenkov IB, Remizova JA, Stavchansky VV, et al (2023)

Synthetic Adrenocorticotropic Peptides Modulate the Expression Pattern of Immune Genes in Rat Brain following the Early Post-Stroke Period.

Genes, 14(7):.

Ischemic stroke is an acute local decrease in cerebral blood flow due to a thrombus or embolus. Of particular importance is the study of the genetic systems that determine the mechanisms underlying the formation and maintenance of a therapeutic window (a time interval of up to 6 h after a stroke) when effective treatment can be provided. Here, we used a transient middle cerebral artery occlusion (tMCAO) model in rats to study two synthetic derivatives of adrenocorticotropic hormone (ACTH). The first was ACTH(4-7)PGP, which is known as Semax. It is actively used as a neuroprotective drug. The second was the ACTH(6-9)PGP peptide, which is elucidated as a prospective agent only. Using RNA-Seq analysis, we revealed hundreds of ischemia-related differentially expressed genes (DEGs), as well as 131 and 322 DEGs related to the first and second peptide at 4.5 h after tMCAO, respectively, in dorsolateral areas of the frontal cortex of rats. Furthermore, we showed that both Semax and ACTH(6-9)PGP can partially prevent changes in the immune- and neurosignaling-related gene expression profiles disturbed by the action of ischemia at 4.5 h after tMCAO. However, their different actions with regard to predominantly immune-related genes were also revealed. This study gives insight into how the transcriptome depends on the variation in the structure of the related peptides, and it is valuable from the standpoint of the development of measures for early post-stroke therapy.

RevDate: 2023-07-31

Deņisova A, Pilmane M, D Kažoka (2023)

Antimicrobial Peptides and Interleukins in Cleft Soft Palate.

Children (Basel, Switzerland), 10(7):.

Cleft palate is one of the most common and well-studied congenital anomalies; however, the role of protective tissue factors in its pathophysiology is still debated. The aim of our study was to evaluate interleukin and antimicrobial peptide appearance and distribution in cleft palate. Eight soft palate samples were obtained during veloplasty procedures. Immunohistochemical staining was applied to detect HBD-2-, HBD-3-, HBD-4-, LL-37-, IL-10-, and CD-163-positive cells via light microscopy. For statistical evaluation, the Mann-Whitney U test and Spearman's rank correlation coefficient were used. A significant difference between study groups was observed for HBD-2 and IL-10 in epithelial and connective tissue as well as HBD-4 in connective tissue. The number of HBD-3-positive cells was moderate in the patients, and few were observed in the controls. The number of LL-37-positive cells varied from a moderate amount to a numerous amount in both study groups, whilst CD-163 marked a moderate number of positive cells in patients, and a few-to-moderate amount was observed in the controls. Numerous correlations between studied factors were revealed in cleft tissues. The increase in antimicrobial peptides HBD-2 and HBD-4 and anti-inflammatory cytokine IL-10 suggested a wide compensatory elevation of the local immune system against cleft-raised tissue changes. The correlations between the studied factors (HBD-2, HBD-3, HBD-4, LL-37, and IL-10) proved the synergistic involvement of common local defense factors in postnatal cleft palate morphopathogenesis.

RevDate: 2023-09-24
CmpDate: 2023-09-08

Pawar H, Rymbekova A, Cuadros-Espinoza S, et al (2023)

Ghost admixture in eastern gorillas.

Nature ecology & evolution, 7(9):1503-1514.

Archaic admixture has had a substantial impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. In great apes, archaic admixture has been identified in chimpanzees and bonobos but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole-genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using approximate Bayesian computation with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic 'ghost' lineage into the common ancestor of eastern gorillas but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, probably more than 40 thousand years ago and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.

RevDate: 2023-07-28
CmpDate: 2023-07-28

Pigolkin YI, Shigeev SV, Denisova AV, et al (2023)

[Forensic medical assessment of lidocaine and bupivacaine systemic toxicity].

Sudebno-meditsinskaia ekspertiza, 66(4):62-66.

Was to assess the lidocaine and bupivacaine systemic toxicity in forensic medical practice. The number of patients' clinical observations equal three with local anesthetic systemic toxicity (LAST) from the practice of forensic medical experts were studied, and a search of scientific publications for the last 5 years in PubMed database was conducted. The amount of publications, describing cases with LAST, equal four were selected. Differential diagnostic features between LAST and anaphylaxis were considered. The literature data about relationship between lidocaine's concentration in the blood serum and clinical features are shown. The forensic medical assessment of LAST is proposed.

RevDate: 2023-08-17
CmpDate: 2023-08-11

Kaulen LD, Denisova E, Hinz F, et al (2023)

Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.

Acta neuropathologica, 146(3):499-514.

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV[+]) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV[+] PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV[+] PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV[-] PCNSL. Instead, EBV[+] PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV[+] PCNSL. In addition to novel insights into the pathobiology of EBV[+] PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.

RevDate: 2023-09-09
CmpDate: 2023-09-08

Denisova OV, Merisaari J, Huhtaniemi R, et al (2023)

PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells.

Molecular oncology, 17(9):1803-1820.

Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting AKT (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogeneous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined AKT and PDK targeting. Biochemically, the combined AKT and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial apoptosis but failed to induce apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which AKT and PDK inhibition was combined with the pharmacological reactivation of protein phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154, and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial oxidative phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting mitochondrial metabolism to overcome therapy tolerance in brain tumors.

RevDate: 2023-10-10
CmpDate: 2023-10-10

Yang C, Zhou Y, Song Y, et al (2023)

The complete and fully-phased diploid genome of a male Han Chinese.

Cell research, 33(10):745-761.

Since the release of the complete human genome, the priority of human genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid human genome from a Han Chinese male individual (CN1), in which the assemblies of both haploids achieve the telomere-to-telomere (T2T) level. Comparison of this diploid genome with the CHM13 haploid T2T genome revealed significant variations in the centromere. Outside the centromere, we discovered 11,413 structural variations, including numerous novel ones. We also detected thousands of CN1 alleles that have accumulated high substitution rates and a few that have been under positive selection in the East Asian population. Further, we found that CN1 outperforms CHM13 as a reference genome in mapping and variant calling for the East Asian population owing to the distinct structural variants of the two references. Comparison of SNP calling for a large cohort of 8869 Chinese genomes using CN1 and CHM13 as reference respectively showed that the reference bias profoundly impacts rare SNP calling, with nearly 2 million rare SNPs miss-called with different reference genomes. Finally, applying the CN1 as a reference, we discovered 5.80 Mb and 4.21 Mb putative introgression sequences from Neanderthal and Denisovan, respectively, including many East Asian specific ones undetected using CHM13 as the reference. Our analyses reveal the advances of using CN1 as a reference for population genomic studies and paleo-genomic studies. This complete genome will serve as an alternative reference for future genomic studies on the East Asian population.

RevDate: 2023-10-19

Larivière D, Abueg L, Brajuka N, et al (2023)

Scalable, accessible, and reproducible reference genome assembly and evaluation in Galaxy.

bioRxiv : the preprint server for biology.

Improvements in genome sequencing and assembly are enabling high-quality reference genomes for all species. However, the assembly process is still laborious, computationally and technically demanding, lacks standards for reproducibility, and is not readily scalable. Here we present the latest Vertebrate Genomes Project assembly pipeline and demonstrate that it delivers high-quality reference genomes at scale across a set of vertebrate species arising over the last ~500 million years. The pipeline is versatile and combines PacBio HiFi long-reads and Hi-C-based haplotype phasing in a new graph-based paradigm. Standardized quality control is performed automatically to troubleshoot assembly issues and assess biological complexities. We make the pipeline freely accessible through Galaxy, accommodating researchers even without local computational resources and enhanced reproducibility by democratizing the training and assembly process. We demonstrate the flexibility and reliability of the pipeline by assembling reference genomes for 51 vertebrate species from major taxonomic groups (fish, amphibians, reptiles, birds, and mammals).

RevDate: 2023-11-21
CmpDate: 2023-07-03

Shevchenko JA, Perik-Zavodskii RY, Nazarov KV, et al (2023)

Immunoregulatory properties of erythroid nucleated cells induced from CD34+ progenitors from bone marrow.

PloS one, 18(6):e0287793.

CD 71+ erythroid nucleated cells have pronounced immunoregulatory properties in normal and pathological conditions. Many populations of cells with immunoregulatory properties are considered candidates for cellular immunotherapy for various pathologies. This study characterized the immunoregulatory properties of CD71+ erythroid cells derived from CD34-positive bone marrow cells under the influence of growth factors that stimulate differentiation into erythroid cells. CD34-negative bone marrow cells were used to isolate CD71+ erythroid nuclear cells. The resulting cells were used to assess the phenotype, determine the mRNA spectrum of the genes responsible for the main pathways and processes of the immune response, and obtain culture supernatants for the analysis of immunoregulatory factors. It was found that CD71+ erythroid cells derived from CD34+ cells carry the main markers of erythroid cells, but differ markedly from natural bone marrow CD71+ erythroid cells. The main differences are in the presence of the CD45+ subpopulation, distribution of terminal differentiation stages, transcriptional profile, secretion of certain cytokines, and immunosuppressive activity. The properties of induced CD71+ erythroid cells are closer to the cells of extramedullary erythropoiesis foci than to natural bone marrow CD71+ erythroid cells. Thus, when cultivating CD71+ erythroid cells for clinical experimental studies, it is necessary to take into account their pronounced immunoregulatory activity.

RevDate: 2023-11-13
CmpDate: 2023-10-06

Derenko M, Denisova G, Litvinov A, et al (2023)

Mitogenomics of the Koryaks and Evens of the northern coast of the Sea of Okhotsk.

Journal of human genetics, 68(10):705-712.

Due to the geographical proximity of the northern coast of the Sea of Okhotsk and Kamchatka Peninsula to the Beringia, the indigenous populations of these territories are of great interest for elucidating the human settlement history of northern Asia and America. Meanwhile, there is a clear shortage of genetic studies of the indigenous populations of the northern coast of the Sea of Okhotsk. Here, in order to examine their fine-scale matrilineal genetic structure, ancestry and relationships with neighboring populations, we analyzed 203 complete mitogenomes (174 of which are new) from population samples of the Koryaks and Evens of the northern coast of the Sea of Okhotsk and the Chukchi of the extreme northeast Asia. The patterns observed underscore the reduced level of genetic diversity found in the Koryak, Even, and Chukchi populations, which, along with the high degree of interpopulation differentiation, may be the result of genetic drift. Our phylogeographic analysis reveals common Paleo-Asiatic ancestry for 51.1% of the Koryaks and 17.8% of the Evens. About third of the mitogenomes found in the Koryaks and Evens might be considered as ethno-specific, as these are virtually absent elsewhere in North, Central and East Asia. Coalescence ages of most of these lineages coincide well with the emergence and development of the Tokarev and Old Koryak archaeological cultures associated with the formation of the Koryaks, as well as with the period of separation and split of the North Tungusic groups migrated northwards from the Lake Baikal or the Amur River area.

RevDate: 2023-06-22
CmpDate: 2023-06-15

Shunatova N, Denisova S, Shchenkov S, et al (2023)

Colonial system of integration and communication pores in a polymorphic bryozoan Dendrobeania fruticosa (Bryozoa: Cheilostomata).

Journal of morphology, 284(7):e21601.

Bryozoan colonies are composed of zooids, which can differ in structure and function. Autozooids supply heteromorphic zooids with nutrients, which are usually unable to feed. To date, the ultrastructure of the tissues providing nutrient transfer is almost unexplored. Here, we present a detailed description of the colonial system of integration (CSI) and the different types of pore plates in Dendrobeania fruticosa. All cells of the CSI are joined by tight junctions that isolate its lumen. The lumen of the CSI is not a single structure, but a dense network of small interstices filled with a heterogeneous matrix. In autozooids, the CSI is composed of two types of cells: elongated and stellate. Elongated cells form the central part of the CSI, including two main longitudinal cords and several main branches to the gut and pore plates. Stellate cells compose the peripheral part of the CSI, which is a delicate mesh starting from the central part and reaching various structures of autozooids. Autozooids have two tiny muscular funiculi, which start from the caecum apex and run to the basal wall. Each funiculus includes a central cord of extracellular matrix and two longitudinal muscle cells; together they are enveloped with a layer of cells. The rosette complexes of all types of pore plates in D. fruticosa display a similar cellular composition: a cincture cell and a few special cells; limiting cells are absent. Special cells have bidirectional polarity in interautozooidal and avicularian pore plates. This is probably due to the need for bidirectional transport of nutrients during degeneration-regeneration cycles. Cincture cells and epidermal cells of pore plates contain microtubules and inclusions resembling dense-cored vesicles, which are typical of neurons. Probably, cincture cells are involved in the signal transduction from one zooid to another and can be a part of the colony-wide nervous system.

RevDate: 2023-06-28
CmpDate: 2023-06-14

Rigaud S, Rybin EP, Khatsenovich AM, et al (2023)

Symbolic innovation at the onset of the Upper Paleolithic in Eurasia shown by the personal ornaments from Tolbor-21 (Mongolia).

Scientific reports, 13(1):9545.

Figurative depictions in art first occur ca. 50,000 years ago in Europe, Africa, and Southeast Asia. Considered by most as an advanced form of symbolic behavior, they are restricted to our species. Here, we report a piece of ornament interpreted as a phallus-like representation. It was found in a 42,000 ca.-year-old Upper Paleolithic archaeological layer at the open-air archaeological site of Tolbor-21, in Mongolia. Mineralogical, microscopic, and rugosimetric analyses points toward the allochthonous origin of the pendant and a complex functional history. Three-dimensional phallic pendants are unknown in the Paleolithic record, and this discovery predates the earliest known sexed anthropomorphic representation. It attests that hunter-gatherer communities used sex anatomical attributes as symbols at a very early stage of their dispersal in the region. The pendant was produced during a period that overlaps with age estimates for early introgression events between Homo sapiens and Denisovans, and in a region where such encounters are plausible.

RevDate: 2023-06-13

Kou SH, Li J, Tam B, et al (2023)

TP53 germline pathogenic variants in modern humans were likely originated during recent human history.

NAR cancer, 5(3):zcad025.

TP53 is crucial for maintaining genome stability and preventing oncogenesis. Germline pathogenic variation in TP53 damages its function, causing genome instability and increased cancer risk. Despite extensive study in TP53, the evolutionary origin of the human TP53 germline pathogenic variants remains largely unclear. In this study, we applied phylogenetic and archaeological approaches to identify the evolutionary origin of TP53 germline pathogenic variants in modern humans. In the phylogenic analysis, we searched 406 human TP53 germline pathogenic variants in 99 vertebrates distributed in eight clades of Primate, Euarchontoglires, Laurasiatheria, Afrotheria, Mammal, Aves, Sarcopterygii and Fish, but we observed no direct evidence for the cross-species conservation as the origin; in the archaeological analysis, we searched the variants in 5031 ancient human genomes dated between 45045 and 100 years before present, and identified 45 pathogenic variants in 62 ancient humans dated mostly within the last 8000 years; we also identified 6 pathogenic variants in 3 Neanderthals dated 44000 to 38515 years before present and 1 Denisovan dated 158 550 years before present. Our study reveals that TP53 germline pathogenic variants in modern humans were likely originated in recent human history and partially inherited from the extinct Neanderthals and Denisovans.

RevDate: 2023-06-03

Garcia-Heras J (2023)

The 2022 Nobel Prize in Physiology or Medicine.

Journal of the Association of Genetic Technologists, 49(2):56-67.

The Nobel Assembly at the Karolinska Institute awarded the 2022 Nobel Prize in Physiology or Medicine to Svante Pääbo (Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany). This award acknowledged his discoveries about the genomes of extinct hominins (Neandertal man and the Denisovans), the molecular genetic insights of human origin and evolutionary history, and the understanding of phylogenetic relationships between archaic hominins and modern humans. The scientific advances included detection of Neandertal and Denisovan DNA carried by modern humans due to past admixture events, which in turn stimulated active research about the functional and phenotypic significance of such archaic ancestry on non-disease and disease phenotypic features in modern populations. In addition, comparative genomic studies started to delineate the genes and genetic regulation mechanisms that distinguish modern-day humans from the archaic hominins and our immediate ancestors, the anatomically modern humans. These breakthroughs allowed a more thorough understanding of ancestral and modern human population genetics, and propelled the take-off of human paleogenomics as a new scientific discipline in its own right.

RevDate: 2023-11-17
CmpDate: 2023-05-18

Rong S, Neil CR, Welch A, et al (2023)

Large-scale functional screen identifies genetic variants with splicing effects in modern and archaic humans.

Proceedings of the National Academy of Sciences of the United States of America, 120(21):e2218308120.

Humans coexisted and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here, we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,169 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 962 exonic splicing mutations that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than that in Neanderthals. Adaptively introgressed variants were enriched for moderate-effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly compelling examples, we characterized a unique tissue-specific alternative splicing variant at the adaptively introgressed innate immunity gene TLR1, as well as a unique Neanderthal introgressed alternative splicing variant in the gene HSPG2 that encodes perlecan. We further identified potentially pathogenic splicing variants found only in Neanderthals and Denisovans in genes related to sperm maturation and immunity. Finally, we found splicing variants that may contribute to variation among modern humans in total bilirubin, balding, hemoglobin levels, and lung capacity. Our findings provide unique insights into natural selection acting on splicing in human evolution and demonstrate how functional assays can be used to identify candidate causal variants underlying differences in gene regulation and phenotype.

RevDate: 2023-05-15

Adzhieva OA, Gringolts ML, Denisova YI, et al (2023)

Effect of Chain Structure on the Various Properties of the Copolymers of Fluorinated Norbornenes with Cyclooctene.

Polymers, 15(9):.

Fluorinated polymers are attractive due to their special thermal, surface, gas separation, and other properties. In this study, new diblock, multiblock, and random copolymers of cyclooctene with two fluorinated norbornenes, 5-perfluorobutyl-2-norbornene and N-pentafluorophenyl-exo-endo-norbornene-5,6-dicarboximide, are synthesized by ring-opening metathesis copolymerization and macromolecular cross-metathesis in the presence of the first- to third-generation Grubbs' Ru-catalysts. Their thermal, surface, bulk, and solution characteristics are investigated and compared using differential scanning calorimetry, water contact angle measurements, gas permeation, and light scattering, respectively. It is demonstrated that they are correlated with the chain structure of the copolymers. The properties of multiblock copolymers are generally closer to those of diblock copolymers than of random ones, which can be explained by the presence of long blocks capable of self-organization. In particular, diblock and multiblock fluorine-imide-containing copolymers show a tendency to form micelles in chloroform solutions well below the overlap concentration. The results obtained may be of interest to a wide range of researchers involved in the design of functional copolymers.

RevDate: 2023-11-16
CmpDate: 2023-06-12

Brand CM, Colbran LL, JA Capra (2023)

Resurrecting the alternative splicing landscape of archaic hominins using machine learning.

Nature ecology & evolution, 7(6):939-953.

Alternative splicing contributes to adaptation and divergence in many species. However, it has not been possible to directly compare splicing between modern and archaic hominins. Here, we unmask the recent evolution of this previously unobservable regulatory mechanism by applying SpliceAI, a machine-learning algorithm that identifies splice-altering variants (SAVs), to high-coverage genomes from three Neanderthals and a Denisovan. We discover 5,950 putative archaic SAVs, of which 2,186 are archaic-specific and 3,607 also occur in modern humans via introgression (244) or shared ancestry (3,520). Archaic-specific SAVs are enriched in genes that contribute to traits potentially relevant to hominin phenotypic divergence, such as the epidermis, respiration and spinal rigidity. Compared to shared SAVs, archaic-specific SAVs occur in sites under weaker selection and are more common in genes with tissue-specific expression. Further underscoring the importance of negative selection on SAVs, Neanderthal lineages with low effective population sizes are enriched for SAVs compared to Denisovan and shared SAVs. Finally, we find that nearly all introgressed SAVs in humans were shared across the three Neanderthals, suggesting that older SAVs were more tolerated in human genomes. Our results reveal the splicing landscape of archaic hominins and identify potential contributions of splicing to phenotypic differences among hominins.

RevDate: 2023-06-13
CmpDate: 2023-06-13

Essel E, Zavala EI, Schulz-Kornas E, et al (2023)

Ancient human DNA recovered from a Palaeolithic pendant.

Nature, 618(7964):328-332.

Artefacts made from stones, bones and teeth are fundamental to our understanding of human subsistence strategies, behaviour and culture in the Pleistocene. Although these resources are plentiful, it is impossible to associate artefacts to specific human individuals[1] who can be morphologically or genetically characterized, unless they are found within burials, which are rare in this time period. Thus, our ability to discern the societal roles of Pleistocene individuals based on their biological sex or genetic ancestry is limited[2-5]. Here we report the development of a non-destructive method for the gradual release of DNA trapped in ancient bone and tooth artefacts. Application of the method to an Upper Palaeolithic deer tooth pendant from Denisova Cave, Russia, resulted in the recovery of ancient human and deer mitochondrial genomes, which allowed us to estimate the age of the pendant at approximately 19,000-25,000 years. Nuclear DNA analysis identifies the presumed maker or wearer of the pendant as a female individual with strong genetic affinities to a group of Ancient North Eurasian individuals who lived around the same time but were previously found only further east in Siberia. Our work redefines how cultural and genetic records can be linked in prehistoric archaeology.

RevDate: 2023-08-26
CmpDate: 2023-05-22

Witt KE, Funk A, Añorve-Garibay V, et al (2023)

The Impact of Modern Admixture on Archaic Human Ancestry in Human Populations.

Genome biology and evolution, 15(5):.

Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, which have shaped genetic ancestry in modern humans. For example, populations in the Americas are often mosaics of different ancestries due to recent admixture events as part of European colonization. Admixed individuals also often have introgressed DNA from Neanderthals and Denisovans that may have come from multiple ancestral populations, which may affect how archaic ancestry is distributed across an admixed genome. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual's archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight increase of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.

RevDate: 2023-03-31
CmpDate: 2023-03-30

Makarova E, Dubinina A, Denisova E, et al (2023)

Genetic Obesity in Pregnant A[y] Mice Does Not Affect Susceptibility to Obesity and Food Choice in Offspring.

International journal of molecular sciences, 24(6):.

Maternal diet and obesity (MO) may influence taste preferences and increase the susceptibility to obesity in offspring, but the impact of MO per se to these influences is poorly understood. We evaluated the influence of MO on food choice and susceptibility to obesity in offspring when mothers consumed a standard diet (SD). Mice with the Lethal yellow mutation (A[y]/a) develop obesity consuming an SD. Metabolic parameters were assessed in pregnant and lactating A[y]/a (obesity) and a/a (control) mothers. Metabolic response to the consumption of a sweet-fat diet (SFD: SD, lard, and sweet biscuits) and the choice of components of this diet were evaluated in their male and female offspring. Compared to control mothers, pregnant obese mothers had higher levels of insulin, leptin, and FGF21. MO increased food intake and liver expression of lipogenesis genes in male offspring consuming the SD. SFD consumption caused obesity development and insulin resistance, increased liver expression of glycolytic and lipogenesis genes, and affected hypothalamic expression of anorexigenic and orexigenic genes. In offspring of both sexes, MO had no effect on food choice and metabolic response to SFD intake. Therefore, when obese mothers consume a balanced diet, MO does not affect food choice and development of diet-induced obesity in offspring.

RevDate: 2023-04-24
CmpDate: 2023-03-30

Toncheva D, Marinova M, Chobanov T, et al (2023)

Pathogenic Variants Associated with Rare Monogenic Diseases Established in Ancient Neanderthal and Denisovan Genome-Wide Data.

Genes, 14(3):.

Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.

RevDate: 2023-04-01
CmpDate: 2023-04-01

Xiao F, Li J, Lagniton PNP, et al (2023)

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans.

Biomolecules, 13(3):.

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in MUTYH damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between MUTYH variation and cancer development. In this study, we analyzed the origins of pathogenic germline variants in human MUTYH. Using a phylogenic approach, we searched MUTYH pathogenic variants in modern humans in the MUTYH of 99 vertebrates across eight clades. We did not find pathogenic variants shared between modern humans and the non-human vertebrates following the evolutionary tree, ruling out the possibility of cross-species conservation as the origin of human pathogenic variants in MUTYH. We then searched the variants in the MUTYH of 5031 ancient humans and extinct Neanderthals and Denisovans. We identified 24 pathogenic variants in 42 ancient humans dated between 30,570 and 480 years before present (BP), and three pathogenic variants in Neanderthals dated between 65,000 and 38,310 years BP. Data from our study revealed that human MUTYH pathogenic variants mostly arose in recent human history and partially originated from Neanderthals.

RevDate: 2023-04-10
CmpDate: 2023-03-30

Primak AL, Orlov NA, Peigneur S, et al (2023)

AgTx2-GFP, Fluorescent Blocker Targeting Pharmacologically Important Kv1.x (x = 1, 3, 6) Channels.

Toxins, 15(3):.

The growing interest in potassium channels as pharmacological targets has stimulated the development of their fluorescent ligands (including genetically encoded peptide toxins fused with fluorescent proteins) for analytical and imaging applications. We report on the properties of agitoxin 2 C-terminally fused with enhanced GFP (AgTx2-GFP) as one of the most active genetically encoded fluorescent ligands of potassium voltage-gated Kv1.x (x = 1, 3, 6) channels. AgTx2-GFP possesses subnanomolar affinities for hybrid KcsA-Kv1.x (x = 3, 6) channels and a low nanomolar affinity to KcsA-Kv1.1 with moderate dependence on pH in the 7.0-8.0 range. Electrophysiological studies on oocytes showed a pore-blocking activity of AgTx2-GFP at low nanomolar concentrations for Kv1.x (x = 1, 3, 6) channels and at micromolar concentrations for Kv1.2. AgTx2-GFP bound to Kv1.3 at the membranes of mammalian cells with a dissociation constant of 3.4 ± 0.8 nM, providing fluorescent imaging of the channel membranous distribution, and this binding depended weakly on the channel state (open or closed). AgTx2-GFP can be used in combination with hybrid KcsA-Kv1.x (x = 1, 3, 6) channels on the membranes of E. coli spheroplasts or with Kv1.3 channels on the membranes of mammalian cells for the search and study of nonlabeled peptide pore blockers, including measurement of their affinity.

RevDate: 2023-03-14

Alexeeva E, Krekhova E, Dvoryakovskaya T, et al (2023)

Efficacy and safety of canakinumab as a second line biologic after tocilizumab treatment failure in children with systemic juvenile idiopathic arthritis: A single-centre cohort study using routinely collected health data.

Frontiers in pediatrics, 11:1114207.

BACKGROUND: A significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (bDMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required.

METHODS: Patients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the paediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS-71 = 0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up from time first canakinumab dose administered was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from electronic outpatient medical records.

RESULTS: During the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at baseline was 8.2 [interquartile range (IQR) 4.0-12.9] years, with the median sJIA duration being 1.8 (IQR 0.8-5.8) years; 37 (80%) patients received at least one conventional DMARD (cDMARD; oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (IQR 282-404) days. During the follow-up, 1 patient discontinued canakinumab due to tuberculosis detection and the dose was reduced or the injection interval increased in 4 (9%) patients. In total, 27 (60%) patients continued to receive at least one cDMARD. Improvement according to the ACR30 criteria was achieved in 43 patients [96%; 95% confidence interval (CI) 85-99], inactive disease in 42 (93%; 95%CI 82-98), and remission in 37 (82%; 95% CI 69-91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 AEs (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases.

CONCLUSIONS: One-year canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA.

RevDate: 2023-04-11
CmpDate: 2023-02-27

Wang PY, Yang Y, Shi XQ, et al (2023)

Distilling functional variations for human UGT2B4 upstream region based on selection signals and implications for phenotypes of Neanderthal and Denisovan.

Scientific reports, 13(1):3134.

Our previous work identified one region upstream human UGT2B4 (UDP glucuronosyltransferase family 2 member B4) which is associated with breast cancer and under balancing selection. However, the distribution, functional variation and molecular mechanism underlying breast cancer and balancing selection remain unclear. In current study, the two haplotypes with deep divergence are described by analyzing 1000 genomes project data and observed to be with high frequencies in all human populations. Through population genetics analysis and genome annotation, the potential functional region is identified and verified by reporter gene assay. Further mutagenesis indicates that the functional mutations are rs66862535 and rs68096061. Both SNPs can alter the interaction efficiency of transcription factor POU2F1 (POU class 2 homeobox 1). Through chromosome conformation capture, it is identified that the enhancer containing these two SNPs can interact with UGT2B4 promoter. Expression quantitative trait loci analysis indicates that UGT2B4 expression is dependent on the genotype of this locus. The common haplotype in human is lost in four genomes of archaic hominins, which suggests that Neanderthal and Denisovan should present relatively lower UGT2B4 expression and further higher steroid hormone level. This study provides new insight into the contribution of ancient population structure to human phenotypes.

RevDate: 2023-10-19

Velazquez-Arcelay K, Colbran LL, McArthur E, et al (2023)

Archaic Introgression Shaped Human Circadian Traits.

bioRxiv : the preprint server for biology.

INTRODUCTION: When the ancestors of modern Eurasians migrated out of Africa and interbred with Eurasian archaic hominins, namely Neanderthals and Denisovans, DNA of archaic ancestry integrated into the genomes of anatomically modern humans. This process potentially accelerated adaptation to Eurasian environmental factors, including reduced ultra-violet radiation and increased variation in seasonal dynamics. However, whether these groups differed substantially in circadian biology, and whether archaic introgression adaptively contributed to human chronotypes remains unknown.

RESULTS: Here we traced the evolution of chronotype based on genomes from archaic hominins and present-day humans. First, we inferred differences in circadian gene sequences, splicing, and regulation between archaic hominins and modern humans. We identified 28 circadian genes containing variants with potential to alter splicing in archaics (e.g., CLOCK, PER2, RORB, RORC), and 16 circadian genes likely divergently regulated between present-day humans and archaic hominins, including RORA. These differences suggest the potential for introgression to modify circadian gene expression. Testing this hypothesis, we found that introgressed variants are enriched among eQTLs for circadian genes. Supporting the functional relevance of these regulatory effects, we found that many introgressed alleles have associations with chronotype. Strikingly, the strongest introgressed effects on chronotype increase morningness, consistent with adaptations to high latitude in other species. Finally, we identified several circadian loci with evidence of adaptive introgression or latitudinal clines in allele frequency.

CONCLUSIONS: These findings identify differences in circadian gene regulation between modern humans and archaic hominins and support the contribution of introgression via coordinated effects on variation in human chronotype.

RevDate: 2023-03-17

Hagymási K (2023)

The Nobel prize in physiology and medicine - 2022.

Structural chemistry, 34(2):733-736.

The Nobel Assembly at Karolinska Institutet awarded the 2022 Nobel Prize in Physiology or Medicine to a Swedish geneticist, Svante Pääbo, for his discoveries concerning the genomes of extinct hominins and human evolution, for the sequencing of the genome of the Neanderthal, the discovery of a previously unknown hominin, Denisova, and the establishment of a new scientific discipline, paleogenomics.

RevDate: 2023-02-11

Ermakov PN, Vorobyeva EV, Denisova EG, et al (2022)

Recognition of Emotional and Neutral Visual Scenes in Carriers of the MAOA, COMT, DRD4, and 5HT2A Gene Polymorphisms.

Psychology in Russia : state of the art, 15(4):159-169.

BACKGROUND: It is known that some genes regulate neurochemical metabolism, and their polymorphisms affect cognitive performance, including the ability to categorize emotionally significant information.

OBJECTIVE: The aim of our study was to analyze the recognition of emotional and neutral visual scenes in carriers of different polymorphic variants of the MAOA, COMT, DRD4, and 5HT2A genes.

DESIGN: The study sample consisted of 87 university students (Caucasians, women 63%, average age 20.4±2.6 years). The genotypes of the COMT, 5HT2A, and DRD4 genes were determined by polymerase chain reaction. Agarose gel electrophoresis was used to determine the number of tandem repeats of the MAOA gene. Three hundred sixty (360) photographic images of scenes of different emotional valence (positive, negative, and neutral - 120 images for each category) were used as stimuli. These images were classified by expert assessments. The images were presented in a random sequence. The exposure time was 700 ms. The research participants were asked to determine the emotional valence of each scene.

RESULTS: We found that only the COMT gene genotype affected the recognition of emotional and neutral visual scenes. Carriers of the COMT Val/Val genotype, which causes dopamine to stay in the synaptic space for a shorter time, are better in recognizing and demonstrate higher sensitivity to the emotional content of scenes. Carriers of the Val/Met genotype demonstrated the worst ability to differentiate the emotional valence of visual scenes.

CONCLUSION: This study has shown that the length of stay of monoamines in the synaptic space regulated by the COMT gene affects the recognition of emotional visual information.

RevDate: 2023-04-05
CmpDate: 2023-04-05

Cheng T, Wang F, Denisova K, et al (2023)

Normative exophthalmometry values in Hispanic individuals.

Archivos de la Sociedad Espanola de Oftalmologia, 98(4):199-205.

PURPOSE: Normative exophthalmometry values have been established in Caucasians, Asians, and Black individuals. While prior studies have examined periocular measurements in different racial and ethnic groups, this study is the first to establish a set of normative exophthalmometry values in a Hispanic population in New York City.

METHODS: This prospective, cross-sectional cohort study was IRB approved and HIPAA compliant. Adult patients self-identifying as Hispanic were included. The degree of ocular prominence (exophthalmometry value, EV) and the inter-orbital distance (Hertel's base, IOD) was obtained by Hertel exophthalmometry. Differences in EV between sexes were evaluated using two sample t-tests. Multivariable linear regression was utilized to determine the effect of age, sex, and body mass index (BMI) on EV.

RESULTS: Of the 277 Hispanic individuals included, 189 (68.2%) were female and the mean age was 63.0 years (SD = 15.0). The mean Hertel's base and mean EV for all participants was 92.0 mm (SD = 4.1) and 16.7 mm (SD = 2.4), respectively. Average exophthalmometry values for men were significantly higher than women's (17.6 mm and 16.2 mm, respectively, p ≤ 0.001). Higher EVs were positively associated with male gender (ß = -1.60, p < 0.0001) and BMI (ß = 0.084, p = 0.001), but not age.

CONCLUSIONS: The mean EV in Hispanic individuals is 16.7 mm, higher than that reported for most Caucasians and Asians, but less than that of Black individuals. Higher EV is significantly associated with male sex and increased BMI. This study is the first to create a set of normative exophthalmometry values in a Hispanic population, which may serve as a valuable tool for clinicians to reference when diagnosing and monitoring orbital disease.

RevDate: 2023-02-02
CmpDate: 2023-02-02

Borshchevskaya VN, Denisova AV, Todorov SS, et al (2023)

[Forensic medical assessment of venous thromboembolic complications of mechanical injury of the lower limb after surgery].

Sudebno-meditsinskaia ekspertiza, 66(1):35-38.

In forensic medical practice, venous thromboembolic complications (VTEC) are relatively rare, due to hereditary and acquired factors. The issue of expert evaluation of the VTEC after the performed surgical intervention as an alleged defect in medical care causes discussion. The purpose of this publication is to demonstrate an expert case in the assessment of VTEC mechanical injury of the lower limb after surgery. The above case with the development of PATE after surgery clearly demonstrates the possibility of the appearance of a «medical case». The key to the correct expert assessment of the alleged defect of medical care during the forensic medical examination is not only a thorough and scrupulous study of medical documentation, but also a qualitatively performed forensic medical examination of the corpse.

RevDate: 2023-09-20

Flegontov P, Işıldak U, Maier R, et al (2023)

Modeling of African population history using f -statistics can be highly biased and is not addressed by previously suggested SNP ascertainment schemes.

bioRxiv : the preprint server for biology.

f -statistics have emerged as a first line of analysis for making inferences about demographic history from genome-wide data. These statistics can provide strong evidence for either admixture or cladality, which can be robust to substantial rates of errors or missing data. f -statistics are guaranteed to be unbiased under "SNP ascertainment" (analyzing non-randomly chosen subsets of single nucleotide polymorphisms) only if it relies on a population that is an outgroup for all groups analyzed. However, ascertainment on a true outgroup that is not co-analyzed with other populations is often impractical and uncommon in the literature. In this study focused on practical rather than theoretical aspects of SNP ascertainment, we show that many non-outgroup ascertainment schemes lead to false rejection of true demographic histories, as well as to failure to reject incorrect models. But the bias introduced by common ascertainments such as the 1240K panel is mostly limited to situations when more than one sub-Saharan African and/or archaic human groups (Neanderthals and Denisovans) or non-human outgroups are co-modelled, for example, f 4 -statistics involving one non-African group, two African groups, and one archaic group. Analyzing panels of SNPs polymorphic in archaic humans, which has been suggested as a solution for the ascertainment problem, cannot fix all these problems since for some classes of f -statistics it is not a clean outgroup ascertainment, and in other cases it demonstrates relatively low power to reject incorrect demographic models since it provides a relatively small number of variants common in anatomically modern humans. And due to the paucity of high-coverage archaic genomes, archaic individuals used for ascertainment often act as sole representatives of the respective groups in an analysis, and we show that this approach is highly problematic. By carrying out large numbers of simulations of diverse demographic histories, we find that bias in inferences based on f -statistics introduced by non-outgroup ascertainment can be minimized if the derived allele frequency spectrum in the population used for ascertainment approaches the spectrum that existed at the root of all groups being co-analyzed. Ascertaining on sites with variants common in a diverse group of African individuals provides a good approximation to such a set of SNPs, addressing the great majority of biases and also retaining high statistical power for studying population history. Such a "pan-African" ascertainment, although not completely problem-free, allows unbiased exploration of demographic models for the widest set of archaic and modern human populations, as compared to the other ascertainment schemes we explored.

RevDate: 2023-05-18

Witt KE, Funk A, Fang LL, et al (2023)

The impact of modern admixture on archaic human ancestry in human populations.

bioRxiv : the preprint server for biology.

Admixture, the genetic merging of parental populations resulting in mixed ancestry, has occurred frequently throughout the course of human history. Numerous admixture events have occurred between human populations across the world, as well as introgression between humans and archaic humans, Neanderthals and Denisovans. One example are genomes from populations in the Americas, as these are often mosaics of different ancestries due to recent admixture events as part of European colonization. In this study, we analyzed admixed populations from the Americas to assess whether the proportion and location of admixed segments due to recent admixture impact an individual’s archaic ancestry. We identified a positive correlation between non-African ancestry and archaic alleles, as well as a slight enrichment of Denisovan alleles in Indigenous American segments relative to European segments in admixed genomes. We also identify several genes as candidates for adaptive introgression, based on archaic alleles present at high frequency in admixed American populations but low frequency in East Asian populations. These results provide insights into how recent admixture events between modern humans redistributed archaic ancestry in admixed genomes.

RevDate: 2023-02-02

de March CA, Matsunami H, Abe M, et al (2023)

Genetic and functional odorant receptor variation in the Homo lineage.

iScience, 26(1):105908.

Humans, Neanderthals, and Denisovans independently adapted to a wide range of geographic environments and their associated food odors. Using ancient DNA sequences, we explored the in vitro function of thirty odorant receptor genes in the genus Homo. Our extinct relatives had highly conserved olfactory receptor sequence, but humans did not. Variations in odorant receptor protein sequence and structure may have produced variation in odor detection and perception. Variants led to minimal changes in specificity but had more influence on functional sensitivity. The few Neanderthal variants disturbed function, whereas Denisovan variants increased sensitivity to sweet and sulfur odors. Geographic adaptations may have produced greater functional variation in our lineage, increasing our olfactory repertoire and expanding our adaptive capacity. Our survey of olfactory genes and odorant receptors suggests that our genus has a shared repertoire with possible local ecological adaptations.

RevDate: 2023-02-01
CmpDate: 2023-01-24

Zhou Z, M A Swagemakers S, S Lourens M, et al (2022)

Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?.

Asian Pacific journal of allergy and immunology, 40(4):422-434.

BACKGROUND: Neanderthals were a species of archaic humans that became extinct around 40,000 years ago. Modern humans have inherited 1-6% of Neanderthal DNA as a result of interbreeding. These inherited Neanderthal genes have paradoxical influences, while some can provide protection to viral infections, some others are associated with autoimmune/auto-inflammatory diseases.

OBJECTIVE: We aim to investigate whether genetic variants with strong detrimental effects on the function of the immune system could have potentially contributed to the extinction of the Neanderthal population.

METHODS: We used the publically available genome information from an Altai Neanderthal and filtered for potentially damaging variants present in genes associated with inborn errors of immunity (IEI) and checked whether these variants were present in the genomes of the Denisovan, Vindija and Chagyrskaya Neanderthals.

RESULTS: We identified 24 homozygous variants and 15 heterozygous variants in IEI-related genes in the Altai Neanderthal. Two homozygous variants in the UNC13D gene and one variant in the MOGS gene were present in all archaic genomes. Defects in the UNC13D gene are known to cause a severe and often fatal disease called hemophagocytic lymphohistiocystosis (HLH). One of these variants p.(N943S) has been reported in patients with HLH. Variants in MOGS are associated with glycosylation defects in the immune system affecting the susceptibility for infections.

CONCLUSIONS: Although the exact functional impact of these three variants needs further elucidation, we speculate that they could have resulted in an increased susceptibility to severe diseases and may have contributed to the extinction of Neanderthals after exposure to specific infections.

RevDate: 2023-01-24

Mikhailova SV, Ivanoshchuk DE, Yushkevich EA, et al (2022)

Prevalence of Common Alleles of Some Stress Resilience Genes among Adolescents Born in Different Periods Relative to the Socioeconomic Crisis of the 1990s in Russia.

Current issues in molecular biology, 45(1):51-65.

Social stress is common among people and is considered one of the causes of the declining birth rate. Predisposition to stress and stress-induced disorders is largely determined genetically. We hypothesized that due to differences in stress resistance, carriers of different genetic variants of genes associated with stress resilience and stress-induced diseases may have dissimilar numbers of offspring under conditions of long-term social stress. To test this hypothesis, a comparative analysis of frequencies of seven common polymorphic regions [exon 3 variable number of tandem repeats (VNTR) of the DRD4 gene, rs4680 of COMT, STin2 VNTR and the 5-HTTLPR (rs774676466) insertion/deletion polymorphism of SLC6A4, rs4570625 of TPH2, rs6265 of BDNF, and rs258747 of NR3C1] was performed on standardized groups of randomly selected adolescents born before, during, and after severe socioeconomic deprivation (the crisis of the 1990s in Russia). There were significant differences in frequencies of "long" alleles of the DRD4 gene (p = 0.020, χ[2] = 5.492) and rs4680 (p = 0.022, χ[2] = 5.289) in the "crisis" group as compared to the combined "noncrisis" population. It is possible that the dopaminergic system had an impact on the successful adaptation of a person to social stress.

RevDate: 2023-02-28
CmpDate: 2023-01-13

Filippenkov IB, Remizova JA, Denisova AE, et al (2023)

Differential gene expression in the contralateral hemisphere of the rat brain after focal ischemia.

Scientific reports, 13(1):573.

Ischemic stroke is one of the most severe polygenic brain diseases. Here, we performed further functional genetic analysis of the processes occurring in the contralateral hemisphere (CH) after ischemia-reperfusion injury in rat brain. Comparison of RNA sequencing data for subcortical samples from the ipsilateral hemisphere (IH) and CH after 90 min of transient middle cerebral artery occlusion (tMCAO) and corresponding sham-operated (SO) controls showed four groups of genes that were associated with ischemic processes in rat brain at 24 h after tMCAO. Among them, 2672 genes were differentially expressed genes (DEGs) for IH but non-DEGs for CH, 34 genes were DEGs for CH but non-DEGs for IH, and 114 genes had codirected changes in expression in both hemispheres. The remaining 16 genes exhibited opposite changes at the mRNA level in the two brain hemispheres after tMCAO. These findings suggest that the ischemic process caused by a focal ischemia induces complex bilateral reactions at the transcriptome level in the rat brain. We believe that specific genome responses in the CH and IH may provide a useful model for the study of the potential for brain repair after stroke.

RevDate: 2023-03-22
CmpDate: 2023-02-23

Aqil A, Speidel L, Pavlidis P, et al (2023)

Balancing selection on genomic deletion polymorphisms in humans.

eLife, 12:.

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains an imperative exercise. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS (genome-wide association studies) associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years.

RevDate: 2023-11-20
CmpDate: 2023-02-01

Zhang X, Kim B, Singh A, et al (2023)

MaLAdapt Reveals Novel Targets of Adaptive Introgression From Neanderthals and Denisovans in Worldwide Human Populations.

Molecular biology and evolution, 40(1):.

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events. Moreover, population genetic processes unrelated to AI, such as background selection or heterosis, may create similar genomic signals to AI, compromising the reliability of methods that rely on neutral null distributions. In recent years, machine learning (ML) methods have been increasingly applied to population genetic questions. Here, we present a ML-based method called MaLAdapt for identifying AI loci from genome-wide sequencing data. Using an Extra-Trees Classifier algorithm, our method combines information from a large number of biologically meaningful summary statistics to capture a powerful composite signature of AI across the genome. In contrast to existing methods, MaLAdapt is especially well-powered to detect AI with mild beneficial effects, including selection on standing archaic variation, and is robust to non-AI selective sweeps, heterosis from deleterious mutations, and demographic misspecification. Furthermore, MaLAdapt outperforms existing methods for detecting AI based on the analysis of simulated data and the validation of empirical signals through visual inspection of haplotype patterns. We apply MaLAdapt to the 1000 Genomes Project human genomic data and discover novel AI candidate regions in non-African populations, including genes that are enriched in functionally important biological pathways regulating metabolism and immune responses.

RevDate: 2023-01-09
CmpDate: 2022-12-26

Stavchansky VV, Filippenkov IB, Remizova JA, et al (2022)

Insight into Glyproline Peptides' Activity through the Modulation of the Inflammatory and Neurosignaling Genetic Response Following Cerebral Ischemia-Reperfusion.

Genes, 13(12):.

Glyprolines are Gly-Pro (GP)- or Pro-Gly (PG)-containing biogenic peptides. These peptides can act as neutrophil chemoattractants, or atheroprotective, anticoagulant, and neuroprotective agents. The Pro-Gly-Pro (PGP) tripeptide is an active factor of resistance to the biodegradation of peptide drugs. The synthetic Semax peptide, which includes Met-Glu-His-Phe (MEHF) fragments of adrenocorticotropic hormone and the C-terminal tripeptide PGP, serves as a neuroprotective drug for the treatment of ischemic stroke. Previously, we revealed that Semax mostly prevented the disruption of the gene expression pattern 24 h after a transient middle cerebral artery occlusion (tMCAO) in a rat brain model. The genes of this pattern were grouped into an inflammatory cluster (IC) and a neurotransmitter cluster (NC). Here, using real-time RT-PCR, the effect of other PGP-containing peptides, PGP and Pro-Gly-Pro-Leu (PGPL), on the expression of a number of genes in the IC and NC was studied 24 h after tMCAO. Both the PGP and PGPL peptides showed Semax-unlike effects, predominantly without changing gene expression 24 h after tMCAO. Moreover, there were IC genes (iL1b, iL6, and Socs3) for PGP, as well as IC (iL6, Ccl3, Socs3, and Fos) and NC genes (Cplx2, Neurod6, and Ptk2b) for PGPL, that significantly changed in expression levels after peptide administration compared to Semax treatment under tMCAO conditions. Furthermore, gene enrichment analysis was carried out, and a regulatory gene network was constructed. Thus, the spectra of the common and unique effects of the PGP, PGPL, and Semax peptides under ischemia-reperfusion were distinguished.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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One of the most intriguing, and philosophically suggestive, recent scientific findings has been the discovery that the human lineage included several branches at the species level in which each species had developed culture (tool making, mastery of fire, burial of the dead). Before the Chicxulub impact that ended the realm of the dinosaurs, sentience and culture had not occurred in any lineage, despite several hundred million years of evolution. However, in the mammalian radiation that occurred afterwards, several primate lineages occurred. In just the last few million years, one of those lineages diverged into several sentient, culture-developing species. This book explores how only one of those species (ours) survived, while the others went extinct. Recommended. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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RJR Picks from Around the Web (updated 11 MAY 2018 )