The genetically predicted causal associations between circulating 3-hydroxybutyrate levels and malignant neoplasms: A pan-cancer Mendelian randomization study.

OBJECTIVE: The ketogenic diet or exogenous supplementation with 3-hydroxybutyrate (3HB) is progressively gaining recognition as a valuable therapeutic or health intervention strategy. However, the effects of 3HB on cancers have been inconsistent in previous studies. This study aimed to comprehensively investigate the causal effects of circulating 3HB levels on 120 cancer phenotypes, and explore the 3HB mediation effect between liver fat accumulation and cancers. METHODS: Univariate Mendelian randomization (UVMR) was used in this study to investigate the causal impact of circulating 3HB levels on cancers. We conducted meta-analyses for 3HB-cancer associations sourced from different exposure data. In multivariate MR(MVMR), the body mass index, alcohol frequency and diabetes were included as covariates to investigate the independent effect of 3HB on cancer risk. Additionally, utilizing mediation MR analysis, we checked the potential mediating role of 3HB in the association between liver fat and cancer. RESULTS: Integrating findings from UVMR and MVMR, we observed that elevated circulating 3HB levels were associated with reduced risk of developing diffuse large B-cell lymphoma(DLBCL) (OR[95%CI] = 0.28[0.14-0.57] p = 3.92e-04), biliary malignancies (OR[95%CI] = 0.30[0.15-0.60], p = 7.67e-04), hepatocellular carcinoma(HCC) (OR[95%CI] = 0.25[0.09-0.71], p = 9.33e-03), primary lymphoid and hematopoietic malignancies (OR[95%CI] = 0.76[0.58-0.99], p = 0.045). Further UVMR analysis revealed that an increase in the percent liver fat was associated with reduced 3HB levels (Beta[95%CI] = -0.073[-0.122∼-0.024], p = 0.0034) and enhanced susceptibility to HCC (OR[95%CI] = 13.9[9.76-19.79], p = 3.14e-48), biliary malignancies (OR[95%CI] = 4.04[3.22-5.07], p = 1.64e-33), nasopharyngeal cancer (OR[95%CI] = 3.26[1.10-9.67], p = 0.03), and primary lymphoid and hematopoietic malignancies (OR[95%CI] = 1.27[1.13-1.44], p = 1.04e-4). Furthermore, 3HB fully mediated the effect of liver fat on susceptibility to DLBCL (OR[95%CI] = 1.076[1.01-1.15], p = 0.034). CONCLUSIONS: Circulating 3HB is associated with a reduced susceptibility to developing DLBCL, HCC, biliary malignancies, and primary lymphoid and hematopoietic malignancies. The impaired ketogenesis induced by metabolic-dysfunction associated fatty liver disease (MAFLD) contributes to risk of DLBCL.

Craniometric variation and the ancestry of modern humans.

OBJECTIVES: Ancient and contemporary DNA provide information about geographic variation in the ancestry of present-day humans. All living populations have ancestry from early Homo sapiens originating in sub-Saharan Africa. Populations of Eurasian descent also have a small amount of Neandertal ancestry. This study examines whether craniometric distances between recent modern human samples reflect this geographic variation in ancestry. Among recent modern humans, Eurasians are expected to be more similar to Neandertals, whereas both sub-Saharan Africans and Eurasians are expected to be equidistant from early H. sapiens. MATERIALS AND METHODS: Data on 33 craniometric traits from 2524 recent modern humans were compared with data from the literature for Neandertals and early H. sapiens. Mahalanobis distances were computed for each modern specimen to both the Neandertal and early H. sapiens means. These distances were examined for differences between recent humans from sub-Saharan Africa (N = 373) and those of Eurasian descent (N = 2151). RESULTS: Eurasians as a group are significantly closer than sub-Saharan Africans to Neandertals. There is no significant difference between the distances of sub-Saharan Africans and Eurasians to early H. sapiens. DISCUSSION: The differences between sub-Saharan Africans and Eurasians for both Neandertals and early H. sapiens are as expected. Although there has been geographic differentiation among recent modern humans, including differences in Neandertal admixture, these differences have not affected overall similarity of recent modern sub-Saharan Africans and Eurasians to the earliest samples of H. sapiens.

An assessment of puberty status in adolescents from the European Upper Paleolithic.

Childhood and adolescence are two life-history stages that are either unique to humans, or significantly expanded in the human life course relative to other primates. While recent studies have deepened our knowledge of childhood in the Upper Paleolithic, adolescence in this period remains understudied. Here, we use bioarchaeological maturational markers to estimate puberty status of 13 Upper Paleolithic adolescents from sites in Russia, Czechia, and Italy to 1) evaluate the feasibility of the application of bioarchaeological puberty assessment methods to Upper Paleolithic (Homo sapiens) skeletal individuals, 2) estimate the timing and tempo of puberty in Upper Paleolithic adolescents compared to other archaeological populations analyzed using the same method, and 3) characterize adolescence in the Upper Paleolithic by contextualizing the results of this puberty assessment with data on individual and population-level health, morbidity and burial practices. Our results revealed that while puberty had begun by 13.5 years of age for the majority of individuals, there was a lot of variability, with the adolescents from Arene Candide (AC1 and AC16), both aged around 16 years when they died, taking several years longer to progress through puberty than their peers. Assessing the age of menarche was challenging due to the paucity of female adolescents, but based on the available evidence, it appears to have occurred between 16 and 17 years of age. For some, full adulthood had been achieved by 17-22 years, similar to the patterns seen in modern wealthy countries and in advance of historic populations living in urbanized environments. The bioarchaeological analysis of puberty among Upper Paleolithic adolescents has important implications for the study of the emergence of adolescence within human-life histories, as well as for understanding the developmental plasticity of sexual maturation across past and present human populations.

Adhesive technology based on biomass tar documents engineering capabilities in the African Middle Stone Age.

The foragers of the southern African Middle Stone Age were among the first humans to adapt their environment and its resources to their needs. They heat-treated stone to alter its mechanical properties, transformed yellow colorants into red pigments and produced moldable adhesive substances from plants. Until now, only Podocarpus conifers have been identified as the botanical origin of Middle Stone Age adhesives. This is curious as these conifers do not produce sticky exudations that could be recognized as potential adhesives. To obtain an adhesive, tar must be made with a technical process based on fire. However, the nature of these technical processes has remained unknown, hampering our understanding of the meaning of this adhesive technology for the cultural evolution of early Homo sapiens. Here, we present the first evidence of a technique used for tar making in the Middle Stone Age. We created an experimental reference collection containing naturally available adhesives along manufactured tars from plants available in the Middle Stone Age and compared these to artifacts using gas chromatography-mass spectrometry and infrared spectroscopy. We found that, in the Howiesons Poort at Sibhudu Cave, tar was made by condensation, an efficient above-ground process. Even more surprisingly, the condensation method was not restricted to Podocarpus. The inhabitants of Sibhudu also produced tar from the leaves of other plants. These tars were then used, either without further transformation or were processed into ochre-based compound adhesives, suggesting that people needed different moldable substances with distinct mechanical properties. This has important implications for our understanding of Middle Stone Age H. sapiens, portraying them as skilled engineers who used and transformed their resources in a knowledgeable way.

A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution.

The definition of molecular and cellular mechanisms contributing to brain ontogenetic trajectories is essential to investigate the evolution of our species. Yet their functional dissection at an appropriate level of granularity remains challenging. Capitalizing on recent efforts that have extensively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework to perform trajectory inference and gene regulatory network reconstruction, (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and paleogenomic analysis for a higher-resolution mapping of derived regulatory variants in our species in comparison with our closest relatives. We provide evidence for cell type-specific regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a key role for a cholesterol program in outer radial glia, regulated by zinc-finger transcription factor KLF6. A cartography of the regulatory landscape impacted by Homo sapiens-derived variants reveals signals of selection clustering around regulatory regions associated with GLI3, a well-known regulator of radial glial cell cycle, and impacting KLF6 regulation. Our study contributes to the evidence of significant changes in metabolic pathways in recent human brain evolution.

Morphological and morphometric study of the hominin dental casts from Grotta-Riparo di Uluzzo C (Apulia, southern Italy).

OBJECTIVES: Grotta-Riparo di Uluzzo C (Apulia, southern Italy) is a pivotal site for investigating the evolution of the Middle Paleolithic and the earliest phases of the Upper Paleolithic in southern Italy, as the extensive stratigraphic record of this site includes a thick Mousterian sequence followed by the Uluzzian. Here, we investigate the taxonomic affinity of seven unpublished deciduous human teeth retrieved from the site of Uluzzo C in 1960. MATERIALS AND METHODS: The teeth are represented by seven plaster dental casts, which are housed at the Museo Civico di Paleontologia e Paletnologia in Maglie (Lecce, Apulia). The location of the original specimens remains unknown, rendering these casts the only human remains evidence yielded by Uluzzo C to date. Based on occlusal-view photographs and digital models of the casts, we examined the external morphology and morphometry of the teeth, comparing them to Homo sapiens and H. neanderthalensis samples. Through geometric morphometric methods and statistical analyses, we analyzed the crown outline of the deciduous molars. RESULTS: The teeth show morphological and morphometric features that are variably found in H. neanderthalensis, H. sapiens, or both. Specifically, crown outline analysis shows that all molars fall within H. neanderthalensis variability, except for Uluzzo 853 (lower right deciduous first molar), which falls within H. sapiens variability. DISCUSSION: This study provides the first taxonomic assessment of the hominin teeth from Uluzzo C. The results contribute additional insights into the Paleolithic peopling of southern Italy during a crucial period marked by the persistence of post-Tyrrhenian Neanderthal techno-complexes and the arrival of H. sapiens.

A pre-Campanian Ignimbrite techno-cultural shift in the Aurignacian sequence of Grotta di Castelcivita, southern Italy.

The Aurignacian is the first European technocomplex assigned to Homo sapiens recognized across a wide geographic extent. Although archaeologists have identified marked chrono-cultural shifts within the Aurignacian mostly by examining the techno-typological variations of stone and osseous tools, unraveling the underlying processes driving these changes remains a significant scientific challenge. Scholars have, for instance, hypothesized that the Campanian Ignimbrite (CI) super-eruption and the climatic deterioration associated with the onset of Heinrich Event 4 had a substantial impact on European foraging groups. The technological shift from the Protoaurignacian to the Early Aurignacian is regarded as an archaeological manifestation of adaptation to changing environments. However, some of the most crucial regions and stratigraphic sequences for testing these scenarios have been overlooked. In this study, we delve into the high-resolution stratigraphic sequence of Grotta di Castelcivita in southern Italy. Here, the Uluzzian is followed by three Aurignacian layers, sealed by the eruptive units of the CI. Employing a comprehensive range of quantitative methods-encompassing attribute analysis, 3D model analysis, and geometric morphometrics-we demonstrate that the key technological feature commonly associated with the Early Aurignacian developed well before the deposition of the CI tephra. Our study provides thus the first direct evidence that the volcanic super-eruption played no role in this cultural process. Furthermore, we show that local paleo-environmental proxies do not correlate with the identified patterns of cultural continuity and discontinuity. Consequently, we propose alternative research paths to explore the role of demography and regional trajectories in the development of the Upper Paleolithic.

A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens.

Changes in gene regulatory elements play critical roles in human phenotypic divergence. However, identifying the base-pair changes responsible for the distinctive morphology of Homo sapiens remains challenging. Here, we report a noncoding single-nucleotide polymorphism (SNP), rs41298798, as a potential causal variant contributing to the morphology of the skull base and vertebral structures found in Homo sapiens. Screening for differentially regulated genes between Homo sapiens and extinct relatives revealed 13 candidate genes associated with basicranial development, with TBX1, implicated in DiGeorge syndrome, playing a pivotal role. Epigenetic markers and in silico analyses prioritized rs41298798 within a TBX1 intron for functional validation. CRISPR editing revealed that the 41-base-pair region surrounding rs41298798 modulates gene expression at 22q11.21. The derived allele of rs41298798 acts as an allele-specific enhancer mediated by E2F1, resulting in increased TBX1 expression levels compared to the ancestral allele. Tbx1-knockout mice exhibited skull base and vertebral abnormalities similar to those seen in DiGeorge syndrome. Phenotypic differences associated with TBX1 deficiency are observed between Homo sapiens and Neanderthals (Homo neanderthalensis). In conclusion, the regulatory divergence of TBX1 contributes to the formation of skull base and vertebral structures found in Homo sapiens.

Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs.

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.

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

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.

The driving force behind tool-stone selection in the African Middle Stone Age.

In the Stone Age, the collection of specific rocks was the first step in tool making. Very little is known about the choices made during tool-stone acquisition. Were choices governed by the knowledge of, and need for, specific properties of stones? Or were the collected raw materials a mere by-product of the way people moved through the landscape? We investigate these questions in the Middle Stone Age (MSA) of southern Africa, analyzing the mechanical properties of tool-stones used at the site Diepkloof Rock Shelter. To understand knapping quality, we measure flaking predictability and introduce a physical model that allows calculating the relative force necessary to produce flakes from different rocks. To evaluate their quality as finished tools, we investigate their resistance during repeated use activities (scraping or cutting) and their strength during projectile impacts. Our findings explain tool-stone selection in two emblematic periods of the MSA, the Still Bay and Howiesons Poort, as being the result of a deep understanding of these mechanical properties. In both cases, people chose those rocks, among many others, that allowed the most advantageous trade-off between anticipated properties of finished tools and the ease of acquiring rocks and producing tools. The implications are an understanding of African MSA toolmakers as engineers who carefully weighed their choices taking into account workability and the quality of the tools they made.

Noncanonical usage of stop codons in ciliates expands proteins with structurally flexible Q-rich motifs.

Serine(S)/threonine(T)-glutamine(Q) cluster domains (SCDs), polyglutamine (polyQ) tracts and polyglutamine/asparagine (polyQ/N) tracts are Q-rich motifs found in many proteins. SCDs often are intrinsically disordered regions that mediate protein phosphorylation and protein-protein interactions. PolyQ and polyQ/N tracts are structurally flexible sequences that trigger protein aggregation. We report that due to their high percentages of STQ or STQN amino acid content, four SCDs and three prion-causing Q/N-rich motifs of yeast proteins possess autonomous protein expression-enhancing activities. Since these Q-rich motifs can endow proteins with structural and functional plasticity, we suggest that they represent useful toolkits for evolutionary novelty. Comparative Gene Ontology (GO) analyses of the near-complete proteomes of 26 representative model eukaryotes reveal that Q-rich motifs prevail in proteins involved in specialized biological processes, including Saccharomyces cerevisiae RNA-mediated transposition and pseudohyphal growth, Candida albicans filamentous growth, ciliate peptidyl-glutamic acid modification and microtubule-based movement, Tetrahymena thermophila xylan catabolism and meiosis, Dictyostelium discoideum development and sexual cycles, Plasmodium falciparum infection, and the nervous systems of Drosophila melanogaster, Mus musculus and Homo sapiens. We also show that Q-rich-motif proteins are expanded massively in 10 ciliates with reassigned TAAQ and TAGQ codons. Notably, the usage frequency of CAGQ is much lower in ciliates with reassigned TAAQ and TAGQ codons than in organisms with expanded and unstable Q runs (e.g. D. melanogaster and H. sapiens), indicating that the use of noncanonical stop codons in ciliates may have coevolved with codon usage biases to avoid triplet repeat disorders mediated by CAG/GTC replication slippage.

Hsa-miR-21-5p reflects synovitis and tenosynovitis components of musculoskeletal ultrasonography Seven-joint scores in rheumatoid arthritis disease and predicts the disease flare.

Rheumatoid arthritis (RA) is characterized by progressive joint destruction with subsequent serious disability. Objective biomarkers of RA course progression are lacking, which necessitates the discovery of activity indicators and predictors of the disease outcome. Musculoskeletal Ultrasound Seven-joint Score (MSUS7) is proposed as a reliable technique to evaluate radiographic RA progression. Homo sapiens-microRNA-21-5p (hsa-miR-21-5p) plays an important role during joint remodeling and the pro-inflammatory process driving RA progression. We aimed to evaluate plasma hsa-miR-21-5p as a noninvasive RA activity biomarker and to investigate if hsa-miR-21-5p is linked to MSUS7 components in the context of RA activity. This cross-sectional study included 71 RA patients classified into inactive (n = 36) and active (n = 35) groups according to the Disease Activity Score 28-joint count with ESR (DAS28-ESR). Joints were assessed by MSUS7. Gray-scale ultrasound (GSUS) and power Doppler ultrasound (PDUS) were used to rate the synovitis, tenosynovitis, and erosion in the joints. Plasma hsa-miR-21-5p expression was measured by real-time PCR. The absolute count of regulatory T cell (Treg) was calculated after Treg frequency was assessed by flow cytometry. Results: Hsa-miR-21 expression was significantly up-regulated in the active RA group with a median fold change of 51.6 in comparison to the inactive cases with a median fold change of 7.7 (p < 0.001). Hsa-miR-21-5p was positively correlated with DAS28-ESR, C reactive protein (CRP), and rheumatoid factor (r = 0.7, p < 0.001, r = 0. 0.6, p < 0.001, and r = 0.4, p = 0.002, respectively), while negatively correlated with Treg absolute count (r = -0.4, p < 0.001). Hsa-miR-21-5p levels were correlated with synovitis and tenosynovitis in GSUS (r = 0.4, p < 0.001, r = 0.3, p = 0.025, respectively) and in PDUS (r = 0.5, p < 0.001 and 0.4, p = 0.001, respectively). The hsa-miR-21-5p accurately distinguished RA activity [AUC 0.933, 94.3% sensitivity, and 86.1% specificity]. Logistic regression analysis revealed hsa-miR-21-5p as an independent predictor for RA flare (OR = 1.228, p = 0.004). Hsa-miR-21-5p was linked to synovitis and tenosynovitis components of the MSUS7. Up-regulated hsa-miR-21-5p can be utilized as a predictor for RA disease flare.

Effect of South African Herb Hoodia gordonii on Liver Glucolipid Metabolism and PI3K/Akt/FoxO1 Signalling Pathway in db/db Mice / 中国实验方剂学杂志

ObjectiveTo observe the effects of the South African herb Hoodia gordonii （HG） on glucolipid metabolism in diabetic db/db mice and explore the possible mechanisms of HG on the liver of db/db mice based on the phosphoinositide-3 kinase （PI3K）/protein kinase B （Akt）/factor forkhead protein O1 （FoxO1） signaling pathway. MethodA total of 30 db/db mice were randomly divided into five groups according to fasting blood glucose： model group， metformin group （0.195 g·kg-1）， and low dose （0.39 g·kg-1）， medium dose （0.78 g·kg-1）， and high dose （1.56 g·kg-1） HG groups， with six m/m mice in each group， and another six m/m mice were set as normal group. The mice in the normal and model groups were given saline of 9 mL·kg-1 by gavage. Body weight， water intake， and fasting blood glucose of the mice in each group were measured weekly. After six weeks of continuous administration， serum insulin （FINS）， low-density lipoprotein cholesterol （LDL）， total cholesterol （TC）， triglyceride （TG）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， urea， and creatinine （CREA） were measured， and liver sections were embedded and stained with hematoxylin-eosin （HE）， periodic acid-Schiff （PAS）， and oil red O. Protein expression of PI3K p85， p-Akt， and p-FoxO1 in liver was detected by immunohistochemistry. The mRNA expression of PI3K， Akt， and FoxO1 in liver tissue was detected by real-time polymerase chain reaction （Real-time PCR）. ResultAfter six weeks of administration intervention， it was found that fasting blood glucose was significantly downregulated in mice in the three HG groups （P<0.05）. The level of islet resistance index was significantly reduced in both the low and medium dose HG groups （P<0.05）. The expression levels of TC， TG， and LDL were reduced in all HG groups （P<0.05， P<0.01）. Pathologically， HG could alleviate hepatocyte steatosis， reduce the volume and content of lipid droplets in liver， and increase the distribution of glycogen granules in liver to some extent in mice. Immunohistochemical assays revealed that PI3K p85 protein expression was significantly increased in the low， medium， and high dose HG groups compared with the model group （P<0.01）. p-Akt protein expression was significantly increased in the medium and high dose HG groups （P<0.05， P<0.01）. p-FoxO1 protein expression was significantly increased in the low， medium， and high dose HG groups （P<0.05， P<0.01）. Compared with the model group， PI3K mRNA was increased in low dose， medium dose， and high dose HG groups （P<0.05）， and Akt mRNA was increased in high dose HG group （P<0.05）. FoxO1 mRNA was decreased in low dose， medium dose， and high dose HG groups （P<0.05）. ConclusionHG can ameliorate the disorder of glucolipid metabolism in db/db mice， which may be related to its activation of the hepatic PI3K/Akt/FoxO1 signaling pathway.

Gene polymorphisms associated with sudden decreases in heart rate during extensive peritoneal lavage with distilled water after gastrectomy.

BACKGROUND: Our previous study found that the telomerase-associated protein 1 (TEP1, rs938886 and rs1713449) and homo sapiens RecQ like helicase 5 (RECQL5, rs820196) single nucleotide polymorphisms (SNPs) were associated with changes in heart rate (HR) ≥ 30% during peritoneal lavage with distilled water after gastrectomy. This study established a single tube method for detecting these three SNPs using two-dimensional (2D) polymerase chain reaction (PCR), and investigated whether SNP-SNP and SNP-environment interactions increase the risk of high HR variability (HRV). AIM: To investigate whether genotypes, genetic patterns, SNP-SNP and SNP-environment interactions were associated with HRV. METHODS: 2D PCR was used to establish a single-tube method to detect TEP1 rs938886 and rs1713449 and RECQL5 rs820196, and the results were compared with those of sanger sequencing. After adjusting for confounders such as age, sex, smoking, hypertension, and thyroid dysfunction, a nonconditional logistic regression model was used to assess the associations between the genotypes and the genetic patterns (codominant, dominant, overdominant, recessive, and additive) of the three SNPs and a risk ≥ 15% or ≥ 30% of a sudden drop in HR during postoperative peritoneal lavage in patients with gastric cancer. Gene-gene and gene-environment interactions were analyzed using generalized multifactor dimensionality reduction. RESULTS: The coincidence rate between the 2D PCR and sequencing was 100%. When the HRV cutoff value was 15%, the patients with the RECQL5 (rs820196) TC genotype had a higher risk of high HRV than those who had the TT genotype (odds ratio = 1.97; 95%CI: 1.05-3.70; P = 0.045). Under the codominant and overdominant models, the TC genotype of RECQL5 (rs820196) was associated with a higher risk of HR decrease relative to the TT and TT + CC genotypes (P = 0.031 and 0.016, respectively). When the HRV cutoff value was 30%, patients carrying the GC-TC genotypes of rs938886 and rs820196 showed a higher HRV risk when compared with the GG-TT genotype carriers (P = 0.01). In the three-factor model of rs938886, rs820196, and rs1713449, patients carrying the GC-TC-CT genotype had a higher risk of HRV compared with the wild-type GG-TT-CC carriers (P = 0.01). For rs820196, nonsmokers with the TC genotype had a higher HRV risk compared with nonsmokers carrying the TT genotype (P = 0.04). When the HRV cutoff value was 15%, patients carrying the TT-TT and the TC-CT genotypes of rs820196 and rs1713449 showed a higher HRV risk when compared with TT-CC genotype carriers (P = 0.04 and 0.01, respectively). Patients carrying the GC-CT-TC genotypes of rs938886, rs1713449, and rs820196 showed a higher HRV risk compared with GG-CC-TT genotype carriers (P = 0.02). When the HRV cutoff value was 15%, the best-fitting models for the interactions between the SNPs and the environment were the rs820196-smoking (P = 0.022) and rs820196-hypertension (P = 0.043) models. Consistent with the results of the previous grouping, for rs820196, the TC genotype nonsmokers had a higher HRV risk compared with nonsmokers carrying the TT genotype (P = 0.01). CONCLUSION: The polymorphism of the RECQL5 and TEP1 genes were associated with HRV during peritoneal lavage with distilled water after gastrectomy.

Temporal Variation in Introgressed Segments' Length Statistics Computed from a Limited Number of Ancient Genomes Sheds Light on Past Admixture Pulses.

Hybridization is recognized as an important evolutionary force, but identifying and timing admixture events between divergent lineages remain a major aim of evolutionary biology. While this has traditionally been done using inferential tools on contemporary genomes, the latest advances in paleogenomics have provided a growing wealth of temporally distributed genomic data. Here, we used individual-based simulations to generate chromosome-level genomic data for a 2-population system and described temporal neutral introgression patterns under a single- and 2-pulse admixture model. We computed 6 summary statistics aiming to inform the timing and number of admixture pulses between interbreeding entities: lengths of introgressed sequences and their variance within genomes, as well as genome-wide introgression proportions and related measures. The first 2 statistics could confidently be used to infer interlineage hybridization history, peaking at the beginning and shortly after an admixture pulse. Temporal variation in introgression proportions and related statistics provided more limited insights, particularly when considering their application to ancient genomes still scant in number. Lastly, we computed these statistics on Homo sapiens paleogenomes and successfully inferred the hybridization pulse from Neanderthal that occurred approximately 40 to 60 kya. The scarce number of genomes dating from this period prevented more precise inferences, but the accumulation of paleogenomic data opens promising perspectives as our approach only requires a limited number of ancient genomes.

Problems with studying directional natural selection in humans.

The review describes the main methods for assessing directional selection in human populations. These include bioinformatic analysis of DNA sequences via detection of linkage disequilibrium and of deviations from the random distribution of frequencies of genetic variants, demographic and anthropometric studies based on a search for a correlation between fertility and phenotypic traits, genome-wide association studies on fertility along with genetic loci and polygenic risk scores, and a comparison of allele frequencies between generations (in modern samples and in those obtained from burials). Each approach has its limitations and is applicable to different periods in the evolution of Homo sapiens. The main source of error in such studies is thought to be sample stratification, the small number of studies on nonwhite populations, the impossibility of a complete comparison of the associations found and functionally significant causative variants, and the difficulty with taking into account all nongenetic determinants of fertility in contemporary populations. The results obtained by various methods indicate that the direction of human adaptation to new food products has not changed during evolution since the Neolithic; many variants of immunity genes associated with inflammatory and autoimmune diseases in modern populations have undergone positive selection over the past 2-3 thousand years owing to the spread of bacterial and viral infections. For some genetic variants and polygenic traits, an alteration of the direction of natural selection in Europe has been documented, e. g., for those associated with an immune response and cognitive abilities. Examination of the correlation between fertility and educational attainment yields conflicting results. In modern populations, to a greater extent than previously, there is selection for variants of genes responsible for social adaptation and behavioral phenotypes. In particular, several articles have shown a positive correlation of fertility with polygenic risk scores of attention deficit/hyperactivity disorder.

Transcriptome analysis reveals molecular signature and cell-type difference of Homo sapiens endothelial-to-mesenchymal transition.

Endothelial-to-mesenchymal transition (EndoMT), a specific form of epithelial-to-mesenchymal transition, drives a growing number of human (Homo sapiens) pathological conditions. This emerging knowledge opens a path to discovering novel therapeutic targets for many EndoMT-associated disorders. Here, we constructed an atlas of the endothelial-cell transcriptome and demonstrated EndoMT-induced global changes in transcriptional gene expression. Our gene ontology analyses showed that EndoMT could be a specific checkpoint for leukocyte chemotaxis, adhesion, and transendothelial migration. We also identified distinct gene expression signatures underlying EndoMT across arterial, venous, and microvascular endothelial cells. We performed protein-protein interaction network analyses, identifying a class of highly connected hub genes in endothelial cells from different vascular beds. Moreover, we found that the short-chain fatty acid acetate strongly inhibits the transcriptional program of EndoMT in endothelial cells from different vascular beds across tissues. Our results reveal the molecular signature and cell-type difference of EndoMT across distinct tissue- and vascular-bed-specific endothelial cells, providing a powerful discovery tool and resource value. These results suggest that therapeutically manipulating the endothelial transcriptome could treat an increasing number of EndoMT-associated pathological conditions.

Thirty Years with ERH: An mRNA Splicing and Mitosis Factor Only or Rather a Novel Genome Integrity Protector?

ERH is a 100 to about 110 aa nuclear protein with unique primary and three-dimensional structures that are very conserved from simple eukaryotes to humans, albeit some species have lost its gene, with most higher fungi being a noteworthy example. Initially, studies on Drosophila melanogaster implied its function in pyrimidine metabolism. Subsequently, research on Xenopus laevis suggested that it acts as a transcriptional repressor. Finally, studies in humans pointed to a role in pre-mRNA splicing and in mitosis but further research, also in Caenorhabditis elegans and Schizosaccharomyces pombe, demonstrated its much broader activity, namely involvement in the biogenesis of mRNA, and miRNA, piRNA and some other ncRNAs, and in repressive heterochromatin formation. ERH interacts with numerous, mostly taxon-specific proteins, like Mmi1 and Mei2 in S. pombe, PID-3/PICS-1, TOST-1 and PID-1 in C. elegans, and DGCR8, CIZ1, PDIP46/SKAR and SAFB1/2 in humans. There are, however, some common themes in this wide range of processes and partners, such as: (a) ERH homodimerizes to form a scaffold for several complexes involved in the metabolism of nucleic acids, (b) all these RNAs are RNA polymerase II transcripts, (c) pre-mRNAs, whose splicing depends on ERH, are enriched in transcripts of DNA damage response and DNA metabolism genes, and (d) heterochromatin is formed to silence unwanted transcription, e.g., from repetitive elements. Thus, it seems that ERH has been adopted for various pathways that serve to maintain genome integrity.

Nascent transcription upon interferon-α2 stimulation on human and rhesus macaque lymphoblastoid cell lines.

OBJECTIVES: The interferon-triggered innate immune response has been observed to be under strong diversifying selection to counteract the many pathogens hosts have to defend against. In particular, rewiring of gene transcription regulation allows organisms to rapidly acquire new phenotypes by removing and adding genes into the innate immune gene network. Dissecting the molecular processes by which this rewiring takes place, either by changing the DNA regulatory elements or by changing the activity of the regulators across species, is key to better understand this evolutionary process. DATA DESCRIPTION: To better comprehend the evolutionary dynamics that have occurred in the initial transcriptional response to interferon in primates, we present Precision Run-On (PRO-seq) datasets made after 1 h of interferon-α2 stimulation on human and rhesus macaque lymphoblastoid cell lines. Further, we tested the difference between using either species' cognate interferon versus using the other orthologous interferon to account for any potential impacts in the interaction of the orthologous interferons with their cellular membrane receptors. This data provides insights into the regulatory mechanisms that drive species-specific responses to environmental perturbations, such as the one driven by the interactions of pathogens and their hosts.