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Over the past 40 years, the climate has been changing and human disturbance has increased in the vast Qinghai–Tibet Plateau (QTP). These 2 factors are expected to affect the distribution of a large number of endemic vertebrate species. However, quantitative relationships between range shifts and climate change and human disturbance of these species in the QTP have rarely been evaluated. We used occurrence records of 19 terrestrial vertebrate species (birds, mammals, amphibians, and reptiles) occurring in the QTP from 1980 to 2020 to quantify the effects of climate change and anthropogenic impacts on the distribution of these 4 taxonomic groups and estimated species range changes in each species. The trend in distribution changes differed among the taxonomic groups, although, generally, ranges shifted to central QTP. Climate change contributed more to range variation than human disturbance (the sum of the 4 climatic variables contributed more than the sum of the 4 human disturbance variables for all 4 taxonomic groups). Suitable geographic range increased for most mammals, amphibians, and reptiles (+27.6%, +18.4%, and +27.8% on average, respectively), whereas for birds range decreased on average by 0.9%. Quantitative evidence for climate change and human disturbance associations with range changes for endemic vertebrate species in the QTP can provide useful insights into biodiversity conservation under changing environments. [ABSTRACT FROM AUTHOR]

The exchange of biotas between Eurasia and North America across the Bering land bridge had a major impact on ecosystems of both continents throughout the Cenozoic. This exchange has received particular attention regarding placental mammals dispersing into the Americas, including humans after the last glacial period, and also as an explanation for the disjunct distribution of related seed plants in eastern Asia and eastern North America. Here, we investigate bi-directional dispersal across the Bering land bridge from estimates of dispersal events based on time-calibrated phylogenies of a broad range of plant, fungus and animal taxa. We reveal a long-lasting phase of asymmetrical biotic interchange, with a peak of dispersal from Asia into North America during the late Oligocene warming (26–24 Ma), when dispersal in the opposite direction was greatly decreased. Influx from North America into Asia was lower than in the opposite direction throughout the Cenozoic, but with peak rates of dispersal at the end of the Eocene (40–34 Ma) and again in the early to middle Miocene (16–14 Ma). The strong association between dispersal patterns and environmental changes suggests that plants, fungi and animals have likely dispersed from stable to perturbed environments of North America and Eurasia throughout the Cenozoic. [ABSTRACT FROM AUTHOR]

It has been hypothesized that populations at the margins of the distributional range of a species show reduced genetic diversity and increased inter-population differentiation compared to central populations. Here, we test this hypothesis by examining the structure of genetic diversity in marginal populations of black poplar, Populus nigra L. (Salicaceae). This species occurs mainly in Europe but its range extends to central Asia. We collected 117 individuals from 10 populations at the edge of the distributional range of the species in central Asia to examine the structure of genetic diversity based on genetic polymorphisms at 20 microsatellite markers. As expected, the genetic diversity within these marginal populations is relatively low, with an average observed heterozygosity H o of 0.337 and an average expected heterozygosity H e of 0.466, compared to the genetic diversity of populations from central distributions. However, we recovered very low genetic differentiation between populations, with an average F st of 0.0745, a value similar to those reported for central populations. AMOVA analyses confirmed this result, showing that only 9.2% of the total variation could be attributed to between-population variance ( P < 0.001). Our findings do not fully support hypotheses about the structure of genetic diversity in marginal populations formed from observations on other species. We suggest that a high rate of outcrossing and possible postglacial colonization at the edge of the distributional range of this long-lived poplar may explain the observed structure of the genetic diversity. [ABSTRACT FROM AUTHOR]

Key message: Using RNA sequencing analysis, we identified 9,216 regulatory and salt-related genes with differential expression and temporal expression trends which provide a clear picture of transcriptomic dynamics in response to continuous salinity stress in a desert poplar, Populus pruinosa. Abstract: Populus pruinosa Schrenk is native to the desert region of western China and extraordinarily well adapted to the local salt stress. Thus, it is an ideal model for studying plants' adaptation to salt stress, but its transcriptomic responses have not been previously characterized. Thus, we analyzed time- courses of these responses via a series of sequencings. In total, we generated 157.4 million 100 bp paired-end clean reads and identified 9,216 differentially expressed genes (DEGs) between salt-stressed calli and controls. Gene ontology classification analysis revealed that salt stress-related categories--including 'oxidation reduction', 'transcription factor activity', 'membrane' and 'ion channel activity'--were highly enriched among these DEGs. In addition, we grouped the 9,216 DEGs by their expression dynamics into four clusters, and the genes in each cluster showed enrichment for particular functional categories. We also found that most DEGs were activated within 24 h of the stress and their expression stabilized after 48 h. All these findings suggest that gene expression rapidly and coordinately changes during this species' adaptation to salt stress. In addition, the identified DEGs provide critical genetic resources for further functional analyses and indications of potential transgenic modifications for developing salt-tolerant poplars. [ABSTRACT FROM AUTHOR]

Understanding how and why species evolve requires knowledge on intraspecific divergence. In this study, we examined intraspecific divergence in the endangered hot‐spring snake (Thermophis baileyi), an endemic species on the Qinghai‐Tibet Plateau (QTP). Whole‐genome resequencing of 58 sampled individuals from 15 populations was performed to identify the drivers of intraspecific divergence and explore the potential roles of genes under selection. Our analyses resolved three groups, with major intergroup admixture occurring in regions of group contact. Divergence probably occurred during the Pleistocene as a result of glacial climatic oscillations, Yadong‐Gulu rift, and geothermal fields differentiation, while complex gene flow between group pairs reflected a unique intraspecific divergence pattern on the QTP. Intergroup fixed loci involved selected genes functionally related to divergence and local adaptation, especially adaptation to hot spring microenvironments in different geothermal fields. Analysis of structural variants, genetic diversity, inbreeding, and genetic load indicated that the hot‐spring snake population has declined to a low level with decreased diversity, which is important for the conservation management of this endangered species. Our study demonstrated that the integration of demographic history, gene flow, genomic divergence genes, and other information is necessary to distinguish the evolutionary processes involved in speciation. [ABSTRACT FROM AUTHOR]

Background: Populus is an ecologically and economically important genus of trees, but distinguishing between wild species is relatively difficult due to extensive interspecific hybridization and introgression, and the high level of intraspecific morphological variation. The DNA barcoding approach is a potential solution to this problem. Methodology/Principal Findings: Here, we tested the discrimination power of five chloroplast barcodes and one nuclear barcode (ITS) among 95 trees that represent 21 Populus species from western China. Among all single barcode candidates, the discrimination power is highest for the nuclear ITS, progressively lower for chloroplast barcodes matK (M), trnG-psbK (G) and psbK-psbI (P), and trnH-psbA (H) and rbcL (R); the discrimination efficiency of the nuclear ITS (I) is also higher than any two-, three-, or even the five-locus combination of chloroplast barcodes. Among the five combinations of a single chloroplast barcode plus the nuclear ITS, H+I and P+I differentiated the highest and lowest portion of species, respectively. The highest discrimination rate for the barcodes or barcode combinations examined here is 55.0% (H+I), and usually discrimination failures occurred among species from sympatric or parapatric areas. Conclusions/Significance: In this case study, we showed that when discriminating Populus species from western China, the nuclear ITS region represents a more promising barcode than any maternally inherited chloroplast region or combination of chloroplast regions. Meanwhile, combining the ITS region with chloroplast regions may improve the barcoding success rate and assist in detecting recent interspecific hybridizations. Failure to discriminate among several groups of Populus species from sympatric or parapatric areas may have been the result of incomplete lineage sorting, frequent interspecific hybridizations and introgressions. We agree with a previous proposal for constructing a tiered barcoding system in plants, especially for taxonomic groups that have complex evolutionary histories (e.g. Populus). [ABSTRACT FROM AUTHOR]

Heart failure (HF) has been recognized as a global epidemic with high rates of morbidity, hospitalization, and mortality. The role of amino acids, which provide the body with energy, in the development of HF is still unclear. The aim of this study was to explore changes in serum amino acids in patients with HF and identify potential biomarkers. First, the serum amino acid metabolism profiles of 44 patients with HF and 30 healthy controls (Con) were quantitatively measured. Then, candidate markers were identified through the utilization of T test, multivariate statistical analysis, and receiver operating characteristic (ROC) curve analysis. The results found that there were 11 amino acid levels that were significantly different between patients with HF and Con. Based on ROC curve analysis, the biomarkers of eight amino acids (Glutamic acid, Taurine, l-aspartic acid, l-ornithine, Ethanolamine, l-Serine, l-Sarcosine, and Cysteine) showed high sensitivity and specificity (AUC > 0.90), and binary logistic regression analysis was used in MetaboAnalyst 5.0. Among the amino acids examined, six exhibited notable alterations in accordance with the severity of HF. In conclusion, this study cannot only provide clinicians with an objective diagnostic approach for the early identification of HF, but also enhances comprehension of the underlying mechanisms involved in the pathogenesis of HF. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) constitutes a worldwide health threat, and the underlying mechanism for the development and progression of T2D is complex and multifactorial. During the last decade, gut commensal bacteria have been found to play a crucial role in the regulation of T2D and related metabolic disorders. However, as a considerable component in gut microbiome, the relationship between mycobiota and T2D and related metabolic disorders remains unclear. As a proof-of-concept, we observed that the ablation of the commensal fungi in mice can protect HFD (High fat diet) induced insulin resistance and related metabolic disorders. Both ITS2 (internal transcribed spacer 2) sequencing and culture-dependent analysis show the enrichment of Candida albicans in samples from individuals with T2D (Chinese Clinical Trial Registry, ChiCTR2100042049). Repopulation with C. albicans in HFD mice accelerated insulin resistance and related disorders. Mechanically, we found the β-glucan from C. albicans mirrored the deteriorating effect of C. albicans through the dectin-1 dependent pathway. Our current findings support that gut mycobiota play an important role in the progress of T2D and indicated the preventing of gut mycobiota is a promising strategy to alleviate insulin resistance and related metabolic dysfunctions. β-glucan from Candida albicans promotes high-fat diet induced insulin resistance and related metabolic disorders in mice and C. albicans is enriched in type 2 diabetes (T2D) patients, supporting a role of gut mycobiota in the progress of T2D. [ABSTRACT FROM AUTHOR]

Medulloblastoma is a malignancy of the central nervous system that occurs most frequently in childhood and is often difficult to diagnose due to its similarities to conventional imaging findings for other pediatric intracranial tumors such as astrocytomas and ependymomas. The purpose of this study was to identify new metabolites and differential metabolic pathways by analyzing the significantly different metabolites present in the plasma of children with medulloblastoma in comparison with those with other intracranial tumors. Plasma was collected from 37 children with medulloblastoma and 34 children with other intracranial tumors. Targeted and non-targeted metabolomics based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analyses were performed to determine metabolic changes in pediatric medulloblastomas versus other intracranial tumors. Based on multivariate statistical analysis and regression models, we identified differential metabolites in the plasma and investigated different metabolic pathways. A total of 61 differential metabolites in the plasma of children with medulloblastoma were identified by non-targeted metabolomics analysis. In addition, targeted metabolomics analysis identified four differential amino acids, thus allowing us to establish a diagnostic model for children with medulloblastoma. Metabolic pathway analysis showed that there were significant differences in patients with medulloblastoma in terms of glycerophospholipid and α-linolenic acid metabolism pathways as well as several amino acid metabolism pathways (phenylalanine, tyrosine, and tryptophan biosynthesis). We identified differential profiles of key plasma metabolites between children with medulloblastoma and other forms of intracranial tumor, thus providing a basis for identifying early diagnostic markers of medulloblastoma and new therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]

Purpose. The use of formulary systems and pharmacy and therapeutics (P&T) committees in the Western Pacific Region (WPR) and the factors associated with their use were explored. Methods. Minor additions were made to a previously validated survey and reviewed by a WPR advisory committee. The Basel Statements 26 and 27 survey was made available in eight languages and sent electronically to 1989 hospital pharmacy directors through respective hospital pharmacy associations in the WPR. Results. A total of 797 responses (40%) from 34 nations were received. Of these responses, 87% of hospitals (691 of 797) used a formulary. Also, 93% of respondents (619 of 664) indicated that their hospital had a P&T committee. However, only 44% of respondents (274 of 626) reported that more than half of their formulary medicines were linked to standard treatment guidelines. Furthermore, only 41% of hospitals (247 of 601) had a policy for off-label medication use. The pharmacy directors' perceived benefits of formularies were correlated with having more formulary medicines linked to standard treatment guidelines, basing their use on the best available evidence, and having a policy for the use of off-label medicines. Conclusion. A large proportion of hospitals in the WPR have implemented formularies and P&T committees. Although formularies are commonly used, their effectiveness may be limited, as formularies are often not linked to standard treatment guidelines or the best available evidence. [ABSTRACT FROM AUTHOR]

The RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK (RAF/MEK/ERK) signaling cascade serves a prominent role in hepatocellular carcinoma (HCC) proliferation. Sorafenib (BAY 43‑9006) is a potent multikinase inhibitor of RAF kinases and a few receptor tyrosine kinases. Additionally, sorafenib causes apoptosis in a number of human tumor cell lines such as leukemia cell lines. Sorafenib is the first targeted drug to prolong the overall survival of patients with advanced HCC. However, sorafenib activity is less favorable in certain cancers, including sarcomas and melanomas, due to patient insensitivity and drug resistance. In the present study, a novel bi‑aryl urea, N‑(3‑trifluoromethylphenyl)‑N'-(2-methyl-4-(6‑cyclopropanecarboxamido-pyrimidin-4-yl) oxyphenyl) urea (CBI‑5725), is shown to be a potential candidate for the treatment of liver cancer. In the present study, the in vitro activities of CBI‑5725 and sorafenib in PLC/PRF/5 HCC cells were examined and the corresponding in vivo antitumor activities in PLC/PRF/5 human tumor xenografts. An alamar blue assay confirmed that CBI‑5725 was more cytotoxic than sorafenib to PLC/PRF/5 cells, suggesting that CBI‑5725 inhibited tumor cell proliferation more potently than sorafenib. CBI‑5725 inhibited the RAF/MEK/ERK signaling pathway to the same extent as sorafenib. In addition, CBI‑5725 elicited cell cycle arrest in the G2/M phase, while sorafenib did not markedly alter the cell cycle. Furthermore, CBI‑5725 induced apoptosis more strongly than sorafenib in a dose‑dependent manner, which may be attributed to greater caspase‑3 and poly(adenosine 5'‑diphosphate‑ribose) polymerase activation by CBI‑5725. In the PLC/PRF/5 xenograft model, 2 mg/kg CBI‑5725 inhibited tumor growth by 73%. At doses ranging from 6 to 18 mg/kg, CBI‑5725 nearly completely prevented tumor growth. These results imply that the antitumor efficacy of CBI‑5725 in HCC models may result from the suppression of the RAF/MEK/ERK signaling pathway, the induction of cell cycle arrest in the G2/M phase, and the initiation of caspase‑3‑dependent apoptosis. These observations suggested that CBI‑5725 may be a potent novel compound for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Populus pruinosa and P. euphratica , are two desert poplars characterized by extreme adaptation to salt stress. In contrast, P. trichocarpa and P. tomentosa are two salt sensitive congeners. In order to identify the adaptations to salt stress that are common to each type of these poplars, we compared transcriptome changes in the four poplar species after exposure to continuous salt stress. We identified 7822 1:1 orthologs between the four species and 702 differentially expressed genes (DEGs) during the 48 h time course. The result of hierarchical clustering suggested that the patterns of gene expression were significantly different between the two types of poplar. These genes were mainly involved in ‘Oxidoreductase activity’, ‘Primary metabolic processes’, ‘Transport’ and ‘Nucleic acid binding transcription factor activity’. Among these DEGs, in which the functions related to responses to salt exposure are significantly over-represented, 11 genes were found to be continuously up or down-regulated in response to salt stress in the two types. We also found that most of the orthologous candidate genes evolved under purifying selection and one ortholog ( GDSL ) showed positive selection. These genes probably played important roles when their ancestral clade underwent adaptive divergence into the two types, differentiated by habitat salt-content. [ABSTRACT FROM AUTHOR]

With the extensive recent use of warfarin and traditional Chinese medicine (TCM) in combination, TCM has been found to affect warfarin's pharmacokinetic and pharmacodynamic parameters. Warfarin is a widely used oral anticoagulant, which has a narrow therapeutic window and a high likelihood of interacting with other drugs and resulting in serious adverse reactions. Contrary to widespread public expectations, TCM, despite being natural, is not always safe. To report the adverse drug reactions (ADR) resulting from the use of Chinese medicine and warfarin sodium tablets in combination. According to a hospital ADR monitoring report, we collected data on four clinical cases involving warfarin and single Chinese herbal medicine, warfarin and proprietary traditional Chinese medicine product, warfarin and Chinese medicinal injection, and warfarin and compound decoction. The Naranjo ADR score evaluation scale was used to analyze the relationships between warfarin and Chinese medicines. Fluctuations in the international normalized ratio (INR) were accompanied by bleeding in some patients who regularly and simultaneously utilized warfarin and Chinese medicine. The potential risk of bleeding due to the interaction between TCM and warfarin is easily and often overlooked by both Western and TCM doctors. Warfarin in combination with different traditional Chinese herbal medicines poses risks of INR fluctuations and adverse reactions such as bleeding. In the future, the safety awareness regarding reasonable administration of warfarin and herbal medicine should be emphasized. Image 1 [ABSTRACT FROM AUTHOR]