Exploring CYP2D6 polymorphisms and angiotensin receptor blocker response in the Bai hypertensive population.

OBJECTIVE: The CYP2D6 enzyme is crucial for the metabolism and disposition of a variety of drugs. This study was conducted to examine the relationship between CYP2D6 gene polymorphisms and the response to angiotensin receptor blocker (ARB)-based treatment in patients of Chinese Bai ethnicity with hypertension. METHODS: Seventy-two hypertensive adults from the Chinese Bai ethnic group, exhibiting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, were recruited. Targeted regional sequencing was utilized to genotype single nucleotide polymorphisms in the CYP2D6 gene, aiming to assess their frequency and to evaluate their influence on the therapeutic efficacy of ARB medications. RESULTS: Our research identified nine significant CYP2D6 polymorphisms associated with the efficacy of ARB treatment in the Bai hypertensive cohort. Specifically, patients possessing certain mutant genotype at rs111564371 exhibited substantially greater reductions in SBP and DBP, with P-values of 0.021 and 0.016, respectively, compared to those carrying the wild genotype. Additionally, these mutant genotype at rs111564371 and rs112568578 were linked to approximately 20% higher overall efficacy rates and a 10% increased achievement rate relative to the wild genotype. CONCLUSION: Our research with the Bai hypertensive group shows that certain CYP2D6 polymorphisms significantly influence ARB treatment outcomes. Mutations at rs111564371 led to better blood pressure control (P-values: 0.021 for SBP, 0.016 for DBP), improving ARB efficacy by appromixately 20% and increasing treatment goal achievement by 10% over the wild-type genotype. STATEMENTS: Our investigation into CYP2D6 polymorphisms within the Bai hypertensive cohort marks a substantial advancement towards personalized healthcare, underscoring the pivotal influence of genetic constitution on the effectiveness of ARB therapy.

Genomic epidemiology reveals multiple mechanisms of linezolid resistance in clinical enterococci in China.

BACKGROUND: Infections caused by linezolid-resistant enterococci (LRE) are clinically difficult to treat and threaten patient health. However, there is a lack of studies on long time-span LRE strains in China. For this reason, our study comprehensively revealed the resistance mechanisms of LRE strains collected in a Chinese tertiary care hospital from 2011 to 2022. METHODS: Enterococcal strains were screened and verified after retrospective analysis of microbial data. Subsequently, 65 LRE strains (61 Enterococcus faecalis and 4 Enterococcus faecium, MIC ≥ 8 µg/ml), 1 linezolid-intermediate Enterococcus faecium (MIC = 4 µg/ml) and 1 linezolid-susceptible Enterococcus faecium (MIC = 1.5 µg/ml) were submitted for whole-genome sequencing (WGS) analysis and bioinformatics analysis. RESULTS: The optrA gene was found to be the most common linezolid resistance mechanism in our study. We identified the wild-type OptrA and various OptrA variants in 98.5% of LRE strains (61 Enterococcus faecalis and 3 Enterococcus faecium). We also found one linezolid-resistant Enterococcus faecium strain carried both optrA and cfr(D) gene, while one linezolid-resistant Enterococcus faecium only harbored the poxtA gene. Most optrA genes (55/64) were located on plasmids, with impB-fexA-optrA, impB-fexA-optrA-erm(A), fexA-optrA-erm(A), and fexA-optrA segments. A minority of optrA genes (9/64) were found on chromosomes with the Tn6674-like platform. Besides, other possible linezolid resistance-associated mechanisms (mutations in the rplC and rplD genes) were also found in 26 enterococcal strains. CONCLUSIONS: Our study suggested that multiple mechanisms of linezolid resistance exist among clinical LRE strains in China.

Dynamic analysis of SARS-CoV-2 evolution based on different countries.

Since late 2019, COVID-19 has significantly impacted the world. Understanding the evolution of SARS-CoV-2 is crucial for protecting against future infectious pathogens. In this study, we conducted a comprehensive chronological analysis of SARS-CoV-2 evolution by examining mutation prevalence from the source countries of VOCs: United Kingdom, India, Brazil, South Africa, plus two countries: United States, Russia, utilizing genomic sequences from GISAID. Our methodological approach involved large-scale genomic sequence alignment using MAFFT, Python-based data processing on a high-performance computing platform, and advanced statistical methods the Maximal Information Coefficient (MIC), and also Long Short-Term Memory (LSTM) models for correlation analysis. Our findings elucidate the dynamics of SARS-CoV-2 evolution, highlighting the virus's changing behaviour over various pandemic stages. Key results include the discovery of three temporal mutation patterns-lineage distinct, long-span, and competitive mutations-with varying levels of impact on the virus. Notably, we observed a convergence of advantageous mutations in the spike protein, especially in the later stages of the pandemic, indicating a substantial evolutionary pressure on the virus. One of the most significant revelations is the predominant role of natural immunity over vaccination-induced immunity in driving these evolutionary changes. This emphasizes the critical need for regular vaccine updates to maintain efficacy against evolving strains. In conclusion, our study not only sheds light on the evolutionary trajectory of SARS-CoV-2 but also underscores the urgency for robust, continuous global data collection and sharing. It highlights the necessity for rapid adaptations in medical countermeasures, including vaccine development, to stay ahead of pathogen evolution. This research provides valuable insights for future pandemic preparedness and response strategies.

Impact of LDLR polymorphisms on lipid levels and atorvastatin's efficacy in a northern Chinese adult Han cohort with dyslipidemia.

BACKGROUND: Dyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia. METHODS: In this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3' untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview. RESULTS: Eleven distinct polymorphisms at LDLR 3' UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin's efficacy. CONCLUSIONS: This research outlined the complex genetic architecture surrounding LDLR 3' UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care. TRIAL REGISTRATION: This multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).

Anaerostipes hadrus, a butyrate-producing bacterium capable of metabolizing 5-fluorouracil.

Anaerostipes hadrus (A. hadrus) is a dominant species in the human gut microbiota and considered a beneficial bacterium for producing probiotic butyrate. However, recent studies have suggested that A. hadrus may negatively affect the host through synthesizing fatty acid and metabolizing the anticancer drug 5-fluorouracil, indicating that the impact of A. hadrus is complex and unclear. Therefore, comprehensive genomic studies on A. hadrus need to be performed. We integrated 527 high-quality public A. hadrus genomes and five distinct metagenomic cohorts. We analyzed these data using the approaches of comparative genomics, metagenomics, and protein structure prediction. We also performed validations with culture-based in vitro assays. We constructed the first large-scale pan-genome of A. hadrus (n = 527) and identified 5-fluorouracil metabolism genes as ubiquitous in A. hadrus genomes as butyrate-producing genes. Metagenomic analysis revealed the wide and stable distribution of A. hadrus in healthy individuals, patients with inflammatory bowel disease, and patients with colorectal cancer, with healthy individuals carrying more A. hadrus. The predicted high-quality protein structure indicated that A. hadrus might metabolize 5-fluorouracil by producing bacterial dihydropyrimidine dehydrogenase (encoded by the preTA operon). Through in vitro assays, we validated the short-chain fatty acid production and 5-fluorouracil metabolism abilities of A. hadrus. We observed for the first time that A. hadrus can convert 5-fluorouracil to α-fluoro-ß-ureidopropionic acid, which may result from the combined action of the preTA operon and adjacent hydA (encoding bacterial dihydropyrimidinase). Our results offer novel understandings of A. hadrus, exceptionally functional features, and potential applications. IMPORTANCE: This work provides new insights into the evolutionary relationships, functional characteristics, prevalence, and potential applications of Anaerostipes hadrus.

VarEPS-Influ:an risk evaluation system of occurred and virtual variations of influenza virus genomes.

Influenza viruses undergo frequent genomic mutations, leading to potential cross-species transmission, phenotypic changes, and challenges in diagnostic reagents and vaccines. Accurately evaluating and predicting the risk of such variations remain significant challenges. To address this, we developed the VarEPS-Influ database, an influenza virus variations risk evaluation system (VarEPS-Influ). This database employs a 'multi-dimensional evaluation of mutations' strategy, utilizing various tools to assess the physical and chemical properties, primary, secondary, and tertiary structures, receptor affinity, antibody binding capacity, antigen epitopes, and other aspects of the variation's impact. Additionally, we consider space-time distribution, host species distribution, pedigree analysis, and frequency of mutations to provide a comprehensive risk evaluation of mutations and viruses. The VarEPS-Influ database evaluates both observed variations and virtual variations (variations that have not yet occurred), thereby addressing the time-lag issue in risk predictions. Our current one-stop evaluation system for influenza virus genomic variation integrates 1065290 sequences from 224 927 Influenza A, B and C isolates retrieved from public resources. Researchers can freely access the data at https://nmdc.cn/influvar/.

Comparative genomic analysis of Fusobacterium nucleatum reveals high intra-species diversity and cgmlst marker construction.

BACKGROUND: Fusobacterium nucleatum is a one of the most important anaerobic opportunistic pathogens in the oral and intestinal tracts of human and animals. It can cause various diseases such as infections, Lemierre's syndrome, oral cancer and colorectal cancer. The comparative genomic studies on the population genome level, have not been reported. RESULTS: We analyzed all publicly available Fusobacterium nucleatums' genomic data for a comparative genomic study, focusing on the pan-genomic features, virulence genes, plasmid genomes and developed cgmlst molecular markers. We found the pan-genome shows a clear open tendency and most of plasmids in Fusobacterium nucleatum are mainly transmitted intraspecifically. CONCLUSIONS: Our comparative analysis of Fusobacterium nucleatum systematically revealed the open pan-genomic features and phylogenetic tree based on cgmlst molecular markers. What's more, we also identified common plasmid typing among genomes. We hope that our study will provide a theoretical basis for subsequent functional studies.

Large-scale genomic survey and characterization of mcr genes carried by foodborne Cronobacter isolates.

IMPORTANCE: Cronobacter is an emerging foodborne opportunistic pathogen, which can cause neonatal meningitis, bacteremia, and NEC by contaminating food. However, the entire picture of foodborne Cronobacter carriage of the mcr genes is not known. Here, we investigated the mcr genes of Cronobacter isolates by whole-genome sequencing and found 133 previously undescribed Cronobacter isolates carrying mcr genes. Further genomic analysis revealed that these mcr genes mainly belonged to the mcr-9 and mcr-10. Genomic analysis of the flanking structures of mcr genes revealed that two core flanking structures were prevalent in foodborne Cronobacter isolates, and the flanking structure carrying IS1R was found for the first time in this study.

A Novel Prognostic Signature of comprising Nine NK Cell signatures Based on Both Bulk RNA Sequencing and Single-Cell RNA Sequencing for Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) has limited prognostic prediction due to its heterogeneity. Understanding the role of natural killer (NK) cells in HCC is vital for prognosis and immunotherapy guidance. We aimed to identify NK cell marker genes through scRNA-seq and develop a prognostic signature for HCC. Methods: We analyzed scRNA-seq data (GSE149614) from 10 patients and bulk RNA-seq data from 786 patients with clinicopathological information. NK cell marker genes were identified using clustering and marker finding functions. A predictive risk signature was constructed using LASSO-COX algorithm. Functional annotations and immune cell infiltration analysis were performed, and the nomogram's performance was evaluated. Results: We identified 79 NK cell marker genes associated with NK cell-mediated cytotoxicity, apoptosis, and immune response. The multigene signature significantly correlated with overall survival (OS) in TCGA-LIHC cohort and was validated in other cohorts. Low-risk patients exhibited higher immune cell infiltration, including CD8+ T cells. The risk signature was an independent prognostic factor for OS (HR > 1, p < 0.001). The nomogram combining the risk signature and clinical predictors demonstrated robust prognostic ability. Conclusion: We developed a nine-gene signature prognostic model based on NK cell marker genes to accurately assess the prognostic risk of HCC. This model can be a valuable tool for personalized evaluation post-surgery. Our study underscores the potential of NK cells in HCC prognosis and highlights the importance of scRNA-seq analysis in identifying prognostic markers.

Plasmer: an Accurate and Sensitive Bacterial Plasmid Prediction Tool Based on Machine Learning of Shared k-mers and Genomic Features.

Identification of plasmids in bacterial genomes is critical for many factors, including horizontal gene transfer, antibiotic resistance genes, host-microbe interactions, cloning vectors, and industrial production. There are several in silico methods to predict plasmid sequences in assembled genomes. However, existing methods have evident shortcomings, such as unbalance in sensitivity and specificity, dependency on species-specific models, and performance reduction in sequences shorter than 10 kb, which has limited their scope of applicability. In this work, we proposed Plasmer, a novel plasmid predictor based on machine-learning of shared k-mers and genomic features. Unlike existing k-mer or genomic-feature based methods, Plasmer employs the random forest algorithm to make predictions using the percent of shared k-mers with plasmid and chromosome databases combined with other genomic features, including alignment E value and replicon distribution scores (RDS). Plasmer can predict on multiple species and has achieved an average the area under the curve (AUC) of 0.996 with accuracy of 98.4%. Compared to existing methods, tests of both sliding sequences and simulated and de novo assemblies have consistently shown that Plasmer has outperforming accuracy and stable performance across long and short contigs above 500 bp, demonstrating its applicability for fragmented assemblies. Plasmer also has excellent and balanced performance on both sensitivity and specificity (both >0.95 above 500 bp) with the highest F1-score, which has eliminated the bias on sensitivity or specificity that was common in existing methods. Plasmer also provides taxonomy classification to help identify the origin of plasmids. IMPORTANCE In this study, we proposed a novel plasmid prediction tool named Plasmer. Technically, unlike existing k-mer or genomic features-based methods, Plasmer is the first tool to combine the advantages of the percent of shared k-mers and the alignment score of genomic features. This has given Plasmer (i) evident improvement in performance compared to other methods, with the best F1-score and accuracy on sliding sequences, simulated contigs, and de novo assemblies; (ii) applicability for contigs above 500 bp with highest accuracy, enabling plasmid prediction in fragmented short-read assemblies; (iii) excellent and balanced performance between sensitivity and specificity (both >0.95 above 500 bp) with the highest F1-score, which eliminated the bias on sensitivity or specificity that commonly existed in other methods; and (iv) no dependency of species-specific training models. We believe that Plasmer provides a more reliable alternative for plasmid prediction in bacterial genome assemblies.

A food poisoning caused by ST7 Staphylococcal aureus harboring sea gene in Hainan province, China.

ST7 Staphylococcus aureus is highly prevalent in humans, pigs, as well as food in China; however, staphylococcal food poisoning (SFP) caused by this ST type has rarely been reported. On May 13, 2017, an SFP outbreak caused by ST7 S. aureus strains occurred in two campuses of a kindergarten in Hainan Province, China. We investigated the genomic characteristics and phylogenetic analysis of ST7 SFP strains combined with the 91 ST7 food-borne strains from 12 provinces in China by performing whole-genome sequencing (WGS). There was clear phylogenetic clustering of seven SFP isolates. Six antibiotic genes including blaZ, ANT (4')-Ib, tetK, lnuA, norA, and lmrS were present in all SFP strains and also showed a higher prevalence rate in 91 food-borne strains. A multiple resistance plasmid pDC53285 was present in SFP strain DC53285. Among 27 enterotoxin genes, only sea and selx were found in all SFP strains. A ФSa3int prophage containing type A immune evasion cluster (sea, scn, sak, and chp) was identified in SFP strain. In conclusion, we concluded that this SFP event was caused by the contamination of cakes with ST7 S. aureus. This study indicated the potential risk of new emergencing ST7 clone for SFP.

Insights into the genomic evolution and the alkali tolerance mechanisms of Agaricus sinodeliciosus by comparative genomic and transcriptomic analyses.

Agaricus sinodeliciosus is a rare wild edible mushroom from northwest China, and grows naturally in mild saline-alkali soil, which is also unusual in mushrooms. A. sinodeliciosus represents a potential model organism for explaining saline-alkali tolerance mechanisms and revealing related physiological processes in mushrooms. Here, we provide a high-quality genome of A. sinodeliciosus. Comparative genomic analyses reveal A. sinodeliciosus has numerous changes to its genome organization after a solitary evolutionary history under saline-alkali environments, such as gene family contraction, retrotransposon expansion and rapid evolution of adaptative genes. Our saline and alkali tolerance tests show that mycelium growth and fruit body formation of this species are effected by mild alkalinity. Transcriptomic analyses reveal that genes involved in carbon and nitrogen utilization, cell stability and fruit body formation of A. sinodeliciosus could be activated under mildly alkaline conditions. In particular, the 'starch and sucrose metabolism', 'biosynthesis of amino acids' and 'phenylpropanoid biosynthesis' pathways are important for mildly alkaline tolerance of A. sinodeliciosus. Like plants and arbuscular mycorrhizal fungi, in the rot fungus A. sinodeliciosus, the biosynthesis of intracellular small molecules could be enhanced to counter osmotic and oxidative stresses caused by mild alkalinity, and the biosynthesis of monolignol could be suppressed to increase cell wall infiltrates under mildly alkaline conditions. This research provides an understanding of the genomic evolution and mechanisms of A. sinodeliciosus in tolerance to saline-alkali environments. The A. sinodeliciosus genome constitutes a valuable resource for evolutionary and ecological studies of Agaricus.

Gut microbiome and mycobiome in inflammatory bowel disease patients with Clostridioides difficile infection.

Background: Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD) and has been reported as a risk factor for poor outcome. However, gut microbiome and mycobiome of IBD patients with CDI have been barely investigated. This study aimed to assess the gut microbiome and mycobiome in IBD patients with CDI. Methods: We collected fecal samples from patients with active IBD and concomitant CDI (IBD-CDI group, n=25), patients with active IBD and no CDI (IBD-only group, n=51), and healthy subjects (HC, n=40). Patients' characteristics including demographic data, disease severity, and medication history were collected. Metagenomic sequencing, taxonomic and functional analysis were carried out in the samples. Results: We found that the bacterial alpha diversity of the IBD-CDI group was decreased. The bacterial and fungal beta diversity variations between IBD patients and HC were significant, regardless of CDI status. But the IBD-CDI group did not significantly cluster separately from the IBD-only group. Several bacterial taxa, including Enterococcus faecium, Ruminococcus gnavus, and Clostridium innocuum were overrepresented in the IBD-CDI group. Furthermore, IBD patients with CDI were distinguished by several fungal taxa, including overrepresentation of Saccharomyces cerevisiae. We also identified functional differences in IBD patients with CDI include enrichment of peptidoglycan biosynthesis. The network analysis indicated specific interactions between microbial markers in IBD-CDI patients. Conclusion: IBD patients with CDI had pronounced microbial dysbiosis. Gut micro-ecological changes in IBD patients with CDI might provide insight into the pathological process and potential strategies for diagnosis and treatment in this subset of patients.

Tracing Foodborne Botulism Events Caused by Clostridium botulinum in Xinjiang Province, China, Using a Core Genome Sequence Typing Scheme.

Foodborne botulism is a rare but life-threatening illness resulting from the action of a potent toxin mainly produced by Clostridium botulinum. It grows in an oxygen-deficient environment and is extremely viable in meat and soy products, making it one of the most virulent bacteria. How to track foodborne botulism events quickly and accurately has become a key issue. Here, we investigated two foodborne botulism events that occurred in Xinjiang in 2019 based on whole-genome sequencing and also successfully traced the relationship between clinical and food C. botulinum isolates using whole-genome core gene markers. All 59 isolates were classified as group I strains. Of the strains isolated in this study, 44 were found to be botulinum toxin A(B), and 15 isolates contained only the toxin B locus. Both the toxin A and B gene segments were located on the chromosome and organized in an ha cluster. Antibiotic resistance and virulence factors were also investigated. A set of 329 universal core gene markers were established using C. botulinum strains from a public database. These core gene markers were applied to the published C. botulinum genomes, and three outbreaks were identified. This work demonstrates that universal core gene markers can be used to trace foodborne botulism events, and we hope that our work will facilitate this effort in future. IMPORTANCE In this study, we analyzed 59 foodborne botulism (FB)-related strains isolated in Xinjiang Province, China. Our findings not only reveal the group classification, neurotoxin locus organization, antibiotic resistance and virulence factors of these strains but also establish a set of core gene markers for tracing foodborne botulism events, which was verified using published genomes. These findings indicate that these gene markers might be used as a potential tracing tool for FB events caused by C. botulinum group I strains, which have relatively stable genomic components.

Pan-Genome Analysis of Staphylococcus aureus Reveals Key Factors Influencing Genomic Plasticity.

The massive quantities of bacterial genomic data being generated have facilitated in-depth analyses of bacteria for pan-genomic studies. However, the pan-genome compositions of one species differed significantly between different studies, so we used Staphylococcus aureus as a model organism to explore the influences driving bacterial pan-genome composition. We selected a series of diverse strains for pan-genomic analysis to explore the pan-genomic composition of S. aureus at the species level and the actual contribution of influencing factors (sequence type [ST], source of isolation, country of isolation, and date of collection) to pan-genome composition. We found that the distribution of core genes in bacterial populations restrained under different conditions differed significantly and showed "local core gene regions" in the same ST. Therefore, we propose that ST may be a key factor driving the dynamic distribution of bacterial genomes and that phylogenetic analyses using whole-genome alignment are no longer appropriate in populations containing multiple ST strains. Pan-genomic analysis showed that some of the housekeeping genes of multilocus sequence typing (MLST) are carried at less than 60% in S. aureus strains. Consequently, we propose a new set of marker genes for the classification of S. aureus, which provides a reference for finding a new set of housekeeping genes to apply to MLST. In this study, we explored the role of driving factors influencing pan-genome composition, providing new insights into the study of bacterial pan-genomes. IMPORTANCE We sought to explore the impact of driving factors influencing pan-genome composition using Staphylococcus aureus as a model organism to provide new insights for the study of bacterial pan-genomes. We believe that the sequence type (ST) of the strains under consideration plays a significant role in the dynamic distribution of bacterial genes. Our findings indicate that there are a certain number of essential genes in Staphylococcus aureus; however, the number of core genes is not as high as previously thought. The new classification method proposed herein suggests that a new set of housekeeping genes more suitable for Staphylococcus aureus must be identified to improve the current classification status of this species.

Central gene transcriptional regulatory networks shaping monocyte development in bone marrow.

The development of monocytes in bone marrow is a complex process with multiple steps. We used RNA-seq data to analyze the transcriptome profiles in developing stages of monocytes, including hematopoietic stem cells (HSCs), common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), and monocytes. We found that genes related to potassium and other cation transmembrane activities and ion binding were upregulated during the differentiation of HSCs into CMPs. Protein transport and membrane surface functional molecules were significantly upregulated in the GMP stage. The CD42RAC and proteasome pathways are significantly upregulated during the development of HSCs into monocytes. Transcription factors Ank1, Runx2, Hmga2, Klf1, Nfia, and Bmyc were upregulated during the differentiation of HSCs into CMPs; Gfi1 and Hmgn2 were highly expressed during the differentiation of CMPs into GMPs; Seventeen transcription factors including Foxo1, Cdkn2d, Foxo3, Ep300, Pias1, Nfkb1, Creb1, Bcl6, Ppp3cb, Stat5b, Nfatc4, Mef2a, Stat6, Ifnar2, Irf7, Irf5, and Cebpb were identified as potentially involved in the development of GMPs into monocytes in mice and humans. In metabolism pathway regulation, HSCs have high glucose, lipid, and nucleic acid metabolism activities; CMPs mainly up regulate the TCA cycle related genes; and GMPs have extremely active metabolisms, with significantly elevated pentose phosphate pathway, TCA cycle, histidine metabolism, and purine metabolism. In the monocyte phase, the tricarboxylic acid (TCA) cycle is reduced, and the anaerobic glycolysis process becomes dominated. Overall, our studies offer the kinetics and maps of gene transcriptional expressions and cell metabolisms during monocyte development in bone marrow.

Improved pea reference genome and pan-genome highlight genomic features and evolutionary characteristics.

Complete and accurate reference genomes and annotations provide fundamental resources for functional genomics and crop breeding. Here we report a de novo assembly and annotation of a pea cultivar ZW6 with contig N50 of 8.98 Mb, which features a 243-fold increase in contig length and evident improvements in the continuity and quality of sequence in complex repeat regions compared with the existing one. Genome diversity of 118 cultivated and wild pea demonstrated that Pisum abyssinicum is a separate species different from P. fulvum and P. sativum within Pisum. Quantitative trait locus analyses uncovered two known Mendel's genes related to stem length (Le/le) and seed shape (R/r) as well as some candidate genes for pod form studied by Mendel. A pan-genome of 116 pea accessions was constructed, and pan-genes preferred in P. abyssinicum and P. fulvum showed distinct functional enrichment, indicating the potential value of them as pea breeding resources in the future.

Identification of a Putative CodY Regulon in the Gram-Negative Phylum Synergistetes.

CodY is a dominant regulator in low G + C, Gram-positive Firmicutes that governs the regulation of various metabolic pathways and cellular processes. By using various bioinformatics analyses and DNA affinity precipitation assay (DAPA), this study confirmed the presence of CodY orthologues and corresponding regulons in Gram-negative Synergistetes. A novel palindromic sequence consisting of AT-rich arms separated by a spacer region of variable length and sequence was identified in the promoters of the putative codY-containing operons in Synergistetes. The consensus sequence from genera Synergistes and Cloacibacillus (5'-AATTTTCTTAAAATTTCSCTTGATATTTACAATTTT) contained three AT-rich regions, resulting in two palindromic sequences; one of which is identical to Firmicutes CodY box (5'-AATTTTCWGAAAATT). The function of the consensus sequence was tested by using a recombinant CodY protein (His-CodYDSM) of Cloacibacillus evryensis DSM19522 in DAPA. Mutations in the central AT-rich sequence reduced significantly the binding of His-CodYDSM, whereas mutations in the 5' or 3' end AT-rich sequence slightly reduced the binding, indicating that CodYDSM could recognize both palindromic sequences. The proposed binding sequences were found in the promoters of multiple genes involved in amino acids biosynthesis, metabolism, regulation, and stress responses in Synergistetes. Thus, a CodY-like protein from Synergistetes may function similarly to Firmicutes CodY.

Preliminary Screening of a Familial Tuberous Sclerosis Complex Pathogenic Gene.

Purpose: The aim of this study was to screen the possible pathogenic genes of one family with tuberous sclerosis complexes (TSCs). Patients and Methods: All family members were examined through detailed clinical evaluations, auxiliary examinations and CT. Then, we selected five members from this TSC family as the test samples. They were analysed by a new exon group sequencing method. Single nucleotide polymorphisms (SNPs) were screened by using databases, such as dbSNP and HAPMAP, and then the candidate genes were selected. Genes were analysed, and finally, the most likely mutation sites were screened. The results were examined by Sanger sequencing. Results: In this TSC family, we identified c.913+2T>G, a splicing site mutation in the 9th intron region of TSC1. Family members without TSC did not have this mutation. Conclusion: The mutations in the intron regions cannot be ruled out as a pathogenic factor for TSC.

A genome and gene catalog of glacier microbiomes.

Glaciers represent a unique inventory of microbial genetic diversity and a record of evolution. The Tibetan Plateau contains the largest area of low-latitude glaciers and is particularly vulnerable to global warming. By sequencing 85 metagenomes and 883 cultured isolates from 21 Tibetan glaciers covering snow, ice and cryoconite habitats, we present a specialized glacier microbial genome and gene catalog to archive glacial genomic and functional diversity. This comprehensive Tibetan Glacier Genome and Gene (TG2G) catalog includes 883 genomes and 2,358 metagenome-assembled genomes, which represent 968 candidate species spanning 30 phyla. The catalog also contains over 25 million non-redundant protein-encoding genes, the utility of which is demonstrated by the exploration of secondary metabolite biosynthetic potentials, virulence factor identification and global glacier metagenome comparison. The TG2G catalog is a valuable resource that enables enhanced understanding of the structure and functions of Tibetan glacial microbiomes.