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The purpose of this study was to evaluate the influence of high-definition transcranial direct current stimulation (HD-tDCS) on finger motor skill acquisition. Thirty-one healthy adult males were randomly assigned to one of three groups: online HD-tDCS (administered during motor skill learning), offline HD-tDCS (delivered before motor skill learning), and a sham group. Participants engaged in a visual isometric pinch task for three consecutive days. Overall motor skill learning and speed-accuracy tradeoff function were used to evaluate the efficacy of tDCS. Electroencephalography was recorded and power spectral density was calculated. Both online and offline HD-tDCS total motor skill acquisition was significantly higher than the sham group (P < 0.001 and P < 0.05, respectively). Motor skill acquisition in the online group was higher than offline (P = 0.132, Cohen's d = 1.46). Speed-accuracy tradeoff function in the online group was higher than both offline and sham groups in the post-test. The online group exhibited significantly lower electroencephalography activity in the frontal, fronto-central, and centro-parietal alpha band regions compared to the sham (P < 0.05). The findings suggest that HD-tDCS application can boost finger motor skill acquisition, with online HD-tDCS displaying superior facilitation. Furthermore, online HD-tDCS reduces the power of alpha rhythms during motor skill execution, enhancing information processing and skill learning efficiency., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Translation initiation of the human immunodeficiency virus-type 1 (HIV-1) genomic mRNA (vRNA) is cap-dependent or mediated by an internal ribosome entry site (IRES). The HIV-1 IRES requires IRES-transacting factors (ITAFs) for function. In this study, we evaluated the role of the heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a potential ITAF for the HIV-1 IRES. In HIV-1-expressing cells, the depletion of hnRNPK reduced HIV-1 vRNA translation. Furthermore, both the depletion and overexpression of hnRNPK modulated HIV-1 IRES activity. Phosphorylations and protein arginine methyltransferase 1 (PRMT1)-induced asymmetrical dimethylation (aDMA) of hnRNPK strongly impacted the protein's ability to promote the activity of the HIV-1 IRES. We also show that hnRNPK acts as an ITAF for the human T cell lymphotropic virus-type 1 (HTLV-1) IRES, present in the 5'UTR of the viral sense mRNA, but not for the IRES present in the antisense spliced transcript encoding the HTLV-1 basic leucine zipper protein (sHBZ). This study provides evidence for a novel role of the host hnRNPK as an ITAF that stimulates IRES-mediated translation initiation for the retroviruses HIV-1 and HTLV-1., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Aims: Common to adult electrophysiology studies (EPSs), intracardiac echocardiography (ICE) use in paediatric and congenital heart disease (CHD) EPS is limited. The purpose of this study was to assess the efficacy of ICE use and incidence of associated complications in paediatric and CHD EPS., Methods and Results: This single-centre retrospective matched cohort study reviewed EPS between 2013 and 2022. Demographics, CHD type, and EPS data were collected. Intracardiac echocardiography cases were matched 1:1 to no ICE controls to assess differences in complications, ablation success, fluoroscopy exposure, procedure duration, and arrhythmia recurrence. Cases and controls with preceding EPS within 5 years were excluded. Intracardiac echocardiography cases without an appropriate match were excluded from comparative analyses but included in the descriptive cohort. We performed univariable and multivariable logistic regression to assess associations between variables and outcomes. A total of 335 EPS were reviewed, with ICE used in 196. The median age of ICE cases was 15 [interquartile range (IQR) 12-17; range 3-47] years, and median weight 57 [IQR 45-71; range 15-134] kg. There were no ICE-related acute or post-procedural complications. There were 139 ICE cases matched to no ICE controls. Baseline demographics and anthropometrics were similar between cases and controls. Fluoroscopy exposure (P = 0.02), procedure duration (P = 0.01), and arrhythmia recurrence (P = 0.01) were significantly lower in ICE cases., Conclusion: Intracardiac echocardiography in paediatric and CHD ablations is safe and reduces procedure duration, fluoroscopy exposure, and arrhythmia recurrence. However, not every arrhythmia substrate requires ICE use. Thoughtful selection will ensure the judicious and strategic application of ICE to enhance outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Virus-encoded circular RNA (circRNA) participates in the immune response to viral infection, affects the human immune system, and can be used as a target for precision therapy and tumor biomarker. The coronaviruses SARS-CoV-1 and SARS-CoV-2 (SARS-CoV-1/2) that have emerged in recent years are highly contagious and have high mortality rates. In coronaviruses, little is known about the circRNA encoded by the SARS-CoV-1/2. Therefore, this study explores whether SARS-CoV-1/2 encodes circRNA and characteristics and functions of circRNA. Based on RNA-seq data of SARS-CoV-1 and SARS-CoV-2 infections, we used circRNA identification tools (circRNA&#95;finder, find&#95;circ and CIRI2) to identify circRNAs. The number of circRNAs encoded by SARS-CoV-1 and SARS-CoV-2 was identified as 151 and 470, respectively. It can be found that SARS-CoV-2 shows more prominent circRNA encoding ability than SARS-CoV-1. Expression analysis showed that only a few circRNAs encoded by SARS-CoV-1/2 showed high expression levels, and the positive strand produced more abundant circRNAs. Then, based on the identified SARS-CoV-1/2-encoded circRNAs, we performed circRNA identification and characterization using the previously developed CirRNAPL. Finally, target gene prediction and functional enrichment analysis were performed. It was found that viral circRNA is closely related to cancer and has a potential role in regulating host cell functions. This study studied the characteristics and functions of viral circRNA encoded by coronavirus SARS-CoV-1/2, providing a valuable resource for further research on the function and molecular mechanism of coronavirus circRNA., (© The Author(s) 2024. Published by Oxford University Press.)

Anthocyanin biosynthesis in plants is influenced by a wide range of environmental factors, such as light, temperature and nutrient availability. In this study, we revealed that the potassium-repressed anthocyanin accumulation in radish hypocotyls was associated with altered sugar distribution and sugar signaling pathways rather than changes in oxidative stress status. Sugar-feeding experiments suggested a hexokinase-independent glucose signal acted as a major contributor in regulating anthocyanin biosynthesis, transport and regulatory genes at the transcriptional level. Several R2R3-MYBs were identified as anthocyanin-related MYBs. Phylogenetic and protein sequence analyses suggested that RsMYB75 met the criteria of subgroup 6 MYB activator, while RsMYB39 and RsMYB82 seemed to be a non-canonical MYB anthocyanin activator and repressor, respectively. Through yeast-one-hybrid, dual-luciferase and transient expression assays, we confirmed that RsMYB39 strongly induced the promoter activity of anthocyanin transport-related gene RsGSTF12, while RsMYB82 significantly reduced anthocyanin biosynthesis gene RsANS1 expression. Molecular models are proposed in the discussion, allowing speculation on how these novel RsMYBs may regulate the expression levels of anthocyanin-related structural genes. Together, our data evidenced the strong impacts of potassium on sugar metabolism and signaling and its regulation of anthocyanin accumulation through different sugar signals and R2R3-MYBs in a hierarchical regulatory system., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acute pancreatitis is initiated within pancreatic exocrine cells and sustained by dysregulated systemic inflammatory responses mediated by neutrophils. Store-operated Ca 2+ entry (SOCE) through ORAI1 channels in pancreatic acinar cells triggers acute pancreatitis, and ORAI1 inhibitors ameliorate experimental acute pancreatitis, but the role of ORAI1 in pancreatitis-associated acute lung injury has not been determined. Here, we showed mice with pancreas-specific deletion of Orai1 ( Orai1 ΔPdx1 , ∼70% reduction in the expression of Orai1) are protected against pancreatic tissue damage and immune cell infiltration, but not pancreatitis-associated acute lung injury, suggesting the involvement of unknown cells that may cause such injury through SOCE via ORAI1. Genetic ( Orai1 ΔMRP8 ) or pharmacological inhibition of ORAI1 in murine and human neutrophils decreased Ca 2+ influx and impaired chemotaxis, reactive oxygen species production, and neutrophil extracellular trap formation. Unlike pancreas-specific Orai1 deletion, mice with neutrophil-specific deletion of Orai1 ( Orai1 ΔMRP8 ) were protected against pancreatitis- and sepsis-associated lung cytokine release and injury, but not pancreatic injury in experimental acute pancreatitis. These results define critical differences between contributions from different cell types to either pancreatic or systemic organ injury in acute pancreatitis. Our findings suggest that any therapy for acute pancreatitis that targets multiple rather than single cell types is more likely to be effective., Competing Interests: None declared, (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

People with human immunodeficiency virus have an increased risk of developing cardiovascular disease. RNA-Seq was performed on hearts from simian immunodeficiency virus (SIV)-infected rhesus macaques with or without antiretroviral therapy (ART). SIV infection led to high plasma viral load with very little myocardial viral RNA. SIV infection promoted an inflammatory environment in the heart through interferon and pathogen signaling, in the absence of myocardial viral RNA. While ART dampened interferon and cytokine response in the heart, SIV-infected animals receiving ART had deficits in the expression of genes directly involved in fatty acid metabolism relative to SIV-uninfected animals., Competing Interests: Potential conflicts of interest. T. H. B. is a member of the scientific advisory board and holds equity in Excision BioTherapeutics (unrelated to the current study). All other authors declare no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Protein-protein interactions (PPIs) are a major component of the cellular biochemical reaction network. Rich sequence information and machine learning techniques reduce the dependence of exploring PPIs on wet experiments, which are costly and time-consuming. This paper proposes a PPI prediction model, multi-scale architecture residual network for PPIs (MARPPI), based on dual-channel and multi-feature. Multi-feature leverages Res2vec to obtain the association information between residues, and utilizes pseudo amino acid composition, autocorrelation descriptors and multivariate mutual information to achieve the amino acid composition and order information, physicochemical properties and information entropy, respectively. Dual channel utilizes multi-scale architecture improved ResNet network which extracts protein sequence features to reduce protein feature loss. Compared with other advanced methods, MARPPI achieves 96.03%, 99.01% and 91.80% accuracy in the intraspecific datasets of Saccharomyces cerevisiae, Human and Helicobacter pylori, respectively. The accuracy on the two interspecific datasets of Human-Bacillus anthracis and Human-Yersinia pestis is 97.29%, and 95.30%, respectively. In addition, results on specific datasets of disease (neurodegenerative and metabolic disorders) demonstrate the ability to detect hidden interactions. To better illustrate the performance of MARPPI, evaluations on independent datasets and PPIs network suggest that MARPPI can be used to predict cross-species interactions. The above shows that MARPPI can be regarded as a concise, efficient and accurate tool for PPI datasets., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Drought is one of the major limiting factors in the growth of terrestrial plants. Abscisic acid (ABA) and pyrabactin resistance 1/prabactin resistance-1 like/regulatory components of ABA receptors (PYR/PYL/RCARs) play a key role in response to drought stress. However, the underlying mechanisms of this control remain largely elusive in trees. In this study, PePYL4, a potential ortholog of the PYR/PYL/RCARs gene, was cloned from Populus euphratica. It was localized in the cytoplasm and nucleus, induced by ABA, osmotic and dehydration treatments. To study the potential biological functions of PePYL4, transgenic triploid white poplars (Populus tomentosa 'YiXianCiZhu B38') overexpressing PePYL4 were generated. PePYL4 overexpression significantly increased ABA sensitivity and reduced stomatal aperture. Compared with wild-type plants, transgenic plants had higher water-use efficiency (WUE) and lower transpiration. When exposed to drought stress, PePYL4 overexpression plants maintained higher photosynthetic activity and accumulated more biomass. Moreover, overexpression of PePYL4 improved antioxidant enzyme activity and ascorbate content to accelerate reactive oxygen species scavenging. Meanwhile, upregulation expression of the stress-related genes also contributed to improving the drought tolerance of transgenic plants. In conclusion, our data suggest that PePYL4 is a promising gene target for regulating WUE and drought tolerance in Populus., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Microglia and macrophages are essential for homeostatic maintenance and innate immune response in the brain. They are the first line of defense against infections such as HIV/SIV in the brain. However, they are susceptible to infection and function as viral reservoirs even under effective viral suppression. While current antiretroviral regimens successfully suppress viremia and improve quality of life and lifespan, neurologic complications persist and are in part attributed to activated microglia. We sought to test the hypothesis that brain microglia return to a more homeostatic-like state when viremia is suppressed by combination antiretroviral therapy. Using the SIV-rhesus macaque model, we combined single-cell RNA sequencing, bioinformatics, and pathway analysis to compare gene expression profiles of brain myeloid cells under 4 conditions: uninfected, SIV infected, SIV infected with cART suppression, and SIV encephalitis (SIVE). Our study reveals greater myeloid diversity and an elevated proinflammatory state are associated with untreated SIV infection compared with uninfected animals. The development of encephalitis and suppression of viremia both reduced myeloid diversity. However, they had converse effects on the activation state of microglia and inflammation. Notably, suggestive of a restoration of a homeostatic state in microglia, gene expression and activation of pathways related to inflammation and immune response in cART-suppressed monkeys were most similar to that in uninfected monkeys. Untreated SIV infection shared characteristics, especially in brain macrophages to SIVE, with SIVE showing dramatic inflammation. In support of our hypothesis, our study demonstrates that cART indeed restores this key component of the brain's homeostatic state. Summary: ScRNA-seq of rhesus monkey microglia reveals clusters of cells in activated states in the setting of SIV infection, which is primarily reversed by suppressing viremia with combination antiretroviral therapy., (© 2022 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.)

Brassinosteroid (BR) phytohormones play crucial roles in regulating internode elongation in rice (Oryza sativa). However, the underlying mechanism remains largely unclear. The dwarf and low-tillering (dlt) mutant is a mild BR-signaling-defective mutant. Here, we identify two dlt enhancers that show more severe shortening of the lower internodes compared to the uppermost internode (IN1). Both mutants carry alleles of ORYZA SATIVA HOMEOBOX 15 (OSH15), the founding gene for dwarf6-type mutants, which have shortened lower internodes but not IN1. Consistent with the mutant phenotype, OSH15 expression is much stronger in lower internodes, particularly in IN2, than IN1. The osh15 single mutants have impaired BR sensitivity accompanied by enhanced BR synthesis in seedlings. DLT physically interacts with OSH15 to co-regulate many genes in seedlings and internodes. OSH15 targets and promotes the expression of the BR receptor gene BR INSENSITIVE1 (OsBRI1), and DLT facilitates this regulation in a dosage-dependent manner. In osh15, dlt, and osh15 dlt, BR levels are higher in seedlings and panicles, but unexpectedly lower in internodes compared with the wild-type. Taken together, our results suggest that DLT interacts with OSH15, which functions in the lower internodes, to modulate rice internode elongation via orchestrating BR signaling and metabolism., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Motivation: With the analysis of the characteristic and function of circular RNAs (circRNAs), people have realized that they play a critical role in the diseases. Exploring the relationship between circRNAs and diseases is of far-reaching significance for searching the etiopathogenesis and treatment of diseases. Nevertheless, it is inefficient to learn new associations only through biotechnology., Results: Consequently, we present a computational method, GMNN2CD, which employs a graph Markov neural network (GMNN) algorithm to predict unknown circRNA-disease associations. First, used verified associations, we calculate semantic similarity and Gaussian interactive profile kernel similarity (GIPs) of the disease and the GIPs of circRNA and then merge them to form a unified descriptor. After that, GMNN2CD uses a fusion feature variational map autoencoder to learn deep features and uses a label propagation map autoencoder to propagate tags based on known associations. Based on variational inference, GMNN alternate training enhances the ability of GMNN2CD to obtain high-efficiency high-dimensional features from low-dimensional representations. Finally, 5-fold cross-validation of five benchmark datasets shows that GMNN2CD is superior to the state-of-the-art methods. Furthermore, case studies have shown that GMNN2CD can detect potential associations., Availability and Implementation: The source code and data are available at https://github.com/nmt315320/GMNN2CD.git., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Circular RNAs (circRNAs) are non-coding RNAs with a special circular structure produced formed by the reverse splicing mechanism, which play an important role in a variety of biological activities. Viruses can encode circRNA, and viral circRNAs have been found in multiple single-stranded and double-stranded viruses. However, the characteristics and functions of viral circRNAs remain unknown. Sequence alignment showed that viral circRNAs are less conserved than circRNAs in animal, indicating that the viral circRNAs may evolve rapidly. Through the analysis of the sequence characteristics of viral circRNAs and circRNAs in animal, it was found that viral circRNAs and animals circRNAs are similar in nucleic acid composition, but have obvious differences in secondary structure and autocorrelation characteristics. Based on these characteristics of viral circRNAs, machine learning algorithms were employed to construct a prediction model to identify viral circRNA. Additionally, analysis of the interaction between viral circRNA and miRNAs showed that viral circRNA is expected to interact with 518 human miRNAs, and preliminary analysis of the role of viral circRNA. And it has been also found that viral circRNAs may be involved in many KEGG pathways related to nervous system and cancer. We curated an online server, and the data and code are available: http://server.malab.cn/viral-CircRNA/., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Translation initiation of the viral genomic mRNA (vRNA) of human immunodeficiency virus-type 1 (HIV-1) can be mediated by a cap- or an internal ribosome entry site (IRES)-dependent mechanism. A previous report shows that Staufen1, a cellular double-stranded (ds) RNA-binding protein (RBP), binds to the 5'untranslated region (5'UTR) of the HIV-1 vRNA and promotes its cap-dependent translation. In this study, we now evaluate the role of Staufen1 as an HIV-1 IRES-transacting factor (ITAF). We first confirm that Staufen1 associates with both the HIV-1 vRNA and the Gag protein during HIV-1 replication. We found that in HIV-1-expressing cells, siRNA-mediated depletion of Staufen1 reduces HIV-1 vRNA translation. Using dual-luciferase bicistronic mRNAs, we show that the siRNA-mediated depletion and cDNA-mediated overexpression of Staufen1 acutely regulates HIV-1 IRES activity. Furthermore, we show that Staufen1-vRNA interaction is required for the enhancement of HIV-1 IRES activity. Interestingly, we find that only Staufen1 harboring an intact dsRNA-binding domain 3 (dsRBD3) rescues HIV-1 IRES activity in Staufen1 CRISPR-Cas9 gene edited cells. Finally, we show that the expression of Staufen1-dsRBD3 alone enhances HIV-1 IRES activity. This study provides evidence of a novel role for Staufen1 as an ITAF promoting HIV-1 vRNA IRES activity., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Sepsis is an overwhelming inflammatory response to microbial infection. Sepsis management remains a clinical challenge. The role of the gut microbiome in sepsis has gained some attention. Recent evidence has demonstrated that gut microbiota regulate host physiological homeostasis mediators, including the immune system, gut barrier function and disease susceptibility pathways. Therefore, maintenance or restoration of microbiota and metabolite composition might be a therapeutic or prophylactic target against critical illness. Fecal microbiota transplantation and supplementation of probiotics are microbiota-based treatment methods that are somewhat limited in terms of evidence-based efficacy. This review focuses on the importance of the crosstalk between the gastrointestinal ecosystem and sepsis to highlight novel microbiota-targeted therapies to improve the outcomes of sepsis treatment., (© The Author(s) 2021. Published by Oxford University Press.)

Background: Antibiotic tolerance allows bacteria to overcome antibiotic treatment transiently and potentially accelerates the emergence of resistance. However, our understanding of antibiotic tolerance at the genetic level during adaptive evolution of Staphylococcus aureus remains incomplete. We sought to identify the mutated genes and verify the role of these genes in the formation of vancomycin tolerance in S. aureus., Methods: Vancomycin-susceptible S. aureus strain Newman was used to induce vancomycin-tolerant isolates in vitro by cyclic exposure under a high concentration of vancomycin (20× MIC). WGS and Sanger sequencing were performed to identify the genetic mutations. The function of mutated genes in vancomycin-tolerant isolates were verified by gene complementation. Other phenotypes of vancomycin-tolerant isolates were also determined, including mutation frequency, autolysis, lysostaphin susceptibility, cell wall thickness and cross-tolerance., Results: A series of vancomycin-tolerant S. aureus (VTSA) strains were isolated and 18 mutated genes were identified by WGS. Among these genes, pbp4, htrA, stp1, pth and NWMN&#95;1068 were confirmed to play roles in VTSA formation. Mutation of mutL promoted the emergence of VTSA. All VTSA showed no changes in growth phenotype. Instead, they exhibited reduced autolysis, decreased lysostaphin susceptibility and thickened cell walls. In addition, all VTSA strains were cross-tolerant to antibiotics targeting cell wall synthesis but not to quinolones and lipopeptides., Conclusions: Our results demonstrate that genetic mutations are responsible for emergence of phenotypic tolerance and formation of vancomycin tolerance may lie in cell wall changes in S. aureus., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Water availability is a main limiting factor for plant growth, development, and distribution throughout the world. Stomatal movement mediated by abscisic acid (ABA) is particularly important for drought adaptation, but the molecular mechanisms in trees are largely unclear. Here, we isolated an ABA-responsive element binding factor, PeABF3, in Populus euphratica. PeABF3 was preferentially expressed in the xylem and young leaves, and was induced by dehydration and ABA treatments. PeABF3 showed transactivation activity and was located in the nucleus. To study its functional mechanism in poplar responsive to drought stress, transgenic triploid white poplars (Populus tomentosa 'YiXianCiZhu B385') overexpressing PeABF3 were generated. PeABF3 overexpression significantly enhanced stomatal sensitivity to exogenous ABA. When subjected to drought stress, PeABF3 overexpression maintained higher photosynthetic activity and promoted cell membrane integrity, resulting in increased water-use efficiency and enhanced drought tolerance compared with wild-type controls. Moreover, a yeast one-hybrid assay and an electrophoretic mobility shift assay revealed that PeABF3 activated the expression of Actin-Depolymerizing Factor-5 (PeADF5) by directly binding to its promoter, promoting actin cytoskeleton remodeling and stomatal closure in poplar under drought stress. Taken together, our results indicate that PeABF3 enhances drought tolerance via promoting ABA-induced stomatal closure by directly regulating PeADF5 expression., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glaucoma is characterized by a progressive degeneration of retinal ganglion cells (RGCs), leading to irreversible vision loss. Currently, there is no effective treatment for RGC degeneration. We used a disease-in-a-dish stem cell model to examine the developmental susceptibility of RGCs to glaucomatous degeneration, which may inform on the formulation of therapeutic approaches. Here, we used single-cell transcriptome analysis of SIX6 risk allele (SIX6 risk allele ) primary open angle glaucoma patient-specific and control hRGCs to compare developmental trajectories in terms of lineage- and stage-specific transcriptional signature to identify dysregulated stages/genes, and subtype composition to estimate the relative vulnerability of RGCs to degeneration because their ability to regenerate axons are subtype-specific. The developmental trajectories, beginning from neural stem cells to RGCs, were similar between SIX6 risk allele and control RGCs. However, the differentiation of SIX6 risk allele RGCs was relatively stalled at the retinal progenitor cell stage, compromising the acquisition of mature phenotype and subtype composition, compared with controls, which was likely due to dysregulated mTOR and Notch signaling pathways. Furthermore, SIX6 risk allele RGCs, as compared with controls, expressed fewer genes corresponding to RGC subtypes that are preferentially resistant to degeneration. The immature phenotype of SIX6 risk allele RGCs with underrepresented degeneration-resistant subtypes may make them vulnerable to glaucomatous degeneration., (© 2020 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Maintaining stable, high yields under fluctuating environmental conditions is a long-standing goal of crop improvement but is challenging due to internal trade-off mechanisms, which are poorly understood. Here, we identify ARGONAUTE2 (AGO2) as a candidate target for achieving this goal in rice ( Oryza sativa ). Overexpressing AGO2 led to a simultaneous increase in salt tolerance and grain length. These benefits were achieved via the activation of BIG GRAIN3 ( BG3 ), encoding a purine permease potentially involved in cytokinin transport. AGO2 can become enriched on the BG3 locus and alter its histone methylation level, thus promoting BG3 expression. Cytokinin levels decreased in shoots but increased in roots of AGO2 -overexpressing plants. While bg3 knockout mutants were hypersensitive to salt stress, plants overexpressing BG3 showed strong salt tolerance and large grains. The knockout of BG3 significantly reduced grain length and salt tolerance in AGO2 -overexpressing plants. Both genes were transcriptionally suppressed by salt treatment. Salt treatment markedly increased cytokinin levels in roots but decreased them in shoots, resulting in a hormone distribution pattern similar to that in AGO2 -overexpressing plants. These findings highlight the critical roles of the spatial distribution of cytokinins in both stress responses and grain development. Therefore, optimizing cytokinin distribution represents a promising strategy for improving both grain yield and stress tolerance in rice., (© 2020 American Society of Plant Biologists. All rights reserved.)

Potassium (K+) is a critical determinant of salinity tolerance, and H2O2 has been recognized as an important signaling molecule that mediates many physiological responses. However, the details of how H2O2 signaling regulates K+ uptake in the root under salt stress remain elusive. In this study, salt-sensitive cucumber and salt-tolerant pumpkin which belong to the same family, Cucurbitaceae, were used to answer the above question. We show that higher salt tolerance in pumpkin was related to its superior ability for K+ uptake and higher H2O2 accumulation in the root apex. Transcriptome analysis showed that salinity induced 5816 (3005 up- and 2811 down-) and 4679 (3965 up- and 714 down-) differentially expressed genes (DEGs) in cucumber and pumpkin, respectively. DEGs encoding NADPH oxidase (respiratory burst oxidase homolog D; RBOHD), 14-3-3 protein (GRF12), plasma membrane H+-ATPase (AHA1), and potassium transporter (HAK5) showed higher expression in pumpkin than in cucumber under salinity stress. Treatment with the NADPH oxidase inhibitor diphenylene iodonium resulted in lower RBOHD, GRF12, AHA1, and HAK5 expression, reduced plasma membrane H+-ATPase activity, and lower K+ uptake, leading to a loss of the salinity tolerance trait in pumpkin. The opposite results were obtained when the plants were pre-treated with exogenous H2O2. Knocking out of RBOHD in pumpkin by CRISPR/Cas9 [clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9] editing of coding sequences resulted in lower root apex H2O2 and K+ content and GRF12, AHA1, and HAK5 expression, ultimately resulting in a salt-sensitive phenotype. However, ectopic expression of pumpkin RBOHD in Arabidopsis led to the opposite effect. Taken together, this study shows that RBOHD-dependent H2O2 signaling in the root apex is important for pumpkin salt tolerance and suggests a novel mechanism that confers this trait, namely RBOHD-mediated transcriptional and post-translational activation of plasma membrane H+-ATPase operating upstream of HAK5 K+ uptake transporters., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

DNA methylation, the most intensively studied epigenetic modification, plays an important role in understanding the molecular basis of diseases. Furthermore, epigenome-wide association study (EWAS) provides a systematic approach to identify epigenetic variants underlying common diseases/phenotypes. However, there is no comprehensive database to archive the results of EWASs. To fill this gap, we developed the EWASdb, which is a part of 'The EWAS Project', to store the epigenetic association results of DNA methylation from EWASs. In its current version (v 1.0, up to July 2018), the EWASdb has curated 1319 EWASs associated with 302 diseases/phenotypes. There are three types of EWAS results curated in this database: (i) EWAS for single marker; (ii) EWAS for KEGG pathway and (iii) EWAS for GO (Gene Ontology) category. As the first comprehensive EWAS database, EWASdb has been searched or downloaded by researchers from 43 countries to date. We believe that EWASdb will become a valuable resource and significantly contribute to the epigenetic research of diseases/phenotypes and have potential clinical applications. EWASdb is freely available at http://www.ewas.org.cn/ewasdb or http://www.bioapp.org/ewasdb.

The treatment of multiple myeloma (MM) with bortezomib (BTZ) is promising; however, the emergence of resistance is challenging in the clinical treatment. Thus, a novel targeted treatment or exploring the mechanism underlying BTZ resistance is an urgent requisite. The current data showed that high expression of USP7 in myeloma was a predictor of short overall survival and poor outcome. USP7 knockout significantly suppressed the colony formation, inhibited the proliferation of BTZ-resistant MM cells even in the presence of growth factors, and overcame BTZ resistance. The knockout markedly inhibited the tumor growth and prolonged the survival of mice bearing BTZ-resistant MM cells. Mechanistically, USP7 knockout remarkably increased the sensitivity to BTZ by stabilizing ΙκΒα and blocking the NF-κB pathway. Not surprisingly, when IκBα was knocked down by siRNA transfection, the MM cells restored the BTZ resistance. Importantly, usage of USP7 inhibitors also suppressed the activation of NF-κB and combination with BTZ triggered the synergistic antitumor activity in BTZ-resistant MM cells. Taken together, this study provides the rationale for clinical protocols evaluating USP7 inhibition, alone and in combination with BTZ, to overcome BTZ resistance and improve the patient outcome in MM., (©2018 Society for Leukocyte Biology.)

The murine model serves as an important experimental system in biomedical science because of its high degree of similarities at the sequence level with human. Recent studies have compared the transcriptional landscapes between human and mouse, but the general co-expression landscapes have not been characterized. Here, we calculated the general co-expression coefficients and constructed the general co-expression maps for human and mouse. The differences and similarities of the general co-expression maps between the two species were compared in detail. The results showed low similarities in the human and mouse, with only about 36.54% of the co-expression relationships conserved between the two species. These results indicate that researchers should pay attention to these differences when performing research using the expression data of human and mouse. To facilitate use of this information, we also developed the human-mouse general co-expression difference database (coexpressMAP) to search differences in co-expression between human and mouse. This database is freely available at http://www.bioapp.org/coexpressMAP.

Tissue tolerance to salinity stress is a complex physiological trait composed of multiple 'sub-traits' such as Na+ compartmentalization, K+ retention, and osmotic tolerance. Previous studies have shown that some Cucurbita species employ tissue tolerance to combat salinity and we aimed to identify the physiological and molecular mechanisms involved. Five C. maxima (salt-tolerant) and five C. moschata (salt-sensitive) genotypes were comprehensively assessed for their salt tolerance mechanisms and the results showed that tissue-specific transport characteristics enabled the more tolerant lines to deal with the salt load. This mechanism was associated with the ability of the tolerant species to accumulate more Na+ in the leaf vein and to retain more K+ in the leaf mesophyll. In addition, C. maxima more efficiently retained K+ in the roots when exposed to transient NaCl stress and it was also able to store more Na+ in the xylem parenchyma and cortex in the leaf vein. Compared with C. moschata, C. maxima was also able to rapidly close stomata at early stages of salt stress, thus avoiding water loss; this difference was attributed to higher accumulation of ABA in the leaf. Transcriptome and qRT-PCR analyses revealed critical roles of high-affinity potassium (HKT1) and intracellular Na+/H+ (NHX4/6) transporters as components of the mechanism enabling Na+ exclusion from the leaf mesophyll and Na+ sequestration in the leaf vein. Also essential was a higher expression of NCED3s (encoding 9-cis-epoxycarotenoid dioxygenase, a key rate-limiting enzyme in ABA biosynthesis), which resulted in greater ABA accumulation in the mesophyll and earlier stomata closure in C. maxima.

Motivation: Mathematical modelling based on ordinary differential equations (ODEs) is widely used to describe the dynamics of biological systems, particularly in systems and pathway biology. Often the kinetic parameters of these ODE systems are unknown and have to be inferred from the data. Approximate parameter inference methods based on gradient matching (which do not require performing computationally expensive numerical integration of the ODEs) have been getting popular in recent years, but many implementations are difficult to run without expert knowledge. Here, we introduce ShinyKGode, an interactive web application to perform fast parameter inference on ODEs using gradient matching., Results: ShinyKGode can be used to infer ODE parameters on simulated and observed data using gradient matching. Users can easily load their own models in Systems Biology Markup Language format, and a set of pre-defined ODE benchmark models are provided in the application. Inferred parameters are visualized alongside diagnostic plots to assess convergence., Availability and Implementation: The R package for ShinyKGode can be installed through the Comprehensive R Archive Network (CRAN). Installation instructions, as well as tutorial videos and source code are available at https://joewandy.github.io/shinyKGode., Supplementary Information: Supplementary data are available at Bioinformatics online.

Accumulating evidence indicates that transcription factor (TF) binding sites, or cis-regulatory elements (CREs), and their clusters termed cis-regulatory modules (CRMs) play a more important role than do gene-coding sequences in specifying complex traits in humans, including the susceptibility to common complex diseases. To fully characterize their roles in deriving the complex traits/diseases, it is necessary to annotate all CREs and CRMs encoded in the human genome. However, the current annotations of CREs and CRMs in the human genome are still very limited and mostly coarse-grained, as they often lack the detailed information of CREs in CRMs. Here, we integrated 620 TF ChIP-seq datasets produced by the ENCODE project for 168 TFs in 79 different cell/tissue types and predicted an unprecedentedly completely map of CREs in CRMs in the human genome at single nucleotide resolution. The map includes 305 912 CRMs containing a total of 1 178 913 CREs belonging to 736 unique TF binding motifs. The predicted CREs and CRMs tend to be subject to either purifying selection or positive selection, thus are likely to be functional. Based on the results, we also examined the status of available ChIP-seq datasets for predicting the entire regulatory genome of humans.

Plant salt tolerance can be improved by grafting onto salt-tolerant rootstocks. However, the underlying signaling mechanisms behind this phenomenon remain largely unknown. To address this issue, we used a range of physiological and molecular techniques to study responses of self-grafted and pumpkin-grafted cucumber plants exposed to 75 mM NaCl stress. Pumpkin grafting significantly increased the salt tolerance of cucumber plants, as revealed by higher plant dry weight, chlorophyll content and photochemical efficiency (Fv/Fm), and lower leaf Na+ content. Salinity stress resulted in a sharp increase in H2O2 production, reaching a peak 3 h after salt treatment in the pumpkin-grafted cucumber. This enhancement was accompanied by elevated relative expression of respiratory burst oxidase homologue (RBOH) genes RbohD and RbohF and a higher NADPH oxidase activity. However, this increase was much delayed in the self-grafted plants, and the difference between the two grafting combinations disappeared after 24 h. The decreased leaf Na+ content of pumpkin-grafted plants was achieved by higher Na+ exclusion in roots, which was driven by the Na+/H+ antiporter energized by the plasma membrane H+-ATPase, as evidenced by the higher plasma membrane H+-ATPase activity and higher transcript levels for PMA and SOS1. In addition, early stomatal closure was also observed in the pumpkin-grafted cucumber plants, reducing water loss and maintaining the plant's hydration status. When pumpkin-grafted plants were pretreated with an NADPH oxidase inhibitor, diphenylene iodonium (DPI), the H2O2 level decreased significantly, to the level found in self-grafted plants, resulting in the loss of the salt tolerance. Inhibition of the NADPH oxidase-mediated H2O2 signaling in the root also abolished a rapid stomatal closure in the pumpkin-grafted plants. We concluded that the pumpkin-grafted cucumber plants increase their salt tolerance via a mechanism involving the root-sourced respiratory burst oxidase homologue-dependent H2O2 production, which enhances Na+ exclusion from the root and promotes an early stomatal closure.

Deoxycytidine monophosphate deaminase (dCMP deaminase, DCD) is crucial to the production of dTTP needed for DNA replication and damage repair. However, the effect of DCD deficiency and its molecular mechanism are poorly understood in plants. Here, we isolated and characterized a rice albinic leaf and growth retardation (alr) mutant that is manifested by albinic leaves, dwarf stature and necrotic lesions. Map-based cloning and complementation revealed that ALR encodes a DCD protein. OsDCD was expressed ubiquitously in all tissues. Enzyme activity assays showed that OsDCD catalyses conversion of dCMP to dUMP, and the ΔDCD protein in the alr mutant is a loss-of-function protein that lacks binding ability. We report that alr plants have typical DCD-mediated imbalanced dNTP pools with decreased dTTP; exogenous dTTP recovers the wild-type phenotype. A comet assay and Trypan Blue staining showed that OsDCD deficiency causes accumulation of DNA damage in the alr mutant, sometimes leading to cell apoptosis. Moreover, OsDCD deficiency triggered cell cycle checkpoints and arrested cell progression at the G1/S-phase. The expression of nuclear and plastid genome replication genes was down-regulated under decreased dTTP, and together with decreased cell proliferation and defective chloroplast development in the alr mutant this demonstrated the molecular and physiological roles of DCD-mediated dNTP pool balance in plant development., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cold seeps are widespread chemosynthetic ecosystems in the deep-sea environment, and cold seep microbial communities of the South China Sea are poorly constrained. Here we report on the archaeal communities, particularly those involved in methane metabolization, in sediments of a newly discovered cold seep (named 'Haima') on the northwest slope of the South China Sea. Archaeal diversity, abundance and distribution were investigated in two piston cores collected from a seep area (QDN-14B) and a non-seep control site (QDN-31B). Geochemical investigation of the QDN-14B core identified an estimated sulfate-methane transition zone (Estimated SMTZ) at 300-400 cm below sea floor (cmbsf), where a high abundance of anaerobic methane-oxidizing archaea (ANME) occurred, as revealed by analysis of the 16S rRNA gene and the gene (mcrA) encoding the α-subunit of the key enzyme methyl-coenzyme M reductase. ANME-2a/b was predominant in the upper and middle layers of the estimated SMTZ, whereas ANME-1b outcompeted ANME-2 in the sulfate-depleted bottom layers of the estimated SMTZ and the methanogenic zone. Fine-scale phylogenetic analysis further divided the ANME-1b group into three subgroups with different distribution patterns: ANME-1bI, ANME-1bII and ANME-1bIII. Multivariate analyses indicated that dissolved inorganic carbon and sulfate may be important factors controlling the composition of the methane-metabolizing community. Our study on ANME niche separation and interactions with other archaeal groups improves our understanding of the metabolic diversity and flexibility of ANME, and the findings further suggest that ANME subgroups may have evolved diversified/specified metabolic capabilities other than syntrophic anaerobic oxidation of methane coupled with sulfate reduction in marine sediments., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Artificial pit muds (APMs) is produced by peats, aged pit muds, yellow and black clays etc. and is one of essential factors for Luzhou-flavour liquor production. The microbial community of APMs significantly influence the quality of Luzhou-flavour liquor. The aim of this study was to investigate the differences in bacterial, archaeal and fungal community of APMs, starters and materials., Methods and Results: Multiphase culture-independent technology were employed in this study, including nested PCR-denaturing gradient gel electrophoresis (nested PCR-DGGE), phospholipid fatty acid (PLFA), phospholipid ether lipids (PLEL) and fluorescence in situ hybridization (FISH) analysis. Results suggested that the microbial diversity significantly changed under environmental stress and different culture patterns during APMs cultivation. The dominant bacteria in APMs mainly fell into Clostridiales, Lactobacillales, Bacteroidales and Rhizobiales, Archaea affiliated with Methanomicrobiales and Methanosarcinales, and fungi belonged to Saccharomycetales and Eurotiales. Furthermore, the microbial community structures of APMs cultured by ground pile pattern were more similar with that of aged pit muds, meanwhile, the relative bands intensities of microbes, which are the main contributors for liquor brewing, increased with the culture times., Conclusions: Not only the niche selection and biogeochemical properties of APMs, but also the mutual collaboration and constraint between different microbes may result in enriching different liquor-brewing microbes into APMs., Significance and Impact of the Study: APM cultivation technology was necessary to promote enriching functional liquor-brewing microbes into APMs. These results may facilitate understanding the microbial succession during APMs manufacture., (© 2015 The Society for Applied Microbiology.)

A multicenter, double-blind, placebo-controlled trial randomized 28 patients with primary (acute) human immunodeficiency virus (HIV)-1 infection (PHI) to receive zidovudine, 1000 mg daily, or placebo for 24 weeks. At week 48, compared with placebo patients, zidovudine-treated patients had significantly higher CD4 cell counts (zidovudine, 666 cells/mm3; placebo, 362; P = .004) and lower peripheral blood mononuclear cell (PBMC) culture titers (zidovudine, 0.58 log infectious units per million cells; placebo, 1.68; P = .02) but no difference in plasma RNA (zidovudine, 3.93 log copies/mL; placebo, 4.00; P = .83). Serious adverse events and minor clinical events were infrequent and comparable in both arms. There were two deaths: 1 patient died of sepsis and renal disease (zidovudine arm), and 1 patient died of sepsis and tension pneumothorax (placebo arm). Six months of high-dose zidovudine initiated during PHI results in higher CD4 cell counts and lower PBMC culture titers but no difference in plasma HIV-1 RNA. Further studies with more potent antiretroviral combination therapies are warranted.

Initiation of antiretroviral monotherapy early in the course of infection with human immunodeficiency virus may result in a temporary slowing in the rate of disease progression; however, little is known about the virologic effects of early therapy. Virus load was measured in peripheral blood and lymph nodes from 16 antiretroviral-naive patients with a mean CD4 T lymphocyte count of 659 cells/microliter at baseline and after 8 weeks of either no treatment or zidovudine therapy. CD4 T lymphocyte counts and all virologic parameters examined remained unchanged regardless of zidovudine treatment status. Histopathology and virus distribution within lymph nodes remained constant between baseline and week 8 in each patient, indicating that the virologic and histologic parameters examined in a single lymph node are representative of a systemic process. Early antiretroviral monotherapy with zidovudine had no effect on virologic parameters in this group of patients with relatively high CD4 T lymphocyte counts and low measures of virus load at baseline.

Primary human immunodeficiency virus type 1 (HIV-1) infection can present clinically as the abrupt onset of a febrile illness resembling acute mononucleosis. The symptoms coincide with high titers of culturable plasma viremia, cell-associated virus, and antigenemia, which rapidly decrease coincident with the emergence of detectable HIV-specific antibody and HIV-specific cytotoxic T lymphocytes. This article reviews the human and animal model data on the virologic and immunologic events that occur during primary HIV-1 and animal retrovirus infections, evaluates the prophylactic treatment experience of retrovirus infections in the animal model, and provides a plausible rationale for treatment intervention of primary HIV-1 infection in humans. Recent work delineating the pathogenesis of primary HIV-1 infection provides insight into the major mechanisms of viral dissemination and host immune response. The results from retrovirus-infected animal models treated with antiviral agents suggests that therapy at the time of viral dissemination may be an effective strategy that may modify disease progression. Clinical trials to evaluate this approach are in progress.

A multistate outbreak of hepatitis A was traced to frozen strawberries processed at a single plant. Among 827 students and 60 teachers at an elementary school in Georgia during a 2-week period, 15 developed hepatitis A. Three months later, among 174 residents and 467 staff in an institution for the developmentally disabled in Montana during a 3-week period, 13 developed hepatitis A. Primary attack rates were 10% in the school and 8% in the institution. Cohort analysis in the school implicated consumption of strawberry shortcake in hepatitis A virus (HAV) infection (relative risk, 7.6; 95% confidence interval, 1.04-55.6). In the institution, such analysis implicated desserts and uncooked strawberries as the most biologically plausible vehicle of HAV transmission. Molecular analysis of HAV from patients in the two outbreaks revealed that the viral genomes were genetically identical and distinct from other known US strains. Contamination of food products before retail distribution is rare but should be considered in investigating common-source outbreaks of hepatitis A.