Variation of TaMyb10 and their function on grain color and pre-harvest sprouting resistance of wheat.

Pre-harvest sprouting (PHS) is a significant threat to global food security due to its association with losses in both yield and quality. Among the genes involved in PHS resistance in wheat, PHS-3D (TaMyb10-D) plays a crucial role. Here, we characterized the sequence variations of TaMyb10 genes in 416 bread wheat and 302 Aegilops tauschii accessions. Within TaMyb10-A sequences, we identified a deletion ranging from 214 to 305 bp in the signal and amino acid coding region, present in 61.3% of the accessions. Similarly, 79.3% of the TaMyb10-B sequences within the third exon region exhibited a 19 bp deletion. Additionally, 40.8% of the accessions lacked the 2.4 Mb fragment (in/del mutations) on Chr3D, where TaMyb10-D/PHS-3D was located. Interestingly, the geographical distribution of accessions showed little correlation with the divergence of TaMyb10. TaMyb10-A-IIIDele, TaMyb10-B-IVDele, and TaMyb10-D-VDele genotypes were prevalent in wheat populations across continents. Despite their structural variations, the five distinct protein types exhibited comparable ability to bind the promoters of downstream genes in the flavonoid and ABA pathways, such as CHS, DFR, and NCED. Furthermore, the combination of TaMyb10 homologs was significantly associated with grain color and germination percentages. Accessions exclusively harboring TaMyb10-D displayed red seed color and reduced germination percentages, indicating the predominant role of TaMyb10-D compared to TaMyb10-A and TaMyb10-B. This comprehensive investigation enhances our understanding of the structural variations and functional divergence of TaMyb10, providing valuable insights and resources for improving PHS resistance in wheat.

Dynamic category-sensitive hypergraph inferring and homo-heterogeneous neighbor feature learning for drug-related microbe prediction.

MOTIVATION: The microbes in human body play a crucial role in influencing the functions of drugs, as they can regulate the activities and toxicities of drugs. Most recent methods for predicting drug-microbe associations are based on graph learning. However, the relationships among multiple drugs and microbes are complex, diverse, and heterogeneous. Existing methods often fail to fully model the relationships. In addition, the attributes of drug-microbe pairs exhibit long-distance spatial correlations, which previous methods have not integrated effectively. RESULTS: We propose a new prediction method named DHDMP which is designed to encode the relationships among multiple drugs and microbes and integrate the attributes of various neighbor nodes along with the pairwise long-distance correlations. First, we construct a hypergraph with dynamic topology, where each hyperedge represents a specific relationship among multiple drug nodes and microbe nodes. Considering the heterogeneity of node attributes across different categories, we developed a node category-sensitive hypergraph convolution network to encode these diverse relationships. Second, we construct homogeneous graphs for drugs and microbes respectively, as well as drug-microbe heterogeneous graph, facilitating the integration of features from both homogeneous and heterogeneous neighbors of each target node. Third, we introduce a graph convolutional network with cross-graph feature propagation ability to transfer node features from homogeneous to heterogeneous graphs for enhanced neighbor feature representation learning. The propagation strategy aids in the deep fusion of features from both types of neighbors. Finally, we design spatial cross-attention to encode the attributes of drug-microbe pairs, revealing long-distance correlations among multiple pairwise attribute patches. The comprehensive comparison experiments showed our method outperformed state-of-the-art methods for drug-microbe association prediction. The ablation studies demonstrated the effectiveness of node category-sensitive hypergraph convolution network, graph convolutional network with cross-graph feature propagation, and spatial cross-attention. Case studies on three drugs further showed DHDMP's potential application in discovering the reliable candidate microbes for the interested drugs. AVAILABILITY AND IMPLEMENTATION: Source codes and supplementary materials are available at https://github.com/pingxuan-hlju/DHDMP.

Multi-scale topology and position feature learning and relationship-aware graph reasoning for prediction of drug-related microbes.

MOTIVATION: The human microbiome may impact the effectiveness of drugs by modulating their activities and toxicities. Predicting candidate microbes for drugs can facilitate the exploration of the therapeutic effects of drugs. Most recent methods concentrate on constructing of the prediction models based on graph reasoning. They fail to sufficiently exploit the topology and position information, the heterogeneity of multiple types of nodes and connections, and the long-distance correlations among nodes in microbe-drug heterogeneous graph. RESULTS: We propose a new microbe-drug association prediction model, NGMDA, to encode the position and topological features of microbe (drug) nodes, and fuse the different types of features from neighbors and the whole heterogeneous graph. First, we formulate the position and topology features of microbe (drug) nodes by t-step random walks, and the features reveal the topological neighborhoods at multiple scales and the position of each node. Second, as the features of nodes are high-dimensional and sparse, we designed an embedding enhancement strategy based on supervised fully connected autoencoders to form the embeddings with representative features and the more discriminative node distributions. Third, we propose an adaptive neighbor feature fusion module, which fuses features of neighbors by the constructed position- and topology-sensitive heterogeneous graph neural networks. A novel self-attention mechanism is developed to estimate the importance of the position and topology of each neighbor to a target node. Finally, a heterogeneous graph feature fusion module is constructed to learn the long-distance correlations among the nodes in the whole heterogeneous graph by a relationship-aware graph transformer. Relationship-aware graph transformer contains the strategy for encoding the connection relationship types among the nodes, which is helpful for integrating the diverse semantics of these connections. The extensive comparison experimental results demonstrate NGMDA's superior performance over five state-of-the-art prediction methods. The ablation experiment shows the contributions of the multi-scale topology and position feature learning, the embedding enhancement strategy, the neighbor feature fusion, and the heterogeneous graph feature fusion. Case studies over three drugs further indicate that NGMDA has ability in discovering the potential drug-related microbes. AVAILABILITY AND IMPLEMENTATION: Source codes and Supplementary Material are available at https://github.com/pingxuan-hlju/NGMDA.

Quantifying inactive lithium in lithium metal batteries.

Lithium metal anodes offer high theoretical capacities (3,860 milliampere-hours per gram)1, but rechargeable batteries built with such anodes suffer from dendrite growth and low Coulombic efficiency (the ratio of charge output to charge input), preventing their commercial adoption2,3. The formation of inactive ('dead') lithium- which consists of both (electro)chemically formed Li+ compounds in the solid electrolyte interphase and electrically isolated unreacted metallic Li0 (refs 4,5)-causes capacity loss and safety hazards. Quantitatively distinguishing between Li+ in components of the solid electrolyte interphase and unreacted metallic Li0 has not been possible, owing to the lack of effective diagnostic tools. Optical microscopy6, in situ environmental transmission electron microscopy7,8, X-ray microtomography9 and magnetic resonance imaging10 provide a morphological perspective with little chemical information. Nuclear magnetic resonance11, X-ray photoelectron spectroscopy12 and cryogenic transmission electron microscopy13,14 can distinguish between Li+ in the solid electrolyte interphase and metallic Li0, but their detection ranges are limited to surfaces or local regions. Here we establish the analytical method of titration gas chromatography to quantify the contribution of unreacted metallic Li0 to the total amount of inactive lithium. We identify the unreacted metallic Li0, not the (electro)chemically formed Li+ in the solid electrolyte interphase, as the dominant source of inactive lithium and capacity loss. By coupling the unreacted metallic Li0 content to observations of its local microstructure and nanostructure by cryogenic electron microscopy (both scanning and transmission), we also establish the formation mechanism of inactive lithium in different types of electrolytes and determine the underlying cause of low Coulombic efficiency in plating and stripping (the charge and discharge processes, respectively, in a full cell) of lithium metal anodes. We propose strategies for making lithium plating and stripping more efficient so that lithium metal anodes can be used for next-generation high-energy batteries.

Mining the Carbon Intermediates in Plastic Waste Upcycling for Constructing C-S Bond.

Postconsumer plastics are generally perceived as valueless with only a small portion of plastic waste being closed-loop recycled into similar products while most of them are discarded in landfills. Depositing plastic waste in landfills not only harms the environment but also signifies a substantial economic loss. Alternatively, constructing value-added chemical feedstocks via mining the waste-derived intermediate species as a carbon (C) source under mild electrochemical conditions is a sustainable strategy to realize the circular economy. This proof-of-concept work provides an attractive "turning trash to treasure" strategy by integrating electrocatalytic polyethylene terephthalate (PET) plastic upcycling with a chemical C-S coupling reaction to synthesize organosulfur compounds, hydroxymethanesulfonate (HMS). HMS can be produced efficiently (Faradaic efficiency, FE of ∼70%) via deliberately capturing electrophilic intermediates generated in the PET monomer (ethylene glycol, EG) upcycling process, followed by coupling them with nucleophilic sulfur (S) species (i.e., SO32- and HSO3-). Unlike many previous studies conducted under alkaline conditions, PET upcycling was performed over an amorphous MnO2 catalyst under near-neutral conditions, allowing for the stabilization of electrophilic intermediates. The compatibility of this strategy was further investigated by employing biomass-derived compounds as substrates. Moreover, comparable HMS yields can be achieved with real-world PET plastics, showing its enormous potential in practical application. Lastly, Density function theory (DFT) calculation reveals that the C-C cleavage step of EG is the rate-determining step (RDS), and amorphous MnO2 significantly decreases the energy barriers for both RDS and C-S coupling when compared to the crystalline counterpart.

The origin and spread of HIV-1 CRF59_01B epidemic in China: A molecular network and phylogeographic analysis.

Human immunodeficiency virus type 1 CRF59_01B, identified in China in 2013, has been detected nationwide, exhibiting notably high prevalence in Guangzhou and its vicinity. This study aimed to unravel its origin and migration. A data set was established, incorporating all available CRF59_01B pol gene sequences and their metadata from Guangzhou and the public database. Bayesian phylogeographic analysis demonstrated that CRF59_01B originated in Shenzhen, the neighboring city of Guangzhou, around 1998 with posterior probability of 0.937. Molecular network analysis detected 1131 transmission links and showed a remarkably high clustering rate (78.9%). Substantial inter-city transmissions (26.5%, 300/1131) were observed between Shenzhen and Guangzhou while inter-region transmissions linked Guangzhou with South (46) and Southwest (64) China. The centre of Guangzhou was the hub of CRF59_01B transmission, including the inflow from Shenzhen (3.57 events/year) and outflow to the outskirts of Guangzhou (>2 events/year). The large-scale analysis revealed significant migration from Shenzhen to Guangzhou (5.08 events/year) and North China (0.59 events/year), and spread from Guangzhou to Central (0.47 events/year), East (0.42 events/year), South (0.76 events/year), Southwest China (0.76 events/year) and Shenzhen (1.89 events/year). Shenzhen and Guangzhou served as the origin and the hub of CRF59_01B circulation, emphasizing inter-city cooperation and data sharing to confine its nationwide diffusion.

Efficacy of prophylactic antibiotics for the prevention of neutropenic fever in patients with multiple myeloma receiving high-dose cyclophosphamide for stem cell mobilization.

High-dose cyclophosphamide (HD-Cy) (3 g/m2) plus granulocyte colony-stimulating factor (G-CSF) is a very effective regimen for peripheral blood stem cell (PBSC) mobilization. Unfortunately, it is associated with an increased risk of neutropenic fever (NF). We analyzed the effect of NF on PBSC apheresis results and the efficacy of prophylactic antibiotics for the prevention of NF associated with HD-Cy plus G-CSF for PBSC mobilization in patients with newly diagnosed multiple myeloma (MM). First, patients were divided into NF ( +) and NF ( -) groups according to whether they suffered from NF during mobilization. Second, we divided patients into an antibiotic prophylaxis group and a nonantibiotic prophylaxis group according to whether antibiotic prophylaxis was used during the mobilization period. Our study showed that NF( +) patients (n = 44) had lower CD34 + cell dose collection (median 2.60 versus 5.34 × 106/kg, P < 0.001) and slower neutrophil engraftment and platelet engraftment (median 11 versus 10 days, P = 0.002, and median 13 versus 11 days, P = 0.043, respectively) than NF( -) patients (n = 234). Of note, the nonantibiotic prophylaxis group patients (n = 30) had a 26.7% incidence of NF. In the patients receiving antibiotic prophylaxis (n = 227), the incidence was reduced to 9.3% (P = 0.01). The antibiotic prophylaxis patients had higher CD34 + cell collection (median 5.41 versus 2.27 × 106/kg, P < 0.001) and lower hospitalization cost of mobilization ($ median 3108.02 versus 3702.39, p = 0.012). Thus, our results demonstrate that NF is associated with lower CD34 + cell collection and that antibiotic prophylaxis can reduce the incidence of NF and improve stem cell mobilization and collection outcomes, which reduces the hospitalization cost of mobilization.

Comprehensive analysis of phospholipid in milk and their biological roles as nutrients and biomarkers.

Phospholipids (PL) have garnered significant attention due to their physiological activities. Milk and other dairy products are important dietary sources for humans and have been extensively used to analyze the presence of PL by various analytical techniques. In this paper, the analysis techniques of PL were reviewed with the eight trigrams of phospholipidomics and a comprehensive fingerprint of 1295 PLs covering 8 subclasses in milk and other dairy products, especially. Technology is the primary productive force. Based on phospholipidomics technology, we further review the relationship between the composition of PL and factors that may be involved in processing and experimental operation, and emphasized the significance of the biological role played by PL in dietary supplements and biomarkers (production, processing and clinical research), and providing the future research directions.

Gating-Enhanced Hierarchical Structure Learning in Hyperbolic Space and Multi-scale Neighbor Topology Learning in Euclidean Space for Prediction of Microbe-Drug Associations.

Identifying drug-related microbes may help us explore how the microbes affect the functions of drugs by promoting or inhibiting their effects. Most previous methods for the prediction of microbe-drug associations focused on integrating the attributes and topologies of microbe and drug nodes in Euclidean space. The heterogeneous network composed of microbes and drugs has a hierarchical structure, and the hyperbolic space is helpful for reflecting the structure. However, the previous methods did not fully exploit the structure. We propose a multi-space feature learning enhanced microbe-drug association prediction method, MFLP, to fuse the hierarchical structure of microbe and drug nodes in hyperbolic space and the multiscale neighbor topologies in Euclidean space. First, we project the nodes of the microbe-drug heterogeneous network on the sphere in hyperbolic space and then construct a topology which implies hierarchical structure and forms a hierarchical attribute embedding. The node information from multiple types of neighbor nodes with the new topological structure in the tangent plane space of a sphere is aggregated by the designed gating-enhanced hyperbolic graph neural network. Second, the gate at the node feature level is constructed to adaptively fuse the hierarchical features of microbe and drug nodes from two adjacent graph neural encoding layers. Third, multiple neighbor topological embeddings for each microbe and drug node are formed by neighborhood random walks on the microbe-drug heterogeneous network, and they cover neighborhood topologies with multiple scales, respectively. Finally, as each scale of topological embedding contains its specific neighborhood topology, we establish an independent graph convolutional neural network for the topology and form the topological representations of microbe and drug nodes in Euclidean space. The comparison experiments based on cross validation showed that MFLP outperformed several advanced prediction methods, and the ablation experiments verified the effectiveness of MFLP's major innovations. The case studies on three drugs further demonstrated MFLP's ability in being applied to discover potential candidate microbes for the given drugs.

Deciphering the Coevolutionary Dynamics of L2 ß-Lactamases via Deep Learning.

L2 ß-lactamases, serine-based class A ß-lactamases expressed by Stenotrophomonas maltophilia, play a pivotal role in antimicrobial resistance (AMR). However, limited studies have been conducted on these important enzymes. To understand the coevolutionary dynamics of L2 ß-lactamase, innovative computational methodologies, including adaptive sampling molecular dynamics simulations, and deep learning methods (convolutional variational autoencoders and BindSiteS-CNN) explored conformational changes and correlations within the L2 ß-lactamase family together with other representative class A enzymes including SME-1 and KPC-2. This work also investigated the potential role of hydrophobic nodes and binding site residues in facilitating the functional mechanisms. The convergence of analytical approaches utilized in this effort yielded comprehensive insights into the dynamic behavior of the ß-lactamases, specifically from an evolutionary standpoint. In addition, this analysis presents a promising approach for understanding how the class A ß-lactamases evolve in response to environmental pressure and establishes a theoretical foundation for forthcoming endeavors in drug development aimed at combating AMR.

Retrieval flexibility links to creativity: evidence from computational linguistic measure.

Creativity, the ability to generate original and valuable products, has long been linked to semantic retrieval processes. The associative theory of creativity posits flexible retrieval ability as an important basis for creative idea generation. However, there is insufficient research on how flexible memory retrieval acts on creative activities. This study aimed to capture different dynamic aspects of retrieval processes and examine the behavioral and neural associations between retrieval flexibility and creativity. We developed 5 metrics to quantify retrieval flexibility based on previous studies, which confirmed the important role of creativity. Our findings showed that retrieval flexibility was positively correlated with multiple creativity-related behavior constructs and can promote distinct search patterns in different creative groups. Moreover, high flexibility was associated with the lifetime of a specific brain state during rest, characterized by interactions among large-scale cognitive brain systems. The flexible functional connectivity within and between default mode, executive control, and salience provides further evidence on brain dynamics of creativity. Retrieval flexibility mediated the links between the lifetime of the related brain state and creativity. This new approach is expected to enhance our knowledge of the role of retrieval flexibility in creativity from a dynamic perspective.

New sexually transmitted HIV infections from 2016 to 2050 in Guangdong Province, China: a study based on a dynamic compartmental model.

BACKGROUND: In Guangdong Province, China, there is lack of information on the HIV epidemic among high-risk groups and the general population, particularly in relation to sexual transmission, which is a predominant route. The new HIV infections each year is also uncertain owing to HIV transmission from men who have sex with men (MSM) to women, as a substantial proportion of MSM also have female sexual partnerships to comply with social demands in China. METHODS: A deterministic compartmental model was developed to predict new HIV infections in four risk groups, including heterosexual men and women and low- and high-risk MSM, in Guangdong Province from 2016 to 2050, considering HIV transmission from MSM to women. The new HIV infections and its 95% credible interval (CrI) were predicted. An adaptive sequential Monte Carlo method for approximate Bayesian computation (ABC-SMC) was used to estimate the unknown parameter, a mixing index. We calibrated our results based on new HIV diagnoses and proportions of late diagnoses. The Morris and Sobol methods were applied in the sensitivity analysis. RESULTS: New HIV infections increased during and 2 years after the COVID-19 pandemic, then declined until 2050. New infections rose from 8,828 [95% credible interval (CrI): 6,435-10,451] in 2016 to 9,652 (95% CrI: 7,027-11,434) in 2019, peaking at 11,152 (95% CrI: 8,337-13,062) in 2024 before declining to 7,084 (95% CrI: 5,165-8,385) in 2035 and 4,849 (95% CrI: 3,524-5,747) in 2050. Women accounted for approximately 25.0% of new HIV infections, MSM accounted for 40.0% (approximately 55.0% of men), and high-risk MSM accounted for approximately 25.0% of the total. The ABC-SMC mixing index was 0.504 (95% CrI: 0.239-0.894). CONCLUSIONS: Given that new HIV infections and the proportion of women were relatively high in our calibrated model, to some extent, the HIV epidemic in Guangdong Province remains serious, and services for HIV prevention and control are urgently needed to return to the levels before the COVID-19 epidemic, especially in promoting condom-based safe sex and increasing awareness of HIV prevention to general population.

Rsad2 mediates Bisphenol A-induced actin cytoskeletal disruption in mouse spermatocytes.

Bisphenol A (BPA) is widely exposed in populations worldwide and has negative effects on spermatogenesis both in animals and humans. The homeostasis of the actin cytoskeleton in the spermatogenic epithelium is crucial for spermatogenesis. Actin cytoskeleton destruction in the seminiferous epithelium is one of the important reasons for BPA-induced spermatogenesis disorder. However, the underlying molecular mechanisms remain largely unexplored. Herein, we explored the role and mechanism of Rsad2, an interferon-stimulated gene in BPA-induced actin cytoskeleton disorder in mouse GC-2 spermatocyte cell lines. After BPA exposure, the actin cytoskeleton was dramatically disrupted and the cell morphology was markedly altered accompanied by a significant increase in Rsad2 expression both in mRNA and protein levels in GC-2 cells. Furthermore, the phalloidin intensities and cell morphology were restored obviously when interfering with the expression of Rsad2 in BPA-treated GC-2 cells. In addition, we observed a significant decrease in intracellular ATP levels after BPA treatment, while the ATP level was obviously upregulated when knocking down the expression of Rsad2 in BPA-treated cells compared to cells treated with BPA alone. Moreover, Rsad2 relocated to mitochondria after BPA exposure in GC-2 cells. BPA promoted Rsad2 expression by activating type I IFN-signaling in GC-2 cells. In summary, Rsad2 mediated BPA-induced actin cytoskeletal disruption in GC-2 cells, which provided data to reveal the mechanism of BPA-induced male reproductive toxicity.

Exploring the relationship between illness perception, self-management and quality of life among HIV-positive men who have sex with men.

AIMS: This study aimed to explore the mediating effect of self-management (SM) on the relationship between illness perception and quality of life (QOL) among Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). DESIGN: A cross-sectional study. METHODS: We explored the effect of illness perception and self-management on QOL using the multiple regression model. Moreover, we conducted a simple mediation analysis to examine the role of SM in the relationship between illness perception and QOL. In addition, a parallel mediation analysis was performed to investigate the differences in domains of SM on the relationship between illness perception and QOL. RESULTS: Among 300 Chinese HIV-positive MSM, the mean score of SM was 39.9 ± 6.97, with a range of 14.0-54.0. The higher score in SM indicated a higher level of HIV SM. SM was negatively related to illness perception (r = -0.47) while positively related to QOL (r = 0.56). SM partially mediated the relationship between illness perception and QOL, accounting for 25.3% of the total effect. Specifically, both daily self-management health practices and the chronic nature of the self-management domain played a parallel role in mediating the relationship between illness perception and QOL. CONCLUSION: Our study demonstrated that SM was a significant factor influencing QOL among HIV-positive MSM. Focusing on daily self-management health practices and the chronic nature of self-management could be the potential key targets for enhancing HIV self-management strategies. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study emphasized the role of SM in the well-being of HIV-positive MSM and underscored the importance of developing interventions that integrate SM strategies to improve QOL in this population. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

The Structural Role of N170 in Substrate-Assisted Deacylation in KPC-2 ß-Lactamase.

The amino acid substitutions in Klebsiella pneumoniae carbapenemase 2 (KPC-2) that have arisen in the clinic are observed to lead to the development of resistance to ceftazidime-avibactam, a preferred treatment for KPC bearing Gram-negative bacteria. Specific substitutions in the omega loop (R164-D179) result in changes in the structure and function of the enzyme, leading to alterations in substrate specificity, decreased stability, and more recently observed, increased resistance to ceftazidime/avibactam. Using accelerated rare-event sampling well-tempered metadynamics simulations, we explored in detail the structural role of R164 and D179 variants that are described to confer ceftazidime/avibactam resistance. The buried conformation of D179 substitutions produce a pronounced structural disorder in the omega loop - more than R164 mutants, where the crystallographic omega loop structure remains mostly intact. Our findings also reveal that the conformation of N170 plays an underappreciated role impacting drug binding and restricting deacylation. The results further support the hypothesis that KPC-2 D179 variants employ substrate-assisted catalysis for ceftazidime hydrolysis, involving the ring amine of the aminothiazole group to promote deacylation and catalytic turnover. Moreover, the shift in the WT conformation of N170 contributes to reduced deacylation and an altered spectrum of enzymatic activity.

c-Abl kinase-mediated phosphorylation of γ-tubulin promotes γ-tubulin ring complexes assembly and microtubule nucleation.

Cytoskeletal microtubules (MTs) are nucleated from γ-tubulin ring complexes (γTuRCs) located at MT organizing centers (MTOCs), such as the centrosome. However, the exact regulatory mechanism of γTuRC assembly is not fully understood. Here, we showed that the nonreceptor tyrosine kinase c-Abl was associated with and phosphorylated γ-tubulin, the essential component of the γTuRC, mainly on the Y443 residue by in vivo (immunofluorescence and immunoprecipitation) or in vitro (surface plasmon resonance) detection. We further demonstrated that phosphorylation deficiency significantly impaired γTuRC assembly, centrosome construction, and MT nucleation. c-Abl/Arg deletion and γ-tubulin Y443F mutation resulted in an abnormal morphology and compromised spindle function during mitosis, eventually causing uneven chromosome segregation. Our findings reveal that γTuRC assembly and nucleation function are regulated by Abl kinase-mediated γ-tubulin phosphorylation, revealing a fundamental mechanism that contributes to the maintenance of MT function.

Regulatory B cells protect against chronic hypoxia-induced pulmonary hypertension by modulating the Tfh/Tfr immune balance.

Hypoxia-induced pulmonary hypertension (HPH) is a progressive and lethal disease characterized by the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) and obstructive vascular remodelling. Previous research demonstrated that Breg cells were involved in the pathogenesis of pulmonary hypertension. This work aimed to evaluate the regulatory function of Breg cells in HPH. HPH mice model were established and induced by exposing to chronic hypoxia for 21 days. Mice with HPH were treated with anti-CD22 or adoptive transferred of Breg cells. The coculture systems of Breg cells with CD4+ T cells and Breg cells with PASMCs in vitro were constructed. Lung pathology was evaluated by HE staining and immunofluorescence staining. The frequencies of Breg cells, Tfh cells and Tfr cells were analysed by flow cytometry. Serum IL-21 and IL-10 levels were determined by ELISA. Protein levels of Blimp-1, Bcl-6 and CTLA-4 were determined by western blot and RT-PCR. Proliferation rate of PASMCs was measured by EdU. Compared to the control group, mean PAP, RV/(LV + S) ratio, WA% and WT% were significantly increased in the model group. Anti-CD22 exacerbated abnormal hemodynamics, pulmonary vascular remodelling and right ventricle hypertrophy in HPH, which ameliorated by adoptive transfer of Breg cells into HPH mice. The proportion of Breg cells on day 7 induced by chronic hypoxia was significantly higher than control group, which significantly decreased on day 14 and day 21. The percentage of Tfh cells was significantly increased, while percentage of Tfr cells was significantly decreased in HPH than those of control group. Anti-CD22 treatment increased the percentage of Tfh cells and decreased the percentage of Tfr cells in HPH mice. However, Breg cells restrained the Tfh cells differentiation and expanded Tfr cells differentiation in vivo and in vitro. Additionally, Breg cells inhibited the proliferation of PASMCs under hypoxic condition in vitro. Collectively, these findings suggested that Breg cells may be a new therapeutic target for modulating the Tfh/Tfr immune balance in HPH.

TC2N Promotes Cell Proliferation and Metastasis in Hepatocellular Carcinoma by Targeting the Wnt/ß-Catenin Signaling Pathway.

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancer worldwide, has an exceedingly poor prognosis. Tandem C2 domain nuclear protein (TC2N) has been implicated in tumorigenesis and serves as an oncogene or tumor suppressor in different types of cancer. Here, we explore the possible regulatory activities and molecular mechanisms of TC2N in HCC progression. However, TC2N expression was significantly upregulated in HCC tissues and hepatoma cell lines, and this upregulation was positively correlated with tumor progression in HCC patients. The ectopic overexpression of TC2N accelerated the proliferation, migration, and invasion of HCC cells, whereas its knockdown showed the opposite effects. Bioinformatics analysis showed that TC2N participates in the regulation of the Wnt/ß-catenin signaling pathway. Mechanistically, TC2N activated the Wnt/ß-catenin signaling pathway by regulating the expression levels of ß-catenin and its downstream targets CyclinD1, MMP7, c-Myc, c-Jun, AXIN2, and glutamine synthase. Furthermore, the deletion of ß-catenin effectively neutralized the regulation of TC2N in HCC proliferation and metastasis. Overall, this study showed that TC2N promotes HCC proliferation and metastasis by activating the Wnt/ß-catenin signaling pathway, indicating that TC2N might be a potential molecular target for the treatment of HCC.

Replacing of sedentary behavior with physical activity and the risk of mortality in people with prediabetes and diabetes: a prospective cohort study.

BACKGROUND: Sedentary behavior is prevalent among people with diabetes and is associated with unfavorable cardiometabolic health. However, there is limited evidence regarding the impact of replacing sedentary time (ST) with physical activity on mortality in people with prediabetes and diabetes. We prospectively examined the association between accelerometer-measured ST and mortality among people with prediabetes and diabetes after adjusting for demographic characteristics, lifestyle factors, and moderate- to vigorous-intensity PA (MVPA). We further determined the effect of replacing ST with equal time of different types of physical activities on all-cause mortality. METHODS: We included 1242 adults with prediabetes and 1037 with diabetes from the National Health and Nutrition Examination Survey. Restricted cubic splines were fitted to determine the dose-response association between ST and overall mortality. Isotemporal substitution modeling was used to explore the hazard ratio (HR) effects of ST replacement. RESULTS: During a median follow-up of 14.1 years, 424 adults with prediabetes and 493 with diabetes died. Compared with the lowest tertile of ST, the multivariable-adjusted HRs for all-cause mortality in the highest tertile were 1.76 (95% confidence interval [CI] 1.19, 2.60) for participants with prediabetes and 1.76 (1.17, 2.65) for those with diabetes. Additionally, a linear association between ST and all-cause mortality was observed in adults with prediabetes and diabetes, with HRs for each 60 min/day increment in ST of 1.19 (1.10, 1.30) and 1.25 (1.12, 1.40), respectively. Isotemporal substitution results indicated that individuals with prediabetes whose ST was replaced by 30 min of light-intensity physical activity (LPA) and MVPA had 9% and 40% lower all-cause mortality, respectively. In people with diabetes, replacing sedentary behavior with an equivalent time of LPA and MVPA was also associated with mortality risk reduction (HR 0.89; 95% CI 0.84, 0.95 for LPA; HR 0.73; 95% CI 0.49, 1.11 for MVPA). CONCLUSIONS: Higher ST was associated in a dose-response manner with an increased risk of premature mortality among adults with prediabetes and diabetes. Statistically replacing ST with LPA was potentially beneficial for health in this high-risk population.

Association Between the Awareness of Antiretroviral Drugs-Related Services and Drug Accessibility During the COVID-19 Pandemic Among Patients Undergoing Antiretroviral Therapy: A Cross-Sectional Study.

In a cross-sectional survey from 21 February to 6 March, 2020, we analyzed the awareness and utilization of antiretroviral drugs (ARVs)-related services among people living with HIV during the COVID-19 pandemic in Guangzhou, China. In addition, a subgroup analysis was performed among those who needed to go to hospital to access their drugs, and we explored the association between the awareness of ARVs-related services and the accessibility of ARVs. Of 375 participants, 89.9% were aware of drug-borrowing service, 90.7% were aware of drug-delivery service and 86.9% were aware of information-assistance service. Knowing about the drug-borrowing service or the information-assistance service, knowing about at least two services and knowing about all of the three services were all positively associated with ARVs accessibility. In addition, 35 (39.3%) of those who had acquired their drugs on time received them via the drug-delivery service. To some extent, the three ARVs-related services have alleviated the difficulties in accessing ARVs during the pandemic, especially the drug-delivery service.