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The ring-shaped chaperonin T-complex protein ring complex (TRiC; also known as chaperonin containing TCP-1, CCT) is an ATP-driven protein-folding machine that is essential for maintenance of cellular homeostasis 1,2 . Its dysfunction is related to cancer and neurodegenerative disease 3,4 . Despite its importance, how TRiC works in the cell remains unclear. Here we structurally analysed the architecture, conformational dynamics and spatial organization of the chaperonin TRiC in human cells using cryo-electron tomography. We resolved distinctive open, closed, substrate-bound and prefoldin-associated states of TRiC, and reconstructed its duty cycle in situ. The substrate-bound open and symmetrically closed TRiC states were equally abundant. Closed TRiC containing substrate forms distinctive clusters, indicative of spatial organization. Translation inhibition did not fundamentally change the distribution of duty cycle intermediates, but reduced substrate binding for all states as well as cluster formation. From our in-cell structures, we identified the programmed cell death protein 5 (PDCD5) as an interactor that specifically binds to almost all open but not closed TRiC, in a position that is compatible with both substrate and prefoldin binding. Our data support a model in which TRiC functions at near full occupancy to fold newly synthesized proteins inside cells. Defining the TRiC cycle and function inside cells lays the foundation to understand its dysfunction during cancer and neurodegeneration., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor and a primary cause of cancer-relevant deaths worldwide. The role of reactive oxygen species (ROS) in HCC development is less studied., Methods: Seurat package and CellMarker database were employed for single-cell RNA sequencing (scRNA-seq) analysis based on the GSE189175 dataset from Gene Expression Omnibus (GEO). DAVID and MsigDB database were utilized for pathway analysis. SCENIC analysis was performed to map a transcription factors (TFs) regulatory network. CellChat was used for cellular communication analysis., Results: Six major cell subpopulations were identified, among which hepatocytes accounted for the highest proportion in both cancer and adjacent tissues. The enrichment scores of the 50 hallmark gene sets showed that the ROS pathway was abnormally activated in HCC hepatocytes and positively correlated with energy metabolism-related pathways (glucose metabolism, lipid metabolism, amino acid metabolism, etc.). Then, the hepatocytes were divided into four subgroups. Noticeably, GPX4+  hepatocytes with the highest activity of the ROS pathway was related to a worse prognosis of HCC. Mechanism analysis revealed that JUND was involved in the positive regulation of the ROS pathway in GPX4+  hepatocytes. It was found that the interdependent ligand-receptor interaction between GPX4+  liver cells and immune cells facilitated the malignant development of HCC., Conclusion: ROS pathway was over-activated in the hepatocytes of HCC tissues. GPX4+  hepatocytes having the highest activity of the ROS pathway closely interacted with T cells and M2 macrophage cells. Molecular subtypes and risk score signature based on the ROS pathway and its potential target gene JUND are encouraged to be developed for improving the precision treatment of HCC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

MicroRNAs(miRNAs) are promising biomarkers for early esophageal squamous cell carcinoma (ESCC) detection and prognostic prediction. This study aimed to explore the potential biomarkers and molecular pathogenesis in the early diagnosis of ESCC. Firstly, 48 differentially expressed miRNAs (DEMs) and 1319 differentially expressed genes (DEGs) were identified between 94 ESCC tissues and 13 normal esophageal tissues in TCGA. From miRNA-mRNA regulatory network, there are 6558 target genes of the 48 DEMs, where 400 target genes are also among 1319 DEGs. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment indicate that the 400 DEGs significantly enriched in cell cycle, proteoglycans in cancer, p53 signaling pathway, protein digestion and absorption, transcriptional dysregulation in cancer, and oocyte meiosis. And there are 66 DEGs among these six biological pathways, which we called GO-DEGs. From miRNA-mRNA regulatory network, 32 DEMs regulated the 66 GO-DEGs, where 22 DEMs were verified by different types of experiments in ESCC tissues, cells, or serum from the literature. For the other novel 10 DEMs, single-factor Cox regression analysis show that only hsa-miR-34b-3p showed no significant correlation with the overall survival of ESCC patients. Finally, we obtained the novel 9 ESCC-related DEMs, where three are down-regulated, and six are up-regulated. We analyzed the expression trends of target genes for five miRNAs and identified three significantly different miRNAs (hsa-miR-205-3p, hsa-miR-452-3p, and hsa-miR-6499-3p) confirmed by qPCR. Moreover, the stage-specific miRNAs were also suggested. These three qPCR validated miRNAs are also specific to the early stages of ESCC: hsa-miR-452-3p is specific to Stage I, II and III; hsa-miR-205-3p is specific in Stage II and III; and hsa-miR-6499-3p is Stage II specific. They might be the potential biomarkers for ESCC stage diagnosis. This study identified three novel miRNA markers potentially related to the diagnosis of ESCC and participated in the occurrence and development of ESCC through cell cycle, proteoglycans in cancer, p53 signaling pathway, protein digestion and absorption, transcriptional dysregulation in cancer, and signaling pathway for oocyte meiosis., (© 2024. The Author(s).)

5-Methylcytosine (m5C) RNA modification is a highly abundant and important epigenetic modification in mammals. As an important RNA m5C methyltransferase, NOP2/Sun-domain family member 2 (NSUN2)-mediated m5C RNA modification plays an important role in the regulation of the biological functions in many cancers. However, little is known about the biological role of NSUN2 in hepatocellular carcinoma (HCC). In this study, we found that the expression of NSUN2 was significantly upregulated in HCC, and the HCC patients with higher expression of NSUN2 had a poorer prognosis than those with lower expression of NSUN2. NSUN2 could affect the tumor immune regulation of HCC in several ways. In vitro and in vivo experiments confirmed that NSUN2 knockdown significantly decreased the abilities of proliferation, colony formation, migration and invasion of HCC cells. The methylated RNA immunoprecipitation-sequencing (MeRIP-seq) showed NSUN2 knockdown significantly affected the abundance, distribution, and composition of m5C RNA modification in HCC cells. Functional enrichment analyses and in vitro experiments suggested that NSUN2 could promote the HCC cells to proliferate, migrate and invade by regulating Wnt signaling pathway. SARS2 were identified via the RNA immunoprecipitation-sequencing (RIP-Seq) and MeRIP-seq as downstream target of NSUN2, which may play an important role in tumor-promoting effect of NSUN2-mediated m5C RNA modification in HCC. In conclusion, NSUN2 promotes HCC progression by regulating Wnt signaling pathway and SARS2 in an m5C-dependent manner., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate All methods used in this study were performed in accordance with the relevant guidelines and regulations. All animal experiments in this study were carried out in accordance with the regulations of Experimental Animal Use and Welfare Committee of Zhengzhou University (approval number: ZZU-LAC2024060416)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma with cirrhosis promotes the advancement of malignancy and the development of fibrosis in normal liver tissues. Understanding the pathological mechanisms underlying the development of HCC with cirrhosis is important for developing effective therapeutic strategies. Herein, the RNA-sequencing (RNA-seq) data and corresponding clinical features of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) database using the University of California Santa Cruz (UCSC) Xena platform. The enrichment degree of hallmarkers for each TCGA-LIHC cohort was quantified by ssGSEA algorithm. Weighted gene co-expression network analysis (WGCNA) revealed two gene module eigengenes (MEs) associated with cirrhosis, namely, MEbrown and MEgreen. Analysis of these modules using AUCell showed that MEbrown had higher enrichment scores in all immune cells, whereas MEgreen had higher enrichment scores in malignant cells. The CellChat package revealed that both immune and malignant cells contributed to the fibrotic activity of myofibroblasts through diverse signaling pathways. Additionally, spatial transcriptomic data showed that hepatocytes, proliferating hepatocytes, macrophages, and myofibroblasts were located in closer proximity in HCC tissues. These cells may potentially participate in the process of stimulating myofibroblast fibrotic activity, which may be related to the development of liver fibrosis. In summary, we made full use of multi-omics data to explore gene networks and cell types that may be involved in the development and progression of cirrhosis in HCC., (© 2024. The Author(s).)

As the demand for regional geological disaster risk assessments in large cities continues to rise, our study selected Hangzhou, one of China's megacities, as a model to evaluate the susceptibility to two major geological hazards in the region: ground collapse and ground subsidence. Given that susceptibility assessments for such disasters mainly rely on knowledge-driven models, and data-driven models have significant potential for application, we proposed a high-accuracy Random Forest-Back Propagation Neural Network Coupling Model. By using nine evaluation factors selected based on field surveys and expert recommendations, along with disaster data, the model's predictive results indicate a 3-40% improvement in model performance metrics such as AUC, accuracy, precision, recall, and F1-score, compared to single models and traditional SVM and logistic regression models. Ultimately, using the predictive results of this model, we created susceptibility maps for individual disasters and developed a muti-hazards susceptibility map by employing the expert weight discrimination method and the overlay evaluation method. Furthermore, we discussed the feature importance in the prediction process. Our study validated the feasibility of using advanced machine learning models for urban geological disaster assessment, providing a replicable template for other cities., (© 2024. The Author(s).)

Fatty acid-binding protein 4 (FABP4) plays an essential role in metabolism and inflammation. However, the role of FABP4 in alcoholic steatohepatitis (ASH) remains unclear. This study aimed to investigate the function and underlying mechanisms of FABP4 in the progression of ASH. We first obtained alcoholic hepatitis (AH) datasets from the National Center for Biotechnology Information-Gene Expression Omnibus database and conducted bioinformatics analysis to identify critical genes in the FABP family. We then established ASH models of the wild-type (WT) and Fabp4-deficient (Fabp4 -/- ) mice to investigate the role of FABP4 in ASH. Additionally, we performed transcriptional profiling of mouse liver tissue and analyzed the results using integrative bioinformatics. The FABP4-associated signaling pathway was further verified. FABP4 was upregulated in two AH datasets and was thus identified as a critical biomarker for AH. FABP4 expression was higher in the liver tissues of patients with alcoholic liver disease and ASH mice than in the corresponding control samples. Furthermore, the Fabp4 -/- ASH mice showed reduced hepatic lipid deposition and inflammation compared with the WT ASH mice. Mechanistically, Fabp4 may be involved in regulating the p53 and sirtuin-1 signaling pathways, subsequently affecting lipid metabolism and macrophage polarization in the liver of ASH mice. Our results demonstrate that Fabp4 is involved in the progression of ASH and that Fabp4 deficiency may ameliorate ASH. Therefore, FABP4 may be a potential therapeutic target for ASH treatment., (© 2024. The Author(s).)

Rainstorm is one of the global meteorological disasters that threaten the safety of transportation infrastructure and the connectivity of transportation system. Aiming to support the resilience assessment of transportation infrastructure in three representative regions: Sichuan-Chongqing, Yangtze River Delta, and Beijing-Tianjin-Hebei-Shandong, rainfall data over 40 years in the three regions are collected, and the temporal distribution of rainfall are analyzed. Prediction equations of rainfall are established. For the purpose of this, the probabilistic density function (PDF) is assigned to the rainfall by fitting the frequency distribution histogram. Using the assigned PDF, the rainfall data are transformed into standard normal space where regression of prediction equations is performed and the prediction accuracy is tested. The results show that: (1) The frequency of rainfall in the three regions follows a lognormal distribution based on which the prediction equations of rainfall can be established in standard normal space. The error of regression shows no remarkable dependence on self-variables, and the significance analysis indicates that the equations proposed in this paper are plausible for predicting rainfalls for the three regions. (2) The Yangtze River Delta region has a higher risk of rainstorm disaster compared to the other two regions according to the frequency of rainfall and the return period of precipitation concentration. (3) Over the period of 1980-2021, the Sichuan-Chongqing region witnessed an increase in yearly rainfall but a decrease in rainstorm disasters, whereas the other two regions experienced a consistent rise in both metrics., (© 2024. The Author(s).)

Transcranial ultrasound stimulation (TUS) has been clinically applied as a neuromodulation tool. Particularly, the phase array ultrasound can be applied in TUS to non-invasively focus on the cortex or deep brain. However, the vital phase distortion of the ultrasound induced by the skull limits its clinical application. In the current study, we aimed to develop a hybrid method that combines the ultrashort echo time (UTE) magnetic resonance imaging (MRI) sequences with the prDeep technique to achieve focusing ventral intermediate thalamic nucleus (VIM). The time-reversal (TR) approach of the UTE numerical acoustic model of the skull combined with the prDeep algorithm was used to reduce the number of iterations. The skull acoustic model simulation therapy process was establish to valid this method's prediction and focus performance, and the classical TR method were considered as the gold standard (GS). Our approach could restore 75% of the GS intensity in 25 iteration steps, with a superior the noise immunity. Our findings demonstrate that the phase aberration caused by the skull can be estimated using phase retrieval techniques to achieve a fast and accurate transcranial focus. The method has excellent adaptability and anti-noise capacity for satisfying complex and changeable scenarios., (© 2024. The Author(s).)

For end-stage liver disease in children, living donor liver transplantation (LDLT) is often the important standard curative treatment. However, there is a lack of research on early recovery of graft function after pediatric LDLT. This is a single-center, ambispective cohort study. We collected the demographic and clinicopathological data of donors and recipients, and determined the risk factors of postoperative delayed recovery of hepatic function (DRHF) by univariate and multivariate Logistic analyses. 181 cases were included in the retrospective cohort and 50 cases in the prospective cohort. The incidence of DRHF after LDLT in children was 29.4%, and DRHF could well evaluate the early recovery of graft function after LDLT. Through Logistic analyses and AIC score, preoperative liver function of donors, ischemia duration level of the liver graft, Ln (Cr of recipients before operation) and Ln (TB of recipients on the 3rd day after operation) were predictive indicators for DRHF after LDLT in children. Using the above factors, we constructed a predictive model to evaluate the incidence of postoperative DRHF. Self-verification and prospective internal verification showed that this prediction model had good accuracy and clinical applicability. In conclusion, we pointed many risk factors for early delayed recovery of graft function after LDLT in children, and developed a visual and personalized predictive model for them, offering valuable insights for clinical management., (© 2024. The Author(s).)

Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278 ). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples., (© 2024. The Author(s).)

We examined the remains of an individual who was unearthed from the Tuchengzi site and was believed to be from the Warring States period in China. The remains exhibited segmental femoral fracture. We aimed to deduce the cause of fracture, medical interventions, healing process, and motion behavior after fracture healing using several techniques, including macroscopic observation, computed tomography (CT), and finite element analysis. Based on the morphology of the long bones, it appeared that the individual was male. The fractures resulted in an adduction angle of 5.47° and an anterior flexion angle of 21.34° in the proximal femur, while the femoral neck anteversion angle had been replaced by a retroversion angle of 10.74°. Additionally, the distal femur formed an abnormal anterior convex angle of 144.60°. CT revealed mature callus formation and visible trabecular bundles. The finite element analysis indicated that the maximum von Mises stress in the femur was 17.44 MPa during standing and 96.46 MPa during walking. We suggest that medical practitioners in the Warring States period possessed a good knowledge of thigh anatomy, enabling them to perform fracture reduction and fixation. Reasonable medical intervention facilitated fracture healing and load recovery. Satisfactory fracture healing ensured that the individual could engage in normal standing and walking activities after rehabilitation., (© 2024. The Author(s).)

N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer's disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class., (© 2023. The Author(s).)

In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox., (© 2023. The Author(s).)

A sustainable future depends on increasing agricultural carbon (C) and nitrogen (N) sequestration. Winter rapeseeds are facing severe yield loss after waterlogging due to the effects of extreme rainfall, especially in the seedling stage, where rainfall is most sensitive. Uncertainty exists over the farming greenhouse gas (GHG) release of rapeseed seedlings following the onset of waterlogging. The effect of waterlogging on GHG release and leaf gas exchange in winter rapeseed was examined in a pot experiment. The experiment included waterlogging treatments lasting 7-day and 21-day and normal irrigation as a control treatment. According to our findings, (1) The ecosystem of rapeseed seedlings released methane (CH 4 ) and nitrous oxide (N 2 O) in a clear up change that was impacted by ongoing waterlogging. Among them, N 2 O release had a transient rise during the early stages under the effect of seedling fertilizer. (2) The net photosynthetic rate, transpiration rate, stomatal conductance, plant height, soil moisture, and soil oxidation-reduction potential of rapeseed all significantly decreased due to the ongoing waterlogging. However, rapeseed leaves showed a significant increase in intercellular carbon dioxide (CO 2 ) concentration and leaf chlorophyll content values after waterlogging. Additionally, the findings demonstrated an extremely significant increase in the sustained-flux global warming potential of the sum CO 2 -eq of CH 4 and N 2 O throughout the entire waterlogging stress period. Therefore, continuous waterlogging can increase C and N release from rapeseed seedlings ecosystem and decrease yield. Therefore, we suggest increasing drainage techniques to decrease the release of agricultural GHGs and promote sustainable crop production., (© 2023. The Author(s).)

As a enrichment plant, ramie can be used for the phytoremediation of cadmium (Cd)-contaminated soil. However, it is worth exploring the role of plant growth regulators and foliar fertilizers in the process of plant growth and development and Cd adsorption. By measuring the agronomic traits, Cd content of aboveground and underground ramie, calculating the Cd transfer coefficient (TF) and Cd bioconcentration factors (BCF), and the correlation between various indicators. This study examined the effects of plant growth regulators and foliar fertilizers on ramie's capacity for Cd accumulation and transportation. Plant growth regulators and foliar fertilizers increased the Cd content of the aboveground ramie, reduced the Cd content of the underground ramie, and increased the TF. Among them, GA-1 increased the Cd content of the aboveground ramie to 3 times more than that of the control and reduced the Cd content of the underground ramie by 54.76%. Salicylic acid (SA) increased the Cd content of the aboveground ramie to three times more than that of the control. The combination of GA and foliar fertilizer reduced the Cd content of the aboveground and underground ramie and the TF and BCF of the underground ramie. After the hormones were sprayed, the TF of ramie had a significant positive correlation with the Cd content of the aboveground ramie; the BCF of the aboveground ramie had a significant positive correlation with the Cd content and TF of the aboveground ramie. The results indicate that Brassinolide (BR), gibberellin (GA), ethephon (ETH), polyamines (PAs), and salicylic acid (SA) have different effects on the enrichment and transport of Cd in ramie. This study provided an effective method to improve the capacity for ramie to adsorb heavy metals during cultivation., (© 2023. The Author(s).)

Parkinson's disease (PD) is a common neurological disorder that causes quiescent tremors, motor delays, depression, and sleep disturbances. Existing treatments can only improve symptoms, not stop progression or cure the disease, but effective treatments can significantly improve patients' quality of life. There is growing evidence that chromatin regulatory proteins (CRs) are involved in a variety of biological processes, including inflammation, apoptosis, autophagy, and proliferation. But the relationship of chromatin regulators in Parkinson's disease has not been studied. Therefore, we aim to investigate the role of CRs in the pathogenesis of Parkinson's disease. We collected 870 chromatin regulatory factors from previous studies and downloaded data on patients with PD from the GEO database. 64 differentially expressed genes were screened, the interaction network was constructed and the key genes with the top 20 scores were calculated. Then we discussed its correlation with the immune function of PD. Finally, we screened potential drugs and miRNAs. Five genes related to the immune function of PD, BANF1, PCGF5, WDR5, RYBP and BRD2, were obtained by using the absolute value of correlation greater than 0.4. And the disease prediction model showed good predictive efficiency. We also screened 10 related drugs and 12 related miRNAs, which provided a reference for the treatment of PD. BANF1, PCGF5, WDR5, RYBP and BRD2 are related to the immune process of Parkinson's disease and can predict the occurrence of Parkinson's disease, which is expected to become a new target for the diagnosis and treatment of Parkinson's disease., (© 2023. The Author(s).)

Fibroblasts are a major cell population that perform critical functions in the wound healing process. In response to injury, they proliferate and migrate into the wound space, engaging in extracellular matrix (ECM) production, remodeling, and contraction. However, there is limited knowledge of how fibroblast functions are altered in diabetes. To address this gap, several state-of-the-art microscopy techniques were employed to investigate morphology, migration, ECM production, 2D traction, 3D contraction, and cell stiffness. Analysis of cell-derived matrix (CDM) revealed that diabetic fibroblasts produce thickened and less porous ECM that hindered migration of normal fibroblasts. In addition, diabetic fibroblasts were found to lose spindle-like shape, migrate slower, generate less traction force, exert limited 3D contractility, and have increased cell stiffness. These changes were due, in part, to a decreased level of active Rac1 and a lack of co-localization between F-actin and Waskott-Aldrich syndrome protein family verprolin homologous protein 2 (WAVE2). Interestingly, deletion of thrombospondin-2 (TSP2) in diabetic fibroblasts rescued these phenotypes and restored normal levels of active Rac1 and WAVE2-F-actin co-localization. These results provide a comprehensive view of the extent of diabetic fibroblast dysfunction, highlighting the regulatory role of the TSP2-Rac1-WAVE2-actin axis, and describing a new function of TSP2 in regulating cytoskeleton organization., (© 2022. The Author(s).)

We aimed to validate and prove the novel risk score models of acute myeloid leukemia (AML)-specific disease risk group (AML-DRG) and AML-Hematopoietic Cell Transplant-composite risk (AML-HCT-CR) in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (AHCT). Among the 172 AML patients analysed, 48.3% (n = 83) were females. Median age was 31.5 years (range 14 to 62 years), two patients was more than 60 years old (1.2%). Median follow-up was 44 months (range 1 to 94 months). According to the AML-DRG model, 109, 49 and 14 patients were in low-, intermediate- and high-risk group, respectively. According to the AML-HCT-CR model, 108, 30, 20 and 14 patients were in low-, intermediate-, high- and very high-risk group, respectively. Our results showed that the AML-DRG and AML-HCT-CR models significantly predicted cumulative incidence of relapse (p < 0.001; p < 0.001). But AML-DRG model was not associated with NRM (p = 0.072). Univariate analysis showed that the AML-DRG model could better stratify AML patients into different risk groups compared to the AML-HCT-CR model. Multivariate analysis confirmed that prognostic impact of AML-DRG and AML-HCT-CR models on post-transplant OS was independent to age, sex, conditioning type, transplant modality, and stem cell source (p < 0.001; p < 0.001). AML-DRG and AML-HCT-CR models can be used to effectively predict post-transplant survival in patients with AML receiving AHCT. Compared to AML-HCT-CR score, the AML-DRG score allows better stratification and improved survival prediction of AML patients post-transplant., (© 2022. The Author(s).)

Land cover change affects the carbon emissions of ecosystems in some way. The qualitative and quantitative understanding of carbon emissions from human activities (e.g., land cover change, industrial production, etc.) is highly significant for realizing the objective of carbon neutrality. Therefore, this paper used GlobeLand30 land cover maps, annual average normalised difference vegetation index (NDVI) data, annual average net ecosystem productivity (NEP) data and statistical yearbook data from 2000 to 2020 to explore the relationship between land cover change and carbon emissions. Specifically, it included land cover change, carbon storage changes influenced by land cover change, spatial and temporal analysis of carbon sources and sinks, land use intensity change and anthropogenic carbon emissions. The results of the study show that the main land cover changes in Shandong province during 2000-2020 was cultivated land conversion to artificial surfaces. Among them, the area of cultivated land converted to artificial surfaces from 2000 to 2010 was 4930.62 km 2 , and the proportion of cultivated land converted to artificial surfaces from 2010 to 2020 was as high as 78.35%. The total carbon stock of vegetation affected by land cover change decreased by 463.96 × 10 4  t and 193.50 × 10 4  t in 2000-2010 and 2010-2020 respectively. The spatial and temporal distribution of carbon sources and sinks differed more markedly from 2000 to 2020, and land use intensity changes in Shandong Province showed an upward trend. Of the total energy production, industry has the largest energy consumption, followed closely by total energy consumption in transportation, storage and postal services., (© 2022. The Author(s).)

Myeloid sarcoma is a rare manifestation of acute myeloid leukemia (AML) and is associated with poor overall survival (OS). The optimal treatment remains unclear. The study retrospectively evaluated 118 patients with myeloid sarcoma who were treated at the First Affiliated Hospital of Zhengzhou University from January 2010 to July 2021. All cases were diagnosed by tissue biopsy. 41 patients underwent genetic mutation analysis. The most frequent genetic mutations were KIT (16.6%), followed by TET2 (14.6%), and NRAS (14.6%). The median survival time of 118 patients was 4 months (range, 1-51 months), while the median survival time of 11 patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) was 19 months (range, 8-51 months). 4 (36.4%) of the 11 patients experienced relapse within 1 year after transplantation. 1 patient died from a severe infection. Of the 6 surviving patients, 5 patients have received maintenance treatment with decitabine after transplantation, and all remained in a state of recurrence-free survival. Patients with myeloid sarcoma have a very unfavorable outcome. Allo-HSCT is an effective treatment option. Recurrence remains the main cause of transplant failure. Maintenance treatment with decitabine after transplantation can prolong the recurrence-free survival time, although these results must be verified in a study with expanded sample size., (© 2022. The Author(s).)

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01&#95;AE, CRF07&#95;BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count < 200 cells/µL) in patients with HIV subtype B, CRF01&#95;AE, and CRF07&#95;BC. Of the 20,663 sequences, 9,156 (44.3%) were CRF01&#95;AE. CRF07&#95;BC was responsible for 28.3% of infections, followed by B (13.9%). In multivariable analysis, the risk of AIDSAD differed significantly according to HIV subtype (OR for CRF07&#95;BC vs. B: 0.46, 95% CI 0.39─0.53), age (OR for ≥ 65 years vs. < 18 years: 4.3 95% CI 1.81─11.8), and transmission risk groups (OR for men who have sex with men vs. heterosexuals: 0.67 95% CI 0.6─0.75). These findings suggest that HIV diversity in China is constantly evolving and gaining in complexity. CRF07&#95;BC is less pathogenic than subtype B, while CRF01&#95;AE is as pathogenic as B., (© 2022. The Author(s).)

Urban functional fragmentation plays an important role in assessing Nitrogen Dioxide (NO 2 ) emissions and variations. While the mediated impact of anthropogenic-emission restriction has not been comprehensively discussed, the lockdown response to the novel coronavirus disease 2019 (COVID-19) provides an unprecedented opportunity to meet this goal. This study proposes a new idea to explore the effects of urban functional fragmentation on NO 2 variation with anthropogenic-emission restriction in China. First, NO 2 variations are quantified by an Autoregressive Integrated Moving Average with external variables-Dynamic Time Warping (SARIMAX-DTW)-based model. Then, urban functional fragmentation indices including industrial/public Edge Density (ED) and Landscape Shape Index (LSI), urban functional Aggregation Index (AI) and Number of Patches (NP) are developed. Finally, the mediated impacts of anthropogenic-emission restriction are assessed by evaluating the fragmentation-NO 2 variation association before and during the lockdown during COVID-19. The findings reveal negative effects of industrial ED, public LSI, urban functional AI and NP and positive effects of public ED and industrial LSI on NO 2 variation based on the restricted anthropogenic emissions. By comparing the association analysis before and during lockdown, the mediated impact of anthropogenic-emission restriction is revealed to partially increase the effect of industrial ED, industrial LSI, public LSI, urban functional AI and NP and decrease the effect of public ED on NO 2 variation. This study provides scientific findings for redesigning the urban environment in related to the urban functional configuration to mitigating the air pollution, ultimately developing sustainable societies.

With the rapid increase in HIV prevalence of men who have sex with men (MSM) in recent years and common human migration and travelling across different provinces in China, MSM are now finding it easier to meet each other, which might contribute to local HIV epidemics as well as fueling cross-province transmission. We performed a cross-sectional survey in 2018-2019 to investigate the current HIV subtype diversity and inferred HIV strain transmission origin among MSM in Guangxi province, China based on a phylogenetic analysis. Based on 238 samples, we found that the HIV-1 subtype diversity was more complicated than before, except for three major HIV subtypes/circulating recombinant forms (CRFs): CRF07&#95;BC, CRF01&#95;AE, CRF55&#95;01B, five other subtypes/CRFs (CRF59&#95;01B, B, CRF08&#95;BC, CRF67&#95;01B, CRF68&#95;01B) and five unique recombinant forms (URFs) were detected. In total, 76.8% (169/220) of samples were infected with HIV from local circulating strains, while others originated from other provinces, predominantly Guangdong and Shanghai. The high diversity of HIV recombinants and complicated HIV transmission sources in Guangxi MSM indicates that there has been an active sexual network between HIV positive MSM both within and outside Guangxi without any effective prevention. Inter-province collaboration must be enforced to provide tailored HIV prevention and control services to MSM in China.

To assess whether human immunodeficiency virus type 1 (HIV-1) genotype influences baseline CD4+ T lymphocyte (CD4+) cell count and mortality of patients. The study was conducted from 2014 to 2019 in Guangxi, China, and included 2845 newly diagnosed HIV patients. We used a median regression model to compare CD4+ cell counts in patients newly diagnosed with different HIV-1 genotypes, and a Cox regression model to analyze the associations between HIV-1 genotypes and mortality before and after antiretroviral treatment (ART). In newly diagnosed HIV patients, the baseline CD4+ cell counts of patients with CRF01&#95;AE were significantly lower than those of patients with CRF07&#95;BC, CRF08&#95;BC, and other genotypes. Compared with CRF01&#95;AE, patients infected with CRF07&#95;BC (hazard ratio, 0.55; 95% CI 0.36-0.85), CRF08&#95;BC (hazard ratio, 0.67; 95% CI 0.52-0.85), or other genotypes (hazard ratio, 0.52; 95% CI 0.29-0.94) had significantly lower mortality rates before ART. There were no significant associations between different HIV-1 genotypes and mortality after ART. HIV-1 genotype significantly influences baseline CD4+ cell count and mortality before ART in newly diagnosed HIV patients. We find no significant difference in the outcome of death after ART in patients with different HIV-1 genotypes.

In this contribution, we optimize the structure of double-input capacitively coupled contactless conductivity detector (DIC 4 D) that proposed before by our group and successfully applied it in the capillary electrophoresis of inorganic ion analysis. Furthermore, we present the detail theoretical analysis and simulation to exploring the working mechanism of DIC 4 D. Compared with C 4 D, under identical experimental conditions and by using the same current-to-voltage converter, both the theoretical and experimental results suggest that the effectiveness and feasibility of DIC 4 D. The improved DIC 4 D diminished the baseline drift effects in C 4 D, provides lower noise, higher sensitivity and notably stable baseline. The LODs of DIC 4 D are 1.0 μM for K + and 1.5 μM for Li + (S/N = 3). DIC 4 D provides a better linear relationship (R = 0.997 and 0.998 for K + and Li + , respectively) with the range of 2.0 μM ~ 2.5 mM.

Cancer is a highly heterogeneous disease in term of molecular signature even though it is originated from the same tissue type. Cancer heterogeneity may occur during its development or treatment, which is the main cause resulting in drug resistance and recurrence. Precision medicine refers to matching the right medicine to the right patients based on their molecular signatures. Therefore, a thorough understanding of the mechanism of tumorigenesis and drug resistance is essential to precision medicine. CRISPR-cas9 system is a powerful tool for gene editing and CRISPR-based high-throughput screening has been widely applied especially in searching for tumor-driven or synergistic lethal genes aiming to overcome drug resistance. In this review, we describe the progress of CRISPR-cas9-based unbiased screening in precision medicine including identification of new drug targets, biomarkers and elucidation of mechanisms leading to drug resistance. The existing challenges as well as the future directions are also discussed.

Recent cancer studies have found that the netrin family of proteins plays vital roles in the development of some cancers. However, the functions of the many variants of these proteins in cancer remain incompletely understood. In this work, we used the most comprehensive database available, including more than 10000 samples across more than 30 tumor types, to analyze the six members of the netrin family. We performed comprehensive analysis of genetic change and expression of the netrin genes and analyzed epigenetic and pathway relationships, as well as the correlation of expression of these proteins with drug sensitivity. Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397). Interestingly, the highest mutation rate of a netrin family member is 38% for NTNG1 (152 of 397). Netrin proteins may participate in the development of endocrine-related tumors and sex hormone-targeting organ tumors. Additionally, the participation of NTNG1 and NTNG2 in various cancers shows their potential for use as new tumor markers and therapeutic targets. This analysis provides a broad molecular perspective of this protein family and suggests some new directions for the treatment of cancer.

HIV with HBV co-infection can result in greater HIV-related immunosuppression, morbidity and mortality. Currently, there are few studies to evaluate direct treatment effects on mortality and attrition rates between first-line antiretroviral therapy (ART) based-on tenofovir (TDF) and/or lamivudine (3TC) in a real-world setting. We used Cox proportional hazard models to evaluate direct treatment effects of the first-line ART containing stavudine (d4T), azidothymidine (AZT) and TDF on death and attrition among HIV patients with HBV coinfection. A total of 3912 patients met study eligibility criteria. The overall mortality rate and attrition rate was 2.85 (95% CI: 2.55-3.16) and 8.87 (95% CI: 8.32-9.41) per 100 person-years, respectively. The ART containing TDF had a significantly lower risk of death [adjusted hazard ratio (AHR) = 0.58, 95% CI: 0.44-0.77] when compared to the ART containing d4T, but the risk of death was not significantly different when compared to the ART containing AZT (AHR = 0.91, 95% CI: 0.69-1.20). Patients with HIV/HBV coinfection receiving the ART containing TDF had significantly lower risk rates of attrition compared to those receiving the ART containing d4T (AHR = 0.72, 95% CI: 0.60-0.86) or AZT (AHR = 0.67, 95% CI: 0.58-0.77). Compared with the ART containing d4T, the ART containing AZT was significant and not significant associated with a lower risk of death and attrition, respectively. The ART containing TDF had significant effects on both of death and attrition among HIV patients with HBV coinfection.

High-entropy alloys (HEAs) have inspired considerable interest due to their attractive physical and mechanical properties. In this work, the microstructural evolution induced by different heat treatments on rapidly solidified hypoeutectic precursors of a Fe 26.7 Co 26.7 Ni 26.7 Si 8.9 B 11 HEA is investigated and correlated with the corresponding mechanical properties. The microstructures of the rapidly solidified precursors are composed of primary fcc solid solution dendrites embedded in a eutectic matrix. When the samples are annealed at different temperatures after furnace cooling or quenching, respectively, the eutectic structure gradually decomposes into fcc, tetragonal (Fe,Co) 2 B, and hexagonal Ni 31 Si 12 crystals with increasing annealing temperature, leading to a gradual increase of the content of the fcc crystals and both their aggregation and coarsening. Then the dominant structural framework gradually transforms from eutectic structures to fcc dendrites and ultimately the (Fe,Co) 2 B crystals become isolated as dominant reinforcement particles distributed in the interdendritic regions. This gradual microstructural transition from hypoeutectic to quasi-duplex structures leads to the change of the dominant deformation mechanism from crack-controlled to dislocation-dominated deformation, which allows to control both ductility and strength in a wide range. Hence, this study provides some guideline for how to tune the microstructure and mechanical properties of HEAs.

Although the Guangxi region accounts for 10% of all HIV-1 cases new reported in 2011 in China, the sources of the transmitted HIV-1 strains are virtually unknown. To determine the extent to which recent HIV infections were derived from already circulating local strains as opposed to recently introduced strains, we performed a cross-sectional molecular epidemiological investigation of recent infections across Guangxi during 2012-2013. HIV-1 nucleotide sequences were amplified and sequenced. Phylogenetic analyses of pol gene regions were used to determine HIV-1 transmission source strains. Based on 229 sequences generated, the subtype/CRF distribution was as follows: CRF01&#95;AE (61.1%), CRF07&#95;BC (18.8%), CRF08&#95;BC (16.6%), CRF55&#95;01B (3.1%), and subtype B' (0.4%). In total, 213 of 229 (93.0%) sequenced transmission strains were derived from already-circulating local strains. Multivariate logistic regression analysis showed that only an age of 18-25 years was significantly associated with transmission from outside Guangxi (compared to >25 years, AOR: 5.15, 95% CI: 1.18-22.48, p < 0.01). This is the first study to use a Bayesian discrete phylogeographic approach to analyze transmission source strains in China. Our results provide useful data for designing evidence-based prevention strategies and methods for combating the rapid spread of sexually transmitted HIV in Guangxi.

This study aimed to evaluate the imaging quality of head and neck computed tomographic angiography (CTA) in pediatric patients at a lowered radiation dose by combining an iterative model reconstruction (IMR) with low voltage scanning. Eighty-three pediatric patients were randomized into two groups as follows: Group A (n = 42), 100 kV/50 ml contrast media (CM), using filtered back projection (FBP); and Group B (n = 41), 80 kV/30 ml CM, using IMR. The enhanced CT value of the arteries, the image noise, the signal-to-noise ratio (SNR)/contrast-to-noise ratio (CNR), the image quality, the effective radiation dose (ED) and the iodine intake were compared between the two groups. The mean ED and iodine intake of group B were reduced by 69.8% and 40.0%, respectively, compared to those of group A. The mean CT values of the arteries in group B were higher than those in group A (p < 0.01), whereas the image noise of group B was lower than that of group A (p < 0.01). Group B exhibited a better image quality and a higher mean CNR/SNR than that of group A (p < 0.01). Compared to FBP, IMR in head and neck CTA enables a significant reduction in the radiation dose while preserving the diagnostic image quality. Thus, IMR, combined with low tube voltage scanning, provided an excellent solution for improving the image quality of craniocervical vessels in children.

To investigate the prevalence and temporal trend of transmitted drug resistance (TDR), a nationwide cross-sectional survey was conducted among 5627 ART naïve newly diagnosed HIV-infected individuals in 2015 in China. Totally 4704 partial pol sequences were obtained. Among them, the most common HIV-1 circulating recombinant form (CRF) or subtype was CRF01&#95;AE (39.0%), followed by CRF07&#95;BC (35.6%), CRF08&#95;BC (8.9%), and subtype B (5.5%). TDR mutations were found in 3.6% of the cases, with 1.1% harboring TDR to protease inhibitors (PIs), 1.3% having TDR to nucleoside reverse transcriptase inhibitors (NRTIs), and 1.6% to non-nucleoside reverse transcriptase inhibitors (NNRTIs). No significant difference was found in the prevalence of TDR, as compared with the results of another nationwide survey performed among ART naïve HIV-infected people in between 2004 and 2005, except in the 16-25 year-old group. In addition, four drug-resistant transmission clusters were identified in phylogenetic trees, accounting for 6.2% (9/145) of the individuals with TDR. Although the rate of TDR remained relatively low in the past 10 years in China, surveillance is still needed to monitor the trend of TDR and to optimize the first-line regimens.

Early antiretroviral therapy (ART) initiation is a recommended public health approach for the prevention of HIV-1 transmission. In this cohort study, we included 13132 serodiscordant couples. ART was initiated for patients with CD4+ T cell counts less than 200 cells/uL, 350 cells/uL, and 500 cells/uL respectively. This divided the ART treated couples into three groups. Univariate and multivariate intention-to-treat analyses were performed to examine the association between the study groups. Early-ART initiation was associated with a 45% lower risk of partner infection than was late-ART initiation (AHR 0.55, 95% CI, 0.37-0.81). Mid-ART initiation was associated with a 39% lower risk of partner infection than was late-ART initiation (AHR 0.61, 95% CI, 0.48-0.78). However, the risk reduction between the early and mid-ART groups was not significant. Drug compliance (AHR 1.55, 95% CI 1.03-2.35) and increased baseline viral load (AHR 1.41, 95% CI 1.33-1.51) were associated with an increased risk of infections among partners in the treatment. Prevention of HIV transmission as a result of early ART initiation was feasible on national and regional scales; however, many factors, such as the motivation to commence ART, adherence, and attrition, may affect the impact of this strategy in programmatic settings.

Pentatricopeptide repeat (PPR) proteins, which are characterized by tandem 30-40 amino acid sequence motifs, constitute of a large gene family in plants. Some PPR proteins have been identified to play important roles in organellar RNA metabolism and organ development in Arabidopsis and rice. However, functions of PPR genes in woody species remain largely unknown. Here, we identified and characterized a total of 626 PPR genes containing PPR motifs in the Populus trichocarpa genome. A comprehensive genome-wide analysis of the poplar PPR gene family was performed, including chromosomal location, phylogenetic relationships and gene duplication. Genome-wide transcriptomic analysis showed that 154 of the PtrPPR genes were induced by biotic and abiotic treatments, including Marssonina brunnea, salicylic acid (SA), methyl jasmonate (MeJA), mechanical wounding, cold and salinity stress. Quantitative RT-PCR analysis further investigated the expression profiles of 11 PtrPPR genes under different stresses. Our results contribute to a comprehensive understanding the roles of PPR proteins and provided an insight for improving the stress tolerance in poplar.

Hepatitis B virus (HBV) has been suspected to contribute to several autoimmune diseases, including Sjögren's syndrome (SS), although the exact mechanism is unknown. The 2'-5' oligoadenylate synthetase (OAS1) is one of the most important components of the immune system and has significant antiviral functions. We studied a polymorphism rs10774671 of OAS1 gene in Han Chinese descent. The minor allele G was significantly associated with a decreased risk for SS, anti-SSA-positive SS, and anti-SSA-positive SS complicated with HBV infection, which have not been seen in anti-SSA-negative SS and HBcAb-negative SS patients. Gene expression analysis showed that the risk-conferring A allele was correlated with lower expression of p46 and increased expression of p42, p48, and p44. A functional study of enzymatic activities revealed that the p42, p44, and p48 isoforms display a reduced capacity to inhibit HBV replication in HepG2 cells compared to the normal p46 isoform. Our data demonstrated that the functional variant, rs10774671, is associated with HBV infection and anti-SSA antibody-positive SS. The SAS variant switches the primary p46 isoform to three alternatives with decreased capacities to inhibit HBV replication. These data indicated that individuals harboring the risk allele might be susceptible to hepatitis B infection and SS development.

Previous studies on the association between thyroid hormones and prognosis of acute ischemic stroke (AIS) reported conflicting results. We conducted a meta-analysis to assess the prognostic value of thyroid hormones in AIS. The PubMed, EMBASE, and Cochrane library databases were searched through May 12, 2017 to identify eligible studies on this subject. Out of 2,181 studies retrieved, 11 studies were finally included with a total number of 3,936 acute stroke patients for analysis. Odds ratio (OR) for predicting poor outcome or standardized mean difference (SMD) of thyroid hormone levels with 95% confidence intervals (95% CI) obtained from the studies were pooled using Review Manager 5.3. From the results, in AIS, patients with a poor outcome had lower levels of triiodothyronine (T3) and higher thyroxine (T4). Pooled OR confirmed the same association. Our study provides statistical evidence supporting the utility of thyroid hormone levels in prognosis of acute stroke.

Triple-negative breast cancer (TNBC) refers to one aggressive histological subtype of breast cancer with high heterogeneity and poor prognosis after standard therapy. Lack of clearly established molecular mechanism driving TNBC progression makes personalized therapy more difficult. Thus, identification of genetic variants associated with TNBC prognosis will show clinic significance for individualized treatments. Our study is aimed to evaluate the prognostic value of the genome wide association study (GWAS)-identified CHST9 rs1436904 and AQP4 rs527616 genetic variants in our established early-stage TNBC sample database. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). CHST9 rs1436904G allele was significantly associated with decreased disease-free survival time (DFS) (8.5 months shorter in GG genotype carriers compared to TT genotype carriers, HR = 1.70, 95% CI = 1.03-2.81, P = 0.038). Stratified analyses showed an increased risk of cancer progression in CHST9 rs1436904G allele carriers harboring larger tumor (tumor size > 2 cm), without lymph-node metastasis, being premenopausal at diagnosis or with vascular invasion (P = 0.032, 0.017, 0.008 or 0.003). Our findings demonstrate that the GWAS-identified 18q11.2 CHST9 rs1436904 polymorphism significantly contributes to prognosis of early-stage TNBC, suggesting its clinical potential in the screening of high-risk TNBC patients for recurrence and the possibility of patient-tailored therapeutic decisions.

Interindividual heterogeneity in the disease progression of HIV-1-infected patients receiving long-term antiretroviral therapy suggests that some host-related factors may have limited treatment efficacy. To understand the nature of factors contributing to treatment failure, we performed a retrospective cohort study of 45 chronically HIV-1-infected individuals sharing a similar demographics and route of infection, compared the differences between virologically suppressed (VS) and treatment failure (TF) patients with respect to clinical, immunological and virological characteristics. We found that the baseline diversity of HIV-1 env quasispecies was the major difference between VS and TF group, and higher baseline diversity in TF patients. We further predicted TF-related env mutations using a selection pressure-based approach, followed by an analysis of these mutations based on the available three-dimensional structures of gp120/gp41 or their complexes with neutralizing antibodies. Notably, almost all of the identified residues could be mapped to the epitopes of known HIV-1 neutralizing antibodies, especially the epitopes of broadly neutralizing antibodies, and these mutations tended to compromise antibody-antigen interactions. These results indicate that the escape of HIV-1 from host humoral immunity may play a direct role in TF in long-term antiretroviral-experienced patients and that based on env gene sequence of the viruses in the patients.

As the most dominant HIV-1 strain in China, CRF01&#95;AE needs to have its evolutionary and demographic history documented. In this study, we provide phylogenetic analysis of all CRF01&#95;AE pol sequences identified in mainland China. CRF01&#95;AE sequences were collected from the Los Alamos HIV Sequence Database and the local Chinese provincial centers of disease control and prevention. Phylogenetic trees were constructed to identify major epidemic clusters. Bayesian coalescent-based method was used to reconstruct the time scale and demographic history. There were 2965 CRF01&#95;AE sequences from 24 Chinese provinces that were collected, and 5 major epidemic clusters containing 85% of the total CRF01&#95;AE sequences were identified. Every cluster contains sequences from more than 10 provinces with 1 or 2 dominant transmission routes. One cluster arose in the 1990s and 4 clusters arose in the 2000s. Cluster I is in the decline stage, while the other clusters are in the stable stage. Obvious lineage can be observed among sequences from the same transmission route but not the same area. Two large clusters in high-level prevalence were found in MSM (Men who have sex with men), which highlighted that more emphasis should be placed on MSM for HIV control in mainland China.

Current WHO guidelines recommend initiating ART regardless of CD4+ cell count. In response, we conducted an observational cohort study to assess the effects of pre-ART CD4+ cell count levels on death, attrition, and death or attrition in HIV treated patients. This large HIV treatment cohort study (n = 49,155) from 2010 to 2015 was conducted in Guangxi, China. We used a Cox regression model to analyze associations between pre-ART CD4+ cell counts and death, attrition, and death or attrition. The average mortality and ART attrition rates among all treated patients were 2.63 deaths and 5.32 attritions per 100 person-years, respectively. Compared to HIV patients with <350 CD4+ cells/mm 3 at ART initiation, HIV patients with >500 CD4+ cells/mm 3 at ART initiation had a significantly lower mortality rate (Adjusted hazard ratio: 0.56, 95% CI: 0.40-0.79), but significantly higher ART attrition rate (AHR: 1.17, 95% CI: 1.03-1.33). Results from this study suggest that HIV patients with high CD4+ cell counts at the time of ART initiation may be at greater risk of treatment attrition. To further reduce ART attrition, it is imperative that patient education and healthcare provider training on ART adherence be enhanced and account for CD4 levels at ART initiation.

This study aimed to identify microRNAs (miRs), the deregulated expression of which leads to the activation of oncogenic pathways in human breast cancer (BC). miRs are classes of endogenous, small, noncoding RNAs that regulate gene expression aberrantly in human tumor tissues. A total of 39 out of 123 tumoral and matched uninvolved peritumoral breast specimens from 3 independent subsets of patients were analyzed for the expression of 851 human miRs using an Agilent platform. The remaining 84 samples were used to validate miRs differentially expressed between tumoral and matched peritumoral specimens by quantitative polymerase chain reaction. Animal assay was further used to test the role of miR-9 and Her-2 in the pathogenesis of BC. All 39 matched samples were analyzed by unsupervised cluster analysis. This analytical approach identified a signature of miRs (miR-9, miR-148a, miR-31, miR-375, miR-21, miR-135b, miR-196a and miR-196b) that were significantly modulated between tumoral and peritumoral tissues in both subsets of patients. Her-2 protein staining increased in tumoral specimens when miR-9 downregulation correlated with the prognostic value. The ectopic expression of miR-9 inhibited the colony-forming ability, migration and tumor engraftment of BC cells. miR-9 targeted the Her-2 messenger RNA and increased responsiveness of BC cells to docetaxel (DOC) or cyclophosphamide treatment. The ectopic expression of Her-2 protein counteracted the miR-9 proapoptotic activity in response to DOC. These findings suggested that the modulation of aberrant expression of miR-9, which in turn induces oncogenic Her-2 protein activity, might hold promise for preventive and therapeutic management of BC.

The aim of this study was to explore the associations and differences in influencing factors between alcoholic liver disease (ALD) coupled with Helicobacter pylori infection and atherosclerosis and to determine whether there is a "double hit phenomenon" in atherosclerosis patients with ALD and H. pylori infections. Included cases (n = 160) were categorized into 4 groups: 41 cases of ALD coupled with H. pylori infections (group A), 35 cases of H. pylori infections without ALD (group B), 37 cases of ALD without H. pylori infections (group C), and 47 normal control cases (group D). CIMT was significantly greater in group A than in groups B and D (P = 0.005 and P = 0.001, respectively). The GLM univariate analysis found that CIMT was significantly greater in group A than in groups B, C and D (P = 0.018, P = 0.001 and P = 0.009, respectively). We found that BMI and ALT, AST and ApoB levels were independent predictors of CIMT (P = 0.000, P = 0.000, P = 0.012 and P = 0.014, respectively). ALD coupled with H. pylori infection may result in significant CIMT thickening, but H. pylori infection without ALD and ALD without H. pylori infection does not, suggesting that a "double hit phenomenon" occurs. Additionally, BMI, and ALT, AST and ApoB levels were independent risk factors for increased CIMT.

1-Ethyl-3-methylimidazolium acetate is introduced as a robust organocatalyst for solvent-free cyanosilylation of carbonyl compounds with trimethylsilyl cyanide (TMSCN). The catalyst loading can be reduced to as low as 0.1-0.0001 mol % under mild reaction conditions, giving considerably high TOF values from 10,843 h -1 to 10,602,410 h -1 in the field of organocatalyzed transformations. The present protocol not only tolerates with extensive carbonyl compounds but also provides somewhat insight into the mechanism of ionic liquids (ILs)-catalyzed reactions.

To identify genomic markers associated with the response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. A total of 596 patients with stage IA2-IIIB cervical cancer were enrolled in this study. One single nucleotide polymorphism (SNP) (rs6812281, per allele OR = 2.37, P = 9.0 × 10 -9 ) located at 4q34.3 reached GWAS significance (P < 5.0 × 10 -8 ). Another three SNPs, rs4590782 (10q26.2, P = 1.59 × 10 -5 , per allele OR = 0.48), rs1742101 (14q32.11, P = 7.11 × 10 -6 , per allele OR = 0.52), and rs1364121 (16q23.3, P = 3.15 × 10 -6 , per allele OR = 1.98), exhibited strong evidence of associations with response to neoadjuvant chemotherapy. Patients with a C allele (CT + CC) of rs4590782 had better 5-year overall survival rates (82.9% vs. 75.8%, P = 0.083) and 5-year disease-free survival rate (80.8% vs. 72.7%, P = 0.021) than those without a C allele. Our findings help to characterize the genetic etiology of the response to neoadjuvant chemotherapy in patients with cervical cancer.