Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

The repertoire of copy number alteration signatures in human cancer.

Copy number alterations (CNAs) are a predominant source of genetic alterations in human cancer and play an important role in cancer progression. However comprehensive understanding of the mutational processes and signatures of CNA is still lacking. Here we developed a mechanism-agnostic method to categorize CNA based on various fragment properties, which reflect the consequences of mutagenic processes and can be extracted from different types of data, including whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) array. The 14 signatures of CNA have been extracted from 2778 pan-cancer analysis of whole genomes WGS samples, and further validated with 10 851 the cancer genome atlas SNP array dataset. Novel patterns of CNA have been revealed through this study. The activities of some CNA signatures consistently predict cancer patients' prognosis. This study provides a repertoire for understanding the signatures of CNA in cancer, with potential implications for cancer prognosis, evolution and etiology.

TLimmuno2: predicting MHC class II antigen immunogenicity through transfer learning.

Major histocompatibility complex (MHC) class II molecules play a pivotal role in antigen presentation and CD4+ T cell response. Accurate prediction of the immunogenicity of MHC class II-associated antigens is critical for vaccine design and cancer immunotherapies. However, current computational methods are limited by insufficient training data and algorithmic constraints, and the rules that govern which peptides are truly recognized by existing T cell receptors remain poorly understood. Here, we build a transfer learning-based, long short-term memory model named 'TLimmuno2' to predict whether epitope-MHC class II complex can elicit T cell response. Through leveraging binding affinity data, TLimmuno2 shows superior performance compared with existing models on independent validation datasets. TLimmuno2 can find real immunogenic neoantigen in real-world cancer immunotherapy data. The identification of significant MHC class II neoantigen-mediated immunoediting signal in the cancer genome atlas pan-cancer dataset further suggests the robustness of TLimmuno2 in identifying really immunogenic neoantigens that are undergoing negative selection during cancer evolution. Overall, TLimmuno2 is a powerful tool for the immunogenicity prediction of MHC class II presented epitopes and could promote the development of personalized immunotherapies.

Integrated Thermal Proteome Profiling and Affinity Ultrafiltration Mass Spectrometry (iTPAUMS): A Novel Paradigm for Elucidating the Mechanism of Action of Natural Products.

Natural products (NPs) are foundational to drug discovery, offering a rich repertoire of molecular diversity with multifaceted modes of action against a broad array of targets. Despite their potential, deconvoluting the intricate mechanism of action (MoA) of NPs, characterized by their multicomponent, multitarget, and multilevel interactions, remains a formidable challenge. Here, we introduce an innovative pipeline called integrated thermal proteome profiling and affinity ultrafiltration mass spectrometry (iTPAUMS). This approach combines the high-throughput capacity of thermal proteome profiling (TPP) with the specificity of affinity ultrafiltration mass spectrometry (AUMS), creating a powerful toolkit for elucidating complex MoAs of NPs. Significantly, our investigation represents a pioneering application of TPP to delineate the target group of NPs mixtures and overcome the long-standing obstacle of mapping specific component-target interactions through AUMS. Our findings demonstrate the utility of iTPAUMS in constructing a comprehensive component-target atlas, providing a robust analytical foundation for unraveling the intricate pharmacological landscapes of NPs and advancing drug discovery.

Hiplot: a comprehensive and easy-to-use web service for boosting publication-ready biomedical data visualization.

Complex biomedical data generated during clinical, omics and mechanism-based experiments have increasingly been exploited through cloud- and visualization-based data mining techniques. However, the scientific community still lacks an easy-to-use web service for the comprehensive visualization of biomedical data, particularly high-quality and publication-ready graphics that allow easy scaling and updatability according to user demands. Therefore, we propose a community-driven modern web service, Hiplot (https://hiplot.org), with concise and top-quality data visualization applications for the life sciences and biomedical fields. This web service permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be conducted by senior bioinformatics or biostatistics researchers. It covers most of the daily demands of biomedical researchers with its equipped 240+ biomedical data visualization functions, involving basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modelling, etc. Moreover, to improve the efficiency in use and development of plugins, we introduced some core advantages on the client-/server-side of the website, such as spreadsheet-based data importing, cross-platform command-line controller (Hctl), multi-user plumber workers, JavaScript Object Notation-based plugin system, easy data/parameters, results and errors reproduction and real-time updates mode. Meanwhile, using demo/real data sets and benchmark tests, we explored statistical parameters, cancer genomic landscapes, disease risk factors and the performance of website based on selected native plugins. The statistics of visits and user numbers could further reflect the potential impact of this web service on relevant fields. Thus, researchers devoted to life and data sciences would benefit from this emerging and free web service.

Benzo(a)anthracene Targeting SLC1A5 to Synergistically Enhance PAH Mixture Toxicity.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) as mutagenic and carcinogenic pollutants in the environment often occurs in the form of mixtures. Although the mixture effects of PAHs have been previously recognized, the toxicological mechanisms to explain them still remain quite unclear. This study combined metabolomics and chemical proteomics methods to comprehensively understand the mixture effects of a PAH mixture including benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), benzo(a)pyrene (BaP), and chrysene (CHR). Among them, BaA has shown a strong synergistic effect with other PAHs. Interestingly, BaA alone is not a potent oxidative stress inducer in liver cells but dose-dependently amplifies oxidative damage caused by the PAH mixture. Global metabolomics analysis results revealed damage to the antioxidant glutathione synthesis, which was caused by the glutamine depletion caused by BaA in the mixture. Subsequently, the label-free chemical proteomics and cellular thermal shift analysis (CETSA) demonstrated that the PAH mixture altered the thermal shift of glutamine transporter SLC1A5. Furthermore, Western blotting and the isothermal titration calorimetry (ITC) interaction measurements showed nanomolar KD values between BaA and SLC1A5. Overall, this study showed that BaA synergistically contributed to PAH mixture induced oxidative damage by targeting SLC1A5 to inhibit glutamate transport into cells, resulting in the inhibition of glutathione synthesis.

Copy number signature analysis tool and its application in prostate cancer reveals distinct mutational processes and clinical outcomes.

Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool "sigminer" has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.

24-epibrassinolide as a multidimensional regulator of rice (Oryza sativa) physiological and molecular responses under isoproturon stress.

Brassinosteroids (BRs) can regulate various processes in plant development and defense against environmental stress. In this study, the contribution of BRs in the degradation of isoproturon (IPU) in rice has been established. IPU has a significant effect on rice growth, chlorophyll content, and membrane permeability. When treated with 1.0 µmol/L 24-epibrassinolide (EBR), a BR analogue, the associated symptoms of rice poisoning were alleviated as the IPU levels in the rice and growth media were decreased. In the presence of EBR, the activities of several IPU-related detoxification enzymes were enhanced to cope with the stress due to IPU. An RNA-sequencing (RNA-Seq) has been performed to determine the variation of transcriptomes and metabolic mechanisms in rice treated with EBR, IPU, or IPU+EBR. Some of the differentially expressed genes (DEGs) were Phase I-III reaction components of plants, such as cytochrome P450 (CYP450), glutathione S-transferase (GST), glycosyltransferases (GTs), and the ATP-binding cassette transporter (ABC transporter). The expression of some signal transduction genes was significantly up-regulated. The relative content of low-toxicity IPU metabolites increased due to the presence of EBR as determined by UPLC/Q-TOF-MS/MS. The IPU metabolic pathways include enzyme-catalyzed demethylation, hydroxylation, hydrolysis, glycosylation, and amino acid conjugation processes. The results suggest that EBR plays a key role in the degradation and detoxification of IPU. This study has provided evidence that BRs regulate the metabolism and detoxification of IPU in rice, and offers a new approach to ensuring cleaner crops by eliminating pesticide residues in the environment.

Transcriptomics reveals the mechanism of terbuthylazine-induced nephrotoxicity in chickens: Insights from AMPK/p53-mediated apoptosis perspective.

As a commonly used pesticide, the widespread use of terbuthylazine (TBA) may cause toxic effects in animals and human. However, the nephrotoxicity induced by TBA is unclear. Here, we explored the mechanism of TBA-induced nephrotoxicity through transcriptomics and molecular biology techniques in broilers. Pathologic analysis showed that TBA could cause renal cell vacuolation and fibrosis in broilers. Additionally, transcriptomic analysis showed that TBA can cause significant changes in the expression of some apoptosis-related genes, and GO and KEGG analysis also found that TBA can significantly change the functions of apoptosis pathway and AMPK signaling pathway in kidney. Subsequently, the protein expression levels of Bax, Bak-1, FADD, and cleaved Caspase-3/Caspase-3 were elevated significantly and the number of TUNEL-positive cells was increased markedly in kidney under TBA exposure. Meanwhile, we also found that TBA could activate AMPK/p53 pathway, as evidenced by the upregulated levels of AMPKα1 phosphorylation and protein expression of p53. Therefore, our results suggested that TBA could induce apoptosis via AMPK/p53 pathway in kidney. These findings identified the nephrotoxic mechanism of TBA through transcriptomics, providing a new insight into TBA toxicology.

UCSCXenaShiny: an R/CRAN package for interactive analysis of UCSC Xena data.

SUMMARY: UCSC Xena platform provides huge amounts of processed cancer omics data from large cancer research projects (e.g. TCGA, CCLE and PCAWG) or individual research groups and enables unprecedented research opportunities. However, a graphical user interface-based tool for interactively analyzing UCSC Xena data and generating elegant plots is still lacking, especially for cancer researchers and clinicians with limited programming experience. Here, we present UCSCXenaShiny, an R Shiny package for quickly searching, downloading, exploring, analyzing and visualizing data from UCSC Xena data hubs. This tool could effectively promote the practical use of public data, and can serve as an important complement to the current Xena genomics explorer. AVAILABILITY AND IMPLEMENTATION: UCSCXenaShiny is an open source R package under GPLv3 license and it is freely available at https://github.com/openbiox/UCSCXenaShiny or https://cran.r-project.org/package=UCSCXenaShiny. The docker image is available at https://hub.docker.com/r/shixiangwang/ucscxenashiny. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

AOSD endotypes based on immune cell profiles: patient stratification with hierarchical clustering analysis.

OBJECTIVES: This study aimed to analyse the immune cell profiles of adult-onset Still's disease (AOSD) and to stratify disease-associated endotypes. METHODS: We included 95 cases of treatment-naïve patients with AOSD and 66 cases of healthy controls. Patients with AOSD were classified via an unbiased hierarchical cluster analysis based on circulating immune cells. Their clinical and laboratory characteristics, treatment management, systemic scores and outcomes were then analysed. RESULTS: The proportions of neutrophils and CD8+ T cells were significantly higher while monocytes and natural killer and CD4+ T cells were decreased in patients with AOSD (all P < 0.005). Unbiased hierarchical cluster analysis classified 95 AOSD into three endotype-based groups: group 1 had the highest percentage of neutrophils (neu-dominant group), group 2 had the highest percentage of monocytes (mono-dominant group) and group 3 had the highest percentage of CD8+ T cells (CD8-dominant group). Patients in group 3 had the highest systemic score at diagnosis and were more likely to have pulmonary infiltrates, pericarditis, splenomegaly and poorer treatment responses. A correlation study revealed that the CD4 to CD8 ratio was negatively correlated with the systemic score and positively correlated with treatment response in patients with AOSD (P = 0.001 and P = 0.0091). During the 24.6 (15.2) months of follow-up, the highest total number of disease flares occurred in group 3 (P < 0.0001). CONCLUSION: Hierarchical cluster analysis of peripheral immune cells classified AOSD into three disease-related endotypes. Group 3 showed higher systemic score and poorer treatment responses.

Influence of arbuscular mycorrhizal fungi on mercury accumulation in rice (Oryza sativa L.): From enriched isotope tracing perspective.

The microorganisms that co-exist between soil and rice systems in heavy metal-contaminated soil environments play important roles in the heavy metal pollution states of rice, as well as in the growth of the rice itself. In this study, in order to further examine the effects of soil microorganisms on the mercury (Hg) uptake of rice plants and determine potential soil phytoremediation agents, an enriched 199Hg isotope was spiked in a series of pot experiments to trace the absorption and migration of Hg and rice growth in the presence of arbuscular mycorrhizal fungi (AMF). It was observed that the AMF inoculations significantly reduced the Hg concentration in the rice. The Hg concentration in rice in the AMF inoculation group was between 52.82% and 96.42% lower than that in the AMF non-inoculation group. It was also interesting to note that the presence of AMF tended to cause Hg (especially methyl-Hg (Me199Hg)) to migrate and accumulate in the non-edible parts of the rice, such as the stems and leaves. Under the experimental conditions selected in this study, the proportion of Me199Hg in rice grains decreased from 9.91% to 27.88%. For example, when the exogenous Hg concentration was 0.1 mg/kg, the accumulated methyl-Hg content in the grains of the rice in the AMF inoculation group accounted for only 20.19% of the Me199Hg content in the rice plants, which was significantly lower than that observed in the AMF non-inoculated group (48.07%). AMF also inhibited the absorption of Hg by rice plants, and the decrease in the Hg concentration levels in rice resulted in significant improvements in growth indices, including biomass and micro-indexes, such as antioxidant enzyme activities. The improvements occurred mainly because the AMF formed symbiotic structures with the roots of rice plants, which fixed Hg in the soil. AMF also reduce the bioavailability of Hg by secreting a series of substances and changing the physicochemical properties of the rhizosphere soil. These findings suggest the possibility of using typical co-existing microorganisms for the remediation of soil heavy metal contamination and provide valuable insights into reducing human Hg exposure through rice consumption.

Enhancement of oral bioavailability and anti-colitis effect of luteolin-loaded polymer micelles with RA (rosmarinic acid)-SS-mPEG as carrier.

OBJECTIVE: Polymer micelles were prepared (L-RSPMs) with luteolin and synthetic RA-SS-mPEG polymeric material before evaluation of their anti-inflammatory effect on 2, 4, 6-trinitro-benzene-sulfonic acid (TNBS)-induced ulcerative colitis (UC) model in rats. METHODS: The synthetic RA-SS-mPEG was characterized with NMR spectroscopy, before preparation of luteolin-coated RA-SS-mPEG polymer micelles. The in vitro characterization and evaluation of the formulation were accomplished, couple with its pharmacokinetic parameters. The levels of PEG2, MDA, CRP and GSH, as well as concentrations of TNF-α, IL1-ß, IL-6 and IL-10 in serum and colon tissue were detected via ELISA kit. The degree of colon injury and inflammation was evaluated via histopathologic examination. RESULTS: L-RSPMs displayed small average droplet size (133.40 ± 4.52 nm), uniformly dispersed (PDI: 0.163 ± 0.011), good stability, slow release and enhanced solubility. We observed 353.28% increase in the relative bioavailability of L-RSPMs compared to free luteolin, while the half-life of the micelle was extended by 6.16h. Compared to model (M) group, luteolin (low and high doses) and L-RSPMs (low and high doses) significantly reduced levels of MDA, PEG2, CRP, TNF-α, IL-6 and IL-1ß in colon tissue and serum of colitic rats but dose dependently increased IL-10 and SOD levels (p < 0.01). Histopathologic examination of colon showed that luteolin (low and high doses) and L-RSPMs (low and high doses) improved colonic inflammation in colitic rats to varying degrees compared to M group. CONCLUSION: L-RSPMs could improve TNBS-induced colon inflammation by enhancing bioavailability, promoting antioxidant effects and regulating cytokine release, which may become a potential agent for UC treatment in clinical settings.

Sigflow: an automated and comprehensive pipeline for cancer genome mutational signature analysis.

SUMMARY: Mutational signatures are recurring DNA alteration patterns caused by distinct mutational events during the evolution of cancer. In recent years, several bioinformatics tools are available for mutational signature analysis. However, most of them focus on specific type of mutation or have limited scope of application. A pipeline tool for comprehensive mutational signature analysis is still lacking. Here we present Sigflow pipeline, which provides an one-stop solution for de novo signature extraction, reference signature fitting, signature stability analysis, sample clustering based on signature exposure in different types of genome DNA alterations including single base substitution, doublet base substitution, small insertion and deletion and copy number alteration. A Docker image is constructed to solve the complex and time-consuming installation issues, and this enables reproducible research by version control of all dependent tools along with their environments. Sigflow pipeline can be applied to both human and mouse genomes. AVAILABILITY AND IMPLEMENTATION: Sigflow is an open source software under academic free license v3.0 and it is freely available at https://github.com/ShixiangWang/sigflow or https://hub.docker.com/r/shixiangwang/sigflow. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Does preoperative gamma knife treatment affect the result of microresection of vestibular schwannoma?

PURPOSE: We aimed to explore the influence of preoperative gamma knife treatment on the clinical effect of microsurgical resection of vestibular schwannoma. METHODS: The data of patients who underwent vestibular schwannoma resection in our hospital between November 2010 and December 2019 were retrospectively collected. According to the data collected retrospectively and the inclusion and exclusion criteria, we selected these patients and divided them into Group A (with preoperative gamma knife treatment) and Group B (without preoperative gamma knife treatment). The pre/postoperative clinical manifestations, neurological function grade, postoperative complications, tumor recurrence and increase were collected and compared between the two groups. RESULTS: There were 40 and 823 patients enrolled in Groups A and B, respectively. There were no significant differences in the general condition, tumor size and side, or neurological performance of the patients in those two groups before the operation. At the last follow-up, the number of patients with poor facial nerve function was 15 (39.5%) in Group A and 170 (20.7%) in Group B (P = 0.021 < 0.05). In Group A and Group B, disequilibrium occurred in 14 (36.8%) patients and 124 (15.1%) patients, respectively, after the operation (P = 0.012 < 0.05). Seven (17.5%) patients had pneumonia in Group A, and 21 (2.6%) patients had pneumonia in Group B (P = 0.04 < 0.05) after the operation. CONCLUSION: When a patient with vestibular schwannoma undergoes microsurgical surgery, the preoperative history with gamma knife treatment may make recovery from postoperative facial paralysis difficult for the patients, making them more prone to suffer from postoperative disequilibrium and postoperative pneumonia.

Electrical impedance tomography for titration of positive end-expiratory pressure in acute respiratory distress syndrome patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of most common comorbidities in acute respiratory distress syndrome (ARDS). There are few specific studies on the appropriate ventilation strategy for patients with ARDS comorbid with COPD, especially regarding on positive end-expiratory pressure (PEEP) titration. METHODS: To compare the respiratory mechanics in mechanical ventilated ARDS patients with or without COPD and to determine whether titration of PEEP based on electrical impedance tomography (EIT) is superior to the ARDSnet protocol. This is a single center, perspective, repeated measure study. ARDS patients requiring mechanical ventilation who were admitted to the intensive care unit between August 2017 and December 2020 were included. ARDS patients were divided according to whether they had COPD into a COPD group and a non-COPD group. Respiratory mechanics, gas exchange, and hemodynamics during ventilation were compared between the groups according to whether the PEEP level was titrated by EIT or the ARDSnet protocol. RESULTS: A total of twenty-seven ARDS patients including 14 comorbid with and 13 without COPD who met the study eligibility criteria were recruited. The PEEP levels titrated by EIT and the ARDSnet protocol were lower in the COPD group than in the non-COPD group (6.93 ± 1.69 cm H2O vs. 12.15 ± 2.40 cm H2O, P < 0.001 and 10.43 ± 1.20 cm H2O vs. 14.0 ± 3.0 cm H2O, P < 0.001, respectively). In the COPD group, the PEEP level titrated by EIT was lower than that titrated by the ARDSnet protocol (6.93 ± 1.69 cm H2O vs. 10.43 ± 1.20 cm H2O, P < 0.001), as was the global inhomogeneity (GI) index (0.397 ± 0.040 vs. 0.446 ± 0.052, P = 0.001), plateau airway pressure (16.50 ± 4.35 cm H2O vs. 20.93 ± 5.37 cm H2O, P = 0.001), dead space ventilation ratio (48.29 ± 6.78% vs. 55.14 ± 8.85%, P < 0.001), ventilation ratio (1.63 ± 0.33 vs. 1.87 ± 0.33, P < 0.001), and mechanical power (13.92 ± 2.18 J/min vs. 15.87 ± 2.53 J/min, P < 0.001). The cardiac index was higher when PEEP was treated by EIT than when it was titrated by the ARDSnet protocol (3.41 ± 0.50 L/min/m2 vs. 3.02 ± 0.43 L/min/m2, P < 0.001), as was oxygen delivery (466.40 ± 71.08 mL/min/m2 vs. 411.10 ± 69.71 mL/min/m2, P = 0.001). CONCLUSION: Titrated PEEP levels were lower in patients with ARDS with COPD than in ARDS patients without COPD. In ARDS patient comorbid with COPD, application of PEEP titrated by EIT was lower than those titrated by the ARDSnet protocol, which contributed to improvements in the ventilation ratio, mechanical energy, cardiac index, and oxygen delivery with less of an adverse impact on hemodynamics.

Establishment of SARS-CoV-2 Immunoglobulins (IgM, IgG) Reference Intervals for Elder Population in China based on 3,733 Samples.

BACKGROUND: Establishment of reference intervals (RIs) for different biomarkers is essential for clinical monitoring. The purpose of this study was to establish laboratory RIs of SARS-CoV-2 IgM and IgG for elder population. MATERIALS: Performance verification was conducted with reference to the Clinical and Laboratory Standards Institute (CLSI) guidelines, including linearity, imprecision, and allowable dilution ratio. Based on CLSI C28-A3 document, a total of 3,734 serum samples were collected, and 3,733 serum samples were used for the establishment of RIs for SARS-CoV-2 IgM and IgG. The subjects were grouped by gender and age. The age groups were as follows: 60 - 69 years, 70 - 79 years, 80 - 89 years, and 90 - 101 years. The RI was defined by nonparametric 95th percentile intervals. RESULTS: Percentage deviation of all the seven dilutions were all less than 12.5% during linearity evaluation. The inter-assay and intra-assay imprecision were all less than 5%. There is no significant difference between different gender and age groups for IgM (p = 0.0818, p = 0.7094), and there is significant difference between different gender and age groups for IgG (p = 0.0011, p = 0.0013). Harris-Boyd's test did not indicate partitioning for IgM and IgG. Cutoff values of RI for SARS-CoV-2 IgM and IgG were defined as 0.1523 S/CO and 0.2663 S/CO, respectively. CONCLUSIONS: RIs of SRAR-CoV-2 IgM and IgG were established for elder population, which can play an important role in the prevention and control of the epidemic.

Exposure to zinc induces lysosomal-mitochondrial axis-mediated apoptosis in PK-15 cells.

Zinc (Zn), a kind of metallic element, can cause poisonous effects on host physiology when its excess exposure. Lysosomes and mitochondria are the toxic targets of heavy metals, and the lysosomal-mitochondrial axis is also verified to take part in apoptosis, but the related underlying mechanisms in Zn-induced cytotoxicity remain undefined. Here, we identified that excess Zn could cause cell damage in PK-15 cells accompanied by the lysosomal and mitochondrial dysfunction, with the evidence by the elevated levels of cathepsin B/D (CTSB/CTSD) in cytoplasm and decrease of Lyso-Tracker Red signal, red fluorescence intensity of AO staining, mitochondrial complex enzyme activities and ATP production. Additionally, the number of Annexin V+/PI--stained cells, apoptosis-related genes (Bax, Bid, Bak1, Caspase-9, and Caspase-3) and proteins levels of Bax, Bak1, Caspase-9, cleaved Caspase-3 and cytoplasmic Cyt C were signally elevated under Zn exposure, while the protein levels of Bcl2 and mitochondrial Cyt C were observably decreased. Importantly, Pepstatin A (the activity inhibitor of CTSD) and RNA interference of CTSD (si-CTSD) was used to reduce the release of lysosomal CTSD to the cytoplasm, which could signally alleviated Zn-induced mitochondrial damage and apoptosis. In summary, these results suggested that Zn could induced lysosomal and mitochondrial dysfunction in PK-15 cells, and the CTSD played an important role in Zn-induced lysosomal-mitochondrial axis-mediated apoptosis. Our results provided a new insight in Zn-induced toxicology, which for protecting the ecological environment and public health.

ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis.

Elevated glycolysis is a common metabolic trait of cancer, but what drives such metabolic reprogramming remains incompletely clear. We report here a novel transcriptional repressor-mediated negative regulation of glycolysis. ZBTB7A, a member of the POK (POZ/BTB and Krüppel) transcription repressor family, directly binds to the promoter and represses the transcription of critical glycolytic genes, including GLUT3, PFKP, and PKM. Analysis of The Cancer Genome Atlas (TCGA) data sets reveals that the ZBTB7A locus is frequently deleted in many human tumors. Significantly, reduced ZBTB7A expression correlates with up-regulation of the glycolytic genes and poor survival in colon cancer patients. Remarkably, while ZBTB7A-deficient tumors progress exceedingly fast, they exhibit an unusually heightened sensitivity to glycolysis inhibition. Our study uncovers a novel tumor suppressor role of ZBTB7A in directly suppressing glycolysis.

A Golgi-Located Transmembrane Nine Protein Gene TMN11 Functions in Manganese/Cadmium Homeostasis and Regulates Growth and Seed Development in Rice.

Metal transporters play crucial roles in plant nutrition, development, and metal homeostasis. To date, several multi-proteins have been identified for metal transport across the plasma membrane and tonoplast. Nevertheless, Golgi endomembrane metal carriers and their mechanisms are less documented. In this study, we identified a new transmembrane nine (TMN) family gene, TMN11, which encodes a Mn transport protein that was localized to the cis-Golgi endomembrane in rice. OsTMN11 contains a typically conserved long luminal N-terminal domain and nine transmembrane domains. OsTMN11 was ubiquitously expressed over the lifespan of rice and strongly upregulated in young rice under excess Mn(II)/Cd(II) stress. Ectopic expression of OsTMN11 in an Mn-sensitive pmr1 mutant (PMR1 is a Golgi-resident Mn exporter) yeast (Saccharomyces cerevisiae) restored the defective phenotype and transported excess Mn out of the cells. As ScPMR1 mediates cellular Mn efflux via a vesicle-secretory pathway, the results suggest that OsTMN11 functions in a similar manner. OsTMN11 knockdown (by RNAi) compromised the growth of young rice, manifested as shorter plant height, reduced biomass, and chlorosis under excessive Mn and Cd conditions. Two lifelong field trials with rice cropped in either normal Mn supply conditions or in Cd-contaminated farmland demonstrated that knockdown of OsTMN11 impaired the capacity of seed development (including panicle, spikelet fertility, seed length, grain weight, etc.). The mature RNAi plants contained less Mn but accumulated Cd in grains and rice straw, confirming that OsTMN11 plays a fundamental role in metal homeostasis associated with rice growth and development even under normal Mn supply conditions.