Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.

The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.

Somatic mutation landscapes at single-molecule resolution.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

Ascorbic acid-mediated reactive oxygen species homeostasis modulates the switch from tapetal cell division to cell differentiation in Arabidopsis.

The major antioxidant L-ascorbic acid (AsA) plays important roles in plant growth, development, and stress responses. However, the importance of AsA concentration and the regulation of AsA metabolism in plant reproduction remain unclear. In Arabidopsis (Arabidopsis thaliana) anthers, the tapetum monolayer undergoes cell differentiation to support pollen development. Here, we report that a transcription factor, DEFECTIVE IN TAPETAL DEVELOPMENT AND FUNCTION 1 (TDF1), inhibits tapetal cell division leading to cell differentiation. We identified SKEWED5-SIMILAR 18 (SKS18) as a downstream target of TDF1. Enzymatic assays showed that SKS18, annotated as a multicopper oxidase-like protein, has ascorbate oxidase activity, leading to AsA oxidation. We also show that VITAMIN C DEFECTIVE1 (VTC1), an AsA biosynthetic enzyme, is negatively controlled by TDF1 to maintain proper AsA contents. Consistently, either knockout of SKS18 or VTC1 overexpression raised AsA concentrations, resulting in extra tapetal cells, while SKS18 overexpression in tdf1 or the vtc1-3 tdf1 double mutant mitigated their defective tapetum. We observed that high AsA concentrations caused lower accumulation of reactive oxygen species (ROS) in tapetal cells. Overexpression of ROS scavenging genes in tapetum restored excess cell divisions. Thus, our findings demonstrate that TDF1-regulated AsA balances cell division and cell differentiation in the tapetum through governing ROS homeostasis.

A point mutation in the meiotic crossover formation gene HEI10/TFS2 leads to thermosensitive genic sterility in rice.

Thermosensitive genic female sterility (TGFS) is a promising property to be utilized for hybrid breeding. Here, we identified a rice TGFS line, tfs2, through an ethyl methyl sulfone (EMS) mutagenesis strategy. This line showed sterility under high temperature and became fertile under low temperature. Few seeds were produced when the tfs2 stigma was pollinated, indicating that tfs2 is female sterile. Gene cloning and genetic complementation showed that a point mutation from leucine to phenylalanine in HEI10 (HEI10tfs2), a crossover formation protein, caused the TGFS trait of tfs2. Under high temperature, abnormal univalents were formed, and the chromosomes were unequally segregated during meiosis, similar to the reported meiotic defects in oshei10. Under low temperature, the number of univalents was largely reduced, and the chromosomes segregated equally, suggesting that crossover formation was restored in tfs2. Yeast two-hybrid assays showed that HEI10 interacted with two putative protein degradation-related proteins, RPT4 and SRFP1. Through transient expression in tobacco leaves, HEI10 were found to spontaneously aggregate into dot-like foci in the nucleus under high temperature, but HEI10tfs2 failed to aggregate. In contrast, low temperature promoted HEI10tfs2 aggregation. This result suggests that protein aggregation at the crossover position contributes to the fertility restoration of tfs2 under low temperature. In addition, RPT4 and SRFP1 also aggregated into dot-like foci, and these aggregations depend on the presence of HEI10. These findings reveal a novel mechanism of fertility restoration and facilitate further understanding of HEI10 in meiotic crossover formation.

Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer.

OBJECTIVE: Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations. DESIGN: We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC. RESULTS: We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor geneTrp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth. CONCLUSION: These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers.

Global Burden of Digestive Diseases: A Systematic Analysis of the Global Burden of Diseases Study, 1990 to 2019.

BACKGROUND & AIMS: This study assessed the worldwide burden of digestive diseases between 1990 and 2019. METHODS: We analyzed data from the Global Burden of Diseases study, covering 18 digestive diseases across 204 countries and territories. Key disease burden indicators, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs), were studied. Linear regression analysis was applied to the natural logarithm of age-standardized outcomes to determine the annual percent change. RESULTS: In 2019, there were 7.32 billion incidents and 2.86 billion prevalent cases of digestive diseases, resulting in 8 million deaths and 277 million DALYs lost. Little to no decrease in global age-standardized incidence and prevalence of digestive diseases was observed between 1990 and 2019, with 95,582 and 35,106 cases per 100,000 individuals in 2019, respectively. The age-standardized death rate was 102 per 100,000 individuals. Digestive diseases accounted for a significant portion of the overall disease burden, with more than one-third of prevalent cases having a digestive etiology. Enteric infections were the primary contributor to incidence, death, and DALYs lost, whereas cirrhosis and other chronic liver diseases had the highest prevalence rate. The burden of digestive diseases was inversely related to the sociodemographic index, with enteric infections being the predominant cause of death in low and low-middle quintiles and colorectal cancer in the high quintile. CONCLUSIONS: Despite significant reductions in deaths and DALYs due to digestive diseases from 1990 to 2019, they remain prevalent. A significant disparity in the burden of digestive diseases exists among countries with different development levels.

Development of a Bioorthogonal Click-to-Release Reaction for Hydrogen Polysulfide (H2Sn) Detection.

In this study, we present an innovative "click-to-release" strategy for the design of highly specific H2Sn bioorthogonal probes that undergo a specific click reaction with H2Sn and release fluorophores by a following rearrangement. A library of cyclooctyne derivatives was established and successfully demonstrated the availability of the release strategy. Then, a model probe CM-CT was synthesized, which can achieve effective fluorophore release (>80%) in the presence of a H2Sn donor. To further validate the application of this class of probes, a new probe QN-RHO-CT based on Rhodamine 110 was developed. This probe showed good water solubility (>160 µM) and fast release kinetics and can achieve selective H2Sn detection in living cells. We used this probe to study the process of H2S-mediated protein S-persulfidation and demonstrated that excess H2S would directly react with protein persulfides to generate H2S2 and reduce the persulfides to thiols. Additionally, we elucidated the click-to-release mechanism in our design through a detailed mechanistic study, confirming the generation of the key intermediate α, ß-unsaturated cyclooctanethione. This bioorthogonal click-to-release reaction provides a useful tool for investigating the function of H2Sn and paves the way for biological studies on H2Sn.

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.

Integrative analysis of cuproptosis-associated genes for predicting immunotherapy response in single-cell and multi-cohort studies.

BACKGROUND: The role of genes associated with the cuproptosis cell signaling pathway in prognosis and immunotherapy in ovarian cancer (OC) has been extensively investigated. In this study, we aimed to explore these mechanisms and establish a prognostic model for patients with OC using bioinformatics techniques. METHODS: We obtained the single cell sequencing data of ovarian cancer from the Gene Expression Omnibus (GEO) database and preprocessed the data. We analyzed a variety of factors including cuproptosis cell signal score, transcription factors, tumorigenesis and progression signals, gene set variation analysis (GSVA) and intercellular communication. Differential gene analysis was performed between groups with high and low cuproptosis cell signal scores, as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Using bulk RNA sequencing data from The Cancer Genome Atlas, we used the least absolute shrinkage and selection operator (LASSO)-Cox algorithm to develop cuproptosis cell signaling pathword-related gene signatures and validated them with GEO ovarian cancer datasets. In addition, we analyzed the inherent rules of the genes involved in building the model using a variety of bioinformatics methods, including immune-related analyses and single nucleotide polymorphisms. Molecular docking is used to screen potential therapeutic drugs. To confirm the analysis results, we performed various wet experiments such as western blot, cell counting kit 8 (CCK8) and clonogenesis tests to verify the role of the Von Willebrand Factor (VWF) gene in two ovarian cancer cell lines. RESULTS: Based on single-cell data analysis, we found that endothelial cells and fibroblasts showed active substance synthesis and signaling pathway activation in OC, which further promoted immune cell suppression, cancer cell proliferation and metastasis. Ovarian cancer has a high tendency to metastasize, and cancer cells cooperate with other cells to promote disease progression. We developed a signature consisting of eight cuproptosis-related genes (CRGs) (MAGEF1, DNPH1, RARRES1, NBL1, IFI27, VWF, OLFML3 and IGFBP4) that predicted overall survival in patients with ovarian cancer. The validity of this model is verified in an external GEO validation set. We observed active infiltrating states of immune cells in both the high- and low-risk groups, although the specific cells, genes and pathways of activation differed. Gene mutation analysis revealed that TP53 is the most frequently mutated gene in ovarian cancer. We also predict small molecule drugs associated with CRGs and identify several potential candidates. VWF was identified as an oncogene in ovarian cancer, and the protein was expressed at significantly higher levels in tumor samples than in normal samples. The high-score model of the cuproptosis cell signaling pathway was associated with the sensitivity of OC patients to immunotherapy. CONCLUSIONS: Our study provides greater insight into the mechanisms of action of genes associated with the cuproptosis cell signaling pathway in ovarian cancer, highlighting potential targets for future therapeutic interventions.

Racial Disparities in Liver Disease Mortality Trends Among Black and White Populations in the United States, 1999-2020: An Analysis of CDC WONDER Database.

INTRODUCTION: Liver disease is a significant public health problem in the United States, with notable racial disparities in mortality. This study examines liver disease mortality trends among Black and White populations during 1999-2020. METHODS: We used CDC WONDER database to ascertain liver disease age-standardized mortality rates in Black and White Americans. Annual percent change was calculated. Age-standardized absolute rate difference and rate ratios were computed by subtracting and dividing the White population's rate from that of the Black population. RESULTS: Liver diseases accounted for 171,627 Black and 1,314,903 White deaths during 1999-2020. Age-standardized mortality rates for Blacks decreased from 22.5 to 20.1 per 100,000 person-years (annual percentage change -0.4%, -0.6% to -0.2%), whereas an increase was observed for Whites, from 17.9 to 25.3 per 100,000 person-years (annual percentage change 1.4%, 1.4% to 1.7%). The rate ratio decreased from 1.26 (1.22-1.29) in 1999 to 0.79 (0.78-0.81) in 2020. This pattern was evident in all census regions, more pronounced among the younger (age 25-64 years) than older (age 65+ years) population and observed across different urbanization levels. The pattern may be attributable to increasing alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease-related deaths in Whites and tapering in viral hepatitis and primary liver cancer-related deaths in Blacks. Despite notable improvement, racial disparities persist in primary liver cancer and viral hepatitis among the Black population. DISCUSSION: The rise in alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease-related deaths among Whites, and enduring liver cancer and viral hepatitis disparities in the Black population, underscores the urgent need for tailored public health interventions.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Vaginal microbial profile of cervical cancer patients receiving chemoradiotherapy: the potential involvement of Lactobacillus iners in recurrence.

The vaginal microbiome is an immune defense against reproductive diseases and can serve as an important biomarker for cervical cancer. However, the intrinsic relationship between the recurrence and the vaginal microbiome in patients with cervical cancer before and after concurrent chemoradiotherapy is poorly understood. Here, we analyzed 125 vaginal microbial profiles from a patient cohort of stage IB-IVB cervical cancer using 16S metagenomic sequencing and deciphered the microbial composition and functional characteristics of the recurrent and non-recurrent both before and after chemoradiotherapy. We demonstrated that the abundance of beneficial bacteria and stability of the microbial community in the vagina decreased in the recurrence group, implying the unique characteristics of the vaginal microbiome for recurrent cervical cancer. Moreover, using machine learning, we identified Lactobacillus iners as the most important biomarker, combined with age and other biomarkers (such as Ndongobacter massiliensis, Corynebacterium pyruviciproducens ATCC BAA-1742, and Prevotella buccalis), and could predict cancer recurrence phenotype before chemoradiotherapy. This study prospectively employed rigorous bioinformatics analysis and highlights the critical role of vaginal microbiota in post-treatment cervical cancer recurrence, identifying promising biomarkers with prognostic significance in the context of concurrent chemoradiotherapy for cervical cancer. The role of L. iners in determining chemoradiation resistance in cervical cancer warrants further detailed investigation. Our results expand our understanding of cervical cancer recurrence and help develop better strategies for prognosis prediction and personalized therapy.

Single-cell transcriptomics dissects the transcriptome alterations of hematopoietic stem cells in myelodysplastic neoplasms.

BACKGROUND: Myelodysplastic neoplasms (MDS) are myeloid neoplasms characterized by disordered differentiation of hematopoietic stem cells and a predisposition to acute myeloid leukemia (AML). The underline pathogenesis remains unclear. METHODS: In this study, the trajectory of differentiation and mechanisms of leukemic transformation were explored through bioinformatics analysis of single-cell RNA-Seq data from hematopoietic stem and progenitor cells (HSPCs) in MDS patients. RESULTS: Among the HSPC clusters, the proportion of common myeloid progenitor (CMP) was the main cell cluster in the patients with excess blasts (EB)/ secondary AML. Cell cycle analysis indicated the CMP of MDS patients were in an active proliferative state. The genes involved in the cell proliferation, such as MAML3 and PLCB1, were up-regulated in MDS CMP. Further validation analysis indicated that the expression levels of MAML3 and PLCB1 in patients with MDS-EB were significantly higher than those without EB. Patients with high expression of PLCB1 had a higher risk of transformation to AML. PLCB1 inhibitor can suppress proliferation, induce cell cycle arrest, and activate apoptosis of leukemic cells in vitro. CONCLUSION: This study revealed the transcriptomic change of HSPCs in MDS patients along the pseudotime and indicated that PLCB1 plays a key role in the transformation of MDS into leukemia.

The Residual Activity of Fatty Acyl-CoA Reductase Underlies Thermo-Sensitive Genic Male Sterility in Rice.

Photoperiod/thermo-sensitive genic male sterility (P/TGMS) is critical for rice two-line hybrid system. Previous studies showed that slow development of pollen is a general mechanism for sterility-to-fertility conversion of TGMS in Arabidopsis. However, whether this mechanism still exists in rice is unknown. Here, we identified a novel rice TGMS line, ostms16, which exhibits abnormal pollen exine under high temperature and fertility restoration under low temperature. In mutant, a single base mutation of OsTMS16, a fatty acyl-CoA reductase (FAR), reduced its enzyme activity, leading to defective pollen wall. Under high temperature, the mOsTMS16M549I couldn't provide sufficient protection for the microspores. Under low temperature, the enzyme activity of mOsTMS16M549I is closer to that of OsTMS16, so that the imperfect exine could still protect microspore development. These results indicated whether the residual enzyme activity in mutant could meet the requirement in different temperature is a determinant factor for fertility conversion of P/TGMS lines. Additionally, we previously found that res2, the mutant of a polygalacturonase for tetrad pectin wall degradation, restored multiple TGMS lines in Arabidopsis. In this study, we proved that the osres2 in rice restored the fertility of ostms16, indicating the slow development is also suitable for the fertility restoration in rice.

Cytotoxicity effect and transcriptome analysis of PCV3-infected cells revealed potential viral pathogenic mechanisms.

Porcine circovirus type 3 (PCV3) has become an important pathogen in the global swine industry and poses a threat to pig health, but its pathogenic mechanism remains unknown. In this study, we constructed an innovative, linear infectious clone of PCV3 for rescuing the virus, and explored the transcriptome of infected cells to gain insights into its pathogenic mechanisms. Subsequently, an in vivo experiment was conducted to evaluate the pathogenicity of the rescued virus in pig. PCV3 nucleic acid was distributed across various organs, indicating systemic circulation via the bloodstream and viremia. Immunohistochemical staining also revealed a significant presence of PCV3 antigens in the spleen, lungs, and lymph nodes, indicating that PCV3 had tropism for these organs. Transcriptome analysis of infected ST cells revealed differential expression of genes associated with apoptosis, immune responses, and cellular metabolism. Notably, upregulation of genes related to the hypoxia-inducible factor-1 pathway, glycolysis, and the AGE/RAGE pathway suggests activation of inflammatory responses, ultimately leading to onset of disease. These findings have expanded our understanding of PCV3 pathogenesis, and the interplay between PCV3 and host factors.

Higher-Than-Expected Burden of Alcohol-Related Liver Diseases During COVID-19 Pandemic in the USA, with a Tapering Trend.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has led to an increase in alcohol-related liver disease (ALD). The aim of this study was to evaluate the magnitude of ALD hospitalization surge during the pandemic in the USA. MAIN MEASURES: A retrospective trend analysis of adult hospitalizations for ALD at acute care hospitals across the USA in 2016-2020 was conducted. Hospitalizations were identified using the International Classification of Diseases 10 codes for ALD and non-alcoholic-related liver disease. Outcomes measured included the predicted monthly volume of hospitalizations for ALD and inpatient mortality rates. KEY RESULTS: During the 2020 pandemic, monthly ALD hospitalizations reached 10,247 representing a 20.7% increase compared to pre-pandemic monthly average of 8490. Additional 4163 ALD hospitalizations occurred during the pandemic, in addition to a pre-pandemic uptrend. The peak of excess ALD hospitalizations was from May to October (monthly excess of 1138) decreasing to monthly excess of 280 in November and December. The excess increase in ALD hospitalizations was primarily observed in young adults, totaling 5256 cases affecting both male (2101 excess cases) and females (2041 excess cases). The age-standardized monthly mortality rate during the pandemic was notably higher than expected at 0.9% (95% CI 0.4 to 1.4%). CONCLUSIONS: The COVID-19 pandemic led to a significant increase in ALD hospitalizations, above and beyond the pre-existing upward trend, which tapered towards the end of 2020, suggesting a possible decline in the pandemic's impact. The excess increase in ALD hospitalizations was observed primarily in young adults and affected both males and females. These findings highlight the need for further attention to the long-term consequences of the pandemic.

Rising Obesity-Associated Mortality in Men: Exploration of Gender Disparity from the Global Burden of Disease Study, 1990-2019.

OBJECTIVES: The global rise in overweight, obesity, and related diseases is undeniable; however, the pathogenesis of obesity and obesity-associated diseases is heterogeneous, with varied complications and a discordant response to treatment. Intriguingly, men have a shorter lifespan than women, despite being half as likely to be obese. This paradox suggests a potential gender disparity in the impact of obesity on mortality, with men potentially being more vulnerable to obesity-associated health risks. METHODS: This retrospective study utilized Global Burden of Diseases data from 204 countries/territories to bridge the knowledge gap in understanding gender disparities in obesity-related mortality. Outcomes were obesity-associated mortality, years of life lost, years lived with disability, and disability-adjusted life years (DALYs). RESULTS: In 2019, the global overweight/obesity-related disease burden reached 160.2 million DALYs, with 5.02 million associated deaths. From 1990 to 2019, the age-standardized death rates increased in males (from 58.19 to 66.55 per 100,000 person-years, APC = 0.36%, 95% CI: 0.30 to 0.42%, P < 0.001), while females experienced a decrease in age-standardized death rates (from 59.31 to 58.14 per 100,000 person-years, APC = -0.22%, 95% CI: -0.29% to -0.14%, P < 0.001). Age-standardized DALYs increased more in males (1632.5 to 2070.34 per 100,000 years, APC = 0.74%, 95% CI: 0.70% to 0.78%, P < .001) compared to females (1618.26 to 1789.67 per 100,000 years, APC = 0.24%, 95% CI: 0.19% to 0.29%, P < 0.001). Disparities were more pronounced in countries with a higher socioeconomic status and predominantly affected younger populations. CONCLUSIONS: Overweight/obesity-related morbidity and mortality are higher among male sex. Identifying differences in pathogenesis, complications and treatment response is crucial to develop targeted interventions and equitable public health policies to combat this global burden.

ENDOLUMINAL RADIOFREQUENCY ABLATION WITH STENTING VS STENTING ONLY IN PATIENTS WITH MALIGNANT BILIARY OBSTRUCTION: A META-ANALYSIS OF RANDOMISED TRIALS.

INTRODUCTION: Endoluminal radiofrequency ablation (RFA) is a palliative treatment for patients suffering from malignant biliary obstruction. We aimed to conduct a meta-analysis to evaluate the impact of RFA on stent patency, patient survival, and adverse events. METHODS: Major databases were searched through November 2023 for patients who underwent stenting with or without RFA for extra-hepatic malignant biliary obstruction. A random effects model was employed for analysis and results conveyed using relative risk ratio with 95% confidence interval. RESULTS: Nine RCTs involving 750 subjects (n=374 RFA plus stent vs. n=376 stent only) with malignant biliary obstruction were included. Meta-analysis revealed similar risks of stent patency at 3 months (RR = 1.01; 95% CI [0.92 - 1.11], I2=4% for RFA plus stenting vs. stent only). Meta-analysis showed improved survival at 6 months (RR = 0.84; 95% CI [0.73 - 0.96], I2=21%, P=0.01 for RFA plus stenting vs. stent only). Subgroup analysis comparing plastic vs uncovered metal stents showed that stent patency was unaffected at 3 months (RR = 1.06; 95% CI [0.91 - 1.23]; I2=17%). Subgroup analysis showed that patients with cholangiocarcinoma experienced an overall survival benefit with RFA plus stenting vs. stent only (P<0.001), however, stent patency remained unaffected (P=0.08). An increased incidence of cholecystitis was noted with RFA plus stent vs. stent only (5.1%; 95% CI [3.1% - 7.8%] vs 0.3%; 95% CI [0.01% - 1.5%], respectively). CONCLUSION: Combining endoluminal RFA and stenting may improve overall survival in patients with malignant biliary obstruction. RFA did not impact stent patency significantly.

Cold Endoscopic Mucosal Resection (c-EMR) of Nonpedunculated Colorectal Polyps ≥20 mm: A Systematic Review and Meta-analysis.

BACKGROUND: There is increasing evidence that cold endoscopic mucosal resection (c-EMR) can effectively treat large colorectal polyps. We aim to appraise the current literature and evaluate outcomes following c-EMR for nonpedunculated colonic polyps ≥20 mm. METHODS: Major databases were searched. Primary outcomes included recurrence rate and adverse events. Meta-analysis was performed using a random-effects model. RESULTS: Nine articles were included in the final analysis, which included 817 patients and 1077 colorectal polyps. Average polyp size was 28.8 (±5.1) mm. The pooled recurrence rate of polyps of any histology at 4 to 6 months was 21.0% (95% CI: 9.0%-32.0%, P <0.001, I2 =97.3, P <0.001). Subgroup analysis showed that recurrence was 10% for proximal lesions (95% CI: 0.0%-20.0%, P =0.054, I2 =93.7%, P =0.054) and 9% for distal lesions (95% CI: 2.0%-21.0%, P =0.114, I2 =95.8%, P =0.114). Furthermore, subgroup analysis showed that recurrence was 12% for adenoma (95% CI: 4.0%-19.0%, P =0.003, I2 =98.0%, P =0.003), and 3% for sessile serrated polyps (95% CI: 1.0%-5.0%, P =0.002, I2 =34.4%, P =0.002). Post-polypectomy bleeding occurred in 1% (n=8/817) of patients, whereas abdominal pain occurred in 0.2% (n=2/817) of patients. CONCLUSIONS: C-EMR for nonpedunculated colorectal polyps ≥20 mm shows an excellent safety profile with a very low rate of delayed bleeding as well as significantly less recurrence for sessile serrated polyps than adenomas.

Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish.

Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses.