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Abstract Background Serum (1,3)-β-D-glucan (BDG) detection for diagnosis of Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus (HIV) immunocompromised patients lacks intensive care unit (ICU)-specific data. We aimed to assess its performance and determine the optimal cutoff for PJP in ICU population. Methods This retrospective study included critically ill non-HIV immunocompromised patients admitted to a medical ICU with suspected pneumonia, undergoing simultaneous microbiological testing for P. jirovecii on lower respiratory tract specimens and serum BDG. Confounders affecting BDG positivity were explored by multivariable logistic regression. Optimal cut-offs were derived from Youden’s index for the entire cohort and subgroups stratified by confounders. Diagnostic performance of serum BDG was estimated at different cutoffs. Results Of 400 patients included, 42% were diagnosed with PJP and 58.3% had positive serum BDG. Serum BDG’s area under the receiver operating characteristic curve was 0.90 (0.87–0.93). At manufacturer’s 150 pg/ml cut-off, serum BDG had high sensitivity and negative predictive value (94%), but low specificity and positive predictive value (67%). Confounders associated with a positive serum BDG in PJP diagnosis included IVIG infusion within 3 days (odds ratio [OR] 9.24; 95% confidence interval [CI] 4.09–20.88, p

Abstract Tissue-derived extracellular vesicles (EVs) are emerging as pivotal players to maintain organ homeostasis, which show promise as a next-generation candidate for medical use with extensive source. However, the detailed function and therapeutic potential of tissue EVs remain insufficiently studied. Here, through bulk and single-cell RNA sequencing analyses combined with ultrastructural tissue examinations, we first reveal that in situ liver tissue EVs (LT-EVs) contribute to the intricate liver regenerative process after partial hepatectomy (PHx), and that hepatocytes are the primary source of tissue EVs in the regenerating liver. Nanoscale and proteomic profiling further identify that the hepatocyte-specific tissue EVs (Hep-EVs) are strengthened to release with carrying proliferative messages after PHx. Moreover, targeted inhibition of Hep-EV release via AAV-shRab27a in vivo confirms that Hep-EVs are required to orchestrate liver regeneration. Mechanistically, Hep-EVs from the regenerating liver reciprocally stimulate hepatocyte proliferation by promoting cell cycle progression through Cyclin-dependent kinase 1 (Cdk1) activity. Notably, supplementing with Hep-EVs from the regenerating liver demonstrates translational potential and ameliorates insufficient liver regeneration. This study provides a functional and mechanistic framework showing that the release of regenerative Hep-EVs governs rapid liver regeneration, thereby enriching our understanding of physiological and endogenous tissue EVs in organ regeneration and therapy.

Abstract Background Cliffs are recognized as one of the most challenging environments for plants, characterized by harsh conditions such as drought, infertile soil, and steep terrain. However, they surprisingly host ancient and diverse plant communities and play a crucial role in protecting biodiversity. The Taihang Mountains, which act as a natural boundary in eastern China, support a rich variety of plant species, including many unique to cliff habitats. However, it is little known how cliff plants adapt to harsh habitats and the demographic history in this region. Results To better understand the demographic history and adaptation of cliff plants in this area, we analyzed the chromosome-level genome of a representative cliff plant, T. rupestris var. ciliata, which has a genome size of 769.5 Mb, with a scaffold N50 of 104.92 Mb. The rapid expansion of transposable elements may have contributed to the increasing genome and its ability to adapt to unique and challenging cliff habitats. Comparative analysis of the genome evolution between Taihangia and non-cliff plants in Rosaceae revealed a significant expansion of gene families associated with oxidative phosphorylation, which is likely a response to the abiotic stresses faced by cliff plants. This expansion may explain the long-term adaptation of Taihangia to harsh cliff environments. The effective population size of the two varieties has continuously decreased due to climatic fluctuations during the Quaternary period. Furthermore, significant differences in gene expression between the two varieties may explain the varied leaf phenotypes and adaptations to harsh conditions in different natural distributions. Conclusion Our study highlights the extraordinary adaptation of T. rupestris var. ciliata, shedding light on the evolution of cliff plants worldwide.

Abstract Introduction The impact of immunosuppression on prognosis of carbapenem-resistant organism (CRO) bloodstream infection (BSI) remains unclear. The aim of this study was to clarify the relationship between immunosuppression and mortality of CRO-BSI and to identify the risk factors associated with mortality in immunosuppressed patients. Methods This retrospective study included 279 patients with CRO-BSI from January 2018 to March 2023. Clinical characteristics and outcomes were compared between the immunosuppressed and immunocompetent patients. The relationship between immunosuppression and 30-day mortality after BSI onset was assessed through logistic-regression analysis, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Factors associated with mortality in immunosuppressed patients were analyzed using multivariable logistic regression analysis. Results A total of 88 immunocompetent and 191 immunosuppressed patients were included, with 30-day all-cause mortality of 58.8%. Although the 30-day mortality in immunosuppressed patients was significantly higher than in immunocompetent patients (46.6% vs. 64.4%, P = 0.007), immunosuppression was not an independent risk factor for mortality in multivariate logistic regression analysis (odds ratio [OR] 3.53, 95% confidence interval [CI] 0.74–18.89; P = 0.123), PSM (OR 1.38, 95% CI 0.60–3.18; P = 0.449,) or IPTW (OR 1.40, 95% CI 0.58–3.36; P = 0.447). For patients with CRO-BSI, regardless of immune status, appropriate antibiotic therapy was associated with decreased 30-day mortality, while Charlson comorbidity index (CCI), intensive care unit (ICU)-acquired infection and thrombocytopenia at CRO-BSI onset were associated with increased mortality. Conclusion Despite the high mortality rate of CRO-BSI, immunosuppression did not affect the mortality. Appropriate antibiotic therapy is crucial for improving the prognosis of CRO-BSI, regardless of the immune status.

Abstract Background The recently identified methylation patterns specific to cell type allows the tracing of cell death dynamics at the cellular level in health and diseases. This study used COVID-19 as a disease model to investigate the efficacy of cell-specific cell-free DNA (cfDNA) methylation markers in reflecting or predicting disease severity or outcome. Methods Whole genome methylation sequencing of cfDNA was performed for 20 healthy individuals, 20 cases with non-hospitalized COVID-19 and 12 cases with severe COVID-19 admitted to intensive care unit (ICU). Differentially methylated regions (DMRs) and gene ontology pathway enrichment analyses were performed to explore the locus-specific methylation difference between cohorts. The proportion of cfDNA derived from lung and immune cells to a given sample (i.e. tissue fraction) at cell-type resolution was estimated using a novel algorithm, which reflects lung injuries and immune response in COVID-19 patients and was further used to evaluate clinical severity and patient outcome. Results COVID‑19 patients had globally reduced cfDNA methylation level compared with healthy controls. Compared with non-hospitalized COVID-19 patients, the cfDNA methylation pattern was significantly altered in severe patients with the identification of 11,156 DMRs, which were mainly enriched in pathways related to immune response. Markedly elevated levels of cfDNA derived from lung and more specifically alveolar epithelial cells, bronchial epithelial cells, and lung endothelial cells were observed in COVID-19 patients compared with healthy controls. Compared with non-hospitalized patients or healthy controls, severe COVID-19 had significantly higher cfDNA derived from B cells, T cells and granulocytes and lower cfDNA from natural killer cells. Moreover, cfDNA derived from alveolar epithelial cells had the optimal performance to differentiate COVID-19 with different severities, lung injury levels, SOFA scores and in-hospital deaths, with the area under the receiver operating characteristic curve of 0.958, 0.941, 0.919 and 0.955, respectively. Conclusion Severe COVID-19 has a distinct cfDNA methylation signature compared with non-hospitalized COVID-19 and healthy controls. Cell type-specific cfDNA methylation signature enables the tracing of COVID-19 related cell deaths in lung and immune cells at cell-type resolution, which is correlated with clinical severities and outcomes, and has extensive application prospects to evaluate tissue injuries in diseases with multi-organ dysfunction.

Abstract Organic heterostructures (OHTs) with the desired geometry organization on micro/nanoscale have undergone rapid progress in nanoscience and nanotechnology. However, it is a significant challenge to elucidate the epitaxial-growth process for various OHTs composed of organic units with a lattice mismatching ratio of > 3%, which is unimaginable for inorganic heterostructures. Herein, we have demonstrated a vivid visualization of the morphology evolution of epitaxial-growth based on a doped interfacial-layer, which facilitates the comprehensive understanding of the hierarchical self-assembly of core-shell OHT with precise spatial configuration. Significantly, the barcoded OHT with periodic shells obviously illustrate the shell epitaxial-growth from tips to center parts along the seeded rods for forming the core-shell OHT. Furthermore, the diameter, length, and number of periodic shells were modulated by finely tuning the stoichiometric ratio, crystalline time, and temperature, respectively. This epitaxial-growth process could be generalized to organic systems with facile chemical/structural compatibility for forming the desired OHTs.

Abstract Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010–37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

IntroductionObesity is a multi-factorial disease frequently associated with poor nutritional habits and linked to many detrimental health outcomes. Individuals with obesity are more likely to have increased levels of persistent inflammatory and metabolic dysregulation. The goal of this study was to compare four dietary patterns differentiated by macronutrient content in a postmenopausal model. Dietary patterns were high carbohydrate (HC), high fat (HF), high carbohydrate plus high fat (HCHF), and high protein (HP) with higher fiber.MethodsChanges in body weight and glucose levels were measured in female, ovariectomized C57BL/6 mice after 15 weeks of feeding. One group of five mice fed the HCHF diet was crossed over to the HP diet on day 84, modeling a 21-day intervention. In a follow-up study comparing the HCHF versus HP dietary patterns, systemic changes in inflammation, using an 80-cytokine array and metabolism, by untargeted liquid chromatography-mass spectrometry (LCMS)-based metabolomics were evaluated.ResultsOnly the HF and HCHF diets resulted in obesity, shown by significant differences in body weights compared to the HP diet. Body weight gains during the two-diet follow-up study were consistent with the four-diet study. On Day 105 of the 4-diet study, glucose levels were significantly lower for mice fed the HP diet than for those fed the HC and HF diets. Mice switched from the HCHF to the HP diet lost an average of 3.7 grams by the end of the 21-day intervention, but this corresponded with decreased food consumption. The HCHF pattern resulted in dramatic inflammatory dysregulation, as all 80 cytokines were elevated significantly in the livers of these mice after 15 weeks of HCHF diet exposure. Comparatively, only 32 markers changed significantly on the HP diet (24 up, 8 down). Metabolic perturbations in several endogenous biological pathways were also observed based on macronutrient differences and revealed dysfunction in several nutritionally relevant biosynthetic pathways.ConclusionOverall, the HCHF diet promoted detrimental impacts and changes linked to several diseases, including arthritis or breast neoplasms. Identification of dietary pattern-specific impacts in this model provides a means to monitor the effects of disease risk and test interventions to prevent poor health outcomes through nutritional modification.

BackgroundThe association between body mass index (BMI) and rapid eye-movement (REM) sleep-related behavioral disorder (RBD) in Parkinson’s disease (PD) remains unknown. Our study was to investigate the association of BMI with RBD in PD patients.MethodsIn this cross-sectional study, a total of 1,115 PD participants were enrolled from Parkinson’s Progression Markers Initiative (PPMI) database. BMI was calculated as weight divided by height squared. RBD was defined as the RBD questionnaire (RBDSQ) score with the cutoff of 5 or more assessed. Univariable and multivariable logistic regression models were performed to examine the associations between BMI and the prevalence of RBD. Non-linear correlations were explored with use of restricted cubic spline (RCS) analysis. And the inflection point was determined by the two-line piecewise linear models.ResultsWe identified 426 (38.2%) RBD. The proportion of underweight, normal, overweight and obese was 2.61, 36.59, 40.36, and 20.44%, respectively. In the multivariate logistic regression model with full adjustment for confounding variables, obese individuals had an odds ratio of 1.77 (95% confidence interval: 1.21 to 2.59) with RBD compared with those of normal weight. In the RCS models with three knots, BMI showed a non-linear association with RBD. The turning points of BMI estimated from piecewise linear models were of 28.16 kg/m2, 28.10 kg/m2, and 28.23 kg/m2 derived from univariable and multivariable adjusted logistic regression models. The effect modification by depression on the association between BMI and RBD in PD was also found in this study. Furthermore, the sensitivity analyses linked with cognition, education, and ethnic groups indicated the robustness of our results.ConclusionThe current study found a significant dose–response association between BMI and RBD with a depression-based difference in the impact of BMI on RBD in PD patients.

The cytochrome P450 enzyme is one of the largest protein families identified in cuticle biosynthesis, plant growth, development, and stress response. In the present study, 28 members of the MdCYP86A family were identified in apple (Malus × domestica Borkh.). Chromosomal localization analysis found that 28 genes were distributed on 13 chromosomes in apple. Phylogenetic and conserved motifs analysis showed that MdCYP86As in apple is evolutionarily most closely related to Arabidopsis thaliana. Each gene contains a cytochrome P450 domain, suggesting that MdCYP86As are highly conserved during the evolution of the species. Cis-acting element analysis of the promoter identified various elements associated with stress response. MdCYP86A21 was cloned in the apple genome to investigate the function of MdCYP86A family genes. MdCYP86A21 responded to abiotic stress, including PEG, NaCl, and ABA. The tissue-specific expression patterns revealed that the highest expression tissue was in flower by real-time quantitative reverse transcription (RT-qPCR). Subcellular localization showed that MdCYP86A21 was localized in the endoplasmic reticulum. Further, the function of MdCYP86A21 to enhance the resistance to PEG and NaCl stress in apple calli was verified. These results contribute to further study on the function of MdCYP86As and provide a molecular basis for the study of apple stress tolerance.

Abstract Limited endoscopic sphincterotomy (EST) combined with endoscopic papillary balloon dilation (EPBD) is widely used. However, the optimal duration of small balloon dilation in choledocholithiasis remains controversial. We aimed to determine the optimal duration for 10 mm diameter balloon dilation after limited EST in choledocholithiasis. In this randomized controlled clinical trial, 320 patients were randomly assigned to receive small balloon dilation (10 mm in diameter) for 1 min (n = 160) or 3 min (n = 160) after deep bile duct cannulation. No significant difference in success rate of stone extraction between the two groups was observed. The incidence of post-ERCP pancreatitis (PEP) was higher in the 1 min group (10.6%) than in the 3 min group (4.4%) (P = 0.034). The logistic regression analysis showed that guidewire into the pancreatic duct, cannulation time > 5 min and 1 min balloon dilation were independent risk factors for PEP. There were no significant differences in other post-ERCP adverse events such as acute cholangitis, bleeding, perforation, etc. between the two groups. In conclusion, 3 min in duration was determined to be the optimal dilation condition for the removal of common bile duct stones.

Plants encounter numerous adversities during growth, necessitating the identification of common stress activators to bolster their resistance. However, the current understanding of these activators’ mechanisms remains limited. This study identified three anti-stress activators applicable to apple trees, all of which elevate plant proline content to enhance resistance against various adversities. The results showed that the application of these sugar substitutes increased apple proline content by two to three times compared to the untreated group. Even at a lower concentration, these activators triggered plant stress resistance without compromising apple fruit quality. Therefore, these three sugar substitutes can be exogenously sprayed on apple trees to augment proline content and fortify stress resistance. Given their effectiveness and low production cost, these activators possess significant application value. Since they have been widely used in the food industry, they hold potential for broader application in plants, fostering apple industry development.

Angelica dahurica is a kind of Chinese traditional herbs with economic and ornament value, widely distributed in China. Despite its significance, there have been limited comprehensive investigations on the genome of A. dahurica, particularly regarding mitochondrial genomes. To investigate the conversion between mitochondrial genome and chloroplast genome, a complete and circular mitochondrial genome was assembled using Oxford Nanopore Technologies (ONT) long reads. The mitochondrial genome of A. dahurica had a length of 228,315 base pairs (bp) with 45.06% GC content. The mitochondrial genome encodes 56 genes, including 34 protein-coding genes, 19 tRNA genes and 3 rRNA genes. Moreover, we discovered that 9 homologous large fragments between chloroplast genome and mitochondrial genome based on sequence similarity. This is the first report for A. dahurica mitochondrial genome, which could provide an insight for communication between plastid genome, and also give a reference genome for medicinal plants within the Angelica family.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.

Cutaneous carcinoma is one of the most common neoplasm tumors in the West. Its incidence rate is one of the fastest growing tumors in China. The Krüppel-like factor 6 (KLF6) is a latent tumor suppressor. Decreased KLF6 is related to the occurrence and progression of many cancers in human. Our previous studies have demonstrated that KLF6 was down-regulation in cutaneous malignant melanoma (CMM), and was significant correlated with ulcer, lymph node metastasis and clinical stage, suggesting that KLF6 loss is expected to become a biological indicator of poor prognosis in CMM patients. In this research, we would further study the features of KLF6 in the malignant progression of CMM. The expression of KLF6 was up-regulated by lentivirus infection containing KLF6, and short hairpin RNA (shRNA) was used for knockdown of KLF6 in CMM cells. Western blot, RT-qpcr, CCK8 assay, transwell migration assays, wound healing assay and flow cytometry were used to test the role of KLF6 in the CMM. We found that reduced expression of KLF6 significantly enhanced proliferation, migration and invasion. Moreover, KLF6 induced CMM cell apoptosis and G1 cycle arrest. The decreased KLF6 expression is expected to be a biological indicator of poor prognosis in CMM patients.

Abstract Background RNA splicing plays significant roles in fundamental biological activities. However, our knowledge about the roles of alternative splicing and underlying mechanisms during spermatogenesis is limited. Results Here, we report that Serine/arginine-rich splicing factor 2 (SRSF2), also known as SC35, plays critical roles in alternative splicing and male reproduction. Male germ cell-specific deletion of Srsf2 by Stra8-Cre caused complete infertility and defective spermatogenesis. Further analyses revealed that deletion of Srsf2 disrupted differentiation and meiosis initiation of spermatogonia. Mechanistically, by combining RNA-seq data with LACE-seq data, we showed that SRSF2 regulatory networks play critical roles in several major events including reproductive development, spermatogenesis, meiotic cell cycle, synapse organization, DNA recombination, chromosome segregation, and male sex differentiation. Furthermore, SRSF2 affected expression and alternative splicing of Stra8, Stag3 and Atr encoding critical factors for spermatogenesis in a direct manner. Conclusions Taken together, our results demonstrate that SRSF2 has important functions in spermatogenesis and male fertility by regulating alternative splicing.

Abstract Background Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. Methods Real-time quantitative PCR (RT–qPCR) and immunofluorescence were used to analyze the expression of ZFX and WNT3 in CML CD34+ cells compared with normal control cells. Short hairpin RNAs (shRNAs) and clustered regularly interspaced short palindromic repeats/dead CRISPR-associated protein 9 (CRISPR/dCas9) technologies were used to study the role of ZFX in growth and drug response of CML cells. Microarray data were generated to compare ZFX-silenced CML CD34+ cells with their controls. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to study the molecular mechanisms of ZFX to regulate WNT3 expression. RT–qPCR and western blotting were used to study the effect of ZFX on β-catenin signaling. Results We showed that ZFX expression was significantly higher in CML CD34+ cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. Microarray data and subsequent validation revealed that WNT3 transcription was conservatively regulated by ZFX. WNT3 was highly expressed in CML CD34+ cells, and WNT3 regulated the growth and IM response of these cells similarly to ZFX. Moreover, WNT3 overexpression partially rescued ZFX silencing-induced growth inhibition and IM hypersensitivity. ZFX silencing decreased WNT3/β-catenin signaling, including c-MYC and CCND1 expression. Conclusion The present study identified a novel ZFX/WNT3 axis that modulates the growth and IM response of CML stem/progenitor cells.

Abstract Background This meta-analysis was conducted to systematically evaluate the impact of problem-based learning (PBL) and lecture-based learning (LBL) teaching models on students’ learning in surgical education. Methods We systematically searched the publications related to the application of PBL and LBL in surgical courses in PubMed, Embase, Web of Science and Cochrane Library databases, the last retrieval time is September 20, 2022. After screening the literature according to the inclusion and exclusion criteria, extracting data and evaluating the methodological treatment of the included studies, Stata 17.0 software was used to perform meta-analysis. Results Nine studies were included totally. The results showed that compared with LBL, PBL was superior in clinical competence (SMD = 0.81, 95% CI: 0.12 ~ 1.49, P = 0.020) and student satisfaction (SMD = 2.13, 95% CI: 1.11 ~ 3.15, P

Abstract Marginalized populations experience disproportionate rates of preterm birth and early term birth. Exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to reduce length of gestation, but the underlying mechanisms are unknown. In the present study, we characterized the molecular signatures of prenatal PFAS exposure and gestational age at birth outcomes in the newborn dried blood spot metabolome among 267 African American dyads in Atlanta, Georgia between 2016 and 2020. Pregnant people with higher serum perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations had increased odds of an early birth. After false discovery rate correction, the effect of prenatal PFAS exposure on reduced length of gestation was associated with 8 metabolomic pathways and 52 metabolites in newborn dried blood spots, which suggested perturbed tissue neogenesis, neuroendocrine function, and redox homeostasis. These mechanisms explain how prenatal PFAS exposure gives rise to the leading cause of infant death in the United States.

Older individuals with macular diseases, such as age-related macular degeneration, experience central vision loss (CVL) due to degeneration of their photoreceptors and retinal cells. Patients with CVL may experience various vision impairments, including of visual acuity, fixation stability, contrast sensitivity, and stereoacuity. After CVL, most patients develop a preferred retinal locus outside the affected macular region, which serves as a new visual reference. In this review, we provide an overview of the visual function and impairment in individuals with CVL. In addition, the important role of biofeedback training on the visual function and activity of individuals with CVL is also reviewed. Accordingly, the location and development of the preferred retinal loci are discussed. Finally, this review discusses how to conduct biofeedback training to treat individuals with CVL.

Abstract Erlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU‐1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU‐1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c‐MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p‐PLCG1 and p‐Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient‐derived xenograft (PDX) models, AU‐1 monotherapy exhibited remarkable tumor‐inhibiting activity and is synergistic anti‐tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c‐MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.

Copper-induced cell death, also known as cuproptosis, is distinct from other types of cell death such as apoptosis, necrosis, and ferroptosis. It can trigger the accumulation of lethal reactive oxygen species, leading to the onset and progression of aging. The significant increases in copper ion levels in the aging populations confirm a close relationship between copper homeostasis and vascular aging. On the other hand, vascular aging is also closely related to the occurrence of various cardiovascular diseases throughout the aging process. However, the specific causes of vascular aging are not clear, and different living environments and stress patterns can lead to individualized vascular aging. By exploring the correlations between copper-induced cell death and vascular aging, we can gain a novel perspective on the pathogenesis of vascular aging and enhance the prognosis of atherosclerosis. This article aims to provide a comprehensive review of the impacts of copper homeostasis on vascular aging, including their effects on endothelial cells, smooth muscle cells, oxidative stress, ferroptosis, intestinal flora, and other related factors. Furthermore, we intend to discuss potential strategies involving cuproptosis and provide new insights for copper-related vascular aging.

Summary: The zona pellucida (ZP) is an extracellular glycoprotein matrix surrounding mammalian oocytes. Recently, numerous mutations in genes encoding ZP proteins have been shown to be possibly related to oocyte abnormality and female infertility; few reports have confirmed the functions of these mutations in living animal models. Here, we identified a novel heterozygous missense mutation (NM_001376231.1:c.1616C>T, p.Thr539Met) in ZP2 from a primary infertile female. We showed that the mutation reduced ZP2 expression and impeded ZP2 secretion in cell lines. Furthermore, we constructed the mouse model with the mutation (Zp2T541M) using CRISPR-Cas9. Zp2WT/T541M female mice had normal fertility though generated oocytes with the thin ZP, whereas Zp2T541M female mice were completely infertile due to degeneration of oocytes without ZP. Additionally, ZP deletion impaired folliculogenesis and caused female infertility in Zp2T541M mice. Our study not only expands the spectrum of ZP2 mutation sites but also, more importantly, increases the understanding of pathogenic mechanisms of ZP2 mutations.

Abstract Identifying conservation units is crucial for the effective conservation of threatened species. Previous cases are almost exclusively based on large‐scale but coarse sampling for genetic structure analyses. Significant genetic structure can occur within a small range, and thus multiple conservation units may exist in narrowly distributed plants. However, small‐scale genetic structure is often overlooked in conservation planning especially for wind‐pollinated and wind‐dispersed trees, largely due to the absence of dense and elaborate sampling. In this study, we focused on a representative endangered relict plant, Metasequoia glyptostroboides. Using both nuclear microsatellites (nSSRs) and chloroplast DNA (cpDNA) fragments, we sampled across the narrow distribution range of this species and determined its conservation units by exploring its genetic structure and historical demography. cpDNA haplotypes were classified into two groups, but mixed in space, suggesting that the existent wild trees of M. glyptostroboides cannot be divided into different evolutionarily significant units. However, using nSSRs, we detected strong spatial genetic structure, with significant genetic differentiation and weak gene flow between the samples in the east of the species' distribution range and other samples. The divergence between the two nSSR groups was dated to the Last Glacial Maximum (c. 19.6 kya), suggesting that such spatial genetic structure has been maintained for a long term. Therefore, these two nSSR groups should be considered as different conservation units, that is, management units, to protect intergroup genetic variations, which is likely to be the outputs of local adaptation. Our findings highlight the necessity to reveal small‐scale genetic structure and population demography to improve the conservation strategies of evolutionary potential of endangered plants.

Abstract Lead halide perovskites have made remarkable progress in the field of radiation detection owing to the excellent and unique optoelectronic properties. However, the instability and the toxicity of lead‐based perovskites have greatly hindered its practical applications. Alternatively, lead‐free perovskites with high stability and environmental friendliness thus have fascinated significant research attention for direct X‐ray detection. In this review, the current research progress of X‐ray detectors based on lead‐free halide perovskites is focused. First, the synthesis methods of lead‐free perovskites including single crystals and films are discussed. In addition, the properties of these materials and the detectors, which can provide a better understanding and designing satisfactory devices are also presented. Finally, the challenge and outlook for developing high‐performance lead‐free perovskite X‐ray detectors are also provided.

A number of enzymes and transcription factors involved in cuticular wax biosynthesis have been identified in numerous plant species. The pathway of wax biosynthesis is relatively definite. The molecular basis of cuticular wax deposition is still unclear, especially the transport mechanism of cuticular wax from endoplasmic reticulum (ER) to the cell wall. It has been found that the ABCG transporter family is involved in the wax export process in some model plants. However, whether ABCG transporters participate in wax transport in apple is unknown. In this study, MdABCG25, encoding an ABCG transporter, was isolated from apple (Malus domestica Brokh.). MdABCG25, containing an AAA domain and an ABC2_membrane domain, is highly expressed in apple pericarp and induced by drought, salt and ABA conditions. The heterologous expression of MdABCG25 in Arabidopsis leads to an increasing cuticular wax accumulation of stems and leaves. The epidermal permeability, water loss rate and chlorophyll extraction rate of MdABCG25 transgenic Arabidopsis were decreased. The expression of MdABCG25 improved the drought and salt tolerance of apple calli and Arabidopsis.

Abstract Containing the largest number of species, the orchid family provides not only materials for studying plant evolution and environmental adaptation, but economically and culturally important ornamental plants for human society. Previously, we collected genome and transcriptome information of Dendrobium catenatum, Phalaenopsis equestris, and Apostasia shenzhenica which belong to two different subfamilies of Orchidaceae, and developed user-friendly tools to explore the orchid genetic sequences in the OrchidBase 4.0. The OrchidBase 4.0 offers the opportunity for plant science community to compare orchid genomes and transcriptomes and retrieve orchid sequences for further study. In the year 2022, two whole-genome sequences of Orchidoideae species, Platanthera zijinensis and Platanthera guangdongensis, were de novo sequenced, assembled and analyzed. In addition, systemic transcriptomes from these two species were also established. Therefore, we included these datasets to develop the new version of OrchidBase 5.0. In addition, three new functions including synteny, gene order, and miRNA information were also developed for orchid genome comparisons and miRNA characterization. OrchidBase 5.0 extended the genetic information to three orchid subfamilies (including five orchid species) and provided new tools for orchid researchers to analyze orchid genomes and transcriptomes. The online resources can be accessed at https://cosbi.ee.ncku.edu.tw/orchidbase5/

Abstract Background Bronchiectasis is a highly heterogeneous chronic airway disease with marked geographic and ethnic variations. Most influential cohort studies to date have been performed in Europe and USA, which serve as the examples for developing a cohort study in China where there is a high burden of bronchiectasis. The Establishment of China Bronchiectasis Registry and Research Collaboration (BE-China) is designed to: (1) describe the clinical characteristics and natural history of bronchiectasis in China and identify the differences of bronchiectasis between the western countries and China; (2) identify the risk factors associated with disease progression in Chinese population; (3) elucidate the phenotype and endotype of bronchiectasis by integrating the genome, microbiome, proteome, and transcriptome with detailed clinical data; (4) facilitate large randomized controlled trials in China. Methods The BE-China is an ongoing prospective, longitudinal, multi-center, observational cohort study aiming to recruit a minimum of 10,000 patients, which was initiated in January 2020 in China. Comprehensive data, including medical history, aetiological testing, lung function, microbiological profiles, radiological scores, comorbidities, mental status, and quality of life (QoL), will be collected at baseline. Patients will be followed up annually for up to 10 years to record longitudinal data on outcomes, treatment patterns and QoL. Biospecimens, if possible, will be collected and stored at − 80 °C for further research. Up to October 2021, the BE-China has enrolled 3758 patients, and collected 666 blood samples and 196 sputum samples from 91 medical centers. The study protocol has been approved by the Shanghai Pulmonary Hospital ethics committee, and all collaborating centers have received approvals from their local ethics committee. All patients will be required to provide written informed consent to their participation. Conclusions Findings of the BE-China will be crucial to reveal the clinical characteristics and natural history of bronchiectasis and facilitate evidence-based clinical practice in China. Trial registration Registration Number in ClinicalTrials.gov: NCT03643653

AIM: To study the effect of leech extract on the expression of vascular endothelial growth factor(VEGF)in retinoblastoma(WERI-RB-1 cells)and the related molecular mechanism.METHODS: WERI-RB-1 cells cultured in vitro were divided into control group, 0.04U/mL leech extract group and 0.08U/mL leech extract group. The control group was cultured with complete medium for 48h, and the leech extract group was cultured with 0.04 and 0.08U/mL drug-containing medium for 48h, respectively. The expression level of VEGF in conditioned medium of cell culture was detected by ELISA. The mRNA levels of hypoxia-inducible factor-1a(HIF-1a)and matrix metalloproteinase-9(MMP-9)were detected by RT-PCR. The expression levels of HIF-1a, MMP-9, phosphatidylinositol 3-kinase(PI3K)and human phosphorylated AKT(p-AKT)were detected by Western Blot.RESULTS: Compared with the control group, the expression of VEGF in the conditioned medium with the concentration of 0.04U/ mL and 0.08U/mL of leech extract was decreased(P

Objective To predict the risk factors for cardiovascular events within 5 years in patients with peritoneal dialysis-associated peritonitis and establish a nomogram for clinical prediction.Methods A prediction model was established by conducting an observational study in 150 patients with peritoneal dialysis-associated peritonitis obtained from the Information Database of AnHui Medical University Affiliated Hospital. The nomogram was constructed using the multivariate COX regression model. The C-index and the calibration plot were used to assess the discrimination and calibration of the prediction model.Results The elderly [HR = 2.453 (1.071–5.619)], history of cardiovascular events [HR = 2.296 (1.220–4.321)], alkaline phosphatase [HR = 1.004 (1.002–1.005)] and culture-positive [HR= 2.173 (1.009–4.682)] were identified as risk predictors of cardiovascular events, while serum albumin [HR = 0.396(0.170–0.924)] was identified as protective predictors of cardiovascular events. Combined with clinical studies, we constructed a nomogram based on the minimum value of the Akaike Information Criterion or Bayesian Information Criterion. The C index of the nomogram is 0.732, revealing great discrimination and appropriate calibration. Through the total score of the nomogram and the result of ROC, we classify patients into high-risk groups (cardiovascular events group) and low-risk groups (no cardiovascular events group). Cardiovascular events were significantly different for patients in the high-risk group compared to the low-risk group (HR = 3.862(2.202–6.772; p

AIM: To evaluate the application of optical coherence tomography angiography(OCTA)in diabetic patients without retinopathy(NDR)by Meta-analysis.METHODS: CNKI, WanFang Data, VIP, CBM, PubMed, and Embase databases were searched for relevant studies. The retrieval time was from the establishment of the database to October 2021. Two investigators independently screened the literature, extracted data and evaluated the quality of the included studies using the NOS scale. Meta-analysis and publication bias evaluation was performed using RevMan 5.3 and STATA, and sensitivity analysis was performed for results with large heterogeneity to ensure the accuracy of the results.RESULTS: A total of 44 studies, including 2 053 patients(2 600 eyes)with NDR and 1 775 healthy control patients(2 117 eyes), were included. The Meta-analysis was performed on 17 indexes including the area and perimeters of the foveal avascular zone(FAZ), the vascular density(VD)of FAZ-300um(FD300), acircularity index(AI), VD of macular area, ganglion cell complex(GCC)thickness and retinal nerve fiber layer(RNFL)thickness. Meta-analysis results showed that the area and perimeter of FAZ in superficial capillary plexus(SCP)and deep capillary plexus(DCP)in the NDR group were higher than those of healthy control patients, and FD300, VD of macular area and RNFL thickness were all lower than those in the control group(all P0.05).CONCLUSIONS: Compared to the healthy control group, NDR patients had increased FAZ area and perimetry, decreased VD of macular area and RNFL thickness and early retinal microvascular damage and neurodegenerative lesions. OCTA could be used as an auxiliary tool for early diagnosis of DR.

Abstract Background A significant proportion of women with preeclampsia (PE) exhibit persistent postpartum hypertension (PHTN) at 3 months postpartum associated with cardiovascular morbidity. This study aimed to screen patients with PE to identify the high-risk population with persistent PHTN. Methods This retrospective cohort study enrolled 1,000 PE patients with complete parturient and postpartum blood pressure (BP) profiles at 3 months postpartum. The enrolled patients exhibited new-onset hypertension after 20 weeks of pregnancy, while those with PE superimposed upon chronic hypertension were excluded. Latent class cluster analysis (LCCA), a method of unsupervised learning in machine learning, was performed to ascertain maternal exposure clusters from eight variables and 35 subordinate risk factors. Logistic regression was applied to calculate odds ratios (OR) indicating the association between clusters and PHTN. Results The 1,000 participants were classified into three exposure clusters (subpopulations with similar characteristics) according to persistent PHTN development: high-risk cluster (31.2%), medium-risk cluster (36.8%), and low-risk cluster (32.0%). Among the 1,000 PE patients, a total of 134 (13.4%) were diagnosed with persistent PHTN, while the percentages of persistent PHTN were24.68%, 10.05%, and 6.25% in the high-, medium-, and low-risk clusters, respectively. Persistent PHTN in the high-risk cluster was nearly five times higher (OR, 4.915; 95% confidence interval (CI), 2.92–8.27) and three times (OR, 2.931; 95% CI, 1.91–4.49) than in the low- and medium-risk clusters, respectively. Persistent PHTN did not differ between the medium- and low-risk clusters. Subjects in the high-risk cluster were older and showed higher BP, poorer prenatal organ function, more adverse pregnancy events, and greater medication requirement than the other two groups. Conclusion Patients with PE can be classified into high-, medium-, and low-risk clusters according to persistent PHTN severity; each cluster has cognizable clinical features. This study’s findings stress the importance of controlling persistent PHTN to prevent future cardiovascular disease.

BackgroundThe Swanson Nolan, and Pelham scale version IV (SNAP-IV) is the most critical tool for ADHD screening and diagnosis, which has two scoring methods. ADHD requires symptom assessment in multiple scenarios, and parent and teacher reports are indispensable for diagnosing ADHD. But the differences of assessment results from fathers, mothers and teachers, and the consistency of results from different scoring methods are unknown. Therefore, we carried out this study to understand the differences in the scores of fathers, mothers and teachers using SNAP-IV for children with ADHD and to explore the differences in scoring results under different scoring methods.MethodsThe SNAP-IV scale and Demographics Questionnaire and Familiarity Index were used to survey fathers, mothers and head teachers. Measurement data are expressed as the mean ± standard deviation (x ± s). The enumeration data were described by frequency and percentage. ANOVA was used to compare group differences in mothers’, fathers’, and teachers’ mean SNAP-IV scores. The Bonferroni method was used for post hoc multiple comparison tests. Cochran’s Q test was used to compare the differences in the abnormal rate of SNAP-IV score results of mothers, fathers and teachers. Dunn’s test was used for post hoc multiple comparison tests.ResultsThere were differences in scores among the three groups, and the differences showed inconsistent trends across the different subscales. Differences between groups were calculated again with familiarity as a control variable. The results showed the familiarity of parents and teachers with the patients did not affect the differences in their scores. The evaluation results were different under two assessment methods.ConclusionResults concluded that fathers did not appear to be an appropriate candidate for evaluation. When using the SNAP-V for assessment, it should be comprehensively considered from both the scorer and symptom dimensions.

The immune system provides full protection for the body by specifically identifying ‘self’ and removing ‘others’; thus protecting the body from diseases. The immune system includes innate immunity and adaptive immunity, which jointly coordinate the antitumor immune response. T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are the main tumor-killing immune cells active in three antitumor immune cycle. Cancer immunotherapy focusses on activating and strengthening immune response or eliminating suppression from tumor cells in each step of the cancer-immunity cycle; thus, it strengthens the body’s immunity against tumors. In this review, the antitumor immune cycles of T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are discussed. Co-stimulatory and co-inhibitory molecules in the three activity cycles and the development of drugs and delivery systems targeting these molecules are emphasized, and the current state of the art of drug delivery systems for cancer immunotherapy are summarized.

Pulmonary hypertension (PH) is a chronic pulmonary vascular disorder characterized by an increase in pulmonary vascular resistance and pulmonary arterial pressure. The detailed molecular mechanisms remain unclear. In recent decades, increasing evidence shows that altered immune microenvironment, comprised of immune cells, mesenchymal cells, extra-cellular matrix and signaling molecules, might induce the development of PH. Myeloid-derived suppressor cells (MDSCs) have been proposed over 30 years, and the functional importance of MDSCs in the immune system is appreciated recently. MDSCs are a heterogeneous group of cells that expand during cancer, chronic inflammation and infection, which have a remarkable ability to suppress T-cell responses and may exacerbate the development of diseases. Thus, targeting MDSCs has become a novel strategy to overcome immune evasion, especially in tumor immunotherapy. Nowadays, severe PH is accepted as a cancer-like disease, and MDSCs are closely related to the development and prognosis of PH. Here, we review the relationship between MDSCs and PH with respect to immune cells, cytokines, chemokines and metabolism, hoping that the key therapeutic targets of MDSCs can be identified in the treatment of PH, especially in severe PH.

AIM: To explore the changes of retinal optical coherence tomography angiography(OCTA)vessel density in Patients with Alzheimer's disease(AD)by Meta-analysis, and to explore the value of OCTA in early diagnosis of AD patients.METHODS: Embase, PubMed and Cochrane Library data were searched from January 2016 to September 2021 for relevant studies on vessel density in macular area of AD patients. Two researchers independently screened the literature, extracted the data, and evaluated the risk of inclusion bias using Newcastle-Ottawa Scale(NOS). Meta-analysis was performed using RevMan 5.3 software.RESULTS: A total of 740 cases(eyes)were included in 10 literatures, including 321 cases from the AD group and 419 cases from the control group(age-matched people with normal cognitive abilities). The results of the Meta-analysis showed that the superficial vessel density in macular area of AD patients was lower than that in control group(MD=-1.58, 95%CI -2.60- -0.55, P=0.003). The deep vessel density in macular area of AD patients was lower than that in control group(MD=-2.72, 95%CI -4.36- -1.07, P=0.001). The parafoveal vessel density in AD patients was lower than that in control group(MD=-1.44, 95%CI -1.94- -0.94, P

BackgroundRecently, more and more Chinese patent drugs have been proved to be effective in the treatment of diabetic peripheral neuropathy (DPN). Tongmai Jiangtang capsule (TJC) is one of the representative ones. The present meta-analysis integrated data from several independent studies to determine the efficacy and safety of TJCs combined with routine hypoglycemic therapy for DPN patients, and to evaluate the quality of evidence.MethodsSinoMed, Cochrane Library, PubMed, EMBASE, Web of Science, CNKI, Wanfang, VIP databases and registers were searched for randomized controlled trials (RCTs) involving TJC treatment of DPN up to February 18, 2023. Two researchers independently used the Cochrane risk bias tool and comprehensive reporting criteria for Chinese medicine trials to evaluate the methodological quality and reporting quality of the qualified studies. RevMan5.4 was used for Meta-analysis and evidence evaluation, with scores determined for recommendations, evaluation, development and GRADE. The Cochrane Collaboration ROB tool was used to evaluate the quality of the literature. The results of Meta-analysis were represented by forest plots.ResultsA total of 8 studies were included involving a total sample size of 656 cases. TJCs combined with conventional treatment (CT) could significantly accelerate myoelectricity graphic nerve conduction velocity, including that median nerve motor conduction velocity was faster than those of CT alone [mean difference (MD) = 5.20, 95% confidence interval (CI): 4.31–6.10, P < 0.00001], peroneal nerve motor conduction velocity was faster than those of CT alone (MD = 2.66, 95% CI: 1.63–3.68; P < 0.00001), median nerve sensory conduction velocity was faster than those of CT alone (MD = 3.06, 95% CI: 2.32–3.81, P < 0.00001), and peroneal nerve sensory conduction velocity was faster than those of CT alone (MD = 4.23, 95% CI: 3.30–5.16, P < 0.00001). The total efficiency of the TJCs + CT group was higher than that of the CT group (RR = 1.41, 95% CI: 1.28–1.56, P < 0.00001). The HbA1c after treatment in the TJCs + CT group was lower than that in the CT group (P < 0.05). No adverse drug reactions (ADRs) were reported in the combined TJCs or CT groups.ConclusionsTJCs combined with CT reduced the severity of DPN symptoms and no treatment-associated ADRs were reported. However, these results should be considered with caution because there was marked heterogeneity in the research data. Therefore, more stringent RCTs should be designed to validate the efficacy of TJCs in DPN patients.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=264522, identifier: CRD42021264522.

ClpP activators ONC201 and related small molecules (TR compounds, Madera Therapeutics), have demonstrated significant anti-cancer potential in vitro and in vivo studies, including clinical trials for refractory solid tumors. Though progress has been made in identifying specific phenotypic outcomes following ClpP activation, the exact mechanism by which ClpP activation leads to broad anti-cancer activity has yet to be fully elucidated. In this study, we utilized a multi-omics approach to identify the ClpP-dependent proteomic, transcriptomic, and metabolomic changes resulting from ONC201 or the TR compound TR-57 in triple-negative breast cancer cells. Applying mass spectrometry-based methods of proteomics and metabolomics, we identified ∼8,000 proteins and 588 metabolites, respectively. From proteomics data, 113 (ONC201) and 191 (TR-57) proteins significantly increased and 572 (ONC201) and 686 (TR-57) proteins significantly decreased in this study. Gene ontological (GO) analysis revealed strong similarities between proteins up- or downregulated by ONC201 or TR-57 treatment. Notably, this included the downregulation of many mitochondrial processes and proteins, including mitochondrial translation and mitochondrial matrix proteins. We performed a large-scale transcriptomic analysis of WT SUM159 cells, identifying ∼7,700 transcripts (746 and 1,100 significantly increasing, 795 and 1,013 significantly decreasing in ONC201 and TR-57 treated cells, respectively). Less than 21% of these genes were affected by these compounds in ClpP null cells. GO analysis of these data demonstrated additional similarity of response to ONC201 and TR-57, including a decrease in transcripts related to the mitochondrial inner membrane and matrix, cell cycle, and nucleus, and increases in other nuclear transcripts and transcripts related to metal-ion binding. Comparison of response between both compounds demonstrated a highly similar response in all -omics datasets. Analysis of metabolites also revealed significant similarities between ONC201 and TR-57 with increases in α-ketoglutarate and 2-hydroxyglutaric acid and decreased ureidosuccinic acid, L-ascorbic acid, L-serine, and cytidine observed following ClpP activation in TNBC cells. Further analysis identified multiple pathways that were specifically impacted by ClpP activation, including ATF4 activation, heme biosynthesis, and the citrulline/urea cycle. In summary the results of our studies demonstrate that ONC201 and TR-57 induce highly similar and broad effects against multiple mitochondrial processes required for cell proliferation.

BackgroundThe prognosis of patients with dilated cardiomyopathy (DCM) is poor and new indicators are urgently needed to predict lethal cardiac events. This study aimed to investigate the value of summed motion score (SMS) in predicting cardiac death of DCM patients using gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).Methods and resultsEighty-one patients with DCM who underwent 99mTc-MIBI gated SPECT MPI were retrospectively enrolled and were divided into cardiac death and survivor groups. The functional parameters of left ventricle including SMS were measured using quantitative gated SPECT software. During the follow-up period of 44 (25, 54) months, 14 (17.28%) cardiac deaths were observed. Compared with the survivor group, SMS was significantly higher in the cardiac death group. Multivariate cox regression analysis showed that SMS was an independent predictor for cardiac death (HR 1.34, 95% CI 1.02–1.77, P = 0.034). SMS also provided incremental prognostic value over other variables in the multivariate model as determined by likelihood ratio global chi-squared test. In the Kaplan-Meier survival analysis, the event-free survival rate was significantly lower in the high-SMS (HSMS) group than the low-SMS (LSMS) (log-rank P

Abstract Cadmium (Cd) is a high‐risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd‐induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd‐induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP‐response element binding protein at Ser133(CREBS133) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage‐dependent anion‐selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.

Both eutrophication and salinization are growing global environmental problems in freshwater ecosystems, threatening the water quality and various aquatic organisms. However, little is known about their interactive effects on theses stressors and the role of lake depth on these interactions. We used field surveys to compared zooplankton assemblages over four seasons in eight Yunnan Plateau lakes with different trophic states, salinization levels, and water depths. The results showed that: 1) the species number (S), density (DZoop), and biomass (BZoop) of zooplankton exhibited strong seasonal dynamics, being overall higher in the warm seasons. 2) Data collected over four seasons and summer data both revealed highly significant positive relationships of S, DZoop, and BZoop with total nitrogen (TN), total phosphorus (TP), and phytoplankton chlorophyll a (Chl a). 3) S, DZoop, and BZoop displayed a unimodal relationship with salinity, peaking at 400–1000 μS/cm (conductivity, to reflect salinity). 4) The two large-sized taxa (cladocerans and copepods) generally increased at low-moderate levels of TN, TP, Chl a, and Cond and was constant or decreased at high levels. The average body mass (biomass/density) of crustaceans decreased with increasing TN, TP, Chl a, and conductivity. Our findings indicate that zooplankton may be more vulnerable in deep lakes than in shallow lakes when exposed to conductivity stress even under mesotrophic conditions, and the overall decrease in size in zooplankton assemblages under the combined stress of eutrophication and salinization may result in a lowered grazing effect on phytoplankton.

Abstract Background The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer. Methods Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages. Results A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer. Conclusions By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.

Cuticular wax covers the surface of the apple epidermis and plays an important role in water loss and pathogen resistance. However, little is known about wax biosynthesis during apple fruit development. In this study, the morphological structure and chemical composition of wax and the transcription patterns of wax-related genes were investigated in the 'Red Delicious' and 'Golden Delicious' cultivars. The results showed that accumulation of the waxy layer was synchronized with enlargement and maturation of fruit. The crystal structure, major chemical components (very long chain fatty acids and triterpenes) of wax and the expression levels of wax-related genes varied significantly 90 days after flowering (DAF), indicating that the critical period for biosynthesis of cuticular wax was about 90 DAF. This finding is valuable for further study of the regulatory mechanism of wax biosynthesis at both the molecular and physiological levels.

Carex malipoensis, a new species from southeast Yunnan, China, is here described and illustrated. It is morphologically similar to C. trichophylla in sect. Euprepes, but differs from it by its longer inflorescences and peduncles, pendulous spikes, hispidulous female glumes, densely hispidulous utricles, and longer nutlets.

BackgroundPhysical activity (PA) is associated with various health benefits, especially in improving chronic health conditions. However, the metabolic changes in host metabolism in response to PA remain unclear, especially in racially/ethnically diverse populations.ObjectiveThis study is to assess the metabolic profiles associated with the frequency of PA in White and African American (AA) men.MethodsUsing the untargeted metabolomics data collected from 698 White and AA participants (mean age: 38.0±8.0, age range: 20-50) from the Louisiana Osteoporosis Study (LOS), we conducted linear regression models to examine metabolites that are associated with PA levels (assessed by self-reported regular exercise frequency levels: 0, 1-2, and ≥3 times per week) in White and AA men, respectively, as well as in the pooled sample. Covariates considered for statistical adjustments included race (only for the pooled sample), age, BMI, waist circumstance, smoking status, and alcohol drinking.ResultsOf the 1133 untargeted compounds, we identified 7 metabolites associated with PA levels in the pooled sample after covariate adjustment with a false discovery rate of 0.15. Specifically, compared to participants who did not exercise, those who exercised at a frequency ≥3 times/week showed higher abundances in uracil, orotate, 1-(1-enyl-palmitoyl)-2-oleoyl-GPE (P-16:0/18:1) (GPE), threonate, and glycerate, but lower abundances in salicyluric glucuronide and adenine in the pooled sample. However, in Whites, salicyluric glucuronide and orotate were not significant. Adenine, GPE, and threonate were not significant in AAs. In addition, the seven metabolites were not significantly different between participants who exercised ≥3 times/week and 1-2 times/week, nor significantly different between participants with 1-2 times/week and 0/week in the pooled sample and respective White and AA groups.ConclusionsMetabolite responses to PA are dose sensitive and may differ between White and AA populations. The identified metabolites may help advance our knowledge of guiding precision PA interventions. Studies with rigorous study designs are warranted to elucidate the relationship between PA and metabolites.

There is increasing data showing that some environmental chemicals can increase susceptibility to follow-up stress or injuries, possibly thereby contributing to certain clinical and subclinical diseases. Previous studies reported that tetrabromobisphenol A (TBBPA), one of the most used brominated flame retardants, exerted little male reproductive toxicity in terms of conventional endpoints but affected testis development and thereby caused testicular alterations at the molecular and cellular levels. Here, we aimed to reveal whether developmental exposure to TBBPA can increase testicular susceptibility to follow-up stress in adulthood. For this purpose, newborn mice were exposed to 50 or 500 μg/kg/d TBBPA for 56 days to confirm adverse effects on testes, followed by a single intraperitoneal injection of 3 mg/kg busulfan (BSF) to induce spermatogenic stress. Four weeks after BSF injection, TBBPA-treated mice exhibited severe pathological alterations, including reduced testis weight, damaged testicular histological structure, declined sperm count, apoptosis of spermatogenic cells, while no remarkable damage was observed in mice without historical exposure to TBBPA. These results demonstrate that historical exposure to TBBPA, either 50 or 500 µg/kg/d, increased the susceptibility of mouse testes to BSF-induced spermatogenic stress, resulting in severe adverse reproductive outcomes. Further analysis indicates that TBBPA-caused microtubule and microfilament damage, along with spermatogonia and spermatocyte reduction, could contributed to the increased susceptibility of testes, suggesting that these non-conventional reproductive lesions caused by chemicals should not be ignored. This is the first study to investigate the reproductive hazard of chemicals from the perspective of testicular susceptibility to stress, thereby opening a new avenue to identify environmental chemicals possibly contributing to male infertility and subfertility.

As an alternative to legacy perfluorooctane sulfonate (PFOS), the wide usage of chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA) in China has generated considerable concerns. The study aimed to investigate the associations between cord serum emerging Cl-PFESA (6:2 Cl-PFESA and 8:2 Cl-PFESA) levels and suboptimal birth size, including low birth weight (LBW), macrosomia, small or large for gestational age (SGA or LGA) among 1048 newborns in Wuhan, China. 6:2 Cl-PFESA and 8:2 Cl-PFESA were 0.76 ng/mL and 0.03 ng/mL, respectively, higher than previously reported levels in newborns from other cities in China. We did not find significant associations between the Cl-PFESAs and suboptimal birth size when considering each Cl-PFESA as a single exposure. However, when integrating emerging Cl-PFESAs and legacy PFASs (PFOS and perfluorooctanoate acid (PFOA)) as a mixture using Bayesian kernel machine regression (BKMR) models, we found that the mixture of legacy PFASs and emerging Cl-PFESAs had inverse associations with SGA and LGA. Two legacy PFASs and two Cl-PFESAs had similar contributions to the association with SGA, whereas the majority of the association with LGA was driven by PFOS. The results demonstrated these legacy PFASs were still the predominant PFASs associated with suboptimal birth size while emerging Cl-PFESAs had a less but nonnegligible contribution to the association with SGA. Further studies in different regions with varied Cl-PFESA levels are needed to replicate the associations.

Armillariella tabescens is a traditional Chinese medicinal and edible fungus which holds importance for treatment of gastrointestinal disorders. This study was aimed to evaluate the effect of methanol extract of A. tabescens (AME) in dextran sulfate sodium (DSS) induced ulcerative colitis (UC). The results showed that AME significantly attenuated UC symptoms, suppressed the activity of myeloperoxidase (MPO), decreased the levels of LPS, TNF-α, IL-1β, IL-18, and increased the level of IL-10 in serum. Besides, AME could improve the expression of tight junction proteins ZO-1, occludin and claudin-1. Moreover, AME inhibited the activation of TLR4/NF-κB and NLRP3 signaling pathways in colon tissue. In addition, eight compounds were identification in AME by high performance liquid chromatography (HPLC)-high resolution mass spectroscopy (HRMS). Therefore, this study indicated that AME was potential to be further developed into a suitable functional food additive or promising therapeutic agent for UC treatment.

BackgroundEndoscopic retrograde cholangiopancreatography (ERCP) has become an important method to diagnose and treat biliary-pancreatic diseases. Perforations are infrequent but serious complications can occur during ERCPs. However, it is unclear which patients are suitable for surgery and when these patients should receive surgery.AimTo analyze the outcome of 45 patients with endoscopic retrograde cholangiopancreatography (ERCP) related perforation.Materials and methodsWe retrospectively reviewed all 45 patients with ERCP-related perforation between January 2003 and December 2017, and observed the location and causes of perforation, treatment strategies, and mortality.ResultsTwenty thousand four hundred and seventy-nine patients received ERCP procedures from January 2003 to December 2017 in our digestive endoscopy center. Forty-five patients suffered from ERCP-related perforations. The incidence rate of ERCP-related perforations was 0.22%. Twenty-six patients suffered from periampullary perforations, 15 patients suffered from duodenal wall perforations, 1 patient suffered from a fundus perforation, 1 patient suffered from a residual gallbladder duct perforation, 1 patient suffered from a papillary diverticulum perforation, and 1 patient suffered from an intrahepatic bile duct perforation. Six patients with duodenal perforations underwent surgery, and the other patients received conservative treatment. One patient with a duodenal perforation and ERCP-related pancreatitis died of heart failure, and all the other patients recovered. The mortality rate was 2.2%.ConclusionEndoscopic closure is seen as the first method for treating Stapfer type I perforations in the early phase, and surgery is seen as a remedial method when local treatment was failed. The Stapfer type II to type IV perforations can recover by conservative treatment.