Multi-omics analysis reveals the impact of gut microbiota on antipsychotic-induced weight gain in schizophrenia.

Emerging evidence indicates that gut microbial dysbiosis is associated with the development of antipsychotic-induced weight gain in schizophrenia (SZ). However, the exact taxonomic composition and functionality that constitute the "obesogenic" microbial profile remain elusive. Our retrospective survey identified two groups of the SZ population separated by BMI, with 1/3 of patients developing overweight/obesity after chronic antipsychotic treatment. Based on multi-omics analysis, we observed altered gut microbiota in SZ patients with overweight/obesity, characterized by a reduction in several beneficial bacteria genera, including Bacteroides, Parabacteroides, Akkermansia, and Clostridium. This microbial dysbiosis was accompanied by disrupted energy expenditure and nutritional metabolism, worsened metabolic indices, and reduced levels of beneficial metabolites, e.g. indole-3-carboxylic acid and propionic acid. Moreover, leveraging data from first-episode drug-naïve schizophrenia (FSZ) patients at one-month and one-year follow-up, both artificial neural network and random forest classifier-based prediction models demonstrated a strong ability of microbial profiles to predict antipsychotic-induced weight gain. Importantly, FSZ patients with higher relative abundance of Parabacteria distasonis were less susceptible to antipsychotic-induced weight gain. Thus, gut microbiota could serve as a noninvasive approach to predict antipsychotic-induced weight gain, guiding clinical antipsychotics administration and developing novel therapeutic strategies for weight management in SZ.

Acupuncture modulation of the ACE/Ang II/AT1R and ACE2/Ang(1-7)/MasR pathways in the rostral ventrolateral medulla reduces sympathetic output and prevents cardiac injury caused by SHR hypertension.

Acupuncture can reduce blood pressure, heart rate (HR), and ameliorate cardiac damage by modulating the excitability of the sympathetic nervous system, but the exact mechanism of this effect remains unclear. This study investigated the potential mechanisms of acupuncture in the treatment of cardiac damage in hypertension. Spontaneously hypertensive rats (SHR) were used as the hypertension model with Wistar-Kyoto rats as the control. Manual acupuncture, electroacupuncture, and metoprolol were used as interventions. Systolic and diastolic blood pressure (SBP, DBP) plus HR were monitored with cardiac structure determined using Masson staining. Angiotensin II (Ang II) and norepinephrine in myocardium were detected with ELISA as was Ang(1-7) and gamma aminobutyric acid (GABA) in the rostral ventrolateral medulla (RVLM). Expression of mRNA for collagen type I (Col-I), Col-III, actin α1 (ACTA1), and thrombospondin 4 (THBS4) in myocardium was detected using real-time PCR. Expression of angiotensin converting enzyme (ACE), Ang II, angiotensin II type 1 receptor (AT1R), ACE2, and Mas receptor (MasR) proteins in RVLM was monitored using western blot. After manual acupuncture and electroacupuncture treatment, SHRs showed decreased SBP, DBP and HR, reduced myocardial damage. There was decreased expression of the ACE/Ang II/AT1R axis, and increased expression of the ACE2/Ang(1-7)/MasR axis within the RVLM. GABA levels were increased within the RVLM and norepinephrine levels were decreased in myocardial tissue. Metoprolol was more effective than either manual acupuncture or electroacupuncture. Acupuncture directed against hypertensive cardiac damage may be associated with regulation of ACE/Ang II/AT1R and the ACE2/Ang(1-7)/MasR pathway within the RLVM to reduce cardiac sympathetic excitability.

Ceftazidime/avibactam versus polymyxin B in carbapenem-resistant Klebsiella pneumoniae infections: a propensity score-matched multicenter real-world study.

OBJECTIVES: In this retrospective observational multicenter study, we aimed to assess efficacy and mortality between ceftazidime/avibactam (CAZ/AVI) or polymyxin B (PMB)-based regimens for the treatment of Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, as well as identify potential risk factors. METHODS: A total of 276 CRKP-infected patients were enrolled in our study. Binary logistic and Cox regression analysis with a propensity score-matched (PSM) model were performed to identify risk factors for efficacy and mortality. RESULTS: The patient cohort was divided into PMB-based regimen group (n = 98, 35.5%) and CAZ/AVI-based regimen group (n = 178, 64.5%). Compared to the PMB group, the CAZ/AVI group exhibited significantly higher rates of clinical efficacy (71.3% vs. 56.1%; p = 0.011), microbiological clearance (74.7% vs. 41.4%; p < 0.001), and a lower incidence of acute kidney injury (AKI) (13.5% vs. 33.7%; p < 0.001). Binary logistic regression revealed that the treatment duration independently influenced both clinical efficacy and microbiological clearance. Vasoactive drugs, sepsis/septic shock, APACHE II score, and treatment duration were identified as risk factors associated with 30-day all-cause mortality. The CAZ/AVI-based regimen was an independent factor for good clinical efficacy, microbiological clearance, and lower AKI incidence. CONCLUSIONS: For patients with CRKP infection, the CAZ/AVI-based regimen was superior to the PMB-based regimen.

Allogeneic hematopoietic stem cell transplant for familial hemophagocytic lymphohistiocytosis: a case report and literature review.

Objectives: This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene. Methods: A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions. Results: According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved. Conclusions: Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.

Identification and characterization of three monoclonal antibodies targeting the SFTSV glycoprotein and displaying a broad spectrum recognition of SFTSV-related viruses.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne viral pathogen that causes severe fever with thrombocytopenia syndrome (SFTS). The disease was initially reported in central and eastern China, then later in Japan and South Korea, with a mortality rate of 13-30%. Currently, no vaccines or effective therapeutics are available for SFTS treatment. In this study, three monoclonal antibodies (mAbs) targeting the SFTSV envelope glycoprotein Gn were obtained using the hybridoma technique. Two mAbs recognized linear epitopes and did not neutralize SFTSV, while the mAb 40C10 can effectively neutralized SFTSV of different genotypes and also the SFTSV-related Guertu virus (GTV) and Heartland virus (HRTV) by targeting a spatial epitope of Gn. Additionally, the mAb 40C10 showed therapeutic effect in mice infected with different genotypes of SFTSV strains against death by preventing the development of lesions and by promoting virus clearance in tissues. The therapeutic effect could still be observed in mice infected with SFTSV which were administered with mAb 40C10 after infection even up to 4 days. These findings enhance our understanding of SFTSV immunogenicity and provide valuable information for designing detection methods and strategies targeting SFTSV antigens. The neutralizing mAb 40C10 possesses the potential to be further developed as a therapeutic monoclonal antibody against SFTSV and SFTSV-related viruses.

Fluorescent identification of immunomagnetically captured CTCs using triplex-aptamer-targeted dendritic SiO2@Fe3O4 nanocomposite.

The enumeration of circulating tumor cells (CTCs) in peripheral blood plays a crucial role in the early diagnosis, recurrence monitoring, and prognosis assessment of cancer patients. There is a compelling need to develop an efficient technique for the capture and identification of these rare CTCs. However, the exclusive reliance on a single criterion, such as the epithelial cell adhesion molecule (EpCAM) antibody or aptamer, for the specific recognition of epithelial CTCs is not universally suitable for clinical applications, as it usually falls short in identifying EpCAM-negative CTCs. To address this limitation, we propose a straightforward and cost-effective method involving triplex fluorescently labelled aptamers (FAM-EpCAM, Cy5-PTK7, and Texas Red-CSV) to modify Fe3O4-loaded dendritic SiO2 nanocomposite (dmSiO2@Fe3O4/Apt). This multi-recognition-based strategy not only enhanced the efficiency in capturing heterogeneous CTCs, but also facilitated the rapid and accurate identification of CTCs. The capture efficiency of heterogenous CTCs reached up to 93.33%, with a detection limit as low as 5 cells/mL. Notably, the developed dmSiO2@Fe3O4/Apt nanoprobe enabled the swift identification of captured cells in just 30 min, relying solely on the fluorescently modified aptamers, which reduced the identification time by approximately 90% compared with the conventional immunocytochemistry (ICC) technique. Finally, these nanoprobe characteristics were validated using blood samples from patients with various types of cancers.

Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1-AKT-Lipogenesis Pathway.

SCOPE: Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD. METHODS AND RESULTS: This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, and the expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT) phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1) and phosphorylation of ACC1 in a Bmal1-dependent manner. CONCLUSION: Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.

PMBC: a manually curated database for prognostic markers of breast cancer.

Breast cancer is notorious for its high mortality and heterogeneity, resulting in different therapeutic responses. Classical biomarkers have been identified and successfully commercially applied to predict the outcome of breast cancer patients. Accumulating biomarkers, including non-coding RNAs, have been reported as prognostic markers for breast cancer with the development of sequencing techniques. However, there are currently no databases dedicated to the curation and characterization of prognostic markers for breast cancer. Therefore, we constructed a curated database for prognostic markers of breast cancer (PMBC). PMBC consists of 1070 markers covering mRNAs, lncRNAs, miRNAs and circRNAs. These markers are enriched in various cancer- and epithelial-related functions including mitogen-activated protein kinases signaling. We mapped the prognostic markers into the ceRNA network from starBase. The lncRNA NEAT1 competes with 11 RNAs, including lncRNAs and mRNAs. The majority of the ceRNAs in ABAT belong to pseudogenes. The topology analysis of the ceRNA network reveals that known prognostic RNAs have higher closeness than random. Among all the biomarkers, prognostic lncRNAs have a higher degree, while prognostic mRNAs have significantly higher closeness than random RNAs. These results indicate that the lncRNAs play important roles in maintaining the interactions between lncRNAs and their ceRNAs, which might be used as a characteristic to prioritize prognostic lncRNAs based on the ceRNA network. PMBC renders a user-friendly interface and provides detailed information about individual prognostic markers, which will facilitate the precision treatment of breast cancer. PMBC is available at the following URL: http://www.pmbreastcancer.com/.

Development and validation of a nomogram for oral mucosal membrane pressure injuries in ICU patients: A prospective cohort study.

AIMS: Establishing a nomogram to estimate the probability of oral mucosal membrane pressure injury of endotracheal tube-intubated hospitalized patients in intensive care unit. DESIGN: Multicentre prospective cohort study. METHODS: Using Lasso regression and COX regression, variable selection was performed on demographic, clinical and laboratory data of 1037 ICU endotracheal tube-intubated hospitalized patients from West China Hospital, to construct a nomogram. External validation was conducted on 484 ICU endotracheal tube-intubated patients from People's Hospital of Zhongjiang County. RESULTS: Among 38 potential predictors, five variables emerged as independent predictors, integrated into the nomogram: administration of antibiotics, nutritional therapy duration, agitation, hypotension and albumin levels. CONCLUSIONS: We established a nomogram based on the hospital characteristics of ICU endotracheal tube-intubated patients, aiding in the prediction of the occurrence of oral mucosal membrane pressure injury. REPORTING METHOD: The study followed TRIPOD guidelines. RELEVANCE TO CLINICAL PRACTICE: The nomogram we developed can assist clinical worker in better identifying at-risk patients and risk factors. It enables the implementation of evidence-based nursing interventions in care to prevent the development of oral mucosal membrane pressure injury. TRIAL REGISTRATION: The study has been registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn) under registration number ChiCTR2200056615.

Experience Sharing in Pathological Diagnosis of Early Adenocarcinoma of the Lung.

Background: In daily work, there are still many pathologists who have difficulty handling the diagnosis of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma, and the boundaries are not clear enough. Sometimes, the diagnosis is difficult, and there is sometimes poor reproducibility between different pathologists. Accurate diagnosis and differential diagnosis require a certain amount of experience. Methods: During the COVID-19 pandemic, we collected a large number (n = 381) of specimens of early lung adenocarcinoma, most of which (n = 356) were solitary lesions and 25 were multifocal lesions. There were 78 nodules in multifocal lesions, total 434 nodules. We summarized very careful microscopic observation and comparative analysis on all frozen and paraffin sections collected from many early lung adenocarcinoma specimens, continuously summarizing our experience. Results: Based on the World Health Organization's 2021 classification and diagnostic criteria for lung adenocarcinoma, new perspectives have been proposed on how to distinguish between atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma. In particular, new perspectives have been proposed on how to identify invasive aspects, and there are also some new perspectives on early lung mucinous lesions. Conclusion: Atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic adenocarcinoma all have corresponding morphological diagnostic criteria, but the morphological boundaries are sometimes not easy to determine and require some experience accumulation. The intraoperative frozen pathological diagnosis of early adenocarcinoma of the lung needs to be closely combined with imaging examination, and has very rich morphological experience.

Built-in Electric Fields in Heterostructured Lamellar Membranes Enable Highly Efficient Rejection of Charged Mass.

Separation membranes with homogeneous charge channels are the mainstream to reject charged mass by forming electrical double layer (EDL). However, the EDL often compresses effective solvent transport space and weakens channel-ion interaction. Here, built-in electric fields (BIEFs) are constructed in lamellar membranes by assembling the heterostructured nanosheets, which contain alternate positively-charged nanodomains and negatively-charged nanodomains. We demonstrate that the BIEFs are perpendicular to horizontal channel and the direction switches alternately, significantly weakening the EDL effect and forces ions to repeatedly collide with channel walls. Thus, highly efficient rejection for charged mass (salts, dyes, and organic acids/bases) and ultrafast water transport are achieved. Moreover, for desalination on four-stage filtration option, salt rejection reaches 99.9 % and water permeance reaches 19.2 L m-2 h-1 bar-1. Such mass transport behavior is quite different from that in homogeneous charge channels. Furthermore, the ion transport behavior in nanochannels is elucidated by validating horizontal projectile motion model.

Subdural effusion associated with COVID-19 encephalopathy: A case report.

BACKGROUND: The precise mechanism by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacts the central nervous system remains unclear, with manifestations spanning from mild symptoms (e.g., olfactory and gustatory deficits, hallucinations, and headache) to severe complications (e.g., stroke, seizures, encephalitis, and neurally demyelinating lesions). The occurrence of single-pass subdural effusion, as described below, is extremely rare. CASE SUMMARY: A 56-year-old male patient presented with left-sided limb weakness and slurred speech as predominant clinical symptoms. Through comprehensive imaging and diagnostic assessments, he was diagnosed with cerebral infarction complicated by hemorrhagic transformation affecting the right frontal, temporal, and parietal regions. In addition, an intracranial infection with SARS-CoV-2 was identified during the rehabilitation process; consequently, an idiopathic subdural effusion developed. Remarkably, the subdural effusion underwent absorption within 6 d, with no recurrence observed during the 3-month follow-up. CONCLUSION: Subdural effusion is a potentially rare intracranial complication associated with SARS-CoV-2 infection.

The correlation of sarcopenia and adverse events of imatinib therapy postoperatively in gastrointestinal stromal tumor through computed tomography quantitative body composition.

PURPOSE: This study aimed to investigate the correlation between sarcopenia and adverse events (AEs) of postoperative imatinib therapy through computed tomography (CT) quantitative body composition for intermediate- and high-risk gastrointestinal stromal tumors (GISTs). METHODS: The study retrospectively analyzed the clinical data of 208 patients with intermediate- and high-risk GIST treated surgically and treated with imatinib afterward at the First Affiliated Hospital of Wenzhou Medical University between October 2011 and October 2021. Images of preoperative CT scans within 1 month were used to determine the body composition of the patients. On the basis of the L3 skeletal muscle index, patients were classified into sarcopenia and nonsarcopenia groups. In 2 groups, AEs related to imatinib were analyzed. RESULTS: The proportion of AEs related to imatinib in the sarcopenia group was higher, and this disparity had a significant statistical significance (P = .013). Sarcopenia was significantly associated with hemoglobin reduction compared with nonsarcopenia (P = .015). There was a significant difference between the sarcopenia group and the nonsarcopenia group in the ratio of severe AEs (grades 3-4). Hemoglobin content (odds ratio [OR], 0.981; 95% CI, 0.963-1.000; P = .045), sex (OR, 0.416; 95% CI, 0.192-0.904; P = .027), and sarcopenia (OR, 5.631; 95% CI, 2.262-14.014; P < .001) were the influential factors of imatinib severe AEs in patients with intermediate- and high-risk GIST within 1 year after imatinib treatment. CONCLUSION: Patients with preoperative sarcopenia have a higher incidence and severity of AEs during adjuvant imatinib therapy.

Analyzing the changing trend of corneal biomechanical properties under different influencing factors in T2DM patients.

To analyze the changing trend of CH and CRF values under different influencing factors in T2DM patients. A total of 650 patients with T2DM were included. We discovered that the course of T2DM, smoking history, BMI, and FBG, DR, HbA1c, TC, TG, and LDL-C levels were common risk factors for T2DM, while HDL-C levels were a protective factor. Analyzing the CH and CRF values according to the course of diabetes, we discovered that as T2DM continued to persist, the values of CH and CRF gradually decreased. Moreover, with the increase in FBG levels and the accumulation of HbA1c, the values of CH and CRF gradually decreased. In addition, in patients with HbA1c (%) > 12, the values of CH and CRF decreased the most, falling by 1.85 ± 0.33 mmHg and 1.28 ± 0.69 mmHg, respectively. Compared with the non-DR group, the CH and CRF values gradually decreased in the mild-NPDR, moderate-NPDR, severe-NPDR and PDR groups, with the lowest CH and CRF values in the PDR group. In patients with T2DM, early measurement of corneal biomechanical properties to evaluate the change trend of CH and CRF values in different situations will help to identify and prevent diabetic keratopathy in a timely manner.

The impact of sestrin2 on reactive oxygen species in diabetic retinopathy.

Diabetic retinopathy (DR) is a significant complication of diabetes that often leads to blindness, impacting Müller cells, the primary retinal macroglia involved in DR pathogenesis. Reactive oxygen species (ROS) play a crucial role in the development of DR. The objective of this study was to investigate the involvement of sestrin2 in DR using a high-glucose (HG)-induced Müller cell model and assessing cell proliferation with 5-ethynyl-2-deoxyuridine (EdU) labeling. Following this, sestrin2 was upregulated in Müller cells to investigate its effects on ROS, tube formation, and inflammation both in vitro and in vivo, as well as its interaction with the nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway. The findings demonstrated a gradual increase in the number of EdU-positive cells over time, with a subsequent decrease after 72 h of exposure to high glucose levels. Additionally, the expression of sestrin2 exhibited a progressive increase over time, followed by a decrease at 72 h. The rh-sestrin2 treatment suppressed the injury of Müller cells, decreased ROS level, and inhibited the tube formation. Rh-sestrin2 treatment enhanced the expression of sestrin2, Nrf2, heme oxygenase-1 (HO-1), and glutamine synthetase (GS); however, the ML385 treatment reversed the protective effect of rh-sestrin2. Finally, we evaluated the effect of sestrin2 in a DR rat model. Sestrin2 overexpression treatment improved the pathological injury of retina and attenuated the oxidative damage and inflammatory reaction. Our results highlighted the inhibitory effect of sestrin2 in the damage of retina, thus presenting a novel therapeutic sight for DR.

Mechanisms of inflammation modulation by different immune cells in hypertensive nephropathy.

Hypertensive nephropathy (HTN) is the second leading cause of end-stage renal disease (ESRD) and a chronic inflammatory disease. Persistent hypertension leads to lesions of intrarenal arterioles and arterioles, luminal stenosis, secondary ischemic renal parenchymal damage, and glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Studying the pathogenesis of hypertensive nephropathy is a prerequisite for diagnosis and treatment. The main cause of HTN is poor long-term blood pressure control, but kidney damage is often accompanied by the occurrence of immune inflammation. Some studies have found that the activation of innate immunity, inflammation and acquired immunity is closely related to the pathogenesis of HTN, which can cause damage and dysfunction of target organs. There are more articles on the mechanism of diabetic nephropathy, while there are fewer studies related to immunity in hypertensive nephropathy. This article reviews the mechanisms by which several different immune cells and inflammatory cytokines regulate blood pressure and renal damage in HTN. It mainly focuses on immune cells, cytokines, and chemokines and inhibitors. However, further comprehensive and large-scale studies are needed to determine the role of these markers and provide effective protocols for clinical intervention and treatment.

Production and characterization of recrystallized linear α-glucans at different temperatures for controllable thermostability and digestibility.

Molecular structure of linear α-glucans (LAGs) and crystallization temperature have great effects on the thermostability and digestibility of recrystallized LAGs, but the recrystallization behaviors of LAGs in response to temperature remain unclear. Here LAGs with different lengths were prepared from amylopectin via chain elongation and debranching. Recrystallization of LAGs at 4 °C yielded B-type crystalline structure with relative crystallinity ranged from 23.7% to 46.1%. With a chain length of 40.2, an A-type allomorph was observed for a slow recrystallization at 50 °C. Differential scanning calorimetry suggested that A-type crystal had a higher thermostability than the B-type crystal, and increasing LAGs' chain length improved the dimension of double helices, whose assembly produced starch crystallites that enhanced the thermostability and decreased the in vitro digestibility of recrystallized LAGs. An improved thermostability of recrystallized LAGs preserved their ordered structures and kept the resistance to digestive enzymes, with a RS content up to 75.4%.

Occurrence and Exposure Assessment of Nickel in Zhejiang Province, China.

Nickel (Ni) is a silver-white metal with high antioxidative properties, often existing in a bivalent form in the environment. Despite being the fifth most abundant metal on Earth, anthropogenic activities, including industrial processes, have elevated Ni levels in environmental media. This study investigated Ni contamination in various food groups in Zhejiang Province, China, mainly focusing on Ni levels in beans, vegetables, aquatic foods, meat products, cereal products, and fruits. A total of 2628 samples were collected and analyzed. Beans exhibited the highest Ni content in all samples. The overall detection rate of Ni was 86.5%, with variation among food categories. For plant-origin foods, legumes had the highest Ni concentration while for animal-origin foods, shellfish showed the highest median Ni concentration. The results indicate generally acceptable Ni exposure levels among Zhejiang residents, except for children aged 0-6. Beans were identified as the primary contributor to high Ni exposure risk. The paper suggests monitoring Ni contamination in food, especially for vulnerable populations, and provides insights into exposure risks in different age groups.

Association of the second birth mode of delivery and interval with maternal pelvic floor changes: a prospective cohort study.

BACKGROUND: This study aimed to explore the association of the second birth delivery mode and interval with maternal pelvic floor changes. METHODS: This prospective cohort study included women who had a first delivery and were in weeks 36-41 of a subsequent pregnancy at Panzhihua Central Hospital between July 2017 and June 2018. The primary outcomes of the study were the hiatus area at 6 months postpartum and bladder neck (mm) at rest and during a maximum Valsalva maneuver. RESULTS: There were 112 women with vaginal delivery and 182 with Cesarean section. The hiatus area and hiatus circumference decreased at all time points (all P < 0.001). The women with Cesarean section had a smaller hiatus area and circumference (P < 0.001 and P < 0.001). The hiatus diameters decreased with time in both groups (all P < 0.001) and were smaller after Cesarean section (both P < 0.001). The bladder neck at maximum Valsalva increased with time (all P < 0.001) without significant differences between the two groups. Finally, the proportion of patients with POP-Q stage 0/I increased with time in both groups (all P < 0.001), with the proportions being higher in the Cesarean group (P = 0.002). The birth interval was negatively correlated with the hiatus area (B=-0.17, 95%CI: -0.25, -0.08, P < 0.001) and positively correlated with the bladder neck at rest (B = 0.22, 95%CI: 0.08, 0.35, P = 0.001) and at maximum Valsalva (B = 0.85, 95%CI: 0.65, 1.05, P < 0.001). CONCLUSIONS: In conclusion, the mode of delivery at the second birth could influence the hiatus area and circumference and bladder neck size. The birth interval was negatively correlated with the hiatus area and positively correlated with the bladder neck at rest and at maximum Valsalva.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.