Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS.

BACKGROUND AND AIMS: Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. APPROACH AND RESULTS: Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine-induced HCC mouse model was screened using a quantitative mass spectrometry-based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL-6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL-6 in HcPCs, causing the acyl protein thioesterase 1-mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL-6 in HcPCs. Clinically, GαS, especially K28-acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. CONCLUSIONS: Malignant progression of HcPCs requires increased K28-acetylated and cytoplasm-translocated GαS, causing enhanced response to IL-6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.

Interferon-responsive neutrophils and macrophages extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.

The SARS-CoV-2 Omicron variant is characterized by its high transmissibility, which has caused a worldwide epidemiological event. Yet, it turns ominous once the disease progression degenerates into severe pneumonia and sepsis, presenting a horrendous lethality. To elucidate the alveolar immune or inflammatory landscapes of Omicron critical-ill patients, we performed single-cell RNA-sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) from the patients with critical pneumonia caused by Omicron infection, and analyzed the correlation between the clinical severity scores and different immune cell subpopulations. In the BALF of Omicron critical patients, the alveolar violent myeloid inflammatory environment was determined. ISG15+ neutrophils and CXCL10+ macrophages, both expressed the interferon-stimulated genes (ISGs), were negatively correlated with clinical pulmonary infection score, while septic CST7+ neutrophils and inflammatory VCAN+ macrophages were positively correlated with sequential organ failure assessment. The percentages of ISG15+ neutrophils were associated with more protective alveolar epithelial cells, and may reshape CD4+ T cells to the exhaustive phenotype, thus preventing immune injuries. The CXCL10+ macrophages may promote plasmablast/plasma cell survival and activation as well as the production of specific antibodies. As compared to the previous BALF scRNA-seq data from SARS-CoV-2 wild-type/Alpha critical patients, the subsets of neutrophils and macrophages with pro-inflammatory and immunoregulatory features presented obvious distinctions, suggesting an immune disparity in Omicron variants. Overall, this study provides a BALF single-cell atlas of Omicron critical patients, and suggests that alveolar interferon-responsive neutrophils and macrophages may extricate SARS-CoV-2 Omicron critical patients from the nasty fate of sepsis.

An internet-based platform with a low-calorie dietary intervention improves cardiometabolic risk factors in overweight and obese people in China: Half-year follow-up results of a randomized controlled trial.

AIM: To explore the effectiveness of the Metawell programme on cardiometabolic risk factors in China, which combines meal replacement biscuits, a wireless scale, and a mobile phone application. METHODS: In this two-arm, parallel-design randomized study, 220 participants were randomly assigned to an intervention (n = 110) and a control (n = 110) group. Participants in the intervention group were instructed to use meal replacement products and scales for weight loss and monitoring, whereas participants in the control group received printed materials containing a sample diet and face-to-face weight loss education at enrolment. The trial lasted 6 months, including a weight loss period in Months 1-3 and a weight maintenance period in Months 3-6. Generalized estimating equations were used to compare differences between the two groups. RESULTS: The median (interquartile range) ages of the intervention and control groups were 32.00 (28.00, 39.00) years and 33.00 (28.25, 41.00) years, with body mass indices of 28.20 (26.30, 30.95) kg/m2 and 27.70 (26.02, 29.70) kg/m2, respectively. Participants in the intervention group experienced significantly greater decreases in waist circumference, hip circumference, triglycerides, total cholesterol: high-density lipoprotein cholesterol ratio, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance index compared to the control group (p < 0.01). Among participants who did not regain weight during the maintenance period after weight loss, the reductions in systolic and diastolic blood pressure were significantly greater in the intervention group than in the control group (p < 0.05). CONCLUSIONS: The Metawell programme of caloric restriction and remote monitoring can be adapted to overweight and obese people in China to reduce their cardiometabolic risk factors. Furthermore, there was a better improvement in blood pressure in participants who maintained the effects of weight loss.

Correlation between Body Composition and Bone Mineral Density Differs by Sex and Skeletal Site in Overweight and Obese Chinese Subjects.

Previous studies have yielded inconsistent results regarding the relationship between obesity and bone mineral density (BMD). The aim of this study was to determine the influence of body composition on BMD and the serum sclerostin level in overweight and obese adults. The study had a cross-sectional design and included 90 men and 118 women with a body mass index ≥25. Fat mass, lean mass, and spinal and pelvic BMD were measured using dual-emission X-ray absorptiometry. Subcutaneous fat, visceral fat, and lean mass were measured between L2 and L3 by 16-slice spiral computed tomography. The serum sclerostin level was determined by enzyme-linked immunosorbent assay. Pearson analysis showed that fat mass and appendicular lean mass were positively correlated with spinal BMD in both sexes. A positive association of both fat mass and lean mass with pelvic BMD, which was stronger in women, was also found. Partial correlation analysis showed the positive association between fat mass and BMD was significantly attenuated but the positive association between lean mass and pelvic BMD remained after adjustment for age and body weight. A negative correlation was observed between visceral fat and spinal and pelvic BMD only in women, and the positive association between lean mass with pelvic BMD was more obvious in women than in men, indicating body composition seemed to have a greater impact on the BMD in women. The serum sclerostin level was positively associated with BMD but not with body composition. These findings suggest that the correlation between body composition and BMD is influenced by sex and skeletal site.

Characterization of a Ge1-x-ySiySnx/Ge1-xSnx multiple quantum well structure grown by sputtering epitaxy.

A high-quality Ge0.88Si0.08Sn0.04/Ge0.94Sn0.06 multiple quantum well (MQW) structure was grown on a Ge (001) substrate by sputtering epitaxy. The MQW structure was characterized by high-resolution x-ray diffraction and transmission electron microscopy. Surface-illuminated Ge0.88Si0.08Sn0.04/Ge0.94Sn0.06 MQW pin photodetectors were fabricated with cutoff wavelengths of up to 2140 nm. The analysis of transitions from spectral response was fitted well with the theoretical calculations. Results suggest that sputtering epitaxy is a promising method for preparing high-quality low-dimensional Sn-based group IV materials and that Ge1-x-ySiySnx/Ge1-xSnx MQWs have potential applications in the development of efficient Si-based photonic devices.

[Isolation and Study on the Aflatoxin Genes of Aflatoxin-producing Fungi in Paprika Samples in Chengdu].

OBJECTIVE: To isolate aflatoxin-producing strains from paprika samples and to do a preliminarily study on the relationship between aflatoxin-producing ability and the genes aflR, omt-1 and ver-1. METHODS: Fungi were isolated by traditional culture method. Potential aflatoxin-producing strains were screened by phenotypic traits and multiplex PCR. After these potential aflatoxin-producing strains cultured in the toxigenic culture medium, the levels of aflatoxin B, (AFB1) of the cultures were tested with ELISA method. The phylogenetic tree of aflR, omt-1 and ver-1 was constructed to explore the relationship between these genes and the AFB1-producing capacity. RESULTS: 17 potential aflatoxin-producing fungi were isolated. The ratio of positive toxigenic strains is 64. 71%. 11 isolates were positive in AFB1 detection while existing high sequence homology with AS 3. 4408, 6 isolates were negative in AFB1 detection while existing high sequence homology with Aspergillus oryzae. CONCLUSION: Aspergillus flavus are potential candidates for aflatoxin control. Not all Aspergillus flavus have AFB1-producing capacity, aflR gene had a direct relation to AFB1-producing capacity, while ver-1 and omt-1 were related to the level of AFB1 producing.

Versatile synthesis of thiol- and amine-bifunctionalized silica nanoparticles based on the ouzo effect.

In this article, we report a novel, nanoprecipitation-based method for preparing silica nanoparticles with thiol and amine cofunctionalization. (3-Mercaptopropyl)trimethoxysilane (MPTMS) and 3-aminopropyltrimethoxysilane (APTMS) were used as the organosilane precursors, which were subjected to acid-catalyzed polycondensation in an organic phase containing a water-miscible solvent (e.g., dimethyl sulfoxide). A pale colloidal solution could be immediately formed when the preincubated organic phase was directly injected into water. The initial composition ratio between MPTMS and APTMS is an important factor governing the formation of nanoparticles. Specifically, large, unstable micrometer-sized particles were formed for preparation using MPTMS as the sole silane source. In contrast, when APTMS was used alone, no particles could be formed. By reducing the fraction of APTMS (or increasing that of MPTMS) in the initial mixture of organosilanes, the formation of nanometer-sized particles occurred at a critical fraction of APTMS (i.e., 25%). Remarkably, a tiny fraction (e.g., 1%) of APTMS was sufficient to produce stable nanoparticles with a hydrodynamic diameter of about 200 nm. Other factors that would also affect particle formation were determined. Moreover, an interesting temperature effect on particle formation was observed. The TEM micrographs show spherical nanospheres with mean sizes of 130-150 nm in diameter. The solid-state (29)Si NMR spectra demonstrate that the hybrid silica materials contain fully and partially condensed silicon structures. The bifunctionalized silica nanoparticles have positive zeta potentials whose magnitudes are positively correlated with the amount of APTMS. The total thiol content, however, is negatively correlated with the amount of APTMS. The cationic nanoparticles can bind an antisense oligonucleotide in a composition-dependent manner.

Impact of altitude on the development of low bone mineral density and osteoporosis in individuals aged 50 years and older: protocol for a multicentre prospective cohort study.

INTRODUCTION: Osteoporotic fractures are a leading cause of disability and contribute significantly to medical care costs worldwide. Variations in bone mineral density and the risk of osteoporosis are notably influenced by altitude. This study aims to longitudinally examine individuals with osteoporosis and low bone mass at three different altitudes (low, high and very high) to understand the effects of high-altitude environments on bone density. METHODS AND ANALYSIS: This multicentre, prospective cohort study will involve 893 participants divided into three groups based on altitude: low (500-1500 m), high (2500-4500 m) and very high (4500-5500 m). Participants will undergo comprehensive diagnostic assessments, including demographic data collection, structured questionnaires, medical examinations and clinical laboratory tests. Follow-up visits will occur annually for a minimum of 5 years. The primary outcome will be changes in bone mineral density values. Secondary outcomes will include the incidence of osteoporosis and osteoporotic fractures. Cox proportional hazard models will be used to calculate the risk associated with osteoporotic events and related fractures. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (No: 2024-70). The acquired insights will be disseminated via academic forums, scholarly articles and stakeholder engagement sessions. TRIAL REGISTRATIONNUMBER: ChiCTR2300078872.

Light-activated hypoxia-sensitive biomimetic decoy efficiently cascading photodynamic-chemo therapy for breast cancer.

The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.

Influence of High-Altitude Residential History on Optimal HbA1c Cutoff for Detecting Abnormal Glucose Metabolism.

Aims: To explore the influence of recent high-altitude residential history on the optimal cutoff of glycosylated hemoglobin (HbA1c) for detecting abnormal glucose metabolism. Methods: The study included 505 self-reported healthy Han participants of age 18-65 years, recruited in Chengdu and categorized based on recent (within 3 months) high-altitude (>2,500 m) residential history. The 1999 WHO criteria was used as the gold standard for defining prediabetes and diabetes. HbA1c test performance was assessed using receiver operating characteristic curve, with the optimal cutoff determined by Maximum Youden index. Propensity score matching with 0.02 calipers and nearest neighbor method was used to balance confounding factors between groups. Results: Of the participants, 238 (47.13%) were populations with recent high-altitude residential history (HA group), and 267 (52.87%) were low-altitude dwellers (LA group). The HA group had slightly higher HbA1c levels (p > 0.05) and higher erythrocyte and hemoglobin levels (p < 0.05), compared to the LA group. Weak correlations between prediabetes and HbA1c levels were observed in the HA group (rs = 0.21, p < 0.05) and the LA group (rs = 0.07, p = 0.25). The optimal cutoff for the detection of diabetes was 6.5% (area under the curve [AUC] 0.94) in the HA group and 5.9% (AUC 0.97) in the LA group, which remained unchanged after adjustment for confounders. Conclusions: The optimal cutoff of HbA1c for the detection of diabetes in populations with recent history of living at high altitude was higher than that in general populations living at low altitude, and the diagnostic value of HbA1c for prediabetes was also inadequate.

Mobile-Based Platform With a Low-Calorie Dietary Intervention Involving Prepackaged Food for Weight Loss for People With Overweight and Obesity in China: Half-Year Follow-Up Results of a Randomized Controlled Trial.

Background: Obesity is a rapidly increasing health problem in China, causing massive economic and health losses annually. Many techniques have emerged to help people with obesity better adhere to intervention programs and achieve their weight loss goals, including food replacement and internet-delivered weight loss consultations. Most studies on weight loss interventions mainly focused on the change in body weight or BMI; however, body fat, especially visceral fat mass, is considered the main pathogenic factor in obesity. In China, more reliable evidence is required on this topic. Moreover, it is unclear whether an integrated weight loss program combining food replacement products, mobile app-based platforms, and daily body composition monitoring using a wireless scale is useful and practical in China. Objective: In this 2-arm, parallel-designed, randomized study, we explored the effectiveness and safety of the Metawell (Weijian Technologies Inc) weight loss program in China, which combines prepackaged biscuits, a wireless scale, and a mobile app. Methods: Participants in the intervention group were guided to use food replacement products and a scale for weight loss and monitoring, whereas participants in the control group received printed material with a sample diet and face-to-face education on weight loss at enrollment. The intervention lasted for 3 months, and follow-up visits were conducted at months 3 and 6 after enrollment. Dual-energy x-ray absorptiometry and quantitative computed tomography were used to assess body fat. A multilevel model for repeated measurements was used to compare differences between the 2 groups. Results: In total, 220 patients were randomly assigned to intervention (n=110) and control (n=110) groups. Participants in the intervention group had significantly greater decreases in BMI, total body fat, visceral adipose area, and subcutaneous adipose area (all P<.001) than those in the control group. However, the rate of change in lean mass was not significantly different between the 2 groups (P=.62). Further, 35 participants in the intervention group reported adverse events. Constipation was the most frequently reported adverse event (11/110), followed by dizziness (6/110), hypoglycemia (4/110), fatigue (3/110), and gastritis (3/35). Conclusions: The Metawell program was effective for weight loss. After the intervention, participants in the intervention group lost more body weight and body fat while retaining muscle mass than those in the control group.

Therapeutic effect of bloodletting on bone deterioration induced by hypobaric hypoxia in young rats.

OBJECTIVES: High-altitude regions, comprising hypoxic condition, are associated with different altitude-induced pathologies, including a reduction in bone density. Elucidating the mechanisms underlying bone degradation in such environments and developing targeted interventions and therapeutics is important. Bloodletting therapy has promising clinical applications, but its effects on the skeletal system and bone homeostasis are not well understood. The aim of this study was to investigate the effects of a hypobaric hypoxia environment on specific femoral morphological and structural properties, including the bone volume, cortical thickness, and trabecular microarchitecture, in juvenile Sprague-Dawley (SD) rats, and to explore the potential modulating effects of a bloodletting intervention on these parameters. METHODS: Male SD rats, 6 weeks of age, were subjected to a simulated hypobaric hypoxia environment, replicating a 5000-m altitude, for 12 weeks. For the bloodletting intervention group, rats were subjected to a weekly 500 µL tail vein blood withdrawal. Micro-CT technology, hematoxylin and eosin staining, and tartrate-resistant acid phosphatase staining were employed to comprehensively assess the femoral microstructure, tissue architecture, and cellular morphology. Additionally, immunofluorescence analysis was conducted to quantify the expression of key proteins, and transcriptome analysis was performed to identify differentially expressed genes. RESULTS: Exposing rats to hypobaric hypoxia led to a significant reduction in the bone mineral content, trabecular bone number, and cortical bone thickness, suggesting a deterioration of bone microstructure. Additionally, the hypoxic environment upregulated the expression of RANKL and HIF-1α, while downregulating RUNX2 expression. Notably, although bloodletting intervention did not significantly reverse these bone structural changes, transcriptome analysis revealed its regulatory influence on the expression of key genes, particularly Mmp2, Fosl2, and URS0000B2A65A, which are implicated in pathways governing the hypoxic response, osteoclast differentiation, and PI3K-Akt signaling. CONCLUSION: This study highlights the detrimental effect of hypobaric hypoxia on the bone microstructure of juvenile rats and underscores the therapeutic potential of bloodletting to ameliorate this condition. Additionally, our study on the regulatory mechanisms mediating the effects of bloodletting on gene expression offers new perspectives on bone alterations. It suggests promising avenues for the development of novel preventative measures and targeted therapies to address the challenges posed by related bone disorders.

Accuracy of FreeStyle Libre flash glucose monitoring in patients with type 2 diabetes who migrated from highlands to plains.

BACKGROUND: The FreeStyle Libre flash glucose monitoring (FGM) system entered the Chinese market in 2017 to complement the self-monitoring of blood glucose. Due to its increased usage in clinics, the number of studies investigating its accuracy has increased. However, its accuracy has not been investigated in highland popu-lations in China. AIM: To evaluate measurements recorded using the FreeStyle Libre FGM system compared with capillary blood glucose measured using the enzyme electrode method in patients with type 2 diabetes (T2D) who had migrated within 3 mo from highlands to plains. METHODS: Overall, 68 patients with T2D, selected from those who had recently migrated from highlands to plains (within 3 mo), were hospitalized at the Department of Endocrinology from August to October 2017 and underwent continuous glucose monitoring (CGM) with the FreeStyle Libre FGM system for 14 d. Throughout the study period, fingertip capillary blood glucose was measured daily using the enzyme electrode method (Super GL, China), and blood glucose levels were read from the scanning probe during fasting and 2 h after all three meals. Moreover, the time interval between reading the data from the scanning probe and collecting fingertip capillary blood was controlled to < 5 min. The accuracy of the FGM system was evaluated according to the CGM guidelines. Subsequently, the factors influencing the mean absolute relative difference (MARD) of this system were analyzed by a multiple linear regression method. RESULTS: Pearson's correlation analysis showed that the fingertip and scanned glucose levels were positively correlated (R = 0.86, P = 0.00). The aggregated MARD of scanned glucose was 14.28 ± 13.40%. Parker's error analysis showed that 99.30% of the data pairs were located in areas A and B. According to the probe wear time of the FreeStyle Libre FGM system, MARD1 d and MARD2-14 d were 16.55% and 14.35%, respectively (t = 1.23, P = 0.22). Multiple stepwise regression analysis showed that MARD did not correlate with blood glucose when the largest amplitude of glycemic excursion (LAGE) was < 5.80 mmol/L but negatively correlated with blood glucose when the LAGE was ≥ 5.80 mmol/L. CONCLUSION: The FreeStyle Libre FGM system has good accuracy in patients with T2D who had recently migrated from highlands to plains. This system might be ideal for avoiding the effects of high hematocrit on blood glucose monitoring in populations that recently migrated to plains. MARD is mainly influenced by glucose levels and fluctuations, and the accuracy of the system is higher when the blood glucose fluctuation is small. In case of higher blood glucose level fluctuations, deviation in the scanned glucose levels is the highest at extremely low blood glucose levels.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

Baseline Serum BCAAs are Related to the Improvement in Insulin Resistance in Obese People After a Weight Loss Intervention.

Background: Branched chain amino acids (BCAAs) have been revealed to be closely related to insulin resistance and obesity. This study aimed to investigate if BCAA levels at baseline are related to an improvement in insulin resistance after implementing a weight loss program intervention. Methods: Stored blood samples from participants in previous trials were used for BCAA evaluation. Linear regression was used to analyze the relationship between baseline amino acid levels and changes in the insulin resistance index (HOMA-IR) and blood glucose. Results: A total of 48 participants were enrolled. After the intervention, the body weight (78.29± 12.68 vs 72.06 ± 13.30 kg, p=0.020), fasting glucose (4.76 ± 0.43 vs 4.48 ± 0.39 mmol/L, p=0.001), fasting insulin (18.41±13.58 vs 12.87±10.88, p=0.028), and HOMA-IR (4.01±3.39 vs 2.62± 2.18, p=0.018) were improved significantly. BCAA levels were related to the improvement in HOMA-IR (ß=-0.006, p=0.039), and valine was found to be the most closely related to the improvement in HOMA-IR (ß=-0.013, p=0.017). Conclusion: The baseline BCAA is related to the improvement in insulin resistance among participants after a weight loss intervention.

Depth-dependent patterns of soil microbial community in the E-waste dismantling area.

The long-term dismantling of electronic waste (E-waste) has contaminated the soil environment considerably. In spite of this, it is unknown if it affects the depth-resolved microbial communities. In the present research, six soil profiles (dismantling sites and the surrounding farmland) were collected from one of the largest Chinese E-waste disposal centers to identify depth-resolved microbiota and assess how heavy metal contamination affects microbial adaptation. Results suggested that cadmium (0.12-7.22 mg kg-1) and copper (18.99-11282.03 mg kg-1) were the main pollutants in the test soil profiles, and their concentrations gradually decreased with depth. The surrounding contaminated farmland has a more complex interaction and higher modularity (0.77-0.85) among microbes, indicating a stronger niche differentiation to enhance functional diversity. The proportion of positive interactions between taxa decreased with depth, as high heavy metals contamination in the topsoil results in the co-occurrence of microorganisms with the same ecological niche that collaborated to face environmental stress. Soil physicochemical properties, heavy metals concentration, and soil depth critically affect microbial communities. Microbial community assembly processes in the topsoil were affected by environmental filtering, i.e., by deterministic processes (NST: 13-52%), while were more stochastic (NST: 46-72%) in the subsoil due to the environment of soil becoming more homogeneous as soil depth increased.

Age at menopause was not associated with microvascular complications in patients with type 2 diabetes mellitus.

This study aimed to determine whether there is an association between the age at menopause (AM) and diabetic microvascular complications. This cross-sectional study included 298 postmenopausal women with type 2 diabetes mellitus. They were divided into 3 groups according to AM (in years; group 1: AM < 45 years, n = 32; group 2:45 ≤ AM < 50 years, n = 102; group 3: AM ≥ 50 years, n = 164). Clinical data related to the duration of type 2 diabetes, body mass index, smoking status, hypertension status, AM, biochemical indices, and diabetic microvascular complications (retinopathy, nephropathy, and neuropathy) were collected. Logistic regression analysis was performed to identify the association between the AM and diabetic microvascular complications. No statistical differences were observed in the prevalence of diabetic retinopathy, chronic kidney disease, or diabetic peripheral neuropathy between the groups. After adjusting for possible confounders, AM did not correlate with the presence of diabetic retinopathy (ß = 1.03, 95% confidence interval [CI]: 0.94-1.14, P = .511), chronic kidney disease (ß = 1.04, 95% CI: 0.97-1.12, P = .280), and diabetic peripheral neuropathy (ß = 1.01, 95% CI: 0.93-1.09, P = .853). Our findings suggest that early menopause (age < 45 years) was not associated with microvascular diabetic complications. Further prospective studies are needed to clarify this issue.

Abundant fungi dominate the complexity of microbial networks in soil of contaminated site: High-precision community analysis by full-length sequencing.

During the past decade, the characterization of microbial community in soil of contaminated sites was primarily done by high-throughput short-read amplicon sequencing. However, due to the similarity of 16S rRNA and ITS genes amplicon sequences, the short-read approach often limits the microbial composition analysis at the species level. Here, we simultaneously performed full-length and short-read amplicon sequencing to clarify the community composition and ecological status of different microbial taxa in contaminated soil from a high-resolution perspective. We found that (1) full-length 16S rRNA gene sequencing gave better resolution for bacterial identification at all levels, while there were no significant differences between the two sequencing platforms for fungal identification in some samples. (2) Abundant taxa were vital for microbial co-occurrences network constructed by both full-length and short-read sequencing data, and abundant fungal species such as Mortierella alpine, Fusarium solani, Mrakia frigida, and Chaetomium homopilatum served as the keystone species. (3) Heavy metal correlated with the microbial community significantly, and bacterial community and its abundant taxa were assembled by deterministic process, while the other taxa were dominated by stochastic process. These findings contribute to the understanding of the ecological mechanisms and microbial interactions in site soil ecosystems and demonstrate that full-length sequencing has the potential to provide more details of microbial community.

Mitochondrial IRG1 traps MCL-1 to induce hepatocyte apoptosis and promote carcinogenesis.

Hepatocarcinogenesis is initiated by repeated hepatocyte death and liver damage, and the underlying mechanisms mediating cell death and the subsequent carcinogenesis remain to be fully investigated. Immunoresponsive gene 1 (IRG1) and its enzymatic metabolite itaconate are known to suppress inflammation in myeloid cells, and its expression in liver parenchymal hepatocytes is currently determined. However, the potential roles of IRG1 in hepatocarcinogenesis are still unknown. Here, using the diethylnitrosamine (DEN)-induced hepatocarcinogenesis mouse model, we found that IRG1 expression in hepatocytes was markedly induced upon DEN administration. The DEN-induced IRG1 was then determined to promote the intrinsic mitochondrial apoptosis of hepatocytes and liver damage, thus enhancing the subsequent hepatocarcinogenesis. Mechanistically, the mitochondrial IRG1 could associate and trap anti-apoptotic MCL-1 to inhibit the interaction between MCL-1 and pro-apoptotic Bim, thus promoting Bim activation and downstream Bax mitochondrial translocation, and then releasing cytochrome c and initiating apoptosis. Thus, the inducible mitochondrial IRG1 promotes hepatocyte apoptosis and the following hepatocarcinogenesis, which provides mechanistic insight and a potential target for preventing liver injury and HCC.

Integrated biomarker profiling of the metabolome associated with type 2 diabetes mellitus among Tibetan in China.

INTRODUCTION: Metabolomic signatures of type 2 diabetes mellitus (T2DM) in Tibetan Chinese population, a group with high diabetes burden, remain largely unclear. Identifying the serum metabolite profile of Tibetan T2DM (T-T2DM) individuals may provide novel insights into early T2DM diagnosis and intervention. METHODS: Hence, we conducted untargeted metabolomics analysis of plasma samples from a retrospective cohort study with 100 healthy controls and 100 T-T2DM patients by using liquid chromatography-mass spectrometry. RESULTS: The T-T2DM group had significant metabolic alterations that are distinct from known diabetes risk indicators, such as body mass index, fasting plasma glucose, and glycosylated hemoglobin levels. The optimal metabolite panels for predicting T-T2DM were selected using a tenfold cross-validation random forest classification model. Compared with the clinical features, the metabolite prediction model provided a better predictive value. We also analyzed the correlation of metabolites with clinical indices and found 10 metabolites that were independently predictive of T-T2DM. CONCLUSION: By using the metabolites identified in this study, we may provide stable and accurate biomarkers for early T-T2DM warning and diagnosis. Our study also provides a rich and open-access data resource for optimizing T-T2DM management.