The catalytic asymmetric polyene cyclization of homofarnesol to ambrox.

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon-carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1-3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (-)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4-7. Here we report a diastereoselective and enantioselective synthesis of (-)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork-Eschenmoser hypothesis8-10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Osteocalcin of maternal and embryonic origins synergize to establish homeostasis in offspring.

Many physiological osteocalcin-regulated functions are affected in adult offspring of mothers experiencing unhealthy pregnancy. Furthermore, osteocalcin signaling during gestation influences cognition and adrenal steroidogenesis in adult mice. Together these observations suggest that osteocalcin may broadly function during pregnancy to determine organismal homeostasis in adult mammals. To test this hypothesis, we analyzed in unchallenged wildtype and Osteocalcin-deficient, newborn and adult mice of various genotypes and origin maintained on different genetic backgrounds, the functions of osteocalcin in the pancreas, liver and testes and their molecular underpinnings. This analysis revealed that providing mothers are Osteocalcin-deficient, Osteocalcin haploinsufficiency in embryos hampers insulin secretion, liver gluconeogenesis, glucose homeostasis, testes steroidogenesis in adult offspring; inhibits cell proliferation in developing pancreatic islets and testes; and disrupts distinct programs of gene expression in these organs and in the brain. This study indicates that osteocalcin exerts dominant functions in most organs it influences. Furthermore, through their synergistic regulation of multiple physiological functions, osteocalcin of maternal and embryonic origins contributes to the establishment and maintenance of organismal homeostasis in newborn and adult offspring.

Genome-wide association analysis identify candidate genes for feed efficiency and growth traits in Wenchang chickens.

BACKGROUND: Wenchang chickens are one of the most popular local chicken breeds in the Chinese chicken industry. However, the low feed efficiency is the main shortcoming of this breed. Therefore, there is a need to find a more precise breeding method to improve the feed efficiency of Wenchang chickens. In this study, we explored important candidate genes and variants for feed efficiency and growth traits through genome-wide association study (GWAS) analysis. RESULTS: Estimates of genomic heritability for growth and feed efficiency traits, including residual feed intake (RFI) of 0.05, average daily food intake (ADFI) of 0.21, average daily weight gain (ADG) of 0.24, body weight (BW) at 87, 95, 104, 113 days of age (BW87, BW95, BW104 and BW113) ranged from 0.30 to 0.44. Important candidate genes related to feed efficiency and growth traits were identified, such as PLCE1, LAP3, MED28, QDPR, LDB2 and SEL1L3 genes. CONCLUSION: The results identified important candidate genes for feed efficiency and growth traits in Wenchang chickens and provide a theoretical basis for the development of new molecular breeding technology.

Cuprotosis clusters predict prognosis and immunotherapy response in low-grade glioma.

Cuprotosis, an emerging mode of cell death, has recently caught the attention of researchers worldwide. However, its impact on low-grade glioma (LGG) patients has not been fully explored. To gain a deeper insight into the relationship between cuprotosis and LGG patients' prognosis, we conducted this study in which LGG patients were divided into two clusters based on the expression of 18 cuprotosis-related genes. We found that LGG patients in cluster A had better prognosis than those in cluster B. The two clusters also differed in terms of immune cell infiltration and biological functions. Moreover, we identified differentially expressed genes (DEGs) between the two clusters and developed a cuprotosis-related prognostic signature through the least absolute shrinkage and selection operator (LASSO) analysis in the TCGA training cohort. This signature divided LGG patients into high- and low-risk groups, with the high-risk group having significantly shorter overall survival (OS) time than the low-risk group. Its predictive reliability for prognosis in LGG patients was confirmed by the TCGA internal validation cohort, CGGA325 cohort and CGGA693 cohort. Additionally, a nomogram was used to predict the 1-, 3-, and 5-year OS rates of each patient. The analysis of immune checkpoints and tumor mutation burden (TMB) has revealed that individuals belonging to high-risk groups have a greater chance of benefiting from immunotherapy. Functional experiments confirmed that interfering with the signature gene TNFRSF11B inhibited LGG cell proliferation and migration. Overall, this study shed light on the importance of cuprotosis in LGG patient prognosis. The cuprotosis-related prognostic signature is a reliable predictor for patient outcomes and immunotherapeutic response and can help to develop new therapies for LGG.

Identifying drug-target interactions via heterogeneous graph attention networks combined with cross-modal similarities.

Accurate identification of drug-target interactions (DTIs) plays a crucial role in drug discovery. Compared with traditional experimental methods that are labor-intensive and time-consuming, computational methods are more and more popular in recent years. Conventional computational methods almost simply view heterogeneous networks which integrate diverse drug-related and target-related dataset instead of fully exploring drug and target similarities. In this paper, we propose a new method, named DTIHNC, for $\mathbf{D}$rug-$\mathbf{T}$arget $\mathbf{I}$nteraction identification, which integrates $\mathbf{H}$eterogeneous $\mathbf{N}$etworks and $\mathbf{C}$ross-modal similarities calculated by relations between drugs, proteins, diseases and side effects. Firstly, the low-dimensional features of drugs, proteins, diseases and side effects are obtained from original features by a denoising autoencoder. Then, we construct a heterogeneous network across drug, protein, disease and side-effect nodes. In heterogeneous network, we exploit the heterogeneous graph attention operations to update the embedding of a node based on information in its 1-hop neighbors, and for multi-hop neighbor information, we propose random walk with restart aware graph attention to integrate more information through a larger neighborhood region. Next, we calculate cross-modal drug and protein similarities from cross-scale relations between drugs, proteins, diseases and side effects. Finally, a multiple-layer convolutional neural network deeply integrates similarity information of drugs and proteins with the embedding features obtained from heterogeneous graph attention network. Experiments have demonstrated its effectiveness and better performance than state-of-the-art methods. Datasets and a stand-alone package are provided on Github with website https://github.com/ningq669/DTIHNC.

YTHDF2 Regulates Cell Growth and Cycle by Facilitating KDM1A mRNA Stability.

Breast cancer is the leading cause of cancer death in women. The physiological functions of N6-methyladenosine methylation in cancer have been the focus of studies in recent years. Herein, four data sets (GSE70947, GSE45827, GSE42586, and The Cancer Genome Atlas Breast Cancer) were analyzed to confirm the differentially expressed N6-methyladenosine genes. YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) was found to be highly expressed in breast cancer tissues and cells. In vitro, YTHDF2 affects cell proliferation, cell cycle, and invasive ability. Tumorigenesis in xenograft nude mice confirmed that YTHDF2 interference reduced the tumor formation ability of cancer cells. Pearson correlation analysis demonstrated a positive correlation between YTHDF2 and lysine-specific histone demethylase 1A (KDM1A) expression. An online tool, Sequence-based RNA Adenosine Methylation Site Predictor (SRAMP), predicted eight methylation sites in the KDM1A mRNA sequence. The expression of KDM1A was dramatically increased in breast cancer tissues and cells. Down-regulation of YTHDF2 reduced KDM1A expression and the methylation level of KDM1A mRNA. YTHDF2 interference promoted the degradation of KDM1A mRNA, which suggested an interaction between YTHDF2 and KDM1A. KDM1A interference altered cell proliferation, cell cycle, and invasive ability, whereas YTHDF2 overexpression rescued KDM1A interference-induced cell phenotypic changes. In conclusion, YTHDF2 promotes breast cancer cell growth and cell cycle progression by facilitating KDM1A mRNA stability. This study provides new therapeutic targets for breast cancer treatment in the future.

3-ketoacyl-CoA synthase 19 contributes to the biosynthesis of seed lipids and cuticular wax in Arabidopsis and abiotic stress tolerance.

Very-long-chain fatty acids (VLCFAs) are essential precursors for plant membrane lipids, cuticular waxes, suberin, and storage oils. Integral to the fatty acid elongase (FAE) complex, 3-ketoacyl-CoA synthases (KCSs) function as crucial enzymes in the VLCFA pathway, determining the chain length of VLCFA. This study explores the in-planta role of the KCS19 gene. KCS19 is predominantly expressed in leaves and stem epidermis, sepals, styles, early silique walls, beaks, pedicels, and mature embryos. Localized in the endoplasmic reticulum, KCS19 interacts with other FAE proteins. kcs19 knockout mutants displayed reduced total wax and wax crystals, particularly alkanes, while KCS19 overexpression increased these components and wax crystals. Moreover, the cuticle permeability was higher for the kcs19 mutants compared to the wild type, rendering them more susceptible to drought and salt stress, whereas KCS19 overexpression enhanced drought and salt tolerance. Disrupting KCS19 increased C18 species and decreased C20 and longer species in seed fatty acids, indicating its role in elongating C18 to C20 VLCFAs, potentially up to C24 for seed storage lipids. Collectively, KCS19-mediated VLCFA synthesis is required for cuticular wax biosynthesis and seed storage lipids, impacting plant responses to abiotic stress.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which defective T cells, immune complex deposition and other immune system alterations contribute to pathological changes of multiple organ systems. The vitamin D metabolite c is a critical immunomodulator playing pivotal roles in the immune system. Epidemiological evidence indicates that vitamin D deficiency is correlated with the severity of SLE. Our aim is to investigate the effects of 1,25(OH)2D3 (VitD3) on the activation of myeloid dendritic cells (mDCs) by autologous DNA-containing immune complex (DNA-ICs), and the effects of VitD3 on immune system balance during SLE. We purified DNA-ICs from the serum of SLE patients and isolated mDCs from normal subjects. In vitro studies showed that DNA-ICs were internalized and consumed by mDCs. VitD3 blocked the effects of DNA-ICs on RelB, IL-10 and TNF-α in mDCs. Further analysis indicated that DNA-ICs stimulated histone acetylation in the RelB promoter region, which was inhibited by VitD3. Knockdown of the histone deacetylase 3 gene (HDAC3) blocked these VitD3-mediated effects. Co-culture of mDCs and CD4+ T cells showed that VitD3 inhibited multiple processes mediated by DNA-ICs, including proliferation, downregulation of IL-10, TGF-ß and upregulation of TNF-α. Moreover, VitD3 could also reverse the effects of DNA-IC-induced imbalance of CD4+ CD127- Foxp3+ T cells and CD4+ IL17+ T cells. Taken together, our results indicated that autologous DNA-ICs stimulate the activation of mDCs in the pathogenesis of SLE, and VitD3 inhibits this stimulatory effects of DNA-ICs by negative transcriptional regulation of RelB gene and maintaining the Treg/Th17 immune cell balance. These results suggest that vitamin D may have therapeutic value for the treatment of SLE.

Brainnetome atlas of preadolescent children based on anatomical connectivity profiles.

During the preadolescent period, when the cerebral thickness, curvature, and myelin are constantly changing, the brain's regionalization patterns underwent persistent development, contributing to the continuous improvements of various higher cognitive functions. Using a brain atlas to study the development of these functions has attracted much attention. However, the brains of children do not always have the same topological patterns as those of adults. Therefore, age-specific brain mapping is particularly important, serving as a basic and indispensable tool to study the normal development of children. In this study, we took advantage of longitudinal data to create the brain atlas specifically for preadolescent children. The resulting human Child Brainnetome Atlas, with 188 cortical and 36 subcortical subregions, provides a precise period-specific and cross-validated version of the brain atlas that is more appropriate for adoption in the preadolescent period. In addition, we compared and illustrated for regions with different topological patterns in the child and adult atlases, providing a topologically consistent reference for subsequent research studying child and adolescent development.

Two subtypes of schizophrenia identified by an individual-level atypical pattern of tensor-based morphometric measurement.

Difficulties in parsing the multiaspect heterogeneity of schizophrenia (SCZ) based on current nosology highlight the need to subtype SCZ using objective biomarkers. Here, utilizing a large-scale multisite SCZ dataset, we identified and validated 2 neuroanatomical subtypes with individual-level abnormal patterns of the tensor-based morphometric measurement. Remarkably, compared with subtype 1, which showed moderate deficits of some subcortical nuclei and an enlarged striatum and cerebellum, subtype 2, which showed cerebellar atrophy and more severe subcortical nuclei atrophy, had a higher subscale score of negative symptoms, which is considered to be a core aspect of SCZ and is associated with functional outcome. Moreover, with the neuroimaging-clinic association analysis, we explored the detailed relationship between the heterogeneity of clinical symptoms and the heterogeneous abnormal neuroanatomical patterns with respect to the 2 subtypes. And the neuroimaging-transcription association analysis highlighted several potential heterogeneous biological factors that may underlie the subtypes. Our work provided an effective framework for investigating the heterogeneity of SCZ from multilevel aspects and may provide new insights for precision psychiatry.

A nomogram for predicting 28-day mortality in elderly patients with acute kidney injury receiving continuous renal replacement therapy: a secondary analysis based on a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) is a common and serious condition, particularly among elderly patients. It is associated with high morbidity and mortality rates, further compounded by the need for continuous renal replacement therapy in severe cases. To improve clinical decision-making and patient management, there is a need for accurate prediction models that can identify patients at a high risk of mortality. METHODS: Data were extracted from the Dryad Digital Repository. Multivariate analysis was performed using least absolute shrinkage and selection operator (LASSO) logistic regression analysis to identify independent risk factors and construct a predictive nomogram for mortality within 28 days after continuous renal replacement therapy in elderly patients with acute kidney injury. The discrimination of the model was evaluated in the validation cohort using the area under the receiver operating characteristic curve (AUC), and calibration was evaluated using a calibration curve. The clinical utility of the model was assessed using decision curve analysis (DCA). RESULTS: A total of 606 participants were enrolled and randomly divided into two groups: a training cohort (n = 424) and a validation cohort (n = 182) in a 7:3 proportion. A risk prediction model was developed to identify independent predictors of 28-day mortality in elderly patients with AKI. The predictors included age, systolic blood pressure, creatinine, albumin, phosphorus, age-adjusted Charlson Comorbidity Index (CCI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and sequential organ failure assessment (SOFA) score. These predictors were incorporated into a logistic model and presented in a user-friendly nomogram. In the validation cohort, the model demonstrated good predictive performance with an AUC of 0.799. The calibration curve showed that the model was well calibrated. Additionally, DCA revealed significant net benefits of the nomogram for clinical application. CONCLUSION: The development of a nomogram for predicting 28-day mortality in elderly patients with AKI receiving continuous renal replacement therapy has the potential to improve prognostic accuracy and assist in clinical decision-making.

Mining Candidate Genes and Identifying Risk Factors for Leg Disease in Broilers: A Mendelian Randomization Study.

Clinical investigations have highlighted disruptions in bone metabolic processes and abnormal fluctuations in serum indicator levels during the onset of leg disease (LD) in broilers. However, the presence of a genetic causal relationship for this association remains undetermined. Therefore, the aim of this study is to discern the risk factors underlying LD development using 1235 sequenced white-feathered broilers. We employed Mendelian randomization (MR) analysis to assess the associations of bone strength (BS), bone mineral density (BMD), tibial bone weight (TBW), tibial bone length (TBL), tibial bone diameter (TBD), bone ash (BA), ash calcium (Ash Ca), ash phosphorus (Ash P), serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (ALP), and serum osteoprotegerin (OPG) with the incidence of LD. Compelling evidence underscores a causal link between the risk of developing LD and decreased BMD (odds ratio (OR) = 0.998; 95% CI: 0.983, 0.993; P < 0.001) and narrower TBD (OR = 0.985, 95% CI: 0.975, 0.994, P = 0.002). Additionally, serum OPG concentrations (OR: 0.995, 95% CI: 0.992, 0.999, P = 0.008) were associated with BMD (OR = 0.0078, 95% CI = 0.0043 to 0.0140, P < 0.001), indicating a robust genetic relationship between ALP concentrations (OR: 0.988, 95% CI: 0.984, 0.993, P < 0.001) and TBD (OR = 0.0046, 95% CI = 0.0026, 0.0083, P < 0.001). Moreover, elevated serum Ca (OR: 0.564, 95% CI: 0.487, 0.655, P < 0.001) and P (OR: 0.614, 95% CI: 0.539, 0.699, P < 0.001) levels were associated with a narrower TBD. Elevated serum levels of Ca, P, ALP, and OPG contribute to disturbances in bone metabolism, while decreased BMD and narrower TBD are associated with a greater risk of developing LD in broilers. This discovery elucidates the metabolic risk factors for LD in broilers and could provide information on LDs, such as osteoporosis, in humans.

Protective role of the novel cytokine Metrnl/ interleukin-41 in host immunity defense during sepsis by promoting macrophage recruitment and modulating Treg/Th17 immune cell balance.

BACKGROUND: Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited. METHODS: The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-α), interleukin (IL-1)ß, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis. RESULTS: The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (≤ 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-α, IL-1ß, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wild-type (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli. CONCLUSIONS: The present proof-of-concept work suggests that Metrnl-mediated recruitment of macrophages significantly affects sepsis defense in the host and modulates the Treg/Th17 immune cell balance. Findings in this work shed more light on the development of host-directed treatments that can be used to manipulate host immunity to treat sepsis.

Pt-functionalized Amorphous RuOx as Excellent Stability and High-activity Catalysts for Low Temperature MEMS Sensors.

The unsaturated coordination and abundant active sites endow amorphous metals with tremendous potential in improving metal oxide semiconductors' gas-sensing properties. However, the amorphous materials maintain the metastable status and easily transfer into the lower-active crystals during the gas-sensing process at high working temperatures, significantly limiting their further applications. Here, a bimetal amorphous PtRu catalyst is developed by accurately regulating the introduction of Pt species into amorphous RuOx supports to realize the highly active and stable H2 S gas-sensing detection. It is found that incorporation of low-concentration Pt species can effectively maintain the amorphous state of initial RuOx and delay the crystallization temperature as high as 100 °C. Further, ex situ XPS and in situ Raman spectroscopy analysis confirm that active Pt species can facilitate H2 S adsorption by strong Pt-S coordination and dissociate the sulfur species to the surrounding support, which contribute to the chemisorption and sensitization of H2 S. Meanwhile, electron transport at the interface between Pt, RuOx and ZnO further activates the reaction process at the surface of the gas-sensitive material. The final PtRu-modified ZnO (PtRu/ZnO) sensor enables the detection of H2 S in the ultra-low concentration range of 15-2000 ppb with remarkable stability.

Kinetics-Driven Dual Hydrogen Spillover Effects for Ultrasensitive Hydrogen Sensing.

Palladium (Pd)-modified metal oxide semiconductors (MOSs) gas sensors often exhibit unexpected hydrogen (H2 ) sensing activity through a spillover effect. However, sluggish kinetics over a limited Pd-MOS surface seriously restrict the sensing process. Here, a hollow Pd-NiO/SnO2 buffered nanocavity is engineered to kinetically drive the H2 spillover over dual yolk-shell surface for the ultrasensitive H2 sensing. This unique nanocavity is found and can induce more H2 absorption and markedly improve kinetical H2 ab/desorption rates. Meanwhile, the limited buffer-room allows the H2 molecules to adequately spillover in the inside-layer surface and thus realize dual H2 spillover effect. Ex situ XPS, in situ Raman, and density functional theory (DFT) analysis further confirm that the Pd species can effectively combine H2 to form Pd-H bonds and then dissociate the hydrogen species to NiO/SnO2 surface. The final Pd-NiO/SnO2 sensors exhibit an ultrasensitive response (0.1-1000 ppm H2 ) and low actual detection limit (100 ppb) at the operating temperature of 230 °C, which surpass that of most reported H2 sensors.

Engineered ATG8-binding motif-based selective autophagy to degrade proteins and organelles in planta.

Protein-targeting technologies represent essential approaches in biological research. Protein knockdown tools developed recently in mammalian cells by exploiting natural degradation mechanisms allow for precise determination of protein function and discovery of degrader-type drugs. However, no method to directly target endogenous proteins for degradation is currently available in plants. Here, we describe a novel method for targeted protein clearance by engineering an autophagy receptor with a binder to provide target specificity and an ATG8-binding motif (AIM) to link the targets to nascent autophagosomes, thus harnessing the autophagy machinery for degradation. We demonstrate its specificity and broad potentials by degrading various fluorescence-tagged proteins, including cytosolic mCherry, the nucleus-localized bZIP transcription factor TGA5, and the plasma membrane-anchored brassinosteroid receptor BRI1, as well as fluorescence-coated peroxisomes, using a tobacco-based transient expression system. Stable expression of AIM-based autophagy receptors in Arabidopsis further confirms the feasibility of this approach in selective autophagy of endogenous proteins. With its wide substrate scope and its specificity, our concept of engineered AIM-based selective autophagy could provide a convenient and robust research tool for manipulating endogenous proteins in plants and may open an avenue toward degradation of cytoplasmic components other than proteins in plant research.

Meta-analysis of proton pump inhibitor use and the risk of developing gastric cancer or colorectal cancer.

To evaluate the relationship between the use of proton pump inhibitors (PPI) and the risk of gastric cancer and colorectal cancer by using meta-analysis. Computer search PUBMED, EMBASE, Cochrane Library, CNKI and Wanfang database to obtain relevant literature on the use of PPI and the risk of gastric cancer and colorectal cancer, extract relevant data, and use Stata14.0 for Meta-analysis. A total of 24 articles were included, including 12 articles for gastric cancer and 12 articles for colorectal cancer. A total of 5 313 749 persons were included in the study and analysis. Meta-analysis results showed that the risk of gastric cancer in PPI users was significantly increased [risk ratio (RR) = 2.04, 95% confidence interval (CI) (1.33-2.75)], and the regional subgroup analysis results showed that in Europe [RR = 2.01, 95% CI (0.92, 3.09), P < 0.05] and Asia [RR = 2.15, 95% CI (1.16, 3.14), P < 0.05] This risk is higher, and Asia is higher than Europe. The risk of colorectal cancer is slightly increased [RR = 1. 22, 95% CI (1.03, 1.40, P < 0.05], and the regional subgroup analysis results show that in Europe [RR = 1.05 95% CI (0.98, 1.12), P < 0.05] and Asia [RR = 1.18, 95% CI (1.10, 1.27), P < 0.05]. This risk is low, but Asia is higher than Europe. The use of PPI significantly increases gastric cancer However, the risk of colorectal cancer is not significantly increased. The risk of gastric cancer and colorectal cancer in the population using PPI in Asia is higher than that in Europe.

Treatment-related gastrointestinal adverse events of nivolumab plus ipilimumab in randomized clinical trials: a systematic review and meta-analysis.

The authors used a meta-analysis to evaluate the risks of gastrointestinal adverse events in the cotreatment of malignant tumors with nivolumab and ipilimumab. The meta-analysis revealed that the most common gastrointestinal adverse event at all grades was diarrhea, followed by nausea, decreased appetite, vomiting, constipation, colitis and abdominal pain. The most common severe gastrointestinal adverse events were colitis and diarrhea. Different administration schemes differ in the risk of such events, and thus these events may be minimized by modulating the administration scheme of the cotreatment.

Corrigendum: MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

This corrects the article DOI: 10.1038/nature21697.

MC4R-dependent suppression of appetite by bone-derived lipocalin 2.

Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood-brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.