Serum Metabolomic and Lipidomic Profiling Reveals the Signature for Postoperative Obesity among Adult-Onset Craniopharyngioma.

Craniopharyngioma patients often suffer from a diminished quality of life after surgery, which is usually associated with metabolic disorders and hypothalamic obesity. However, the precise etiology of these conditions remains elusive. To identify the metabolic changes after surgery, we conducted a cross-sectional study using metabolomic and lipidomic analysis to profile metabolic alterations in adult-onset craniopharyngioma patients with postoperative obesity. A cohort of 120 craniopharyngioma patients who had undergone surgery were examined. Differential analyses, including clinical characteristics, serum metabolome, and lipidome, were conducted across distinct body mass index (BMI) groups. Our findings indicated no statistically significant differences in age, sex, and fasting blood glucose among postoperative craniopharyngioma patients when stratified by BMI. However, a noteworthy difference was observed in uric acid and blood lipid levels. Further investigation revealed that alterations in metabolites and lipids were evidently correlated with increased BMI, indicating that postoperative obesity of craniopharyngioma patients affected their whole-body metabolism. Additionally, the multi-omics analysis identified specific metabolites and lipids, including uric acid and DG(18:2/20:4), as contributors to the metabolic disorders associated with postoperative obesity of craniopharyngioma patients. This work provides valuable insight into the involvement of metabolites and lipids in metabolic disorders subsequent to craniopharyngioma surgery.

Genomics- and Transcriptomics-Guided Discovery of Clavatols from Arctic Fungi Penicillium sp. MYA5.

Clavatols exhibit a wide range of biological activities due to their diverse structures. A genome mining strategy identified an A5cla cluster from Penicillium sp. MYA5, derived from the Arctic plant Dryas octopetala, is responsible for clavatol biosynthesis. Seven clavatols, including one new clavatol derivate named penicophenone F (1) and six known clavatols (2-7), were isolated from Penicillium sp. MYA5 using a transcriptome mining strategy. These structures were elucidated by comprehensive spectroscopic analysis. Antibacterial, aldose reductase inhibition, and siderophore-producing ability assays were conducted on compounds 1-7. Compounds 1 and 2 demonstrated inhibitory effects on the ALR2 enzyme with inhibition rates of 75.3% and 71.6% at a concentration of 10 µM, respectively. Compound 6 exhibited antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 4.0 µg/mL and 4.0 µg/mL, respectively. Additionally, compounds 1, 5, and 6 also showed potential iron-binding ability.

Divergent and gram-scale syntheses of (-)-veratramine and (-)-cyclopamine.

Veratramine and cyclopamine, two of the most representative members of the isosteroidal alkaloids, are valuable molecules in agricultural and medicinal chemistry. While plant extraction of these compounds suffers from uncertain supply, efficient chemical synthesis approaches are in high demand. Here, we present concise, divergent, and scalable syntheses of veratramine and cyclopamine with 11% and 6.2% overall yield, respectively, from inexpensive dehydro-epi-androsterone. Our synthesis readily provides gram quantities of both target natural products by utilizing a biomimetic rearrangement to form the C-nor-D-homo steroid core and a stereoselective reductive coupling/(bis-)cyclization sequence to establish the (E)/F-ring moiety.

Free-space coupled, large-active-area superconducting microstrip single-photon detector for photon-counting time-of-flight imaging.

Numerous applications at the photon-starved regime require a free-space coupling single-photon detector with a large active area, low dark count rate (DCR), and superior time resolutions. Here, we developed a superconducting microstrip single-photon detector (SMSPD), with a large active area of 260 µm in diameter, a DCR of ∼5k c p s, and a low time jitter of ∼171p s, operated at a near-infrared of 1550 nm and a temperature of ∼2.0K. As a demonstration, we applied the detector to a single-pixel galvanometer scanning system and successfully reconstructed the object information in depth and intensity using a time-correlated photon counting technology.

Comparison of propofol-esketamine versus propofol-sufentanil for deep sedation and analgesia in children with autism: A randomized double-blind clinical trial.

Propofol sedation, routinely used for endoscopic procedures, is safe and acceptable for children. Adjuvants, such as esketamine or sufentanil, are commonly added to improve the efficacy and safety of propofol sedation. This study aimed to compare the clinical efficacy and safety of propofol-esketamine (PE) versus propofol-sufentanil (PS) for deep sedation and analgesia in children with autism undergoing colonoscopy procedure. One hundred and twenty-four children with autism undergoing colonoscopy procedure were included in the study. Patients were randomly assigned to receive one of the two adjuvants: esketamine (0.3 mg/kg) or sufentanil (0.2 µg/kg), subsequently administered propofol 2.0 mg/kg to induce anesthesia. Additional doses of propofol (0.5-1.0 mg/kg) were administered as needed to ensure patient tolerance for the remaining duration of the procedure. Movement during the procedure, hemodynamic variables, the total dose of propofol, recovery time, and adverse events were recorded. The PE group exhibited a significantly lower incidence of severe movement during the procedure compared with the PS group (14.52% vs. 32.26%, p = 0.020). The PE group showed significantly lower incidence of respiratory depression, hypotension, and severe injection pain of propofol than the PS group during the procedure (all p < 0.05). The mean arterial pressure (MAP) decreased significantly after anesthesia induction in the PS group and remained lower than baseline (all p < 0.05). Compared with the combination of low-dose sufentanil (0.2 µg/mg) with propofol, the low-dose esketamine (0.3 mg/kg) combined with propofol provided more stable hemodynamics, higher quality of sedation, and fewer adverse events in children with autism undergoing colonoscopy procedure.

Reliability and validity of the Chinese version of the Information Security Attitude Questionnaire for nurses.

AIM: Nurses play a crucial role within medical institutions, maintaining direct interaction with patient data. Despite this, there is a scarcity of tools for evaluating nurses' perspectives on patient information security. This study aimed to translate the Information Security Attitude Questionnaire into Chinese and validate its reliability and validity among clinical nurses. DESIGN: A cross-sectional design. METHODS: A total of 728 clinical nurses from three hospitals in China participated in this study. The Information Security Attitude Questionnaire (ISA-Q) was translated into Chinese utilizing the Brislin two-way translation method. The reliability was assessed through internal consistency coefficient and test-retest reliability. The validity was determined through the Delphi expert consultation method and factor analysis. RESULTS: The Chinese version of ISA-Q consists of 30 items. Cronbach's α coefficient of the questionnaire was 0.930, and Cronbach's α coefficient of the six dimensions ranged from 0.781 to 0.938. The split-half reliability and test-retest reliability were 0.797 and 0.848, respectively. The content validity index (S-CVI) was 0.962. Exploratory factor analysis revealed a 6-factor structure supported by eigenvalues, total variance interpretation, and scree plots, accounting for a cumulative variance contribution rate of 69.436%. Confirmatory factor analysis further validated the 6-factor structure, demonstrating an appropriate model fit. CONCLUSION: The robust reliability and validity exhibited by the Chinese version of ISA-Q establish it as a dependable tool for evaluating the information security attitudes of clinical nurses. IMPLICATIONS FOR NURSING PRACTICE: The Chinese iteration of the ISA-Q questionnaire offers a profound insight into the information security attitudes held by clinical nurses. This understanding serves as a foundation for nursing managers to develop targeted intervention strategies aimed at fortifying nurses' information security attitudes, thereby enhancing patient safety.

Impacts of DRG-Based Prepayment Reform on the Cost and Quality of Patients with Neurologic Disorders: Evidence from a Quasi-Experimental Analysis in Beijing, China.

Purpose: As one of the pioneering pilot cities in China's extensive Diagnosis Related Groups (DRG) -based prepayment reform, Beijing is leading a comprehensive overhaul of the prepayment system, encompassing hospitals of varying affiliations and tiers. This systematic transformation is rooted in extensive patient group data, with the commencement of actual payments on March 15, 2022. This study aims to evaluate the effectiveness of DRG payment reform by examining how it affects the cost, volume, and utilization of care for patients with neurological disorders. Patients and Methods: Utilizing the exogenous shock resulting from the implementation of the DRG-based prepayment system, we adopted the Difference-in-Differences (DID) approach to discern changes in outcome variables among DRG payment cases, in comparison to control cases, both before and following the enactment of the DRG policy. The analytical dataset was derived from patients diagnosed with neurological disorders across all hospitals in Beijing that underwent the DRG-based prepayment reform. Strict data inclusion and exclusion criteria, including reasonableness tests, were applied, defining the pre-reform timeframe as March 15th through October 31st, 2021, and the post-reform timeframe as the corresponding period in 2022. The extensive dataset encompassed 53 hospitals and encompassed hundreds of thousands of cases. Results: The implementation of DRG-based prepayment resulted in a substantial 12.6% decrease in total costs per case and a reduction of 0.96 days in length of stay. Additionally, the reform was correlated with significant reductions in overall in-hospital mortality and readmission rates. Surprisingly, the study unearthed unintended consequences, including a significant reduction in the proportion of inpatient cases classified as surgical patients and the Case Mix Index (CMI), indicating potential strategic adjustments by providers in response to the introduction of DRG payments. Conclusion: The DRG payment reform demonstrates substantial effects in restraining cost escalation and enhancing quality. Nevertheless, caution must be exercised to mitigate potential issues such as patient selection bias and upcoding.

Oil Palm AP2 Subfamily Gene EgAP2.25 Improves Salt Stress Tolerance in Transgenic Tobacco Plants.

AP2/ERF transcription factor genes play an important role in regulating the responses of plants to various abiotic stresses, such as cold, drought, high salinity, and high temperature. However, less is known about the function of oil palm AP2/ERF genes. We previously obtained 172 AP2/ERF genes of oil palm and found that the expression of EgAP2.25 was significantly up-regulated under salinity, cold, or drought stress conditions. In the present study, the sequence characterization and expression analysis for EgAP2.25 were conducted, showing that it was transiently over-expressed in Nicotiana tabacum L. The results indicated that transgenic tobacco plants over-expressing EgAP2.25 could have a stronger tolerance to salinity stress than wild-type tobacco plants. Compared with wild-type plants, the over-expression lines showed a significantly higher germination rate, better plant growth, and less chlorophyll damage. In addition, the improved salinity tolerance of EgAP2.25 transgenic plants was mainly attributed to higher antioxidant enzyme activities, increased proline and soluble sugar content, reduced H2O2 production, and lower MDA accumulation. Furthermore, several stress-related marker genes, including NtSOD, NtPOD, NtCAT, NtERD10B, NtDREB2B, NtERD10C, and NtP5CS, were significantly up-regulated in EgAP2.25 transgenic tobacco plants subjected to salinity stress. Overall, over-expression of the EgAP2.25 gene significantly enhanced salinity stress tolerance in transgenic tobacco plants. This study lays a foundation for further exploration of the regulatory mechanism of the EgAP2.25 gene in conferring salinity tolerance in oil palm.

Gualou-Xiebai-Banxia-Tang regulates liver-gut axis to ameliorate Metabolic Syndrome in HFD-fed mice.

BACKGROUND: Metabolic syndrome (MetS), characterized by obesity, hyperglycemia, and abnormal blood lipid levels, is the pathological basis of many cardiovascular diseases. Gualou-Xiebai-Banxia-Tang decoction (GT) was first described in the Synopsis of the Golden Chamber, the earliest traditional Chinese medicine (TCM) monograph on diagnosis and treatment of miscellaneous diseases in China. According to TCM precepts, based on its ability to activate yang to release stagnation, activate qi to reduce depression, remove phlegm, and broaden the chest, GT has been used for more than 2,000 years to treat cardiovascular ailments. However, the molecular bases of its therapeutic mechanisms remain unclear. PURPOSE: The aim of this study was to identify lipid- and glucose-related hepatic genes differentially regulated by GT, and to assess GT impact on gut microbiota composition, in mice with high-fat diet (HFD)-induced MetS. STUDY DESIGN AND METHODS: ApoE-/- mice were fed with an HFD for 24 weeks, with or without concurrent GT supplementation, to induce MetS. At the study's end, body weight, visceral fat weight, blood lipid levels, and insulin sensitivity were measured, and histopathological staining was used to evaluate hepatosteatosis and intestinal barrier integrity. Liver transcriptomics was used for analysis of differentially expressed genes in liver and prediction of relevant regulatory pathways. Hepatic lipid/glucose metabolism-related genes and proteins were detected by RT-qPCR and western blotting. Gut microbial composition was determined by 16S rRNA gene sequencing. RESULTS: GT administration reduced MetS-related liver steatosis and weight gain, promoted insulin sensitivity and lipid metabolism, and beneficially modulated gut microbiota composition by decreasing the relative abundance of g_Lachnospiraceae_NK4A136_group and increasing the relative abundance of g_Alistipes. Liver transcriptomics revealed that GT regulated the expression of genes related to lipid and glucose metabolism (Pparγ, Igf1, Gpnmb, and Trem2) and of genes encoding chemokines/chemokine receptors (e.g. Cxcl9 and Cx3cr1). Significant, positive correlations were found for Ccr2, Ccl4, Ccr1, and Cx3cr1 and the g_Lachnospiraceae_NK4A136_group, and between Cxcl9, Ccr2, Ccl4, and Cx3cr1 and g_Desulfovibrio. GT treatment downregulated the protein expressions of SCD1 and CX3CR1 and upregulated the expression of PCK1 protein. CONCLUSION: GT supplementation alleviates HFD-induced MetS in mice by improving hepatic lipid and glucose metabolism. The anti-metabolic syndrome effects of GT may be related to the regulation of the gut-liver axis.

Sodium p-perfluorinated noneoxybenzen sulfonate (OBS) induced neurotoxicity in zebrafish through mitochondrial dysfunction.

Sodium p-perfluorous nonenoxybenzene sulfonate (OBS)-one of the main alternatives to perfluorooctane sulfonate-has been increasingly detected in both aquatic environments and human bodies. Therefore, the pathogenic risks of OBS exposure warrant attention, especially its central nervous system toxicity mechanism under long-term exposure. In this study, the effects and mechanisms of OBS on the zebrafish brain at 40 days post exposure were examined. The results demonstrated that at 3.2 µg/L, OBS had no significant effect on the zebrafish brain, but 32 µg/L OBS caused depression or poor social behavior in zebrafish and reduced both their memory and survival ability. These changes were accompanied by histological damage and cell apoptosis. Furthermore, OBS caused the accumulation of excessive reactive oxygen species in the fish brain, leading to oxidative stress and subsequently cell apoptosis. Moreover, an imbalance of both inflammatory factors (IL-6, IL-1ß, IL-10, TNF-α, and NF-κB) and neurotransmitters (GABA and Glu) led to neuroinflammation. Additionally, 32 µg/L OBS induced decreases in mitochondrial membrane potential and Na+-K+-ATPase activity, leading to both mitochondrial structural damage and the emergence of mitochondrial autophagosomes, partly explaining the neurotoxicity of OBS. These results help to analyze the target sites and molecular mechanisms of OBS neurotoxicity and provide a basis for the scientific evaluation of its health risks to humans.

Gut microbiota dysbiosis in hyperuricaemia promotes renal injury through the activation of NLRP3 inflammasome.

BACKGROUND: The prevalence of hyperuricaemia (HUA), a metabolic disorder characterized by elevated levels of uric acid, is on the rise and is frequently associated with renal injury. Gut microbiota and gut-derived uremic toxins are critical mediators in the gut-kidney axis that can cause damage to kidney function. Gut dysbiosis has been implicated in various kidney diseases. However, the role and underlying mechanism of the gut microbiota in HUA-induced renal injury remain unknown. RESULTS: A HUA rat model was first established by knocking out the uricase (UOX). HUA rats exhibited apparent renal dysfunction, renal tubular injury, fibrosis, NLRP3 inflammasome activation, and impaired intestinal barrier functions. Analysis of 16S rRNA sequencing and functional prediction data revealed an abnormal gut microbiota profile and activation of pathways associated with uremic toxin production. A metabolomic analysis showed evident accumulation of gut-derived uremic toxins in the kidneys of HUA rats. Furthermore, faecal microbiota transplantation (FMT) was performed to confirm the effects of HUA-induced gut dysbiosis on renal injury. Mice recolonized with HUA microbiota exhibited severe renal injury and impaired intestinal barrier functions following renal ischemia/reperfusion (I/R) surgery. Notably, in NLRP3-knockout (NLRP3-/-) I/R mice, the deleterious effects of the HUA microbiota on renal injury and the intestinal barrier were eliminated. CONCLUSION: Our results demonstrate that HUA-induced gut dysbiosis contributes to the development of renal injury, possibly by promoting the production of gut-derived uremic toxins and subsequently activating the NLRP3 inflammasome. Our data suggest a potential therapeutic strategy for the treatment of renal diseases by targeting the gut microbiota and the NLRP3 inflammasome. Video Abstract.

Iodine-doped carbon nanotubes boosting the adsorption effect and conversion kinetics of lithium-sulfur batteries.

Compared with lithium-ion batteries (LIBs), lithium-sulfur batteries (LSBs), based on electrochemical reactions involving multi-step 16-electron transformations provide higher specific capacity (1672 mAh g-1) and specific energy (2600 Wh kg-1), exhibiting great potential in the field of energy storage. However, the inherent insulation of sulfur, slow electrochemical reaction kinetics and detrimental shuttle-effect of lithium polysulfides (LiPSs) restrict the development of LSBs in practical applications. Herein, the iodine-doped carbon nanotubes (I-CNTs) is firstly reported as sulfur host material to the enhance the adsorption-conversion kinetics of LSBs. Iodine doping can significantly improve the polarity of I-CNTs. Iodine atoms with lone pair electrons (Lewis base) in iodine-doped CNTs can interact with lithium cations (Lewis acidic) in LiPSs, thereby anchoring polysulfides and suppressing subsequent shuttling behavior. Moreover, the charge transfer between iodine species (electron acceptor) and CNTs (electron donor) decreases the gap band and subsequently improves the conductivity of I-CNTs. The enhanced adsorption effect and conductivity are beneficial for accelerating reaction kinetics and enhancing electrocatalytic activity. The in-situ Raman spectroscopy, quasi in-situ electrochemical impedance spectroscopy (EIS) and Li2S potentiostatic deposition current-time (i-t) curves were conducted to verify mechanism of complex sulfur reduction reaction (SRR). Owing to above advantages, the I-CNTs@S composite cathode exhibits an ultrahigh initial capacity of 1326 mAh g-1 as well as outstanding cyclicability and rate performance. Our research results provide inspirations for the design of multifunctional host material for sulfur/carbon composite cathodes in LSBs.

Towards more precise automatic analysis: a systematic review of deep learning-based multi-organ segmentation.

Accurate segmentation of multiple organs in the head, neck, chest, and abdomen from medical images is an essential step in computer-aided diagnosis, surgical navigation, and radiation therapy. In the past few years, with a data-driven feature extraction approach and end-to-end training, automatic deep learning-based multi-organ segmentation methods have far outperformed traditional methods and become a new research topic. This review systematically summarizes the latest research in this field. We searched Google Scholar for papers published from January 1, 2016 to December 31, 2023, using keywords "multi-organ segmentation" and "deep learning", resulting in 327 papers. We followed the PRISMA guidelines for paper selection, and 195 studies were deemed to be within the scope of this review. We summarized the two main aspects involved in multi-organ segmentation: datasets and methods. Regarding datasets, we provided an overview of existing public datasets and conducted an in-depth analysis. Concerning methods, we categorized existing approaches into three major classes: fully supervised, weakly supervised and semi-supervised, based on whether they require complete label information. We summarized the achievements of these methods in terms of segmentation accuracy. In the discussion and conclusion section, we outlined and summarized the current trends in multi-organ segmentation.

Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway.

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism. METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p-Akt) in the small intestine was analyzed via Western blotting. RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine. CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

Regulation of SETD2 maintains immune regulatory function in macrophages to suppress airway allergy.

SET domain-containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs.

Plexin D1 negatively regulates macrophage-derived foam cell migration via the focal adhesion kinase/Paxillin pathway.

BACKGROUND: Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis. METHODS: We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis. RESULTS: Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE-/- mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK. CONCLUSION: Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.

Peptidome profiling of human, bovine, and donkey colostrum through label-free quantitative analysis reveals proteolysis of milk proteins.

Proteins and peptides play vital roles in different biological processes in vivo. As a dynamic hydrolysis system, milk is rich in proteins and proteases and provides a constant supply of endogenous bioactive peptides to newborn mammals. Previous studies have primarily focused on researching bioactive peptides by adding exogenous enzymes to milk samples. However, such an approach overlooks the significance of endogenous peptides and parent proteins that naturally exist in milk. Herein, we analyzed and compared parent proteins and their releasing peptides in human colostrum (HC), bovine colostrum (BC), and donkey colostrum (DC). The predominant proteins and hydrolyzed peptides in the three types of milk were identified. Among them, peptides were found to possess common bioactivities, including ACE inhibitory, antioxidant, antibacterial and immunomodulatory properties in HC, BC, and DC. Furthermore, the biological functions of these parent proteins were clarified using bioinformatics. These insights offer a novel perspective on natural bioactive peptides and the potential utilization of specific parent proteins and peptides to develop infant formulae derived from diverse milk sources.

PPP1R15A-expressing monocytic MDSCs promote immunosuppressive liver microenvironment in fibrosis-associated hepatocellular carcinoma.

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy. Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro-generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models. Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A (PPP1R15A), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-ß signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-ß upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1+S100A8/9+ M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ+GZMB+CD8+ T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs. Conclusions: PPP1R15A+ M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies. Impact and implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma.

Chemical Dynamics of Selenium Nanoparticles in Archaeal Systems.

Methanogenic archaea, characterized by their cell membrane lipid molecules consisting of isoprenoid chains linked to glycerol-1-phosphate via ether bonds, exhibit exceptional adaptability to extreme environments. However, this distinct lipid architecture also complicates the interactions between methanogenic archaea and nanoparticles. This study addresses this challenge by exploring the interaction and transformation of selenium nanoparticles (SeNPs) within archaeal Methanosarcina acetivorans C2A. We demonstrated that the effects of SeNPs are highly concentration-dependent, with chemical stimulation of cellular processes at lower SeNPs concentrations as well as oxidative stress and metabolic disruption at higher concentrations. Notably, we observed the formation of a protein corona on SeNPs, characterized by the selective adsorption of enzymes critical for methylotrophic methanogenesis and those involved in selenium methylation, suggesting potential alterations in protein function and metabolic pathways. Furthermore, the intracellular transformation of SeNPs into both inorganic and organic selenium species highlighted their bioavailability and dynamic transformation within archaea. These findings provide vital insights into the nano-bio interface in archaeal systems, contributing to our understanding of archaeal catalysis and its broader applications.