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Abstract Autoimmune attack toward pancreatic β cells causes permanent loss of glucose homeostasis in type 1 diabetes (T1D). Insulin secretory granules store and secrete insulin but are also thought to be tissue messengers for T1D. Here, we show that the crinophagic granules (crinosome), a minor set of vesicles formed by fusing lysosomes with the conventional insulin dense-core granules (DCG), are pathogenic in T1D development in mouse models. Pharmacological inhibition of crinosome formation in β cells delays T1D progression without affecting the dominant DCGs. Mechanistically, crinophagy inhibition diminishes the epitope repertoire in pancreatic islets, including cryptic, modified and disease-relevant epitopes derived from insulin. These unconventional insulin epitopes are largely undetectable in the MHC-II epitope repertoire of the thymus, where only canonical insulin epitopes are presented. CD4+ T cells targeting unconventional insulin epitopes display autoreactive phenotypes, unlike tolerized T cells recognizing epitopes presented in the thymus. Thus, the crinophagic pathway emerges as a tissue-intrinsic mechanism that transforms insulin from a signature thymic self-protein to a critical autoantigen by creating a peripheral-thymic mismatch in the epitope repertoire.

Summary: The lymphatic fluid is the conduit by which part of the tissue “omics” is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the lymph inflammatory and damage-associated molecular pattern signatures, microbiome-derived by-products, and immunomodulatory molecules, including metabolites of the gut-brain axis, mapped in the afferent mesenteric lymph. Our data point to the relevance of the lymphatic fluid to probe the tissue-specific antigenic and inflammatory load transported to the draining lymph node for immunosurveillance.

There is accumulating evidence that pathogenic T cells in T1D recognize epitopes formed by post-translational modifications of β-cell antigens, including hybrid insulin peptides (HIPs). The ligands for several CD4 T-cell clones derived from the NOD mouse are HIPs composed of a fragment of proinsulin joined to peptides from endogenous β-cell granule proteins. The diabetogenic T-cell clone BDC-6.9 reacts to a fragment of C-peptide fused to a cleavage product of pro-islet amyloid polypeptide (6.9HIP). In this study, we used a monoclonal antibody (MAb) to the 6.9HIP to determine when and where HIP antigens are present in NOD islets during disease progression and with which immune cells they associate. Immunogold labeling of the 6.9HIP MAb and organelle-specific markers for electron microscopy were employed to map the subcellular compartment(s) in which the HIP is localized within β-cells. While the insulin B9-23 peptide was present in nearly all islets, the 6.9HIP MAb stained infiltrated islets only in NOD mice at advanced stages of T1D development. Islets co-stained with the 6.9HIP MAb and antibodies to mark insulin, macrophages, and dendritic cells indicate that 6.9HIP co-localizes within insulin-positive β-cells as well as intra-islet antigen-presenting cells (APCs). In electron micrographs, the 6.9HIP co-localized with granule structures containing insulin alone or both insulin and LAMP1 within β-cells. Exposing NOD islets to the endoplasmic reticulum (ER) stress inducer tunicamycin significantly increased levels of 6.9HIP in subcellular fractions containing crinosomes and dense-core granules (DCGs). This work demonstrates that the 6.9HIP can be visualized in the infiltrated islets and suggests that intra-islet APCs may acquire and present HIP antigens within islets.

Cronobacter sakazakii is an opportunistic foodborne pathogen primarily found in powdered infant formula (PIF). To date, it remains challenging to control the growth of this ubiquitous bacterium. Herein, antimicrobial photodynamic inactivation (aPDI) was first employed to inactivate C. sakazakii. Through 460 nm light irradiation coupled with hypocrellin B, the survival rate of C. sakazakii was diminished by 3~4 log. The photokilling effect was mediated by the attenuated membrane integrity, as evidenced by PI staining. Besides, scanning electron microscopy showed the deformed and aggregated cell cluster, and intracellular ROS was augmented by 2~3 folds when light doses increase. In addition to planktonic cells, the biofilm formation of C. sakazakii was also affected, showing an OD590nm decline from 0.85 to 0.25. In terms of molecular aspects, a two-component system called CpxRA, along with their target genes, was deregulated during illumination. Using the knock-out strain of ΔCpxA, the bacterial viability was reduced by 2 log under aPDI, a wider gap than the wildtype strain. Based on the promoted expression of CpxR and OmpC, aPDI is likely to play its part through attenuating the function of CpxRA-OmpC pathway. Finally, the aPDI system was applied to PIF, and C. sakazakii was inactivated under various desiccated or heated storage conditions. Collectively, aPDI serves as an alternative approach to decontaminate C. sakazakii, providing a new strategy to reduce the health risks caused by this prevalent foodborne pathogen.

Acute kidney injury (AKI) is a complex kidney disorder that leads to numerous complications, such as elevated nitrogenous wastes, metabolic acidosis, high potassium levels and even death. The pathogenesis of AKI is very complicated, and its causes are commonly categorized as prerenal, intrinsic or postrenal. In the past few years, evidence has accumulated showing that non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have significant potential to aid the development of diagnostic and therapeutic strategies of AKI. In this review, we briefly summarize the current understanding of the mechanisms underlying AKI and the main functions of ncRNAs. We mainly focus on revealing the functions of miRNAs (e.g., miR-21, miR-24, miR-30 family, miR-126, miR-127, miR-150, miR-494 and miR-687) and lncRNAs (e.g., TapSAKI, AK139328 and lncRNA-PRINS) in the pathogenesis of AKI.

In this paper, finite-time synchronization of neural networks (NNs) with discontinuous activation functions (DAFs), Markovian switching, and proportional delays is studied in the framework of Filippov solution. Since proportional delay is unbounded and different from infinite-time distributed delay and classical finite-time analytical techniques are not applicable anymore, new 1-norm analytical techniques are developed. Controllers with and without the sign function are designed to overcome the effects of the uncertainties induced by Filippov solutions and further synchronize the considered NNs in a finite time. By designing new Lyapunov functionals and using M-matrix method, sufficient conditions are derived to guarantee that the considered NNs realize synchronization in a settling time without introducing any free parameters. It is shown that, though the proportional delay can be unbounded, complete synchronization can still be realized, and the settling time can be explicitly estimated. Moreover, it is discovered that controllers with sign function can reduce the control gains, while controllers without the sign function can overcome chattering phenomenon. Finally, numerical simulations are given to show the effectiveness of theoretical results.

There is accumulating evidence that pathogenic T cells in T1D recognize epitopes formed by post-translational modifications of β-cell antigens, including hybrid insulin peptides (HIPs). The ligands for several CD4 T-cell clones derived from the NOD mouse are HIPs composed of a fragment of proinsulin joined to peptides from endogenous β-cell granule proteins. The diabetogenic T-cell clone BDC-6.9 reacts to a fragment of C-peptide fused to a cleavage product of pro-islet amyloid polypeptide (6.9HIP). In this study, we used a monoclonal antibody (MAb) to the 6.9HIP to determine when and where HIP antigens are present in NOD islets during disease progression and with which immune cells they associate. Immunogold labeling of the 6.9HIP MAb and organelle-specific markers for electron microscopy were employed to map the subcellular compartment(s) in which the HIP is localized within β-cells. While the insulin B9-23 peptide was present in nearly all islets, the 6.9HIP MAb stained infiltrated islets only in NOD mice at advanced stages of T1D development. Islets co-stained with the 6.9HIP MAb and antibodies to mark insulin, macrophages, and dendritic cells indicate that 6.9HIP co-localizes within insulin-positive β-cells as well as intra-islet antigen-presenting cells (APCs). In electron micrographs, the 6.9HIP co-localized with granule structures containing insulin alone or both insulin and LAMP1 within β-cells. Exposing NOD islets to the endoplasmic reticulum (ER) stress inducer tunicamycin significantly increased levels of 6.9HIP in subcellular fractions containing crinosomes and dense-core granules (DCGs). This work demonstrates that the 6.9HIP can be visualized in the infiltrated islets and suggests that intra-islet APCs may acquire and present HIP antigens within islets. [ABSTRACT FROM AUTHOR]

In the general smelting process, nonmetallic compounds manifest as inclusions. These inclusions, typically larger than 5 μm, can significantly reduce the strength, toughness, and processability of steel. More critically, they pose a threat to the service life of steel. To mitigate these adverse effects, the practice of inclusion modification has been developed. Typically, calcium and magnesium elements are employed for this purpose. However, despite these efforts, the size of modified inclusions often remains at the micron level. Although there is some improvement in mechanical properties, the presence of these inclusions still compromises the steel matrix. Therefore, controlling the size, quantity, and distribution of nonmetallic inclusions during steel manufacturing becomes imperative. When inclusions are reduced to nanometer size, the formation of a high density of nanosized second-phase particles can substantially improve the strength and toughness of the steel. In this study, we prepared Fe–0.04C–1.5Mn–0.5Ti–0.5Al2O3 (Fe–TAMO) steel by applying a dynamic magnetic field during the smelting process. This was followed by grain size optimization and equiaxed optimization through rolling and annealing processes. Transmission electron microscopy revealed that the second-phase particles were uniformly dispersed within the as-cast Fe–TAMO steel matrix. The density of these particles reached 3.3 × 1015 m−2, with an average diameter of 2.75 ± 0.803 nm. Energy-dispersive x-ray spectroscopy analysis identified these particles as oxides of Ti–Al–Mn. The compressive mechanical properties of Fe–TAMO steel, in its as-cast, as-rolled, and as-annealed states, were evaluated using a universal testing machine. The grain size of the as-cast Fe–TAMO steel is 143 μm, with a compressive yield strength of 150 MPa, approximately double that of as-cast pure ferritic steel. After rolling, the grain size decreased to 119 μm, and the compressive yield strength increased to 484 MPa. Following annealing, the grain size was further reduced to 64 μm, with a compressive yield strength of 334 MPa. These results demonstrate that the applied method effectively minimizes the size of the second-phase particles, with most controlled within 5 nm. The densely distributed second-phase nanoparticles significantly improve the steel strength, while subsequent heat treatments allow for adjustments in grain size to further enhance mechanical properties. This method streamlines the process flow to a single step, achieving uniform dispersion of ultrafine nanosized second-phase particles in the steel matrix in about a mere 3 minutes. Moreover, it holds great potential for industrial production, offering a new avenue for the mass production of high-performance steel.

Abstract Introduction Different initial manifestations of peritoneal dialysis-associated peritonitis (PDAP) may depend on the type of pathogenic organism. We investigated the association between the clinical characteristics of PDAP and susceptibility to vancomycin and investigated the possibility of using vancomycin monotherapy alone as an initial treatment regimen for some PDAP patients to avoid unnecessary antibiotic exposure and secondary infection. Methods Patients with culture-positive PDAP were retrospectively analyzed and divided into two groups: peritonitis with only cloudy effluent (PDAP-cloudy) or with cloudy effluent, abdominal pain and/or fever (PDAP-multi). The bacterial culture of PD effluent and antibiotic sensitivity test results were compared between groups. Logistic regression was used to investigate factors predicting susceptibility to vancomycin. Results Of 162 episodes of peritonitis which had a positive bacterial culture of PD fluid, 30 peritonitis were in the PDAP-cloudy group, and 132 peritonitis were in the PDAP-multi group. Thirty (100%) peritonitis in the PDAP-cloudy group had gram-positive bacterial infections, which was significantly greater than that in the PDAP-multi group (51.5%) (P

Paralytic shellfish toxins (PSTs) pose significant ecological and food safety hazards in China and the world. Consequently, there is a global consensus to intensify safety monitoring of these toxins to safeguard consumers. In recent years, the occurrence of harmful algal blooms (known as "red tides") has increased due to human activities and climate change. The contamination risk posed by PSTs is a pressing concern. This problem poses significant ecological and food safety risks in China and the world, leading to a global consensus on strengthening the safety monitoring of PSTs to ensure consumer safety. Several countries and regions, including the European Union, the United States, and Canada, have established strict regulatory limits (800 μg STXeq/kg) for PSTs and implemented monitoring programs. Currently, the main methods for detecting and monitoring PSTs include enzyme-linked immunosorbent assay, mouse bioassay, high-performance liquid chromatography, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Among them, LC-MS/MS has gained international attention due to its high throughput and sensitivity, allowing detailed analysis of toxin profiles in contaminated shellfish. However, the complexity of aquatic food matrices often introduces interference during detection, affecting the accuracy and precision of the results. Using matrix reference materials as quality controls during the analysis can effectively mitigate the errors caused by matrix effects. In recent years, research has been conducted in China on the preparation techniques of matrix reference materials. However, existing techniques have limitations, such as unstable raw materials, limited toxin types, and lack of commercial production. There is still a lack of PST standard materials in China that possess traceability, certification, and physical specimens. To meet the quality control and validation needs for PST detection and analysis, and to enhance the regulation of shellfish quality and safety, the preparation of various PST matrix reference materials has become a top priority.In this study, six PST-producing algae species from four major Chinese coastal areas were compared as the raw material for toxin production: Alexandrium catenella (GY-H25), Gymnodinium catenatum (GY-H65), Alexandrium tamarense (GY-H31 and AT5-3), Alexandrium pacificum (TI0989), and Alexandrium minutum (GY-H46). Through three-step extended culture, all strains achieved mean cell densities ranging from 4.0 × 106 to 4.0 × 107 cells/L. Single cell toxin producing capacity was ordered from highest to lowest as GY-H46, GY-H31, AT5-3, GY-H25, GY-H65, and TI0989. After comparing the toxin production per cell, algal cell density, and toxin composition of the six strains, GY-H46, GY-H31, GY-H25, and GY-H65 were selected for the exposure experiments. These four species of toxic algae (up to 1.0 × 105 cells) were fed to mussels (Mytilus galloprovincialis) for 7 days under controlled conditions. The results demonstrated that the toxin composition of contaminated mussels clustered with those of the causative algae and may separate from one another significantly during the different accumulation phases. GY-H46, GY-H31, and GY-H25 showed consistent toxin profiles with those found in mussels, but varied in the proportions of individual toxin components. GY-H65 exhibited significant differences in toxin composition and proportions in mussels. We also detected a new conversion component (dcSTX) with a maximum proportion of 29.6%. The proportion of dcNEO increased from 1.9% to 13.2% in GY-H65 and mussels. In addition, a high proportion of conversion from C2 to C1 was observed in mussels fed GY-H25 and GY-H65. The mean accumulation rates of toxins from the four toxic algae species in mussels ranged from 39.7% to 83.1%, with the highest toxicity reaching (1, 151.0 ± 7.6) μg STXeq/kg in mussels. Individual exposure experiments with the four toxic algae species demonstrated that mussels are capable of accumulating multiple components and high levels of PSTs. Based on the above observations, the feeding ratios of the low- and high-density groups in the mixed exposure experiment were determined as 1∶1∶1 ∶4 and 1∶1.6∶2.4∶8 for GY-H25, GY-H65, GY-H31, and GY-H46, respectively. The total algae feeding amount per mussel per day was 3.5 × 104 cells in the low-density group and 2.6 × 105 cells in the high-density group. When examining the PST content in mussels from the two mixed exposure groups, it was observed that the mean accumulation conversion rates were comparable at 41.4% and 44.6%, which were lower than the theoretical rates of 48.7% and 47.5%, respectively. The overall toxicity of the low- and high-density groups was (535.0±5.6) and (2, 636.0±12.4) μg STXeq/kg, respectively. After mixed exposure, both experimental groups of mussels accumulated a total of 12 PST components (NEO, dcSTX, dcNEO, GTX1, GTX4, GTX2, GTX3, GTX5, dcGTX2, dcGTX3, C1, and C2).This study demonstrates that mixed exposure of mussels to four toxin-producing algae species, namely A. catenella, A. tamarense, G. catenatum, and A. minutum, can result in the stable and manageable presence of 12 PST components. This provides technical support for the preparation of matrix reference materials that can be used in industrial regulation and industry services. The development of a preparation technology for matrix reference materials with multiple PST components, which do not exceed international limits, holds promise for water quality monitoring and the assessment of marine pollution risks, and provides reference materials for theoretical studies on PSTs risk formation mechanisms.

Abstract We aimed to investigate the preventive effect of vitamin D2 on COVID-19 and the improvement of symptoms after COVID-19 infection. The study recruited 228 health care workers who tested negative PCR or antigen for COVID-19. Subjects were randomly allocated to vitamin D2 or non-intervention at a ratio 1:1. Subjects recorded PCR or antigen tests and the symptoms of COVID-19 twice a week during the follow-up visit. The concentration of serum 25-hydroxyvitamin D (25(OH)D), C-reaction protein (CRP), complement component C1q and inflammatory cytokines were measured. The rates of COVID-19 infection were 50.5% in the vitamin D2 group and 52.4% in the non-intervention group (P = 0.785). There was no difference in the COVID-19 symptoms between the two groups. The mean 25(OH)D level significantly increased from 14.1 to 31.1 ng/mL after administration (P 30 ng/mL) and deficient groups (

Abstract Inverse vulcanization exploits S8 to synthesize polysulfides. However, evolution of products and its mechanism during inverse vulcanization remains elusive. Herein, inverse vulcanization curves are obtained to describe the inverse vulcanization process in terms of three stages: induction, curing and over-cure. The typical curves exhibit a moduli increment before declining or plateauing, reflecting the process of polysulfide network formation and loosing depending on monomers. For aromatic alkenes, in the over-cure, the crosslinked polysulfide evolves significantly into a sparse network with accelerated relaxation, due to the degradation of alkenyl moieties into thiocarbonyls. The inverse vulcanization product of olefins degrades slowly with fluctuated relaxation time and modulus because of the generation of thiophene moieties, while the inverse vulcanization curve of dicyclopentadiene has a plateau following curing stage. Confirmed by calculations, the mechanisms reveal the alkenyl groups react spontaneously into thiocarbonyls or thiophenes via similar sulfur-substituted alkenyl intermediates but with different energy barriers.

Abstract Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer and the third leading cause of cancer mortality globally. Despite surgical resection being the preferred approach for early-stage HCC, most patients are diagnosed at intermediate to advanced stages, limiting treatment options to chemotherapy and immunotherapy, which often yield poor outcomes. Extracellular vesicles (EVs), minute lipid-bilayered particles released by diverse cells under various physiological and pathological conditions, are crucial for mediating communication between cells. Mounting evidence indicates that EVs sourced from different cells can profoundly influence the HCC tumor microenvironment (TME), thereby affecting the progression of HCC. Given their immunogenicity and liver-targeting properties, these EVs not only hold promise for HCC treatment but also provide avenues for advancing early diagnostic methods and assessing prognosis. This review not only describes the function of EVs within the HCC tumor microenvironment but also analyzes their therapeutic advantages and explores their significance in various therapeutic approaches for HCC, including chemotherapy, immunotherapy, combination therapy, and their role as innovative drug delivery carriers. Furthermore, it highlights the potential of EVs as biomarkers for the diagnosis and prognosis of HCC.

Dermal fibroblasts play a crucial role in the formation of granulation tissue in skin wounds. Consequently, the differentiation, migration, and proliferation of dermal fibroblasts are considered key factors in the skin wound healing process. However, in patients with diabetic foot ulcers, the proliferation and migration of fibroblasts are impaired by reactive oxygen species and inflammatory factors impair. Therefore, a novel magnetic gelatin-hesperidin microrobots drug delivery system was developed using microfluidics. The morphology, motility characteristics, and drug release of the microrobot were assessed, along with its impact on the proliferation and migration of human dermal fibroblasts under high-glucose conditions. Subjected to a rotating magnetic field, the microrobots exhibit precise, controllable, and flexible autonomous motion, achieving a maximum speed of 9.237 μm/s. In vitro drug release experiments revealed that approximately 78% of the drug was released within 30 min. It was demonstrated through cellular experiments that the proliferation of human dermal fibroblasts was actively promoted by the nanorobot, the migration ability of fibroblasts in a high-glucose state was enhanced, and good biocompatibility was exhibited. Hence, our study may provide a novel drug delivery system with significant potential for promoting the healing of diabetic foot wounds.

Introduction and Hypothesis The aim was to conduct a scoping review of the literature on the use of machine learning (ML) in female urinary incontinence (UI) over the last decade. Methods A systematic search was performed among the Medline, Google Scholar, PubMed, and Web of Science databases using the following keywords: [Urinary incontinence] and [(Machine learning) or (Predict) or (Prediction model)]. Eligible studies were considered to have applied ML model to explore different management processes of female UI. Data analyzed included the field of application, type of ML, input variables, and results of model validation. Results A total of 798 papers were identified while 23 finally met the inclusion criteria. The vast majority of studies applied logistic regression to establish models (91.3%, 21/23). Most frequently ML was applied to predict postpartum UI (39.1%, 9/23), followed by de novo incontinence after pelvic floor surgery (34.8%, 8/23).There are also three papers using ML models to predict treatment outcomes and three papers using ML models to assist in diagnosis. Variables for modeling included demographic characteristics, clinical data, pelvic floor ultrasound, and urodynamic parameters. The area under receiver operating characteristic curve of these models fluctuated from 0.56 to 0.95, and only 11 studies reported sensitivity and specificity, with sensitivity ranging from 20% to 96.2% and specificity from 59.8% to 94.5%. Conclusion Machine learning modeling demonstrated good predictive and diagnostic abilities in some aspects of female UI, showing its promising prospects in near future. However, the lack of standardization and transparency in the validation and evaluation of the models, and the insufficient external validation greatly diminished the applicability and reproducibility, thus a focus on filling this gap is strongly recommended for future research.

IntroductionThe primary objective of this systematic review was to provide an overview of the efficacy and safety of various lipid-lowering therapies in patients post-kidney transplant (PKT), given the limited existing literature. Considering the restricted number of available studies, this work aimed to summarize the existing evidence regarding the effectiveness of different lipid-lowering treatments in PKT patients. The effects of various lipid-lowering therapeutic regimens on lipid levels were compared, and their safety was assessed, with the heterogeneity of treatment protocols acknowledged.Material and MethodsRandomized controlled trials investigating different treatment regimens (DTRs) for regulating lipid levels in PKT patients were systematically retrieved from PubMed, Cochrane Library, and Embase, from inception to March 2024. Literature quality was assessed employing the Cochrane risk of bias assessment tool. Data analysis and graphical representation were performed employing RevMan5.3 and Stata 20.0. The surface under the cumulative ranking area (SUCRA) compared the effects of DTRs on lipid profiles, incidence of adverse events, and all-cause mortality in PKT patients.ResultsFifteen studies were included, comprising 5,768 PKT patients and involving 9 treatment regimens. The results revealed that, for changes in high-density lipoprotein cholesterol (HDL-C), the SUCRA rankings from highest to lowest among PKT patients receiving DTRs were statins + ezetimibe (70%), placebo (61.5%), fibrates (57.2%), statins (44.1%), and fish oil (17.3%). Regarding changes in low-DL-C (LDL-C), the SUCRA rankings from highest to lowest among PKT patients receiving DTRs were statins (68.2%), statins + ezetimibe (67.5%), fish oil (53.4%), fibrates (34.5%), and placebo (26.5%). For the change in total cholesterol (TC) levels, a network meta-analysis (NMA) revealed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for TC change were statins + ezetimibe (97.6%), proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors) (74.3%), fish oil (64.3%), statins (61.6%), fibrates (47.2%), placebo (31.6%), calcineurin phosphatase inhibitors (11.9%), and immunosuppressants (11.4%). Regarding the change in triglyceride (TG) levels, a NMA showed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for TG change were fibrates (99.9%), statins (68.9%), PCSK9 inhibitors (66.6%), statins + ezetimibe (55.1%), placebo (49.2%), fish oil (45.0%), immunosuppressants (7.8%), and calcineurin phosphatase inhibitors (7.6%). For the occurrence of kidney transplant failure, a NMA revealed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for reducing the incidence of kidney transplant failure were PCSK9 inhibitors (69.0%), calcineurin phosphatase inhibitors (63.0%), statins (61.5%), placebo (55.1%), steroids (51.8%), immunosuppressants (27.1%), and fibrates (22.5%). Regarding all-cause mortality, a NMA showed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for reducing all-cause mortality were PCSK9 inhibitors (90.5%), statins (55.8%), and placebo (3.7%).ConclusionIn reducing lipid levels in PKT patients, combination therapy with statins and ezetimibe demonstrated notable advantages and higher effectiveness. PCSK9 inhibitors exhibited greater advantages in reducing adverse events and mortality rates in PKT patients, with higher safety.

ABSTRACT Unraveling the effects of spatial gradients on microbiome assembly and association is a challenging topic that remains understudied in the coastal ecosystem. Here, we aimed to investigate the effects of spatial variation on the network complexity and stability of plankton microbiomes in the Bohai Sea and Yellow Sea. These seas serve as spawning and nursery grounds for economically important fisheries valued at billions of dollars annually. Environmental heterogeneity structures microbial communities into distinct spatial patterns, leading to complex direct/indirect relationships and broader ecological niches of bacterioplankton compared to microeukaryotic communities. Interestingly, salinity gradients positively influenced the richness of rare subgroups of bacterioplankton, while the rare microeukaryotic subgroups showed an opposite trend. Abundant subgroups of prokaryotic/eukaryotic microbiomes exhibited greater environmental niche breadth and lower phylogenetic distance compared to the rare subgroups. Stochastic processes contributed greatly to microbiome dynamics, and deterministic processes governed the bacterioplankton organization with a lower phylogenetic turnover rate. Compared to microeukaryotes, bacterioplankton exhibit higher network modularity, complexity, and robustness and lower fragmentation, and vulnerability. These observations offer vital insights into the anti-interference ability and resistance of plankton microbiomes in response to environmental gradients in terms of organization and survival strategy as well as their adaptability to environmental disturbances.IMPORTANCEAn in-depth understanding of community organization and stability of coastal microbiomes is crucial to determining the sustainability of marine ecosystems, such as the Bohai Sea and Yellow Sea. Distinct responses between prokaryotic and eukaryotic microbiomes to spatial heterogeneity were observed in terms of geographical distribution, phylogenetic distance, niche breadth, and community assembly process. Environmental variations are significantly correlated with the dynamics of rare eukaryotic plankton subcommunities compared to prokaryotic plankton subcommunities. Deterministic processes shaped prokaryotic plankton community organization with a lower phylogenic turnover rate. Rare subgroups had noticeably higher phylogenetic distance and lower niche breadth than the corresponding abundant subgroups. Prokaryotic microbiomes had higher molecular network complexity and stability compared to microeukaryotes. Results presented here show how environmental gradients alter both the geographical characteristics of the microbial organization in coastal seas and also their co-occurrence network complexity and stability and thus have critical implications for nutrient and energy cycling.

IntroductionIntrauterine transfusion of platelet-rich plasma (PRP) has become a new treatment for thin endometrium (TE) in recent years, but its low efficacy due to rapid release of growth factors limits its clinical use. Platelet-rich fibrin (PRF) starts the coagulation cascade reaction immediately after the blood comes into contact with the test tube. The natural coagulation process results in stable platelet activation and the slow release of growth factors.MethodsIn our study, primary human endometrial stromal cells (hESCs) were extracted from endometrial tissue. PRP and PRF were prepared from the patient cubital vein blood. Stromal cells were cultured in conditioned medium supplemented with PRP and PRF. Differences in cell behavior were observed by cell proliferation test and cell migration test. The relative expression levels of apoptotic Bax and antiapoptotic Bcl-2 genes were measured by qRT-PCR. The release of growth factors from PRP and PRF was detected by ELISA.ResultsWe found that both PRP and PRF inhibited apoptosis of hESCs, which favored cell proliferation and migration. In addition, PRF releases growth factors for a longer period of time compared to PRP.DiscussionPRF offer a more sustained therapeutic effect compared to PRP, which provides a new idea for endometrial regeneration and repair.

Abstract Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

Purposes Osteoarthritis (OA) is a degenerative joint disease that commonly occurs in middle-aged and elderly people. Mechanical microenvironment is one of the most significant factors in the development of OA. However, when the mechanical microenvironment changes, the inflammatory response of chondrocyte is elusive. Methods By adopting polydimethylsiloxane (PDMS) substrates with varying stiffness which can mimic the physiological stiffness of chondrocyte pericellular matrix (PCM), influences of co-regulated substrate stiffness and inflammatory factors interleukin-1β (IL-1β) on chondrocyte morphology, inflammatory mediators, and PCM remodeling protein expression are quantitatively analyzed. First, prostaglandin E2 (PGE2) and nitric oxide (NO) released in different stiffness substrates and IL-1β stimulated substrates with chondrocytes are detected. Second, the changes in different stiffness substrates and IL-1β stimulated substrates through immunofluorescence technique are observed and recorded. Third, the protein expressions of type Ⅱ collagen (COLII) and matrix metalloproteinase-13 (MMP13) are measured by Western blot assay. Findings The experimental results identify that substrate stiffness regulates the response of chondrocyte to inflammatory signals. Soft substrate dramatically enhances the release of PGE2 and NO (P

Abstract Background Intervertebral disc degeneration and sarcopenia are both age-related diseases without effective treatments. Their comorbidities may worsen the prognosis, and further studies on interaction and therapy are needed. The purpose of the study was to investigate the prevalence of sarcopenia in intervertebral disc degeneration, and to compare the characteristics of intervertebral disc degeneration with and without sarcopenia and effects of interferential current. Methods One hundred twenty disc degeneration patients were included from 2021 to 2022 in a single institute. Medical records, examination results and radiological reports were reviewed. Patients with sarcopenia were screened and grouped according to Asian Working Group for Sarcopenia 2019. VAS, ODI, SARC-F, SMI, gait speed (GS), grip strength, disc Pfirrmann grading, standard cross-sectional area (SCSA), degree of fatty infiltration (DFF), and nerve conduction velocity (NCV) were assessed before and after treatment. Results The prevalence of sarcopenia in intervertebral disc degeneration was 28.3%. The difference of VAS, ODI, disc Pfirrmann grading, SCSA, DFF and NCV between two groups were significant before intervention (P 0.05). Conclusion The prevalence of sarcopenia was high in intervertebral disc degeneration, and paravertebral muscles degeneration correlated with the degree of disc degeneration. Compared to those without sarcopenia, intervertebral disc degeneration patients with sarcopenia have more severe pain, poorer mobility and neurological function. Interferential current is effective in intervertebral disc degeneration patients and sarcopenia patients.

Chemical exposure and local hypoxia caused by mask-wearing may result in skin physiology changes. The effects of methylparaben (MeP), a commonly used preservative in personal care products, and hypoxia on skin health were investigated by HaCaT cell and ICR mouse experiments. MeP exposure resulted in lipid peroxidation and interfered with cellular glutathione metabolism, while hypoxia treatment disturbed phenylalanine, tyrosine, and tryptophan biosynthesis pathways and energy metabolism to respond to oxidative stress. A hypoxic environment increased the perturbation of MeP on the purine metabolism in HaCaT cells, resulting in increased expression of proinflammatory cytokines. The synergistic effects were further validated in a mouse model with MeP dermal exposure and “mask-wearing” treatment. CAT, PPARG, and MMP2 were identified as possible key gene targets associated with skin health risks posed by MeP and hypoxia. Network toxicity analysis suggested a synergistic effect, indicating the risk of skin inflammation and skin barrier aging.

Fungal peritonitis, an uncommon complication in continuous ambulatory peritoneal dialysis (CAPD), has recently garnered increased attention due to its incidence and potential mortality. To the best of our knowledge, this is the first confirmed case of Neosartorya hiratsukae (N. hiratsukae) causing CAPD-related peritonitis in a patient with chronic nephrotic syndrome in Guangzhou, China. After prompt removal of the peritoneal catheter and active antifungal therapy, no clinical manifestations of peritonitis were observed. Our report underscores the importance of enhancing clinical awareness regarding N. hiratsukae and ensuring timely diagnosis in cases of CAPD-related fungal peritonitis.

The accumulation of coal gangue (CG), fly ash (FA) and the burning of corn straw (CS) cause severe environmental issues. The study was carried out to prepare CG–FA–CS porous aggregate (CFCA) by sintering. The physical properties of CFCA were tested, XRD, FTIR, SEM, TEM, and MIP were used to characterize the microstructure and pore structure of CFCA. Furthermore, the skeleton and pore structure formation mechanisms of CFCA were revealed. Results showed that the maximum cylinder compressive strength of CFCA is 5.89 MPa, and the minimum thermal conductivity of CFCA is 0.086 W/(m·K). The main crystal phase of CFCA is anorthite (CaAl2Si2O8), and the secondary crystal phase is mullite (Al6Si2O13). Moreover, crystal phase accumulates to form the skeleton structure, providing the strength of aggregate. The pore volume of medium pores (103–104 nm) of CFCA accounted for the largest percentage, which accounted for 66.65 %–92.29 % of the total pore volume. The CFCA prepared in this study exhibits a multi-type pore structure. The study provides a feasible way for the comprehensive utilization of solid waste, which can also reduce the environmental problems caused by exploitation of natural resources.

Circular RNAs (circRNAs) are a class of single-stranded closed-loop RNAs that have become a popular research subject in biology. Compared to linear RNAs, they are more stable, more conserved, and more widely distributed, and they play crucial biological functions in many diseases. CircHECTD1, a newly identified member of the circRNA family, is widely distributed in humans. Recent studies have shown that circHECTD1 is abnormally expressed in various human diseases, including glioma, hepatocellular carcinoma, gastric cancer, acute ischaemic stroke, silicosis, acute lung injury, ulcerative colitis, atherosclerosis, and hypertrophic scarring. In malignant tumours, circHECTD1 is thought to be an oncogene that promotes malignant tumour behaviours and influences tumour prognosis. In nontumour diseases, it plays a dual role, promoting disease in silicosis, stroke, and other diseases, while alleviating the disease process in ulcerative colitis, acute lung injury, and atherosclerosis. This article provides a review of the regulatory roles and mechanisms of action of circHECTD1 in different diseases. We also discuss and prospectively evaluate the clinical potential of circHECTD1 as a diagnostic biomarker and a therapeutic target for related diseases, providing new insights for developing new therapeutic strategies.

Circular RNAs (circRNAs) are a type of non-coding RNA (ncRNA) that possesses a unique single-stranded circular structure. They are primarily formed through alternative splicing of pre-mRNA (messenger RNA). The primary biological function of circRNAs is to regulate gene expression at both the transcriptional and post-transcriptional levels. Recent studies have increasingly demonstrated a close association between the dysregulation of circRNAs and the progression of diverse cancers, where they can function as either tumor suppressors or oncogenes. circWHSC1 (circNSD2) is a circular ncRNA that originates from the first 2 exons of the Wolf-Hirschhorn syndrome candidate gene (WHSC1). As Chen 2019 discovery that circWHSC1 (circNSD2) functions as a sponge for miRNAs and promotes cancer, this circRNA has garnered significant interest among researchers. circWHSC1 (circNSD2) has been found to be up-regulated in various malignant tumors, including nasopharyngeal carcinoma, lung cancer, breast cancer, liver cancer, colorectal cancer, ovarian cancer, cervical cancer, and endometrial cancer. It exerts its effects on cancer by either inhibiting or promoting the expression of related genes through direct or indirect pathways, ultimately affecting cancer proliferation, invasion, and prognosis. This article provides a comprehensive review and discussion of the biological roles of circWHSC1 (circNSD2) and its target genes in various cancers, as well as the latest research progress on related molecular biological regulatory mechanisms. Furthermore, the potential significance of circWHSC1 (circNSD2) in future clinical applications and transformations is thoroughly analyzed and discussed.

Despite increasing waste-to-energy (WtE) capacities, there remain deficiencies in comprehension of 136 kinds of tetra- through octa-chlorinated dibenzo-p-dioxin and dibenzofurans (136 PCDD/Fs) originating from incineration sources. Samples from twenty typical WtE plants, encompassing coal-fired power plants (CPP), grate incinerators (GI), fluidized bed incinerators (FBI), and rotary kilns (RK), yielded extensive PCDD/F datasets. Research was conducted on fingerprint mapping, formation pathways, emission profiles, and diagnostic analysis of PCDD/Fs in WtE plants. Fingerprints revealed a prevalence of TCDF, followed by PeCDF, while CPP and RK respectively generated more PCDD and HxCDD. De novo synthesis was the predominant formation pathway except one plant, where CP-route dominated. DD/DF chlorination also facilitated PCDD/F formation, showing general trends of FBI > GI > CPP > RK. The PCDD/F emission intensities emitted in air pollution control system inlet (APCSI) and outlet (APCSO) followed the statistical sequence of RK > FBI > GI > CPP, with the average I-TEQ concentrations in APCSO reaching 0.18, 0.08, 0.11, and 0.04 ng I-TEQ·Nm−3. Emission spectrum were accordingly formed. Four clusters were segmented for diagnosis analysis, where PCDD/Fs in GI and FBI were similar, grouped as a single cluster. PCDD/Fs in CPP and RK demonstrated distinctive features in TCDD, HxCDD, and HxCDF. The WtE plants exceeding the limit value tended to generate and retain fewer TCDD and TCDF yet had higher fractions of HxCDD and HxCDF. The failure of APCS coupled with the intrinsic source strength of PCDD/Fs directly led to exceedance, highlighting safe operational practices. This study motivated source tracing and precise evaluation of 136 PCDD/Fs based on the revealed fingerprint profiles for WtE processes.

Queue-jumping is widely acknowledged as one of the most vexing driving behaviors and a prevalent traffic violation at urban intersections in China, exerting detrimental effects on both traffic operational efficiency and safety. To investigate the motivational factors underlying drivers' queue-jumping behavior at urban intersections, a questionnaire was designed to collect data based on an extended theory of planned behavior (TPB). A total of 427 valid responses were received through an online self-reported questionnaire survey conducted in China. The Pearson's chi-square test was employed to examine potential demographic disparities in self-reported queue-jumping behavior among drivers at urban intersections. Covariance-based structural equation modeling (CB-SEM) with bootstrapping was utilized to elucidate the impact of various factors on drivers' engagement in queue-jumping behavior. The findings revealed significant gender and age differences regarding drivers' propensity for queue-jumping at urban intersections, with male and young drivers exhibiting higher inclination compared to female and older counterparts, respectively. Furthermore, the extended TPB effectively accounted for both behavioral intention and actual occurrence of queue-jumping among drivers at urban intersections. Behavioral intention (β = 0.391, p = 0.002) and perceived behavior control (β = 0.282, p = 0.002) emerged as influential determinants of queue-jumping. Among all influencing factors shaping drivers' behavioral intention toward engaging queue-jumping at urban intersections, attitude (β = 0.316, p = 0.005) proved to be the most significant factor followed by perceived risk (β = 0.230, p = 0.001), moral norms (β = 0.184, p = 0.002), subjective norms (β = 0.175, p = 0.002), and perceived behavior control (β = 0.122, p = 0.05). These results offer valuable insights for urban road traffic managers seeking effective strategies for public awareness campaigns as well as practical intervention measures aimed at curbing improper driving behavior of queue-jumping at urban intersections.

Abstract Background/aims Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. Methods PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. Results Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P