Quantitative changes in platelet count in response to different pathogens: an analysis of patients with sepsis in both retrospective and prospective cohorts.

BACKGROUND: Thrombocytopenia is commonly observed in patients with sepsis and is an independent risk factor for poor prognosis. However, the changes of platelet count caused by different pathogens can vary significantly. Our study aims to evaluate the quantitative changes in platelet count in response to various pathogens. MATERIAL AND METHODS: We retrospectively analysed data of 3044 patients with sepsis from Medical Information Mart for Intensive Care (MIMIC, 2008-2019) database and prospectively collected data of 364 patients with sepsis from our local cohort of the Shandong Bloodstream Infection and Sepsis Collaboration Study (SBISC, 2020-2022). Propensity score matching (PSM) was employed to control for baseline differences in variables, except for the causative pathogen. RESULTS: Multivariate logistic analyses of both original and PSM populations identified Candida, Escherichia, Klebsiella, and Serratia species posing a higher risk for thrombocytopenia compared to others. Restricted cubic spline (RCS) curves showed L- or U-shaped associations between platelet count and 28-mortality with various cut-off values among different pathogens: ranging from 96 × 109/L in Candida species - 190 × 109/L in Klebsiella species. CONCLUSION: Our present findings indicate a pathogen-specific effect on platelet count, highlighting the importance of monitoring thrombocytopenia in patients infected with above microorganisms. Clinicians need to consider pathogen-specific thresholds when intervene on platelet count.

This study validated the differential incidence of thrombocytopenia among various pathogens within two distinct populations.Candida, Escherichia, Klebsiella, and Serratia species were identified as having a notably higher risk of causing thrombocytopenia compared to other pathogens.We observed L- or U-shaped relationships between platelet counts and 28-day mortality in Candida species, Enterococcus species, Escherichia species, Enterobacter species, Staphylococcus species, and Klebsiella species with platelet count cutoff values of 96 × 10⁹/L, 100 × 10⁹/L, 100 × 10⁹/L, 146 × 10⁹/L, 152 × 10⁹/L, and 190 × 10⁹/L, respectively.

The use of metagenomic and untargeted metabolomics in the analysis of the effects of the Lycium barbarum glycopeptide on allergic airway inflammation induced by Artemesia annua pollen.

ETHNOPHARMACOLOGICAL RELEVANCE: The prevalence of allergic airway inflammation (AAI) worldwide is high. Artemisia annua L. pollen is spread worldwide, and allergic diseases caused by its plant polysaccharides, which are closely related to the intestinal microbiota, have anti-inflammatory effects. Further isolation and purification of Lycium barbarum L. yielded its most effective component Lycium barbarum L. glycopeptide (LbGP), which can inhibit inflammation in animal models. However, its therapeutic effect on AAI and its mechanism of regulating the intestinal flora have not been fully investigated. AIM OF THE STUDY: To explore LbGP in APE-induced immunological mechanisms of AAI and the interaction mechanism of the intestinal flora and metabolites. METHODS: A mouse model of AAI generated from Artemisia annua pollen was constructed, and immunological indices related to the disease were examined. A combination of macrogenomic and metabolomic analyses was used to investigate the effects of LbGP on the gut microbial and metabolite profiles of mice with airway inflammation. RESULTS: LbGP effectively alleviated Artemisia. annua pollen extract (APE)-induced AAI, corrected Th1/Th2 immune dysregulation, decreased Th17 cells, increased Treg cells, and altered the composition and function of the intestinal microbiota. LbGP treatment increased the number of OdoribacterandDuncaniella in the intestines of the mice, but the numble of Alistipes and Ruminococcus decreased. Metabolite pathway enrichment analysis were used to determine the effects of taurine and hypotaurine metabolism, bile acid secretion, and pyrimidine metabolism pathways on disease. CONCLUSION: Our results revealed significant changes in the macrogenome and metabolome following APE and LbGP intervention, revealed potential correlations between gut microbial species and metabolites, and highlighted the beneficial effects of LbGP on AAI through the modulation of the gut microbiome and host metabolism.

Stable carbon isotope reveals high impact of fishing ship activities on total carbon from PM2.5 in Qingdao, China.

Although total carbon (TC) is an important component of fine particulate matter (PM2.5: particulate matter with aerodynamic diameter of <2.5 µm); its sources remain partially unidentified, especially in coastal urban areas. With ongoing development of the global economy and maritime activities, ship-generated TC emissions in port areas cannot be neglected. In this study, from September 11, 2017 to August 31, 2018, we collected 355 p.m.2.5 samples in Qingdao, China, to determine the water-soluble ion concentrations, TC concentrations, and stable carbon isotopes (δ13CTC). During the open fishing season (OFS; September 11, 2017 to April 30, 2018) and the closed fishing season (CFS; May 1, 2018 to August 31, 2018), the TC concentrations were 9.30 ± 5.38 µg/m3 and 3.36 ± 2.10 µg/m3 respectively, and the corresponding δ13CTC values were -24.53‰ ± 1.17‰ and -27.03‰ ± 0.91‰, respectively, indicating significant differences (p < 0.05) between the two periods. The differences in TC concentrations and the δ13CTC values between the OFS and CFS reflect changes in the source of contamination. Bayesian model was used to quantify the contributions of different TC sources, revealing that ship emissions accounted for approximately 35.3% of the total, which was close to the contribution from the largest source, i.e., motor vehicles (39%). Using the ship emission inventory, Qingdao's ship emissions were further quantified at 455 metric tons, representing 35%-40% of the total TC emissions around Qingdao. Notably, fishing ships contributed approximately 40% of the total ship emissions. These findings underscore the considerable impact of ship emissions, particularly those from fishing ships, on TC concentrations in coastal urban areas.

Controllable Microparticle Spinning via Light without Spin Angular Momentum.

The spin angular momentum (SAM) of an elliptically or circularly polarized light beam can be transferred to matter to drive a spinning motion. It is counterintuitive to find that a light beam without SAM can also cause the spinning of microparticles. Here, we demonstrate controllable spinning of birefringent microparticles via a tightly focused radially polarized vortex beam that has no SAM prior to focusing. To this end, the orbital Hall effect is proposed to control the radial separation of two spin components in the focused field, and tunable transfer of local SAM to microparticles is achieved by manipulating the twisted wavefront of the source light. Our work broadens the perspectives for controllable exertion of optical torques via the spin-orbit interactions.

Knowledge, attitudes, and perceptions of farmers towards urban agroecology in Malaysia.

Adopting agroecological approaches to build resilient urban food systems has recently gained traction around the world, but there is little to no reliable literature on the knowledge, attitudes, and perspectives of urban farmers towards these nature-based solutions in many developing nations, including Malaysia. The present study conducted an online survey to determine the extent to which local urban farmers understand and employ agroecology, as well as to assess their awareness and views on using agroecological practices and sustainable farm management. We found that the majority of respondents are unfamiliar with agroecological principles, with 79 % agreeing or strongly agreeing that implementing sustainable agricultural practices is challenging. However, more than 90 % of respondents are aware of the environmental consequences of excessive input utilisation. Our findings highlight the need for improved initiatives to promote agroecological approaches among farmers by sharing knowledge and best practices. In light of the growing threat posed by urban heat islands and the rapid urbanisation, this study offers novel insights into the knowledge gaps and perceptions about agroecological approaches among urban farmers, challenges that must be addressed to promote sustainable agriculture, and the potential role of farmers in achieving the three fundamental pillars of sustainability-planet, people, and prosperity.

Digital Light Processing to Afford High Resolution and Degradable CO2-Derived Copolymer Elastomers.

Vat photopolymerization 3D printing has proven very successful for the rapid additive manufacturing (AM) of polymeric parts at high resolution. However, the range of materials that can be printed and their resulting properties remains narrow. Herein, we report the successful AM of a series of poly(carbonate-b-ester-b-carbonate) elastomers, derived from carbon dioxide and bio-derived ϵ-decalactone. By employing a highly active and selective Co(II)Mg(II) polymerization catalyst, an ABA triblock copolymer (Mn=6.3 kg mol-1, ÐM=1.26) was synthesized, formulated into resins which were 3D printed using digital light processing (DLP) and a thiol-ene-based crosslinking system. A series of elastomeric and degradable thermosets were produced, with varying thiol cross-linker length and poly(ethylene glycol) content, to produce complex triply periodic geometries at high resolution. Thermomechanical characterization of the materials reveals printing-induced microphase separation and tunable hydrophilicity. These findings highlight how utilizing DLP can produce sustainable materials from low molar mass polyols quickly and at high resolution. The 3D printing of these functional materials may help to expedite the production of sustainable plastics and elastomers with potential to replace conventional petrochemical-based options.

Green Manuring Enhances Soil Multifunctionality in Tobacco Field in Southwest China.

The use of green manure can substantially increase the microbial diversity and multifunctionality of soil. Green manuring practices are becoming popular for tobacco production in China. However, the influence of different green manures in tobacco fields has not yet been clarified. Here, smooth vetch (SV), hairy vetch (HV), broad bean (BB), common vetch (CV), rapeseed (RS), and radish (RD) were selected as green manures to investigate their impact on soil multifunctionality and evaluate their effects on enhancing soil quality for tobacco cultivation in southwest China. The biomass of tobacco was highest in the SV treatment. Soil pH declined, and soil organic matter (SOM), total nitrogen (TN), and dissolved organic carbon (DOC) content in CV and BB and activity of extracellular enzymes in SV and CV treatments were higher than those in other treatments. Fungal diversity declined in SV and CV but did not affect soil multifunctionality, indicating that bacterial communities contributed more to soil multifunctionality than fungal communities. The abundance of Firmicutes, Rhizobiales, and Micrococcales in SV and CV treatments increased and was negatively correlated with soil pH but positively correlated with soil multifunctionality, suggesting that the decrease in soil pH contributed to increases in the abundance of functional bacteria. In the bacteria-fungi co-occurrence network, the relative abundance of key ecological modules negatively correlated with soil multifunctionality and was low in SV, CV, BB, and RS treatments, and this was associated with reductions in soil pH and increases in the content of SOM and nitrate nitrogen (NO3--N). Overall, we found that SV and CV are more beneficial for soil multifunctionality, and this was driven by the decrease in soil pH and the increase in SOM, TN, NO3--N, and C- and N-cycling functional bacteria.

Validation of the Barthel Index in Chinese nursing home residents: an item response theory analysis.

Background: The Barthel Index (BI) is used to standardize the grading of assessments for clinical needs, insurance support, and long-term care resource allocation in China. However, its psychometric properties among nursing home residents remain unclear. Therefore, this study aims to assess and modify the psychometric properties of BI in nursing home residents. Methods: A total of 1,402 individuals undergoing evaluation in a nursing home facility in China were included in this study from November 2021 to November 2022. Correlations between items were examined to identify the potential multicollinearity concerns. The unidimensional item response theory (IRT) was used to validate and modify the single structure of BI. Furthermore, the logistic regression/IRT hybrid DIF detection method was conducted to assess differential item functioning (DIF) between the dementia group and the normal group. Results: The pairing of items 5 ("bowl control") and 6 ("bladder control") revealed a local dependence issue, leading to their consolidation. Items 56 (bowel and bladder control) and 9 (mobility) both displayed poor fit indices and underwent category collapsing. Through the application of the generalized partial credit model, the adjusted scale displayed better fit indices, demonstrating a robust discriminative power (DC >1.5) and orderly thresholds. Furthermore, non-uniform DIF was identified in item 2 (bathing) between the dementia group and the normal group. Conclusion: The modified BI demonstrated favorable psychometric properties and proved to be suitable for evaluating nursing home residents experiencing moderate functional impairment, which may provide a precise evaluation for long-term care resource allocation. Future studies could explore integrating supplementary measurements, such as objective indices, to assess a broader spectrum of functional statuses to potentially enhance the limited precision width observed in BI.

Assessment of antimicrobial prescribing patterns, guidelines compliance, and appropriateness of antimicrobial prescribing in surgical-practice units: point prevalence survey in Malaysian teaching hospitals.

Objectives: This study sought to investigate the quality of antimicrobial prescribing among adult surgical inpatients besides exploring the determinants of non-compliance and inappropriate prescribing to inform stewardship activities. Methods: A cross-sectional point prevalence study employing Hospital National Antimicrobial Prescribing Survey (Hospital NAPS) was conducted in April 2019 at two teaching hospitals in Malaysia. Results: Among 566 surgical inpatients, 44.2% were receiving at least one antimicrobial, for a total of 339 prescriptions. Antimicrobials belonging to the World Health Organization's Watch group were observed in 57.8% of cases. Both hospitals exhibited similar types of antimicrobial treatments prescribed and administration routes. A significant difference in antimicrobial choice was observed between hospitals (p < 0.001). Hospital with electronic prescribing demonstrated better documentation practice (p < 0.001). Guidelines compliance, 32.8% (p = 0.952) and appropriateness, 55.2% (p = 0.561) did not significantly differ. The major contributors of inappropriateness were incorrect duration, (15%) and unnecessary broad-spectrum coverage, (15.6%). Non-compliance and inappropriate prescribing were found to be 2 to 4 times significantly higher with antimicrobial prophylaxis prescription compared to empirical therapy. Conclusion: Antimicrobial stewardship efforts to improve appropriate surgical prescribing are essential. These initiatives should prioritize surgical prophylaxis prescribing, focusing on reducing unnecessarily prolonged use and broad-spectrum antimicrobials, raising awareness among prescribers and promoting proper documentation.

Predicting the risk of primary Sjögren's syndrome with key N7-methylguanosine-related genes: A novel XGBoost model.

Objectives: N7-methylguanosine (m7G) plays a crucial role in mRNA metabolism and other biological processes. However, its regulators' function in Primary Sjögren's Syndrome (PSS) remains enigmatic. Methods: We screened five key m7G-related genes across multiple datasets, leveraging statistical and machine learning computations. Based on these genes, we developed a prediction model employing the extreme gradient boosting decision tree (XGBoost) method to assess PSS risk. Immune infiltration in PSS samples was analyzed using the ssGSEA method, revealing the immune landscape of PSS patients. Results: The XGBoost model exhibited high accuracy, AUC, sensitivity, and specificity in both training, test sets and extra-test set. The decision curve confirmed its clinical utility. Our findings suggest that m7G methylation might contribute to PSS pathogenesis through immune modulation. Conclusions: m7G regulators play an important role in the development of PSS. Our study of m7G-realted genes may inform future immunotherapy strategies for PSS.

Quantitative HBeAg is a strong predictor of HBeAg loss among patients receiving pegylated interferon.

BACKGROUND: HBeAg loss is an important endpoint for antiviral therapy in chronic hepatitis B (CHB), however there are no reliable biomarkers to identify patients who will respond to the addition of pegylated interferon to nucleos(t)ide analogue (NA) therapy. AIM: To evaluate the use of serum biomarkers to predict HBeAg loss. METHODS: HBeAg positive CHB participants on NAs who switched-to or added-on 48 weeks pegylated interferon alpha2b (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBeAg loss. The predictive ability of qHBeAg, qHBsAg, HBV RNA and clinical variables for HBeAg loss were investigated. RESULTS: HBeAg loss occurred in 15/55 (27.3%) participants who completed 48 weeks of pegylated interferon. There was a lower baseline qHBeAg (1.18 IU/mL [2.27] versus 10.04 IU/mL [24.87], P = 0.007) among participants who lost HBeAg. Baseline qHBeAg (OR = 0.15, 95% CI 0.03-0.66, P = 0.01) and detectable HBV DNA at baseline (OR = 25.00, 95% CI 1.67-374.70, P = 0.02) were independent predictors of HBeAg loss. In addition, on-treatment qHBeAg was also a strong predictor of HBeAg loss (OR = 0.39, 95% CI 0.18-0.81, P = 0.012). The models combining detectable baseline HBV DNA with baseline (C-statistic 0.82) and on-treatment (C-statistic 0.83) had good accuracy for predicting HBeAg loss. A rise in qHBeAg ≥ 10 IU/ml was a predictor of flare (ALT ≥ 120 U/ml) on univariable analysis but not after adjustment for treatment arm. CONCLUSIONS: Baseline and on-treatment qHBeAg is a useful biomarker that can identify participants on NA therapy who may benefit from adding or switching to pegylated interferon.

Medical students' perceptions of prosocial behaviors: a grounded theory study in China.

INTRODUCTION: Prosocial behavior has been shown to be protective against burnout. Yet, we know little about prosocial behavior in medical students. We wanted to know what are chinese medical students' understanding of prosocial behavior and which factors influence their participation in it? METHODS: We undertook a grounded theory study, following Corbin & Strauss. We used convenience sampling and conducted semi-structured individual interviews. We analyzed data using open, axial, and selective coding techniques. Next, we grouped data into concepts. We noticed these concepts aligned with three existing social theories, so we developed our theory in concert with these: the Theory of Planned Behavior, Self-Determination Theory, and Social Support Theory. RESULTS: Twenty-eight medical students participated in this study. Medical students hold especial views on the roles of medical physicians, and most of these views align with students' core values, including the value of prosocial behavior. Students are intrinsically motivated to engage in prosocial behaviors that align with their core values. Personal values, personality traits, perceived self-competence, career motivation, environmental factors, and family influences are the core factors influencing medically positive prosocial behavior. CONCLUSIONS: This study supports a focus on prosocial behavior instead of altruistic behavior in medical education. We anticipate that promoting prosocial behavior through medical curricula will reduce moral distress and burnout among medical students.

Exploring the Role of Guidelines in Contributing to Medication Errors: A Descriptive Analysis of National Patient Safety Incident Data.

INTRODUCTION: Clinical guidelines can contribute to medication errors but there is no overall understanding of how and where these occur. OBJECTIVES: We aimed to identify guideline-related medication errors reported via a national incident reporting system, and describe types of error, stages of medication use, guidelines, drugs, specialties and clinical locations most commonly associated with such errors. METHODS: Retrospective analysis of reports to the National Reporting and Learning System for England and Wales. A hierarchical task analysis (HTA) was developed, describing expected practice when using guidelines. A free-text search was conducted of medication incident reports (2016-2021) using search terms related to common guidelines. All identified reports linked to moderate-severe harm or death, and a random sample of 5100 no/low-harm reports were coded to describe deviations from the HTA. A random sample of 500 cases were independently double-coded. RESULTS: In total, 28,217 reports were identified, with 608 relating to moderate-severe harm or death. Fleiss' kappa for interrater reliability was 0.46. Of the 5708 reports coded, 642 described an HTA step discrepancy (including four linked to a death), suggesting over 3200 discrepancies in the entire dataset of 28,217 reports. Discrepancies related to finding guidelines (n = 300 reports), finding information within guidelines (n = 166) and using information (n = 176). Discrepancies were most frequently identified for guidelines produced by a local organisation (n = 405), and most occurred during prescribing (n = 277) or medication administration (n = 241). CONCLUSION: Difficulties finding and using information from clinical guidelines contribute to thousands of prescribing and medication administration incidents, some of which are associated with substantial patient harm.

Warm Acupuncture Reduces Pain and Inflammation in Rats with Lumbar Disc Herniation Induced by Autologous Nucleus Pulposus Transplantation via Regulating p38MAPK/NF-κB Pathway.

Background: : Warm acupuncture (WA) has analgesic and anti-inflammatory effects. However, the underlying mechanism of these effects remain unclear. Objectives: : To explore the analgesic and anti-inflammatory effects of WA and the potential underlying mechanism in male Sprague-Dawley rats with non-compressive lumbar disk herniation (LDH) caused by autologous nucleus pulposus (NP) transplantation. Methods: : We used low-frequency (2 Hz) electrical stimulation and WA (40℃) to treat GB30 and BL54 acupoints in rats for 30 mins per day. We monitored the paw withdrawal threshold of rats during the experiment and measured serum cytokine levels using commercial kits. Dorsal root ganglion (DRG) tissue pathology was analyzed via H&E staining. We used qRT-PCR to measure the mRNA expression levels of IL-1ß, IL-6, and TNF-α genes in DRG. Western blot was used to analyze the expression levels of IL-1ß, IL-6, TNFα, P-p38MAPK, p38MAPK, P-IκBα, IκB α, and NF-κB p65 proteins. Results: : WA treatment significantly increased the pain threshold of rats, reduced serum IL-6, PEG2, NO, SP, NP-Y, and MMP-3 levels, and effected histopathological improvements in the DRG in rats. Moreover, WA treatment significantly downregulated the expression levels of inflammation-associated genes (Il-1ß, Il-6, and Tnf-α) and proteins (IL-1ß, IL-6, TNF-α, P-p38MAPK, P-IκBα, and NF-κB p65) in the DRG of non-compressive LDH rats. Conclusion: : WA can alleviate pain and inhibit inflammatory response in rats with non-compressive LDH caused by autologous NP transplantation, and these effects are likely associated with the inhibition of the p38MAPK/NF-κB pathway.

Risk factors for short-term all-cause mortality in patients with end stage renal disease: a scoping review.

OBJECTIVES: There is a lack of prognostic information to guide the prediction of short-term all-cause mortality in patients with end-stage renal disease (ESRD). The aim was to review the risk factors that influenced the risk of short-term all-cause mortality in patients with ESRD. METHODS: MEDLINE, Embase, PubMed, CINAHL, the Cochrane Library and Web of Science databases were searched for articles published between 2000 and 2020. Articles describing risk factors predicting short-term mortality (≤ 3 years) in patients with ESRD were included. Four reviewers independently performed title, abstract, full text screening and data extraction. Assessment of risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool checklist. RESULTS: 20,840 articles were identified and 113 papers were included for this review. Of the 113 papers, 6.2% included only peritoneal dialysis (PD) patients, 67.3% included only hemodialysis (HD) patients, 20.4% included both PD and HD patients, with the remaining papers featuring patients on conservative management or awaiting renal transplant. Risk factors were categorised into 13 domains: 1)demographics/ lifestyle, 2) comorbidities 3)intradialytic blood pressure, 4)biomarkers, 5)cardiovascular measurements, 6)frailty status, 7)medications, 8)treatment related indicators, 9)renal related parameters, 10)health status, 11)cause of ESRD, 12)access to healthcare care/ information and, 13)proxy measures for poor health. C-reactive protein(CRP), age, and functional status were observed to have higher percentage of instances of being significantly associated with all-cause mortality. CONCLUSION: Commonly examined risk factors observed from this review may be used to build a general prognostic model for patients with ESRD, with specific treatment related risk factors added on to enhance the accuracy of the models.

Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice.

BACKGROUND: Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated. METHODS: Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression. RESULTS: We identified a SNP rs2678907 located in the 5' upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lower VRK2 mRNA expression, which is consistent with the observations of reduced VRK2 level in the patients with major depression compared with controls. Notably, Vrk2-/- mice exhibited depressive-like behaviors compared to Vrk2+/+ mice and specifically repressing Vrk2 in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared with Vrk2+/+ mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered in Vrk2-/- mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways in Vrk2-/- mice. CONCLUSIONS: Vrk2 deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.

Toward controllable and predictable synthesis of high-entropy alloy nanocrystals.

High-entropy alloy (HEA) nanocrystals have attracted extensive attention in catalysis. However, there are no effective strategies for synthesizing them in a controllable and predictable manner. With quinary HEA nanocrystals made of platinum-group metals as an example, we demonstrate that their structures with spatial compositions can be predicted by quantitatively knowing the reduction kinetics of metal precursors and entropy of mixing in the nanocrystals under dropwise addition of the mixing five-metal precursor solution. The time to reach a steady state for each precursor plays a pivotal role in determining the structures of HEA nanocrystals with homogeneous alloy and core-shell features. Compared to the commercial platinum/carbon and phase-separated counterparts, the dendritic HEA nanocrystals with a defect-rich surface show substantial enhancement in catalytic activity and durability toward both hydrogen evolution and oxidation. This quantitative study will lead to a paradigm shift in the design of HEA nanocrystals, pushing away from the trial-and-error approach.

AMPK reduces macrophage endotoxin tolerance through inhibition of TGF-ß1 production and its signaling pathway.

Adenosine monophosphate-activated protein kinase (AMPK) is involved in suppression of the development of endotoxin tolerance, which is a driver of the immunosuppression induced by sepsis. However, the mechanism by which AMPK inhibits the development of endotoxin tolerance has not been clearly elucidated. Therefore, the present study was performed to investigate the mechanism by which the AMPK activator, metformin, inhibits the development of endotoxin tolerance. Lipopolysaccharide (LPS) increased the production of transforming growth factor (TGF)-ß1 in macrophages, which was inhibited by metformin and resveratrol. Knockdown of AMPKα1 inhibited the suppressive effect of metformin on LPS-induced TGF-ß1 production. TGF-ß neutralizing antibody and TGF-ß type I receptor inhibitor increased the production of TNF-α and IL-6 via LPS restimulation in tolerized macrophages. LPS increased Smad2 phosphorylation, but this was inhibited in cells treated with TGF-ß neutralizing antibody or metformin. Smad2 knockdown inhibited the development of endotoxin tolerance, as evidenced by increased TNF-α production in response to LPS restimulation in tolerized macrophages. TGF-ß1 expression was increased, and the levels of TNF-α and IL-6 production induced by LPS stimulation were decreased, in splenocytes of cecal ligation and puncture (CLP) model mice compared to sham-operated controls. However, metformin treatment suppressed the production of TGF-ß1, and enhanced the production of TNF-α and IL-6 induced by LPS stimulation in splenocytes of CLP mice. These results indicated that AMPK activation inhibits LPS-induced TGF-ß1 production and its signaling pathway, thus suppressing the development of endotoxin tolerance in macrophages.

Single-Cell RNA Sequencing Reveals Unique Alterations in the Immune Panorama and Treg Subpopulations in Mice during the Late Stages of Echinococcus granulosus Infection.

Cystic echinococcosis (CE) is a common zoonotic parasitic disease that seriously impacts public health. However, the full spectrum of immune cell changes in Echinococcus granulosus infection, especially the negative immune regulation of subpopulations of regulatory T (Treg) cells, are not yet well understood. In this study, we used single-cell RNA sequencing and immunome repertoire (IR) sequencing to analyze 53,298 cells from the spleens and peripheral blood mononuclear cells (PBMCs) of healthy and E. granulosus-infected mice. We used immunofluorescence combined with RNA fluorescence in situ hybridization and quantitative real-time PCR to verify the sequencing results. Our results showed tissue-specific immune system alterations in mice infected with E. granulosus. E. granulosus-infected mice induced a subpopulation of CD4+ cells with type I interferon production potential. Furthermore, there were six different Treg cell subpopulations in vivo at three stages of differentiation, and Treg subpopulations of different classes and different stages of differentiation showed tissue specificity. After infection, the Lag3hi Treg and Gpr83+Igfbp4+ naive Treg subpopulations were specifically induced in PBMCs and the spleen, respectively. Furthermore, T follicular helper 2 (Tfh2) cells with high expression of Cxxc5 and Spock2 were found in E. granulosus-infected mice. Our data uncovered changes in the full spectrum of immune cells in mice following the late stages of E. granulosus infection, including subpopulations of cells that have not been emphasized in previous studies. These results further enrich the study of the bidirectional immunomodulatory mechanism and offer a different perspective for subsequent studies of infection in E. granulosus.