The relationship between lactate dehydrogenase to albumin ratio and all-cause mortality during ICU stays in patients with sepsis: A retrospective cohort study with propensity score matching.

Background: Sepsis is a prevalent and severe medical condition which is frequently observed in the intensive care unit (ICU). Although numerous biomarkers have been identified to predict the prognosis of sepsis, the lactate dehydrogenase to albumin ratio (LDH/ALB ratio) has not been extensively investigated. The principal objective of this study is to assess the relationship between LDH/ALB ratio and all-cause mortality in patients with sepsis. Methods: This study included all adult critically ill patients with sepsis from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.0) database. Propensity score matching (PSM) analysis was conducted to mitigate bias, and Kaplan-Meier curves were performed to evaluate the cumulative survival across different groups. The association between the LDH/ALB ratio and mortality was examined through restricted cubic spline (RCS) analysis and Cox regression analysis. The robustness of the findings was confirmed through subgroup analyses. Additionally, the prognostic capability of the LDH/ALB ratio was further evaluated using receiver operating characteristic (ROC) curve analysis. Results: There were 6059 adult patients with sepsis enrolled in the final analysis. RCS revealed a non-linear relationship between the LDH/ALB ratio and an increased risk of ICU all-cause mortality (χ2 = 46.900, P < 0.001). Following PSM analysis, 1553 matched pairs were obtained. As comparison to the low LDH/ALB ratio group, the mortality rate in the high LDH/ALB ratio group was significantly higher (P < 0.001). Kaplan-Meier curves, both before and after PSM, revealed that the ICU cumulative survival rate for patients with sepsis was significantly lower in the high LDH/ALB ratio group compared to the low LDH/ALB ratio group (χ2 = 93.360, P < 0.001; χ2 = 14.400, P < 0.001). Even after adjusting for a range of potential confounders, multivariate Cox regression analysis indicated that an elevated LDH/ALB ratio was a significant predictor of all-cause mortality in these patients. ROC curve analysis demonstrated that the LDH/ALB ratio had an area under the ROC curve (AUC) of 0.688 for predicting ICU mortality, with a sensitivity of 69.2% and a specificity of 58.6%. Conclusions: An elevated LDH/ALB ratio (≥10.57) was associated with all-cause mortality in critically ill patients with sepsis, and it might serve as a prognostic marker. Clinicians should pay closer attention to sepsis patients presenting with an LDH/ALB ratio of 10.57 or higher.

Endolysosomal trafficking controls yolk granule biogenesis in vitellogenic Drosophila oocytes.

Endocytosis and endolysosomal trafficking are essential for almost all aspects of physiological functions of eukaryotic cells. As our understanding on these membrane trafficking events are mostly from studies in yeast and cultured mammalian cells, one challenge is to systematically evaluate the findings from these cell-based studies in multicellular organisms under physiological settings. One potentially valuable in vivo system to address this challenge is the vitellogenic oocyte in Drosophila, which undergoes extensive endocytosis by Yolkless (Yl), a low-density lipoprotein receptor (LDLR), to uptake extracellular lipoproteins into oocytes and package them into a specialized lysosome, the yolk granule, for storage and usage during later development. However, by now there is still a lack of sufficient understanding on the molecular and cellular processes that control yolk granule biogenesis. Here, by creating genome-tagging lines for Yl receptor and analyzing its distribution in vitellogenic oocytes, we observed a close association of different endosomal structures with distinct phosphoinositides and actin cytoskeleton dynamics. We further showed that Rab5 and Rab11, but surprisingly not Rab4 and Rab7, are essential for yolk granules biogenesis. Instead, we uncovered evidence for a potential role of Rab7 in actin regulation and observed a notable overlap of Rab4 and Rab7, two Rab GTPases that have long been proposed to have distinct spatial distribution and functional roles during endolysosomal trafficking. Through a small-scale RNA interference (RNAi) screen on a set of reported Rab5 effectors, we showed that yolk granule biogenesis largely follows the canonical endolysosomal trafficking and maturation processes. Further, the data suggest that the RAVE/V-ATPase complexes function upstream of or in parallel with Rab7, and are involved in earlier stages of endosomal trafficking events. Together, our study provides s novel insights into endolysosomal pathways and establishes vitellogenic oocyte in Drosophila as an excellent in vivo model for dissecting the highly complex membrane trafficking events in metazoan.

Prediction of Hydrogen Abstraction Rate Constants at the Allylic Site between Alkenes and OH with Multiple Machine Learning Models.

Hydrogen abstraction reactions between hydrocarbons and hydroxyl radicals are important propagation steps in radical chain reactions, playing a crucial role in atmospheric and combustion chemistry. This study focuses on predicting the rate constants of the prototype of the reaction class of hydrogen abstractions, i.e., the primary allylic hydrogen abstraction from alkenes by the OH radical, via utilizing machine learning (ML) methods. Specifically, three distinct models, namely, feedforward neural network (FNN), support vector regression (SVR), and Gaussian process regression (GPR), have been employed to construct robust ML models for prediction. We proposed a novel strategy that seamlessly integrates descriptor preprocessing, a pairwise linear correlation analysis, and a model-specific Wrapper method to enhance the effectiveness of the feature selection procedure. The selected feature subset was then evaluated using two cross-validation techniques, i.e., leave-one-group-out (LOGO) and K-fold cross-validations, for each of the three ML models (FNN, SVR, and GPR) to assess their predictive and stability performance. The results demonstrate that the FNN model, trained with seven representative descriptors, achieves superior performance compared to the other two methods. For the FNN model, the average percentage deviation is 39.06% on the test set by performing LOGO cross-validation, while the repeated 10-fold cross-validation achieves a percentage prediction deviation of 19.1%. Two larger alkenes with 10 carbons were selected to test the prediction performance of the trained FNN model on primary allylic hydrogen abstraction. Results show that the kinetic predictions follow well the modified three-parameter Arrhenius equation, indicating the reliable performance of FNN in predicting hydrogen abstraction rate constants, especially for the primary allylic site. Hopefully, this work can shed useful light on the application of ML in generating chemical kinetic parameters of hydrocarbon combustion chemistry.

Digital Health Interventions for Quality Improvements in Chronic Kidney Disease Primary Care: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Chronic kidney disease (CKD) is a significant public health issue globally. The importance of its timely identification and early intervention is paramount. However, a systematic approach for early CKD management in the primary care setting is currently lacking, receiving less attention compared to upstream risk factors such as diabetes and hypertension. This oversight may lead to a failure in meeting quality-of-care indicators. Digital health interventions (DHIs), which leverage digital tools to enhance healthcare delivery, have shown effectiveness in managing chronic diseases and improving the quality, safety, and efficiency of primary care. Our research aimed to evaluate the effectiveness of DHIs in the care process, focusing on their reach, uptake, and feasibility. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) assessing DHIs' effectiveness in CKD patient care among adults in primary care settings. The search, conducted on 30 June 2023, included studies published in English from 1 January 2009. Screening was conducted using Covidence, adhering to Cochrane's guidelines for data extraction. We primarily evaluated changes in care processes (testing, documentation, medication use, etc.) and the use of renin-angiotensin-aldosterone system inhibitors (RAASi), referrals, among others. Multilevel meta-analysis was employed to address within-study clustering, and meta-regression analyzed the impact of study characteristics on heterogeneity in effect sizes. Clinical endpoints were recorded where available. Bias risk was assessed using the Cochrane Risk of Bias 2 tool. Data on reach, uptake, and feasibility were narratively summarized. The study is registered with PROSPERO (CRD42023449098). RESULTS: From 679 records, 12 RCTs were included in the narrative synthesis, and 6 studies (encompassing 7 trials) in the meta-analysis. The trials indicated a -0.85% change (95%CI, -5.82% to 4.11%) in the proportion of patients receiving desired care. This result showed considerable heterogeneity (I2 = 91.9%). One study characteristic (co-intervention, education) correlated with larger effects. Although including co-intervention in multivariable meta-regression was significant, it did not diminish heterogeneity. The reported reach varied and was not high, while the uptake was relatively high. Most studies did not explicitly address feasibility, though some statements implied its evaluation. CONCLUSIONS: The current literature on the impact of DHIs in community-based CKD care is limited. The studies suggest a non-significant effect of DHIs on enhancing CKD management in community settings, marked by significant heterogeneity. Future research should focus on rigorous, methodologically sound implementations to better assess the effectiveness of DHIs in the primary care management of CKD.

Exploring genetic associations between vitiligo and mental disorders using Mendelian randomization.

Although a large number of existing studies have confirmed that people with vitiligo are prone to mental disorders, these observational studies may be subject to confounding factors and reverse causality, so the true causal relationship is inconclusive. We conducted a bidirectional Mendelian randomization (MR) analysis to assess the causality between vitiligo and mental disorders, namely depression, anxiety, insomnia, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD). Summary statistics from large available genome-wide association study (GWAS) datasets for generalized vitiligo (n = 44 266), depression (n = 173 005), anxiety (n = 17 310), insomnia (n = 386 988), schizophrenia (n = 130 644), bipolar disorder (n = 413 466), OCD (n = 9725) and ADHD (n = 225 534) were utilized. Inverse-variance weighted (IVW), MR-Egger and weighted median were employed to estimate causal effects. Sensitivity analysis and MR Pleiotropy Residual Sum and Outliers (MR PRESSO) were conducted to assess heterogeneity and pleiotropy, ensuring the robustness of the results. Additionally, we corrected for estimating bias that might be brought on by sample overlap using MRlap. In our findings, none of the rigorous bidirectional MR analyses uncovered a significant causal association. Even after applying the MRlap correction, the effect sizes remained statistically nonsignificant, thereby reinforcing the conclusions drawn via IVW. In summary, our genetic-level investigation did not reveal a causal link between generalized vitiligo and mental disorders.

Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Data-driven prediction of the equivalent sand-grain roughness.

Surface roughness affects the near-wall fluid velocity profile and surface drag, and is commonly quantified by the equivalent sand-grain roughness [Formula: see text]. It is essential to estimate [Formula: see text] for accurate fluid dynamic problem modeling. While numerous roughness correlation formulas have been proposed to predict [Formula: see text] in the fully rough regime, most of them are restricted to certain roughness types, with various geometric parameters considered in each case, leading to ongoing disagreements regarding its parameterization and lack of universality. In this study, a Particle Swarm Optimized Backpropagation (PSO-BP) method is proposed to predict [Formula: see text] based on the selected surface parameters from previous DNS, LES, and experimental results for flow behavior over various surface roughness. The PSO-BP model's ability to predict [Formula: see text] in the fully rough region is evaluated and compared with both the existing roughness correction formulas as well as the traditional BP model. An optimized polynomial function is also proposed to serve as a 'white box' for predicting [Formula: see text]. It turns out that the PSO-BP method has better performance in the evaluation metrics compared to other methods, yielding a Mean Absolute Error (MAE) of 0.0390, a Mean Squared Error (MSE) of 0.0026 and a Mean Absolute Percentage Error (MAPE) of 28.12%. This novel approach for estimating [Formula: see text] has practical applicability and holds promise for improving the precision and efficiency of calculations related to equivalent sand-grain roughness, and thus provides more accurate and effective solutions for CFD and other engineering applications.

Resistance profiles of microbial communities in maize rhizospheres to the introduction of exogenous antibiotics to agricultural systems with a high arsenic geological background.

Metal(loid)s can increase the spread and enrichment of antibiotic resistance in the environmental system by means of a co-selection effect. The effects of introducing antibiotics into the environment on the long-term resistance of microbial communities to metal(loid)s are largely unknown. Here, manure-fertilizers that contained either oxytetracycline (OTC) or sulfadiazine (SD) at four concentrations (0, 1, 10, and 100 mg kg-1) were incorporated into a maize cropping system in an area with a high arsenic geological background. The results showed that the introduction of exogenous antibiotics had a notable effect on the bacterial diversity of the maize rhizosphere soil, as evidenced by alterations in Chao1 and Shannon index values when compared to those of the control. Oxytetracycline exposure did not significantly alter the prevalence of most bacterial phyla, with the exception of Actinobacteria. However, sulfadiazine antibiotic exposure caused a decrease in prevalence as exposure concentrations increased, with the exception of Gemmatimonadetes. The same reaction pattern was observed in the five most prevalent genera, such as Gemmatimonas, Fulvimonas, Luteimonas, Massilia, and Streptomyces. It was observed that the abundance of tetC, tetG, and sul2 antibiotic resistance genes (ARGs) significantly increased in correlation with the concentration of antibiotic exposure, and a strong link was found between these genes and integrons (intl1). The abundance of microbial functional genes related to arsenic transformation (aioA and arsM) increased when there was an increase in oxytetracycline exposure concentrations, whereas a decrease in abundance was observed with increasing sulfadiazine exposure concentrations. Proteobacteria, Actinobacteriota, Acidobacteriota, Chloroflexi, Firmicutes, Bacteroidota, Gemmatimonadota, Cyanobacteria and Planctomycetes were found to be important indicators of the introduction of antibiotics, and may be essential in the development of antibiotic resistance in soils with high arsenic geological background. Planctomycetacia (from Planctomycetes) was significantly negatively correlated with sul2 and intl1 genes, which might play a role in the development of resistance profiles to exogenous antibiotics. This study will expand our understanding of microbial resistance to antibiotic contamination in areas with a high geological background, as well as reveal the hidden ecological effects of combined contamination.

The plasma levels of Dickkopf-1 elevated in patients with Juvenile Idiopathic Arthritis.

BACKGROUND: To explore the role of two major inhibitors of Wnt signal pathway, Dickkopf-1(DKK-1) and Sclerostin (SOST), in the pathogenesis of juvenile idiopathic arthritis (JIA). METHODS: 88 patients with JIA, which including 49 patients with enthesitis-related arthritis (ERA), 21 oligoarthritis (oJIA) and 18 polyarthritis (pJIA), and 36 age-and sex-matched children as healthy controls (HC) were enrolled in this study. The plasma levels of DKK-1 and SOST, measured using commercially available ELISA kits, were analyzed the correlation between the levels of DKK-1/SOST and JIA, and were analyzed in 14 patients with JIA during before and after treatment. RESULTS: Plasma levels of DKK-1 were significantly higher in the patients with JIA than that in HC, the elevation of DKK-1 level was positively correlated with HLA-B27 positive JIA. DKK-1 levels dropped significantly in patient with JIA after treatment (P < 0.05). There was no significant change in SOST levels among different subtypes of JIA, patients with JIA during before and after treatment, and HC. CONCLUSION: It was suggested that the DKK-1 may have a certain correlation with the pathogenesis of JIA, and DKK-1 levels are more closely related to the HLA-B27 positive-ERA. IMPACT: The abnormally elevated levels of Dickkopf-1 (DKK-1) may be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). DKK-1 levels were more closely related to the HLA-B27 positive-enthesitis-related arthritis (ERA). DKK-1 is an inhibitor of Wnt signaling pathway that promotes osteoblastic new bone formation; it is very rare for pediatric patients with HLA-B27 positive-ERA to manifest typical spondylitis, while sacroiliac arthritis is relatively common, which may be related to the high levels of DKK-1, which is consistent with the early stage of ankylosing spondylitis (AS).

Elevated albumin corrected anion gap is associated with poor in-hospital prognosis in patients with cardiac arrest: A retrospective study based on MIMIC-IV database.

Background: Cardiac arrest(CA) is one of the most leading causes of death. Most of the indicators which used to predict the prognosis of patients with CA are not recognized. Previous studies have suggested that albumin corrected anion gap (ACAG) is associated with recovery of spontaneous circulation in patients with CA, but the predictive value of ACAG for prognosis has not been investigated. This study aims to explore the relationship between ACAG and prognosis during hospitalization in patients with CA. Methods: The baseline data of adult patients with CA hospitalized in the intensive care unit (ICU) from 2008 to 2019 in the American Intensive Care Database (MIMIC-IV, version v2.0) were collected. According to the in-hospital prognosis, patients were divided into survival and non-survival group. Based on the criteria of ACAG level in the previous literature, patients enrolled were divided into normal ACAG (12-20 mmol/L) and high ACAG (>20 mmol/L) group. The basic information of patients during hospitalization were compared and analyzed between the two groups with propensity score matching (PSM). The Kaplan-Meier method was used to compare the cumulative survival rates of normal ACAG and high ACAG groups before and after matching. Restricted cubic spline (RCS) method and multivariate COX proportional hazards regressions were used to analyze whether elevated ACAG was associated with all-cause mortality during hospitalization. Results: A total of 764 patients were included. A matched cohort (n = 310) was obtained after PSM analysis. The mortality rate before and after matching in the high ACAG group was higher than that in the normal ACAG group (χ 2 = 25.798; P < 0.001; χ 2 = 6.258; P = 0.012) The Kaplan-Meier survival analysis before and after matching showed that the cumulative survival rate of the high ACAG group was lower (P < 0.05). RCS analysis showed that ACAG had a non-linear relationship with the risk of in-hospital all-cause mortality (χ 2 = 6.060, P < 0.001). Multivariate COX regression analysis before and after PSM suggested that elevated ACAG was an independent risk factor for all-cause mortality in patients with CA during hospitalization (P < 0.01). Conclusions: Elevated ACAG is associated with increased all-cause mortality in patients with CA during hospitalization, it can be an independent risk factor for poor prognosis in patients with CA and remind clinicians to pay more attention to these patients.

Association of preterm outcome with maternal systemic lupus erythematosus: a retrospective cohort study.

BACKGROUND: Maternal systemic lupus erythematosus (SLE) is at greater risk of pregnancy complications and is associated with increased risk of preterm delivery. However hardly any study has looked at the influence of SLE on the outcomes of preterm infants. This study aimed to explore the influence of SLE on the outcomes of preterm infants. METHODS: In this retrospective cohort study, preterm infants born to mothers with SLE from Shanghai Children's Medical Center during 2012 to 2021 were enrolled. Infants were excluded if they were died during hospitalization or has major congenital anomalies and neonatal lupus. Exposure was defined as mother diagnosed SLE before or during pregnancy. Maternal SLE group was matched with Non-SLE group by gestational age, birth weight and gender. Clinical data has been extracted from patients' records and registered. Major morbidities of premature and biochemical parameters in the two groups were compared using multiple logistic regression. RESULTS: One hundred preterm infants born to 95 mothers with SLE were finally enrolled. The mean (standard deviation) of gestational age and birth weight were 33.09 (7.28) weeks and 1768.50 (423.56) g respectively. There was no significant difference in major morbidities between SLE group and non-SLE group. Compared with non-SLE group, SLE off-spring had significantly lower leukocytes, neutrophiles after birth, neutrophils and platlet in one week (mean difference: -2.825, -2.001, -0.842, -45.469, respectively). Among SLE group, lower birth weight and smaller gestational age were observed in SLE mothers with disease active during pregnancy, kidney involved, blood system involved and not taking Aspirin during pregnancy. In the multivariable logistic regression analysis, exposure to aspirin during pregnancy reduced the risk of very preterm birth and increased the incidence of survive without major morbidities among preterm infants born to SLE mothers. CONCLUSION: Born to mothers with SLE may not increase the risk of major premature morbidities, but the hematologic profile of SLE preterm infants may be different from preterm infants born to women without SLE. The outcome of SLE preterm infants is associated with maternal SLE status and may benefit from maternal aspirin administration.

Ecological Responses of Maize Rhizosphere to Antibiotics Entering the Agricultural System in an Area with High Arsenicals Geological Background.

Metal(loid)s can promote the spread and enrichment of antibiotic resistance in the environmental ecosystem through a co-selection effect. Little is known about the ecological effects of entering antibiotics into the environment with long-term metal(loid)s' resistance profiles. Here, cow manure containing oxytetracycline (OTC) or sulfadiazine (SA) at four concentrations (0 (as control), 1, 10, and 100 mg/kg) was loaded to a maize cropping system in an area with high a arsenicals geological background. Results showed that exogenous antibiotics entering significantly changed the nutrient conditions, such as the concentration of nitrate nitrogen, ammonium nitrogen, and available phosphorus in the maize rhizosphere soil, while total arsenic and metals did not display any differences in antibiotic treatments compared with control. Antibiotics exposure significantly influenced nitrate and nitrite reductase activities to reflect the inhibition of denitrification rates but did not affect the soil urease and acid phosphatase activities. OTC treatment also did not change soil dehydrogenase activities, while SA treatment posed promotion effects, showing a tendency to increase with exposure concentration. Both the tested antibiotics (OTC and SA) decreased the concentration of arsenite and arsenate in rhizosphere soil, but the inhibition effects of the former were higher than that of the latter. Moreover, antibiotic treatment impacted arsenite and arsenate levels in maize root tissue, with positive effects on arsenite and negative effects on arsenate. As a result, both OTC and SA treatments significantly increased bioconcentration factors and showed a tendency to first increase and then decrease with increasing concentration. In addition, the treatments decreased translocation capacity of arsenic from roots to shoots and showed a tendency to increase translocation factors with increasing concentration. Microbial communities with arsenic-resistance profiles may also be resistant to antibiotics entering.

Application Effect of Cluster-Based Care in Patients with Hypertensive Disorders of Pregnancy and Osteoarthritis.

Objective: To explore the application effect of cluster-based care in patients with hypertensive disorders of pregnancy and osteoarthritis. Methods: The clinical data of 60 patients with hypertensive disorders of pregnancy and osteoarthritis in our hospital were retrospectively analyzed, among which those receiving routine care from January 2020 to December 2020 were grouped into the control group (30 patients), and those receiving cluster-based care from January 2021 to January 2022 were grouped into the research group (30 patients). Psychological status, care satisfaction, and pregnancy outcomes were compared between the two groups. Results: After intervention, self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores in the research group were lower than those in the control group (P < 0.05). There was no statistical significance in the difference of the modes of delivery between the two groups (χ 2 = 1.763, P > 0.05). Patients in the research group had a lower incidence of perinatal complications than those in the control group (χ 2 = 5.689, P < 0.05). And the satisfaction rate of care in the research group (93.33% vs 70%) was higher than that in the control group (χ 2 = 4.238, P < 0.05). Conclusion: Cluster-based care can reduce patients' negative mood, increase their satisfaction, and improve the maternal and infant outcomes. This type of care offers better quality care measures for patients with pregnancy hypertension and osteoarthritis, and has a wide clinical application prospect.

HAP40 is a conserved central regulator of Huntingtin and a potential modulator of Huntington's disease pathogenesis.

Perturbation of huntingtin (HTT)'s physiological function is one postulated pathogenic factor in Huntington's disease (HD). However, little is known how HTT is regulated in vivo. In a proteomic study, we isolated a novel ~40kDa protein as a strong binding partner of Drosophila HTT and demonstrated it was the functional ortholog of HAP40, an HTT associated protein shown recently to modulate HTT's conformation but with unclear physiological and pathologic roles. We showed that in both flies and human cells, HAP40 maintained conserved physical and functional interactions with HTT. Additionally, loss of HAP40 resulted in similar phenotypes as HTT knockout. More strikingly, HAP40 strongly affected HTT's stability, as depletion of HAP40 significantly reduced the levels of endogenous HTT protein while HAP40 overexpression markedly extended its half-life. Conversely, in the absence of HTT, the majority of HAP40 protein were degraded, likely through the proteasome. Further, the affinity between HTT and HAP40 was not significantly affected by polyglutamine expansion in HTT, and contrary to an early report, there were no abnormal accumulations of endogenous HAP40 protein in HD cells from mouse HD models or human patients. Lastly, when tested in Drosophila models of HD, HAP40 partially modulated the neurodegeneration induced by full-length mutant HTT while showed no apparent effect on the toxicity of mutant HTT exon 1 fragment. Together, our study uncovers a conserved mechanism governing the stability and in vivo functions of HTT and demonstrates that HAP40 is a central and positive regulator of endogenous HTT. Further, our results support that mutant HTT is toxic regardless of the presence of its partner HAP40, and implicate HAP40 as a potential modulator of HD pathogenesis through its multiplex effect on HTT's function, stability and the potency of mutant HTT's toxicity.

Effects of miR-939 and miR-376A on ulcerative colitis using a decoy strategy to inhibit NF-κB and NFAT expression.

The aim of this study was to explore the effects of miR-939 and miR-376A on the pathogenesis of ulcerative colitis (UC) by using a decoy strategy to regulate the expression of nuclear transcription factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Such strategies represent a potential novel treatment for UC. Quantitative polymerase chain reaction (qPCR) analysis was used to detect the differences between the expression of miR-939, miR-376a, NF-κB, NFAT in the tissue samples from the resting and active stages of UC and healthy controls, and analyzed the correlation. The electrophoretic mobility shift assay was used to validate the ability of miRNAs to bind to NF-κB and NFAT. The expression of components of the intestinal barrier in UC and changes in apoptosis-related factors were examined by western blotting, qPCR, and immunofluorescence. After a dextran sulfate sodium (DSS)-induced mouse model of UC was established, the morphological changes in the colonic tissues of mice, the changes in serum inflammatory factors, and the changes in urine protein or urine leukocytes, liver enzymes, and prothrombin time were measured to examine intestinal permeability. The expression of miR-939 and miR-376a in human UC tissue was significantly lower than that in the normal control tissue, and was negatively correlated with the expression of NF-κB and NFAT. miR-939 and miR-376a decoy strategies resulted in a beneficial increase in the expression of claudins, occludins, and ZO-1 protein and inhibited apoptosis in intestinal epithelial cells. The disease activity index of the UC model group was significantly higher than that of the normal control group. The expression of inflammatory factors in the decoy group was higher than that in the UC model group. Therefore, from the experimental results, it can be concluded that using miR-939 and miR-376a to trap NF-κB and NFAT inhibits the activation of transcription factors NF-κB and NFAT, which in turn inhibits the expression of inflammatory factors and results in partial recovery of the intestinal barrier in UC. The decoy strategy inhibited apoptosis in the target cells and had a therapeutic effect in the mice model of UC. This study provides new ideas for the development of future clinical therapies for UC.

Okicamelliaside targets the N-terminal chaperone pocket of HSP90 disrupts the chaperone protein interaction of HSP90-CDC37 and exerts antitumor activity.

Heat shock protein 90 (HSP90) has been recognized as a crucial target in cancer cells. However, various toxic reactions targeting the ATP binding site of HSP90 may not be the best choice for HSP90 inhibitors. In this paper, an ellagic acid derivative, namely, okicamelliaside (OCS), with antitumor effects was found. To identify potential anti-cancer mechanisms, an OCS photosensitive probe was applied to target fishing and tracing. Chemical proteomics and protein-drug interaction experiments have shown that HSP90 is a key target for OCS, with a strong binding affinity (KD = 6.45 µM). Mutation analysis of the target protein and molecular dynamics simulation revealed that OCS could competitively act on the key Glu-47 site at the N-terminal chaperone pocket of HSP90, where the co-chaperone CDC37 binds to HSP90, affect its stability and reduce the ∆Gbind of HSP90-CDC37. It was demonstrated that OCS destroys the protein-protein interactions of HSP90-CDC37; selectively affects downstream kinase client proteins of HSP90, including CDK4, P-AKT473, and P-ERK1/2; and exerts antitumor effects on A549 cells. Furthermore, tumor xenograft experiments demonstrated high antitumor activity and low toxicity of OCS in the same way. Our findings identified a novel N-terminal chaperone pocket natural inhibitor of HSP90, that is, OCS, which selectively inhibits the formation of the HSP90-CDC37 protein complex, and provided further insight into HSP90 inhibitors for anti-cancer candidate drugs.

Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation.

OBJECTIVE: Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. METHODS: Ormdl3-deficient (Ormdl3-/-) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3-/- mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. RESULTS: BAT thermogenesis and WAT browning were significantly impaired in Ormdl3-/- mice upon cold exposure or administration with the ß3 adrenergic agonist. In addition, compared to WT mice, Ormdl3-/- mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3-/- mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3-/- mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. CONCLUSION: Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance.

Case report: Primary immunodeficiency due to a novel mutation in CARMIL2 and its response to combined immunomodulatory therapy.

Capping protein regulator and myosin 1 linker 2 (CARMIL2) is necessary for invadopodia formation, cell polarity, lamellipodial assembly, membrane ruffling, acropinocytosis, and collective cell migration. CARMIL2 deficiency is a rare autosomal recessive disease characterized by dysfunction in naïve T-cell activation, proliferation, differentiation, and effector function and insufficient responses in T-cell memory. In this paper, we report a 9-year-old female patient with a novel pathogenic variant in CARMIL2 (c.2063C > G:p.Thr688Arg) who presented with various symptoms of primary immunodeficiencies including recurrent upper and lower respiratory infections, perioral and perineum papules, reddish impetiginized atopic dermatitis, oral ulcer, painful urination and vaginitis, otitis media, and failure to thrive. A missense mutation leading to insufficient CARMIL2 protein expression, reduced absolute T-cell and natural killer cell (NK cell) counts, and marked skewing to the naïve T-cell form was identified and indicated defective maturation of T cells and B cells. Following 1 year of multitargeted treatment with corticosteroids, hydroxychloroquine, mycophenolate mofetil, and thymosin, the patient presented with significant regression in rashes. CD4+ T-cell, CD8+ T-cell, and NK cell counts were significantly improved.

Dietary Flavone Baicalein Combinate with Genipin Attenuates Inflammation Stimulated by Lipopolysaccharide in RAW264.7 Cells or Pseudomonas aeruginosa in Mice via Regulating the Expression and Phosphorylation of AKT.

Mounting evidence has shown that single-targeted therapy might be inadequate to achieve satisfactory effects. Thus, drug combinations are gaining attention as they can regulate multiple targets to obtain more beneficial effects. Heat shock protein 90 (HSP90) is a molecular chaperone that assists the protein assembly and folding of client proteins and maintains their stability. Interfering with the interaction between HSP90 and its client proteins by inhibiting the latter's activity may offer a new approach toward combination therapy. The HSP90 client protein AKT plays an important role in the inflammatory response syndrome caused by infections. In this study, the dietary flavone baicalein was identified as a novel inhibitor of HSP90 that targeted the N-terminal ATP binding pocket of HSP90 and hindered the chaperone cycle, resulting in AKT degradation. Combining baicalein with genipin, which was extracted from Gardenia jasminoides, could inhibit the pleckstrin homology domain of AKT, significantly increasing the anti-inflammatory effects both in vitro and in vivo. This synergistic effect was attributed to the reduction in AKT expression and phosphorylation. Thus, elucidating the mechanism underlying this effect will provide a new avenue for the clinical application and development of synergistic anti-inflammatory drugs.