X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease (REACH5): interim analysis of a single-arm, multicentre, phase 2 study.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD. METHODS: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing. FINDINGS: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug. INTERPRETATION: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD. FUNDING: Novartis.

Research progress on the mechanism of action and clinical application of remote ischemic post-conditioning for acute ischemic stroke.

Remote ischemic post-conditioning (RIPostC) can reduce cerebral ischemia reperfusion injury (IRI) by inducing endogenous protective effects, the distal limb ischemia post-treatment and in situ ischemia post-treatment were classified according to the site of intervention. And in the process of clinical application distal limb ischemia post-treatment is more widely used and more conducive to clinical translation. Therefore, in this paper, we review the mechanism of action and clinical application of RIPostC in cerebral ischemia, hoping to provide reference help for future experimental directions and clinical translation.

Higher tumor mutational burden is associated with inferior outcomes among pediatric patients with neuroblastoma.

INTRODUCTION: Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. METHODS: Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. RESULTS: We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p = .03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p < .0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. CONCLUSIONS: Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.

Disease burden, management strategies, and unmet needs in α-thalassemia due to hemoglobin H disease.

Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options.

RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.

Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.

PagKNAT2/6b promotes shoot branching by attenuating auxin-strigolactone signalling in poplar.

Shoot branching from axillary bud (AB) directly determines plant architecture. However, the mechanism through which AB remains dormant or emerges to form branches as plants grow remains largely unknown. Here, the auxin-strigolactone (IAA-SL) pathway was first shown to regulate shoot branching in poplar, and we found that PagKNAT2/6b could modulate this pathway. PagKNAT2/6b was expressed mainly in the shoot apical meristem and AB and was induced by shoot apex damage. PagKNAT2/6b overexpressing poplar plants (PagKNAT2/6b OE) exhibited multiple branches that mimicked the branching phenotype of nontransgenic plants after decapitation treatment, while compared with nontransgenic controls, PagKNAT2/6b antisense transgenic poplar and Pagknat2/6b mutant lines exhibited a significantly decreased number of branches after shoot apex damage treatment. In addition, we found that PagKNAT2/6b directly inhibits the expression of the key IAA synthesis gene PagYUC6a, which is specifically expressed in the shoot apex. Moreover, overexpression of PagYUC6a in the PagKNAT2/6b OE background reduced the number of branches after shoot apex damage treatment. Overall, we conclude that PagKNAT2/6b responds to shoot apical injury and regulates shoot branching through the IAA-SL pathway. These findings may provide a theoretical basis and candidate genes for genetic engineering to create new forest tree species with different crown types.

Identification of Gut Microbiome Signatures Associated with Indole Pathway in Tryptophan Metabolism in Patients Undergoing Hemodialysis.

Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner-Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.

[Spatial and Temporal Distribution of Antibiotic Resistance Genes in Different River Sediments in Typical Cities: A Case Study of Shijiazhuang].

Rivers are important reservoirs of antibiotic resistance genes (ARGs). However, most current studies have focused on the temporal and spatial distribution, and data on the differences in the species and abundance of ARGs between urban and rural rivers is still lacking for certain areas. In view of this, two rural rivers and three urban rivers were selected in Shijiazhuang City. In both December 2020 and April 2021, sediments were collected at 15 sampling sites. Metagenomic sequencing technology was used to compare the differences in temporal-spatial variation for ARGs in sediments. The results showed that:① 162 and 79 ARGs were detected in urban (4 776 ±4 452) and rural rivers (1 043 ±632), respectively. The abundance and species of ARGs in urban rivers were higher than those in rural rivers. ② The relative abundances of sulfonamide (SAs,27 %), aminoglycoside (AGs,26 %), and multidrug (MDs,15 %) ARGs had the highest abundance in urban rivers, whereas the relative abundance of MDs ARGs was highest in rural rivers (65 %). On the whole, the complexity of ARGs in urban rivers was higher than that in rural rivers. ③ There was a significant positive correlation between SAs, AGs, MDs, tetracycline, phenicol, macrolides-lincosamids-streptogramins (MLS), ß-lactams, and diaminopyrimidine ARGs in urban rivers (P < 0.01); however, there was a significant negative correlation between glycopeptide ARGs and all types of ARGs (P < 0.05 and P < 0.01). There was a significant positive correlation between MDs and SAs ARGs in rural rivers (P < 0.05), but there was a significant negative correlation between amino aminocoumarin, peptide, rifamycin, and fosfomycin ARGs (P < 0.05 and P < 0.01). ④ For the temporal variation in urban rivers, 162 ARGs (4 776 ±4 452) and 148 ARGs (5 673 ±5 626) were detected in December and April, respectively. For the temporal variation in rural rivers, 79 species (1 043 ±632) and 46 species (467 ±183) were detected in December and April, respectively. ⑤ RDA analysis results showed that the spatial-temporal distributions of ARGs in urban and rural rivers were different. Correlation analysis showed that the ARGs in urban rivers were significantly correlated with the number of industrial enterprises, whereas the ARGs in rural rivers were significantly correlated with the output value of animal husbandry. In general, this study identified the main influencing factors for ARGs in different rivers and provided data support for ARGs risk management in different rivers.

Iron deficiency anemia and platelet dysfunction: A comprehensive analysis of the underlying mechanisms.

AIMS: This research aimed to study the changes in platelet function and their underlying mechanisms in iron deficiency anemia. MAIN METHODS: Initially, we evaluated platelet function in an IDA mice model. Due to the inability to accurately reduce intracellular Fe2+ concentrations, we investigated the impact of Fe2+ on platelet function by introducing varying concentrations of Fe2+. To probe the underlying mechanism, we simultaneously examined the dynamics of calcium in the cytosol, and integrin αIIbß3 activation in Fe2+-treated platelets. Ferroptosis inhibitors Lip-1 and Fer-1 were applied to determine whether ferroptosis was involved in this process. KEY FINDINGS: Our study revealed that platelet function was suppressed in IDA mice. Fe2+ concentration-dependently facilitated platelet activation and function in vitro. Mechanistically, Fe2+ promoted calcium mobilization, integrin αIIbß3 activation, and its downstream outside-in signaling. Additionally, we also demonstrated that ferroptosis might play a role in this process. SIGNIFICANCE: Our data suggest an association between iron and platelet activation, with iron deficiency resulting in impaired platelet function, while high concentrations of Fe2+ contribute to platelet activation and function by promoting calcium mobilization, αIIbß3 activation, and ferroptosis.

BMI, weight change, appetite reduction and cognitive impairment of elderly patients with diabetes.

Body weight is related to both diabetes and cognitive impairment; however, the associations between body mass index (BMI) and cognitive impairment have been reported less frequently among diabetes patients. A total of 1355 patients with type 2 diabetes aged ≥ 60 years were included in this study. The Montreal Cognitive Assessment (MoCA) was administered to assess participants' cognitive status. We collected self-reported body weight, weight loss and appetite loss data using questionnaires. Associations between body weight status (in childhood, midlife age, and late life), weight loss, appetite changes and cognitive impairment were explored using logistic regression. Among the participants, 41.7% exhibited cognitive impairment. Overweight in childhood and late life was associated with cognitive impairment among diabetes patients (OR 2.63, 95% CI 1.52-4.55; OR 1.32, 95% CI 1.03-1.69). Diabetes patients with cognitive impairment were more likely to report a body weight decline and appetite reduction in the past three months (OR 4.18, 95% CI 2.61-6.71; OR 4.41, 95% CI 2.67-7.29). Higher BMI, weight loss, and appetite reduction were positively correlated with cognitive impairment. Given the risk of cognitive impairment, we suggest that body weight and BMI decline should be monitored in patients with diabetes.

Analysis of the dynamic mechanism of trans-boundary pollution collaborative control in the Yangtze River Economic Belt.

Climate change mitigation requires simultaneous reduction of carbon emissions and air pollution. This study examines the synergy between pollution reduction and carbon reduction, identifying key variables and strategies to achieve this goal. Using a Geographical Detector model and a Coupling Degree of Coordination model, 108 cities in the Yangtze River Economic Belt (YREB) are investigated. Results show that while controlling PM2.5 has been more successful than managing carbon emissions in the YREB, synergy between pollution reduction and carbon emissions increased by an average of 7.2% from 2006 to 2019. Spatial analysis reveals higher synergy in upstream areas, indicating significant spatial diversity. The impact of pollution and emission reduction synergies is influenced by societal and environmental variables, including industry structure, technological innovation, energy structure, human capital quality, and economic basis. Synergy is amplified when natural limits align with high-quality development drivers such as technical innovation and the digital economy. Recommendations include enhancing city-to-city contact, improving energy and industrial structures, and fostering technological innovation to address regional variations in synergy levels.

PagJAZ5 regulates cambium activity through coordinately modulating cytokinin concentration and signaling in poplar.

Wood is resulted from the radial growth paced by the division and differentiation of vascular cambium cells in woody plants, and phytohormones play important roles in cambium activity. Here, we identified that PagJAZ5, a key negative regulator of jasmonate (JA) signaling, plays important roles in enhancing cambium cell division and differentiation by mediating cytokinin signaling in poplar 84K (Populus alba × Populus glandulosa). PagJAZ5 is preferentially expressed in developing phloem and cambium, weakly in developing xylem cells. Overexpression (OE) of PagJAZ5m (insensitive to JA) increased cambium activity and xylem differentiation, while jaz mutants showed opposite results. Transcriptome analyses revealed that cytokinin oxidase/dehydrogenase (CKXs) and type-A response regulators (RRs) were downregulated in PagJAZ5m OE plants. The bioactive cytokinins were significantly increased in PagJAZ5m overexpressing plants and decreased in jaz5 mutants, compared with that in 84K plants. The PagJAZ5 directly interact with PagMYC2a/b and PagWOX4b. Further, we found that the PagRR5 is regulated by PagMYC2a and PagWOX4b and involved in the regulation of xylem development. Our results showed that PagJAZ5 can increase cambium activity and promote xylem differentiation through modulating cytokinin level and type-A RR during wood formation in poplar.

Mycorrhizal associations relate to stable convergence in plant-microbial competition for nitrogen absorption under high nitrogen conditions.

Nitrogen (N) immobilization (Nim, including microbial N assimilation) and plant N uptake (PNU) are the two most important pathways of N retention in soils. The ratio of Nim to PNU (hereafter Nim:PNU ratio) generally reflects the degree of N limitation for plant growth in terrestrial ecosystems. However, the key factors driving the pattern of Nim:PNU ratio across global ecosystems remain unclear. Here, using a global data set of 1018 observations from 184 studies, we examined the relative importance of mycorrhizal associations, climate, plant, and soil properties on the Nim:PNU ratio across terrestrial ecosystems. Our results show that mycorrhizal fungi type (arbuscular mycorrhizal (AM) or ectomycorrhizal (EM) fungi) in combination with soil inorganic N mainly explain the global variation in the Nim:PNU ratio in terrestrial ecosystems. In AM fungi-associated ecosystems, the relationship between Nim and PNU displays a weaker negative correlation (r = -.06, p < .001), whereas there is a stronger positive correlation (r = .25, p < .001) in EM fungi-associated ecosystems. Our meta-analysis thus suggests that the AM-associated plants display a weak interaction with soil microorganisms for N absorption, while EM-associated plants cooperate with soil microorganisms. Furthermore, we find that the Nim:PNU ratio for both AM- and EM-associated ecosystems gradually converge around a stable value (13.8 ± 0.5 for AM- and 12.1 ± 1.2 for EM-associated ecosystems) under high soil inorganic N conditions. Our findings highlight the dependence of plant-microbial interaction for N absorption on both plant mycorrhizal association and soil inorganic N, with the stable convergence of the Nim:PNU ratio under high soil N conditions.

Unveiling long COVID symptomatology, co-occurrence trends, and symptom distress post SARS-CoV-2 infection.

BACKGROUND: Long COVID, an emerging public health issue, is characterized by persistent symptoms following SARS-CoV-2 infection. This study aims to explore the relationship between post-COVID-19 symptomatology and patient distress employing Latent Class Analysis to uncover symptom co-occurrence patterns and their association with distress. METHODS: A cross-sectional study was conducted using an online survey among 240 participants from a university and affiliated hospital of southern Taiwan. The survey quantified distress due to persistent symptoms and assessed the prevalence of Long COVID, symptom co-occurrence, and latent symptom classes. Latent Class Analysis (LCA) identified distinct symptom patterns, and multiple regression models evaluated associations between symptom patterns, distress, and demographic factors. RESULTS: The study found that 80 % of participants experienced Long COVID, with symptoms persisting for over three months. Individuals with multiple COVID-19 infections showed a significant increase in general (ß = 1.79), cardiovascular (ß = 0.61), and neuropsychological symptoms (ß = 2.18), and higher total distress scores (ß = 6.35). Three distinct symptomatology classes were identified: "Diverse", "Mild", and "Severe" symptomatology. The "Mild Symptomatology" class was associated with lower distress (-10.61), while the "Severe Symptomatology" class showed a significantly higher distress due to symptoms (13.32). CONCLUSION: The study highlights the significant impact of Long COVID on individuals, with distinct patterns of symptomatology and associated distress. It emphasizes the cumulative effect of multiple COVID-19 infections on symptom severity and the importance of tailored care strategies.

UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions: UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Mechanism of Bile Acid in Regulating Platelet Function and Thrombotic Diseases.

Platelets play a key role in physiological hemostasis and pathological thrombosis. Based on the limitations of current antiplatelet drugs, it's important to elucidate the mechanisms of regulating platelet activation. In addition to dissolving lipid nutrients, bile acids (BAs) can regulate platelet function. However, the specific mechanisms underlying BAs-mediated effects on platelet activation and thrombotic diseases remain unknown. Therefore, the effects of BAs on platelets and intracellular regulatory mechanisms are explored. It is showed that the inhibitory effect of secondary BAs is more significant than that of primary BAs; lithocholic acid (LCA) shows the highest inhibitory effect. In the process of platelet activation, BAs suppress platelet activation via the spleen tyrosine kinase (SYK), protein kinase B (Akt), and extracellular signal-regulated kinase1/2 (Erk1/2) pathways. Nck adaptor proteins (NCK1) deficiency significantly suppress the activity of platelets and arterial thrombosis. Phosphorylated proteomics reveal that LCA inhibited phosphorylation of syntaxin-11 at S80/81 in platelets. Additional LCA supplementation attenuated atherosclerotic plaque development and reduced the inflammation in mice. In conclusion, BAs play key roles in platelet activation via Syk, Akt, ERK1/2, and syntaxin-11 pathways, which are associated with NCK1. The anti-platelet effects of BAs provide a theoretical basis for the prevention and therapy of thrombotic diseases.

Evaluation of twin fetal exposure to radiofrequency field during magnetic resonance imaging.

Fetal development is essential to the human lifespan. As more and more multifetal gestations have been reported recently, clinical diagnosis using magnetic resonance imaging (MRI), which introduced radiofrequency (RF) exposure, raised public concerns. The present study developed two whole-body pregnant models of 31 and 32 gestational weeks (GWs) with twin fetuses and explored RF exposure by 1.5 and 3.0 T MRI. Differences in the relative position of the fetus and changes in fetal weight can cause differences in fetal peak local specific absorption rate averaged over 10 g tissue (pSAR10g). Variation of pSAR10g due to different fetal positions can be ~35%. Numerically, twin and singleton fetal pSAR10g results were not significantly different, however twin results exceeded the limit in some cases (e.g. fetuses of 31 GW at 1.5 T), which indicated the necessity for further research employing anatomically correct twin-fetal models coming from various GWs and particular sequence to be applied.

Counteracting TGM2 by a Fibroin peptide ameliorated Adriamycin-induced nephropathy via regulation of lipid metabolism through PANX1-PPAR α/PANK1 pathway.

Peptide drug discovery for the treatment of chronic kidney disease (CKD) has attracted much attention in recent years due to the urge to find novel drugs and mechanisms to delay the progression of the disease. In this study, we identified a novel short peptide (named YR-7, primary sequence 'YEVEDYR') from the natural Fibroin protein, and demonstrated that it significantly alleviated pathological renal changes in ADR-induced nephropathy. PANX1 was identified as the most notably upregulated component by RNA-sequencing. Further analysis showed that YR-7 alleviated the accumulation of lipid droplets via regulation of the lipid metabolism-related proteins PPAR α and PANK1. Using chemical proteomics, fluorescence polarization, microscale thermophoresis, surface plasmon resonance, and molecular docking, YR-7 was proven to directly bind to ß-barrel domains of TGM2 protein to inhibit lipid accumulation. TGM2 knockdown in vivo increased the protein levels of PPAR α and PANK1 while decreased the levels of fibrotic-related proteins to alleviate nephropathy. In vitro, overexpression TGM2 reversed the protective effects of YR-7. Co-immunoprecipitation indicated that TGM2 interacted with PANX1 to promote lipid deposition, and pharmacological inhibition or knockdown of PANX1 decreased the levels of PPAR α and PANK1 induced by ADR. Taken together, our findings revealed that TGM2-PANX1 interaction in promoting lipid deposition may be a new signaling in promoting ADR-induced nephropathy. And a novel natural peptide could ameliorate renal fibrosis through TGM2-PANX1-PPAR α/PANK1 pathway, which highlight the potential of it in the treatment of CKD.

PagWOX11/12a from hybrid poplar enhances drought tolerance by modulating reactive oxygen species.

WOX11/12 is a homeobox gene of WOX11 and WOX12 in Arabidopsis that plays important roles in crown root development and growth. It has been reported that WOX11/12 participates in adventitious root (AR) formation and different abiotic stress responses, but the downstream regulatory network of WOX11/12 in poplar remains to be further investigated. In this study, we found that PagWOX11/12a is strongly induced by PEG-simulated drought stress. PagWOX11/12a-overexpressing poplar plantlets showed lower oxidative damage levels, greater antioxidant enzyme activities and reactive oxygen species (ROS) scavenging capacity than non-transgenic poplar plants, whereas PagWOX11/12a dominant repression weakened root biomass accumulation and drought tolerance in poplar. RNA-seq analysis revealed that several differentially expressed genes (DEGs) regulated by PagWOX11/12a are involved in redox metabolism and drought stress response. We used RT-qPCR and yeast one-hybrid (Y1H) assays to validate the downstream target genes of PagWOX11/12a. These results provide new insights into the biological function and molecular regulatory mechanism of WOX11/12 in the abiotic resistance processes of poplar.