Multiple pathways of vanadate reduction and denitrification mediated by denitrifying bacterium Acidovorax sp. strain BoFeN1.

Contamination of aquifers by a combination of vanadate [V(V)] and nitrate (NO3-) is widespread nowadays. Although bioremediation of V(V)- and nitrate-contaminated environments is possible, only a limited number of functional species have been identified to date. The present study demonstrates the effectiveness of V(V) reduction and denitrification by a denitrifying bacterium Acidovorax sp. strain BoFeN1. The V(V) removal efficiency was 76.5 ± 5.41 % during 120 h incubation, with complete removal of NO3- within 48 h. Inhibitor experiments confirmed the involvement of electron transport substances and denitrifying enzymes in the bioreduction of V(V) and NO3-. Cyt c and riboflavin were important for extracellular V(V) reduction, with quinone and EPS more significant for NO3- removal. Intracellular reductive compounds including glutathione and NADH directly reduce V(V) and NO3-. Reverse transcription quantitative PCR confirmed the important roles of nirK and napA genes in regulating V(V) reduction and denitrification. Bioaugmentation by strain BoFeN1 increased V(V) and NO3- removal efficiency by 55.3 % ± 2.78 % and 42.1 % ± 1.04 % for samples from a contaminated aquifer. This study proposes new microbial resources for the bioremediation of V(V) and NO3-contaminated aquifers, and contributes to our understanding of coupled vanadium, nitrogen, and carbon biogeochemical processes.

Understanding reliability of the observer-reported communication ability measure within Angelman syndrome through the lens of generalizability theory.

AIMS: Caregivers rate improved communication ability as one of the most desired outcomes for successful interventions for individuals with Angelman syndrome (AS). When measuring communication ability in clinical trials, the reliability of such measures is critical for detecting significant changes over time. This study examined the reliability of the Observed-Reported Communication Ability (ORCA) measure completed by caregivers of individuals with AS. METHODS: The ORCA measure was completed by 249 caregivers with 170 caregivers completing the ORCA measure again after 5-12 days. Generalizability theory was used to examine the following sources of measurement error in ORCA scores: concepts, subdomains, assessment points, and the interactions among those facets and the object of measurement: communication ability. Three generalizability studies were conducted to understand the reliability of the ORCA measure for different measurement designs. Decision studies were carried out to demonstrate the optimization of measurement procedures of the ORCA measure. RESULTS: G and Phi coefficients of the original measurement design exceeded the 0.80 threshold considered sufficiently reliable to make relative and absolute decisions about the communication ability of individuals with AS based on their caregivers' observed scores. The optimization procedures indicated that increasing the number of communication concepts and/or assessment points leads to more reliable estimates of communication. CONCLUSION: The ORCA measure was able to reliably distinguish different levels of communication ability among individuals with AS. Multiple assessment points and or more concepts would provide more precise estimates of an individual's communication ability but at the cost of survey fatigue.

Inflammation and tissue remodeling mediator expression during gingivitis: A comparison between experimental, naturally occurring gingivitis, and periodontal health.

BACKGROUND: The aim of this study is to evaluate the immune regulation and tissue remodeling responses during experimental gingivitis (EG) and naturally occurring gingivitis (NG) to provide a comprehensive analysis of host responses. Gingival crevicular fluid (GCF) was obtained from 2 human studies conducted in university settings. METHODS: The EG study enrolling 26 volunteers provided controls for the baseline (Day 0) from healthy disease-free participants, while Day 21 (the end of EG induction of the same group) was used to represent EG. Twenty-six NG participants age-matched with those of the EG group were recruited. GCF samples were analyzed for 39 mediators of inflammatory/immune responses and tissue remodeling using commercially available bead-based multiplex immunoassays. The differences in GI and mediator expression among groups were determined at a 95% confidence level (p ≤ 0.05) by a 2-way analysis of variance (ANOVA) with a post-hoc Tukey's test. RESULTS: Our findings showed that EG had a greater gingival index than NG and was healthy (p < 0.01 of all comparisons). Furthermore, EG showed significantly higher levels of MPO (p < 0.001), CCL3 (p < 0.05), and IL-1B (p < 0.001) than NG. In contrast, NG had increased levels of MIF (p < 0.05), Fractalkine (p < 0.001), angiogenin (p < 0.05), C3a (p < 0.001), BMP-2 (p < 0.001), OPN (p < 0.05), RANKL (p < 0.001), and MMP-13 (p < 0.001) than EG. CONCLUSIONS: Consistent with the findings from chronic (NG) versus acute (EG) inflammatory lesions, these data reveal that NG displays greater immune regulation, angiogenesis, and bone remodeling compared to EG.

The generation and characterization of a transgenic zebrafish line with lens-specific Cre expression.

Purpose: Danio rerio zebrafish constitute a popular model for studying lens development and congenital cataracts. However, the specific deletion of a gene with a Cre/LoxP system in the zebrafish lens is unavailable because of the lack of a lens-Cre-transgenic zebrafish. This study aimed to generate a transgenic zebrafish line in which Cre recombinase was specifically expressed in the lens. Methods: The pTol2 cryaa:Cre-polyA-cryaa:EGFP (enhanced green fluorescent protein) plasmid was constructed and co-injected with Tol2-transposase into one-to-two-cell-stage wild-type (WT) zebrafish embryos. Whole-mount in situ hybridization (ISH), tissue section, hematoxylin and eosin staining, a Western blot, a split-lamp observation, and a grid transmission assay were used to analyze the Cre expression, lens structure, and lens transparency of the transgenic zebrafish. Results: In this study, we generated a transgenic zebrafish line, zTg(cryaa:Cre-cryaa:EGFP), in which Cre recombinase and EGFP were driven by the lens-specific cryaa promoter. zTg(cryaa:Cre-cryaa:EGFP) began to express Cre and EGFP specifically in the lens at the 22 hpf stage, and this ectopic Cre could efficiently and specifically delete the red fluorescent protein (RFP) signal from the lens when zTg(cryaa:Cre-cryaa:EGFP) embryos were injected with the loxP-flanked RFP plasmid. The overexpression of Cre and EGFP did not impair zebrafish development or lens transparency. Accordingly, this zTg(cryaa:Cre-cryaa:EGFP) zebrafish line is a useful tool for gene editing, specifically with zebrafish lenses. Conclusions: We established a zTg(cryaa:Cre-cryaa:EGFP) zebrafish line that can specifically express an active Cre recombinase in lens tissues. This transgenic zebrafish line can be used as a tool to specifically manipulate a gene in zebrafish lenses.

Uncovering key salt-tolerant regulators through a combined eQTL and GWAS analysis using the super pan-genome in rice.

For sessile plants, gene expression plays a pivotal role in responding to salinity stress by activating or suppressing specific genes. However, our knowledge of genetic variations governing gene expression in response to salt stress remains limited in natural germplasm. Through transcriptome analysis of the Global Mini-Core Rice Collection consisting of a panel of 202 accessions, we identified 22 345 and 27 610 expression quantitative trait loci associated with the expression of 7787 and 9361 eGenes under normal and salt-stress conditions, respectively, leveraging the super pan-genome map. Notably, combined with genome-wide association studies, we swiftly pinpointed the potential candidate gene STG5-a major salt-tolerant locus known as qSTS5. Intriguingly, STG5 is required for maintaining Na+/K+ homeostasis by directly regulating the transcription of multiple members of the OsHKT gene family. Our study sheds light on how genetic variants influence the dynamic changes in gene expression responding to salinity stress and provides a valuable resource for the mining of salt-tolerant genes in the future.

Effects of intraoperative low-dose esketamine on postoperative pain after vestibular schwannoma resection: A prospective randomized, double-blind, placebo-controlled study.

AIMS: Esketamine may reduce acute postoperative pain in several settings. However, the effects of low-dose esketamine on postoperative pain after vestibular schwannoma (VS) resection with propofol/remifentanil total intravenous anaesthesia (TIVA) are unclear. The aim of this study is to observe the effects of intraoperative low-dose esketamine on postoperative pain after vestibular schwannoma resection. METHODS: This single-centre, randomized, placebo-controlled, double-blind trial included 90 adults undergoing VS resection via the retrosigmoid approach with TIVA. The patients were randomly allocated to two groups: esketamine or control (n = 45 in each group). Patients received low-dose esketamine (0.2 mg/kg) or a similar volume of normal saline after dural closure. The primary outcome was the pain score during movement (gentle head movement) at 24 h postoperatively. Secondary outcomes included recovery time, bispectral index (BIS) values and haemodynamic profiles during the first 30 min after esketamine administration, and adverse effects. RESULTS: Low-dose esketamine did not reduce pain scores at rest (P > .05) or with movement (P > .05) within the first 24 h after surgery. Esketamine moderately increased BIS values for at least 30 min after administration (P < .0001) but did not affect heart rate (P = .992) or mean arterial blood pressure (P = .994). Esketamine prolonged extubation time (P = .042, 95% confidence interval: 0.08 to 4.42) and decreased the effect-site concentration of remifentanil at extubation (P = .001, 95% confidence interval: -0.53 to -0.15) but did not affect the time to resumption of spatial orientation. Postoperative nausea and vomiting rates did not differ between groups, and no hallucinations or excessive sedation was observed. CONCLUSION: Intraoperative low-dose esketamine did not significantly reduce acute pain after VS resection with propofol/remifentanil TIVA. However, BIS values increased for at least 30 min after esketamine administration.

Human genetic associations of the airway microbiome in chronic obstructive pulmonary disease.

Little is known about the relationships between human genetics and the airway microbiome. Deeply sequenced airway metagenomics, by simultaneously characterizing the microbiome and host genetics, provide a unique opportunity to assess the microbiome-host genetic associations. Here we performed a co-profiling of microbiome and host genetics with the identification of over 5 million single nucleotide polymorphisms (SNPs) through deep metagenomic sequencing in sputum of 99 chronic obstructive pulmonary disease (COPD) and 36 healthy individuals. Host genetic variation was the most significant factor associated with the microbiome except for geography and disease status, with its top 5 principal components accounting for 12.11% of the microbiome variability. Within COPD individuals, 113 SNPs mapped to candidate genes reported as genetically associated with COPD exhibited associations with 29 microbial species and 48 functional modules (P < 1 × 10-5), where Streptococcus salivarius exhibits the strongest association to SNP rs6917641 in TBC1D32 (P = 9.54 × 10-8). Integration of concurrent host transcriptomic data identified correlations between the expression of host genes and their genetically-linked microbiome features, including NUDT1, MAD1L1 and Veillonella parvula, TTLL9 and Stenotrophomonas maltophilia, and LTA4H and Haemophilus influenzae. Mendelian randomization analyses revealed a potential causal link between PARK7 expression and microbial type III secretion system, and a genetically-mediated association between COPD and increased relative abundance of airway Streptococcus intermedius. These results suggest a previously underappreciated role of host genetics in shaping the airway microbiome and provide fresh hypotheses for genetic-based host-microbiome interactions in COPD.

Effects of mini-basketball training program on social communication impairments and regional homogeneity of brain functions in preschool children with autism spectrum disorder.

BACKGROUND: Social communication impairments (SCI) is a core symptom of autism spectrum disorder (ASD) and is marked by challenges in social interaction. Although physical exercise has been shown to improve SCI, this finding has not been supported by comprehensive scientific evidence. Existing research has established a strong link between the SCI in children with ASD and abnormalities in regional homogeneity (ReHo). Therefore, investigating the effects of physical exercise on SCI and Reho in patients with ASD may help to elucidate the neurological mechanisms involved. METHODS: The present study included 30 preschool children diagnosed with ASD, with 15 participants in each group (experimental and control). The experimental group underwent a 12-week mini-basketball training program (MBTP) based on routine behavioral rehabilitation, while the control group only received routine behavioral rehabilitation. The Social Responsiveness Scale-Second Edition (SRS-2) was employed to assess SCI in both groups. Resting-state functional magnetic resonance imaging technology was used to evaluate ReHo in both groups. RESULTS: After 12-week of MBTP, significant group × time interactions were observed between the experimental and control groups in total SRS-2 scores (F = 14.514, p < 0.001, ηp2 = 0.341), as well as in the domains of social cognition (F = 15.620, p < 0.001, ηp2 = 0.358), social communication (F = 12.460, p < 0.01, ηp2 = 0.308), and autistic mannerisms (F = 9.970, p < 0.01, ηp2 = 0.263). No statistical difference was found in the scores for the social awareness subscale and social motivation subscale in the group × time interaction (all p > 0.05). The experimental group exhibited increased ReHo in the right Cerebellum_Crus1 and right parahippocampal gyrus, coupled with decreased ReHo in the left middle frontal gyrus (orbital part), left superior frontal gyrus (dorsolateral), left postcentral gyrus, and right superior parietal gyrus. Furthermore, a decrease in ReHo in the left postcentral gyrus positively correlated with changes in social communication scores in SCI behaviors (p < 0.05). CONCLUSIONS: Our study underscores the effectiveness of a 12-week MBTP in ameliorating SCI and abnormalities in ReHo among preschool children with ASD. TRIAL REGISTRATION: The trial is retrospectively registered on the Chinese Clinical Trial Registry (ChiCTR1900024973; August 5, 2019).

Umbilical cord blood-derived neutrophils possess higher viability than peripheral blood derived neutrophils.

Neutrophils, a primary type of immune cell, play critical roles in numerous biological processes. Both umbilical cord blood (UCB) and peripheral blood are rich in neutrophils. UCB is more abundant than peripheral blood, with cells generally at a more immature stage. However, comparative data between these two cell sources is lacking. This study aims to elucidate differences between UCB-derived neutrophils (UCBN) and peripheral blood-derived neutrophils (PBN). UCBN and PBN were isolated from fresh human umbilical cord blood and peripheral blood, respectively. Transcriptomic profiling was performed and compared against neutrophil RNA from three different donors. Bioinformatics analysis was employed to compare cell phenotypes. A cytokine cocktail (IFN-ß, IFN-γ, and LPS) was used to activate UCBN and PBN in vitro. A united multi-omic approach, combining transcriptomic and proteomic analysis, was followed by experimental validation through flow cytometry, cell killing assays, and proteome profiler array to verify cell functions. Transcriptomic analysis revealed that the most upregulated genes in freshly isolated umbilical cord blood neutrophils (UCBN) compared to peripheral blood neutrophils (PBN) predominantly involve neutrophil activation and cell-killing functions. Validation through flow cytometry and cell-killing experiments demonstrated that highly viable UCBN exhibited significantly stronger ovarian tumor cell-killing activity in vitro compared to PBN. Both transcriptomic and proteomic analyses indicated that the primary upregulated genes in activated UCBN are chiefly involved in biological processes related to the regulation of cytokine secretion. Integrative multi-omic analysis, including a proteome profiler array, confirmed that UCBN indeed secrete elevated levels of cytokines. In conclusion: UCBN shows higher viability and cellular activity compared with PBN, particularly in tumor cell-killing and cytokine secretion.

Metabolomics-Guided Discovery of New Dimeric Xanthones from Co-Cultures of Mangrove Endophytic Fungi Phomopsis asparagi DHS-48 and Phomopsis sp. DHS-11.

The co-culture strategy, which mimics natural ecology by constructing an artificial microbial community, is a useful tool for the activation of biosynthetic gene clusters (BGCs) to generate new metabolites, as well as to increase the yield of respective target metabolites. As part of our project aiming at the discovery of structurally novel and biologically active natural products from mangrove endophytic fungi, we selected the co-culture of a strain of Phomopsis asparagi DHS-48 with another Phomopsis genus fungus DHS-11, both endophyted in mangrove Rhizophora mangle considering the impart of the taxonomic criteria and ecological data. The competition interaction of the two strains was investigated through morphology observation and scanning electron microscopy (SEM), and it was found that the mycelia of the DHS-48 and DHS-11 compacted and tangled with each other with an interwoven pattern in the co-culture system. A new approach that integrates HPLC chromatogram, 1HNMR spectroscopy, UPLC-MS-PCA, and molecular networking enabled the targeted isolation of the induced metabolites, including three new dimeric xanthones phomoxanthones L-N (1-3), along with six known analogs (4-9). Their planar structures were elucidated by an analysis of their HRMS, MS/MS, and NMR spectroscopic data and the absolute configurations based on ECD calculations. These metabolites showed broad cytotoxic activity against the cancer cells assessed, of which compounds 7-9 displayed significant cytotoxicity towards human liver cells HepG-2 with IC50 values ranging from 4.83 µM to 12.06 µM. Compounds 1-6 exhibited weak immunosuppressive activity against the proliferation of ConA-induced (T-cell) and LPS-induced (B-cell) murine splenic lymphocytes. Therefore, combining co-cultivation with a metabolomics-guided strategy as a discovery tool will be implemented as a systematic strategy for the quick discovery of target bioactive compounds.

An NADH/NAD+-favored aldo-keto reductase facilitates avilamycin A biosynthesis by primarily catalyzing oxidation of avilamycin C.

Avilamycins, which possess potent inhibitory activity against Gram-positive bacteria, are a group of oligosaccharide antibiotics produced by Streptomyces viridochromogenes. Among these structurally related oligosaccharide antibiotics, avilamycin A serves as the main bioactive component in veterinary drugs and animal feed additives, which differs from avilamycin C only in the redox state of the two-carbon branched-chain of the terminal octose moiety. However, the mechanisms underlying assembly and modification of the oligosaccharide chain to diversify individual avilamycins remain poorly understood. Here, we report that AviZ1, an aldo-keto reductase in the avilamycin pathway, can catalyze the redox conversion between avilamycins A and C. Remarkably, the ratio of these two components produced by AviZ1 depends on the utilization of specific redox cofactors, namely NADH/NAD+ or NADPH/NADP+. These findings are inspired by gene disruption and complementation experiments and are further supported by in vitro enzymatic activity assays, kinetic analyses, and cofactor affinity studies on AviZ1-catalyzed redox reactions. Additionally, the results from sequence analysis, structure prediction, and site-directed mutagenesis of AviZ1 validate it as an NADH/NAD+-favored aldo-keto reductase that primarily oxidizes avilamycin C to form avilamycin A by utilizing abundant NAD+ in vivo. Building upon the biological function and catalytic activity of AviZ1, overexpressing AviZ1 in S. viridochromogenes is thus effective to improve the yield and proportion of avilamycin A in the fermentation profile of avilamycins. This study represents, to our knowledge, the first characterization of biochemical reactions involved in avilamycin biosynthesis and contributes to the construction of high-performance strains with industrial value.IMPORTANCEAvilamycins are a group of oligosaccharide antibiotics produced by Streptomyces viridochromogenes, which can be used as veterinary drugs and animal feed additives. Avilamycin A is the most bioactive component, differing from avilamycin C only in the redox state of the two-carbon branched-chain of the terminal octose moiety. Currently, the biosynthetic pathway of avilamycins is not clear. Here, we report that AviZ1, an aldo-keto reductase in the avilamycin pathway, can catalyze the redox conversion between avilamycins A and C. More importantly, AviZ1 exhibits a unique NADH/NAD+ preference, allowing it to efficiently catalyze the oxidation of avilamycin C to form avilamycin A using abundant NAD+ in cells. Thus, overexpressing AviZ1 in S. viridochromogenes is effective to improve the yield and proportion of avilamycin A in the fermentation profile of avilamycins. This study serves as an enzymological guide for rational strain design, and the resulting high-performance strains have significant industrial value.

The effects of football juggling learning on executive function and brain functional connectivity.

This study aimed to explore the relationship between motor skill learning and executive function (EF), with an emphasis on the potential effects of football juggling learning. A randomized controlled trial involving 111 participants aged 17-19 years was conducted. Participants were randomly assigned to either the football juggling learning (FJL) group or a control group. The FJL group underwent 70 sessions of football juggling learning, while the control group engaged in their normal daily activities without any exercise intervention during the same time frame. Both groups were assessed for EF performance and underwent functional magnetic resonance imaging (fMRI) scans before and after the experiment. The executive function test included three tasks, namely, inhibition, working memory, and shifting. The results showed significant improvement in inhibition and shifting in both groups, and the FJL group showed greater improvement in these aspects of EF compared to the control group. Additionally, in comparison to the control group, the FJL group exhibited increased functional connectivity within the frontal, temporal, and cerebellar regions from the pre-test to the post-test. Notably, enhanced functional connectivity between the right superior temporal gyrus (posterior division) and left cerebellum 6 was identified in the FJL group and was associated with improved EF performance induced by football juggling learning. These findings shed light on the potential causal relationship between motor skill learning, EF, and brain plasticity. Importantly, our study provides preliminary evidence supporting the use of motor skill learning, such as football juggling, as a potential avenue for cognitive enhancement.

Local injection of micro-dose guselkumab for palmoplantar pustulosis after partial failure of systemic ixekizumab treatment.

We present a palmoplantar pustulosis case partially resistant to systemic IL-17A inhibitor (ixekizumab) treatment, and then receiving a local injection of 0.1 mL micro-dose (1 mg) IL-23 inhibitor (guselkumab) every 4 weeks for four times. The paradoxical lesion disappeared rapidly following local injection and there was no recurrence after 8 weeks of drug withdrawal. This is the first clinical report on the treatment of palmoplantar pustulosis by local injection of micro-dose guselkumab.

The evolution and impact of sarcopenia in severe aplastic anaemia survivors following allogeneic haematopoietic cell transplantation.

BACKGROUND: Sarcopenia is a potential risk factor for adverse outcomes in haematopoietic cell transplantation (HSCT) recipients. We aimed to explore longitudinal body changes in muscle and adipose mass and their prognostic value in allogeneic HSCT-treated severe aplastic anaemia (SAA) patients. METHODS: We retrospectively analysed consecutive SAA patients who underwent allogeneic HSCT between January 2017 and March 2022. Measurements of pectoral muscle and corresponding subcutaneous fat mass were obtained via chest computed tomography at baseline and at 1 month, 3 months, 6 months, and 12 months following HSCT. Sarcopenia was defined as pectoral muscle index (PMI) lower than the sex-specific median at baseline. Changes in body composition over time were evaluated by generalized estimating equations. Cox regression models were used to investigate prognostic factors affecting overall survival (OS) and failure-free survival (FFS). A nomogram was constructed from the Cox regression model for OS. RESULTS: We included 298 adult SAA patients (including 129 females and 169 males) with a median age of 31 years [interquartile range (IQR), 24-39 years] at baseline. Sarcopenia was present in 148 (148/298, 50%) patients at baseline, 218 (218/285, 76%) patients post-1 month, 209 (209/262, 80%) patients post-3 month, 169 (169/218, 78%) patients post-6 month, and 129 (129/181, 71%) patients post-12 month. A significant decrease in pectoral muscle mass was observed in SAA patients from the time of transplant to 1 year after HSCT, and the greatest reduction occurred in post 1-3 months (P < 0.001). The sarcopenia group exhibited significantly lower 5-year OS (90.6% vs. 100%, log-rank P = 0.039) and 5-year FFS (89.2% vs. 100%, log-rank P = 0.021) than the nonsarcopenia group at baseline. Sarcopenia at baseline (hazard ratio, HR, 6.344; 95% confidence interval, CI: 1.570-25.538; P = 0.01; and HR, 3.275; 95% CI: 1.159-9.252; P = 0.025, respectively) and the delta value of the PMI at 6 months post-transplantation (ΔPMI6) (HR, 0.531; 95% CI: 0.374-0.756; P < 0.001; and HR, 0.666; 95% CI: 0.505-0.879; P = 0.004, respectively) were demonstrated to be independent prognostic factors for OS and FFS in SAA patients undergoing HSCT, and were used to construct the nomogram. The C-index of the nomogram was 0.75, and the calibration plot showed good agreement between the predictions made by the nomogram and actual observations. CONCLUSIONS: Sarcopenia persists in SAA patients from the time of transplant to the 1-year follow-up after HSCT. Both sarcopenia at baseline and at 6 months following HSCT are associated with poor clinical outcomes, especially in patients with persistent muscle mass loss up to 6 months after transplantation.

Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway.

Diabetic nephropathy (DN), one of the more prevalent microvascular complications in patients diagnosed with diabetes mellitus, is attributed as the main cause of end-stage renal disease (ESRD). Lipotoxicity in podocytes caused by hyperglycemia has been recognised as a significant pathology change, resulting in the deterioration of the glomerular filtration barrier. Research has demonstrated how dapagliflozin, a kind of SGLT2i, exhibits a multifaceted and powerful protective effect in DN, entirely independent of the hypoglycemic effect, with the specific mechanism verified. In this present study, we found that dapagliflozin has the potential to alleviate apoptosis and restore cytoskeleton triggered by high glucose (HG) in vivo and in vitro. We also discovered that dapagliflozin could mitigate podocyte cholesterol accumulation by restoring the expression of ABCA1, which is the key pathway for cholesterol outflows. This research also mechanistically demonstrates that the protective effect of dapagliflozin can be mediated by KLF-5, which is the upstream transcription factor of ABCA1. Taken together, our data suggest that dapagliflozin offers significant potential in alleviating podocyte injury and cholesterol accumulation triggered by high glucose. In terms of the mechanism, we herein reveal that dapagliflozin could accelerate cholesterol efflux by restoring the expression of ABCA1, which is directly regulated by KLF-5.

Efficacy of anti-interleukin-17A biological agents for palmoplantar psoriasis and palmoplantar pustulosis: A network meta-analysis.

BACKGROUND: The comparative efficacy of anti-IL (interleukin)-17A biological agents in palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP) are not well established. OBJECTIVE: To investigate the efficacy of different dosage regimens of anti-IL-17A biological agents compared with placebo in PP and PPP. METHODS: A literature search was conducted in PubMed, clinicaltrials.gov, and Embase. Meta-analysis was performed for all outcomes of randomized controlled trials, while network meta-analysis was only performed for the primary outcome. RESULTS: In total, 21 articles exploring the efficacy of 5 treatment options were included, 4 cohort studies were also reviewed. Meta-analysis demonstrated a statistically significant difference favoring anti-IL-17A biological agents versus placebo (OR = 6.84, 95 %[CI] [5.34, 8.76]). On-label secukinumab was identified as the most effective treatment option for patients with PP (OR = 33.50, 95 %[CI] [4.37,256.86]). PPP treated with secukinumab 300 mg showed benefit in terms of PPPASI 75 responses over 52 weeks. CONCLUSION: IL-17A biological agents had better PP disease clearance compared with placebo and on-label secukinumab was identified as the most effective treatment option for PP patients. Secukinumab 300 mg showed benefit for PPP patients.

A novel gain-of-function STAT3 variant in infantile-onset diabetes associated with multiorgan autoimmunity.

BACKGROUND: Germline gain-of-function (GOF) variants in the signal transducer and activator of transcription 3 (STAT3) gene lead to a rare inherited disorder characterized by early-onset multiorgan autoimmunity. METHODS: We described a Chinese patient with infantile-onset diabetes and multiorgan autoimmunity. The patient presented with early-onset type 1 diabetes and autoimmune hypothyroidism at 7 months. During the 7.5-year follow-up, she developed pseudo-celiac enteropathy at 1 year of age and showed severe growth retardation. Whole-exome sequencing was performed and the novel variant was further assessed by in vitro functional assays. RESULTS: Whole-exome sequencing revealed a novel variant (c.1069G>A, p.Glu357Lys) in the DNA-binding domain of STAT3. In vitro functional studies revealed that p.Glu357Lys was a GOF variant by increasing STAT3 transcriptional activity and phosphorylation. In addition, the STAT3 Glu357Lys variant caused dysregulation of insulin gene expression by enhancing transcriptional inhibition of the insulin gene enhancer binding protein factor 1 (ISL1). CONCLUSION: In the current study, we describe clinical manifestations and identify a novel STAT3 GOF variant (c.1069G>A) in a Chinese patient. This activating variant impairs insulin expression by increasing transcriptional inhibition of its downstream transcription factor ISL1, which could be involved in the pathogenesis of early-onset diabetes.

Unveiling the flames: macrophage pyroptosis and its crucial role in liver diseases.

Macrophages play a critical role in innate immunity, with approximately 90% of the total macrophage population in the human body residing in the liver. This population encompasses both resident and infiltrating macrophages. Recent studies highlight the pivotal role of liver macrophages in various aspects such as liver inflammation, regeneration, and immune regulation. A novel pro-inflammatory programmed cell death, pyroptosis, initially identified in macrophages, has garnered substantial attention since its discovery. Studies investigating pyroptosis and inflammation progression have particularly centered around macrophages. In liver diseases, pyroptosis plays an important role in driving the inflammatory response, facilitating the fibrotic process, and promoting tumor progression. Notably, the role of macrophage pyroptosis cannot be understated. This review primarily focuses on the role of macrophage pyroptosis in liver diseases. Additionally, it underscores the therapeutic potential inherent in targeting macrophage pyroptosis.

Prevalence and causes of blindness and distance visual impairment in Chinese adult population in 2022 during the COVID-19 pandemic: a cross-sectional study.

This cross-sectional study aims to investigate the prevalence and causes of visual impairment (VI) and blindness in Jiangsu Province, China in 2022 during the COVID-19 pandemic. Participants (n = 13,208, aged 18-93) underwent comprehensive ocular examinations. The prevalence and causes of binocular VI (presenting visual acuity [VA] ≥ 20/400 and < 20/63 in the better eye) and blindness (presenting VA < 20/400 in the better eye) were assessed according to the World Health Organization (WHO) criteria. The estimation of refractive error prevalence was conducted using the following classification: myopia ≤ - 0.50 diopters (D), high myopia ≤ - 6.00 D, hyperopia ≥ 0.50 D, and anisometropia ≥ 1.00 D. The overall prevalence of binocular VI and blindness was 21.04% (95% confidence interval [CI] 20.35-21.74%) and 0.47% (95% CI 0.37-0.60%). The highest prevalence of binocular VI was in the population aged 18-24 years old (46.29%, [95% CI 44.30-48.28%]), those with education at university and above (43.47%, [95% CI 41.93-45.02%]), students (54.96%, [95% CI 52.73-57.17%]). Uncorrected refractive error (URE) was the leading cause of presenting binocular VI (93.40%) and blindness (50.79%). The prevalence of myopia was 54.75% (95% CI 53.90-55.60%). Actions are needed to control URE and myopia within the adult Chinese population, with a particular emphasis on the younger, well-educated demographic.