Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children.

BACKGROUND: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. METHODS: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method. RESULTS: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events. CONCLUSIONS: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.

Association between Serum Ferritin Levels and Metabolic-associated Fatty Liver Disease in Adults: a Cross-sectional Study Based on the NHANES.

OBJECTIVE: Ferritin, initially acting as an iron-storage protein, was found to be associated with metabolic diseases. Our study was designed to investigate the association between serum ferritin and metabolic-associated fatty liver disease (MAFLD) using data from the National Health and Nutrition Examination Survey (NHANES) of the United State of America. METHODS: A cross-sectional study was conducted, enrolling a total of 2145 participants from the NHANES in the 2017-2018 cycles. Hepatic steatosis and liver fibrosis were assessed by ultrasound images and several non-invasive indexes. Multiple regression analysis was conducted to determine the associations between serum ferritin concentration and MAFLD and liver fibrosis. RESULTS: The analysis revealed that participants with higher serum ferritin levels (Q3 and Q4 groups) had a higher prevalence of MAFLD than those with the lowest serum ferritin levels [Q3 vs. Q1: OR=2.17 (1.33, 3.53), P<0.05 in fatty liver index (FLI); Q4 vs. Q1: OR=3.13 (1.91, 5.13), P<0.05 in FLI]. Additionally, participants with the highest serum ferritin levels (Q4 group) displayed a higher prevalence of liver fibrosis [Q4 vs. Q1: OR=2.59 (1.19, 5.62), P<0.05 in liver stiffness measurement; OR=5.06 (1.12, 22.94), P<0.05 in fibrosis-4 index], with significantly increased risk observed in participants with concomitant diabetes [OR=7.45 (1.55, 35.72), P=0.012]. CONCLUSION: Our study revealed that elevated serum ferritin levels are associated with a higher prevalence of MAFLD and advanced liver fibrosis in patients. Elevated serum ferritin levels combined with diabetes are important risk factors for liver fibrosis.

An evolutionary game and system dynamics approach for the production and consumption of carbon-labeled products-based on a media monitoring perspective.

Carbon label is acknowledged as an effective way to combat the problem of global warming. As a powerful way to encourage individuals to adjust their consumption patterns and to promote the development of green consumption, carbon-labeled products are widely developed in China. To reveal the production and consumption process of carbon-labeled products, the present study constructs a tripartite game model consisting of the government, carbon-labeled products manufacturers and consumers based on a media monitoring perspective. The evolutionary stability strategy (ESS) is firstly determined by solving the replication dynamic equations and stability analysis of the equilibrium point, followed by the strategy analysis and sensitivity analysis through numerical simulation. The results show that media supervision can effectively complement and constrain government supervision. In addition, it can promote enterprises to standardize production and enhance consumers' trust and willingness to buy carbon-labeled products. The introduction of media supervision can well realize the ideal equilibrium of "effective government supervision, enterprise compliance and consumer support for purchase".

Screening and characterization of 133 physiologically-relevant environmental chemicals for reproductive toxicity.

Reproduction is a functional outcome that relies on complex cellular, tissue, and organ interactions that span the developmental period to adulthood. Thus, the assessment of its disruption by environmental chemicals would benefit significantly from scalable and innovative approaches to testing using functionally comparable reproductive models such as the nematode C. elegans. We adapted a previously described low-throughput in vivo chromosome segregation assay using C. elegans predictive of reproductive toxicity and leveraged available public data sources (ToxCast, ICE) to screen and characterize 133 physiologically-relevant chemicals in a high-throughput manner. The screening outcome was further validated in a second, independent in vivo assay assessing embryonic viability. In total, 13 chemicals were classified as reproductive toxicants with the two most active chemicals belonging to the large family of Quaternary Ammonium Compounds (QACs) commonly used as disinfectants but with limited available reproductive toxicity data. We compared the results from the C. elegans assay with ToxCast in vitro data compiled from 700+ cell response assays and 300+ signaling pathways-based assays. We did not observe a difference in the bioactivity or in the average potency (AC50) between the top and bottom chemicals. However, the intended target categories were significantly different between the classified chemicals with, in particular, an over-representation of steroid hormone targets for the high Z-score chemicals. Taken together, these results point to the value of in vivo models that scale to high-throughput level for reproductive toxicity assessment and to the need to prioritize the assessment of QACs impacts on reproduction.

Monocyte-to-high-density lipoprotein cholesterol ratio and the risk of erectile dysfunction: a study from NHANES 2001-2004.

Background: The monocyte-to-high-density lipoprotein cholesterol ratio (MHR) has become a novel inflammation marker with a possible association with erectile dysfunction (ED); however, there are fewer studies exploring the association between MHR and ED. Aim: This study sought to explore the association between MHR and ED. Methods: This study population was drawn from participants in two 2-year cycles of the National Health and Nutrition Examination Survey (2001-2002 and 2003-2004). MHR was calculated as the ratio of monocyte count (103 cells/µL) to high-density lipoprotein cholesterol (mg/dL). The relationship between MHR and ED was explored using survey-weighted logistic regression models with MHR as a continuous variable and divided into tertiles (tertile 1 [T1]: <0.01; T2: 0.01-0.014; T3: >0.014). We also used a smooth curve fit (penalized spline method) to characterize the dose-response relationship between MHR and ED. In addition, subgroup analyses based on age, body mass index, smoking, hypertension, diabetes mellitus, and cardiovascular disease were performed to further analyze the data. Sensitivity analyses were also conducted to further assess the stability of the results. Outcomes: The main outcome measure was the difference in ED prevalence between MHR levels. Results: A total of 1361 participants were enrolled, with 513 (T1), 438 (T2), and 410 (T3) participants in the 3 MHR groups. After adjusting for all potential covariates, survey-weighted logistic regression analyses showed a significant association between MHR and ED (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.26-3.05). When MHR was used as a categorical variable, the adjusted OR for ED prevalence increased significantly with increasing MHR after adjusting for all potential covariates (T3 vs T1: OR, 2.14; 95% CI, 1.29-3.55). The dose-response curves showed that the prevalence of ED increased with increasing MHR. Clinical Implications: Easy to access and low cost, MHR is a convenient clinical tool that helps clinicians in the prevention and treatment of ED. Strengths and Limitations: The present study is the first to examine the association between MHR and ED nationally representative data. However, the study population was derived from a U.S. database, so the findings are limited to the U.S. population. Conclusion: Our study demonstrated that MHR levels were independently associated with ED and that ED patients had higher MHR levels, suggesting that MHR may be a valuable predictor for identifying people at higher risk for ED.

Depletion of protective microbiota promotes the incidence of fruit disease.

Plant-associated microbiomes play important roles in plant health and productivity. However, despite fruits being directly linked to plant productivity, little is known about the microbiomes of fruits and their potential association with fruit health. Here, by integrating 16S rRNA gene, ITS high-throughput sequencing data and microbiological culturable approaches, we reported that roots and fruits (pods) of peanut, a typical plant that bears fruits underground, recruit different bacterial and fungal communities independently of cropping conditions, and that the incidence of pod disease under monocropping conditions is attributed to the depletion of Bacillus genus and enrichment of Aspergillus genus in geocarposphere. On this basis, we constructed a synthetic community (SynCom) consisting of three Bacillus strains from geocarposphere soil under rotation conditions with high culturable abundance. Comparative transcriptome, microbiome profiling and plant phytohormone signaling analysis reveal that the SynCom exhibited more effective Aspergillus growth inhibition and pod disease control than individual strain, which was underpinned by a combination of molecular mechanisms related to fungal cell proliferation interference, mycotoxins biosynthesis impairment and jasmonic acid-mediated plant immunity activation. Overall, our results reveal the filter effect of plant organs on the microbiome, and that depletion of key protective microbial community promotes the fruit disease incidence.

Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.

The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.

Identification of shared potential diagnostic markers in asthma and depression through bioinformatics analysis and machine learning.

BACKGROUND: There is mounting evidence that asthma might exacerbate depression. We sought to examine candidates for diagnostic genes in patients suffering from asthma and depression. METHODS: Microarray data were downloaded from the Gene Expression Omnibus(GEO) database and used to screen for differential expressed genes(DEGs) in the SA and MDD datasets. A weighted gene co-expression network analysis(WGCNA) was used to identify the co-expression modules of SA and MDD. The least absolute shrinkage and selection operatoes(LASSO) and support vector machine(SVM) were used to determine critical biomarkers. Immune cell infiltration analysis was used to investigate the correlation between immune cell infiltration and common biomarkers of SA and MDD. Finally, validation of these analytical results was accomplished via the use of both in vivo and in vitro studies. RESULTS: The number of DEGs that were included in the MDD dataset was 5177, whereas the asthma dataset had 1634 DEGs. The intersection of DEGs for SA and MDD included 351 genes, the strongest positive modules of SA and MDD was 119 genes, which played a function in immunity. The intersection of DEGs and modular hub genes was 54, following the analysis using machine learning algorithms,three hub genes were identified and employed to formulate a nomogram and for the evaluation of diagnostic effectiveness, which demonstrated a significant diagnostic value (area under the curve from 0.646 to 0.979). Additionally, immunocyte disorder was identified by immune infiltration. In vitro studies have revealed that STK11IP deficiency aggravated the LPS/IFN-γinduced up-regulation in M1 macrophage activation. CONCLUSION: Asthma and MDD pathophysiology may be associated with alterations in inflammatory processes and immune pathways. Additionally, STK11IP may serve as a diagnostic marker for individuals with the two conditions.

Association between overactive bladder and depression in American adults: A cross-sectional study from NHANES 2005-2018.

BACKGROUND AND AIM: Overactive bladder (OAB) and depression are both common disorders and there is research suggesting an association between the two, but there is a lack of studies with large samples. The aim of this study is to investigate the association between OAB and depressive symptoms. METHODS: We used data from the National Health and Nutrition Examination Survey (NHANES) database for the period 2005 to 2018. OAB was characterized by the Overactive Bladder Symptom Score (OABSS, score > 3) and depression was diagnosed by the Patient Health Questionnaire (PHQ-9, score ≥ 10). There were three models employed in our analysis: (1) Crude model was unadjusted; (2) Model 1 was adjusted for age, sex, race/ethnicity, educational level, and marital status; (3) Model 2 was adjusted for factors in Model 1 plus the remained potential covariates. We used survey-weighted logistic regression models to assess the association between OAB and depression. Subsequently, subgroup analyses and smoothed curve analyses were used to evaluate the reliability of the findings. RESULTS: Finally, a total of 6612 participants were included in our study, consisting of 1005 participants with diagnosis of OAB and 5607 participants without diagnosis of OAB. After adjusting for all covariates, there was a significant positive association between OAB and depression (OR: 2.89, 95 % CI: 1.91, 4.37). The severity of OAB was also positively associated with depression. Compared to participants without OAB, the fully adjusted ORs for depression were 2.76 (95 % CI: 1.64, 4.65) for those with mild OAB, 3.79 (95 % CI: 1.68, 8.55) for those with moderate OAB, and 5.21 (95 % CI: 1.39, 19.53) for those with severe OAB. CONCLUSIONS: This study revealed a strong association between OAB and depression and a progressive increase in the risk of depression as the severity of OAB (mild, moderate, and severe) increased. Therefore, it is important for clinicians to recognize the assessment of OAB symptoms in patients who are at risk for or have developed depressive symptoms, as well as the mental health of patients with OAB.

The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity.

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²+ was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.IMPORTANCEViral infections disrupt intracellular Ca2+ homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca2+ imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca2+ that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca2+ or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca2+ in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.

Acute ischemic stroke in tuberculous meningitis.

Background: The underlying mechanism for stroke in patients with tuberculous meningitis (TBM) remains unclear. This study aimed to investigate the predictors of acute ischemic stroke (AIS) in TBM and whether AIS mediates the relationship between inflammation markers and functional disability. Methods: TBM patients admitted to five hospitals between January 2011 and December 2021 were consecutively observed. Generalized linear mixed model and subgroup analyses were performed to investigate predictors of AIS in patients with and without vascular risk factors (VAFs). Mediation analyses were performed to explore the potential causal chain in which AIS may mediate the relationship between neuroimaging markers of inflammation and 90-day functional outcomes. Results: A total of 1,353 patients with TBM were included. The percentage rate of AIS within 30 days after admission was 20.4 (95% CI, 18.2-22.6). A multivariate analysis suggested that age ≥35 years (OR = 1.49; 95% CI, 1.06-2.09; P = 0.019), hypertension (OR = 3.56; 95% CI, 2.42-5.24; P < 0.001), diabetes (OR = 1.78; 95% CI, 1.11-2.86; P = 0.016), smoking (OR = 2.88; 95% CI, 1.68-4.95; P < 0.001), definite TBM (OR = 0.19; 95% CI, 0.06-0.42; P < 0.001), disease severity (OR = 2.11; 95% CI, 1.50-2.90; P = 0.056), meningeal enhancement (OR = 1.66; 95% CI, 1.19-2.31; P = 0.002), and hydrocephalus (OR = 2.98; 95% CI, 1.98-4.49; P < 0.001) were associated with AIS. Subgroup analyses indicated that disease severity (P for interaction = 0.003), tuberculoma (P for interaction = 0.008), and meningeal enhancement (P for interaction < 0.001) were significantly different in patients with and without VAFs. Mediation analyses revealed that the proportion of the association between neuroimaging markers of inflammation and functional disability mediated by AIS was 16.98% (95% CI, 7.82-35.12) for meningeal enhancement and 3.39% (95% CI, 1.22-6.91) for hydrocephalus. Conclusion: Neuroimaging markers of inflammation were predictors of AIS in TBM patients. AIS mediates < 20% of the association between inflammation and the functional outcome at 90 days. More attention should be paid to clinical therapies targeting inflammation and hydrocephalus to directly improve functional outcomes.

The clinical value of mNGS of bronchoalveolar lavage fluid versus traditional microbiological tests for pathogen identification and prognosis of severe pneumonia (NT-BALF):study protocol for a prospective multi-center randomized clinical trial.

BACKGROUND: Early, rapid, and accurate pathogen diagnosis can help clinicians select targeted treatment options, thus improving prognosis and reducing mortality rates of severe pneumonia. Metagenomic next-generation sequencing (mNGS) has a higher sensitivity and broader pathogen spectrum than traditional microbiological tests. However, the effects of mNGS-based antimicrobial treatment procedures on clinical outcomes and cost-effectiveness in patients with severe pneumonia have not been evaluated. METHODS: This is a regional, multi-center, open, prospective, randomized controlled trial to evaluate that whether the combination of mNGS and traditional testing methods could decrease 28-day call-cause mortality with moderate cost-effectiveness. A total of 192 patients with severe pneumonia will be recruited from four large tertiary hospitals in China. Bronchoalveolar lavage fluid will be obtained in all patients and randomly assigned to the study group (mNGS combined with traditional microbiological tests) or the control group (traditional microbiological tests only) in a 1:1 ratio. Individualized antimicrobial treatment and strategy will be selected according to the analysis results. The primary outcome is 28-day all-cause mortality. The secondary outcomes are ICU and hospital length of stay (LOS), ventilator-free days and ICU-free days, consistency between mNGS and traditional microbiological tests, detective rate of mNGS and traditional microbiological tests, turn-out time, time from group allocation to start of treatment, duration of vasopressor support, types and duration of anti-infective regimens, source of drug-resistant bacteria or fungi, and ICU cost. DISCUSSION: The clinical benefits of mNGS are potentially significant, but its limitations should also be considered. TRIAL REGISTRATION: ChineseClinicalTrialRegistry.org, ChiCTR2300076853. Registered on 22 October 2023.

[Effect of different cleaning methods on bond strength and surface wettability of high translucency zirconia].

PURPOSE: To study the effect of different cleaning methods on the shear bond strength of self-adhesive resin cement to saliva-contaminated high translucency zirconia and surface wettability. METHODS: Eighty zirconia specimens were randomly divided into 5 groups (n=16), i.e., control group(not contaminated), 75% ethanol group,cleaning paste group,airborne-particle abrasion group, and atmospheric pressure cold plasma group. The contact angles was measured, shear bond strength were examined, and fracture types were determined. SPSS 26.0 software package was used for statistical analysis of the data. RESULTS: The atmospheric pressure cold plasma group produced the lowest contact angle(P＜0.05). The shear bond strength of the airborne-particle abrasion group, the cleaning paste group and the atmospheric pressure cold plasma group respectively were similar to the control group without significant difference(P＞0.05), while those were significantly higher than 75% ethanol group(P＜0.05). The mixed fracture mode of the atmospheric pressure cold plasma group evidently increased. CONCLUSIONS: Airborne-particle abrasion, cleaning paste and atmospheric pressure cold plasma overcome the effects of saliva contamination, producing the shear bond strength to zirconia similar to the control group. The atmospheric pressure cold plasma improves hydrophilicity of high translucency zirconia significantly.

Dual Redox Reaction Sites for Pseudocapacitance Based on Ti and -P Functional Groups of Ti3C2PBrx MXene.

MXenes have extensive applications due to their different properties determined by intrinsic structures and various functional groups. Exploring different functional groups of MXenes leads to improved performance or potential applications. In this work, we prepared new Ti3C2PBrx (x=0.4-0.6) MXene with phosphorus functional groups (-P) through a two-step gas-phase reaction. The acquisition of -P is achieved by replacing bromine functional groups (-Br) of Ti3C2Br2 in the phosphorus vapor. After -Br is replaced with -P, Ti3C2PBrx MXene shows an improved areal capacitance (360 mF cm-2) at 20 mV s-1 compared with Ti3C2Br2 MXene (102 mF cm-2). At a current density of 5 mA cm-2 after 10000 cycles, the capacitance retention of Ti3C2PBrx MXene has not decreased. The pseudocapacitive enhancement mechanism has been discovered based on the dual redox sites of the functional groups -P and Ti.

Regulation of the growth performance and the gastrointestinal microbiota community by the addition of defective pear fermentation to feed of small-tailed Han sheep.

This study investigated the effects of defective pear fermentation (DPF) diets on growth performance and gastrointestinal microbial communities in 60 healthy male small-tailed Han sheep, aged 90 days. The sheep were randomly divided into four groups, each consisting of three replicates with five sheep per replicate. Initially, all groups received a basal diet for seven days during the adaptation stage. Subsequently, for 60 days, group C (control) was fed a basal diet, group X received a basal diet with 2% DPF, group Y had a basal diet with 4% DPF, and group Z was fed a basal diet with 6% DPF. The results indicated that group Y experienced a significant increase in average daily gain (ADG) and average daily feed intake (ADFI). The addition of DPF significantly elevated the levels of GSH-Px and notably reduced MDA content compared to group C. Analysis of gastrointestinal microbiota showed that groups receiving DPF had increased relative abundances of Lachnospiraceae_NK3A20_group, norank_f p-2534-18B5_gut_group, Acetitomaculum, Actinobacteriota, Bacteroidota and Ruminococcus_gauvreauii_group, and decreased abundances of Proteobacteria, Prevotella, Staphylococcus, and Psychrobacter compared to group C. Group X exhibited the highest relative abundance of Olsenella, while group Y showed a significant increase in unclassified_f Lachnospiraceae compared to the other groups. Bacterial function prediction indicated that pathways related to energy metabolism were more prevalent in group X and Y. This study preliminarily confirms the feasibility of using DPF as feed additives, providing a foundation for further research and evaluation of DPF's application in animal production.

Proteome-wide Mendelian randomization identifies therapeutic targets for ankylosing spondylitis.

Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins. Methods: We conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups. Results: The findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P fdr < 0.05). Conclusion: Our investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.

Near-infrared spectroscopy based on colorimetric sensor array coupled with convolutional neural network detecting zearalenone in wheat.

Wheat is a vital global cereal crop, but its susceptibility to contamination by mycotoxins can render it unusable. This study explored the integration of two novel non-destructive detection methodologies with convolutional neural network (CNN) for the identification of zearalenone (ZEN) contamination in wheat. Firstly, the colorimetric sensor array composed of six selected porphyrin-based materials was used to capture the olfactory signatures of wheat samples. Subsequently, the colorimetric sensor array, after undergoing a reaction, was characterized by its near-infrared spectral features. Then, the CNN quantitative analysis model was proposed based on the data, alongside the establishment of traditional machine learning models, partial least squares regression (PLSR) and support vector machine regression (SVR), for comparative purposes. The outcomes demonstrated that the CNN model had superior predictive performance, with a root mean square error of prediction (RMSEP) of 40.92 µ g ∙ kg-1 and a coefficient of determination on the prediction (RP2) of 0.91. These results affirmed the potential of integrating colorimetric sensor array with near-infrared spectroscopy in evaluating the safety of wheat and potentially other grains. Moreover, CNN can have the capacity to autonomously learn and distill features from spectral data, enabling further spectral analysis and making it a forward-looking spectroscopic tool.

Innexin hemichannel activation by Microplitis bicoloratus ecSOD monopolymer reduces ROS.

The extracellular superoxide dismutases (ecSODs) secreted by Microplitis bicoloratus reduce the reactive oxygen species (ROS) stimulated by the Microplitis bicoloratus bracovirus. Here, we demonstrate that the bacterial transferase hexapeptide (hexapep) motif and bacterial-immunoglobulin-like (BIg-like) domain of ecSODs bind to the cell membrane and transiently open hemichannels, facilitating ROS reductions. RNAi-mediated ecSOD silencing in vivo elevated ROS in host hemocytes, impairing parasitoid larva development. In vitro, the ecSOD-monopolymer needed to be membrane bound to open hemichannels. Furthermore, the hexapep motif in the beta-sandwich of ecSOD49 and ecSOD58, and BIg-like domain in the signal peptides of ecSOD67 were required for cell membrane binding. Hexapep motif and BIg-like domain deletions induced ecSODs loss of adhesion and ROS reduction failure. The hexapep motif and BIg-like domain mediated ecSOD binding via upregulating innexins and stabilizing the opened hemichannels. Our findings reveal a mechanism through which ecSOD reduces ROS, which may aid in developing anti-redox therapy.

Adeno-associated virus as a delivery vector for gene therapy of human diseases.

Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.