Risk factor analysis and nomogram for predicting poor symptom control in smoking asthmatics.

BACKGROUND: Smoking induces and modifies the airway immune response, accelerating the decline of asthmatics' lung function and severely affecting asthma symptoms' control level. To assess the prognosis of asthmatics who smoke and to provide reasonable recommendations for treatment, we constructed a nomogram prediction model. METHODS: General and clinical data were collected from April to September 2021 from smoking asthmatics aged ≥14 years attending the People's Hospital of Zhengzhou University. Patients were followed up regularly by telephone or outpatient visits, and their medication and follow-up visits were recorded during the 6-months follow-up visit, as well as their asthma control levels after 6 months (asthma control questionnaire-5, ACQ-5). The study employed R4.2.2 software to conduct univariate and multivariate logistic regression analyses to identify independent risk factors for 'poorly controlled asthma' (ACQ>0.75) as the outcome variable. Subsequently, a nomogram prediction model was constructed. Internal validation was used to test the reproducibility of the model. The model efficacy was evaluated using the consistency index (C-index), receiver operating characteristic (ROC) curve, calibration curve, and decision curve. RESULTS: Invitations were sent to 231 asthmatics who smoked. A total of 202 participants responded, resulting in a final total of 190 participants included in the model development. The nomogram established five independent risk factors (P<0.05): FEV1%pred, smoking index (100), comorbidities situations, medication regimen, and good or poor medication adherence. The area under curve (AUC) of the modeling set was 0.824(95%CI 0.765-0.884), suggesting that the nomogram has a high ability to distinguish poor asthma control in smoking asthmatics after 6 months. The calibration curve showed a C-index of 0.824 for the modeling set and a C-index of 0.792 for the self-validation set formed by 1000 bootstrap sampling, which means that the prediction probability of the model was consistent with reality. Decision curve analysis (DCA) of the nomogram revealed that the net benefit was higher when the risk threshold probability for poor asthma control was 4.5 - 93.9%. CONCLUSIONS: FEV1%pred, smoking index (100), comorbidities situations, medication regimen, and medication adherence were identified as independent risk factors for poor asthma control after 6 months in smoking asthmatics. The nomogram established based on these findings can effectively predict relevant risk and provide clinicians with a reference to identify the poorly controlled population with smoking asthma as early as possible, and to select a better therapeutic regimen. Meanwhile, it can effectively improve the medication adherence and the degree of attention to complications in smoking asthma patients.

Prenatal diagnosis of Silver-Russell syndrome with 8q12 deletion including the PLAG1 gene: a case report and review.

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder. A retrospective analysis predicted that the live birth prevalence of SRS in Estonia is 1:15,886 [Yakoreva et al., Eur J Hum Genet, 2019, 27(11), 1649-1658]. The most common causative genetic mechanism in the proband is loss of paternal methylation in the imprinted control region 1 (ICR1) at 11p15.5 chromosome. A few studies suggested that inherited or de novo loss-of-function alterations of the PLAG1 gene, including the whole-gene deletion and intragenic pathogenic variants, could cause a rare type of SRS. To date, less than 20 unrelated PLAG1-related SRS cases have been reported, and the clinical information about these cases is limited. We report the first prenatal case of SRS with 8q12 deletion (including the PLAG1 gene). The fetus presented with intrauterine growth retardation, small for gestational age, relative macrocephaly at birth, and a protruding forehead. Unlike classical SRS cases, the fetus had micrognathia and did not show body asymmetry. We hope that the literature review in this study provides new insights into genotype-phenotype relationships of PLAG1-related SRS.

Association between oxidative balance score and kidney stones: data from the national health and nutrition examination survey (NHANES).

PURPOSE: Some studies have found that the pathological formation of kidney stones is closely related to injury and inflammatory response. Behaviors such as dietary composition, physical activity, obesity and smoking can all affect the body's oxidative stress levels. In order to evaluate the effects of various diets and lifestyles on the body's oxidative and antioxidant systems, an oxidative balance score was developed. To investigate whether the OBS is associated with the development of kidney stones. METHODS: Data were taken from the National Health and Nutrition Examination Survey (NHANES) from 2007-2018, followed by retrospective observational studies. The association between kidney stones and OBS was analyzed using survey-weighted logistic regression by adjusting for demographics, laboratory tests, and medical comorbidity covariates. The oxidative balance score is calculated by screening 16 nutrients and 4 lifestyle factors, including 5 prooxidants and 15 antioxidants, based on prior information about the relationship between oxidation levels in the body and nutrients or lifestyle factors. RESULTS: A total of 26,786 adult participants were included in the study, of which 2,578, or 9.62%, had a history of nephrolithiasis. Weighted logistic regression analysis found an association between OBS and kidney stones. In the fully tuned model, i.e., model 3, the highest quartile array of OBS was associated with the lowest quartile array of OBS (OR = 0.73 (0.57, 0.92)) with the risk of kidney stone (p = 0.01), and was statistically significant and remained relatively stable in each model. At the same time, the trend test in the model is also statistically significant. With the increase of OBS, the OR value of kidney stones generally tends to decrease. CONCLUSIONS: There is an inverse correlation between OBS and kidney stone disease. At the same time, higher OBS suggests that antioxidant exposure is greater than pro-oxidative exposure in diet and lifestyle, and is associated with a lower risk of kidney stones.

Efficacy and safety of acupuncture for postpartum hypogalactia: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Postpartum hypogalactia (PH) is prominent during lactation and may negatively impact the mother's or infant's health. Acupuncture is widely used to increase maternal breast milk production. However, the effects of acupuncture on PH remain unclear. Therefore, this review aimed to evaluate the efficacy and safety of acupuncture in individuals with PH. MATERIALS AND METHODS: Articles on potentially eligible randomized controlled trials (RCTs) on acupuncture for PH published from database inception to October 2023 were retrieved from the PubMed, Web of Science, Cochrane Library, EMBASE, EBSCO, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, WanFang, and VIP databases. Two reviewers independently screened the records, extracted essential information, and evaluated the methodological quality of the RCTs using the revised Cochrane risk-of-bias (RoB) tool. The primary outcome was a change in serum prolactin (PRL) levels before and after treatment. Secondary outcomes included milk secretion volume (MSV), total effective rate (TER), mammary fullness degree (MFD), and exclusive breastfeeding rate (EBR). Meta-analyses were performed using RevMan v5.4. Finally, the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. RESULTS: This study included 19 RCTs involving 2,400 participants. The included studies were classified as having an unclear to high RoB. Our findings indicated that, overall, acupuncture showed a significant effect in increasing serum PRL levels (standardized mean differences [SMDs] = 1.09, 95% confidence interval [CI]: 0.50, 1.68), MSV (SMD = 1.69, 95% CI: 0.53, 2.86), TER (relative risk [RR] = 1.25, 95% CI: 1.10, 1.42), and EBR (RR = 2.01, 95% CI: 1.07, 3.78) compared to that in the control group; however, no difference in MFD (SMD = 1.17, 95% CI: -0.09, 2.42) was observed. In the subgroup analysis, acupuncture combined with Chinese herbs or conventional treatment was significantly more effective in increasing serum PRL levels, MSV, and TER than did Chinese herbs or conventional treatment alone. Moreover, acupuncture alone resulted in significantly higher serum PRL levels compared to Chinese herbs; however, this benefit was not observed for TER and MFD. The quality of evidence was critically low. CONCLUSION: Acupuncture may effectively increase milk secretion in women with PH. However, owing to the low quality of evidence, further rigorously designed studies are warranted to confirm our findings.

SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive and prevalent brain tumor that poses significant challenges in treatment. SRSF9, an RNA-binding protein, is essential for cellular processes and implicated in cancer progression. Yet, its function and mechanism in GBM need clarification. METHODS: Bioinformatics analysis was performed to explore differential expression of SRSF9 in GBM and its prognostic relevance to glioma patients. SRSF9 and CDK1 expression in GBM cell lines and patients' tissues were quantified by RT-qPCR, Western blot or immunofluorescence assay. The role of SRSF9 in GBM cell proliferation and migration was assessed by MTT, Transwell and colony formation assays. Additionally, transcriptional regulation of CDK1 by SRSF9 was investigated using ChIP-PCR and dual-luciferase assays. RESULTS: The elevated SRSF9 expression correlates to GBM stages and poor survival of glioma patients. Through gain-of-function and loss-of-function strategies, SRSF9 was demonstrated to promote proliferation and migration of GBM cells. Bioinformatics analysis showed that SRSF9 has an impact on cell growth pathways including cell cycle checkpoints and E2F targets. Mechanistically, SRSF9 appears to bind to the promoter of CDK1 gene and increase its transcription level, thus promoting GBM cell proliferation. CONCLUSIONS: These findings uncover the cellular function of SRSF9 in GBM and highlight its therapeutic potential for GBM.

DeepSub: Utilizing Deep Learning for Predicting the Number of Subunits in Homo-Oligomeric Protein Complexes.

The molecular weight (MW) of an enzyme is a critical parameter in enzyme-constrained models (ecModels). It is determined by two factors: the presence of subunits and the abundance of each subunit. Although the number of subunits (NS) can potentially be obtained from UniProt, this information is not readily available for most proteins. In this study, we addressed this gap by extracting and curating subunit information from the UniProt database to establish a robust benchmark dataset. Subsequently, we propose a novel model named DeepSub, which leverages the protein language model and Bi-directional Gated Recurrent Unit (GRU), to predict NS in homo-oligomers solely based on protein sequences. DeepSub demonstrates remarkable accuracy, achieving an accuracy rate as high as 0.967, surpassing the performance of QUEEN. To validate the effectiveness of DeepSub, we performed predictions for protein homo-oligomers that have been reported in the literature but are not documented in the UniProt database. Examples include homoserine dehydrogenase from Corynebacterium glutamicum, Matrilin-4 from Mus musculus and Homo sapiens, and the Multimerins protein family from M. musculus and H. sapiens. The predicted results align closely with the reported findings in the literature, underscoring the reliability and utility of DeepSub.

Study on the dynamic response characteristics of lining structures in large-section tunnel blasting using JH-2 model analysis.

The lining structures of tunnels are typically constructed using sprayed or cast concrete materials, and their performance and quality during tunnel excavation and blasting are crucial for the stability and safety of tunnels. Therefore, the safe distance between the lining structure and blasting source should be determined to avoid concrete damage caused by blasting vibrations. In this study, taking the subway tunnel of Danshan Station in Qingdao as an example, the JH-2 model is introduced as the constitutive model of the tunnel blasting simulation, and the JH-2 model parameters of the local surrounding rock are obtained by experiments, and finally the numerical simulation and theoretical verification are carried out to study the safety distance of shotcrete under various safety judgment standards. The results indicate that the JH-2 model can effectively simulate the propagation of stress waves under different media conditions, and the closer the strength parameters and pressure constant of the lining structure are to those of the surrounding rock, the safer the concrete-rock bonding interface. During tunnel blasting construction using the ring blasting method, the peak particle velocity (PPV) of the lining structure increases with an increase in the arch angle. Based on the numerical simulation results, we recommend that concrete lining be constructed at a distance of at least 62 m from the blasting source to avoid damage caused by vibrations. The effect of concrete tensile failure caused by longitudinal stress is much smaller than the damage to the bonding interface caused by the PPV and can be neglected.

Recyclable Au@R-Fe3O4/g-C3N4 substrates for rapid SERS detection and degradation of multiple pollutants.

Developing a Surface-enhanced Raman spectroscopy (SERS) method with excellent detecting ability, good recyclability and analyzing multiple pollutants rapidly are critical for evaluation of water quality in emergency pollution affairs. While constructing a multifunctional substrate with these characteristics to realize the application of SERS in water quality monitoring remains a challenge. In this work, a reusable Au@R-Fe3O4/g-C3N4 SERS substrate is prepared by loading Au nanoparticles (Au NPs) on Fe3O4 nanorings (R-Fe3O4) and the formed Au@R-Fe3O4 is further combined with g-C3N4 nanosheets through a simple electrostatic assembly method. The Au@R-Fe3O4/g-C3N4 nanocomposite presents multifunction of magnetic enrichment, SERS signal enhancement, multiple pollutants analyzing, and photocatalytic activity, which achieves quantitative detection of rhodamine B (RhB), tetracycline hydrochloride (TC), and 4-chlorophenol (4-CP), with detection limits of 5.30 × 10-9, 7.50 × 10-8, 7.69 × 10-8 mol/L, respectively. Furthermore, the recyclable detection capability of Au@R-Fe3O4/g-C3N4 for multi components is demonstrated by the strong SERS signal after 9 cycles of "detection-degradation" processes. Combined with good uniformity and stability, this SERS method based on Au@R-Fe3O4/g-C3N4 substrate provides a new strategy for the multi-pollutants detection and degradation in water environment.

Peritendinous Submembrane Access Technique for Management of Acute Ruptures of the Achilles Tendon: A Retrospective Study of 249 Cases.

OBJECTIVE: Percutaneous repair is an alternative to open surgical repair of the Achilles tendon with comparable, functional results and low re-rupture and infection rates; however, sural nerve injury is a known complication. The purpose of this study is to design a new surgical procedure, the minimally invasive peritendinous submembrane access technique (MIS-PSAT). It offers optimal results, with excellent functional outcomes, and with minimal soft tissue complications and sural nerve injury. METHODS: This retrospective study included 249 patients with acute closed Achilles tendon ruptures treated at our institution between 2009 and 2019. All patients underwent MIS-PSAT at our institution and were followed up for 8-48 months. Functional evaluation was based on the Achilles tendon total rupture score (ATRS) and the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), associated with local complications and isokinetic tests. RESULTS: None of the patients had infection, necrosis, or sural nerve injury. Re-rupture occurred in two cases. The average times to return to work and sports was 10.4 and 31.6 weeks, respectively. The average ATRS and AOFAS-AHS scores were 90.2 and 95.7, respectively, with an excellent rate of 99.5%. Isokinetic tests showed that ankle function on the affected side was comparable with that on the healthy side (p > 0.05). CONCLUSION: The MIS-PSAT for acute Achilles tendon rupture is easy to perform with few complications. Importantly, the surgical technique reduces the risk of sural nerve injuries. Patients have high postoperative satisfaction, low re-rupture rates, and muscle strength, and endurance can be restored to levels similar to those on the healthy side.

Direct transposition of native DNA for sensitive multimodal single-molecule sequencing.

Concurrent readout of sequence and base modifications from long unamplified DNA templates by Pacific Biosciences of California (PacBio) single-molecule sequencing requires large amounts of input material. Here we adapt Tn5 transposition to introduce hairpin oligonucleotides and fragment (tagment) limiting quantities of DNA for generating PacBio-compatible circular molecules. We developed two methods that implement tagmentation and use 90-99% less input than current protocols: (1) single-molecule real-time sequencing by tagmentation (SMRT-Tag), which allows detection of genetic variation and CpG methylation; and (2) single-molecule adenine-methylated oligonucleosome sequencing assay by tagmentation (SAMOSA-Tag), which uses exogenous adenine methylation to add a third channel for probing chromatin accessibility. SMRT-Tag of 40 ng or more human DNA (approximately 7,000 cell equivalents) yielded data comparable to gold standard whole-genome and bisulfite sequencing. SAMOSA-Tag of 30,000-50,000 nuclei resolved single-fiber chromatin structure, CTCF binding and DNA methylation in patient-derived prostate cancer xenografts and uncovered metastasis-associated global epigenome disorganization. Tagmentation thus promises to enable sensitive, scalable and multimodal single-molecule genomics for diverse basic and clinical applications.

GLP-2 ameliorates D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a signaling pathway in C2C12 cells and mice.

BACKGROUND: The study aimed to investigate the effect of Glucagon-like peptide-2 (GLP-2) on muscle aging in vivo and in vitro. METHODS: Six-week-old C57BL/6J mice were administered with D-galactose (200 mg/kg/day, intraperitoneally) for 8weeks, followed by daily subcutaneous injections of GLP-2 (300 or 600 µg/kg/day) for 4weeks. Skeletal muscle function and mass were evaluated using relative grip strength and muscle weight. The sizes and types of muscle fibers and apoptosis were assessed through histological analysis, immunofluorescence staining, and TUNEL staining, respectively. C2C12 myotubes were treated with D-galactose (40 mg/mL) and GLP-2. Protein expression of differentiation-related myogenic differentiation factor D (MyoD), myogenin (MyoG), and myosin heavy chain (Myhc), degradation-related Muscle RING finger 1 (MuRF-1), and muscle atrophy F-box (MAFbx)/Atrogin-1, and apoptosis-related B-cell leukemia/lymphoma 2 (Bcl-2) and Bax, were assessed using western blots. The Pi3k inhibitor LY294002 was applied to investigate whether GLP-2 regulated myogenesis and myotube aging via IGF-1/Pi3k/Akt/FoxO3a signaling pathway. RESULTS: The results demonstrated that GLP-2 significantly reversed the decline in muscles weight, relative grip strength, diameter, and cross-sectional area of muscle fibers induced by D-galactose in mice. Apart from suppressing the expressions of MuRF-1 and Atrogin-1 in the muscles and C2C12 myotubes, GLP-2 significantly increased the expressions of MyoD, MyoG, and Myhc compared to the D-galactose. GLP-2 significantly suppressed cell apoptosis. Western blot analysis indicated that the regulation of GLP-2 may be attributed to the activation of theIGF-1/Pi3k/Akt/FoxO3a phosphorylation pathway. CONCLUSIONS: This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway.

A novel glycoglycerolipid from Holotrichia diomphalia Bates: Structure characteristics and protective effect against DNA damage.

A lipidated polysaccharide, HDPS-2II, was isolated from the dried larva of Holotrichia diomphalia, which is used in traditional Chinese medicine. The molecular weight of HDPS-2II was 5.9 kDa, which contained a polysaccharide backbone of →4)-ß-Manp-(1 â†’ 4,6)-ß-Manp-(1 â†’ [6)-α-Glcp-(1]n â†’ 6)-α-Glcp→ with the side chain α-Glcp-(6 â†’ 1)-α-Glcp-(6 â†’ linked to the C-4 of ß-1,4,6-Manp and four types of lipid chains including 4-(4-methyl-2-(methylamino)pentanamido)pentanoic acid, 5-(3-(tert-butyl)phenoxy)hexan-2-ol, N-(3-methyl-5-oxopentan-2-yl)palmitamide, and N-(5-amino-3-methyl-5-oxopentan-2-yl)stearamide. The lipid chains were linked to C-1 of terminal α-1,6-Glcp in carbohydrate chain through diacyl-glycerol. HDPS-2II exhibited DNA protective effects and antioxidative activity on H2O2- or adriamycin (ADM)-induced Chinese hamster lung cells. Furthermore, HDPS-2II significantly ameliorated chromosome aberrations and the accumulation of reactive oxygen species (ROS), reduced γ-H2AX signaling and the expressions of NADPH oxidase (NOX)2, NOX4, P22phox, and P47phox in ADM-induced cardiomyocytes. Mechanistically, HDPS-2II suppressed ADM-induced up-regulation of NOX2 and NOX4 in cardiomyocytes, but not in NOX2 or NOX4 knocked-down cardiomyocytes, indicating that HDPS-2II could relieve intracellular DNA damage by regulating NOX2/NOX4 signaling. These findings demonstrate that HDPS-2II is a new potential DNA protective agent.

MyD88 and Its Inhibitors in Cancer: Prospects and Challenges.

The interplay between the immune system and cancer underscores the central role of immunotherapy in cancer treatment. In this context, the innate immune system plays a critical role in preventing tumor invasion. Myeloid differentiation factor 88 (MyD88) is crucial for innate immunity, and activation of MyD88 promotes the production of inflammatory cytokines and induces infiltration, polarization, and immune escape of immune cells in the tumor microenvironment. Additionally, abnormal MyD88 signaling induces tumor cell proliferation and metastasis, which are closely associated with poor prognosis. Therefore, MyD88 could serve as a novel tumor biomarker and is a promising target for cancer therapy. Current strategies targeting MyD88 including inhibition of signaling pathways and protein multimerization, have made substantial progress, especially in inflammatory diseases and chronic inflammation-induced cancers. However, the specific role of MyD88 in regulating tumor immunity and tumorigenic mechanisms remains unclear. Therefore, this review describes the involvement of MyD88 in tumor immune escape and disease therapy. In addition, classical and non-classical MyD88 inhibitors were collated to provide insights into potential cancer treatment strategies. Despite several challenges and complexities, targeting MyD88 is a promising avenue for improving cancer treatment and has the potential to revolutionize patient outcomes.

Genomic analysis of Clostridium perfringens type D isolates from goat farms.

C. perfringens type D strains are the leading cause of enterotoxaemia in ruminants such as goats, sheep, and cattle. However, there has been no prior research on the genomic characteristics of C. perfringens type D strains from various regions in China. Here, we investigated the antibiotic resistance, genomic characteristics, and phylogenetic relationship of C. perfringens type D isolates recovered from goat farms in Shaanxi, Gansu, and Ningxia provinces. The antibiotic resistance test indicated that the isolates displayed high minimum inhibitory concentration (MIC) values to sulfafurazole, whereas the other antibiotics tested, such as penicillin, enrofloxacin, and florfenicol, worked well on them. Additionally, only tetracycline resistance genes [tetA(P) and tetB(P)] were identified from the isolates. A collective of 13 toxin genes, including etx and cpe were detected among the isolates. Sequence comparison revealed that the etx and cpe genes shared high sequence identities, and they could coexist on a pCW3-like plasmid, representing a potential risk to both animal breeding and public health. Phylogenetic analysis using core genome multi-locus sequence typing (cgMLST) and core genome single nucleotide polymorphisms (SNPs) revealed the close genetic relationship and potential regional/transregional transmission of the C. perfringens type D isolates in Shaanxi and Gansu provinces. Furthermore, pan-genomic analysis suggested the functional differences at the protein-coding gene level, although isolates from the same source shared a close genetic relationship. In conclusion, this study indicated the antibiotic resistance, virulence markers, potential transregional transmission, and genomic diversity of C. perfringens type D strains from various regions in China, which could provide references for the prevention of C. perfringens foodborne diseases and further research.

Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.

Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Folic Acid and Taurine Alleviate the Impairment of Redox Status, Immunity, Rumen Microbial Composition and Fermentation of Lambs under Heat Stress.

The aim of this study was to investigate if the supplementation of folic acid and taurine can relieve the adverse effects of different levels of heat stress (HS) on growth performance, physiological indices, antioxidative capacity, immunity, rumen fermentation and microbiota. A total of 24 Dorper × Hu crossbred lambs (27.51 ± 0.96 kg) were divided into four groups: control group (C, 25 °C), moderate HS group (MHS, 35 °C), severe HS group (SHS, 40 °C), and the treatment group, under severe HS (RHS, 40 °C, 4 and 40 mg/kg BW/d coated folic acid and taurine, respectively). Results showed that, compared with Group C, HS significantly decreased the ADG of lambs (p < 0.05), and the ADG in the RHS group was markedly higher than in the MHS and SHS group (p < 0.05). HS had significant detrimental effects on physiological indices, antioxidative indices and immune status on the 4th day (p < 0.05). The physiological indices, such as RR and ST, increased significantly (p < 0.05) with the HS level and were significantly decreased in the RHS group, compared to the SHS group (p < 0.05). HS induced the significant increase of MDA, TNF-α, and IL-ß, and the decrease of T-AOC, SOD, GPx, IL-10, IL-13, IgA, IgG, and IgM (p < 0.05). However, there was a significant improvement in these indices after the supplementation of folic acid and taurine under HS. Moreover, there were a significant increase in Quinella and Succinivibrio, and an evident decrease of the genera Rikenellaceae_RC9_gut_group and Asteroleplasma under HS (p < 0.05). The LEfSe analysis showed that the genera Butyrivibrio, Eubacterium_ventriosum_group, and f_Bifidobacteriaceae were enriched in the MHS, SHS and RHS groups, respectively. Correlated analysis indicated that the genus Rikenellaceae_RC9_gut_group was positively associated with MDA, while it was negatively involved in IL-10, IgA, IgM, and SOD (p < 0.05); The genus Anaeroplasma was positively associated with the propionate and valerate, while the genus Succinivibrio was negatively involved in TNF-α (p < 0.05). In conclusion, folic acid and taurine may alleviate the adverse effects of HS on antioxidant capacity, immunomodulation, and rumen fermentation of lambs by inducing changes in the microbiome that improve animal growth performance.

ECMpy 2.0: A Python package for automated construction and analysis of enzyme-constrained models.

Genome-scale metabolic models (GEMs) have been widely employed to predict microorganism behaviors. However, GEMs only consider stoichiometric constraints, leading to a linear increase in simulated growth and product yields as substrate uptake rates rise. This divergence from experimental measurements prompted the creation of enzyme-constrained models (ecModels) for various species, successfully enhancing chemical production. Building upon studies that allocate macromolecule resources, we developed a Python-based workflow (ECMpy) that constructs an enzyme-constrained model. This involves directly imposing an enzyme amount constraint in GEM and accounting for protein subunit composition in reactions. However, this procedure demands manual collection of enzyme kinetic parameter information and subunit composition details, making it rather user-unfriendly. In this work, we've enhanced the ECMpy toolbox to version 2.0, broadening its scope to automatically generate ecGEMs for a wider array of organisms. ECMpy 2.0 automates the retrieval of enzyme kinetic parameters and employs machine learning for predicting these parameters, which significantly enhances parameter coverage. Additionally, ECMpy 2.0 introduces common analytical and visualization features for ecModels, rendering computational results more user accessible. Furthermore, ECMpy 2.0 seamlessly integrates three published algorithms that exploit ecModels to uncover potential targets for metabolic engineering. ECMpy 2.0 is available at https://github.com/tibbdc/ECMpy or as a pip package (https://pypi.org/project/ECMpy/).

GPR27 expression correlates with prognosis and tumor progression in gliomas.

Backgrounds: Glioma is a highly aggressive type of brain tumor, and its prognosis is still poor despite recent progress in treatment strategies. G protein-coupled receptor 27 (GPR27) is a member of the G protein-coupled receptor family and has been reported to be involved in various cellular processes, including tumor progression. Nevertheless, the clinical potential and tumor-related role of GPR27 in glioma remain unknown. Here we aimed to explore the function and role of GPR27 in gliomas. Methods: In the current study, we evaluated the expression and clinical significance of GPR27 in gliomas using data from The Cancer Genome Atlas (TCGA) datasets. We also conducted cellular experiments to evaluate the functional role of GPR27 in glioma cell growth. Results: We found that GPR27 expression level was closely associated with disease status of glioma. Of note, GPR27 was negatively correlated with WHO grade, with grade IV samples showing the lowest GPR27 levels, while grade II samples showed the highest levels. Patients with IDH mutation or 1p/19q co-deletion exhibited higher GPR27 levels. In addition, lower GPR27 levels were correlated with higher death possibilities. In cellular experiments, we confirmed that GPR27 inhibited glioma cell growth. Conclusions: Our results indicate that GPR27 may function as a potential prognostic biomarker and therapeutic target in gliomas. Further studies are needed to illustrate the signaling mechanism and clinical implications of GPR27 in gliomas.

Knowledge, concerns, and vaccine acceptance related to Mpox (Monkeypox) among university students in North and Northeast China: An online cross-sectional study.

The growing number of Mpox cases in China has posed a challenge to public health. The prevalence of men who have sex with men behaviors among students has been consistently increasing each year in China, accompanied by a high frequency of unprotected anal sex. As crowded places, schools are highly likely to cause an Mpox outbreak among students through long-term close contact. Understanding university students' perceptions about Mpox and willingness to vaccinate play a vital role in implementing preventive measures in schools. This study aimed to assess knowledge, concerns, and vaccine acceptance toward Mpox among university students in North and Northeast China. A cross-sectional study was conducted among 3831 university students from seven universities in North and Northeast China between September 10 and September 25, 2023. This study found a relative insufficiency in Mpox knowledge among university students (71.60%), with less than half expressing concern about the Mpox outbreak (39.57%), and the majority exhibiting a positive attitude to vaccination (76.30%). Multivariate regression analysis revealed that a good knowledge level was associated with age, study discipline, education level, and a high level of concern about Mpox. Male, elderly, or highly educated participants had a low level of concern about Mpox. Participants with a high level of knowledge toward Mpox were more likely to have the vaccination willingness. This study might help governments and schools to understand students' Mpox perceptions and vaccination intentions, enabling them to implement effective measures in addressing the issue of inadequate understanding regarding Mpox among university students.