Modeling biomarker variability in joint analysis of longitudinal and time-to-event data.

The role of visit-to-visit variability of a biomarker in predicting related disease has been recognized in medical science. Existing measures of biological variability are criticized for being entangled with random variability resulted from measurement error or being unreliable due to limited measurements per individual. In this article, we propose a new measure to quantify the biological variability of a biomarker by evaluating the fluctuation of each individual-specific trajectory behind longitudinal measurements. Given a mixed-effects model for longitudinal data with the mean function over time specified by cubic splines, our proposed variability measure can be mathematically expressed as a quadratic form of random effects. A Cox model is assumed for time-to-event data by incorporating the defined variability as well as the current level of the underlying longitudinal trajectory as covariates, which, together with the longitudinal model, constitutes the joint modeling framework in this article. Asymptotic properties of maximum likelihood estimators are established for the present joint model. Estimation is implemented via an Expectation-Maximization (EM) algorithm with fully exponential Laplace approximation used in E-step to reduce the computation burden due to the increase of the random effects dimension. Simulation studies are conducted to reveal the advantage of the proposed method over the two-stage method, as well as a simpler joint modeling approach which does not take into account biomarker variability. Finally, we apply our model to investigate the effect of systolic blood pressure variability on cardiovascular events in the Medical Research Council elderly trial, which is also the motivating example for this article.

Octanoic acid mitigates busulfan-induced blood-testis barrier damage by alleviating oxidative stress and autophagy.

BACKGROUND: The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched. METHODS: Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells. RESULTS: A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by busulfan. Moreover, OCA intervention reduced busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy. CONCLUSIONS: This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility.

QTL Detection and Candidate Gene Identification for Eating and Cooking Quality Traits in Rice (Oryza sativa L.) via a Genome-Wide Association Study.

The eating and cooking quality (ECQ) directly affects the taste of rice, being closely related to factors such as gelatinization temperature (GT), gel consistency (GC) and amylose content (AC). Mining the quantitative trait loci (QTLs), and gene loci controlling ECQ-related traits is vital. A genome-wide association study on ECQ-related traits was conducted, combining 1.2 million single nucleotide polymorphisms (SNPs) with the phenotypic data of 173 rice accessions. Two QTLs for GT, one for GC and five for AC were identified, of which two were found in previously reported genes, and six were newly found. There were 28 positional candidate genes in the region of qAC11. Based on a linkage disequilibrium (LD) analysis, three candidate genes were screened within the LD region associated with AC. There were significant differences between the haplotypes of LOC_Os11g10170, but no significant differences were found for the other two genes. The qRT-PCR results showed that the gene expression levels in the accessions with high ACs were significantly larger than those in the accessions with low ACs at 35d and 42d after flowering. Hap 2 and Hap 3 of LOC_Os11g10170 reduced the AC by 13.09% and 10.77%, respectively. These results provide a theoretical and material basis for improving the ECQ of rice.

Development and validation of a nomogram to predict recompensation in HBV-related cirrhosis with ascites as the single first decompensating event.

BACKGROUND AND OBJECTIVE: Little is known about the influencing factors for recompensation in HBV-related cirrhosis patients with ascites as the single first decompensating event and it's necessary to build a prediction model for these patients. METHODS: Hepatitis B virus-related cirrhosis patients with ascites hospitalized for the first decompensation were included and they were divided into the training cohort (2010.03-2020.03) and the validation cohort (2020.04-2022.04). All patients received antiviral therapy within 3 months before admission or immediately after admission. Recompensation is defined as the patient's ascites disappeared without diuretics, which were maintained for more than 1 year and no other decompensated complications, hepatocellular carcinoma, or liver transplantation occurred. The nomogram was developed from a training cohort of 279 patients and validated in another cohort of 72 patients. RESULTS: Totally, 42.7% of the decompensated patients achieved recompensation. According to the results of logistic regression and competing risk analysis, six independent factors associated with recompensation were found and these factors comprised the nomogram: age, alanine aminotransferase (ALT), albumin (ALB), serum sodium (Na), alpha-fetoprotein (AFP), and maintained virological response (MVR). Through external validation, the area under the receiver operating characteristic curve (AUC) of the nomogram was 0.848 (95% CI: 0.761, 0.936), which was significantly better than CTP, MELD, MELDNa, MELD 3.0, and ALBI grade. CONCLUSIONS: Age, ALT, ALB, Na, AFP, and MVR are closely related to the recompensation. The nomogram developed based on these items can accurately predict the possibility of recompensation in hepatitis B cirrhosis patients with ascites as the single first decompensating event.

Nitrifier adaptation to low energy flux controls inventory of reduced nitrogen in the dark ocean.

Ammonia oxidation to nitrite and its subsequent oxidation to nitrate provides energy to the two populations of nitrifying chemoautotrophs in the energy-starved dark ocean, driving a coupling between reduced inorganic nitrogen (N) pools and production of new organic carbon (C) in the dark ocean. However, the relationship between the flux of new C production and the fluxes of N of the two steps of oxidation remains unclear. Here, we show that, despite orders-of-magnitude difference in cell abundances between ammonia oxidizers and nitrite oxidizers, the two populations sustain similar bulk N-oxidation rates throughout the deep waters with similarly high affinities for ammonia and nitrite under increasing substrate limitation, thus maintaining overall homeostasis in the oceanic nitrification pathway. Our observations confirm the theoretical predictions of a redox-informed ecosystem model. Using balances from this model, we suggest that consistently low ammonia and nitrite concentrations are maintained when the two populations have similarly high substrate affinities and their loss rates are proportional to their maximum growth rates. The stoichiometric relations between the fluxes of C and N indicate a threefold to fourfold higher C-fixation efficiency per mole of N oxidized by ammonia oxidizers compared to nitrite oxidizers due to nearly identical apparent energetic requirements for C fixation of the two populations. We estimate that the rate of chemoautotrophic C fixation amounts to ∼1 × 1013 to ∼2 × 1013 mol of C per year globally through the flux of ∼1 × 1014 to ∼2 × 1014 mol of N per year of the two steps of oxidation throughout the dark ocean.

Study of the Mechanism of Astragali Radix in Treating Type 2 Diabetes Mellitus and Its Renal Protection Based on Enzyme Activity, Network Pharmacology, and Experimental Verification.

Astragali Radix (AR) is a common Chinese medicine and food. This article aims to reveal the active role of AR in treating Type 2 diabetes mellitus (T2DM) and its renal protective mechanism. The hypoglycemic active fraction was screened by α-glucosidase and identified by UPLC-QE-Orbitrap-MS spectrometry. The targets and KEGG pathway were determined through the application of network pharmacology methodology. Molecular docking and molecular dynamics simulation technology were used for virtual verification. Subsequently, a mouse model of T2DM was established, and the blood glucose and renal function indexes of the mice after administration were analyzed to further prove the pharmacodynamic effect and mechanism of AR in the treatment of T2DM. HA was determined as the best hypoglycemic active fraction by the α-glucosidase method, with a total of 23 compounds identified. The main active components, such as calycoside-7-O-ß-D-glucoside, methylnisoline, and formononetin, were revealed by network pharmacology. In addition, the core targets and the pathway have also been determined. Molecular docking and molecular dynamics simulation techniques have verified that components and targets can be well combined. In vivo studies have shown that AR can reduce blood sugar levels in model mice, enhance the anti-inflammatory and antioxidant activities of kidney tissue, and alleviate kidney damage in mice. And it also has regulatory effects on proteins such as RAGE, PI3K, and AKT. AR has a good therapeutic effect on T2DM and can repair disease-induced renal injury by regulating the RAGE/PI3K/Akt signaling pathway. This study provides ideas for the development of new drugs or dietary interventions for the treatment of T2DM.

UPLC-QE-Orbitrap-Based Cell Metabolomics and Network Pharmacology to Reveal the Mechanism of N-Benzylhexadecanamide Isolated from Maca (Lepidium meyenii Walp.) against Testicular Dysfunction.

Testicular dysfunction (TDF) is characterized by testosterone deficiency and is caused by oxidative stress injury in Leydig cells. A natural fatty amide named N-benzylhexadecanamide (NBH), derived from cruciferous maca, has been shown to promote testosterone production. Our study aims to reveal the anti-TDF effect of NBH and explore its potential mechanism in vitro. This study examined the effects of H2O2 on cell viability and testosterone levels in mouse Leydig cells (TM3) under oxidative stress. In addition, cell metabolomics analysis based on UPLC-Q-Exactive-MS/MS showed that NBH was mainly involved in arginine biosynthesis, aminoacyl-tRNA biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, the TCA cycle and other metabolic pathways by affecting 23 differential metabolites, including arginine and phenylalanine. Furthermore, we also performed network pharmacological analysis to observe the key protein targets in NBH treatment. The results showed that its role was to up-regulate ALOX5, down-regulate CYP1A2, and play a role in promoting testicular activity by participating in the steroid hormone biosynthesis pathway. In summary, our study not only provides new insights into the biochemical mechanisms of natural compounds in the treatment of TDF, but also provides a research strategy that integrates cell metabolomics and network pharmacology in order to promote the screening of new drugs for the treatment of TDF.

Screening of the Active Compounds against Neural Oxidative Damage from Ginseng Phloem Using UPLC-Q-Exactive-MS/MS Coupled with the Content-Effect Weighted Method.

The neuroprotective properties of ginsenosides have been found to reverse the neurological damage caused by oxidation in many neurodegenerative diseases. However, the distribution of ginsenosides in different tissues of the main root, which was regarded as the primary medicinal portion in clinical practice was different, the specific parts and specific components against neural oxidative damage were not clear. The present study aims to screen and determine the potential compounds in different parts of the main root in ginseng. Comparison of the protective effects in the main root, phloem and xylem of ginseng on hydrogen peroxide-induced cell death of SH-SY5Y neurons was investigated. UPLC-Q-Exactive-MS/MS was used to quickly and comprehensively characterize the chemical compositions of the active parts. Network pharmacology combined with a molecular docking approach was employed to virtually screen for disease-related targets and potential active compounds. By comparing the changes before and after Content-Effect weighting, the compounds with stronger anti-nerve oxidative damage activity were screened out more accurately. Finally, the activity of the selected monomer components was verified. The results suggested that the phloem of ginseng was the most effective part. There were 19 effective compounds and 14 core targets, and enriched signaling pathway and biological functions were predicted. After Content-Effect weighting, compounds Ginsenosides F1, Ginsenosides Rf, Ginsenosides Rg1 and Ginsenosides Rd were screened out as potential active compounds against neural oxidative damage. The activity verification study indicated that all four predicted ginsenosides were effective in protecting SH-SY5Y cells from oxidative injury. The four compounds can be further investigated as potential lead compounds for neurodegenerative diseases. This also provides a combined virtual and practical method for the simple and rapid screening of active ingredients in natural products.

Identification and preliminary study of immunogens involved in autoimmune prostatitis in human males.

BACKGROUND: Experimental models have confirmed that autoimmunity is an important factor in the onset of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); however, there is no conclusive evidence on whether autoimmune prostatitis exists in human males. METHODS: Rabbits were immunized with either human prostate tissue homogenates or normal saline and the antiserum was collected. Two-dimensional electrophoresis (2-DE) was performed on the homogenates and Western blotting was conducted on the sera. The identified human prostate tissue immunodominant antigens (HPTIAs) were detected by mass spectrometry. The serum immunoglobulin (Ig)G from the immunized rabbits was purified with protein A-agarose, and the purified IgG was linked with Sepharose to purify HPTIAs by affinity chromatography. Non-obese diabetic (NOD) mice were immunized with the purified HPTIAs, and the levels of serum antibodies, INF-γ, and histopathological changes in their prostate tissues were detected. The purified HPTIAs were coated into polystyrene pores and serum autoantibodies in CP/CPPS patients were detected by enzyme-linked immunosorbent assay (ELISA). Meanwhile, serum interleukin 2 (IL-2), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNFα) levels in CP/CPPS patients were also determined by ELISA. RESULTS: Sixteen HPTIAs were identified. Among them, three types were reported to be associated with prostatic diseases. Prostatitis was induced in mice immunized with the 16-HPTIA complex, with positive serum autoantibody and increased prostatic IFN-γ levels. The positive rate of serum autoantibodies against HPTIAs was significantly higher in CP/CPPS patients (23.1%, 18/78) than in the control (2.7%, 2/75). But there was no significant difference in serum TNFα, IFNγ, and IL-2 levels between the CPPS patients with positive and negative autoantibodies against HPTIAs. CONCLUSIONS: Autoantibodies against HPTIAs exist in part in CP/CPPS patients, which implies that autoimmunity and the 16 HPTIAs are important factors in the onset of CP/CPPS. The detection of serum autoantibodies could be applied in clinical diagnoses of autoimmune prostatitis; treatment protocols might change. Additional studies are needed to determine which of the 16 HPTIAs is the most important.

Phrase mining of textual data to analyze extracellular matrix protein patterns across cardiovascular disease.

Extracellular matrix (ECM) proteins have been shown to play important roles regulating multiple biological processes in an array of organ systems, including the cardiovascular system. Using a novel bioinformatics text-mining tool, we studied six categories of cardiovascular disease (CVD), namely, ischemic heart disease, cardiomyopathies, cerebrovascular accident, congenital heart disease, arrhythmias, and valve disease, anticipating novel ECM protein-disease and protein-protein relationships hidden within vast quantities of textual data. We conducted a phrase-mining analysis, delineating the relationships of 709 ECM proteins with the 6 groups of CVDs reported in 1,099,254 abstracts. The technology pipeline known as Context-Aware Semantic Online Analytical Processing was applied to semantically rank the association of proteins to each CVD and all six CVDs, performing analyses to quantify each protein-disease relationship. We performed principal component analysis and hierarchical clustering of the data, where each protein was visualized as a six-dimensional vector. We found that ECM proteins display variable degrees of association with the six CVDs; certain CVDs share groups of associated proteins, whereas others have divergent protein associations. We identified 82 ECM proteins sharing associations with all 6 CVDs. Our bioinformatics analysis ascribed distinct ECM pathways (via Reactome) from this subset of proteins, namely, insulin-like growth factor regulation and interleukin-4 and interleukin-13 signaling, suggesting their contribution to the pathogenesis of all six CVDs. Finally, we performed hierarchical clustering analysis and identified protein clusters predominantly associated with a targeted CVD; analyses of these proteins revealed unexpected insights underlying the key ECM-related molecular pathogenesis of each CVD, including virus assembly and release in arrhythmias. NEW & NOTEWORTHY The present study is the first application of a text-mining algorithm to characterize the relationships of 709 extracellular matrix-related proteins with 6 categories of cardiovascular disease described in 1,099,254 abstracts. Our analysis informed unexpected extracellular matrix functions, pathways, and molecular relationships implicated in the six cardiovascular diseases.

[Animal models of autoimmune prostatitis and their evaluation criteria].

Chronic prostatitis is a highly prevalent disease of unclear etiology. Researches show that autoimmune reaction is one cause of the problem. An effective animal model may help a lot to understand the pathogenesis and find proper diagnostic and therapeutic strategies of the disease. Currently used autoimmune prostatitis-related animal models include those of age-dependent spontaneous prostatitis, autoimmune regulator-dependent spontaneous prostatitis, self antigen-induced prostatitis, and steroid-induced prostatitis. Whether an animal model of autoimmune prostatitis is successfully established can be evaluated mainly from the five aspects: histology, morphology, specific antigens, inflammatory factors, and pain intensity.

Liver Injury and Its Impact on Prognosis in Patients with HBV-Related Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization Combined with Tyrosine Kinase Inhibitors Plus Immune Checkpoint Inhibitors.

Purpose: Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy. Patients and Methods: Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan-Meier analysis were used to determine prognostic factors for OS. Results: As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050-0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031-3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1-2 and grade 3-4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034). Conclusion: Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy.

Integrated cell metabolomics and network pharmacology approach deciphers the anti-testosterone deficiency mechanisms of Bushen Zhuanggu Tang.

Testicular dysfunction is distinguished by a deficiency in testosterone levels, which can be attributed to the occurrence of oxidative stress injury in Leydig cells. The empirical prescription known as Bushen Zhuanggu Tang, developed by a highly experienced traditional Chinese medicine practitioner with six decades of clinical expertize, aligns with the traditional Chinese medicine principle of "kidney governing bone". Researchers have demonstrated that the administration of BSZGT can effectively enhance testosterone production. The objective of this study is to investigate the potential anti-testicular dysfunction effects of BSZGT and elucidate its underlying mechanism in an in vitro setting. Specifically, the impact of oxidative stress induced by H2O2 on the activity and testosterone levels of Leydig cells (TM3) was examined. Furthermore, the utilization of UPLC-QE-Qrbitrap-MS enabled the identification of the involvement of BSZGT in various metabolic pathways, including arginine biosynthesis, amino acyl-tRNA biosynthesis, Alanine, aspartate and glutamine metabolism, and Citrate Cycle, through the modulation of 25 distinct metabolites. Additionally, a network pharmacological analysis was conducted to investigate the pivotal protein targets associated with the therapeutic effects of BSZGT. The findings demonstrate the identification of six key proteins (CYP19A1, CYP1B1, ALOX5, ARG1, XDH, and MPO) that play a significant role in augmenting testicular function through their involvement in the ovarian steroid production pathway. In summary, our study presents a comprehensive research methodology that combines cell metabonomics and network pharmacology to enhance the discovery of new therapeutic agents for TD.

Identifying the Quantitative Trait Locus and Candidate Genes of Traits Related to Milling Quality in Rice via a Genome-Wide Association Study.

Milling quality directly affects production efficiency in rice, which is closely related to the brown rice recovery (BRR), the milled rice recovery (MRR) and the head milled rice recovery (HMRR). The present study investigated these three traits in 173 germplasms in two environments, finding abundant phenotypic variation. Three QTLs for BRR, two for MRR, and three for HMRR were identified in a genome-wide association study, five of these were identified in previously reported QTLs and three were newly identified. By combining the linkage disequilibrium (LD) analyses, the candidate gene LOC_Os05g08350 was identified. It had two haplotypes with significant differences and Hap 2 increased the BRR by 4.40%. The results of the qRT-PCR showed that the expression of LOC_Os05g08350 in small-BRR accessions was significantly higher than that in large-BRR accessions at Stages 4-5 of young panicle development, reaching the maximum value at Stage 5. The increase in thickness of the spikelet hulls of the accession carrying LOC_Os05g08350TT occurred due to an increase in the cell width and the cell numbers in cross-sections of spikelet hulls. These results help to further clarify the molecular genetic mechanism of milling-quality-related traits and provide genetic germplasm materials for high-quality breeding in rice.

Modeling the optimal seasonal monoclonal antibody administration strategy for respiratory syncytial virus (RSV) prevention based on age-season specific hospitalization rate of RSV in Suzhou, China, 2016-2022.

BACKGROUND: The approval of nirsevimab brings light to reducing the heavy disease burden caused by respiratory syncytial virus (RSV). Considering the seasonality of RSV, the timing of administrating monoclonal antibody (mAb) is critical to maximize health utility. This study aimed to model and seek the optimal seasonal mAb administration strategy for preventing RSV-associated hospitalization. METHODS: Age-season specific hospitalization rates for RSV-associated acute lower respiratory infection (RSV-ALRI) were estimated from a hospital-based birth cohort. Using these rates, we simulated and evaluated the effect of diverse mAb administration strategies on preventing RSV-ALRI hospitalization. Optimal strategies were selected based on their effectiveness and relative cost-effectiveness. RESULTS: Compared with the year-round strategy of administration mAb at birth for all children, 291 out of the 854 candidate strategies, featuring diverse administration timing and age thresholds, demonstrated a greater number of averted RSV-ALRI hospitalizations and a lower number needed to treat (NNT). The NNT represents the number of mAb doses needed to prevent one case of RSV-ALRI hospitalization. Among the 291 strategies, administration mAb to children born in July-January or August-January at birth and administrating to the remaining <12 months old children in September, exhibited the highest increase in averted RSV-ALRI hospitalizations than the year-round strategy, with a magnitude of 23 %, while also achieve an 18 % reduction in NNT. CONCLUSION: Administrating monoclonal antibodies to children born in July to January at birth, and administrating to the remaining <1-year-old children in September or October would be the optimal seasonal mAb administration strategy for children in Suzhou, China.

Impact of COVID-19 Nonpharmaceutical Interventions on Respiratory Syncytial Virus Infections in Hospitalized Children.

BACKGROUND: Nonpharmaceutical interventions (NPIs) targeted at SARS-CoV-2 have remarkably affected the circulation of other respiratory pathogens, including respiratory syncytial virus (RSV). This study aimed to assess the changes in epidemiological and clinical characteristics of RSV infections in hospitalized children before and during the pandemic in Suzhou, China. METHODS: We prospectively enrolled children aged < 18 years who were hospitalized in Soochow University Affiliated Children's Hospital with acute lower respiratory infection (ALRIs) from January 2018 to July 2022. Changes in epidemiological and clinical characteristics of RSV infections were analyzed. RESULTS: Compared with the same period in 2018-2019, the difference in the overall positive rate of RSV was not statistically significant in 2020, while it increased significantly in 2021 (11.8% [662/5621] vs. 20.8% [356/1711], p < 0.001) and 2022 (9.0% [308/3406] vs. 18.9% [129/684], p < 0.001). Specifically, the positive rates declined considerably from October to December 2020 but sharply increased during the summer of 2021. Compared to prepandemic period, RSV infections were more frequently observed in older children during the pandemic. RSV-positive children exhibited milder clinical characteristics during the COVID-19 pandemic, including decreased proportion of patients with hospital stay ≥ 11 days (10.3% vs. 6.7%, p < 0.05), less requirement for oxygen therapy (13.7% vs. 6.9%, p < 0.001), and fewer cases of polypnea (12.2% vs. 9.7%, p < 0.05) and wheeze (50.1% vs. 42.9%, p < 0.001). CONCLUSIONS: The implementation of multilayered NPIs targeted at COVID-19 has affected the activity of RSV. Ongoing monitoring of RSV is warranted as the changing RSV epidemiology can provide valuable insights for future healthcare system planning.

Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating the tight junctions of renal tubular epithelial cells.

As one of the most significant pathological changes of diabetic nephropathy (DN), tubulointerstitial fibrosis (TIF) had a close relationship with tubulointerstitial inflammation (TI), and the occurrence of TI could have resulted from the disrupted tight junctions (TJs) of renal tubular epithelial cells (RTECs). Studies have demonstrated that sodium butyrate (NaB), a typical short chain fatty acid (SCFA), played an important regulatory role in intestinal TJs and inflammation. In this study, our in vivo and in vitro results showed that accompanied by TI, renal tubular TJs were gradually disrupted in the process of DN-related TIF. In HG and LPS co-cultured HK-2 cells and db/db mice, NaB treatment regained the TJs of RTECs via the sphingosine 1-phosphate receptor-1 (S1PR1)/AMPK signaling pathway, relieving inflammation. Small interfering RNA of S1PR1, S1PR1 antagonist W146 and agonist SEW2871, and AMPK agonist AICAR were all used to further confirm the essential role of the S1PR1/AMPK signaling pathway in NaB's TJ protection in RTECs in vitro. Finally, NaB administration not only improved the renal function and TIF, but also relieved the TI of db/db mice. These findings suggested that the use of NaB might be a potential adjuvant treatment strategy for DN-associated TIF, and this protective effect was linked to the TJ modulation of RTECs via the S1PR1/AMPK signaling pathway, leading to the improvement of TI.

Removal of Expression of Concern: Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating tight junction of renal tubular epithelial cells.

Removal of Expression of Concern for 'Sodium butyrate ameliorated diabetic nephropathy-associated tubulointerstitial inflammation by modulating tight junction of renal tubular epithelial cells' by Tingting Yang et al., Food Funct., 2022, Accepted Manuscript, https://doi.org/10.1039/D2FO00940D.

Omega-3 polyunsaturated fatty acids and its metabolite 12-HEPE rescue busulfan disrupted spermatogenesis via target to GPR120.

Busulfan is an antineoplastic, which is always accompanied with the abnormal of spermatogonia self-renewal and differentiation. It has been demonstrated that the omega-3 polyunsaturated fatty acids (PUFAs) benefits mature spermatozoa. However, whether omega-3 can protect endogenous spermatogonia and the detailed mechanisms are still unclear. Evaluate of spermatogenesis function (in vivo) were examined by histopathological analysis, immunofluorescence staining, and western blotting. The levels of lipid metabolites in testicular tissue were determined via liquid chromatography. We investigated the effect of lipid metabolites on Sertoli cells provided paracrine factors to regulate spermatogonia proliferation and differentiation using co-culture system. In our study, we showed that omega-3 PUFAs significantly improved the process of sperm production and elevated the quantity of both undifferentiated Lin28+ spermatogonia and differentiated c-kit+ spermatogonia in a mouse model where spermatogenic function was disrupted by busulfan. Mass spectrometry revealed an increase in the levels of several omega-3 metabolites in the testes of mice fed with omega-3 PUFAs. The eicosapentaenoic acid metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) up-regulated bone morphogenic protein 4 (BMP4) expression through GPR120-ERK1/2 pathway activation in Sertoli cells and restored spermatogonia proliferation and differentiation. Our study provides evidence that omega-3 PUFAs metabolite 12-HEPE effectively protects spermatogonia and reveals that GPR120 might be a tractable pharmacological target for fertility in men received chemotherapy or severe spermatogenesis dysfunction.

HiPrompt: Few-Shot Biomedical Knowledge Fusion via Hierarchy-Oriented Prompting.

Medical decision-making processes can be enhanced by comprehensive biomedical knowledge bases, which require fusing knowledge graphs constructed from different sources via a uniform index system. The index system often organizes biomedical terms in a hierarchy to provide the aligned entities with fine-grained granularity. To address the challenge of scarce supervision in the biomedical knowledge fusion (BKF) task, researchers have proposed various unsupervised methods. However, these methods heavily rely on ad-hoc lexical and structural matching algorithms, which fail to capture the rich semantics conveyed by biomedical entities and terms. Recently, neural embedding models have proved effective in semantic-rich tasks, but they rely on sufficient labeled data to be adequately trained. To bridge the gap between the scarce-labeled BKF and neural embedding models, we propose HiPrompt, a supervision-efficient knowledge fusion framework that elicits the few-shot reasoning ability of large language models through hierarchy-oriented prompts. Empirical results on the collected KG-Hi-BKF benchmark datasets demonstrate the effectiveness of HiPrompt.