TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Two doses of fosaprepitant included prophylactic treatment for the three-day cisplatin-based chemotherapy induced nausea and vomiting.

PURPOSE: Neurokinin 1 receptor antagonists included prophylactic treatment was recommended for patients who receive one-day cisplatin chemotherapy. It is unclear whether the prolonged administration of fosaprepitant is effective for three-day cisplatin-based chemotherapy induced nausea and vomiting (CINV). We aim to explore the prophylactic antiemetic efficacy and safety of two doses of fosaprepitant included regimen in the patients receiving multiple-day cisplatin chemotherapy. METHODS: This randomized, parallel-group, open-labelled study was conducted in nine hospitals between February 2021 and February 2023. Patients diagnosed as lung cancer and chemotherapy naive were screened. Eligible participants were scheduled to be treated with highly emetogenic chemotherapy regimen which including three days of cisplatin. Then they were randomly divided into the experimental group (two doses of fosaprepitant, Group 2DF) and the control group (one dose of fosaprepitant, Group C). The primary endpoints included the safety and the average none CINV days (NCDs). This study was registered on the website of chictr.org.cn, number ChiCTR2100042665. RESULTS: Overall, 204 participants were randomly assigned, and 198 patients were analyzed. No statistical difference in adverse events was found between the two groups. All treatment-related adverse effects for fosaprepitant observed were of grade 1-2. The average NCDs of Group 2DF was significantly more than Group C (18.21 ± 3.40 days vs 16.14 ± 5.20 days, P = 0.001). Furthermore, the better life function score was achieved in Group 2DF according to FLIE questionnaire. CONCLUSION: The administration of two-dose fosaprepitant was safe and more effective than one dose in protecting patients from CINV induced by three-day cisplatin included chemotherapy.

Bibliometric Analyses of the Research Trends of Female Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: The study was aimed at systematically analyzing the research status and trends of pelvic organ prolapse (POP) using bibliometrics. METHODS: We retrieved documents published between 1975 and 2022 from the Web of Science Core Collection (WoSCC) database, and manually selected them for bibliometric analyses of country, institution, journal, highly locally cited documents and research trends based on co-citation clustering and keywords using the R Bibliometricx package and CiteSpace software. RESULTS: A total of 5,703 publications were included. Although the number of annual publications on POP increased, the trend of annual publication reached an obvious plateau in the first half of the 2010s. The USA, China, the UK, the University of Michigan, the University of Pittsburgh, and the University of Sydney were the top three countries and institutions with the most publications respectively. International Urogynecology Journal, American Journal of Obstetrics and Gynecology, and Obstetrics and Gynecology were the journals with the most extensive academic influence on the field of POP research. The international cooperation was lacking and the highly cited documents focused on high-level, evidence-based studies. Epidemiological studies and surgical treatment have achieved a plateau or decline. Recent studies have focused on conservative treatment, physical therapy, and minimally invasive surgery. In addition to evidence-based medicine studies, tissue engineering is the future direction of POP. CONCLUSIONS: This study used bibliometric analyses to provide insights into the status and potential research directions of POP. More high-quality, evidence-based medicine studies and in-depth tissue engineering research should be propelled forward.

Advancements and trends in exosome research in lung cancer from a bibliometric analysis (2004-2023).

Background: Lung cancer, characterized by its high morbidity and lethality, necessitates thorough research to enhance our understanding of its pathogenesis and discover novel therapeutic approaches. Recent studies increasingly demonstrate that lung cancer cells can modulate the tumor microenvironment, promoting tumor growth, and metastasis through the release of exosomes. Exosomes are small vesicles secreted by cells and contain a variety of bioactive molecules such as proteins, nucleic acids, and metabolites. This paper presents a comprehensive review of exosome research in lung cancer and its progress through bibliometric analysis. Methods: Publications related to exosomes in lung cancer patients were systematically searched on the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using VOSviwers, CiteSpace, and the R package "Bibliometrics". Publications were quantitatively analyzed using Microsoft Office Excel 2019. The language of publication was restricted to "English" and the search strategy employed TS=(exosomes or exosomes or exosomes) and TS=(lung cancer). The search period commenced on January 1, 2004, and concluded on November 12, 2023, at noon. The selected literature types included Articles and Reviews. Results: The study encompassed 1699 papers from 521 journals across 71 countries and 2105 institutions. Analysis revealed a consistent upward trend in lung cancer exosome research over the years, with a notable surge in recent times. This surge indicates a growing interest and depth of inquiry into lung cancer exosomes. Major research institutions in China and the United States, including Nanjing Medical University, Shanghai Jiao Tong University, Chinese Academy Of Sciences, and Utmd Anderson Cancer Center, emerged as crucial research hubs. The annual publication count in this field witnessed a continuous rise, particularly in recent years. Key terms such as lung cancer, non-small cell lung cancer (NSCLC), microvesicles, intercellular communication, exosomal miRNAs, and oncology dominated the research landscape. Fields like cell biology, biochemistry, biotechnology, and oncology exhibited close relation with this research. Clotilde Théry emerged as the most cited author in the field, underlining her significant contributions. These results demonstrate the broad impact of exosome research in lung cancer, with key terms covering not only disease-specific aspects such as lung cancer and NSCLC but also basic biological concepts like microvesicles and intercellular communication. Explorations into exosomal microRNAs and oncology have opened new avenues for lung cancer exosome research. In summary, lung cancer exosome research is poised to continue receiving attention, potentially leading to breakthroughs in treatment and prevention. Conclusion: Publications on lung cancer exosomes show a rising trend year by year, with China and the United States ranking first and second in terms of the number of publications. However, there is insufficient academic learning cooperation and exchanges between the two sides, and Chinese universities account for a large proportion of research institutions in this field. Jing Li is the most productive author, Clotilde Théry is the most co-cited author, and Cancers is the journal with the highest number of publications. The current focus in the field of lung cancer exosomes is on biomarkers, liquid biopsies, immunotherapy, and tumor microenvironment.

Incorporating longitudinal history of risk factors into atherosclerotic cardiovascular disease risk prediction using deep learning.

It is increasingly clear that longitudinal risk factor levels and trajectories are related to risk for atherosclerotic cardiovascular disease (ASCVD) above and beyond single measures. Currently used in clinical care, the Pooled Cohort Equations (PCE) are based on regression methods that predict ASCVD risk based on cross-sectional risk factor levels. Deep learning (DL) models have been developed to incorporate longitudinal data for risk prediction but its benefit for ASCVD risk prediction relative to the traditional Pooled Cohort Equations (PCE) remain unknown. Our study included 15,565 participants from four cardiovascular disease cohorts free of baseline ASCVD who were followed for adjudicated ASCVD. Ten-year ASCVD risk was calculated in the training set using our benchmark, the PCE, and a longitudinal DL model, Dynamic-DeepHit. Predictors included those incorporated in the PCE: sex, race, age, total cholesterol, high density lipid cholesterol, systolic and diastolic blood pressure, diabetes, hypertension treatment and smoking. The discrimination and calibration performance of the two models were evaluated in an overall hold-out testing dataset. Of the 15,565 participants in our dataset, 2170 (13.9%) developed ASCVD. The performance of the longitudinal DL model that incorporated 8 years of longitudinal risk factor data improved upon that of the PCE [AUROC: 0.815 (CI 0.782-0.844) vs 0.792 (CI 0.760-0.825)] and the net reclassification index was 0.385. The brier score for the DL model was 0.0514 compared with 0.0542 in the PCE. Incorporating longitudinal risk factors in ASCVD risk prediction using DL can improve model discrimination and calibration.

Quantitative prediction of AFB1 in various types of edible oil based on absorption, scattering and fluorescence signals at dual wavelengths.

This study aims to address the challenge of matrix interference of various types of edible oils on intrinsic fluorescence of aflatoxin B1 (AFB1) by developing a novel solution. Considering the fluorescence internal filtering effect, the absorption (µa) and reduced scattering (µ's) coefficients at dual wavelengths (excitation: 375 nm, emission: 450 nm) were obtained by using integrating sphere technique, and were used to improve the quantitative prediction results for AFB1 contents in six different kinds of edible oils. A research process of "Monte Carlo (MC) simulation - phantom verification - actual sample validation" was conducted. The MC simulation was used to determine interference rule and correction parameters for fluorescence, the results indicated that the escaped fluorescence flux nonlinearly decreased with the µa, µ's at emission wavelength (µa,em, µ's,em) and µa at excitation wavelength (µa,ex), however increased with the µ's at excitation wavelength (µ's,ex). And the required optical parameters to eliminate the interference of matrix on fluorescence intensity are: effective attenuation coefficients at excitation and emission wavelengths (µeff,ex, µeff,em) and µ's,ex. Phantom verification was conducted to explore the feasibility of fluorescence correction based on the identified parameters by MC simulation, and determine the optimal machine learning method. The modelling results showed that least squares support vector regression (LSSVR) model could reach the best performance. Three kinds of edible oil (peanut, rapeseed, corn), each with two brands were used to prepare oil samples with different AFB1 contamination. The LSSVR model for AFB1 based on µeff,ex, µeff,em, µ's,ex and fluorescence intensity at 450 nm was calibrated, both correlation coefficients for calibration (Rc) and the validation (Rv) sets could reach 1.000, root mean square errors for calibration (RMSEC) and the validation (RMSEV) sets were as low as 0.038 and 0.099 respectively. This study proposed a novel method which is based solely on the absorption, scattering, and fluorescence characteristics at excitation and emission wavelengths to achieve accurate prediction of AFB1 content in different types of vegetable oils.

A novel method for determination of peroxide value and acid value of extra-virgin olive oil based on fluorescence internal filtering effect correction.

Peroxide value (PV) and acid value (AV) are widely used indicators for evaluating oxidation degree of olive oils. Fluorescence spectroscopy has been extensively studied on the detection of oil oxidation, however, the detection accuracy is limited due to internal filtering effect (IFE). Due to the primary and secondary IFE, at least two wavelengths of absorption information are required. Least squares support vector regression (LSSVR) models for PV and AV were established based on two absorption coefficients (µa) at 375 nm and emission wavelength and one fluorescence intensity at corresponding wavelength. The regression results proved that the model based on 375 and 475 nm could reach the best performance, with the highest correlation coefficient for prediction (rp) of 0.889 and 0.960 for PV and AV respectively. Finally, the explicit formulations for PV and AV were determined by nonlinear least squares fitting, and the rp could reach above 0.94 for two indicators.

Novel miniature transendoscopic telerobotic system for endoscopic submucosal dissection (with videos).

BACKGROUND AND AIMS: The lack of tissue traction and instrument dexterity to allow for adequate visualization and effective dissection were the main issues in performing endoscopic submucosal dissection (ESD). Robot-assisted systems may provide advantages. In this study we developed a novel transendoscopic telerobotic system and evaluated its performance in ESD. METHODS: A miniature dual-arm robotic endoscopic assistant for minimally invasive surgery (DREAMS) was developed. The DREAMS system contained the current smallest robotic ESD instruments and was compatible with the commercially available dual-channel endoscope. After the system was established, a prospective randomized controlled study was conducted to validate the performance of the DREAMS-assisted ESD in terms of efficacy, safety, and workload by comparing it with the conventional technique. RESULTS: Two robotic instruments can achieve safe collaboration and provide sufficient visualization and efficient dissection during ESD. Forty ESDs in the stomach and esophagus of 8 pigs were completed by DREAMS-assisted ESD or conventional ESD. Submucosal dissection time was comparable between the 2 techniques, but DREAMS-assisted ESD demonstrated a significantly lower muscular injury rate (15% vs 50%, P = .018) and workload scores (22.30 vs 32.45, P < .001). In the subgroup analysis of esophageal ESD, DREAMS-assisted ESD showed significantly improved submucosal dissection time (6.45 vs 16.37 minutes, P = .002), muscular injury rate (25% vs 87.5%, P = .041), and workload (21.13 vs 40.63, P = .001). CONCLUSIONS: We developed a novel transendoscopic telerobotic system, named DREAMS. The safety profile and technical feasibility of ESD were significantly improved with the assistance of the DREAMS system, especially in the narrower esophageal lumen.

Cardioprotective polyphenols from Geum japonicum var. chinense.

Seven undescribed tannins, namely gejaponin A-G, and one dehydrodigallic acid derivative 3,4-dihydroxy-5-(3,4,5-trihydroxy-1-ethoxycarbonyl phenoxy)benzoic acid, together with eighteen known polyphenols were isolated from the 95% ethanol extract of the aerial part of Geum japonicum Thunb. var. chinense F. Bolle. Their structures were elucidated on the basis of comprehensive analysis of UV, IR, NMR, HRMS, and CD spectroscopy experiments. To evaluate their bioactivities, sixteen major compounds were selected to intervene in hydrogen peroxide (H2O2)-induced oxidative damage on H9c2 rat cardiomyoblasts. Some compounds demonstrated high activity in this assay, of which, the known compounds 16 and 21 exhibited strong protective effects against H2O2-induced injury in H9c2 rat cardiomyoblasts, with a comparable cardioprotective activity as that of the positive control trimetazidine, thereby revealing cardioprotective activities from G. japonicum var. chinense.

Molecular mechanism of human ISG20L2 for the ITS1 cleavage in the processing of 18S precursor ribosomal RNA.

The exonuclease ISG20L2 has been initially characterized for its role in the mammalian 5.8S rRNA 3' end maturation, specifically in the cleavage of ITS2 of 12S precursor ribosomal RNA (pre-rRNA). Here, we show that human ISG20L2 is also involved in 18S pre-rRNA maturation through removing the ITS1 region, and contributes to ribosomal biogenesis and cell proliferation. Furthermore, we determined the crystal structure of the ISG20L2 nuclease domain at 2.9 Å resolution. It exhibits the typical αßα fold of the DEDD 3'-5' exonuclease with a catalytic pocket located in the hollow near the center. The catalytic residues Asp183, Glu185, Asp267, His322 and Asp327 constitute the DEDDh motif in ISG20L2. The active pocket represents conformational flexibility in the absence of an RNA substrate. Using structural superposition and mutagenesis assay, we mapped RNA substrate binding residues in ISG20L2. Finally, cellular assays revealed that ISG20L2 is aberrantly up-regulated in colon adenocarcinoma and promotes colon cancer cell proliferation through regulating ribosome biogenesis. Together, these results reveal that ISG20L2 is a new enzymatic member for 18S pre-rRNA maturation, provide insights into the mechanism of ISG20L2 underlying pre-rRNA processing, and suggest that ISG20L2 is a potential therapeutic target for colon adenocarcinoma.

Incorporating longitudinal history of risk factors into atherosclerotic cardiovascular disease risk prediction using deep learning.

Background: It is increasingly clear that longitudinal risk factor levels and trajectories are related to risk for atherosclerotic cardiovascular disease (ASCVD) above and beyond single measures. Currently used in clinical care, the Pooled Cohort Equations (PCE) are based on regression methods that predict ASCVD risk based on cross-sectional risk factor levels. Deep learning (DL) models have been developed to incorporate longitudinal data for risk prediction but its benefit for ASCVD risk prediction relative to the traditional Pooled Cohort Equations (PCE) remain unknown. Objective: To develop a ASCVD risk prediction model that incorporates longitudinal risk factors using deep learning. Methods: Our study included 15,565 participants from four cardiovascular disease cohorts free of baseline ASCVD who were followed for adjudicated ASCVD. Ten-year ASCVD risk was calculated in the training set using our benchmark, the PCE, and a longitudinal DL model, Dynamic-DeepHit. Predictors included those incorporated in the PCE: sex, race, age, total cholesterol, high density lipid cholesterol, systolic and diastolic blood pressure, diabetes, hypertension treatment and smoking. The discrimination and calibration performance of the two models were evaluated in an overall hold-out testing dataset. Results: Of the 15,565 participants in our dataset, 2,170 (13.9%) developed ASCVD. The performance of the longitudinal DL model that incorporated 8 years of longitudinal risk factor data improved upon that of the PCE [AUROC: 0.815 (CI: 0.782-0.844) vs 0.792 (CI: 0.760-0.825)] and the net reclassification index was 0.385. The brier score for the DL model was 0.0514 compared with 0.0542 in the PCE. Conclusion: Incorporating longitudinal risk factors in ASCVD risk prediction using DL can improve model discrimination and calibration.

Evaluation of multiple immunoassay formats for detection of anti-drug antibodies to zinpentraxin alfa.

Zinpentraxin alfa (rhPTX-2; PRM-151) is currently being developed for the treatment of fibrotic diseases such as idiopathic pulmonary fibrosis and myelofibrosis. Notably, because it is administered chronically and has an endogenously expressed counterpart, clinical studies of zinpentraxin alpha must include immunogenicity assessments. Since the typical homogenous bridging ELISA assay does not adequately measure anti-drug antibodies (ADAs) against zinpentraxin alfa, additional assay formats have been developed to evaluate immunogenicity of this therapeutic. Here, we present the evaluation of four distinct assay formats that were used to measure zinpentraxin alpha ADA: step-wise bridging, direct binding, total ADA, and the semi-homogeneous formats, based on multiple parameters including assay sensitivity, precision, and drug tolerance. This paper presents the full details of method development for each of the aforementioned assay formats including evaluation of sample pre-treatment, determination of cut point, and assessment of assay performance by analyzing a subset of clinical samples. Overall, the semi-homogenous ADA assay format with no sample pre-treatment was selected for the measurement of zinpentraxin alpha immunogenicity as it provided the desired sensitivity, drug tolerance, and reproducibility. Our study emphasizes the importance of assay format evaluation during drug development and the necessity to select the most suitable assay format and sample pre-treatment method by which to evaluate therapeutic drug immunogenicity.

Structural and biochemical insights into the interaction mechanism underlying HORMAD1 and its partner proteins.

The mammalian HORMA domain-containing protein 1 (HORMAD1) regulates DNA mismatch repair and homologous recombination (HR) repair in many cancers. Here, we show that the structure of human HORMAD1 adopts a self-closed conformation and displays an intra-molecular HORMA domain-closure motif interaction mode. Structural and biochemical data suggest that the interaction modes of the peptide motifs from HORMAD2 and MCM9 with HORMAD1 are highly similar to that of HORMAD1 own closure motif. The peptide motifs from diverse binding partners of HORMAD1 share a conserved Ser-Glu-Pro sequence. Additionally, structural comparison unveiled the HORMA-peptide motif interaction mode diversity among HORMA-containing proteins. Finally, cell-based assays revealed that this HORMA-closure motif interaction pattern contributes to DNA mismatch repair and is required for HORMAD1-dependent HR repair. Together, our results provide structural and biochemical insights into the common theme and functional plasticity of the HORMA domain-containing protein family, and also reveal a universal regulation mechanism for HORMAD1.

Knowledge, attitude, and practice of monitoring early gastric cancer after endoscopic submucosal dissection.

BACKGROUND: Early gastric cancer (EGC) is typically treated with endoscopic submucosal dissection (ESD). However, recurrence may occur after ESD, requiring surveillance. AIM: To examine the knowledge, attitude, and practice (KAP) of EGC survivors following ESD regarding gastric cancer recurrence. METHODS: This cross-sectional study was conducted between June 1, 2022 and October 1, 2022 in Zhejiang, China. A total of 400 EGC survivors who underwent ESD at the Affiliated Jinhua Hospital, Zhejiang University School of Medicine participated in this study. A self-administered questionnaire was developed to assess KAP monitoring gastric cancer after ESD. RESULTS: The average scores for KAP were 3.34, 23.76, and 5.75 out of 5, 30, and 11, respectively. Pearson correlation analysis revealed positive and significant correlations between knowledge and attitude, knowledge and practice, and attitude and practice (r = 0.405, 0.511, and 0.458, respectively; all P < 0.001). Multivariate logistic regression analysis showed that knowledge, attitude, 13-24 mo since the last ESD (vs ≤ 12 mo since the last ESD), and ≥ 25 mo since the last ESD (vs ≤ 12 mo since the last ESD) were independent predictors of proactive practice (odds ratio = 1.916, 1.253, 3.296, and 5.768, respectively, all P < 0.0001). CONCLUSION: EGC survivors showed inadequate knowledge, positive attitude, and poor practices in monitoring recurrences after ESD. Adequate knowledge, positive attitude, and a longer time since the last ESD were associated with practice.

Safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine (RQ3013) given as the fourth booster following three doses of inactivated vaccines: a double-blinded, randomised, controlled, phase 3b trial.

Background: Heterologous vaccine schedules have been recommended to provide superior immunity and protection against emergent SARS-CoV-2 variants of concern. We aimed to evaluate the safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine RQ3013 compared with adenoviral vectored vaccine Ad5-nCoV and protein subunit vaccine ZF2001 as the fourth dose in adults primed with three doses of inactivated vaccines in China. Methods: We conducted a double-blinded, randomised, controlled, phase 3b trial among healthy Chinese adults at Lancang County, Yunnan, China. Adults who had received three doses of inactivated COVID-19 vaccines at least 6 months prior were randomly allocated (3:1:1) to receive heterologous boosters with RQ3013, Ad5-nCoV, or ZF2001. We assessed safety within 28 days post boost and the serum geometric mean titres (GMTs) of neutralising antibodies (NAbs) against the live SARS-CoV-2 omicron variant BA.5 on day 14 post-boost. We used Poisson regression to assess the vaccine efficacy against the first episode of virologically confirmed symptomatic COVID-19 occurring at least 7 days post boost. Subgroup analyses categorized by age and sex were also performed for safety and immunogenicity outcomes. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2200065281) and is now complete. Findings: Between December 12 and December 18, 2022, a total of 1382 adults were screened, and 1250 were enrolled and randomly assigned to receive one dose of RQ3013 (n = 750), Ad5-nCoV (n = 250), or ZF2001 (n = 250). Although solicited adverse reactions within 28 days post boost were more frequent in the RQ3013 group (175 [23.3%]) compared to the control groups (24 [9.6%] in both the Ad5-nCOV and ZF2001 groups, P < 0.05), incidences of Grade 3 events were low (9 [0.7%]) and comparable across three groups (P > 0.05). On day 14 post-boost, RQ3013 (GMT 69.14, 95% CI 47.90-99.81) elicited 4.8-fold and 5.6-fold higher concentrations of NAbs against BA.5 than did Ad5-nCoV (14.37, 7.78-26.56) and ZF2001 (12.21, 5.13-29.06), respectively. On day 28 post-boost, RQ3013 demonstrated a relative efficacy of 62.2% (95% CI 13.7-83.1, P = 0.02) compared to Ad5-nCoV, and of 69.0% (33.5-85.7, P = 0.002) compared to ZF2001. Interpretation: The administrations of all the three heterologous boosters were well tolerated. The heterologous prime-boost regimen with RQ3013 elicited superior immune responses and demonstrated better protection against symptomatic SARS-CoV-2 infections compared with Ad5-nCoV or ZF2001, supporting the use of RQ3013 as a booster vaccination in adults. Funding: Yunnan Province Science and Technology Department (grant no.202302AA310047).

MicroRNA-9-1 Attenuates Influenza A Virus Replication via Targeting Tankyrase 1.

An unstable influenza genome leads to the virus resistance to antiviral drugs that target viral proteins. Thus, identification of host factors essential for virus replication may pave the way to develop novel antiviral therapies. In this study, we investigated the roles of the poly(ADP-ribose) polymerase enzyme, tankyrase 1 (TNKS1), and the endogenous small noncoding RNA, miR-9-1, in influenza A virus (IAV) infection. Increased expression of TNKS1 was observed in IAV-infected human lung epithelial cells and mouse lungs. TNKS1 knockdown by RNA interference repressed influenza viral replication. A screen using TNKS1 3'-untranslation region (3'-UTR) reporter assays and predicted microRNAs identified that miR-9-1 targeted TNKS1. Overexpression of miR-9-1 reduced influenza viral replication in lung epithelial cells as measured by viral mRNA and protein levels as well as virus production. miR-9-1 induced type I interferon production and enhanced the phosphorylation of STAT1 in cell culture. The ectopic expression of miR-9-1 in the lungs of mice by using an adenoviral viral vector enhanced type I interferon response, inhibited viral replication, and reduced susceptibility to IAV infection. Our results indicate that miR-9-1 is an anti-influenza microRNA that targets TNKS1 and enhances cellular antiviral state.

PI3K/AKT pathway-related microRNA variants in childhood acute lymphoblastic leukemia.

BACKGROUND: Dysregulation of microRNAs (miRNAs) targeting genes in the PI3K/Akt pathway has been implicated in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). However, the impact of genetic variants in these miRNAs on ALL susceptibility has not been extensively explored in the Chinese population. METHODS: To address this gap, we conducted a case-control study to evaluate the association between genetic variants in five PI3K/AKT pathway-related miRNAs (miR-149, miR-126, miR-492, miR-612, and miR-423) and childhood ALL susceptibility in the Chinese population. Additionally, we investigated the effects of the rs2292832 mutation on ALL cell proliferation and apoptosis. RESULTS: Our analyses revealed that the miR-149 rs2292832 mutant heterozygous CT genotype was more frequent in the control group than in the ALL cases, indicating a protective effect against ALL (adjusted odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63-0.97, p = .024). Stratification analyses further revealed that the miR-149 rs2292832 CC genotype was associated with an increased risk of childhood ALL in subgroups of older children, females, those with parents who never smoked or drank alcohol, those living in painted houses, those with B-ALL, and those with high-risk ALL. Finally, we observed that the rs2292832 mutation inhibited ALL cell proliferation and induced apoptosis (p = .001), providing a potential mechanism by which this genetic variant may influence ALL susceptibility. CONCLUSION: Our study highlights the significant association between the miR-149 rs2292832 genetic variant and childhood ALL susceptibility in the Chinese population. These findings expand our understanding of the complex genetic landscape underlying ALL and have implications for the development of personalized therapeutic strategies.

Structural and biochemical insights into the molecular mechanism of TRPT1 for nucleic acid ADP-ribosylation.

Nucleic acid ADP-ribosylation has been established as a novel modification found in a wide diversity of prokaryotic and eukaryotic organisms. tRNA 2'-phosphotransferase 1 (TRPT1/TPT1/KptA) possesses ADP-ribosyltransferase (ART) activity and is able to ADP-ribosylate nucleic acids. However, the underlying molecular mechanism remains elusive. Here, we determined crystal structures of TRPT1s in complex with NAD+ from Homo sapiens, Mus musculus and Saccharomyces cerevisiae. Our results revealed that the eukaryotic TRPT1s adopt common mechanisms for both NAD+ and nucleic acid substrate binding. The conserved SGR motif induces a significant conformational change in the donor loop upon NAD+ binding to facilitate the catalytic reaction of ART. Moreover, the nucleic acid-binding residue redundancy provides structural flexibility to accommodate different nucleic acid substrates. Mutational assays revealed that TRPT1s employ different catalytic and nucleic acid-binding residues to perform nucleic acid ADP-ribosylation and RNA 2'-phosphotransferase activities. Finally, cellular assays revealed that the mammalian TRPT1 is able to promote endocervical HeLa cell survival and proliferation. Together, our results provide structural and biochemical insights into the molecular mechanism of TRPT1 for nucleic acid ADP-ribosylation.

Pharbitidis Semen: A review of botany, traditional uses, phytochemistry, pharmacology, and toxicology.

ETHNOPHARMACOLOGICAL RELEVANCE: Pharbitidis Semen (the seeds of Ipomoea nil (L.) Roth or Ipomoea purpurea (L.) Roth), a popular traditional Chinese medicine, is also known as "Heichou" or "Baichou" (Chinese: , ). It can purge the bowels, promote diuresis, remove stagnated accumulation, and kill worms. It can be used for treating anasarca with constipation and oliguria; dyspnea and cough caused by retained fluid; abdominal pain because of intestinal parasitosis; ascariasis; and taeniasis. AIMS: This review discusses the botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control of Pharbitidis Semen, to obtain a complete understanding of its effects and provide a basis for further research and the development of new drugs. MATERIALS AND METHODS: The literature on Pharbitidis Semen is mainly obtained from pharmacopoeias of different countries, masterpieces of traditional Chinese medicine, Master's and Ph.D. theses, and published articles obtained from literature retrieval websites, such as CNKI, PubMed, SciFinder, WanFang data, Web of Science, Springer, ScienceDirect, Wiley, ACS Publications, Taylor & Francis, J-STAGE, and Google Scholar. Its botany, ethnopharmacology, phytochemistry, pharmacological activities, toxicology, and quality control are discussed to understand its effects and provide a basis for further research. RESULTS: Pharbitidis semen has been used ethnomedically in many tropical and subtropical countries as deobstruents, diuretics, and anthelmintics. About 170 chemical compounds, including terpenoids, phenylpropanoids, resin glycosides, fatty acids and other compounds, have been isolated. It has been reported to have different effects, including laxative, renal-protective, neuroprotective, insecticidal, antitumor, anti-inflammatory, and antioxidant. Moreover, a brief introduction to processing, toxicity, and quality control is provided. CONCLUSIONS: The traditional efficacy of Pharbitidis Semen in diarrhea has been confirmed, but its bioactive and toxic ingredients are not entirely clear. It is necessary to strengthen the research and identification of effective parts or natural active components of Pharbitidis Semen, clarify the molecular mechanism of its toxicity and change rule of endogenous substances to make Pharbitidis Semen better used in clinical practice. Additionally, the imperfect quality standard is also a challenge that must be solved urgently. The study of modern pharmacology has broadened the application of Pharbitidis Semen and provided ideas for better utilization of this resource.

Transmission routes and patterns of helicobacter pylori.

BACKGROUND AND OBJECTIVE: Helicobacter pylori (H. pylori), a gram-negative bacterium that colonizes the stomach, can cause chronic gastritis and peptic ulcers, as well as gastric cancer as a Class I carcinogen. However, the modes of H. pylori transmission are not clear. This review aims to clarify the transmission routes and patterns of H. pylori and identify efficacious prevention measures. METHODS: Studies of H. pylori transmission were identified using PubMed, the Web of Science, and Cochrane Central; the retrieval deadline was October 2022. RESULTS: The transmission routes of H. pylori are discussed, focusing on the five primary transmission routes, namely fecal-oral, oral-oral, gastric-oral, anal-oral, and genital-oral. We propose that H. pylori is contracted through multiple transmission routes. Additionally, we summarize the key transmission patterns of H. pylori, including person-to-person and animal-to-human transmission, as well as foodborne and occupational exposure. CONCLUSION: Fecal-oral appears to be the most common H. pylori transmission routes. Although the oral-oral pathway is also important, the evidence does not support that this route of transmission is universal. The gastric-oral route occurs primarily in children and patients who are prone to vomiting. Meanwhile, the anal-oral and genital-oral routes remain hypothetical. Person-to-person and foodborne infections represent the predominant transmission patterns of H. pylori, whereas strong environmental and occupational limitations are associated with animal-to-human and occupational exposure.