While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by ...tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene
knockout (KO) mutant
unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR
) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR-mediated signaling pathway elevated the expression of
,
, and
genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
There is limited evidence on which immunosuppressive agents produce the best outcomes for adult patients with steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS). This review ...compares the remission rate and adverse effects of various immunosuppressants used. Studies of adult patients with biopsy-proven SDNS/FRNS, administered any immunosuppressive agents and reported complete remission results as one of the clinical outcomes were included. Articles were independently screened by two researchers. ROBINS-I was used for risk of bias assessment. Random-effects model was used for statistical analysis and corresponding 95% confidence intervals (CIs) were calculated. 574 patients across 28 studies were included in the analysis. Patients receiving rituximab have a complete remission rate of 89% (95% CI = 83% to 94%; tau2 = 0.0070; I2 = 62%; overall p < 0.01, low certainty) and adverse event rate of 0.26, cyclosporine (CR 40%; 95% CI = 21% to 59%; tau2 = 0.0205; I2 = 55%; overall p = 0.08, low certainty), tacrolimus (CR 84%; 95% CI = 70% to 98%; tau2 = 0.0060; I2 = 33%; overall p = 0.21, moderate certainty), mycophenolate mofetil (CR 82%; 95% CI = 74% to 90%; tau2 < 0.0001; I2 = 15%; overall p = 0.32, moderate certainty) and cyclophosphamide (CR 79%; 95% CI = 69% to 89%; tau2 = 0; I2 = 0%; overall p = 0.52, moderate certainty). Among the commonly used immunosuppressive agents, only rituximab has a statistically significant effect in achieving complete remission among patients with SDNS/FRNS and has a relatively good safety profile, but this is limited by low quality of evidence with high degree of heterogeneity causing a lack of statistical power.
The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDH defines a distinct subtype of glioma and predicts therapeutic response. IDH mutation ...has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n = 220), immunohistochemistry staining (IHC, n = 220), and gas chromatography mass spectrometry (GC-MS, n = 87) were applied to identify IDH mutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1 mutation in gliomas, but both methods usually take 1–2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1 mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.
Objective
To determine the efficacy of CXCL5 administration in lupus‐prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms.
Methods
CXCL5 expression in blood (obtained from SLE patients ...and Faslpr mice) and major internal organs (obtained from Faslpr mice) was examined by Luminex, real‐time polymerase chain reaction, and immunofluorescent staining analyses. Pharmacokinetic studies were performed in Faslpr mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Faslpr mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing.
Results
In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (P < 0.0001) and negatively correlated with disease activity (P = 0.004). In Faslpr mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Faslpr mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti–double‐stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short‐term (10 weeks) and long‐term (2 years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5‐mediated immunomodulation occurred by promoting energy production in renal‐infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals.
Conclusion
We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid/neutrophil‐targeting therapy for SLE.
A series of connection with screw fasteners were tested to study the behavior of cold-formed steel moment connection. The test specimens included hot-rolled parallel flange channels, cold-formed ...lipped C-Channels, and self-drilling self-fastening screws. Two different lipped C-Channels and a various number of screws per connection were used in this study. The moment-rotation behavior, rotational rigidity, and the connection capacity differed with the number of screws. The connection behaved as a pinned connection when 4 screws were used. However, local buckling was observed in the cold-formed steel sections near the connection when 8, 10 and 14 screws were used. The connection test results were compared with theoretical results calculated in accordance to the Australian Standards. None of the connection tested could achieve the moment capacity of the section connected.
Abstract
Background
National health campaigns are often used to improve lifestyle behaviors in the general population. However, evidence specifically in the young adult population is scarce. Given ...the general deterioration of healthy lifestyle practices from adolescence to young adulthood, it is imperative to study this age group. This study aimed to investigate the behavioral impact of a national health campaign in Singapore on the lifestyle practices of young adults, and whether sex or full-time working and schooling status affected lifestyle practices.
Methods
A total of 594 Singaporean respondents aged 18–39 years old were interviewed via a cross-sectional study in December 2019. Lifestyle practices assessed were diet, exercise, alcohol consumption, current tobacco use, and participation in health screening programs. Other factors investigated included exposure to the national health campaign “War on Diabetes” (WoD), sex, ethnicity, and working/schooling status. Multivariable modified Breslow-Cox proportional hazards models were used to estimate prevalence risk ratios (PRRs) as measures for the associations in this study, after adjusting for potential confounders.
Results
Exposure to the WoD campaign had a significant association with meeting dietary recommendations (PRR = 1.6, 95% CI: 1.0–2.5,
p
= 0.037), participation in screening (PRR = 1.2, 95% CI: 1.0–1.5,
p
= 0.028), and current tobacco use (PRR = 0.5, 95% CI: 0.3–0.8,
p
= 0.003). Males were significantly more likely to meet exercise recommendations (PRR = 2.0, 95% CI: 1.5–2.7,
p
< 0.001), currently use tobacco (PRR = 3.9, 95% CI: 2.2–6.9, p < 0.001), and consume alcohol excessively (PRR = 1.5, 95% CI: 1.0–2.3,
p
= 0.046), as compared to females. Working young adults were significantly less likely to meet exercise recommendations (PRR = 0.7, 95% CI: 0.5–0.9,
p
= 0.019) but significantly more likely to be current tobacco users (PRR = 1.8, 95% CI: 1.1–3.1,
p
= 0.024), as compared to those who were in school.
Conclusions
While this paper affirms that national health campaigns have significant beneficial associations in diet, health screenings and current tobacco use, policymakers should acknowledge that young adults are an age group with different influences that impact their healthy lifestyle habits. Specific interventions that target these subgroups may be required for better health outcomes. Future studies should evaluate other socio-environmental factors that could play a role in modifying the effect of health campaigns among young adults.
Objective The purpose of this study was to look into the associations between lifestyle factors, gender, clinical level, and sleep quality among undergraduate dental students at a private university ...in Malaysia.
Material and Methods A self-administered Pittsburg sleep quality index (PSQI) scale and the lifestyle and habits questionnaire-brief (LHQ-B) were used in this cross-sectional study. A global PSQI score of greater than 5 indicates poor sleep quality. All university dental students were invited to take part. Descriptive statistics and logistic regression analyses were used to analyze the data.
Results A total of 338 students took part in the study, with a response rate of 90.4%. The proportion of females was higher (68.3 %) and more than half of the respondents (56.7 %) were in their clinical years. The prevalence of poor sleep quality was 36.7%. At multivariable level, poor sleep quality was associated with being male (OR=1.72 95% confidence interval (1.05, 2.83) and engaging in an unhealthy lifestyle for psychological health (OR=2.64 95% confidence interval (1.34, 5.21) and nutrition (OR=2.48 95% confidence interval (1.028, 4.82).
Conclusion The prevalence of poor sleep quality among undergraduate dental students in our study was comparable to that found in other studies. Male students were more likely to have poor sleep quality than female students. Our findings indicate that poor sleep quality (PSQI score >5) may be linked to unhealthy lifestyle habits related to psychological health and nutrition. Health education that emphasizes these domains is essential for improving their lifestyle habits and sleep quality.
IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas ...predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.
Recurrence and progression to higher grade lesions are characteristic behaviors of gliomas. Though IDH1 mutation frequently occurs and is considered as an early event in gliomagenesis, little is ...known about its role in the recurrence and progression of gliomas. We therefore analysed IDH1 and IDH2 status at codon 132 of IDH1 and codon 172 of IDH2 by direct sequencing and anti-IDH1-R132H immunohistochemistry in 53 paired samples and their recurrences, including 29 low-grade gliomas, 16 anaplastic gliomas and 8 Glioblastomas. IDH1/IDH2 mutation was detected in 32 primary tumors, with 25 low-grade gliomas and 6 anaplastic gliomas harboring IDH1 mutation and 1 low-grade glioma harboring IDH2 mutation. All of the paired tumors showed consistent IDH1 and IDH2 status. Patients were analyzed according to IDH1 status and tumor-related factors. Malignant progression at recurrence was noted in 22 gliomas and was not associated with IDH1 mutation. Survival analysis revealed patients with IDH1 mutated gliomas had a significantly longer progression-free survival (PFS) and overall survival (OS). In conclusion, this study demonstrated a strong tendency of IDH1/IDH2 status being consistent during progression of glioma. IDH1 mutation was not a predictive marker for malignant progression and it was a potential prognostic marker for gliomas of Chinese patients.
Dengue fever is currently the most prevalent disease caused by mosquito-borne flaviviruses. Despite being potentially fatal, there are no specific antiviral therapies for Dengue virus (DENV) ...infections. Therefore, early, accurate, and rapid diagnosis plays an important role in proper patient management. In this study, we evaluated the performance of a probe-based real-time RT-PCR (rRT-PCR) assay against that of a conventional RT-PCR assay in three sample cohorts from Pakistan (n = 94) and Singapore (first cohort; n = 559, second cohort; n = 123). The Pakistan cohort also included a comparison with virus isolation. The rRT-PCR assay showed relatively lower overall sensitivity (20.2%) in the Pakistan cohort than that in first (90.8%) and second (80.5%) Singapore cohorts. Surprisingly, the overall sensitivity of rRT-PCR assay was lower compared with the virus isolation (26.6%) among Pakistan samples, indicating a high percentage (79.8%) of false negatives due to rRT-PCR assay. The analysis of sequences of failed and successful DENV isolates indicated mismatches in probe binding regions as the likely cause of rRT-PCR assay failure. Our observations testify the importance of utilizing a combination of methods for dengue diagnostics and surveillance. We emphasize that a thorough understanding of the genetic composition of local DENV populations as well as regular monitoring of the performance and reviewing of probe/primer sequences are essential to maintain a consistently high diagnostic accuracy of PCR-based assays.
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