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Novel antitubercular agents are urgently needed to combat the emergence of global drug resistance to human tuberculosis. Mycobacterial membrane protein Large 3 (MmpL3) is a promising drug target because its activity is essential and required for cell-wall biosynthesis. Several classes of MmpL3 inhibitors have been developed against Mycobacterium tuberculosis (Mtb) with potent anti-tuberculosis activity. These include the drug candidate SQ109, which has progressed to phase IIb/III clinical trials. Here, we have determined the crystal structures of MmpL3 in complex with NITD-349 and SPIRO. Both inhibitors bind deep in the central channel of transmembrane domain and cause conformational changes to the protein. The amide nitrogen and indole nitrogen of NITD-349 and the piperidine nitrogen of SPIRO interact and clamp Asp645. Structural analysis of the two structures reveals that these inhibitors target the proton relay pathway to block the activity of MmpL3. The findings presented here enrich our understanding of the binding modes of MmpL3 inhibitors and provide directions to enable further rational drug design targeting MmpL3. Unlabelled Image • Crystal structures of MmpL3 in complex with NITD-349 and SPIRO are determined. • NITD-349 and SPIRO bind inside the proton-translocation channel of MmpL3. • This structural data for mycobacterial MmpL3 enable rational design of new tuberculosis drugs. [ABSTRACT FROM AUTHOR]

We investigated the association of parental physical activity (PA) trajectories with offspring's youth and adult PA. Self-reported PA data were extracted from the Young Finns Study with three follow-ups for parents between 1980 and 1986 and nine follow-ups for their offspring in youth between 1980 and 2011 (aged 9-39 years, n = 2402) and in adulthood in 2018. Accelerometer-derived PA was quantified in 2018-2020 (aged 43-58 years, n = 1134). Data were analyzed using mixture models and conducted in 2022. We identified three trajectories for fathers and mothers (high-stable activity, 20.2%/16.6%; moderate-stable activity, 50.5%/49.6%; and low-stable activity, 29.4%/33.7%) and four for youth male and female offspring (persistently active, 13.4%/5.1%; increasingly active, 32.1%/43.1%; decreasingly active, 14.4%/12.6%; and persistently low-active, 40.1%/39.1%). Compared to low-stable active parents, high-stable active fathers had a higher probability of having their sons and daughters classified as persistently active, increasingly active, and decreasingly active in youth (Brange = 0.50-1.79, all p < 0.008), while high- and moderate-stable active mothers had significantly increased likelihood of having their daughters classified as persistently active and decreasingly active in youth (Brange = 0.63-1.16, all p < 0.009). Fathers' and mothers' high-stable activity was associated with higher self-reported PA of adult offspring than parental low-stable activity. Persistently active and increasingly active offspring in youth accumulated more adult total PA, moderate-to-vigorous PA, step counts, and self-reported PA than persistently low-active ones (all p < 0.036). Parental persistent PA, particularly paternal persistent PA, predicts offspring's PA concurrently and prospectively. Increasing and maintaining PA in youth predicts higher PA levels in midlife. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The aims of the study were to describe the stability of active commuting (AC) behavior (i.e., walking and cycling) over 27years and examine the relationship between AC and physical activity (PA) from youth to early midlife. Methods: The mode and distance of travel were assessed using a self-reported questionnaire at five consecutive measurements between 1980 and 2007, when 2072 individuals were followed up from youth (9–18years) to adulthood (30–45years). PA was also measured using a questionnaire. Results: The prevalence of AC declined sharply with age, particularly after 12years, while AC distances to work or place of study increased substantially. AC was concurrently and prospectively associated with PA in both men and women. Maintained AC, whether walking or cycling and short or long distances, positively predicted adult PA over time. Compared with persistently passive commuters, persistently active commuters had higher adult PA after adjustment for potential covariates. Increasing AC was independently associated with high adult PA, particularly in young adulthood. Conclusions: Walking and cycling to school/work should be encouraged, as regular AC is associated with higher levels of PA over 27years of follow-up, and thus, may contribute to a healthy and active lifestyle through the various stages of life-course. [Copyright &y& Elsevier]

To elucidate the roles of adipose tissue and skeletal muscle in the early development of insulin resistance, we characterized gene expression profiles of isolated adipose cells and skeletal muscle of non-diabetic insulin-resistant first-degree relatives of type 2 diabetic patients using oligonucleotide microarrays. About 600 genes and expressed sequence tags, which displayed a gene expression pattern of cell proliferation, were differentially expressed in the adipose cells. The differentially expressed genes in the skeletal muscle were mostly related to the cellular signal transduction and transcriptional regulation. To verify the microarray findings, we studied expression of genes participating in adipogenesis. The expression of Wnt signaling genes, WNT1, FZD1, DVL1, GSK3β, β-catenin, and TCF1, and adipogenic transcription factors, C/EBPα and β and δ, PPARγ, and SREBP-1, was reduced in the adipose tissue. The expression of adipose-specific proteins related to terminal differentiation, such as adiponectin and aP2, was reduced both in the adipose tissue and in the adipose cells isolated from portions of the biopsies. The adipose cells were enlarged in the insulin-resistant relatives and the cell size inversely correlated with the expression of the Wnt signaling genes, adiponectin, and aP2. Our findings suggest that insulin resistance is associated with an impaired adipogenesis. [Copyright &y& Elsevier]

Uncoupling protein 5 (UCP5) or brain mitochondrial carrier protein-1 (BMCP1) enhances mitochondrial proton leak in vitro and its hepatic and brain expression profiles are modulated by diet and cold exposure in mice. Alternative splicing generates three isoforms: a long form (UCP5L), a short form (UCP5S), and a short form with a 31 amino acid insert (UCP5SI). We investigated the relationship between skeletal muscle UCP5 expression and in vivo energy metabolism in 36 non-diabetic Pima Indians. We determined the expression levels of total UCP5 (UCP5T), and the isoforms UCP5L, UCP5S, and UCP5SI (66.8, 32.5, and 0.8% of UCP5T, respectively). None correlated with body weight or percent body fat. The transcript level of UCP5SI, but not the others, was positively correlated with resting metabolic rate (r=0.38, P=0.02, adjusted for age, sex, fat mass, and fat-free mass) and lipid oxidation rate (adjusted for age, sex, and percent body fat) during a euglycemic clamp with infusion of insulin at a physiologic concentration (r=0.42, P=0.01). [Copyright &y& Elsevier]

The aim of this study was to examine the combined effects of sulfated β-Glucan from Saccharomyces cerevisiae (sGSC) on growth performance, antioxidant ability, nonspecific immunity, and intestinal flora of the red swamp crayfish (Procambarus clarkii). Four experimental diets (sGSC25, sGSC50, sGSC100 and sGSC200) with different levels of sGSC (0.025%, 0.05%, 0.1% and 0.2% in diet, respectively) were fed to juvenile crayfish (average weight: 2.5 ± 0.5 g) for 8 weeks. The control diet was given with 2000 mg/kg GSC (GSC200 group). The based control diet was given without sGSC or GSC (blank group). Each group had 3 parallel test pools, 20 crayfish were reared in each pool. At the end of the growth trial, adding dietary 0.025%–0.1% sGSC could significantly improve the growth performance, antioxidant capacity and immunity of crayfish. Compared with GSC, sGSC had a better effect at lower concentration. Higher concentration of sGSC (>0.1%) would cause some side effects. sGSC also could improve the structure of the intestinal flora and optimize the function of the flora. sGSC would increase the abundances of probiotics such as Hafnia and Acinetobacter , and decreases the abundances of maleficent bacteria such as Enterobacteriaceae. Higher concentration of sGSC (>0.1%) would increase the abundance of Aeromonas. To conclude, 0.025%–0.1% sGSC can be used as a supplement in crayfish feed to increase growth, immunity, and antioxidant capacity and improve the structure of intestinal flora. These results provided a theoretical basis for the application of sGSC instead of GSC in crayfish breeding. It will be necessary to further study the optimal concentration of sGSC in feed additives in different growth stages of crayfish in the future. • Dietary sGSC increased crayfish antioxidant ability and immunity. • Dietary sGSC increases probiotics and reduces harmful bacteria in intestinal flora. • There was dose-dependent on the dietary levels of sGSC for Procambarus clarkii. • The appropriate dietary level of sGSC was 0.025%–0.1%. [ABSTRACT FROM AUTHOR]

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00–0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04–0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, −0.07units/kg/day, 95% CI, −0.11 to −0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, −0.11units/kg/day, 95% CI, −0.23 to −0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D. [Display omitted] • Immunotherapies were associated with the preservation of 2 h and 4 h C-peptide AUC in patients with T1D. • Immunotherapies tended to reduce the daily insulin dosage in patients with T1D. • Immunotherapies did not increase the risk of hypoglycemia in patients with T1D. • TNF-a inhibitor and T cell-targeted immunotherapy might be promising game changers to delay the development of T1D. [ABSTRACT FROM AUTHOR]

Endosulfine α (ENSA) is an endogenous ligand of the sulfonylurea receptor 1 (SUR1) that can stimulate insulin secretion by pancreatic β cells. Originally, an intronless gene coding for this protein was assigned to Chr. 14q, but more recent information available in public databases indicated the position of ENSA on 1q21. We show here that the 1q21 locus represents the expressed gene consisting of 6 exons, whereas the locus on Chr. 14q is apparently a pseudogene. The ENSA gene on 1q21 produces several alternatively spliced transcripts, and is located within a region linked with T2DM in diverse populations including the Pima Indians. We analyzed ENSA in this Native American population and identified seven variants, which fall into three linkage disequilibrium groups. Analysis of representative markers in over 1200 Pima Indians did not reveal any significant association with T2DM, or with differences in insulin action and insulin secretion in a subset of approximately 270 non-diabetic subjects. In addition, we did not detect any significant correlation of skeletal muscle ENSA transcript levels with differences in insulin action in 49 non-diabetic subjects. We conclude that sequence alterations in ENSA are an unlikely cause for the linkage of T2DM with 1q21–q23 in the Pima Indians. [Copyright &y& Elsevier]