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Though jamming transitions are long studied in condensed matter physics and granular systems, much less is known about active jamming (or unjamming), which commonly takes place in living materials. In this paper, we explore, by molecular dynamic simulations, the jamming–unjamming transition in a dense system of active semiflexible filaments. In particular, we characterize the distinct impact of polar vs nematic driving for different filament rigidities and at varying densities. Our results show that high densities of dynamic active filaments can be achieved by only changing the nature of the active force, nematic or polar. Interestingly, while polar driving is more effective at unjamming the system at high densities below confluency, we find that at even higher densities, nematic driving enhances unjamming compared to its polar counterpart. The effect of varying the rigidity of filaments is also significantly different in the two cases: While for nematic driving, lowering the bending rigidity unjams the system, we find an intriguing reentrant jamming–unjamming–jamming transition for polar driving as the filament rigidity is lowered. While the first transition (unjamming) is driven by softening due to reduced rigidity, the second transition (jamming) is a cooperative effect of ordering and coincides with the emergence of nematic order in the system. Together, through a generic model of self-propelled flexible filaments, our results demonstrate how tuning the nature of self-propulsion and flexibility can be employed by active materials to achieve high densities without getting jammed. [ABSTRACT FROM AUTHOR]

We previously identified a novel pathway of testosterone action via the androgen receptor (AR) in bone marrow mesenchymal precursor cells (BM-PCs) to negatively regulate fat mass and improve metabolic function in male mice. This was achieved using our PC-AR Gene Replacement mouse model in which the AR is only expressed in BM-PCs and deleted in all other tissues. We hypothesise that the marke dly reduced fat mass and increased insulin sensitivity of PC-AR Gene Replacements will confer protection from dietinduced overweight and obesity. To test this, 6-week-old male PC-AR Gene Replacements and controls (WT, global-AR knockouts (KOs)) were fed a chow or high-caloric diet (HCD) for 8 or 18 weeks. Following 8 weeks (short-term) of HCD, WT an d Global-ARKOs had markedly increased subcutaneous white adipose tissue (WAT) and retroperitoneal visceral adipose tissue (VAT) mass compared to chow-fed controls. In contrast, PC-AR Gene Replacements were resistant to WAT and VAT accumulation following short-term HCD feeding accompanied by fewer large adipocytes and upregulation of expression of the metabolic genes Acaca and Pnlpa2. Following long-term HCD feeding for 18 weeks, the PC-AR Gene Replacements were no longer resistant to increased WAT and VAT adiposity, however, maintained their improved whole-body insulin sensitivity with an increased rate of glucose disappearance and increased glucose uptake into subcutaneous WAT. In conclusion, the action of testosterone via the AR in BM-PCs to negatively regulate fat mass and improve metabolism confers resistance from short-term diet-induced weight gain and partial protection from long-term diet-induced obesity in male mice. [ABSTRACT FROM AUTHOR]

Summary: Obesity is associated with hypothalamic–pituitary–testicular axis dysregulation in males. Here, we summarize recent evidence derived from clinical trials and studies in preclinical animal models regarding the role of androgen receptor (AR) signaling in the pathophysiology of males with obesity. We also discuss therapeutic strategies targeting the AR for the treatment of obesity and their limitations and provide insight into the future research necessary to advance this field. [ABSTRACT FROM AUTHOR]

α-Amylase inhibitors (α-AIs) target α-amylases and interfere with the carbohydrate digestion of insects. Among different classes of α-AIs, a knottin-type inhibitor from Amaranthus hypochondriacus (AhAI) was found to be specific against coleopteran storage pests. In this report, we have characterized three previously unidentified knottin-type α-AIs from various Amaranthaceae plants namely, Amaranthus hypochondriacus (AhAI2), Alternanthera sessilis (AsAI) and Chenopodium quinoa (CqAI). They contain a signal peptide, pro-peptide, and mature peptide. The mature peptides of the new α-AIs shared 68 to 78% identity with AhAI and have highly variable pro-peptide regions. Along with the cystine-knot fold, they showed conservation of reactive site residues. All recombinant α-AIs were successfully expressed in their active form and native state using an oxidative cytoplasmic environment. Inhibition studies against various amylases revealed that these inhibitors showed selective inhibition of coleopteran recombinant insect α-amylases viz., Tribolium castaneum , and Callosobruchus chinensis. Tribolium castaneum α-amylase inhibition potency was highest for AhAI2 (Ki ~ 15 μM) followed by AsAI (Ki ~ 43 μM) and CqAI (Ki ~ 61 μM). Interaction analysis of these inhibitors illustrated that the reactive site of inhibitors make several non-covalent interactions with the substrate-binding pocket of coleopteran α-amylases. The selectivity of these inhibitors against coleopteran α-amylases highlights their potential in storage grain pest control. • Newly identified α-amylase inhibitors show the conserved knottin-type structure. • They are competitive, selective and specific inhibitors of coleopteran α-amylases. • An oxidizing cytoplasmic environment expressed active inhibitors in the native state. • Structural variations near enzyme active site contribute to inhibitor's specificity. [ABSTRACT FROM AUTHOR]

Introduction: Welding is an occupation associated with tremendous physical and chemical hazards. In spite of the risk involved, usage of Personal Protective Gears (PPGs) among welders in developing countries has been reported to be poor, due to their limited awareness of occupational hazards. Aim: To assess morbidity pattern, awareness of occupational hazards and usage practices of protective gears among welders. Materials and Methods: Cross-sectional study was conducted at welding sites from unorganized sector situated in and around Mangalore. A total of 155 welders chosen randomly from as many sites were interviewed at their workplace using a pilot tested structured interview schedule with both closed and open ended questions. Clinical examination of the participant and inspection of the work site was also done by the investigators. Statistical analysis used for analysis was Chi-Square test, unpaired t-test and ANOVA test. Results: Working >8 hours a day was reported by 30 (19.4%) welders. Overcrowding was present at 10.3%, ventilation status was inadequate at 6.9% and exhaust ventilation was not present at 25.9% sites. Awareness about occupational health hazards associated with welding was present among 97(62.6%) welders. Periodicity of medical examination was associated with awareness of occupational hazards among welders (p=0.032). First aid kit was present at 60 (38.7%) sites. The most common morbidity over the past year was wounds 119 (76.8%). Nonusage of most essential protective gears such as face shields, masks or eye goggles was seen among 18 (11.6%) welders. Mean number of morbidities over the past one month was found to be more, in those welders doing continuous work of ≥6 hours (p=0.05), at sites with overcrowding (p=0.002) and at sites where >10 welders work together (p=0.031). Conclusion: The period prevalence of morbidity was high among the welders surveyed. Ignorance of health hazards associated with occupation and non-usage of protective gears was reported by number of them. Therefore, health education and safety policies need to be strengthened at welding sites. [ABSTRACT FROM AUTHOR]

Human α-thrombin is a serine protease with dual functions. Thrombin acts as a procoagulant, cleaving fibrinogen to make the fibrin clot, but when bound to thrombomodulin (TM), it acts as an anticoagulant, cleaving protein C. A minimal TM fragment consisting of the fourth, fifth, and most of the sixth EGF-like domain (TM456m) that has been prepared has much improved solubility, thrombin binding capacity, and anticoagulant activity versus those of previous TM456 constructs. In this work, we compare backbone amide exchange of human α-thrombin in three states: apo, d-Phe-Pro-Arg-chloromethylketone (PPACK)-bound, and TM456m-bound. Beyond causing a decreased level of amide exchange at their binding sites, TM and PPACK both cause a decreased level of amide exchange in other regions including the γ-loop and the adjacent N-terminus of the heavy chain. The decreased level of amide exchange in the N-terminus of the heavy chain is consistent with the historic model of activation of serine proteases, which involves insertion of this region into the β-barrel promoting the correct conformation of the catalytic residues. Contrary to crystal structures of thrombin, hydrogen-deuterium exchange mass spectrometry results suggest that the conformation of apo-thrombin does not yet have the N-terminus of the heavy chain properly inserted for optimal catalytic activity, and that binding of TM allosterically promotes the catalytically active conformation. [ABSTRACT FROM AUTHOR]

Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs. [ABSTRACT FROM AUTHOR]

Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs. [ABSTRACT FROM AUTHOR]

Graph: Figure 5 BCL6, AR, and ESR1 influence DNA methylation at sDMRs. (a) Methylation levels in male and female Bcl6-LKO (4 females, 4 males) and controls Bcl6-flox mice (6 females, 4 males); (b) Methylation levels in ARKO mice (with genetic and gonadal male sex and genital female sex) and control male and female littermates (3 females, 4 males, and 3 ARKO mice); (c) Methylation levels in wild type controls, heterozygous and homozygous ESR1KO mice (WT: 3 females, 7 males; HET: 4 females, 4 males, KO: 6 females, 4 males). [Extracted from the article]