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Members of the ADF/cofilin family of regulatory proteins bind actin filaments cooperatively, locally change actin subunit conformation and orientation, and sever filaments at 'boundaries' between bare and cofilin-occupied segments. A cluster of bound cofilin introduces two distinct classes of boundaries due to the intrinsic polarity of actin filaments, one at the 'pointed' end-side and the other at the 'barbed' end-side of the cluster; severing occurs more readily at the pointed end side of the cluster ('fast-severing' boundary) than the barbed end side ('slow-severing' boundary). A recent electron-cryomicroscopy (cryo-EM) model of the slow-severing boundary revealed structural 'defects' at the interface that potentially contribute to severing. However, the structure of the fast-severing boundary remains uncertain. Here, we use extensive molecular dynamics simulations to produce atomic resolution models of both severing boundaries. Our equilibrated simulation model of the slow-severing boundary is consistent with the cryo-EM structural model. Our simulations indicate that actin subunits at both boundaries adopt structures intermediate between those of bare and cofilin-bound actin subunits. These 'intermediate' states have compromised intersubunit contacts, but the actin subunit interfaces lacking contacts at the slow-severing boundary are stabilized by cofilin bridging interactions, accounting for its lower fragmentation probability. Simulations where cofilin proteins are removed from cofilactin filaments favor a mechanism in which a cluster of two contiguously bound cofilins is needed to fully stabilize the cofilactin conformation, promote cooperative binding interactions, and accelerate filament severing. Together, these studies provide a molecular-scale foundation for developing coarse-grained and theoretical descriptions of cofilin-mediated actin filament severing.Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release "lipolysis products" that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of Thioredoxin Interacting Protein (TXNIP) degradation. This, in turn, selectively induces GLUT1 surface localization and glucose uptake in 3T3-L1 adipocytes, and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL), and not hormone-sensitive lipase (HSL) or monoacylglycerol lipase (MGL). Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.The eukaryotic kinase domain has multiple intrinsically disordered regions whose conformation dictates kinase activity. Small molecule kinase inhibitors (SMKIs) rely on disrupting the active conformations of these disordered regions to inactivate the kinase. While SMKIs are selected for their ability to cause this disruption, the allosteric effects of conformational changes in disordered regions is limited by a lack of dynamic information provided by traditional structural techniques. In this study, we integrated multi-scale molecular dynamics simulations with FRET sensors to characterize a novel allosteric mechanism that is selectively triggered by SMKI binding to the PKCα kinase domain. The indole maleimide inhibitors BimI and sotrastaurin were found to displace the Gly-rich loop (G-loop) that normally shields the ATP-binding site. Displacement of the Gly-rich loop interferes with a newly identified, structurally conserved binding pocket for the C1a domain on the N lobe of the kinase domain. This binding pocket, in conjunction with the N-terminal regulatory sequence, masks a diacylglycerol (DAG) binding site on the C1a domain. SMKI-mediated displacement of the Gly-rich loop released C1a and exposed the DAG binding site, enhancing PKCα translocation both to synthetic lipid bilayers and to live cell membranes in the presence of DAG. Inhibitor chemotype determined the extent of the observed allosteric effects on the kinase domain, and correlated with the extent of membrane recruitment. Our findings demonstrate the allosteric effects of SMKIs beyond the confines of kinase catalytic conformation, and provide an integrated computational-experimental paradigm to investigate parallel mechanisms in other kinases.Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand NO; sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera Liviidae), is a serious pest of citrus. The insect also transmits Candidatus Liberibacter asiaticus, the pathogen of a devastating citrus disease called Huanglongbing. Clonostachys rosea is a versatile fungus that possesses nematicidal and insecticidal activities. The effect of C. rosea against D. citri remains unclear. Here we examined the pathogenicity of C. rosea against D. citri adults. A mortality rate of 46.67% was observed in adults treated with 1 × 108 conidia/mL spore suspension. Comparative transcriptomic analyses identified 259 differentially-expressed genes (DEGs) between controls and samples treated with fungi. Among the DEGs, 183 were up-regulated and 76 down-regulated. Genes with altered expression included those involved in immunity, apoptosis and cuticle formation. Our preliminary observation indicated that C. rosea is virulent against ACP adults and has the potential as a biological control agent for ACP management in the field.Irisin is a novel myokine/adipokine that is released into the circulation in response to types of exercise and increases energy expenditure. Disorders in the endocrine system related to reproduction, which occur due to the chronic or excessive exercise, cause a decrease in women's sexual desire. However, the role of irisin hormone on sexual desire in women has not been elucidated. We hypothesized that chronic irisin exposure would decrease sexual incentive motivation for male partners by affecting the endocrine system in female rats. We tested this by quantifying and comparing of both sexual incentive motivation and active investigation for sexual partner, and also changes in the serum hormone levels in chronically irisin-treated female rats. As a result, chronic irisin exposure decreased the time spent near the male rat, male preference ratio, and male investigation preference ratio. Furthermore, serum testosterone and progesterone levels significantly decreased and estradiol levels increased while kisspeptin-1 levels were not changed by chronic irisin exposure in female rats. These data indicate that chronic irisin exposure may cause low sexual incentive motivation for opposite-sex partners in female rats via changes in reproductive hormones. The results suggest that irisin hormone may play a role in decreased sexual desire due to long-term exercise in women.
Intracerebroventricular (icv) injections are frequently used in neuroscience research. In addition to histological verification of the injection sites, administration of angiotensin II (ANG II) is often used to verify the injection placements. ANG II is a peptide hormone exerting dipsogenic effects, i.e., it increases drinking, when administered into the cerebral ventricles. This study investigated the accuracy of ANG II-induced drinking as a method to verify icv cannula placements.

Male C57BL/6J mice were implanted with cannulas in the lateral ventricle. Then, icv injections of ANG II were performed and drinking behavior of the mice was recorded. After the behavioral experiment, we histologically verified the cannula placements using dye injections. Based on this, mice were grouped in "icv" and "misplaced". The effects of icv and misplaced ANG II injections on drinking behavior were used to evaluate the accuracy of ANG II-induced drinking as a method to verify icv cannula placements.

In general, ANG II injections in mice with histologically verified icv cannula placements induced robust drinking responses, while misplaced injections did not. However, there were exceptions in both groups. In about one third of the mice, icv ANG II did not induce drinking or misplaced ANG II injections induced drinking, respectively.

These data demonstrated that ANG II-induced drinking is not a perfectly accurate method to verify icv cannula placements in mice. Therefore, we recommend to not base the decision of in- or excluding experimental subjects solely on this method, but also to histologically verify cannula placements.
These data demonstrated that ANG II-induced drinking is not a perfectly accurate method to verify icv cannula placements in mice. Therefore, we recommend to not base the decision of in- or excluding experimental subjects solely on this method, but also to histologically verify cannula placements.
Previous studies have identified sedentary behaviour, physical activity and eating habits as variables that define a healthy lifestyle. selleck chemicals llc The aims of this investigation were to determine the association between lifestyle and body dissatisfaction, as well as to test the mediating effect of fatness and fitness in this relationship in adolescents.

The sample comprised 2216 adolescents aged 13.1±0.90 years, of whom 980 were girls (age 13.1±0.86) and 1236 were boys (age 13.1±0.92). Body composition was measured by body mass index, neck circumference, waist to height ratio and body fat percentage, whereas physical activity, sedentary time, body dissatisfaction and eating habits were self-reported. Physical fitness was evaluated through the ALPHA-Fitness Battery.

The results showed that lifestyle was negatively related with body dissatisfaction. Moreover, physical fitness (β=-0.062; SE=0.022; 95% IC [-0.106, -0.017]) and fatness (β=-0.052; SE=0.011; 95% IC [-0.075, -0.032]) showed a significant mediation effect on the relationship between lifestyle and body dissatisfaction.
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