Bernardcross1588

Voluntary movements are believed to undergo preparation before they are executed. Preparatory activity can benefit reaction time and the quality of planned movements, but the neural mechanisms at work during preparation are unclear. Fluorescein-5-isothiocyanate For example, there are no overt changes in muscle force during preparation. Here, using an instructed-delay manual task, we demonstrate a decrease in human muscle afferent activity (primary spindles) when preparing to reach targets in directions associated with stretch of the spindle-bearing muscle. This goal-dependent modulation of proprioceptors began early after target onset but was markedly stronger at the latter parts of the preparatory period. Moreover, whole-arm perturbations during reach preparation revealed a modulation of stretch reflex gains (shoulder and upper arm muscles) that reflected the observed changes in spindle activity. We suggest that one function of central preparatory activity is to tune muscle stiffness according to task goals via the independent control of muscle spindle sensors.Mechanical stimuli on cells and mechanotransduction are essential in many biological and pathological processes. Glucocorticoid is an important hormone, roles, and mechanisms of which in cellular mechanotransduction remain unknown. Here, we report that glucocorticoid counteracted cellular mechanoresponses dependently on a novel long noncoding RNA (lncRNA), LINC01569 Further, LINC01569 mediated glucocorticoid effects on mechanotransduction by destabilizing messenger RNA (mRNA) of mechanosensors including early growth response protein 1 (EGR1), Cbp/P300-interacting transactivator 2 (CITED2), and bone morphogenic protein 7 (BMP7) in glucocorticoid receptor-mediated mRNA decay (GMD) manner. Mechanistically, LINC01569 directly bound to the GMD factor Y-box-binding protein 1 (YBX1). Then, the LINC01569-YBX1 complex was guided to the mRNAs of EGR1, CITED2, and BMP7 through specific LINC01569-mRNA interaction, thereby contributing to the successful assembly of GMD complex and triggering GMD. Our results uncovered roles of glucocorticoid in cellular mechanotransduction and novel lncRNA-dependent GMD machinery and provided potential strategy for early intervention in mechanical disorder-associated diseases.Soft and conformable optoelectronic devices for wearable and implantable electronics require mechanical stretchability. However, very few researches have been done for intrinsically stretchable light-emitting diodes. Here, we present an intrinsically stretchable organic light-emitting diode, whose constituent materials are all highly stretchable. The resulting intrinsically stretchable organic light-emitting diode can emit light when exposed to strains as large as 80%. The turn-on voltage is as low as 8 V, and the maximum luminance, which is a summation of the luminance values from both the anode and cathode sides, is 4400 cd m-2 It can also survive repeated stretching cycles up to 200 times, and small stretching to 50% is shown to substantially enhance its light-emitting efficiency.Enteric adenoviruses, one of the main causes of viral gastroenteritis in the world, must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We report the 4-Å-resolution structure of a human enteric adenovirus, HAdV-F41, and compare it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base, and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and nonhuman mastadenoviruses. Knowledge of the structure of enteric adenoviruses provides a starting point for the design of vectors suitable for oral delivery or intestinal targeting.Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. link2 Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state-specific therapy.Current therapeutic strategies such as angiogenic therapy and anti-inflammatory therapy for treating myocardial infarction have limited success. An effective approach may benefit from resolution of excessive inflammation combined with enhancement of angiogenesis. Here, we developed a microRNA-21-5p delivery system using functionalized mesoporous silica nanoparticles (MSNs) with additional intrinsic therapeutic effects. These nanocarriers were encapsulated into an injectable hydrogel matrix (Gel@MSN/miR-21-5p) to enable controlled on-demand microRNA-21 delivery triggered by the local acidic microenvironment. In a porcine model of myocardial infarction, we demonstrated that the released MSN complexes notably inhibited the inflammatory response by inhibiting the polarization of M1 macrophage within the infarcted myocardium, while further microRNA-21-5p delivery by MSNs to endothelial cells markedly promoted local neovascularization and rescued at-risk cardiomyocytes. The synergy of anti-inflammatory and proangiogenic effects effectively reduced infarct size in a porcine model of myocardial infarction.Previous results indicate the presence of an interferon (IFN) signature in type 1 diabetes (T1D), capable of inducing chronic inflammation and compromising b cell function. Here, we determined the expression of the IFN response markers MxA, PKR, and HLA-I in the islets of autoantibody-positive and T1D donors. We found that these markers can be coexpressed in the same islet, are more abundant in insulin-containing islets, are highly expressed in islets with insulitis, and their expression levels are correlated with the presence of the enteroviral protein VP1. The expression of these markers was associated with down-regulation of multiple genes in the insulin secretion pathway. The coexistence of an IFN response and a microbial stress response is likely to prime islets for immune destruction. This study highlights the importance of therapeutic interventions aimed at eliminating potentially persistent infections and diminishing inflammation in individuals with T1D.Ice-nucleating particles (INPs) in biomass-burning aerosol (BBA) that affect cloud glaciation, microphysics, precipitation, and radiative forcing were recently found to be driven by the production of mineral phases. BBA experiences extensive chemical aging as the smoke plume dilutes, and we explored how this alters the ice activity of the smoke using simulated atmospheric aging of authentic BBA in a chamber reactor. Unexpectedly, atmospheric aging enhanced the ice activity for most types of fuels and aging schemes. link3 The removal of organic carbon particle coatings that conceal the mineral-based ice-active sites by evaporation or oxidation then dissolution can increase the ice activity by greater than an order of magnitude. This represents a different framework for the evolution of INPs from biomass burning where BBA becomes more ice active as it dilutes and ages, making a larger contribution to the INP budget, resulting cloud microphysics, and climate forcing than is currently considered.Groundwater depletion is becoming a global threat to food security, yet the ultimate impacts of depletion on agricultural production and the efficacy of available adaptation strategies remain poorly quantified. We use high-resolution satellite and census data from India, the world's largest consumer of groundwater, to quantify the impacts of groundwater depletion on cropping intensity, a crucial driver of agricultural production. Our results suggest that, given current depletion trends, cropping intensity may decrease by 20% nationwide and by 68% in groundwater-depleted regions. Even if surface irrigation delivery is increased as a supply-side adaptation strategy, which is being widely promoted by the Indian government, cropping intensity will decrease, become more vulnerable to interannual rainfall variability, and become more spatially uneven. We find that groundwater and canal irrigation are not substitutable and that additional adaptation strategies will be necessary to maintain current levels of production in the face of groundwater depletion.Across academia, men and women tend to publish at unequal rates. Existing explanations include the potentially unequal impact of parenthood on scholarship, but a lack of appropriate data has prevented its clear assessment. Here, we quantify the impact of parenthood on scholarship using an extensive survey of the timing of parenthood events, longitudinal publication data, and perceptions of research expectations among 3064 tenure-track faculty at 450 Ph.D.-granting computer science, history, and business departments across the United States and Canada, along with data on institution-specific parental leave policies. Parenthood explains most of the gender productivity gap by lowering the average short-term productivity of mothers, even as parents tend to be slightly more productive on average than nonparents. However, the size of productivity penalty for mothers appears to have shrunk over time. Women report that paid parental leave and adequate childcare are important factors in their recruitment and retention. These results have broad implications for efforts to improve the inclusiveness of scholarship.Systemic AAV (adeno-associated virus) gene therapy is a promising approach for the treatment of inborn errors of metabolism, but questions remain regarding its potency and durability. Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been shown to block the formation of neutralizing anti-capsid antibodies, thereby enabling vector re-administration. Here, we further demonstrate that ImmTOR admixed with AAV vectors also enhances hepatic transgene expression at the initial dose of AAV vector, independent of its effects on adaptive immunity. ImmTOR enhances AAV trafficking to the liver, resulting in increased hepatic vector copy numbers and transgene mRNA expression. Enhanced transgene expression occurs through a mechanism independent of the AAV receptor and cannot be replicated in vivo with free rapamycin or empty nanoparticles. The multipronged mechanism of ImmTOR action makes it an attractive candidate to enable more efficient transgene expression at first dose while simultaneously inhibiting adaptive responses against AAV to enable repeat dosing.