Explore the vast range of titles available.

Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 ( N ( α )-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro . Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

SPARC is being designed to operate with a normalized beta of $\\beta _N=1.0$, a normalized density of $n_G=0.37$ and a safety factor of $q_{95}\\approx 3.4$, providing a comfortable margin to their respective disruption limits. Further, a low beta poloidal $\\beta _p=0.19$ at the safety factor $q=2$ surface reduces the drive for neoclassical tearing modes, which together with a frozen-in classically stable current profile might allow access to a robustly tearing-free operating space. Although the inherent stability is expected to reduce the frequency of disruptions, the disruption loading is comparable to and in some cases higher than that of ITER. The machine is being designed to withstand the predicted unmitigated axisymmetric halo current forces up to 50 MN and similarly large loads from eddy currents forced to flow poloidally in the vacuum vessel. Runaway electron (RE) simulations using GO+CODE show high flattop-to-RE current conversions in the absence of seed losses, although NIMROD modelling predicts losses of ${\\sim }80$ %; self-consistent modelling is ongoing. A passive RE mitigation coil designed to drive stochastic RE losses is being considered and COMSOL modelling predicts peak normalized fields at the plasma of order $10^{-2}$ that rises linearly with a change in the plasma current. Massive material injection is planned to reduce the disruption loading. A data-driven approach to predict an oncoming disruption and trigger mitigation is discussed.

The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$ T), compact ($R_0 = 1.85$ m, $a = 0.57$ m), superconducting, D-T tokamak with the goal of producing fusion gain $Q>2$ from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of $Q>2$ is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of $H_{98,y2} = 1$, SPARC is projected to attain $Q \\approx 11$ and $P_{\\textrm {fusion}} \\approx 140$ MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\\langle n_{e} \\rangle \\approx 3 \\times 10^{20}\\ \\textrm {m}^{-3}$), high temperature ($\\langle T_e \\rangle \\approx 7$ keV) and high power density ($P_{\\textrm {fusion}}/V_{\\textrm {plasma}} \\approx 7\\ \\textrm {MW}\\,\\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.

This study examines the ways in which parental involvement in children's education changes over time and how it relates to children's social and academic functioning in school. Teachers provided information on parent involvement and school performance for 1,205 urban, kindergarten through third‐grade children for 3 consecutive years. They rated the following four dimensions of parent involvement: frequency of parent‐teacher contact, quality of the parent‐teacher interactions, participation in educational activities at home, and participation in school activites. As predicted, the frequency of parent‐teacher contacts, quality of parent‐teacher interactions, and parent participation at school declined from Years 1 to 3. Every parent involvement variable correlated moderately with school performance and parent involvement in Years 1 and 2, and accounted for a small, but significant amount of variance in Year 3 performance after controlling for initial performance level. Participation in educational activities at home predicted the widest range of performance variables. Results suggest that enhancing parental involvement in children's schooling relates to improvements in school functioning.

BackgroundPhysical and mechanical restraints used in treatment, care, education, and corrections programs for children are high-risk interventions primarily due to their adverse physical, emotional, and fatal consequences. ObjectiveThis study explores the conditions and circumstances of restraint-related fatalities in the United States by asking (1) Who are the children that died due to physical restraint? and (2) How did they die?MethodThe study employs internet search systems to discover and compile information about restraint-related fatalities of children and youth up to 18 years of age from reputable journalism sources, advocacy groups, activists, and governmental and non-governmental agencies. The child cohort from a published study of restraint fatalities in the United States from 1993 to 2003 is combined with restraint fatalities from 2004 to 2018. This study’s scope has expanded to include restraint deaths in community schools, as well as undiscovered restraint deaths from 1993 to 2003 not in the 2006 study.ResultsSeventy-nine restraint-related fatalities occurred over the 26-year period from across a spectrum of children’s out-of-home child welfare, corrections, mental health and disability services. The research provides a data snapshot and examples of how fatalities unfold and their consequences for staff and agencies. Practice recommendations are offered to increase safety and transparency.ConclusionsThe study postulates that restraint fatalities result from a confluence of medical, psychological, and organizational causes; such as cultures prioritizing control, ignoring risk, using dangerous techniques, as well as agencies that lack structures, processes, procedures, and resources to promote learning and to ensure physical and psychological safety.

Critical limb ischemia (CLI) is considered the most severe pattern of peripheral artery disease. It is defined by the presence of chronic ischemic rest pain, ulceration or gangrene attributable to the occlusion of peripheral arterial vessels. It is associated with a high risk of major amputation, cardiovascular events and death. In this review, we presented a complete overview about physiopathology, diagnosis and holistic management of CLI. Revascularization is the first-line treatment, but several challenging cases are not treatable by conventional techniques. Unconventional techniques for the treatment of complex below-the-knee arterial disease are described. Furthermore, the state-of-the-art on gene and cell therapy for the treatment of no-option patients is reported.

The current study examined the impact of a setting-level intervention on the prevention of aggressive or dangerous behavioral incidents involving youth living in group care environments. Eleven group care agencies implemented Children and Residential Experiences (CARE), a principle-based program that helps agencies use a set of evidence-informed principles to guide programming and enrich the relational dynamics throughout the agency. All agencies served mostly youth referred from child welfare. The 3-year implementation of CARE involved intensive agency-wide training and on-site consultation to agency leaders and managers around supporting and facilitating day-to-day application of the principles in both childcare and staff management arenas. Agencies provided data over 48 months on the monthly frequency of behavioral incidents most related to program objectives. Using multiple baseline interrupted time series analysis to assess program effects, we tested whether trends during the program implementation period declined significantly compared to the 12 months before implementation. Results showed significant program effects on incidents involving youth aggression toward adult staff, property destruction, and running away. Effects on aggression toward peers and self-harm were also found but were less consistent. Staff ratings of positive organizational social context (OSC) predicted fewer incidents, but there was no clear relationship between OSC and observed program effects. Findings support the potential efficacy of the CARE model and illustrate that intervening “upstream” at the setting level may help to prevent coercive caregiving patterns and increase opportunities for healthy social interactions.

The authors treated a case of bilateral accessory axillary breast tissue. Excision with histologic examination confirmed the diagnosis of fibroadenoma. Treatment left the woman with incision scars (3.5 cm) in the axillary pyramid, a location often not seen during a patient’s normal movements. Thus, despite a minor aesthetic incision, gives the advantage of complete histologic analysis was gained. Liposuction treatment was used in this case. The scar results were good.