Markov state models and NMR uncover an overlooked allosteric loop in p53.

The tumor suppressor p53 is the most frequently mutated gene in human cancer, and thus reactivation of mutated p53 is a promising avenue for cancer therapy. Analysis of wildtype p53 and the Y220C cancer mutant long-timescale molecular dynamics simulations with Markov state models and validation by NMR relaxation studies has uncovered the involvement of loop L6 in the slowest motions of the protein. Due to its distant location from the DNA-binding surface, the conformational dynamics of this loop has so far remained largely unexplored.

Effects of dominance and female presence on secondary sexual characteristics in male tufted capuchin monkeys ().

Alpha status may lead to physiological changes that enhance secondary sexual characteristics, which may serve as competitive signals to conspecific males, sexual signals to females, or possibly a combination of both. Here, we report measurements of secondary sexual characteristics in captive dominant and subordinate male tufted capuchin monkeys () with varying access to females. An adult male (who had previously been subordinate while housed with other males) was paired with an adult female.

Triage physicians in an academic emergency department: Impact on resident education.

Background: Overcrowding in emergency departments (EDs) in the United States has been linked to worse patient outcomes. Implementation of countermeasures such as a physician-in-triage (PIT) system have improved patient care and decreased wait times. The purpose of this study was to evaluate how a PIT system affects medical resident education in an academic ED.

Ciliary extracellular vesicles are distinct from the cytosolic extracellular vesicles.

Extracellular vesicles (EVs) are cell-derived membrane vesicles that are released into the extracellular space. EVs encapsulate key proteins and mediate intercellular signalling pathways. Recently, primary cilia have been shown to release EVs under fluid-shear flow, but many proteins encapsulated in these vesicles have never been identified.

Pilot study of an Alzheimer's disease risk assessment program in a primary care setting.

Introduction: The goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting.

Methods: Primary care providers (PCPs;  = 6) referred patients ( = 94; = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification.

"Energy is a Finite Resource": Designing Technology to Support Individuals across Fluctuating Symptoms of Depression.

While the HCI field increasingly examines how digital tools can support individuals in managing mental health conditions, it remains unclear how these tools can accommodate these conditions' temporal aspects. Based on weekly interviews with five individuals with depression, conducted over six weeks, this study identifies design opportunities and challenges related to extending technology-based support across fluctuating symptoms. Our findings suggest that participants perceive events and contexts in daily life to have marked impact on their symptoms.

Importance of thorough examination in foreign body exposure: An impressive case of asphyxiation with foam sealant.

Foreign body exposure requires a systematic exploration. There are no specific guidelines regarding cancer screening with prior toxin exposure. More research about the pathophysiology and management may further our knowledge and improve morbidity.

Seven practical strategies to add active learning to a science lecture.

Multiple research studies have shown active learning can increase student performance, reduce fail rates, and increase the success of marginalized students in STEM. In this mini-review we discuss a simple framework for planning and implementing active learning in the classroom. We provide seven strategies to support faculty members who want to implement this framework, with five suggested teaching activities and two mechanisms of creating space in the lecture to use the activities.

Longitudinal assessment of dementia measures in Down syndrome.

Introduction: Early detection of dementia symptoms is critical in Down syndrome (DS) but complicated by clinical assessment barriers. The current study aimed to characterize cognitive and behavioral impairment using longitudinal trajectories comparing several measures of cognitive and behavioral functioning.

Methods: Measures included global cognitive status (Severe Impairment Battery [SIB]), motor praxis (Brief Praxis Test [BPT]), and clinical dementia informant ratings (Dementia Questionnaire for People with Learning Disabilities [DLD]).

Development of a novel cognitive composite outcome to assess therapeutic effects of exercise in the EXERT trial for adults with MCI: The ADAS-Cog-Exec.

Introduction: Use of cognitive composites as primary outcome measures is increasingly common in clinical trials of preclinical and prodromal Alzheimer's disease (AD). Composite outcomes can decrease intra-individual variability, resulting in improved sensitivity to detect longitudinal change and increased statistical power. We developed a novel composite outcome, the ADAS-Cog-Exec, for use in the EXERT trial-a Phase 3 randomized, controlled, 12-month exercise intervention in mild cognitive impairment (MCI).

Feasibility of dual-task gait to estimate Alzheimer's related cognitive decline in Down syndrome.

Introduction: The striatum and frontal lobes have been shown to have early Alzheimer's disease (AD) neuropathology and are critical for motor and cognitive function. We hypothesized gait would be associated with early-stage dementia in Down syndrome (DS), a cohort at risk for AD.

Methods: Twenty-eight participants with DS were enrolled in the study.

Proteomic Identification Reveals the Role of Ciliary Extracellular-Like Vesicle in Cardiovascular Function.

Primary cilia are shown to have membrane swelling, also known as ciliary bulbs. However, the role of these structures and their physiological relevance remains unknown. Here, it is reported that a ciliary bulb has extracellular vesicle (EV)-like characteristics.

Channel Network Control on Seasonal Lake Area Dynamics in Arctic Deltas.

The abundant lakes dotting arctic deltas are hotspots of methane emissions and biogeochemical activity, but seasonal variability in lake extents introduces uncertainty in estimates of lacustrine carbon emissions, typically performed at annual or longer time scales. To characterize variability in lake extents, we analyzed summertime lake area loss (i.e.

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1.

Background: Spinocerebellar ataxia type 1 (SCA-ATXN1) is an inherited progressive ataxia disorder characterized by an adult-onset cerebellar syndrome combined with nonataxia signs. Retinal or optic nerve affection are not systematically described.

Objectives: To describe a retinal phenotype and its functional relevance in SCA-ATXN1.

Access to Academic Female Pelvic Medicine and Reconstructive Surgery Providers for New Patient Visits: How Long Are Wait Times?

Objectives: To determine the wait times to see an academic Female Pelvic Medicine and Reconstructive Surgery (FPMRS) urologist or gynecologist and to identify factors that may impact these wait times.

Methods: We reviewed all Accreditation Council for Graduate Medical Education accredited urology and gynecology residency programs. Offices of FPMRS providers were called to ascertain the earliest available new patient visit for a fictional female patient with "urine leakage.

Development of zirconium-89 PET for imaging of alpha-klotho.

Alpha-klotho is a single-pass membrane protein primarily expressed by the kidneys. Klotho deficiency in chronic kidney disease contributes to an accelerated aging phenotype. We report here development of [Zr]DFO-anti-klotho positron emission tomography (PET) imaging as a novel non-invasive method for assessing whole-body alpha-klotho distribution.

Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

Introduction: Disruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).

Methods: We examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS).

Association of Adverse Pregnancy Outcomes With Hypertension 2 to 7 Years Postpartum.

Background Identifying pregnancy-associated risk factors before the development of major cardiovascular disease events could provide opportunities for prevention. The objective of this study was to determine the association between outcomes in first pregnancies and subsequent cardiovascular health. Methods and Results The Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be Heart Health Study is a prospective observational cohort that followed 4484 women 2 to 7 years (mean 3.

SiRNA silencing of VEGF, IGFs, and their receptors in human retinal microvascular endothelial cells.

Vascular endothelial growth factor (VEGF) is a potent mitogen that regulates proliferation, migration, and tube formation of endothelial cells (EC). VEGF has recently become a target for severe retinopathy of prematurity (ROP) therapy. We tested the hypothesis that a specific VEGF isoform and/or receptor acts synergistically with insulin-like growth factor (IGF)-I to alter normal retinal microvascular EC angiogenesis and RNA interference can be used to reverse VEGF effects.

LOFAR Lightning Imaging: Mapping Lightning With Nanosecond Precision.

Lightning mapping technology has proven instrumental in understanding lightning. In this work we present a pipeline that can use lightning observed by the LOw-Frequency ARray (LOFAR) radio telescope to construct a 3-D map of the flash. We show that LOFAR has unparalleled precision, on the order of meters, even for lightning flashes that are over 20 km outside the area enclosed by LOFAR antennas (∼3,200 km), and can potentially locate over 10,000 sources per lightning flash.

Vulnerability of Southeast Greenland Glaciers to Warm Atlantic Water From Operation IceBridge and Ocean Melting Greenland Data.

We employ National Aeronautics and Space Administration (NASA)'s Operation IceBridge high-resolution airborne gravity from 2016, NASA's Ocean Melting Greenland bathymetry from 2015, ice thickness from Operation IceBridge from 2010 to 2015, and BedMachine v3 to analyze 20 major southeast Greenland glaciers. The results reveal glacial fjords several hundreds of meters deeper than previously thought; the full extent of the marine-based portions of the glaciers; deep troughs enabling warm, salty Atlantic Water (AW) to reach the glacier fronts and melt them from below; and few shallow sills that limit the access of AW. The new oceanographic and topographic data help to fully resolve the complex pattern of historical ice front positions from the 1930s to 2017: glaciers exposed to AW and resting on retrograde beds have retreated rapidly, while glaciers perched on shallow sills or standing in colder waters or with major sills in the fjords have remained stable.

Photochemistry of Solid Films of the Neonicotinoid Nitenpyram.

The environmental fates of nitenpyram (NPM), a widely used neonicotinoid insecticide, are not well-known. A thin solid film of NPM deposited on a germanium attenuated total reflectance (ATR) crystal was exposed to radiation from a low-pressure mercury lamp at 254 nm, or from broadband low pressure mercury photolysis lamps centered at 350 or 313 nm. The loss during photolysis was followed in time using FTIR.