Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits.

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism.

Power dissipation and entropy production rate of high-dimensional optical matter systems.

Entropy production is an essential aspect of creating and maintaining nonequilibrium systems. Despite their ubiquity, calculation of entropy production rates is challenging for high-dimensional systems, so it has only been reported for simple (i.e.

A meta-analysis of the relationship between speech and language development in children with nonsyndromic cleft palate with or without cleft lip.

Objective: Children with nonsyndromic cleft palate with or without cleft lip are at risk of speech production and language delays. In typical development, a strong relationship exists between speech and expressive language development. However, the understanding of this relationship in children with nonsyndromic cleft palate with or without cleft lip is incomplete.

Photobiomodulation and Physical Exercise Modulate of Cell Survival Proteins in the Skeletal Muscle of Rats with Heart Failure and Diabetes Mellitus.

Heart failure (HF) and type 2 diabetes mellitus (DM2) are global health problems that often lead to muscle atrophy. These conditions are associated with increased autophagy and apoptosis in the muscle cells, resulting in decreased muscle mass. Physical exercise associated with photobiomodulation (PBM) seems promising to attenuate the skeletal muscle changes caused by HF and DM2, due to its direct effects on mitochondria, which may result in an increase in antioxidant capacity.

The membrane transporter SLC25A48 enables transport of choline into human mitochondria.

Choline has important physiological functions as a precursor for essential cell components, signaling molecules, phospholipids, and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule requiring transport proteins to cross biological membranes. Although transporters continue to be identified, membrane transport of choline is incompletely understood and knowledge about choline transport into intracellular organelles such as mitochondria remains limited.

Distinct Sub- to Superdiffuse Insulin Granule Transport Behaviors in β-Cells Are Strongly Affected by Granule Age.

Intracellular transport is a complex process that is difficult to describe by a single general model for motion. Here, we study the transport of insulin containing vesicles, termed granules, in live MIN6 cells. We characterize how the observed heterogeneity is affected by different intracellular factors by constructing a MIN6 cell line by CRISPR-CAS9 that constitutively expresses mCherry fused to insulin and is thus packaged in granules.

The impact of enhanced Milieu teaching with phonological emphasis (EMT + PE) on the speech and language outcomes for toddlers with cleft palate in Brazil and the United States of America.

Purpose: The purpose of this study was to compare the speech and language outcomes of children with cleft palate with or without cleft lip (CP+/-L) in the USA to children with CP+/-L in Brazil who underwent intervention with enhanced Milieu teaching with phonological emphasis (EMT + PE), as there are few cross-country intervention comparisons for children with CP+/-L.

Method: This is a retrospective analysis of 29 participants from the USA and 24 participants from Brazil who were matched on age. The US participants were between the ages of 13-35 months ( = 23.

New insights into the hypothalamic-pituitary-thyroid axis: a transcriptome- and proteome-wide association study.

Introduction: Thyroid hormones have systemic effects on the human body and play a key role in the development and function of virtually all tissues. They are regulated via the hypothalamic-pituitary-thyroid (HPT) axis and have a heritable component. Using genetic information, we applied tissue-specific transcriptome-wide association studies (TWAS) and plasma proteome-wide association studies (PWAS) to elucidate gene products related to thyrotropin (TSH) and free thyroxine (FT4) levels.

Dose-Dependent Association Between Body Mass Index and Mental Health and Changes Over Time.

Importance: Overweight and obesity affect 340 million adolescents worldwide and constitute a risk factor for poor mental health. Understanding the association between body mass index (BMI) and mental health in adolescents may help to address rising mental health issues; however, existing studies lack comprehensive evaluations spanning diverse countries and periods.

Objective: To estimate the association between BMI and mental health and examine changes over time from 2002 to 2018.

Electrodynamic Interference and Induced Polarization in Nanoparticle-Based Optical Matter Arrays.

Optical matter (OM) arrays are self-organizing, ordered arrangements of nanometer- to micrometer-size particles, where interparticle forces are mediated by incident and scattered coherent light. The structures that form and their dynamics depend on the properties (e.g.

Impact evaluation of a cash-plus programme for children with disabilities in the Xiengkhouang Province in Lao PDR: study protocol for a non-randomised controlled trial.

Introduction: More than 170 countries have implemented disability-targeted social protection programmes, although few have been rigorously evaluated. Consequently, a non-randomised controlled trial is being conducted of a pilot 'cash-plus' programme implemented by UNICEF Laos and the Laos government for children with disabilities in the Xiengkhouang Province in Laos. The intervention combines a regular cash transfer with provision of assistive devices and access for caregivers to a family support programme.

SLC17 transporters mediate renal excretion of Lac-Phe in mice and humans.

N-lactoyl-phenylalanine (Lac-Phe) is a lactate-derived metabolite that suppresses food intake and body weight. Little is known about the mechanisms that mediate Lac-Phe transport across cell membranes. Here we identify SLC17A1 and SLC17A3, two kidney-restricted plasma membrane-localized solute carriers, as physiologic urine Lac-Phe transporters.

Tandem aberration correction optics (TACO) in wide-field structured illumination microscopy.

Structured illumination microscopy (SIM) is a powerful super-resolution imaging technique that uses patterned illumination to down-modulate high spatial-frequency information of samples. However, the presence of spatially-dependent aberrations can severely disrupt the illumination pattern, limiting the quality of SIM imaging. Conventional adaptive optics (AO) techniques that employ wavefront correctors at the pupil plane are not capable of effectively correcting these spatially-dependent aberrations.

RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo.

Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates.

Safety, pharmacokinetics, and pharmacodynamics of nomlabofusp (CTI-1601) in Friedreich's ataxia.

Objective: Current treatments for Friedreich's ataxia, a neurodegenerative disorder characterized by decreased intramitochondrial frataxin, do not address low frataxin concentrations. Nomlabofusp (previously CTI-1601) is a frataxin replacement therapy with a unique mechanism of action that directly addresses this underlying frataxin deficiency. Phase 1 studies assessed the safety, pharmacokinetic, and pharmacodynamic profiles of subcutaneously administered nomlabofusp in adults with Friedreich's ataxia.

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer.

Background: Approximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high-grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss-of-function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors.

Impact of a disability-targeted microentrepreneurship programme in Kenya: study protocol for a randomised controlled trial of the InBusiness programme.

Background: There is a lack of evidence on the effectiveness of livelihood interventions amongst people with disabilities. In many countries, self-employment or microentrepreneurship is a dominant source of livelihoods for people with disabilities and their caregivers. However, this group may face heightened barriers to successful microentrepreneurship, including discrimination, exclusion from training or inaccessible transport, infrastructure and communication systems.

Long-Term Outcome and Complications of IOL-Exchange.

Purpose: To describe the long-term outcome after intraocular lens (IOL) exchange for IOL-opacification with a focus on any occurring complications.

Patients And Methods: Patients with an IOL exchange for opacified IOLs (Lentis LS-502-1) were identified. Medical records and information from the treating ophthalmologists were reviewed.

Assessment of ChatGPT in the Prehospital Management of Ophthalmological Emergencies - An Analysis of 10 Fictional Case Vignettes.

Background: The artificial intelligence (AI)-based platform ChatGPT (Chat Generative Pre-Trained Transformer, OpenAI LP, San Francisco, CA, USA) has gained impressive popularity in recent months. Its performance on case vignettes of general medical (non-ophthalmological) emergencies has been assessed - with very encouraging results. The purpose of this study was to assess the performance of ChatGPT on ophthalmological emergency case vignettes in terms of the main outcome measures triage accuracy, appropriateness of recommended prehospital measures, and overall potential to inflict harm to the user/patient.

Development of mental health and psychosocial support (MHPSS) guidelines for deaf and hard of hearing children in the Gaza Strip.

Deaf and hard of hearing children in the Gaza Strip may be at risk of mental health conditions and psychological distress, as a result of social exclusion and limited accessible communication. This article presents the process and research methods used to develop guidelines for schools in the Gaza Strip on mental health and psychosocial support for deaf and hard of hearing children. The process was guided by the GIN-McMaster guideline development checklist across four steps: (1) priority settings; (2) searching for evidence; (3) developing recommendations; (4) evaluation.

'Do they ever think about people like us?': The experiences of people with learning disabilities in England and Scotland during the COVID-19 pandemic.

People with learning disabilities in England and Scotland have experienced an increased risk of illness and death during the COVID-19 pandemic. Drawing on data of a longitudinal qualitative study with 71 disabled people and 31 disability organisations, this article examines the experiences of 24 people with learning disabilities in England and Scotland during the pandemic, reflecting on what rendered them vulnerable and placed them at risk. Qualitative interviews were conducted with participants and key informants at two timepoints; June-August 2020 and February-April 2021.