Postnatal transcriptional activity regulates functional properties of PV interneurons.

The transcription factor Aristaless-related X-linked gene () is a monogenic factor in early onset epileptic encephalopathies (EOEEs) and a fundamental regulator of early stages of brain development. However, expression persists in mature GABAergic neurons with an unknown role. To address this issue, we generated a conditional knockout (CKO) mouse in which postnatal was ablated in parvalbumin interneurons (PVIs).

Eosinophilic Esophagitis as a Side Effect of Food Oral Immunotherapy.

Food allergies (FAs) include a spectrum of immune-mediated serious and potentially life-threatening medical conditions with an overall estimated prevalence ranging from 4% to 8% in the U.S. and Europe.

Insights into the Genetic Underpinnings of Endocrine Traits from Large-Scale Genome-Wide Association Studies.

Great strides have been made in genetic association studies of endocrine traits and diseases, with hundreds or thousands of variants associated with height, body mass index, bone density, pubertal timing, and diabetes in recent years. The common variants associated with these traits explain up to half of the trait variation owing to genetic factors, and when aggregated into polygenic risk scores, can also impact clinically relevant phenotypes at the tail ends of the trait distributions. However, pediatric studies tend to lag behind, and it is often unclear how adult-associated variants behave across life.

Inter-Regulation of K4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies.

Background: Genetic variants in voltage-gated sodium channels (Na) encoded by genes, responsible for I, and K4.3 channels encoded by , responsible for the transient outward current (I), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that K4.

Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.

Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE.

Clinical Bioinformatics in Precise Diagnosis of Mitochondrial Disease.

Clinical bioinformatics system is well-established for diagnosing genetic disease based on next-generation sequencing, but requires special considerations when being adapted for the next-generation sequencing-based genetic diagnosis of mitochondrial diseases. Challenges are caused by the involvement of mitochondrial DNA genome in disease etiology. Heteroplasmy and haplogroup are key factors in interpreting mitochondrial DNA variant effects.

Urine Proteomics: Evaluation of Different Sample Preparation Workflows for Quantitative, Reproducible, and Improved Depth of Analysis.

The growing field of urinary proteomics shows promise to expand the number of biomarkers for the diagnosis and prognosis of a number of human diseases. With the rapid developments in mass spectrometry methods for proteome quantification, there exists an opportunity for improved sample processing and separation workflows to make important contributions to urine proteomic analyses. Here we evaluate the performance of four sample preparation methods: MStern, PreOmics in-StageTip (iST), suspension-trapping (S-Trap), and conventional urea In-Solution trypsin hydrolysis for nondepleted urine samples.

Sensitivity and specificity of placental proteins for gestational age screening: An exploratory study.

Objective: To examine the possibility that serum or urine concentrations of pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloproteinase 12 (ADAM-12), placental growth factor (PlGF), human placental lactogen (HPL), glypican-3, pregnancy specific beta-1-glycoprotein 1 (PSG-1) or prolactin could predict gestational age (GA) >70 days, the currently recommended limit for medical abortion in the United States.

Study Design: In this exploratory observational study, we collected serum and urine specimens from 245 healthy individuals with singleton intrauterine pregnancies at GA <40 weeks by ultrasound. We assayed the serum specimens for all seven proteins and the urine specimens for PAPP-A and ADAM-12.

Glutamate Transporters and Mitochondria: Signaling, Co-compartmentalization, Functional Coupling, and Future Directions.

In addition to being an amino acid that is incorporated into proteins, glutamate is the most abundant neurotransmitter in the mammalian CNS, the precursor for the inhibitory neurotransmitter γ-aminobutyric acid, and one metabolic step from the tricarboxylic acid cycle intermediate α-ketoglutarate. Extracellular glutamate is cleared by a family of Na-dependent transporters. These transporters are variably expressed by all cell types in the nervous system, but the bulk of clearance is into astrocytes.

The Genetic Contribution to Type 1 Diabetes.

Purpose Of Review: To provide an updated summary of discoveries made to date resulting from genome-wide association study (GWAS) and sequencing studies, and to discuss the latest loci added to the growing repertoire of genetic signals predisposing to type 1 diabetes (T1D).

Recent Findings: Genetic studies have identified over 60 loci associated with T1D susceptibility. GWAS alone does not specifically inform on underlying mechanisms, but in combination with other sequencing and omics-data, advances are being made in our understanding of T1D genetic etiology and pathogenesis.

Genetic variants of HIF1α are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study.

Background: Studies suggest that right ventricular (RV) fibrosis is associated with RV remodeling and long-term outcomes in patients with tetralogy of Fallot (TOF). Pre-operative hypoxia may increase expression of hypoxia inducible factor-1-alpha (HIF1α) and promote transforming growth factor β1 (TGFβ1)-mediated fibrosis. We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1α variants and RV fibrosis, and (3) HIF1α variants and RV function among post-surgical TOF cases.

SOX9 in cartilage development and disease.

SOX9 is a pivotal transcription factor in chondrocytes, a lineage essential in skeletogenesis. Its mandatory role in transactivating many cartilage-specific genes is well established, whereas its pioneer role in lineage specification, which along with transactivation defines master transcription factors, remains to be better defined. Abundant, but yet incomplete evidence exists that intricate molecular networks control SOX9 activity during the multi-step chondrogenesis pathway.

Open-label pilot study of oral methylprednisolone for the treatment of patients with friedreich ataxia.

Introduction: In this study we assessed the effect of methylprednisolone on safety, tolerability, and ability in Friedreich ataxia (FRDA).

Methods: The study was an open-label trial of pulse methylprednisolone on 11 participants with FRDA. All participants followed a 28-day treatment cycle, repeated 7 times.

Student health administrator perspectives on college vaccine policy development and implementation.

Background: Immunization policies at colleges and universities differ greatly for many reasons, including prior experience with disease outbreaks and state immunization requirements. Few studies comprehensively explore the range of factors that influence the development of college vaccine policies or facilitators and barriers to their implementation.

Objective: To explore the perceptions and decision-making process that influence college vaccine policy development and implementation from the perspective of student health administrators.

Building a Global Health Workforce in North America.

Globally, significant progress in health equity for children has been made, but much work remains. This article discusses why and how the pediatric community in North America is building a global health (GH) workforce, for domestic "local global" and "international global child health" settings. With a focus on children and families, training this workforce entails attaining GH competencies in medical students, residents, fellows, allied medical professionals, and upskilling current practitioners.

Ndfip Proteins Target Robo Receptors for Degradation and Allow Commissural Axons to Cross the Midline in the Developing Spinal Cord.

Commissural axons initially respond to attractive signals at the midline, but once they cross, they become sensitive to repulsive cues. This switch prevents axons from re-entering the midline. In insects and mammals, negative regulation of Roundabout (Robo) receptors prevents premature response to the midline repellant Slit.

Fetal Surgery.

Fetal surgery is an established but still rapidly evolving specialty, born from the rationale that destructive embryologic processes, recognized early in gestation, can be curtailed by prenatal correction. As more and more centers begin offering fetal interventions, quality of care must be verified through transparency about clinical capabilities and resources. Level designations should be assigned based on capability, as in trauma and neonatal ICU centers for excellence, and volume requirements must be set for fetal surgery certification.

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data.

Early-Onset Inflammatory Bowel Disease.

The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This changing landscape of inflammatory bowel disease reflects the new recognition that the youngest children with inflammatory bowel disease are enriched in cases with underlying primary immunodeficiency and monogenic causes.

Human Leukocyte Antigen and Disease Associations: A Broader Perspective.

HLA molecules play a significant role in immunity and disease susceptibility. GWAS studies underline the critical role of the MHC region in a wide range of diseases and remind us that the HLA genes, included within the MHC, interact extensively with other genomic regions which influence their functions. Recently, MHC/HLA genomic sequences encoding for miRNAs have been reported to interact with targets within and outside the MHC, influencing the expression of many transcripts.

Pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of uncommon, yet related metabolic disorders that are characterized by impaired activation of the Gsα/cAMP/PKA signaling pathway by parathyroid hormone (PTH) and other hormones that interact with Gsa-coupled receptors. Proximal renal tubular resistance to PTH and thus hypocalcemia and hyperphosphatemia, frequently in presence of brachydactyly, ectopic ossification, early-onset obesity, or short stature are common features of PHP. Registries and large cohorts of patients are needed to conduct clinical and genetic research, to improve the still limited knowledge regarding the underlying disease mechanisms, and allow the development of novel therapies.

Genetic Disorders of Parathyroid Development and Function.

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia and is due to insufficient levels of circulating parathyroid hormone. Hypoparathyroidism may be an isolated condition or a component of a complex syndrome. Although genetic disorders are not the most common cause of hypoparathyroidism, molecular analyses have identified a growing number of genes that when defective result in impaired formation of the parathyroid glands, disordered synthesis or secretion of parathyroid hormone, or postnatal destruction of the parathyroid glands.

Testicular endothelial cells are a critical population in the germline stem cell niche.

Maintenance of adult tissues depends on stem cell self-renewal in local niches. Spermatogonial stem cells (SSC) are germline adult stem cells necessary for spermatogenesis and fertility. We show that testicular endothelial cells (TECs) are part of the SSC niche producing glial cell line-derived neurotrophic factor (GDNF) and other factors to support human and mouse SSCs in long-term culture.

Alagille Syndrome.

Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system.