Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.

α-AlO Functionalized with Lithium Ions Especially Useful as Inert Catalyst Bed Supports.

The alumina, in the form of α-AlO tabular balls, considered in this study is a high-purity form of aluminum oxide that has been fired at high temperatures (well above 1900 °C), virtually removing porosity. However, the purity and inertness of the surface of the AlO tabular balls minimize the catalytic activity, which is why lithium doping was tried. Thus, the target of this study was the effect of doping with lithium ions in some tabular balls of AlO (the crystalline structure is corundum) on the improvement of the catalytic properties of alumina.

Intraoperative Factors Affecting Pain Management and Postoperative Narcotic Use in Cranial Vault Remodeling: A Retrospective Review.

Perioperative pain control in open cranial vault reconstruction (CVR) poses significant challenges. Narcotic use may confound signs of neurological deterioration and cause medication-induced complications. Previous studies have shown improved health outcomes in CVR with reduced narcotic use.

Impact of excess sugar on the whole genome DNA methylation pattern in human sperm.

Aims, Patients & Methods: Dietary factors may regulate the epigenome. We aimed to explore whether a diet intervention, including excess sugar, affects the methylome in human sperm, and to describe the sperm methylome. We used Whole Genome Bisulfite Sequencing (WGBS) to analyze DNA methylation in sperm taken at three time points from 15 males during a diet intervention; i) at baseline, ii) after one week on a standardized diet, and iii) after an additional week on a high-sugar diet providing 150% of their estimated total energy expenditure.

A chiral hydrogen atom abstraction catalyst for the enantioselective epimerization of -diols.

Hydrogen atom abstraction is an important elementary chemical process but is very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue of their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes -diols by selectively abstracting a hydrogen atom from one carbon center, which then regains a hydrogen atom by abstraction from a thiol.

From Simple to Complex: Preserving and Reconstructing the Traumatized Thumb.

Traumatic thumb injuries significantly affect overall hand function and may result in considerable disability. Reconstructing the traumatized thumb requires a detailed preoperative assessment of the defect and evaluation of the patient's social history and medical comorbidities. Reconstructive techniques can be stratified by the level of thumb injury.

The development, use, and challenges of electromechanical tissue stimulation systems.

Background: Tissue stimulations greatly affect cell growth, phenotype, and function, and they play an important role in modeling tissue physiology. With the goal of understanding the cellular mechanisms underlying the response of tissues to external stimulations, in vitro models of tissue stimulation have been developed in hopes of recapitulating in vivo tissue function.

Methods: Herein we review the efforts to create and validate tissue stimulators responsive to electrical or mechanical stimulation including tensile, compression, torsion, and shear.

Discovery and Development of the Enantioselective Minisci Reaction.

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites.

Surgical Management of Breast Amyloidosis.

Amyloidosis is characterized by extracellular deposition of insoluble misfolded beta-pleated proteins. Amyloid disease involving the breast is rare and there is a paucity of literature guiding surgical management in caring for these patients. In this article we review medical and surgical management with an emphasis on post mastectomy breast reconstruction.

De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost.

Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created through an inverse-electron demand Diels-Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination-aromatization reaction.

Changes in Subspecialty Interest of Plastic Surgery Residents With Progression of Training: Impact on Academic Attrition.

Background: Plastic surgery residency applicants often express interest in academic subspecialties, but only a small percentage of graduating residents pursue academic careers. Identifying reasons for academic attrition may help training programs address this discrepancy.

Methods: A survey was sent to plastic surgery residents through the American Society of Plastic Surgeons Resident Council to assess interest in 6 plastic surgery subspecialties during junior and senior years of training.

Enantioselective Giese Additions of Prochiral α-Amino Radicals.

Amines featuring an adjacent stereocenter are important building blocks, and recent years have seen remarkable growth in methods forming these via prochiral α-amino radical intermediates. However, very few can exert control over the newly formed stereocenter. We disclose a strategy to overcome this in the context of one of the most widely used radical carbon-carbon bond forming reactions, the Giese reaction.

Glucocorticoids and glucolipotoxicity alter the DNA methylome and function of human EndoC-βH1 cells.

Aims: Synthetic glucocorticoids, including dexamethasone (DEX), are clinically prescribed due to their immunoregulatory properties. In excess they can perturb glucose homeostasis, with individuals predisposed to glucose intolerance more sensitive to these negative effects. While DEX is known to negatively impact β-cell function, it is unclear how.

Do Dedicated Research Years during Medical School Predict Academic Productivity during Residency?

Background: Evidence regarding whether medical school research portends resident research is limited. This information will provide program directors with data that may be useful for selecting applicants with a commitment to continued academic productivity.

Methods: A questionnaire distributed via the American Society of Plastic Surgeons Resident Council to residents in 44 plastic surgery training programs in May 2020 assessed participation in dedicated research years during medical school, the number of publications completed before residency, and the total number of publications by each resident at the time of the survey.

Excess of glucocorticoids during late gestation impairs the recovery of offspring's β-cell function after a postnatal injury.

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225.

Novel Approach of Mandibular Distraction to Avoid Tracheostomy in KAT6B-related Gene Disorders.

Previously, severe upper airway obstruction in patients with retrognathia and glossoptosis has been managed with tracheostomy. However, tracheostomy is associated with significant morbidity. In recent years, mandibular distraction has become an alternative management strategy in infants, but these applications have been limited to patient populations with retrognathia and glossoptosis.

Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes.

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin.

Spring-Assisted Distraction Osteogenesis for the Treatment of Shunt-Induced Craniosynostosis.

Shunt-induced craniosynostosis is a rare complication of ventricular shunting for hydrocephalus in pediatric patients. Although the exact pathophysiology of this form of secondary craniosynostosis is not well understood, the current understanding is that persistent drainage of the ventricular shunt causes decreased dural tension, resulting in decreased expansile force on the cranium and premature sutural fusion. Due to the low incidence of this complication, there is no consensus on the ideal treatment for shunt-induced craniosynostosis.

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington's disease.

Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown.

Author Correction: ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.