TMPRSS2 Inhibitor Discovery Facilitated through an and Biochemical Screening Platform.

The COVID-19 pandemic has highlighted the need for new antiviral approaches because many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a promising antiviral target because it plays a role in priming the spike protein before viral entry occurs for the most virulent variants. Further, TMPRSS2 has no established physiological role, thereby increasing its attractiveness as a target for antiviral agents.

Development from a distance: Exploring an international non-profit's interactions with communities during the COVID-19 pandemic.

A case study analysis of an international development non-profit identifies strategies and decision-making processes utilized to engage community members in person and virtually during the first year of the COVID-19 pandemic. The strategies employed led to a continuation of projects in the field, potentially excluding some stakeholder groups from decision-making processes at the community level. Staff members described how power dynamics and geographic distance affected internal decision-making for community involvement, highlighting the importance of adopting a critical self-reflection approach to facilitate communication among an intercultural team for more equitable community engagement.

Allostery in the dynamic coactivator domain KIX occurs through minor conformational micro-states.

The coactivator KIX of CBP uses two binding surfaces to recognize multiple activators and exhibits allostery in ternary complex formation. Activator•coactivator interactions are central to transcriptional regulation, yet the microscopic origins of allostery in dynamic proteins like KIX are largely unknown. Here, we investigate the molecular recognition and allosteric manifestations involved in two KIX ternary systems c-Myb•KIX•MLL and pKID•KIX•MLL.

Advances in glycoscience to understand viral infection and colonization.

Interactions between carbohydrates and the proteins that bind them, (i.e., lectins), are often some of the first between a host cell and a viral invader.

Norstictic Acid Is a Selective Allosteric Transcriptional Regulator.

Inhibitors of transcriptional protein-protein interactions (PPIs) have high value both as tools and for therapeutic applications. The PPI network mediated by the transcriptional coactivator Med25, for example, regulates stress-response and motility pathways, and dysregulation of the PPI networks contributes to oncogenesis and metastasis. The canonical transcription factor binding sites within Med25 are large (∼900 Å) and have little topology, and thus, they do not present an array of attractive small-molecule binding sites for inhibitor discovery.

TMPRSS2 inhibitor discovery facilitated through an and biochemical screening platform.

The COVID-19 pandemic has highlighted the need for new antiviral targets, as many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a highly promising antiviral target, as it plays a direct role in priming the spike protein before viral entry occurs. Further, unlike other targets such as ACE2, TMPRSS2 has no known biological role.

Orthoptic Vision Therapy: Establishing a Protocol for Management of Diplopia Following Orbital Fracture Repair.

Introduction: Persistent diplopia following orbital fracture is a well-recognized problem. While observation is the standard-of-care, symptoms may be protracted. Orthoptic vision therapy is a form of ocular physical therapy that achieves functional rehabilitation through targeted exercises.

Author Correction: The power of children's sleep - Improved declarative memory consolidation in children compared with adults.

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

Germline mutation rates in young adults predict longevity and reproductive lifespan.

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined.

The power of children's sleep - Improved declarative memory consolidation in children compared with adults.

Post-learning slow wave sleep (SWS) is known to support declarative memory consolidation. As SWS is more abundant in young population, we suggested that sleep-dependent memory consolidation processes could occur at a faster pace in school-aged children. After learning new associations between non-objects and their functions, retrieval performance was tested in 30 children (7-12 years) and 34 adults (20-30 years) during an immediate (IR) and a delayed retrieval (DR) session separated by either a Sleep or a Wake condition.

The Influence of Binocular Vision Symptoms on Computerized Neurocognitive Testing of Adolescents With Concussion.

Binocular vision disorders are commonly found postconcussion and associated with high symptom burden. We investigated the relationship between binocular vision symptoms and neurocognitive test performance. Thirty-four adolescents with concussion and 18 without concussion were assessed for cognitive performance using the CogState Brief Battery.

Critical exon indexing improves clinical interpretation of copy number variants in neurodevelopmental disorders.

Objective: To evaluate a new tool to aid interpretation of copy number variants (CNVs) in individuals with neurodevelopmental disabilities.

Methods: Critical exon indexing (CEI) was used to identify genes with critical exons (CEGs) from clinically reported CNVs, which may contribute to neurodevelopmental disorders (NDDs). The 742 pathogenic CNVs and 1,363 variants of unknown significance (VUS) identified by chromosomal microarray analysis in 5,487 individuals with NDDs were subjected to CEI to identify CEGs.

White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates.

Fractionated whole-brain irradiation for the treatment of intracranial neoplasia causes progressive neurodegeneration and neuroinflammation. The long-term consequences of single-fraction high-dose irradiation to the brain are unknown. To assess the late effects of brain irradiation we compared transcriptomic gene expression profiles from nonhuman primates (NHP; rhesus macaques Macaca mulatta) receiving single-fraction total-body irradiation (TBI; n = 5, 6.

Safety of pioglitazone during and after radiation therapy in patients with brain tumors: a phase I clinical trial.

Introduction: Radiation-induced cognitive decline (RICD) is a late effect of radiotherapy (RT) occurring in 30-50% of irradiated brain tumor survivors. In preclinical models, pioglitazone prevents RICD but there are little safety data on its use in non-diabetic patients. We conducted a dose-escalation trial to determine the safety of pioglitazone taken during and after brain irradiation.

Conservation of coactivator engagement mechanism enables small-molecule allosteric modulators.

Transcriptional coactivators are a molecular recognition marvel because a single domain within these proteins, the activator binding domain or ABD, interacts with multiple compositionally diverse transcriptional activators. Also remarkable is the structural diversity among ABDs, which range from conformationally dynamic helical motifs to those with a stable core such as a β-barrel. A significant objective is to define conserved properties of ABDs that allow them to interact with disparate activator sequences.

Fibronectin Produced by Cerebral Endothelial and Vascular Smooth Muscle Cells Contributes to Perivascular Extracellular Matrix in Late-Delayed Radiation-Induced Brain Injury.

Late-delayed radiation-induced brain injury (RIBI) is a major adverse effect of fractionated whole-brain irradiation (fWBI). Characterized by progressive cognitive dysfunction, and associated cerebrovascular and white matter injury, RIBI deleteriously affects quality of life for cancer patients. Despite extensive morphological characterization of the injury, the pathogenesis is unclear, thus limiting the development of effective therapeutics.

Impact of radiosurgical management of geriatric patients with brain metastases: Clinical and quality of life outcomes.

Objectives: Recent trials have shown that whole brain radiotherapy (WBRT) can worsen performance status, particularly in the geriatric population. We reviewed our institutional experience with geriatric patients (> 70 years) with brain metastases treated with radiosurgery (SRS) to determine clinical and quality of life (QOL) outcomes.

Methods: Between 7/2000 and 1/2013, a retrospective review was performed on 467 patients treated with SRS (114 geriatric patients).

Hippocampal dose volume histogram predicts Hopkins Verbal Learning Test scores after brain irradiation.

Purpose: Radiation-induced cognitive decline is relatively common after treatment for primary and metastatic brain tumors; however, identifying dosimetric parameters that are predictive of radiation-induced cognitive decline is difficult due to the heterogeneity of patient characteristics. The memory function is especially susceptible to radiation effects after treatment. The objective of this study is to correlate volumetric radiation doses received by critical neuroanatomic structures to post-radiation therapy (RT) memory impairment.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers.

Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates.

Fractionated whole-brain irradiation (fWBI) is a mainstay of treatment for patients with intracranial neoplasia; however late-delayed radiation-induced normal tissue injury remains a major adverse consequence of treatment, with deleterious effects on quality of life for affected patients. We hypothesize that cerebrovascular injury and remodeling after fWBI results in ischemic injury to dependent white matter, which contributes to the observed cognitive dysfunction. To evaluate molecular effectors of radiation-induced brain injury (RIBI), real-time quantitative polymerase chain reaction (RT-qPCR) was performed on the dorsolateral prefrontal cortex (DLPFC, Brodmann area 46), hippocampus and temporal white matter of 4 male Rhesus macaques (age 6-11 years), which had received 40 Gray (Gy) fWBI (8 fractions of 5 Gy each, twice per week), and 3 control comparators.

Analytical and Clinical Validity Study of FirstStepDx PLUS: A Chromosomal Microarray Optimized for Patients with Neurodevelopmental Conditions.

Introduction: Chromosomal microarray analysis (CMA) is recognized as the first-tier test in the genetic evaluation of children with developmental delays, intellectual disabilities, congenital anomalies and autism spectrum disorders of unknown etiology.

Array Design: To optimize detection of clinically relevant copy number variants associated with these conditions, we designed a whole-genome microarray, FirstStep PLUS (FSDX). A set of 88,435 custom probes was added to the Affymetrix CytoScanHD platform targeting genomic regions strongly associated with these conditions.

Gamma Knife radiosurgery for brain metastases from gastrointestinal primary.

Introduction: In this study, we assessed clinical outcomes of patients with brain metastases from a gastrointestinal (GI) primary cancer and patterns of failure after stereotactic radiosurgery including failure within the radiosurgical volume, distant failure and leptomeningeal failure (LMF). We also assessed other factors associated with the patients' neurologic and extraneuraxial disease that may affect clinical outcomes.

Methods: We reviewed our institutional series of 62 consecutive patients with brain metastases treated with stereotactic radiosurgery, which included 17 patients with oesophageal, 44 patients with colorectal and one patient with anal canal primary.

Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders.

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.