Evolutionary analyses of intrinsically disordered regions reveal widespread signals of conservation.

Intrinsically disordered regions (IDRs) are segments of proteins without stable three-dimensional structures. As this flexibility allows them to interact with diverse binding partners, IDRs play key roles in cell signaling and gene expression. Despite the prevalence and importance of IDRs in eukaryotic proteomes and various biological processes, associating them with specific molecular functions remains a significant challenge due to their high rates of sequence evolution.

Leveraging genomic redundancy to improve inference and alignment of orthologous proteins.

Identifying protein sequences with common ancestry is a core task in bioinformatics and evolutionary biology. However, methods for inferring and aligning such sequences in annotated genomes have not kept pace with the increasing scale and complexity of the available data. Thus, in this work, we implemented several improvements to the traditional methodology that more fully leverage the redundancy of closely related genomes and the organization of their annotations.

Metabolism and pharmacokinetics characterization of metarrestin in multiple species.

Purpose: Metarrestin is a first-in-class pyrrolo-pyrimidine-derived small molecule targeting a marker of genome organization associated with metastasis and is currently in preclinical development as an anti-cancer agent. Here, we report the in vitro ADME characteristics and in vivo pharmacokinetic behavior of metarrestin.

Methods: Solubility, permeability, and efflux ratio as well as in vitro metabolism of metarrestin in hepatocytes, liver microsomes and S9 fractions, recombinant cytochrome P450 (CYP) enzymes, and potential for CYP inhibition were evaluated.

Phosphocyclocreatine is the dominant form of cyclocreatine in control and creatine transporter deficiency patient fibroblasts.

Creatine transporter deficiency (CTD) is a metabolic disorder resulting in cognitive, motor, and behavioral deficits. Cyclocreatine (cCr), a creatine analog, has been explored as a therapeutic strategy for the treatment of CTD. We developed a rapid, selective, and accurate HILIC ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to simultaneously quantify the intracellular concentrations of cCr, creatine (Cr), creatine-d3 (Cr-d3), phosphocyclocreatine (pcCr), and phosphocreatine (pCr).

Preclinical Pharmacological Development of Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is a small, single-stranded, positive-sense RNA virus that infects more than an estimated 70 million people worldwide. Untreated, persistent HCV infection often results in chronic hepatitis, cirrhosis, or liver failure, with progression to hepatocellular carcinoma. Current anti-HCV regimens comprising direct acting antivirals (DAAs) can provide curative treatment; however, due to high costs there remains a need for effective, shorter-duration, and affordable treatments.

Phevor combines multiple biomedical ontologies for accurate identification of disease-causing alleles in single individuals and small nuclear families.

Phevor integrates phenotype, gene function, and disease information with personal genomic data for improved power to identify disease-causing alleles. Phevor works by combining knowledge resident in multiple biomedical ontologies with the outputs of variant-prioritization tools. It does so by using an algorithm that propagates information across and between ontologies.

The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders.

Sanger sequencing of multigenic disorders can be technically challenging, time consuming, and prohibitively expensive. High-throughput next-generation sequencing (NGS) can provide a cost-effective method for sequencing targeted genes associated with multigenic disorders. We have developed a NGS clinical targeted gene assay for the mitochondrial genome and for 108 selected nuclear genes associated with mitochondrial disorders.

A probabilistic disease-gene finder for personal genomes.

VAAST (the Variant Annotation, Analysis & Search Tool) is a probabilistic search tool for identifying damaged genes and their disease-causing variants in personal genome sequences. VAAST builds on existing amino acid substitution (AAS) and aggregative approaches to variant prioritization, combining elements of both into a single unified likelihood framework that allows users to identify damaged genes and deleterious variants with greater accuracy, and in an easy-to-use fashion. VAAST can score both coding and noncoding variants, evaluating the cumulative impact of both types of variants simultaneously.

Global analysis of disease-related DNA sequence variation in 10 healthy individuals: implications for whole genome-based clinical diagnostics.

Background: Understanding how sequence variants within healthy genomes are distributed with respect to ethnicity and disease-implicated genes is an essential first step toward establishing baselines for personalized genomic medicine.

Methods: In this study, we present an analysis of 10 genomes from healthy individuals of various ethnicities, produced using six different sequencing technologies. In total, these genomes contain more than 34 million single-nucleotide variants.

Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis.

Study Design: Validation of a prognostic DNA marker panel.

Objective: The goals of this study were to develop and test the negative predictive value of a prognostic DNA test for adolescent idiopathic scoliosis (AIS) and to establish clinically meaningful endpoints for the test.

Summary Of Background Data: Clinical features do not adequately predict which children diagnosed with minimal or mild AIS will have the progressive form of the disease; genetic markers associated with curve progression might offer clinically useful prognostic insights.