Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults.

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants.

Self-reported exercise engagement and seizure control - A preliminary survey of people with epilepsy at a safety-net hospital.

Benefits of exercise on general health and wellbeing are undeniable. The International League Against Epilepsy has provided some guidance into exercise and sports for epilepsy. However, people with epilepsy are typically misinformed and restricted by fear and lack of evidence about exercise benefits in epilepsy.

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD.

Revascularization for claudication: Changing the natural history of a benign disease!

Objective: The benign natural history of intermittent claudication was first documented in 1960 and has been reconfirmed in several subsequent studies. Excellent outcomes in patients with intermittent claudication can be achieved with exercise therapy and optimal medical management. Professional society guidelines have clearly stated that revascularization procedures should be performed only in patients with incapacitating claudication who have failed conservative therapy.

Violent Video Games and the P300: No Evidence to Support the Neural Desensitization Hypothesis.

It has been proposed that exposure to violent video games (VVGs) resulted in alterations of social behaviors such as increased aggression. The most damaging reported effect of playing VVGs is neural desensitization to violent stimuli and this is a major concern given the reported number of players and time spent playing major video game titles. The aim of this study was to investigate the existence of neural desensitization that was reported at the P300 component of event-related potentials (ERPs) in response to violent stimuli.

Stabilization of the Human DMC1 Nucleoprotein Filament.

The meiosis-specific recombinase, DMC1, is important for the generation of haploids during meiosis. DMC1 forms a helical nucleoprotein filament on ssDNA overhangs located at the processed double-stranded DNA break. The DMC1 filament performs a search for homology in homologous chromosome.

In Vitro Assays for DNA Branch Migration.

Homologous recombination is a high-fidelity DNA double-strand break repair pathway that uses a homologous template to repair the break. Recombinases are the central enzymes that facilitate the strand invasion step of homologous recombination, which forms a DNA joint molecule. These DNA joint molecules can be moved through branch migration activity.

CASAnova: a multiclass support vector machine model for the classification of human sperm motility patterns.

The ability to accurately monitor alterations in sperm motility is paramount to understanding multiple genetic and biochemical perturbations impacting normal fertilization. Computer-aided sperm analysis (CASA) of human sperm typically reports motile percentage and kinematic parameters at the population level, and uses kinematic gating methods to identify subpopulations such as progressive or hyperactivated sperm. The goal of this study was to develop an automated method that classifies all patterns of human sperm motility during in vitro capacitation following the removal of seminal plasma.

Sperm function, protein phosphorylation, and metabolism differ in mice lacking successive sperm-specific glycolytic enzymes.

Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDHS) and phosphoglycerate kinase 2 (PGK2), two isozymes restricted to the male germline, catalyze successive steps in the glycolytic pathway in mammalian sperm. Although gene targeting of each isozyme demonstrated that glycolysis is required for normal sperm motility and male fertility, the phenotype of mice lacking GAPDHS is more severe than that of mice lacking PGK2. This study examined sperm function, signaling pathways, and metabolism to investigate factors that contribute to the phenotypic differences between these knockout models.

The β-isoform of BCCIP promotes ADP release from the RAD51 presynaptic filament and enhances homologous DNA pairing.

Homologous recombination (HR) is a template-driven repair pathway that mends DNA double-stranded breaks (DSBs), and thus helps to maintain genome stability. The RAD51 recombinase facilitates DNA joint formation during HR, but to accomplish this task, RAD51 must be loaded onto the single-stranded DNA. DSS1, a candidate gene for split hand/split foot syndrome, provides the ability to recognize RPA-coated ssDNA to the tumor suppressor BRCA2, which is complexed with RAD51.

Characterization of the recombination activities of the Entamoeba histolytica Rad51 recombinase.

The protozoan parasite responsible for human amoebiasis is Entamoeba histolytica. An important facet of the life cycle of E. histolytica involves the conversion of the mature trophozoite to a cyst.

The Founder Strains of the Collaborative Cross Express a Complex Combination of Advantageous and Deleterious Traits for Male Reproduction.

Surveys of inbred strains of mice are standard approaches to determine the heritability and range of phenotypic variation for biomedical traits. In addition, they may lead to the identification of novel phenotypes and models of human disease. Surprisingly, male reproductive phenotypes are among the least-represented traits in the Mouse Phenome Database.

Metabolic substrates exhibit differential effects on functional parameters of mouse sperm capacitation.

Although substantial evidence exists that sperm ATP production via glycolysis is required for mammalian sperm function and male fertility, conflicting reports involving multiple species have appeared regarding the ability of individual glycolytic or mitochondrial substrates to support the physiological changes that occur during capacitation. Several mouse models with defects in the signaling pathways required for capacitation exhibit reductions in sperm ATP levels, suggesting regulatory interactions between sperm metabolism and signal transduction cascades. To better understand these interactions, we conducted quantitative studies of mouse sperm throughout a 2-h in vitro capacitation period and compared the effects of single substrates assayed under identical conditions.

Classification of mouse sperm motility patterns using an automated multiclass support vector machines model.

Vigorous sperm motility, including the transition from progressive to hyperactivated motility that occurs in the female reproductive tract, is required for normal fertilization in mammals. We developed an automated, quantitative method that objectively classifies five distinct motility patterns of mouse sperm using Support Vector Machines (SVM), a common method in supervised machine learning. This multiclass SVM model is based on more than 2000 sperm tracks that were captured by computer-assisted sperm analysis (CASA) during in vitro capacitation and visually classified as progressive, intermediate, hyperactivated, slow, or weakly motile.

Drug discovery and the impact of the safe harbor provision of the Hatch- Waxman Act.

Many facets of drug discovery involve the use of patented materials and methods, subjecting the researcher to potential liability from infringement of the underlying patents. Enacted in 1984, the Hatch-Waxman Act established a “safe harbor” for activities that would otherwise constitute infringement of a patented invention, if those activities were “solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products”. This article examines the major court decisions interpreting the scope of the safe harbor and their application to various activities in drug development.

Direct, continuous behavioral analysis of drug action on feeding.

Analysis of rodent feeding behavior during the study of anorectic drugs reveals that contextual variables such as type of food, drug, environment, and physiological state influence food intake. Temporal changes in behavior can signal the onset of a feeding modulation process, as is the case with anorectic drugs acting on distinct neurochemical mechanisms that change temporal behavioral profiles. Comparing the effects of anorectic agents in controlled animal assays can identify potential therapeutic drugs that may influence human eating behavior.

A microRNA polycistron as a potential human oncogene.

To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas. Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers.

Chromosome 15q11-13 abnormalities and other medical conditions in individuals with autism spectrum disorders.

Objectives: The frequency of abnormalities of 15q11-q13 and other possibly causal medical disorders including karyotypic abnormalities was investigated in an unselected series of children who were referred to one of two autism assessment centres.

Methods: Two hundred and twenty-one cases were assessed using the Autism Diagnostic Interview and Observation Schedule and, where appropriate, standardized tests of intelligence and language abilities. Medical histories and notes were reviewed, and molecular and cytogenetic investigations used to detect chromosomal abnormalities.

Mutations of the para sodium channel of Drosophila melanogaster identify putative binding sites for pyrethroids.

The effects of two pyrethroids on recombinant wild-type and mutant (pyrethroid-resistant) Na+ channels of Drosophila melanogaster have been studied. Three mutations that confer resistance (kdr/superkdr) to pyrethroids were inserted, either individually or in combination, into the para Na+ channel of D. melanogaster: L1014F in domain IIS6, M918T in the IIS4-S5 linker, and T929I in domain IIS5.

Single nucleotide polymorphisms (SNPs) that map to gaps in the human SNP map.

An international effort is underway to generate a comprehensive haplotype map (HapMap) of the human genome represented by an estimated 300,000 to 1 million 'tag' single nucleotide polymorphisms (SNPs). Our analysis indicates that the current human SNP map is not sufficiently dense to support the HapMap project. For example, 24.

Functional genomics reveals relationships between the retrovirus-like Ty1 element and its host Saccharomyces cerevisiae.

Retroviruses and their relatives, the long terminal repeat (LTR) retrotransposons, carry out complex life cycles within the cells of their hosts. We have exploited a collection of gene deletion mutants developed by the Saccharomyces Genome Deletion Project to perform a functional genomics screen for host factors that influence the retrovirus-like Ty1 element in yeast. A total of 101 genes that presumably influence many different aspects of the Ty1 retrotransposition cycle were identified from our analysis of 4483 homozygous diploid deletion strains.