Ascertainment of uninterrupted CAG repeat length and disease-modifying variants in fragment-based genetic testing for Huntington Disease.

Purpose: In Huntington disease (HD), synonymous variants causing loss or duplication of the interrupting CAA codon in the CAG repeat modify disease onset. These variants are undetectable during HD genetic testing, resulting in inaccurate diagnostic reporting of uninterrupted CAG repeat length. Inaccurate reporting of CAG repeat length results in misdiagnosis of individuals with alleles near diagnostic cut-offs.

The frequency and clinical impact of synonymous HTT loss-of-interruption and duplication-of-interruption variants in a diverse HD cohort.

Purpose: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD).

Methods: We screened symptomatic HD participants from the UBC HD Biobank and 5 research sites for sequence variants. After variant identification, we examined the clinical impact and frequency in the reduced penetrance range.

International consensus statement on the design, delivery and evaluation of sport-based interventions aimed at promoting social, psychological and physical well-being in prison.

Objective: To develop an international consensus statement to advise on designing, delivering and evaluating sport-based interventions (SBIs) aimed at promoting social, psychological and physical well-being in prison.

Design: Modified Delphi using two rounds of survey questionnaires and two consensus workshops.

Participants: A multidisciplinary panel of more than 40 experts from 15 international jurisdictions was formed, including representation from the following groups and stakeholders: professionals working in the justice system; officials from sport federations and organisations; academics with research experience of prisons, secure forensic mental health settings and SBIs; and policy-makers in criminal justice and sport.

Experimental genetic crosses in tsetse flies of the livestock pathogen Trypanosoma congolense savannah.

Background: In tropical Africa animal trypanosomiasis is a disease that has severe impacts on the health and productivity of livestock in tsetse fly-infested regions. Trypanosoma congolense savannah (TCS) is one of the main causative agents and is widely distributed across the sub-Saharan tsetse belt. Population genetics analysis has shown that TCS is genetically heterogeneous and there is evidence for genetic exchange, but to date Trypanosoma brucei is the only tsetse-transmitted trypanosome with experimentally proven capability to undergo sexual reproduction, with meiosis and production of haploid gametes.

Defining eukaryotes to dissect eukaryogenesis.

The origin of eukaryotes is among the most contentious debates in evolutionary biology, attracting multiple seemingly incompatible theories seeking to explain the sequence in which eukaryotic characteristics were acquired. Much of the controversy arises from differing views on the defining characteristics of eukaryotes. We argue that eukaryotes should be defined phylogenetically, and that doing so clarifies where competing hypotheses of eukaryogenesis agree and how we may test among aspects of disagreement.

Development of the livestock pathogen Trypanosoma (Nannomonas) simiae in the tsetse fly with description of putative sexual stages from the proboscis.

Background: Tsetse-transmitted African animal trypanosomiasis is recognised as an important disease of ruminant livestock in sub-Saharan Africa, but also affects domestic pigs, with Trypanosoma simiae notable as a virulent suid pathogen that can rapidly cause death. Trypanosoma simiae is widespread in tsetse-infested regions, but its biology has been little studied compared to T. brucei and T.

Development and Evaluation of a Sound-Swapped Video Database for Misophonia.

Misophonia has been characterized as intense negative reactions to specific trigger sounds (often orofacial sounds like chewing, sniffling, or slurping). However, recent research suggests high-level, contextual, and multisensory factors are also involved. We recently demonstrated that neurotypicals' negative reactions to aversive sounds (e.

Single-cell transcriptomics reveals expression profiles of Trypanosoma brucei sexual stages.

Early diverging lineages such as trypanosomes can provide clues to the evolution of sexual reproduction in eukaryotes. In Trypanosoma brucei, the pathogen that causes Human African Trypanosomiasis, sexual reproduction occurs in the salivary glands of the insect host, but analysis of the molecular signatures that define these sexual forms is complicated because they mingle with more numerous, mitotically-dividing developmental stages. We used single-cell RNA-sequencing (scRNAseq) to profile 388 individual trypanosomes from midgut, proventriculus, and salivary glands of infected tsetse flies allowing us to identify tissue-specific cell types.

pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by mutant huntingtin (mHTT). Phosphorylation at serine-421 (pS421) of mHTT has been shown to be neuroprotective in cellular and rodent models. However, the genetic context of these models differs from that of HD patients.

Correction: Kaiseler, M., et al. The Impact of an Outdoor and Adventure Sports Course on the Wellbeing of Recovering UK Military Personnel: An Exploratory Study. 2019, , 112.

The authors wish to make the following corrections to this paper [...

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range.

Purpose: In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients.

Tracing the mutated HTT and haplotype of the African ancestor who spread Huntington disease into the Middle East.

Purpose: We aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East.

Methods: We performed genetic and genealogical analyses to establish the ancestral origin of the HTT pathgenic variant from a large kindred from Oman (hereafter called the OM-HD-01 pedigree) by single-nucleotide polymorphism and dense haplotype analysis genotyping.

Results: We traced the oldest ancestry of the largest, eight-generation, OM-HD-01 pedigree (n = 302 subjects, with 54 showing manifest HD) back to sub-Saharan Africa and identified a unique HD haplotype carried by all pedigree members, which consisted of portions of the C6 and C9 haplotypes and was carried by all affected members.

Health and Wellbeing in an Outdoor and Adventure Sports Context.

Outdoor and adventure sports (OAS) have been linked to positive health and wellbeing outcomes. This Special Edition brings together cutting-edge research and thought on the implications of this link. An analysis of the papers in this Special Edition reveals important insights into (i) the diverse and powerful outcomes derived from adventure experiences, (ii) how adventure experiences facilitate these outcomes, (iii) how best to design outdoor and adventure experiences.

A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry.

Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.

Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed.

The Impact of an Outdoor and Adventure Sports Course on the Wellbeing of Recovering UK Military Personnel: An Exploratory Study.

UK military personnel have faced increased demands over the last three decades; these have affected their wellbeing and caused multiple physical and mental health problems. Currently, bespoke rehabilitation systems may recommend participation in sports programmes. Although research attention has been drawn to the short-term positive effects of these programmes, their long-term impact on psychological wellbeing is unknown.

Trypanosoma congolense: In Vitro Culture and Transfection.

Trypanosoma congolense, together with T. vivax and T. brucei, causes African animal trypanosomiasis (AAT), or nagana, a livestock disease carried by bloodsucking tsetse flies in sub-Saharan Africa.

The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population.

Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available.

Epidemiology of Huntington disease.

Huntington disease (HD) is an autosomal-dominant neurologic disorder caused by an expanded CAG trinucleotide repeat mutation in patients with characteristic motor signs and specific brain pathology. A repeat of 36 CAG or more can lead to the disease, with increased penetrance and decreased age of onset at longer CAG repeats. The epidemiology of HD thus depends on ascertainment of individuals with the expanded CAG mutation, and on examination of clinical signs to accurately assess disease onset.

A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles.

Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit.

An enhanced Q175 knock-in mouse model of Huntington disease with higher mutant huntingtin levels and accelerated disease phenotypes.

Huntington disease (HD) model mice with heterozygous knock-in (KI) of an expanded CAG tract in exon 1 of the mouse huntingtin (Htt) gene homolog genetically recapitulate the mutation that causes HD, and might be favoured for preclinical studies. However, historically these mice have failed to phenotypically recapitulate the human disease. Thus, homozygous KI mice, which lack wildtype Htt, and are much less relevant to human HD, have been used.

Huntington disease reduced penetrance alleles occur at high frequency in the general population.

Objective: To directly estimate the frequency and penetrance of CAG repeat alleles associated with Huntington disease (HD) in the general population.

Methods: CAG repeat length was evaluated in 7,315 individuals from 3 population-based cohorts from British Columbia, the United States, and Scotland. The frequency of ≥36 CAG alleles was assessed out of a total of 14,630 alleles.