Explore the vast range of titles available.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and a shortened life span. The disease is caused by mutations that reduce or prevent expression of dystrophin, an essential structural protein in skeletal and heart muscle. The gene editing technology CRISPR-Cas9 can correct disease-causing mutations and has yielded promising results in mouse models of DMD. In a small, short-term study, Amoasii et al. tested this strategy in a dog model of DMD that exhibits many features of the human disease. Intramuscular or systemic delivery of the gene editing components resulted in a substantial increase in dystrophin protein levels in skeletal and heart muscle. Restoration of dystrophin expression was accompanied by improved muscle histology. Science , this issue p. 86 Successful CRISPR correction of a dystrophin mutation in dogs increases dystrophin protein expression in skeletal and heart muscle. Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery ( n = 2) or 8 weeks after systemic delivery ( n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

Horse racing is a popular and financially important industry worldwide and researchers and horse owners are interested in genetic and training influences that maximise athletic performance. An association has been found between the presence of a short interspersed nuclear element (SINE) mutation in the myostatin ( MSTN ) gene promoter and optimal race distance in Thoroughbred horses. There is previous laboratory evidence that this mutation reduces MSTN expression in a cell culture model and influences skeletal muscle fibre type proportions in horses. Manipulating MSTN expression has been proposed for illicit gene doping in human and equine athletes and already, researchers have generated homozygous and heterozygous MSTN -null horse embryos following CRISPR/Cas9 editing at the equine MSTN locus and nuclear transfer, aiming artificially to enhance performance. To date however, the role of the naturally-occurring equine MSTN SINE mutation in vivo has remained unclear; here we hypothesised that it reduces, but does not ablate circulating myostatin expression. Following validation of an ELISA for detection of myostatin in equine serum and using residual whole blood and serum samples from 176 Thoroughbred racehorses under identical management, horses were genotyped for the SINE mutation by PCR and their serum myostatin concentrations measured. In our population, the proportions of SINE homozygotes, heterozygotes and normal horses were 27%, 46% and 27% respectively. Results indicated that horses that are homozygous for the SINE mutation have detectable, but significantly lower (p < 0.0001) serum myostatin concentrations (226.8 pg/ml; 69.3–895.4 pg/ml; median; minimum–maximum) than heterozygous (766 pg/ml; 64.6–1182 pg/ml) and normal horses (1099 pg/ml; 187.8–1743 pg/ml). Heterozygotes have significantly lower (p < 0.0001) myostatin concentrations than normal horses. Variation in serum myostatin concentrations across horses was not influenced by age or sex. This is the first study to reveal the direct functional effect of a highly prevalent mutation in the equine MSTN gene associated with exercise performance. Determining the reason for variation in expression of myostatin within SINE-genotyped groups might identify additional performance-associated environmental or genetic influences in Thoroughbreds. Understanding the mechanism by which altered myostatin expression influences skeletal muscle fibre type remains to be determined.

Protecting individuals and households against mosquito bites with long-lasting insecticidal nets (LLINs) or indoor residual spraying (IRS) can suppress entire populations of unusually efficient malaria vector species that predominantly feed indoors on humans. Mosquitoes which usually feed on animals are less reliant on human blood, so they are far less vulnerable to population suppression effects of such human-targeted insecticidal measures. Fortunately, the dozens of mosquito species which primarily feed on animals are also relatively inefficient vectors of malaria, so personal protection against mosquito bites may be sufficient to eliminate transmission. However, a handful of mosquito species are particularly problematic vectors of residual malaria transmission, because they feed readily on both humans and animals. These unusual vectors feed often enough on humans to be potent malaria vectors, but also often enough on animals to evade population control with LLINs, IRS or any other insecticidal personal protection measure targeted only to humans. Anopheles arabiensis and A. coluzzii in Africa, A. darlingi in South America and A. farauti in Oceania, as well as A. culicifacies species E, A. fluviatilis species S, A. lesteri and A. minimus in Asia, all feed readily on either humans or animals and collectively mediate residual malaria transmission across most of the tropics. Eliminating malaria transmission by vectors exhibiting such dual host preferences will require aggressive mosquito population abatement, rather than just personal protection of humans. Population suppression of even these particularly troublesome vectors is achievable with a variety of existing vector control technologies that remain underdeveloped or underexploited.

Hypoglycin A is a plant-derived protoxin that causes atypical myopathy in equids. In atypical myopathy-affected horses, metabolomic and microbiome studies have reported alterations in metabolic markers and faecal microbiota composition, pointing to a potential disruption of microbial homeostasis. However, in vivo observations are strongly confounded by host-related factors, underscoring the need for controlled in vitro approaches. To address this, we used an in vitro static batch fermentation model simulating the equine colon to investigate the direct effects of hypoglycin A on microbiota composition and activity. Faecal inocula from healthy horses were incubated in control and hypoglycin A-treated fermenters for 48 h, with serial analyses of hypoglycin A concentration, short-chain fatty acids, and 16S rRNA gene profiles. Hypoglycin A remained stable in the nutritive medium in the absence of microbiota, confirming that its degradation in inoculated fermenters was microbiota-dependent. The results showed significant microbial-associated hypoglycin A degradation without evidence of toxic metabolite formation. The analysis of α- and β-diversity revealed both an effect of incubation time, reflecting the natural temporal dynamics of microbial communities under batch fermentation, and a specific impact of hypoglycin A exposure, with certain taxa such as Paraclostridium being affected. This study provides the first in vitro evidence that the equine microbiota contributes to hypoglycin A degradation.

Background There is limited Australian epidemiological research that reports on the foot-health characteristics of people with diabetes, especially within rural and regional settings. The objective of this study was to explore the associations between demographic, socio-economic and diabetes-related variables with diabetes-related foot morbidity in people residing in regional and rural Australia. Methods Adults with diabetes were recruited from non-metropolitan Australian publicly-funded podiatry services. The primary variable of interest was the University of Texas diabetic foot risk classification designated to each participant at baseline. Independent risk factors for diabetes-related foot morbidity were identified using multivariable analysis. Results Eight-hundred and ninety-nine participants enrolled, 443 (49.3%) in Tasmania and 456 (50.7%) in Victoria. Mean age was 67 years (SD 12.7), 9.2% had type 1 diabetes, 506 (56.3%) were male, 498 (55.4%) had diabetes for longer than 10 years and 550 (61.2%) either did not know the ideal HbA1c target or reported that it was ≥7.0. A majority had peripheral neuropathy or worse foot morbidity (61.0%). Foot morbidity was associated with male sex (OR 2.42, 95% CI 1.82–3.22), duration of diabetes > 20 years (OR 3.25, 95% CI 2.22–4.75), and Tasmanian residence (OR 3.38, 95% CI 2.35–4.86). Conclusions A high proportion of the regional Australian clinical population with diabetes seen by the publicly-funded podiatric services in this study were at high risk of future limb threatening foot morbidity, and participants residing in Northern Tasmania are more likely to have worse diabetes-related foot morbidity than those from regional Victoria. Service models should be reviewed to ensure that diabetes-related foot services are appropriately developed and resourced to deliver interdisciplinary evidence-based care.

Background Many of the mosquito species responsible for malaria transmission belong to a sibling complex; a taxonomic group of morphologically identical, closely related species. Sibling species often differ in several important factors that have the potential to impact malaria control, including their geographical distribution, resistance to insecticides, biting and resting locations, and host preference. The aim of this study was to define the geographical distributions of dominant malaria vector sibling species in Africa so these distributions can be coupled with data on key factors such as insecticide resistance to aid more focussed, species-selective vector control. Results Within the Anopheles gambiae species complex and the Anopheles funestus subgroup, predicted geographical distributions for Anopheles coluzzii , An. gambiae (as now defined) and An. funestus (distinct from the subgroup) have been produced for the first time. Improved predicted geographical distributions for Anopheles arabiensis , Anopheles melas and Anopheles merus have been generated based on records that were confirmed using molecular identification methods and a model that addresses issues of sampling bias and past changes to the environment. The data available for insecticide resistance has been evaluated and differences between sibling species are apparent although further analysis is required to elucidate trends in resistance. Conclusions Sibling species display important variability in their geographical distributions and the most important malaria vector sibling species in Africa have been mapped here for the first time. This will allow geographical occurrence data to be coupled with species-specific data on important factors for vector control including insecticide resistance. Species-specific data on insecticide resistance is available for the most important malaria vectors in Africa, namely An. arabiensis , An. coluzzii , An. gambiae and An. funestus . Future work to combine these data with the geographical distributions mapped here will allow more focussed and resource-efficient vector control and provide information to greatly improve and inform existing malaria transmission models.

Equine type 1 polysaccharide storage myopathy (PSSM1), a common glycogenosis associated with an R309H founder mutation in the glycogen synthase 1 gene (GYS1), shares pathological features with several human myopathies. In common with related human disorders, the pathogenesis remains unclear in particular, the marked phenotypic variability between affected animals. Given that affected animals accumulate glycogen and alpha-crystalline polysaccharide within their muscles, it is possible that physical disruption associated with the presence of this material could exacerbate the phenotype. The aim of this study was to compare the histopathological changes in horses with PSSM1, and specifically, to investigate the hypothesis that the severity of underlying pathology, (e.g. vacuolation and inclusion formation) would (1) be higher in homozygotes than heterozygotes and (2) correlate with clinical severity. Resting and post-exercise plasma creatine kinase (CK) and aspartate aminotransferase (AST) enzyme activity measurements and muscle pathology were assessed in matched cohorts of PSSM1 homozygotes, heterozygotes or control horses. Median (interquartile range (IR)) resting CK activities were 364 (332-764) U/L for homozygotes, 301 (222-377) U/L for heterozygotes and 260 (216-320) U/L for controls, and mean (+/- SD) AST activity for homozygotes were 502 (+/116) U/L, for heterozygotes, 357 (+/-92) U/L and for controls, 311 (+/-64) U/L and were significantly different between groups (P = 0.04 and P = 0.01 respectively). Resting plasma AST activity was significantly associated with the severity of subsarcolemmal vacuolation (rho = 0.816; P = 0.01) and cytoplasmic inclusions (rho = 0.766; P = 0.01). There were fewer type 2× and more type 2a muscle fibres in PSSM1-affected horses. Our results indicate that PSSM1 has incomplete dominance. Furthermore, the association between plasma muscle enzyme activity and severity of underlying pathology suggests that physical disruption of myofibres may contribute to the myopathic phenotype. This work provides insight into PSSM1 pathogenesis and has implications for related human glycogenoses.

Exertional rhabdomyolysis syndrome is recognised in many athletic horse breeds and in recent years specific forms of the syndrome have been identified. However, although Standardbred horses are used worldwide for racing, there is a paucity of information about the epidemiological and performance-related aspects of the syndrome in this breed. The objectives of this study therefore were to determine the incidence, risk factors and performance effects of exertional rhabdomyolysis syndrome in Standardbred trotters and to compare the epidemiology and genetics of the syndrome with that in other breeds. A questionnaire-based case-control study (with analysis of online race records) was conducted following identification of horses that were determined susceptible to exertional rhabdomyolysis (based on serum biochemistry) from a total of 683 horses in 22 yards. Thirty six exertional rhabdomyolysis-susceptible horses were subsequently genotyped for the skeletal muscle glycogen synthase (GYS1) mutation responsible for type 1 polysaccharide storage myopathy. A total of 44 susceptible horses was reported, resulting in an annual incidence of 6.4 (95% CI 4.6-8.2%) per 100 horses. Female horses were at significantly greater risk than males (odds ratio 7.1; 95% CI 2.1-23.4; p = 0.001) and nervous horses were at a greater risk than horses with calm or average temperaments (odds ratio 7.9; 95% CI 2.3-27.0; p = 0.001). Rhabdomyolysis-susceptible cases performed better from standstill starts (p = 0.04) than controls and had a higher percentage of wins (p = 0.006). All exertional rhabdomyolysis-susceptible horses tested were negative for the R309H GYS1 mutation. Exertional rhabdomyolysis syndrome in Standardbred horses has a similar incidence and risk factors to the syndrome in Thoroughbred horses. If the disorder has a genetic basis in Standardbreds, improved performance in susceptible animals may be responsible for maintenance of the disorder in the population.

Background Malaria remains a heavy burden across sub-Saharan Africa where transmission is maintained by some of the world’s most efficient vectors. Indoor insecticide-based control measures have significantly reduced transmission, yet elimination remains a distant target. Knowing the relative abundance of the primary vector species can provide transmission models with much needed information to guide targeted control measures. Moreover, understanding how existing interventions are impacting on these relative abundances highlights where alternative control (e.g., larval source management) is needed. Methods Using the habitat suitability probabilities generated by predictive species distribution models combined with data collated from the literature, a multinomial generalized additive model was applied to produce relative abundance estimates for Anopheles arabiensis, Anopheles funestus and Anopheles gambiae/Anopheles coluzzii . Using pre- and post-intervention abundance data, estimates of the effect of indoor insecticide-based interventions on these relative abundances were made and are illustrated in post-intervention maps. Results Conditional effect plots and relative abundance maps illustrate the individual species’ predicted habitat suitability and how they interact when in sympatry. Anopheles arabiensis and An. funestus show an affinity in habitat preference at the expense of An. gambiae / An. coluzzii, whereas increasing habitat suitability for An. gambiae / An. coluzzii is conversely less suitable for An. arabiensis but has little effect on An. funestus. Indoor insecticide-based interventions had a negative impact on the relative abundance of An. funestus, and a lesser effect on An. arabiensis . Indoor residual spraying had the greatest impact on the relative abundance of An. funestus, and a lesser effect on An. gambiae / An. coluzzii . Insecticide-treated bed nets reduced the relative abundance of both species equally. These results do not indicate changes in the absolute abundance of these species, which may be reduced for all species overall. Conclusions The maps presented here highlight the interactions between the primary vector species in sub-Saharan Africa and demonstrate that An. funestus is more susceptible to certain indoor-based insecticide interventions than An. gambiae / An. coluzzii , which in turn, is more susceptible than An. arabiensis . This may provide An. arabiensis with a competitive advantage where it is found in sympatry with other more endophilic vectors, and potentially increase the need for outdoor-based vector interventions to deal with any residual transmission barring the way to malaria elimination.

Anopheles mosquitoes were first recognised as the transmitters of human malaria in the late 19th Century and have been subject to a huge amount of research ever since. Yet there is still much that is unknown regarding the ecology, behaviour (collectively ‘bionomics’) and sometimes even the identity of many of the world’s most prominent disease vectors, much less the within-species variation in their bionomics. Whilst malaria elimination remains an ambitious goal, it is becoming increasingly clear that knowledge of vector behaviour is needed to effectively target control measures. A database of bionomics data for the dominant vector species of malaria worldwide has been compiled from published peer-reviewed literature. The data identification and collation processes are described, together with the geo-positioning and quality control methods. This is the only such dataset in existence and provides a valuable resource to researchers and policy makers in this field. Design Type(s) database creation objective Measurement Type(s) bionomics Technology Type(s) digital curation Factor Type(s) geographic location Sample Characteristic(s) Anopheles arabiensis • funestus group • Anopheles gambiae • gambiae species complex • Anopheles funestus • Anopheles nili • Anopheles moucheti • nili species complex • Anopheles melas • Anopheles gambiae (Forest) • Anopheles gambiae M • Anopheles merus • Anopheles ovengensis • Anopheles carnevalei • Anopheles gambiae S • Anopheles gambiae (Savanna) • Anopheles gambiae (Bamako) • Anopheles gambiae (Mopti) • Anopheles albimanus • Anopheles darlingi • pseudopunctipennis group • Anopheles nuneztovari complex • albitarsis group • Anopheles aquasalis • Anopheles marajoara • Anopheles janconnae • Anopheles nuneztovari(Sp. B/C) • Anopheles albitarsis • Anopheles oryzalimnetes • quadrimaculatus species complex • Anopheles quadrimaculatus • Anopheles freeborni • annularis species complex • culicifacies species complex • Anopheles aconitus • subpictus species complex • dirus species complex • Anopheles maculatus group • minimus species complex • fluviatilis species complex • barbirostris group • Anopheles maculatus • Anopheles barbirostris • Anopheles flavirostris • Anopheles sundaicus • sundaicus species complex • Anopheles sinensis • Anopheles harrisoni • Anopheles dirus • Anopheles minimus • Anopheles balabacensis • Anopheles stephensi • Anopheles lesteri • Anopheles baimaii • Anopheles leucosphyrus • Anopheles cracens • Anopheles fluviatilis T • Anopheles culicifacies A • Anopheles culicifacies B • Anopheles culicifacies C • Anopheles fluviatilis S • Anopheles culicifacies D • Anopheles scanloni • Anopheles epiroticus • Anopheles annularis • punctulatus species complex • Anopheles farauti complex • Anopheles koliensis • Anopheles latens • leucosphyrus species complex • Anopheles subpictus (Sp. B) • Anopheles farauti • Anopheles punctulatus • Anopheles hinesorum • Anopheles farauti No. 4 • Anopheles farauti (No. 8) • Anopheles fluviatilis U • Anopheles annularis A • Anopheles culicifacies E • anthropogenic habitat Machine-accessible metadata file describing the reported data (ISA-Tab format)