Terrestrial Alteration Mineral Assemblages in the NWA 10416 Olivine Phyric Shergottite

We report on the alteration history of the olivine-phyric, highly depleted (HD) shergottite, Northwest Africa (NWA) 10416, paying particular attention to the origin of the aqueous alteration seen affecting the meteorite’s olivine megacrysts. The rock’s interior displays 1 mm, zoned, altered olivine megacrysts set in a groundmass of clinopyroxene, unzoned olivine, and interstitial plagioclase and maskelynite. Synchrotron micro X-ray diffraction (µ-XRD) and transmission electron microscopy (TEM) show that plagioclase and maskelynite have been partially replaced by kaolinite. The relict olivine megacryst cores display a unique concentric colouration for Martian meteorites, having central amber-coloured zones surrounded by a brown mantle zone, with the rims remaining clear and unaltered. This colouration is a result of fluid alteration and partial replacement, with hydration. TEM analysis revealed the ∼200 nm scale banded and largely amorphous nature of the alteration, but with some (∼ 20%) relict crystalline olivine patches. Although the coloured olivine zones show cation and anion site vacancies compared to stoichiometric olivine, a relict igneous compositional trend is preserved in the megacrysts, from Mg-rich altered cores (Mg# = 76) to unaltered stoichiometric rims (Fo53). Synchrotron Fe-K X-ray absorption near-edge structure (XANES) analysis revealed that the coloured zones of the megacryst have different Fe oxidation values. High ferric contents are present in the brown mantle zones (Fe3+/ΣFe ≤ 0.92) and the amber zones (Fe3+/ΣFe ≤ 0.30), whereas the clear rims are ferrous. This suggests alteration occurred in an oxidising environment and that the sharp contrast in colour of the megacryst (brown to clear) is a record of a relict fluid reaction front. In order to test the terrestrial or extraterrestrial origin of the alteration, olivine material from a shock-melt vein was analysed by TEM. The analysis revealed 0.952 nm curved d-spacing’s from clay alteration undisturbed by any shock effects, strongly suggesting a terrestrial origin. The d-spacing values most likely represent a collapsed saponite or vermiculite, showing that in some places olivine has been replaced by crystalline clay. Oxygen isotope analysis of bulk (Δ17O = 0.309 ± 0.009 (2σ) ‰) and amber-coloured megacryst material (= 0.271 ± 0.002 (2σ) ‰), are also consistent with terrestrial alteration. We propose a model in which, during the meteorite’s time in Northwest Africa, low-temperature, likely acidic, groundwater exploited fractures. The fluid altered the olivine megacrysts in a way that was controlled by the pre-existing, igneous compositional zonation, with Mg-rich olivine being more susceptible to alteration in this fluid environment. The plagioclase and maskelynite were also altered to a high degree. After the alteration event it is likely that NWA 10416 had a significant residence time in Northwest Africa, accounting for terrestrial calcite and the dehydration of some clay phases

A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient Cavalier King Charles Spaniels is amenable to exon 51 skipping

BACKGROUND Duchenne muscular dystrophy (DMD), which afflicts 1 in 3500 boys, is one of the most common genetic disorders of children. This fatal degenerative condition is caused by an absence or deficiency of dystrophin in striated muscle. Most affected patients have inherited or spontaneous deletions in the dystrophin gene that disrupt the reading frame resulting in unstable truncated products. For these patients, restoration of the reading frame via antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach. The major DMD deletion "hot spot" is found between exons 45 and 53, and skipping exon 51 in particular is predicted to ameliorate the dystrophic phenotype in the greatest number of patients. Currently the mdx mouse is the most widely used animal model of DMD, although its mild phenotype limits its suitability in clinical trials. The Golden Retriever muscular dystrophy (GRMD) model has a severe phenotype, but due to its large size, is expensive to use. Both these models have mutations in regions of the dystrophin gene distant from the commonly mutated DMD "hot spot". METHODOLOGY/PRINCIPAL FINDINGS Here we describe the severe phenotype, histopathological findings, and molecular analysis of Cavalier King Charles Spaniels with dystrophin-deficient muscular dystrophy (CKCS-MD). The dogs harbour a missense mutation in the 5' donor splice site of exon 50 that results in deletion of exon 50 in mRNA transcripts and a predicted premature truncation of the translated protein. Antisense oligonucleotide-mediated skipping of exon 51 in cultured myoblasts from an affected dog restored the reading frame and protein expression. CONCLUSIONS/SIGNIFICANCE Given the small size of the breed, the amiable temperament and the nature of the mutation, we propose that CKCS-MD is a valuable new model for clinical trials of antisense oligonucleotide-induced exon skipping and other therapeutic approaches for DMD

Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy

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

Functional Electrical Stimulation following nerve injury in a Large Animal Model.

INTRODUCTION: Controversy exists over the effects of functional electrical stimulation (FES) on reinnervation. We hypothesized that intramuscular FES would not delay reinnervation after recurrent laryngeal nerve (RLn) axonotmesis. METHODS: RLn cryo-injury and electrode implantation in ipsilateral posterior cricoarytenoid muscle (PCA) were performed in horses. PCA was stimulated for 20 weeks in eight animals; seven served as controls. Reinnervation was monitored through muscle response to hypercapnia, electrical stimulation and exercise. Ultimately, muscle fiber type proportions and minimum fiber diameters, and RLn axon number and degree of myelination were determined. RESULTS: Laryngeal function returned to normal in both groups within 22 weeks. FES improved muscle strength and geometry, and induced increased type I:II fiber proportion (p=0.038) in the stimulated PCA. FES showed no deleterious effects on reinnervation. DISCUSSION: Intramuscular electrical stimulation did not delay PCA reinnervation after axonotmesis. FES can represent a supportive treatment to promote laryngeal functional recovery after RLn injury. This article is protected by copyright. All rights reserved

Assessment of discharge treatment prescribed to women admitted to hospital for hyperemesis gravidarum

Aims: Prescribing drug treatment for the management of hyperemesis gravidarum (HG), the most severe form of nausea and vomiting in pregnancy, remains controversial. Since most manufacturers do not recommend prescribing antiemetics during pregnancy, little is known regarding which treatments are most prevalent among pregnant patients. Here we report for the first time, evidence of actual treatments prescribed in English hospitals.Methods: A retrospective pregnancy cohort was constructed using anonymised electronic records in the Nottingham University Hospitals Trust system for all women who delivered between January 2010 and February 2015. For women admitted to hospital for HG, medications prescribed on discharge were described and variation by maternal characteristics was assessed. Compliance with local and national HG treatment guidelines was evaluated.Results: Of 33,567 pregnancies (among 30,439 women), the prevalence of HG was 1.7%. Among 530 HG admissions with records of discharge drugs, Cyclizine was the most frequently prescribed (almost 73% of admissions). Prochlorperazine and metoclopramide were prescribed mainly in combination with other drugs, however, ondansetron was more common than metoclopramide at discharge from first and subsequent admissions. Steroids were only prescribed following readmissions. Thiamine was most frequently prescribed following readmission while high dose of folic acid was prescribed equally after first or subsequent admissions. Prescribing showed little variation by maternal age, ethnicity, weight, socioeconomic deprivation, or comorbidities.Conclusion: Evidence that management of HG in terms of discharge medications mainly followed local and national recommendations provides reassurance within the health professional community. Wider documentation of drugs prescribed to women with HG is required to enable full assessment of whether optimal drug management is being achieved

Characterizing Rock Abundance At ExoMars Landing Site Candidates

We present preliminary work to characterize surface rock abundance at ExoMars Rover landing site candidates. A challenge in quantifying the abundance of surface rocks is using the population of large (≳1 m) rocks that are resolved in orbital images to infer the size of the smaller, unresolved rock population. This is particularly relevant for the ExoMars Rover mission, where the Landing Module’s clearance of 35 cm makes it necessary to know the probability of encountering rocks where 0.35 < D < 1 m. ‘Float rocks’ are individual fragments of rock not associated with a continuous outcrop or body of rock —e.g. transported rocks or impact debris. These can be identified in Mars Reconnaissence Orbiter HiRISE images, where the mid-afternoon local solar time, dictated by MROs’ orbit, causes float rocks to appear as bright sunlit features adjacent to strong shadows. However, the smallest features resolvable in HiRISE images occupy around 3-4 pixels, corresponding to ~1-m sized rocks. This inherently limits the ability to directly identify from orbit the small, but potentially hazardous rock population. ‘Outcrop’ is defined as continuous expanses of bedrock or surficial deposits exposed at the surface. Both float rocks and outcrop can contribute to slopes that may constitute a hazard for landed missions. We present rock counts at ExoMars Rover landing site candidates and assess approaches to constrain the morphological characteristics of Mars’ surface that are relevant to rover and lander safety

Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1)

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

Towards a first-principles theory of surface thermodynamics and kinetics

Understanding of the complex behavior of particles at surfaces requires detailed knowledge of both macroscopic and microscopic processes that take place; also certain processes depend critically on temperature and gas pressure. To link these processes we combine state-of-the-art microscopic, and macroscopic phenomenological, theories. We apply our theory to the O/Ru(0001) system and calculate thermal desorption spectra, heat of adsorption, and the surface phase diagram. The agreement with experiment provides validity for our approach which thus identifies the way for a predictive simulation of surface thermodynamics and kinetics.Comment: 4 pages including 3 figures. Related publications can be found at http://www.fhi-berlin.mpg.de/th/paper.htm

Identification and validation of genetic variants predictive of gait in standardbred horses

Several horse breeds have been specifically selected for the ability to exhibit alternative patterns of locomotion, or gaits. A premature stop codon in the gene DMRT3 is permissive for “gaitedness” across breeds. However, this mutation is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, respectively, during harness racing. This suggests that modifying alleles must influence the preferred gait at racing speeds in these populations. A genome-wide association analysis for the ability to pace was performed in 542 Standardbred horses (n = 176 pacers, n = 366 trotters) with genotype data imputed to ~74,000 single nucleotide polymorphisms (SNPs). Nineteen SNPs on nine chromosomes (ECA1, 2, 6, 9, 17, 19, 23, 25, 31) reached genome-wide significance (p < 1.44 x 10−6). Variant discovery in regions of interest was carried out via whole-genome sequencing. A set of 303 variants from 22 chromosomes with putative modifying effects on gait was genotyped in 659 Standardbreds (n = 231 pacers, n = 428 trotters) using a high-throughput assay. Random forest classification analysis resulted in an out-of-box error rate of 0.61%. A conditional inference tree algorithm containing seven SNPs predicted status as a pacer or trotter with 99.1% accuracy and subsequently performed with 99.4% accuracy in an independently sampled population of 166 Standardbreds (n = 83 pacers, n = 83 trotters). This highly accurate algorithm could be used by owners/trainers to identify Standardbred horses with the potential to race as pacers or as trotters, according to the genotype identified, prior to initiating training and would enable fine-tuning of breeding programs with designed matings. Additional work is needed to determine both the algorithm’s utility in other gaited breeds and whether any of the predictive SNPs play a physiologically functional role in the tendency to pace or tag true functional alleles