Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models.

Systemic delivery of antisense oligonucleotides (AO) for DMD exon skipping has proven effective for reframing DMD mRNA, rescuing dystrophin expression, and slowing disease progression in animal models. In humans with Duchenne muscular dystrophy treated with AOs, low levels of dystrophin have been induced, and modest slowing of disease progression has been observed, highlighting the need for improved efficiency of human skipping drugs. Here, we demonstrate that dantrolene and Rycals S107 and ARM210 potentiate AO-mediated exon skipping of exon 44 or exon 45 in patient-derived myotube cultures with appropriate mutations. Further, dantrolene is shown to boost AO-mediated exon skipping in patient-derived, induced cardiomyocyte cultures. Our findings further validate the ryanodine receptors (RyR) as the likely target responsible for exon skip boosting and demonstrate potential applicability beyond exon 51 skipping. These data provide preclinical support of dantrolene trial as an adjuvant to AO-mediated exon-skipping therapy in humans and identify a novel Rycal, ARM210, for development as a potential exon-skipping booster. Further, they highlight the value of mutation-specific DMD culture models for basic discovery, preclinical drug screening and translation of personalized genetic medicines

Deep Equatorial Pacific Ocean Oxygenation and Atmospheric CO\u3csub\u3e2\u3c/sub\u3e Over the Last Ice Age

Ventilation of carbon stored in the deep ocean is thought to play an important role in atmospheric CO2 increases associated with Pleistocene deglaciations. The presence of this respired carbon has been recorded by an array of paleoceanographic proxies from various locations across the global ocean. Here we present a new sediment core from the Eastern Equatorial Pacific (EEP) Ocean spanning the last 180,000 years and reconstruct high-resolution 230Th-derived fluxes of 232Th and excess barium, along with redox-sensitive uranium concentrations to examine past variations in dust delivery, export productivity, and bottom-water oxygenation, respectively. Our bottom-water oxygenation record is compared to other similar high-resolution records from across the Pacific and in the Southern Ocean. We suggest that the deep Pacific is a site of respired carbon storage associated with periods of decreased global atmospheric CO2 concentration during the LGM, confirming the conclusions from a wealth of previous studies. However, our study is the first to show a similar relationship beyond the last glacial, extending to at least 70,000 years

High prevalence of anti-hepatitis e virus antibodies among blood donors in central Italy, february to march 2014

Prevalence of anti-hepatitis E virus (HEV) antibodies is highly variable in developed countries, which seems partly due to differences in assay sensitivity. Using validated sensitive assays, we tested 313 blood donors attending a hospital transfusion unit in central Italy in January and February 2014 for anti-HEV IgG and IgM and HEV RNA. Data on HEV exposure were collected from all donors. Overall anti-HEV IgG prevalence was 49% (153/313). Eating raw dried pig-liver sausage was the only independent predictor of HEV infection (adjusted prevalence rate ratio = 2.14; 95% confidence interval: 1.23–3.74). Three donors were positive for either anti-HEV IgM (n = 2; 0.6%) or HEV RNA (n = 2; 0.6%); they were completely asymptomatic, without alanine aminotransferase (ALT) abnormalities. Of the two HEV RNA-positive donors (both harbouring genotype 3), one was anti-HEV IgG- and IgM-positive, the other was anti-HEV IgG- and IgM-negative. The third donor was positive for anti-HEV IgG and IgM but HEV RNA-negative. HEV infection is therefore hyperendemic among blood donors (80% men 18–64 years-old) from central Italy and associated with local dietary habits. Nearly 1% of donors have acute or recent infection, implying potential transmission to blood recipients. Neither ALT nor anti-HEV IgM testing seems useful to prevent transfusion-transmitted HEV infection. © 2016, European Centre for Disease Prevention and Control

Developing and implementing an integrated delirium prevention system of care:a theory driven, participatory research study

Background: Delirium is a common complication for older people in hospital. Evidence suggests that delirium incidence in hospital may be reduced by about a third through a multi-component intervention targeted at known modifiable risk factors. We describe the research design and conceptual framework underpinning it that informed the development of a novel delirium prevention system of care for acute hospital wards. Particular focus of the study was on developing an implementation process aimed at embedding practice change within routine care delivery. Methods: We adopted a participatory action research approach involving staff, volunteers, and patient and carer representatives in three northern NHS Trusts in England. We employed Normalization Process Theory to explore knowledge and ward practices on delirium and delirium prevention. We established a Development Team in each Trust comprising senior and frontline staff from selected wards, and others with a potential role or interest in delirium prevention. Data collection included facilitated workshops, relevant documents/records, qualitative one-to-one interviews and focus groups with multiple stakeholders and observation of ward practices. We used grounded theory strategies in analysing and synthesising data. Results: Awareness of delirium was variable among staff with no attention on delirium prevention at any level; delirium prevention was typically neither understood nor perceived as meaningful. The busy, chaotic and challenging ward life rhythm focused primarily on diagnostics, clinical observations and treatment. Ward practices pertinent to delirium prevention were undertaken inconsistently. Staff welcomed the possibility of volunteers being engaged in delirium prevention work, but existing systems for volunteer support were viewed as a barrier. Our evolving conception of an integrated model of delirium prevention presented major implementation challenges flowing from minimal understanding of delirium prevention and securing engagement of volunteers alongside practice change. The resulting Prevention of Delirium (POD) Programme combines a multi-component delirium prevention and implementation process, incorporating systems and mechanisms to introduce and embed delirium prevention into routine ward practices. Conclusions: Although our substantive interest was in delirium prevention, the conceptual and methodological strategies pursued have implications for implementing and sustaining practice and service improvements more broadly

Dust from Mars-Analog Plains (Iceland): Physico-Compositional Properties as a Function of Grain-Size Fraction

Dust is a key component of the geological and climatic systems of Earth and Mars. On Mars, dust is ubiquitous. It coats rocks and soils, and, in the atmosphere, it interacts strongly with solar and thermal radiation. Yet, key questions remain about the genesis and fate of martian dust, as well as its sources, composition, and properties. We collected wind-blown dust from basaltic plains in SW Iceland at Skjaldbreiauhraun that represent a geologic Mars-analog environment. Icelandic dust differs from the typical continental sources (e.g. Sahara, Asia) because of its basaltic volcanogenic origin, which is similar to Mars. Dust collection took place in July of 2019 as a complementary project to the SAND-E: Semi-Autonomous Navigation for Detrital Environments project. Here we report preliminary analyses of this Mars-analog dust material, with the goal of understanding the processes that control the physico-chemical proper-ties of the different grain-size fractions

UVES observations of QSO 0000-2620: oxygen and zinc abundances in the Damped Ly-alpha galaxy at z_abs=3.3901

Observations of the QSO 0000-2620 with UVES spectrograph at the 8.2m ESO KUEYEN telescope are used for abundance analysis of the damped Ly-alpha system at z_{abs}=3.3901. Several Oxygen lines are identified in the Ly_alpha forest and a measure for the oxygen abundance is obtained at [O/H]=-1.85 +/- 0.1 by means of the unsaturated OI 925 A and OI 950 A lines. This represents the most accurate O measurement in a damped Ly_alpha galaxy so far. We have also detected ZnII 2026 A and CrII 2056, 2062 A redshifted at about 8900 A and found abundances [Zn/H] = -2.07 +/- 0.1 and [Cr/H]=-1.99 +/- 0.1. Furthermore, previous measurements of Fe, Si, Ni and N have been refined yielding [Fe/H]=-2.04 +/- 0.1, [Si/H]=-1.90 +/- 0.1, [Ni/H]=-2.27 +/- 0.1, and [N/H]=-2.68 +/- 0.1. The abundance of the non-refractory element zinc is the lowest among the damped Ly-alpha systems showing that the associated intervening galaxy is indeed in the early stages of its chemical evolution. The fact that the Zn abundance is identical to that of the refractory elements Fe and Cr suggests that dust grains have not formed yet. In this Damped Ly-alpha system the observed [O,S,Si/Zn,Fe,Cr] ratios, in whatever combination are taken, are close to solar (i.e 0.1-0.2 dex) and do not show the [alpha-element/Fe] enhancement observed in Milky Way stars of comparable metallicity. The observed behavior supports a galaxy evolution model characterized by either episodic or low star formation rate rather than a Milky-Way-type evolutionary model.Comment: Accepted by Ap

Updated distribution of Osmoderma eremita in Abruzzo (Italy) and agro-pastoral practices affecting its conservation (Coleoptera: Scarabaeidae)

New records of Osmoderma eremita (Scopoli, 1763) (Coleoptera: Scarabaeidae: Cetoniinae) are reported for Abruzzo (Italy), together with a review of its distribution in this region. O. eremita is a saproxylic beetle dependent on the presence of hollow deciduous trees with abundant wood mould in their cavities. The major threats for the species are habitat loss and fragmentation. EU Habitats Directive requests to the member States its protection and the monitoring of its conservation status. Detection of its occurrence is the first step to protect the species. The surveys have been carried out in ten sites of Abruzzo by using black cross-windows traps baited with specific pheromone. The species has been recorded for the first time in the Sant'Antonio forest and its presence is confirmed in the Peligna Valley, after a decade. The populations seem to be confined to small patches of suitable habitats. At local level, the abandonment of the pollarding practice (willow and beech forests) and the use of pollarded trees as biomass for fuel are the major threats for this species. Indeed some key actions, such as the protection of old hollow trees and the continuation of pollarding practice in rural landscape, could be key factors for the conservation strategies of the species in the study area

Predicting the northward expansion of tropical lineage Rhipicephalus sanguineus sensu lato ticks in the United States and its implications for medical and veterinary health

The tropical lineage within the Rhipicephalus sanguineus species complex is cause for growing concern in the U.S. based on its prominent role in creating and perpetuating multiple recently identified outbreaks of Rocky Mountain spotted fever in the southwestern United States and northern Mexico. This lineage is undergoing a northward range expansion in the United States, necessitating the need for enhanced surveillance for Rh. sanguineus. To inform more focused surveillance efforts we use species distribution models (SDMs) to predict current (2015–2019) and future (2021–2040) habitat for the tropical lineage. Models using the MaxEnt algorithm were informed using geolocations of ticks genetically confirmed to be of the tropical lineage, for which data on 23 climatic and ecological variables were extracted. Models predicted that suitability was optimal where temperatures are relatively warm and stable, and there is minimal precipitation. This translated into habitat being predicted along much of the coast of southern states including California, Texas, Louisiana, and Florida. Although the endophilic nature of tropical Rh. sanguineus somewhat violates the assumptions of SDMs, our models correctly predicted known locations of this tick and provide a starting point for increased surveillance efforts. Furthermore, we highlight the importance of using molecular methods to distinguish between ticks in the Rh. sanguineus species complex.EEA RafaelaFil: Pascoe, Emily L. University of California. School of Veterinary Medicine. Department of Medicine and Epidemiology; Estados UnidosFil: Pascoe, Emily L. Wageningen University & Research. Laboratory of Entomology; Países BajosFil: Nava, Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IDICAL); ArgentinaFil: Nava, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación de la Cadena Láctea (IDICAL); ArgentinaFil: Labruna, Marcelo. Universidade de São Paulo. Faculdade de Medicina Veterinaria e Zootecnia. Departamento de Medicina Veterinaria Preventiva e Saude Animal; BrasilFil: Paddock, Christopher D. United States Department of Health and Human Services. Centers for Disease Control and Prevention. Division of Vector-Borne Diseases. Rickettsial Zoonoses Branch; Estados UnidosFil: Levin, Michael L. United States Department of Health and Human Services. Centers for Disease Control and Prevention. Division of Vector-Borne Diseases. Rickettsial Zoonoses Branch; Estados UnidosFil: Marcantonio, Matteo. Université Catholique de Louvain. Earth & Life Institute. Evolutionary Ecology and Genetics Group; BélgicaFil: Foley, Janet E. University of California. School of Veterinary Medicine. Department of Medicine and Epidemiology; Estados Unido

Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice

Post-operative cognitive dysfunction (POCD) is associated with increased cost of care, morbidity, and mortality. However, its pathogenesis remains largely to be determined. Specifically, it is unknown why elderly patients are more likely to develop POCD and whether POCD is dependent on general anesthesia. We therefore set out to investigate the effects of peripheral surgery on the cognition and Alzheimer-related neuropathology in mice with different ages. Abdominal surgery under local anesthesia was established in the mice. The surgery induced post-operative elevation in brain β-amyloid (Aβ) levels and cognitive impairment in the 18 month-old wild-type and 9 month-old Alzheimer's disease transgenic mice, but not the 9 month-old wild-type mice. The Aβ accumulation likely resulted from elevation of beta-site amyloid precursor protein cleaving enzyme and phosphorylated eukaryotic translation initiation factor 2α. γ-Secretase inhibitor compound E ameliorated the surgery-induced brain Aβ accumulation and cognitive impairment in the 18 month-old mice. These data suggested that the peripheral surgery was able to induce cognitive impairment independent of general anesthesia, and that the combination of peripheral surgery with aging- or Alzheimer gene mutation-associated Aβ accumulation was needed for the POCD to occur. These findings would likely promote more research to investigate the pathogenesis of POCD