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

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

Time-lapsing biodiversity: an open source method for measuring diversity changes by remote sensing

Understanding biodiversity changes in time is crucial to promptly provide management practices against diversity loss. This is overall true when considering global scales, since human-induced global change is expected to make significant changes on the Earth's biota. Biodiversity management and planning is mainly based on field observations related to community diversity, considering different taxa. However, such methods are time and cost demanding and do not allow in most cases to get temporal replicates. In this view, remote sensing can provide a wide data coverage in a short period of time. Recently, the use of Rao's Q diversity as a measure of spectral diversity has been proposed in order to explicitly take into account differences in a neighbourhood considering abundance and relative distance among pixels. The aim of this paper was to extend such a measure over the temporal dimension and to present an innovative approach to calculate remotely sensed temporal diversity. We demonstrated that temporal beta-diversity (spectral turnover) can be calculated pixel-wise in terms of both slope and coefficient of variation and further plotted over the whole matrix / image. From an ecological and operational point of view, for prioritisation practices in biodiversity protection, temporal variability could be beneficial in order to plan more efficient conservation practices starting from spectral diversity hotspots in space and time. In this paper, we delivered a highly reproducible approach to calculate spatio-temporal diversity in a robust and straightforward manner. Since it is based on open source code, we expect that our method will be further used by several researchers and landscape managers

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

The Hip Fracture Surgery in Elderly Patients (HIPELD) study: protocol for a randomized, multicenter controlled trial evaluating the effect of xenon on postoperative delirium in older patients undergoing hip fracture surgery

BackgroundStrategies to protect the brain from postoperative delirium (POD) after hip fracture are urgently needed. The development of delirium often is associated with the loss of independence, poor functional recovery, and increased morbidity, as well as increases in length of hospital stay, discharges to nursing facilities, and healthcare costs. We hypothesize that xenon may reduce the burden of POD, (i) by avoiding the need to provide anesthesia with a drug that targets the γ-amino-butyric acid (GABA)A receptor and (ii) through beneficial anesthetic and organ-protective effects.Methods and designAn international, multicenter, phase 2, prospective, randomized, blinded, parallel group and controlled trial to evaluate the incidence of POD, diagnosed with the Confusion Assessment Method (CAM), in older patients undergoing hip fracture surgery under general anesthesia with xenon or sevoflurane, for a period of 4 days post surgery (primary outcome) is planned. Secondary objectives are to compare the incidence of POD between xenon and sevoflurane, to evaluate the incidence of POD from day 5 post surgery until discharge from hospital, to determine the time to first POD diagnosis, to evaluate the duration of POD, to evaluate the evolution of the physiological status of the patients in the postoperative period, to evaluate the recovery parameters, to collect preliminary data to evaluate the economical impact of POD in the postoperative period and to collect safety data. Patients are eligible if they are older aged (≥ 75 years) and assigned to a planned hip fracture surgery within 48 h after the hip fracture. Furthermore, patients need to be willing and able to complete the requirements of this study including the signature of the written informed consent. A total of 256 randomized patients in the 10 participating centers will be recruited, that is, 128 randomized patients in each of the 2 study groups (receiving either xenon or sevoflurane).Trial registrationEudraCT Identifier: 2009-017153-35; ClinicalTrials.gov Identifier: NCT0119927

PKCε-dependent signalling in cardiac differentiation

The Protein kinase C (PKC) family, composed by 12 different isoforms, plays a pivotal role in many biological contexts such as cell differentiation, proliferation and survival. PKCe has been demonstrated to be relevant for cardio-protection as well as in ischemia-reperfusion injury (Budas et al. 2010). Transgenic mice over-expressing a constitutively active PKCε show concentric hypertrophy (Takeishi et al. 2000) suggesting negative effects of a permanently active PKCε in cardiac cells. Although the effects of PKCε over-expression have been analyzed both from the physiological and morphological points of view, molecular studies of its consequences on early cardiac marker gene expression are still lacking. On the other side Bone Marrow Mesenchymal Stem Cells (BMMSCs) can be induced to acquire a cardiac fate by treatment with 5-azacytidine (5-AZ) (Wakitani et al. 1995), representing a good in vitro model for cardiac differentiation studies. We addressed the role of in vivo PKCε over-expression on early cardiac genes (namely, nkx2.5 and gata4) regulation. Our results suggest a negative role of PKCε, mediated by ERK1/2, on expression of these two genes both in vivo and in ex-vivo rat BMMSCs, showing that this protein is a fine tuner of precursor cardiac cells