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Since the discovery of Rift Valley Fever virus (RVFV) in Kenya in 1930, the virus has become widespread throughout most of Africa and is characterized by sporadic outbreaks. A mosquito-borne pathogen, RVFV is poised to move beyond the African continent and the Middle East and emerge in Europe and Asia. There is a risk that RVFV could also appear in the Americas, similar to the West Nile virus. In light of this potential threat, multiple studies have been undertaken to establish international surveillance programs and diagnostic tools, develop models of transmission dynamics and risk factors for infection, and to develop a variety of vaccines as countermeasures. Furthermore, considerable efforts to establish reliable challenge models of Rift Valley fever virus have been made and platforms for testing potential vaccines and therapeutics in target species have been established. This review emphasizes the progress and insights from a North American perspective to establish challenge models in target livestock such as cattle, sheep, and goats in comparisons to other researchers' reports. A brief summary of the potential role of wildlife, such as buffalo and white-tailed deer as reservoir species will also be discussed.A screening program for hip dysplasia (HD) was introduced in Sweden during the 1950s for German shepherd dogs, before for a few breeds and now any breed. Degree of canine HD was originally graded 1-4 (slight, mild, moderate, and severe) and used in Swedish screening program up to year 2000 and was thereafter replaced by letters A-E with A and B for no signs/near normal, C for mild, D for moderate, and E for severe HD. Final scoring is based on "the worst" side. In Sweden, 70% of all dogs are registered by the Swedish Kennel Club, and in relevant breeds, almost all breeding stock and 30-50% of all dogs are screened for HD. By an extensive database of all dogs registered since 1976 and mandatory identification by microchip, all results can be linked to dogs well-defined by identity and ancestral background. An implementation of structured screening and genetic health programs resulted in markedly decreased prevalence of HD already during the 1980s. The programs are based on open registries and on positive as well as negative results for identified individuals linked to their ancestral background. The successful decrease in moderate and severe HDs is illustrated for seven common breeds. However, there is also the challenge of a further decrease when already almost all breeding is performed with unaffected breeding stock. Handling that and the increased relative prevalence of less severe grades of HD (grade C) calls for breed-specific breeding strategies, taking into account the prevalence and clinical significance in each breed. Further decrease might rather be achieved by using estimated breeding values and genomic selection instead of more extensive and costly screening procedures. For the public perception of HD, the value of a clear distinction between grades D and E as a good predictor of the clinical entity vs. grade C as a tool to refine the selection criteria for breeding stock is indicated.Migrating from a binary approach to risk assessment to a ternary model of disease identification allows for individualized, optimal disease management. Redefining the disease/inflammatory approach has been proven to identify, stabilize, and regress atherosclerosis while adding understanding to the progression of vascular disease. Our previously published results show the beneficial effect of comprehensive, evidence-based management on subclinical atherosclerosis and vulnerable plaque. We argue that this approach does not mitigate the value of utilizing standard risk factor identification, but rather augments it for the benefit of the individual patient.Background Bioprosthetic valve thrombosis (BPVT) is a rare but recognized complication causing valve dysfunction. In subacute valve thrombosis, systemic oral anticoagulation is recommended. However, there is little data comparing the efficacy of warfarin and novel oral anticoagulant (NOAC) therapy in this setting. Case Summary A patient developed subacute BPVT 11 years post-implantation. The patient was initially treated with warfarin for a period of 6 months, with limited effect. Following replacement of warfarin with rivaroxaban, there was significant reversal of the BPVT, as represented by a reduction in transaortic maximal velocity (Vmax) from 4.1 to 3 m/s over 7 months. Discussion Systemic oral anticoagulation can be an effective treatment for subacute valve thrombosis. Guidelines currently recommend warfarin as first line but NOACs can be considered in such patients and may be more effective than warfarin. Randomized controlled trials are required to further establish the optimal anticoagulation for patients with subacute BPVT.Segmentation and 3D reconstruction of the human atria is of crucial importance for precise diagnosis and treatment of atrial fibrillation, the most common cardiac arrhythmia. However, the current manual segmentation of the atria from medical images is a time-consuming, labor-intensive, and error-prone process. The recent emergence of artificial intelligence, particularly deep learning, provides an alternative solution to the traditional methods that fail to accurately segment atrial structures from clinical images. This has been illustrated during the recent 2018 Atrial Segmentation Challenge for which most of the challengers developed deep learning approaches for atrial segmentation, reaching high accuracy (>90% Dice score). However, as significant discrepancies exist between the approaches developed, many important questions remain unanswered, such as which deep learning architectures and methods to ensure reliability while achieving the best performance. In this paper, we conduct an in-depth review of the current state-of-the-art of deep learning approaches for atrial segmentation from late gadolinium-enhanced MRIs, and provide critical insights for overcoming the main hindrances faced in this task.MicroRNAs (miRNA) have emerged as important post-transcriptional regulators of metabolic pathways that contribute to cellular and systemic lipoprotein homeostasis. Here, we identify two conserved miRNAs, miR-224, and miR-520d, which target gene networks regulating hepatic expression of the low-density lipoprotein (LDL) receptor (LDLR) and LDL clearance. In silico prediction of miR-224 and miR-520d target gene networks showed that they each repress multiple genes impacting the expression of the LDLR, including the chaperone molecules PCSK9 and IDOL that limit LDLR expression at the cell surface and the rate-limiting enzyme for cholesterol synthesis HMGCR, which is the target of LDL-lowering statin drugs. Using gain- and loss-of-function studies, we tested the role of miR-224 and miR-520d in the regulation of those predicted targets and their impact on LDLR expression. We show that overexpression of miR-224 or miR-520d dose-dependently reduced the activity of PCSK9, IDOL, and HMGCR 3'-untranslated region (3'-UTR)-luciferase reporter constructs and that this repression was abrogated by mutation of the putative miR-224 or miR-520d response elements in the PCSK9, IDOL, and HMGCR 3'-UTRs. Compared to a control miRNA, overexpression of miR-224 or miR-520d in hepatocytes inhibited PCSK9, IDOL, and HMGCR mRNA and protein levels and decreased PCSK9 secretion. Furthermore, miR-224 and miR-520d repression of PCSK9, IDOL, and HMGCR was associated with an increase in LDLR protein levels and cell surface expression, as well as enhanced LDL binding. Notably, the effects of miR-224 and miR-520d were additive to the effects of statins in upregulating LDLR expression. Finally, we show that overexpression of miR-224 in the livers of Ldlr +/- mice using lipid nanoparticle-mediated delivery resulted in a 15% decrease in plasma levels of LDL cholesterol, compared to a control miRNA. Together, these findings identify roles for miR-224 and miR-520d in the posttranscriptional control of LDLR expression and function.CRISPR-Cas systems employ ribonucleoprotein complexes to identify nucleic acid targets with complementarity to bound CRISPR RNAs. selleck chemical Analyses of the high diversification of these effector complexes suggest that they can exhibit a wide spectrum of target requirements and binding affinities. Therefore, streamlined analysis techniques to study the interactions between nucleic acids and proteins are necessary to facilitate the characterization and comparison of CRISPR-Cas effector activities. Bio-layer Interferometry (BLI) is a technique that measures the interference pattern of white light that is reflected from a layer of biomolecules immobilized on the surface of a sensor tip (bio-layers) in real time and in solution. As streptavidin-coated sensors and biotinylated oligonucleotides are commercially available, this method enables straightforward measurements of the interaction of CRISPR-Cas complexes with different targets in a qualitative and quantitative fashion. Here, we present a general method to carry out binding assays with the Type I-Fv complex from Shewanella putrefaciens and the Type I-F complex from Shewanella baltica as model effectors. We report target specificities, dissociation constants and interactions with the Anti-CRISPR protein AcrF7 to highlight possible applications of this technique.The fatty acid composition of a pre-hibernation diet can influence the depth and duration of metabolic suppression achieved by hibernators. More specifically, a diet high in n-6 polyunsaturated fatty acids (PUFAs) relative to n-3 PUFAs is essential to maximize torpor expression. However, few studies have investigated how diets with different n-6/n-3 PUFA ratios change stress-inducible cell signaling. Garden dormice (Eliomys quercinus) were fed one of three diets designed with different ratios of n-6 PUFA linoleic acid (LA) and n-3 PUFA linolenic acid (ALA). Then, NFκB signaling was assessed in the white adipose, brown adipose, and liver tissues of euthermic and hibernating dormice via multiplex and RT-qPCR analyses of relative protein and transcript levels, respectively. Dormice fed a high LA diet regulated NFκB signaling in a protective manner in all tissues. NFκB signaling was generally decreased in the high LA group, with significant decreases in the protein levels of NFκB mediators IKKα/β, IκBα, and downstream pro-apoptotic protein FADD. Liver and white adipose from torpid dormice fed a high LA diet increased sod2 expression relative to the other diets or relative to euthermic controls, indicating protection against ROS generated from potentially increased β-oxidation of n-6 PUFAs. The low LA diet increased biomarkers for apoptosis relative to other diets and relative to euthermia, suggesting low LA diets may be detrimental to hibernator health. Overall, this study suggests that changes in the ratio of n-6/ n-3 PUFAs in the diet influences apoptotic and antioxidant responses in white adipose, brown adipose, and liver of hibernating garden dormice.Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney.