CRISPR/Cas9-editing of PRNP in Alpine goats.

Misfolding of the cellular PrP (PrP) protein causes prion disease, leading to neurodegenerative disorders in numerous mammalian species, including goats. A lack of PrP induces complete resistance to prion disease. The aim of this work was to engineer Alpine goats carrying knockout (KO) alleles of PRNP, the PrP-encoding gene, using CRISPR/Cas9-ribonucleoproteins and single-stranded donor oligonucleotides.

Deep phenotyping the right ventricle to establish translational MRI biomarkers for characterization of adaptive and maladaptive states in pulmonary hypertension.

Deep phenotyping the right ventricle (RV) is essential for understanding the mechanisms of adaptive and maladaptive RV responses to pulmonary hypertension (PH). In this study, feature selection coupled with machine learning classification/ranking of specific cardiac magnetic resonance imaging (MRI) features from cine-MRI, flow-sensitized, and extracellular-volume techniques were used to assess RV remodelling in monocrotaline (MCT) and Sugen hypoxia (SuHx) PH rats. Early physiological changes associated with RV adaptation were detected along with prediction of RV maladaptive outcomes.

OMERACT Core outcome measurement set for shared decision making in rheumatic and musculoskeletal conditions: a scoping review to identify candidate instruments.

Objectives: Shared decision making (SDM) is a central tenet in rheumatic and musculoskeletal care. The lack of standardization regarding SDM instruments and outcomes in clinical trials threatens the comparative effectiveness of interventions. The Outcome Measures in Rheumatology (OMERACT) SDM Working Group is developing a Core Outcome Set for trials of SDM interventions in rheumatology and musculoskeletal health.

The possible influence of third-order shim coils on gradient-magnet interactions: an inter-field and inter-site study.

Objective: To assess the possible influence of third-order shim coils on the behavior of the gradient field and in gradient-magnet interactions at 7 T and above.

Materials And Methods: Gradient impulse response function measurements were performed at 5 sites spanning field strengths from 7 to 11.7 T, all of them sharing the same exact whole-body gradient coil design.

Intuitive movement-based prosthesis control enables arm amputees to reach naturally in virtual reality.

Impressive progress is being made in bionic limbs design and control. Yet, controlling the numerous joints of a prosthetic arm necessary to place the hand at a correct position and orientation to grasp objects remains challenging. Here, we designed an intuitive, movement-based prosthesis control that leverages natural arm coordination to predict distal joints missing in people with transhumeral limb loss based on proximal residual limb motion and knowledge of the movement goal.

A guide to inter-joint coordination characterization for discrete movements: a comparative study.

Characterizing human movement is essential for understanding movement disorders, evaluating progress in rehabilitation, or even analyzing how a person adapts to the use of assistive devices. Thanks to the improvement of motion capture technology, recording human movement has become increasingly accessible and easier to conduct. Over the last few years, multiple methods have been proposed for characterizing inter-joint coordination.

Psychosomatic states and their correlation with letting-go: two newly evaluated core factors for investigating the therapeutic effect of spa treatment.

Spa therapy (aka crenobalneotherapy) has been the object of criticism due to insufficient evidence of its effectiveness. While further effectiveness studies are needed, others are also required to better evaluate the curative factors involved during spa therapy that may contribute to the effectiveness. The current study used specific scales to investigate two possible curative factors: the psychosomatic state and the letting-go of patients with mental disorders after 3 weeks of spa therapy.

Human Exteroception during Object Handling with an Upper Limb Exoskeleton.

Upper limb exoskeletons may confer significant mechanical advantages across a range of tasks. The potential consequences of the exoskeleton upon the user's sensorimotor capacities however, remain poorly understood. The purpose of this study was to examine how the physical coupling of the user's arm to an upper limb exoskeleton influenced the perception of handheld objects.

Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult.

PGE2 Supplementation of Oocyte Culture Media Improves the Developmental and Cryotolerance Performance of Bovine Blastocysts Derived From a Serum-Free Production System, Mirroring the Inner Cell Mass Transcriptome.

The culture media used throughout the production (IVP) of bovine embryos remain complex. The serum added to culture media in order to improve embryo development negatively impacts the cryotolerance of blastocysts. Periconceptional prostaglandin E2 (PGE2) signaling is known to exert prosurvival effects on -generated blastocysts.

Analysis of blood parameters and molecular endometrial markers during early reperfusion in two ovine models of uterus transplantation.

The dissection of the veins is the trickiest step of Uterine transplantation (UTx). Performing the anastomosis of a single uterine vein could bring a therapeutic benefit and simplification of surgery and serve for managing unilateral venous thromboses. The objectives of this project were to evaluate the expression of early markers of ischemia-reperfusion and to compare findings following one or two vein anastomoses.

Lupin (Lupinus spp.) seeds exert anthelmintic activity associated with their alkaloid content.

The growing range of drug resistant parasitic nematode populations threatens the sustainability of ruminant farming worldwide. In this context, nutraceuticals, animal feed that provides necessary dietary requirements while ensuring parasite control, could contribute to increase farming sustainability in developed and low resource settings. In this study, we evaluated the anthelmintic potential of lupin seed extracts against the major ruminant trichostrongylids, Haemonchus contortus and Teladorsagia circumcincta.

CLIC4/Arf6 Pathway.

Rationale: Increased expression of CLIC4 (chloride intracellular channel 4) is a feature of endothelial dysfunction in pulmonary arterial hypertension, but its role in disease pathology is not fully understood.

Objective: To identify CLIC4 effectors and evaluate strategies targeting CLIC4 signaling in pulmonary hypertension.

Methods And Results: Proteomic analysis of CLIC4-interacting proteins in human pulmonary artery endothelial cells identified regulators of endosomal trafficking, including Arf6 (ADP ribosylation factor 6) GTPase activating proteins and clathrin, while CLIC4 overexpression affected protein regulators of vesicular trafficking, lysosomal function, and inflammation.

3'-Deoxy-3'-[18F]Fluorothymidine Positron Emission Tomography Depicts Heterogeneous Proliferation Pathology in Idiopathic Pulmonary Arterial Hypertension Patient Lung.

Background: Pulmonary vascular cell hyperproliferation is characteristic of pulmonary vascular remodeling in pulmonary arterial hypertension. A noninvasive imaging biomarker is needed to track the pathology and assess the response to novel treatments targeted at resolving the structural changes. Here, we evaluated the application of radioligand 3'-deoxy-3'-[18F]-fluorothymidine (FLT) using positron emission tomography.

Enhanced Anti-lymphoma Activity of CAR19-iNKT Cells Underpinned by Dual CD19 and CD1d Targeting.

Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19 B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo.

Reliability of vulvar blood perfusion in women with provoked vestibulodynia using laser Doppler perfusion imaging and laser speckle imaging.

Background: Microvascular assessment has become increasingly used in gynecology to better understand the pathophysiology of various vulvar conditions and to study sexual function. Alteration in blood perfusion of the vulvar area has been observed using laser technologies in women with provoked vestibulodynia (PVD), the leading cause of vulvar pain. However, no studies have thus far investigated the reliability of and agreement between lasers for evaluating vulvar blood perfusion.

Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.

Aims: RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect.

Methods And Results: The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation.

Balneotherapy Together with a Psychoeducation Program for Benzodiazepine Withdrawal: A Feasibility Study.

Benzodiazepines should be prescribed on a short-term basis, but a significant proportion of patients (%) use them for more than 6 months, constituting a serious public health issue. Indeed, few strategies are effective in helping patients to discontinue long-term benzodiazepine treatments. The aim of this study was to assess the feasibility and the impact of a program including cognitive behavioural therapy, psychoeducation, and balneotherapy in a spa resort to facilitate long-term discontinuation of benzodiazepines.

Reliability and Convergent Validity of the Algometer for Vestibular Pain Assessment in Women with Provoked Vestibulodynia.

Objective: Women with provoked vestibulodynia (PVD) suffer pain at the entry of the vagina elicited by pressure as during vaginal penetration. To quantify vestibular pain, we developed a new instrument, an algometer. The aim of this study was to investigate the test-retest reliability of the algometer and evaluate its convergent validity for vestibular pain assessment in women with PVD.

The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia.

The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling.

Iron homeostasis and pulmonary hypertension: iron deficiency leads to pulmonary vascular remodeling in the rat.

Rationale: Iron deficiency without anemia is prevalent in patients with idiopathic pulmonary arterial hypertension and associated with reduced exercise capacity and survival.

Objectives: We hypothesized that iron deficiency is involved in the pathogenesis of pulmonary hypertension and iron replacement is a possible therapeutic strategy.

Methods And Results: Rats were fed an iron-deficient diet (IDD, 7 mg/kg) and investigated for 4 weeks.

miR-21/DDAH1 pathway regulates pulmonary vascular responses to hypoxia.

The NOS (nitric oxide synthase) inhibitor ADMA (asymmetric dimethylarginine) contributes to the pathogenesis of pulmonary hypertension. Reduced levels of the enzymes metabolizing ADMA, dimethylarginine dimethylaminohydrolases (DDAH1 and DDAH2) and increased levels of miR-21 are linked to disease pathology, but the mechanisms are not understood. In the present study we assessed the potential role of miR-21 in the regulation of hypoxia-induced changes in ADMA metabolism in vitro and in vivo.

Evidence for the involvement of type I interferon in pulmonary arterial hypertension.

Rationale: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH.

Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments.

Background: Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models.