"Blocking-like" effects in attentional set-shifting: Redundant cues facilitate shifting in male rats with medial prefrontal cortex inactivation.

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction.

Stakeholders' expectations of precision medicine: A qualitative study to identify areas of (mis)alignment.

Background And Aims: To sustainably address challenges in implementing precision medicine (PM), coordinated efforts of different stakeholders are required. Understanding their expectations represents a first key step toward aligning on future actions and strategies. Here, we aimed to explore the expectations of different stakeholders from themselves and each other regarding PM.

How can we deliver on the promise of precision medicine in oncology and beyond? A practical roadmap for action.

Background: Precision medicine (PM) is a form of personalized medicine that recognizes that individuals with the same condition may have different underlying factors and uses molecular information to provide tailored treatments. This approach can improve treatment outcomes and transform lives through favorable risk/benefit ratios, avoidance of ineffective interventions, and possible cost savings, as evidenced in the field of lung cancer and other oncology/therapeutic settings, including cardiac disease, diabetes, and rare diseases. However, the potential benefits of PM have yet to be fully realized.

Canine idiopathic orbital inflammation: A case series of four affected dogs (five orbits).

Purpose: In humans, idiopathic orbital inflammation (IOI) is a diagnosis attributed to benign, inflammatory orbital conditions without identifiable local or systemic cause. We describe the clinical signs, imaging and histopathological findings, management and outcome of four dogs diagnosed with IOI.

Methods: Multicentric retrospective study.

Mobilisation of deep crustal sulfide melts as a first order control on upper lithospheric metallogeny.

Magmatic arcs are terrestrial environments where lithospheric cycling and recycling of metals and volatiles is enhanced. However, the first-order mechanism permitting the episodic fluxing of these elements from the mantle through to the outer Earth's spheres has been elusive. To address this knowledge gap, we focus on the textural and minero-chemical characteristics of metal-rich magmatic sulfides hosted in amphibole-olivine-pyroxene cumulates in the lowermost crust.

Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept.

Chloroquine and hydroxychloroquine have been proposed recently as therapy for SARS-CoV-2-infected patients, but during 3 months of extensive use concerns were raised related to their clinical effectiveness and arrhythmogenic risk. Therefore, we estimated for these compounds several proarrhythmogenic risk predictors according to the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm. Experiments were performed with either CytoPatch™2 automated or manual patch-clamp setups on HEK293T cells stably or transiently transfected with hERG1, hNav1.

Evolution of mathematical models of cardiomyocyte electrophysiology.

Advanced computational techniques and mathematical modeling have become more and more important to the study of cardiac electrophysiology. In this review, we provide a brief history of the evolution of cardiomyocyte electrophysiology models and highlight some of the most important ones that had a major impact on our understanding of the electrical activity of the myocardium and associated transmembrane ion fluxes in normal and pathological states. We also present the use of these models in the study of various arrhythmogenesis mechanisms, particularly the integration of experimental pharmacology data into advanced humanized models for in silico proarrhythmogenic risk prediction as an essential component of the Comprehensive in vitro Proarrhythmia Assay (CiPA) drug safety paradigm.

Changes in antimicrobial resistance patterns of ocular surface bacteria isolated from horses in the UK: An eight-year surveillance study (2012-2019).

Purpose: To identify temporal changes in antimicrobial resistance of ocular surface bacteria isolated from clinically symptomatic equine eyes in the South West of the UK.

Study Design: Retrospective.

Methods: Clinical and laboratory records of horses treated for suspected bacterial ocular surface disease (ulcerative and non-ulcerative) at a single facility between January 2011 and December 2019 were reviewed.

Outcome of phacoemulsification in 71 cats: A multicenter retrospective study (2006-2017).

Purpose: To assess outcome of phacoemulsification in cats.

Methods: Records of 71 cats (82 eyes) from five referral centers were reviewed. Groups were divided by cause of cataract (congenital/juvenile [n = 32], traumatic [n = 33], and secondary to uveitis [n = 6]), and group comparisons were performed for the most common complications: postoperative ocular hypertension (POH), uveitis, corneal ulceration, synechia/dyscoria, and posterior capsular opacity (PCO) in three different time periods: immediately postoperatively, at 1-90 days, and at >90 days.

Recording of multiple ion current components and action potentials in human induced pluripotent stem cell-derived cardiomyocytes via automated patch-clamp.

Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes a three-step approach to evaluate proarrhythmogenic liability of drug candidates: effects on individual ion channels in heterologous expression systems, integrating these data into in-silico models of the electrical activity of human cardiomyocytes, and comparison with experiments on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Here we introduce patch-clamp electrophysiology techniques on hiPSC-CM to combine two of the CiPA steps in one assay.

Methods: We performed automated patch-clamp experiments on hiPSC-CM (Cor.

Cataracts in Labrador Retriever and Jack Russell Terrier From the United Kingdom: A Two-Year Retrospective Study.

Cataracts are among the most common ocular diseases, and are a leading cause of vision loss in humans and dogs. Jack Russell Terriers (JRT) and Labrador Retrievers (LR) are among the most popular canine breeds in the United Kingdom, and also among the most affected by cataracts. This study aimed to analyze the clinical features and the surgical outcome of cataracts in JRT and LR in an ophthalmologic reference Veterinary Hospital in the United Kingdom.

Effects of calcium and sodium on ATP-induced vasopressin release from rat isolated neurohypophysial terminals.

ATP-receptors (P2X2, P2X3, P2X4 & P2X7) are found in neurohypophysial terminals (NHT). These purinergic receptor subtypes are known to be cation selective. Here we confirm that both sodium (Na ) and calcium (Ca ) are permeable through these NHT purinergic receptors, but to varying degrees (91% vs.

C2-Modified Sparteine Derivatives Are a New Class of Potentially Long-Acting Sodium Channel Blockers.

The lupin alkaloid sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated sodium channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of sparteine derivatives where the structure of the parent alkaloid is retained. Building on the recent renewed availability of sparteine and derivatives we report herein how modification of sparteine at position 2 produces irreversible blockers of VGSCs.

Pharmacokinetics and metabolism of [C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers.

1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2.

Social media and gamification: Engaging vulnerable parents in an online evidence-based parenting program.

The aim of this study was to examine the feasibility (accessibility, engagement and impact) of adding social media and gaming features (e.g., social sharing with anonymity, badges to incentivize skills practice, an accredited facilitator for support) and access via smartphones to an evidenced-based parenting program, Triple P Online.

Starting a research data management program based in a university library.

As the need for research data management grows, many libraries are considering adding data services to help with the research mission of their institution. The Virginia Commonwealth University (VCU) Libraries created a position and hired a director of research data management in September 2013. The position was new to the libraries and the university.

Late cardiac sodium current can be assessed using automated patch-clamp.

The cardiac late Na (+) current is generated by a small fraction of voltage-dependent Na (+) channels that undergo a conformational change to a burst-gating mode, with repeated openings and closures during the action potential (AP) plateau. Its magnitude can be augmented by inactivation-defective mutations, myocardial ischemia, or prolonged exposure to chemical compounds leading to drug-induced (di)-long QT syndrome, and results in an increased susceptibility to cardiac arrhythmias. Using CytoPatch™ 2 automated patch-clamp equipment, we performed whole-cell recordings in HEK293 cells stably expressing human Nav1.

Action potential characterization of human induced pluripotent stem cell-derived cardiomyocytes using automated patch-clamp technology.

Recent progress in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) research led to high-purity preparations of human cardiomyocytes (CMs) differentiated from these two sources-suitable for tissue regeneration, in vitro models of disease, and cardiac safety pharmacology screening. We performed a detailed characterization of the effects of nifedipine, cisapride, and tetrodotoxin (TTX) on Cor.4U(®) human iPSC-CM, using automated whole-cell patch-clamp recordings with the CytoPatch™ 2 equipment, within a complex assay combining multiple voltage-clamp and current-clamp protocols in a well-defined sequence, and quantitative analysis of several action potential (AP) parameters.

Molecular tolerance of voltage-gated calcium channels is evident after short exposures to alcohol in vasopressin-releasing nerve terminals.

Background: Voltage-gated calcium channels (VGCCs) in rat neurohypophysial terminals exhibit molecular tolerance to alcohol, including desensitization to the drug and increased current density, after 3 weeks of alcohol drinking. Moreover, after this time, terminals from drinking rats exhibit diminished alcohol inhibition of vasopressin (AVP) release.

Methods: We took advantage of organotypic cultures (explants) of the hypothalamo-neurohypophysial system (HNS) to extend our analysis of molecular tolerance to 2 classes of the VGCC.

Failure mode and effects analysis in designing a virtual reality-based training simulator for bilateral sagittal split osteotomy.

Background: Virtual reality-based simulators offer a cost-effective and efficient alternative to traditional medical training and planning. Developing a simulator that enables the training of medical skills and also supports recognition of errors made by the trainee is a challenge. The first step in developing such a system consists of error identification in the real procedure, in order to ensure that the training environment covers the most significant errors that can occur.

Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance.

Background: The defining feature of the main olfactory system in mice is that each olfactory sensory neuron expresses only one of more than a thousand different odorant receptor genes. Axons expressing the same odorant receptor converge onto a small number of targets in the olfactory bulb such that each glomerulus is made up of axon terminals expressing just one odorant receptor. It is thought that this precision in axon targeting is required to maintain highly refined odor discrimination.

P2X purinergic receptor knockout mice reveal endogenous ATP modulation of both vasopressin and oxytocin release from the intact neurohypophysis.

Bursts of action potentials are crucial for neuropeptide release from the hypothalamic neurohypophysial system (HNS). The biophysical properties of the ion channels involved in the release of these neuropeptides, however, cannot explain the efficacy of such bursting patterns on secretion. We have previously shown that ATP, acting via P2X receptors, potentiates only vasopressin (AVP) release from HNS terminals, whereas its metabolite adenosine, via A1 receptors acting on transient Ca(2+) currents, inhibits both AVP and oxytocin (OT) secretion.

Adenosine trisphosphate appears to act via different receptors in terminals versus somata of the hypothalamic neurohypophysial system.

ATP-induced ionic currents were investigated in isolated terminals and somata of the hypothalamic neurohypophysial system (HNS). Both terminals and somata showed inward rectification of the ATP-induced currents and reversal near 0 mV. In terminals, ATP dose-dependently evoked an inactivating, inward current.

Introduction of a modular automated voltage-clamp platform and its correlation with manual human Ether-à-go-go related gene voltage-clamp data.

In investigating ion channel pharmacology, the manual patch clamp is still considered the gold standard for data quality, notwithstanding the major drawbacks of low throughput and the need for skilled operators. The automated patch clamp platform CytoPatch™ Instrument overcomes these restrictions. Its modular fully automated design makes it possible to obtain scalable throughput without the need for well-trained operators.

β3GnT2 maintains adenylyl cyclase-3 signaling and axon guidance molecule expression in the olfactory epithelium.

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase β3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function.