Project description:More than a year after its emergence, COVID-19, the disease caused by SARS-CoV-2, continues to plague the world and dominate our daily lives. Even with the development of effective vaccines, this coronavirus pandemic continues to cause a fervor with the identification of major new variants hailing from the United Kingdom, South Africa, Brazil, and California. Coupled with worries over a distinct mink strain that has caused human infections and potential for further mutations, SARS-CoV-2 variants bring concerns for increased spread and escape from both vaccine and natural infection immunity. Here, we outline factors driving SARS-CoV-2 variant evolution, explore the potential impact of specific mutations, examine the risk of further mutations, and consider the experimental studies needed to understand the threat these variants pose. In this review, Plante et al. examine SARS-CoV-2 variants including B.1.1.7 (UK), B.1.351 (RSA), P.1 (Brazil), and B.1.429 (California). They focus on what factors contribute to variant emergence, mutations in and outside the spike protein, and studies needed to understand the impact of variants on infection, transmission, and vaccine efficacy.
Project description:The first gene therapy clinical trials were initiated more than two decades ago. In the early days, gene therapy shared the fate of many experimental medicine approaches and was impeded by the occurrence of severe side effects in a few treated patients. The understanding of the molecular and cellular mechanisms leading to treatment- and/or vector-associated setbacks has resulted in the development of highly sophisticated gene transfer tools with improved safety and therapeutic efficacy. Employing these advanced tools, a series of Phase I/II trials were started in the past few years with excellent clinical results and no side effects reported so far. Moreover, highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically. With more than 1900 clinical trials to date, gene therapy has moved from a vision to clinical reality. This review focuses on the application of gene therapy for the correction of inherited diseases, the limitations and drawbacks encountered in some of the early clinical trials and the revival of gene therapy as a powerful treatment option for the correction of monogenic disorders.
Project description:Atrial fibrillation has a multifactorial pathophysiology influenced by cardiac autonomic innervation. Both sympathetic and parasympathetic influences are profibrillatory. Innovative therapies targeting the neurocardiac axis include catheter ablation or pharmacologic suppression of ganglionated plexi, renal sympathetic denervation, low-level vagal stimulation, and stellate ganglion blockade. To date, these therapies have variable efficacy. As our understanding of atrial fibrillation and the cardiac nervous system expands, our approach to therapeutic neuromodulation will continue evolving for the benefit of those with AF.
Project description:Despite availability of effective drugs for hypertension therapy, significant numbers of hypertensive patients fail to achieve recommended blood pressure levels on ≥3 antihypertensive drugs of different classes. These individuals have a high prevalence of adverse cardiovascular events and are defined as having resistant hypertension (RHT) although nonadherence to prescribed antihypertensive medications is common in patients with apparent RHT. Furthermore, apparent and true RHT often display increased sympathetic activity. Based on these findings, technology was developed to treat RHT by suppressing sympathetic activity with electrical stimulation of the carotid baroreflex and catheter-based renal denervation (RDN). Over the last 15 years, experimental and clinical studies have provided better understanding of the physiological mechanisms that account for blood pressure lowering with baroreflex activation and RDN and, in so doing, have provided insight into which patients in this heterogeneous hypertensive population are most likely to respond favorably to these device-based therapies. Experimental studies have also played a role in modifying device technology after early clinical trials failed to meet key endpoints for safety and efficacy. At the same time, these studies have exposed potential differences between baroreflex activation and RDN and common challenges that will likely impact antihypertensive treatment and clinical outcomes in patients with RHT. In this review, we emphasize physiological studies that provide mechanistic insights into blood pressure lowering with baroreflex activation and RDN in the context of progression of clinical studies, which are now at a critical point in determining their fate in RHT management.
Project description:To find useful work to do for their colony, individual eusocial animals have to move, somehow staying attentive to relevant social information. Recent research on individual Temnothorax albipennis ants moving inside their colony's nest found a power-law relationship between a movement's duration and its average speed; and a universal speed profile for movements showing that they mostly fluctuate around a constant average speed. From this predictability it was inferred that movement durations are somehow determined before the movement itself. Here, we find similar results in lone T. albipennis ants exploring a large arena outside the nest, both when the arena is clean and when it contains chemical information left by previous nest-mates. This implies that these movement characteristics originate from the same individual neural and/or physiological mechanism(s), operating without immediate regard to social influences. However, the presence of pheromones and/or other cues was found to affect the inter-event speed correlations. Hence we suggest that ants' motor planning results in intermittent response to the social environment: movement duration is adjusted in response to social information only between movements, not during them. This environmentally flexible, intermittently responsive movement behaviour points towards a spatially allocated division of labour in this species. It also prompts more general questions on collective animal movement and the role of intermittent causation from higher to lower organizational levels in the stability of complex systems.
Project description:Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.
Project description:IntroductionOur aim is to develop a novel approach to hyperkinetic movement disorder classification, that combines clinical information, electromyography, accelerometry and video in a computer-aided classification tool. We see this as the next step towards rapid and accurate phenotype classification, the cornerstone of both the diagnostic and treatment process.Methods and analysisThe Next Move in Movement Disorders (NEMO) study is a cross-sectional study at Expertise Centre Movement Disorders Groningen, University Medical Centre Groningen. It comprises patients with single and mixed phenotype movement disorders. Single phenotype groups will first include dystonia, myoclonus and tremor, and then chorea, tics, ataxia and spasticity. Mixed phenotypes are myoclonus-dystonia, dystonic tremor, myoclonus ataxia and jerky/tremulous functional movement disorders. Groups will contain 20 patients, or 40 healthy participants. The gold standard for inclusion consists of interobserver agreement on the phenotype among three independent clinical experts. Electromyography, accelerometry and three-dimensional video data will be recorded during performance of a set of movement tasks, chosen by a team of specialists to elicit movement disorders. These data will serve as input for the machine learning algorithm. Labels for supervised learning are provided by the expert-based classification, allowing the algorithm to learn to predict what the output label should be when given new input data. Methods using manually engineered features based on existing clinical knowledge will be used, as well as deep learning methods which can detect relevant and possibly new features. Finally, we will employ visual analytics to visualise how the classification algorithm arrives at its decision.Ethics and disseminationEthical approval has been obtained from the relevant local ethics committee. The NEMO study is designed to pioneer the application of machine learning of movement disorders. We expect to publish articles in multiple related fields of research and patients will be informed of important results via patient associations and press releases.
Project description:Designing molecular targeted therapy with high specificity based on novel tumor biomarkers is a high priority in lung cancer research. Several molecular aberrations have been already identified in non-small cell lung cancer (NSCLC), with subsequent development of drugs targeted to these aberrations. A more recent actionable target is MET, a multifaceted receptor tyrosine kinase which frequently interacts with other key oncogenic tyrosine kinases including epidermal growth factor receptor (EGFR) and ERBB3 leading to resistance to anti-EGFR therapies. However a phase III trial enrolling only patients with MET-positive tumors was stopped in early March due to futility since there was no evidence that the addition of onartuzumab to erlotinib has any positive effect. From the results of the MET lung phase III trial, we provide new pieces of information that can contribute to further preclinical validation and also be part of the armamentarium for clinical translational research.
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition in patients who have received chemotherapy. The role of neuromodulation therapy in treating pain and improving neurological function in CIPN remains unclear and warrants evidence appraisal. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review to assess change in pain intensity and neurological function after implementation of any neuromodulation intervention for CIPN. Neuromodulation interventions consisted of dorsal column spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), or peripheral nerve stimulation (PNS). In total, 15 studies utilized SCS (16 participants), 7 studies utilized DRG-S (7 participants), and 1 study utilized PNS (50 participants). Per the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria, there was very low-quality GRADE evidence supporting that dorsal column SCS, DRG-S, and PNS are associated with a reduction in pain severity from CIPN. Results on changes in neurological function remained equivocal due to mixed study findings on thermal sensory thresholds and touch sensation or discrimination. Future prospective, well-powered, and comparative studies assessing neuromodulation for CIPN are warranted.