Project description:Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.
Project description:High-throughput DNA sequencing technologies, coupled with advanced bioinformatics tools, have enabled rapid advances in microbial ecology and our understanding of the human microbiome. QIIME (Quantitative Insights Into Microbial Ecology) is an open-source bioinformatics software package designed for microbial community analysis based on DNA sequence data, which provides a single analysis framework for analysis of raw sequence data through publication-quality statistical analyses and interactive visualizations. In this chapter, we demonstrate the use of the QIIME pipeline to analyze microbial communities obtained from several sites on the bodies of transgenic and wild-type mice, as assessed using 16S rRNA gene sequences generated on the Illumina MiSeq platform. We present our recommended pipeline for performing microbial community analysis and provide guidelines for making critical choices in the process. We present examples of some of the types of analyses that are enabled by QIIME and discuss how other tools, such as phyloseq and R, can be applied to expand upon these analyses.
Project description:Although a rare disease, severe therapy-resistant asthma in children is a cause of significant morbidity and results in utilization of approximately 50% of health-care resources for asthma. Improving control for children with severe asthma is, therefore, an urgent unmet clinical need. As a group, children with severe asthma have severe and multiple allergies, steroid resistant airway eosinophilia, and significant structural changes of the airway wall (airway remodeling). Omalizumab is currently the only add-on therapy that is licensed for use in children with severe asthma. However, limitations of its use include ineligibility for approximately one-third of patients because of serum IgE levels outside the recommended range and lack of clinical efficacy in a further one-third. Pediatric severe asthma is thus markedly heterogeneous, but our current understanding of the different mechanisms underpinning various phenotypes is very limited. We know that there are distinctions between the factors that drive pediatric and adult disease since pediatric disease develops in the context of a maturing immune system and during lung growth and development. This review summarizes the current data that give insight into the pathophysiology of pediatric severe asthma and will highlight potential targets for novel therapies. It is apparent that in order to identify novel treatments for pediatric severe asthma, the challenge of undertaking mechanistic studies using age appropriate experimental models and airway samples from children needs to be accepted to allow a targeted approach of personalized medicine to be achieved.
Project description:BackgroundAlthough severe asthma can be life-threatening, many patients are unaware they have this condition.ObjectivesPatient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR) is a novel, multidisciplinary working group aiming to develop and disseminate a global, patient-centered description of severe asthma to improve patient understanding of severe asthma and effect a change in patient behavior whereby patients are encouraged to visit their healthcare professional, when appropriate.MethodsCurrent definitions from patient organization websites, asthma guidelines, and medication information for key asthma drugs were assessed and informed a multidisciplinary working group, convened to identify common concepts and terminology used to define severe asthma. A patient-centered description of severe asthma and patient checklist were drafted based on working-group discussions and reviewed by an external behavioral scientist for patient understanding and relevance. These were tested using an online US/Canadian survey.ResultsThe patient-centered description of severe asthma and patient checklist were reviewed and re-drafted by the authors. The text was simplified following the behavioral-scientist review. The survey (n?=?153) included 105 patients with severe asthma. Of those with severe asthma, 92.2% of patients reported that the description was consistent with their experiences of severe asthma and 92.6% of patients reported that the PULSAR initiative would encourage them to visit their healthcare provider.ConclusionA patient-centered description of severe asthma has been developed and tested using patients with severe asthma; this description will allow patients to assess whether they might have severe asthma and prompt them to visit their healthcare provider, if appropriate.
Project description:In recent years there has been increasing recognition of varying asthma phenotypes that impact treatment response. This has led to the development of biological therapies targeting specific immune cells and cytokines in the inflammatory cascade. Currently, there are two primary asthma phenotypes, Type 2 hi and Type 2 lo, which are defined by eosinophilic and neutrophilic/pauci- granulocytic pattern of inflammation respectively. Most biologics focus on Type 2 hi asthma, including all four biologics approved for treatment of uncontrolled asthma in the United States - omalizumab, mepolizumab, reslizumab, and benralizumab. Potential new targets for drug development are being investigated, such as IL-13, IL-4? receptor, CRTH2, TSLP, IL-25, IL-13, IL-17A receptor, and CXCR2/IL-8. This review will discuss the role of these molecules on the inflammatory response in uncontrolled asthma and the emerging biologics that address them. Through the delineation of distinct immunological mechanisms in severe asthma, targeted biologics are promising new therapies that have the potential to improve asthma control and quality of life.
Project description:Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici, continues to cause severe damage worldwide. Durable resistance is necessary for sustainable control of the disease. High-temperature adult-plant (HTAP) resistance, which expresses when the weather becomes warm and plants grow older, has been demonstrated to be durable. We conducted numerous studies to understand the molecular mechanisms of different types of stripe rust resistance using a transcriptomics approach. Through comparing gene expression patterns with race-specific, all-stage resistance controlled by various genes, we found that a greater diversity of genes is involved in HTAP resistance than in all-stage resistance. The genes involved in HTAP resistance are induced more slowly and their expression induction is less dramatic than genes involved in all-stage resistance. The high diversity of genes and less dramatic induction may explain durability and the incomplete expression level of HTAP resistance. Identification of transcripts may be helpful in identifying resistance controlled by different genes and in selecting better combinations of genes to combine for achieving adequate and durable resistance.
Project description:Coronavirus disease 2019 (COVID-19) continues to spread across the world. Since the beginning of the pandemic, the question of whether asthma is a risk factor for getting the infection or for poor outcomes motivated a great debate. In the field of severe asthma and its treatment during COVID-19 pandemic, several issues are also pending. A literature review focused on the management of severe asthma patients in the context of COVID-19 is performed. The available evidence suggests that severe asthma patients do not have an increased risk of poor COVID-19 outcomes and that it is safe to treat asthmatic patients with inhaled corticosteroids (ICS) and biologics during the pandemic, even though some studies indicate that high doses of ICS may predispose to COVID-19. The chronic use of oral corticosteroid (OCS) might be associated with poor COVID-19 outcomes, although there is no complete agreement. There is very limited evidence concerning the use of triple therapy for asthma in the context of this pandemic. Ultimately, severe asthma patients should maintain their medication during the COVID-19 pandemic, including biologic agents. More studies are needed to address the role of asthma medications and asthma's different phenotypes on the incidence and course of COVID-19.
Project description:Herpes stromal keratitis (HSK) is a disease that commonly affects the cornea and external eye and is caused by Herpes Simplex Virus type 1 (HSV-1). This virus infects approximately 66% of people worldwide; however, only a small portion of these people will develop symptoms in their lifetime. There is no cure or vaccine available for HSV-1; however, there are treatments available that aim to control the inflammation caused by the virus and prevent its recurrence. While these treatments are beneficial to those suffering with HSK, there is a need for more effective treatments to minimise the need for topical steroids, which can have harmful effects, and to prevent bouts of disease reactivation, which can lead to progressive corneal scarring and visual impairment. This review details the current understanding of HSV-1 infection and discusses potential novel treatment options including microRNAs, TLRs, mAbs, and aptamers.
Project description:RationaleSevere asthma (SA) is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of bronchial epithelial cells in individuals with asthma have provided biological insight and underscored possible mechanistic differences between individuals.ObjectivesIdentify networks of genes reflective of underlying biological processes that define SA.MethodsAirway epithelial cell gene expression from 155 subjects with asthma and healthy control subjects in the Severe Asthma Research Program was analyzed by weighted gene coexpression network analysis to identify gene networks and profiles associated with SA and its specific characteristics (i.e., pulmonary function tests, quality of life scores, urgent healthcare use, and steroid use), which potentially identified underlying biological processes. A linear model analysis confirmed these findings while adjusting for potential confounders.Measurements and main resultsWeighted gene coexpression network analysis constructed 64 gene network modules, including modules corresponding to T1 and T2 inflammation, neuronal function, cilia, epithelial growth, and repair mechanisms. Although no network selectively identified SA, genes in modules linked to epithelial growth and repair and neuronal function were markedly decreased in SA. Several hub genes of the epithelial growth and repair module were found located at the 17q12-21 locus, near a well-known asthma susceptibility locus. T2 genes increased with severity in those treated with corticosteroids but were also elevated in untreated, mild-to-moderate disease compared with healthy control subjects. T1 inflammation, especially when associated with increased T2 gene expression, was elevated in a subgroup of younger patients with SA.ConclusionsIn this hypothesis-generating analysis, gene expression networks in relation to asthma severity provided potentially new insight into biological mechanisms associated with the development of SA and its phenotypes.