Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology.

This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fphys.2016.00182The gastrointestinal (GI) tract is an electrically excitable organ system containing multiple cell types, which coordinate electrical activity propagating through this tract. Disruption in its normal electrophysiology is observed in a number of GI motility disorders. However, this is not well characterized and the field of GI electrophysiology is much less developed compared to the cardiac field. The aim of this article is to use the established knowledge of cardiac electrophysiology to shed light on the mechanisms of electrical activation and propagation along the GI tract, and how abnormalities in these processes lead to motility disorders and suggest better treatment options based on this improved understanding. In the first part of the article, the ionic contributions to the generation of GI slow wave and the cardiac action potential (AP) are reviewed. Propagation of these electrical signals can be described by the core conductor theory in both systems. However, specifically for the GI tract, the following unique properties are observed: changes in slow wave frequency along its length, periods of quiescence, synchronization in short distances and desynchronization over long distances. These are best described by a coupled oscillator theory. Other differences include the diminished role of gap junctions in mediating this conduction in the GI tract compared to the heart. The electrophysiology of conditions such as gastroesophageal reflux disease and gastroparesis, and functional problems such as irritable bowel syndrome are discussed in detail, with reference to ion channel abnormalities and potential therapeutic targets. A deeper understanding of the molecular basis and physiological mechanisms underlying GI motility disorders will enable the development of better diagnostic and therapeutic tools and the advancement of this field.Croucher Foundatio

Oral exposure to Ag or TiO2 nanoparticles perturbed gut transcriptome and microbiota in a mouse model of ulcerative colitis : Ag or TiO2 nanoparticles in ulcerative colitis

Publisher Copyright: © 2022 The AuthorsSilver (nAg) and titanium dioxide (nTiO2) nanoparticles improve texture, flavour or anti-microbial properties of various food products and packaging materials. Despite their increased oral exposure, their potential toxicities in the dysfunctional intestine are unclear. Here, the effects of ingested nAg or nTiO2 on inflamed colon were revealed in a mouse model of chemical-induced acute ulcerative colitis. Mice (eight/group) were exposed to nAg or nTiO2 by oral gavage for 10 consecutive days. We characterized disease phenotypes, histology, and alterations in colonic transcriptome (RNA sequencing) and gut microbiome (16S sequencing). Oral exposure to nAg caused only minor changes in phenotypic hallmarks of colitic mice but induced extensive responses in gene expression enriching processes of apoptotic cell death and RNA metabolism. Instead, ingested nTiO2 yielded shorter colon, aggravated epithelial hyperplasia and deeper infiltration of inflammatory cells. Both nanoparticles significantly changed the gut microbiota composition, resulting in loss of diversity and increase of potential pathobionts. They also increased colonic mucus and abundance of Akkermansia muciniphila. Overall, nAg and nTiO2 induce dissimilar immunotoxicological changes at the molecular and microbiome level in the context of colon inflammation. The results provide valuable information for evaluation of utilizing metallic nanoparticles in food products for the vulnerable population.Peer reviewe

Antibody stabilization for thermally accelerated deep immunostaining

Antibodies have diverse applications due to their high reaction specificities but are sensitive to denaturation when a higher working temperature is required. We have developed a simple, highly scalable and generalizable chemical approach for stabilizing off-the-shelf antibodies against thermal and chemical denaturation. We demonstrate that the stabilized antibodies (termed SPEARs) can withstand up to 4 weeks of continuous heating at 55 °C and harsh denaturants, and apply our method to 33 tested antibodies. SPEARs enable flexible applications of thermocycling and denaturants to dynamically modulate their binding kinetics, reaction equilibrium, macromolecular diffusivity and aggregation propensity. In particular, we show that SPEARs permit the use of a thermally facilitated three-dimensional immunolabeling strategy (termed ThICK staining), achieving whole mouse brain immunolabeling within 72 h, as well as nearly fourfold deeper penetration with threefold less antibodies in human brain tissue. With faster deep-tissue immunolabeling and broad compatibility with tissue processing and clearing methods without the need for any specialized equipment, we anticipate the wide applicability of ThICK staining with SPEARs for deep immunostaining

The role of 3D printing in anatomy education and surgical training: A narrative review

Recent expansions in the development and availability of three-dimensional printing (3Dp) have led to the uptake of this valuable and effective technology within the modern context of medical education. It is proposed that 3Dp is entirely appropriate for the creation of anatomical models for purposes of teaching and training due to the ability of this technology to produce accurate 3D physical representations based on a processed data set acquired from sources including magnetic resonance imaging (MRI) and computed tomography (CT). When investigating the currently available educational research with respect to 3Dp, it is important that the best evidence supporting the practical and theoretical benefits of this technology in teaching and training can be identified, while any obstacles to the effective implementation of 3Dp can also be determined. Here, literature describing recent primary research with respect to the capability and utility of 3Dp in anatomy and surgery have been explored in a narrative review. The impact on resources of implementing this technology within medical education have also been investigated. In order to emphasise wider applications in medicine, the role of 3Dp in medical practice and research have also been examined. To identify recent literature appropriate for this review published up to March 2017, suitable search terms were determined and applied using PubMed and results were judged against an established checklist. The research identified was then allocated with respect to the agreed topic areas of anatomy education, surgical training, medical usage and medical research. A student partnership approach was utilised for this review and the focus of the work was driven by undergraduate students in collaboration with anatomy and medical educators. Preliminary findings from this narrative review support the implementation of 3Dp in anatomy education and surgical training as a supplement to traditional learning approaches

The Tpeak – Tend interval as an electrocardiographic risk marker of arrhythmic and mortality outcomes: a systematic review and meta-analysis

Background: The Tpeak – Tend interval, an electrocardiographic marker reflecting transmural dispersion of repolarization, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in different clinical settings. Objective: This systematic review and meta-analysis evaluated the significance of Tpeak – Tend interval in predicting arrhythmic and/or mortality endpoints. Methods: PubMed, Embase, Cochrane Library and CINAHL Plus databases were searched through 30th November 2016.Results: Of the 854 studies identified initially, 33 observational studies involving 155856 patients were included in our meta-analysis. Tpeak – Tend interval prolongation (mean cut-off: 103.3 ± 17.4 ms) was a significant predictor of the arrhythmic or mortality outcomes (odds ratio (OR): 1.14, 95% CI: 1.11 to 1.17, p < 0.001). When different end-points were analyzed, the ORs are as follows: VT/VF (1.10, 95% CI: 1.06 to 1.13, p < 0.0001), SCD (1.27, 95% CI 1.17 to 1.39, p < 0.0001), cardiovascular death (1.40, 95% CI 1.19 to 1.64, p < 0.0001), and all-cause mortality (4.56, 95% CI 0.62 to 33.68, p < 0.0001). Subgroup analysis for each disease revealed that the risk of VT/VF or death was highest for Brugada syndrome (OR: 5.68, 95% CI: 1.57 to 20.53, p < 0.01), followed by hypertension (OR: 1.52, 95% CI: 1.26 to 1.85, p < .0001), heart failure (OR: 1.07, 95% CI: 1.04 to 1.11, p < .0001) and ischemic heart disease (OR: 1.06, 95% CI: 1.02 to 1.10, p = 0.001). In the general population, a prolonged Tpeak – Tend interval also predicted arrhythmic or mortality outcomes (OR: 1.59, 95% CI: 1.21 to 2.09, p < 0.001).Conclusion: The Tpeak – Tend interval is useful risk stratification tool in different diseases and in the general population

Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes

Western-type diets are linked to obesity and diabetes partly because of their high–saturated fatty acid (SFA) content. We found that SFAs, but not unsaturated fatty acids (USFAs), reduced lipid droplets (LDs) within pancreatic β cells. Mechanistically, SFAs, but not USFAs, reduced LD formation by inducing S-acylation and proteasomal, mediated degradation of fat storage–inducing transmembrane protein 2 (FIT2), an endoplasmic reticulum (ER) resident protein important for LD formation. Targeted ablation of FIT2 reduced β cell LD numbers, lowered β cell ATP levels, reduced Ca(2+) signaling, dampened vesicle exocytosis, down-regulated β cell transcription factors, up-regulated unfolded protein response genes, and finally, exacerbated diet-induced diabetes in mice. Subsequent mass spectrometry studies revealed increased C16:0 ceramide accumulation in islets of diet-induced diabetes mice lacking β cell FIT2. Inhibition of ceramide synthases ameliorated the enhanced ER stress and improved insulin secretion. FIT2 was reduced in mouse diabetic islets, and separately, overexpression of FIT2 increased the number of intracellular LDs and rescued SFA-induced ER stress and apoptosis, thereby highlighting the protective role of FIT2 and LDs against β cell lipotoxicity

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Genetic susceptibility to common mycobacterial diseases

Common mycobacterial diseases, including tuberculosis and leprosy, contribute to major mortality and morbidity worldwide. Despite evidence of an important role of host genetic factors in susceptibility to these infections, few compelling genetic associations have been identified with previous candidate gene and linkage approaches.This thesis investigates the genetic factors of human immunity to these mycobacterial diseases using a high-throughput approach of association testing. To assess genetic susceptibility to tuberculosis, I have conducted a genome-wide association study in the Gambian population as part of the Wellcome Trust Case Control Consortium (WTCCC). The study reveals the region flanking CADM1 as a potential susceptibility locus. Combining this study with a Ghanaian cohort further implicates two genetic loci at chromosome 18q11.2 (P = 9.2x10⁻⁹) and PARD3B (P = 1.4x10⁻⁶). For leprosy, I have performed a gene-centric association study in the New Delhi Indian population. Evidence of significant association was observed in the HLA-DRB1/DQA1 (P = 4.9x10⁻14 and TLR1 (P = 1.7x10⁻⁹) loci. These studies identify important genomic regions that may be involved in immunity to tuberculosis and leprosy. Further analysis revealed a significant immunogenetic overlap between tuberculosis and leprosy. This provides proof-of-principle for the subsequent aggregate analysis for mycobacterial susceptibility, which suggests that the steroid biosynthesis pathway may be important in anti-mycobacterial immunity.This thesis represents one of the largest studies to identify the genetic factors for human immunity against mycobacteria. These novel findings will further enhance vaccine and pharmaceutical efforts into prevention and treatment of these mycobacterial diseases.</p

Genetic susceptibility to common mycobacterial diseases

Common mycobacterial diseases, including tuberculosis and leprosy, contribute to major mortality and morbidity worldwide. Despite evidence of an important role of host genetic factors in susceptibility to these infections, few compelling genetic associations have been identified with previous candidate gene and linkage approaches. This thesis investigates the genetic factors of human immunity to these mycobacterial diseases using a high-throughput approach of association testing. To assess genetic susceptibility to tuberculosis, I have conducted a genome-wide association study in the Gambian population as part of the Wellcome Trust Case Control Consortium (WTCCC). The study reveals the region flanking CADM1 as a potential susceptibility locus. Combining this study with a Ghanaian cohort further implicates two genetic loci at chromosome 18q11.2 (P = 9.2x10⁻⁹) and PARD3B (P = 1.4x10⁻⁶). For leprosy, I have performed a gene-centric association study in the New Delhi Indian population. Evidence of significant association was observed in the HLA-DRB1/DQA1 (P = 4.9x10⁻¹⁴) and TLR1 (P = 1.7x10⁻⁹) loci. These studies identify important genomic regions that may be involved in immunity to tuberculosis and leprosy. Further analysis revealed a significant immunogenetic overlap between tuberculosis and leprosy. This provides proof-of-principle for the subsequent aggregate analysis for mycobacterial susceptibility, which suggests that the steroid biosynthesis pathway may be important in anti-mycobacterial immunity. This thesis represents one of the largest studies to identify the genetic factors for human immunity against mycobacteria. These novel findings will further enhance vaccine and pharmaceutical efforts into prevention and treatment of these mycobacterial diseases.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

What is unknown in using microbiota as a therapeutic?

Fecal microbiota transplantation (FMT) has been used extensively in the treatment of various gastrointestinal and extraintestinal conditions, despite that there are still a lot of missing gaps in our knowledge in the gut microbiota and its behavior. This article describes the unknowns in microbiota biology (undetected microbes, uncertain colonization, unclear mechanisms of action, uncertain indications, unsure long-term efficacy, or side effects). We discuss how these unknowns may affect the therapeutic uses of FMT, and the potentials and caveats of other related microbiota-based therapies. When used as an experimental therapy or last resort in difficult conditions, caution should be taken against inadvertent complications. Clear documentations of post-treatment events should be made mandatory, classified, and graded as in clinical trials. Further robust scientific experiments and properly designed clinical studies are needed