Machine Learning Methods for the Discovery and Analysis of MicroRNAs

MicroRNAs are a highly conserved class of small endogenous RNA, about ~22nt in length, involved in post-transcriptional gene silencing and have prominent roles in disease and development. Though the process of microRNA discovery was once an arduous task, the advent of high throughput sequencing technology has resulted in novel microRNAs being discovered at a rapid rate. Several data-driven pipelines and machine learning-based methods have been devised so that the beginning stages of microRNA discovery can be performed in silico. Despite these efforts, several challenges have persisted in the computational prediction of microRNAs. These challenges include the identification of microRNAs with low expression, proper determination of the precursor span, and the precise labeling of the cleavage sites involved in their biogenesis. This thesis addresses these challenges with two new machine learning-based approaches. MiRWoods improves precursor detection and uses stacked random forests for the sensitive detection of microRNAs. We report that miRWoods has a 10% higher recall of annotated microRNAs when compared with other software. We applied this method to the genomes of human, mouse, Felis catus (cat) and Bos Taurus (cow) and identified hundreds of novel microRNAs in small RNA sequencing datasets. Our novel predictions include a microRNA in an intron of tyrosine kinase 2 (TYK2), that is present in both cat and cow, as well as a family of mirtrons with two instances in the human genome. Our predictions support a more expanded miR-2284 family in the bovine genome, a larger mir-548 family in the human genome, and a larger let-7 family in the feline genome. DeepMirCut is a deep learning approach for identifying cleavage sites within microRNAs. This approach is inspired by site-labeling methods for natural language processing, and can accurately predict how the microRNA processing enzymes Dicer and Drosha cleave the microRNA precursor

Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. We used genetic variants associated (P < 5 × 10-8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n = 32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 [2.02, 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 [1.08, 1.49] or 27% increased risk and 0.76 [0.62, 0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes. Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes. [Abstract copyright: © 2022 by the American Diabetes Association.

Understanding Social Situations (USS): A proof-of-concept social–cognitive intervention targeting theory of mind and attributional bias in individuals with psychosis.

In this proof-of-concept trial, we examined the feasibility and preliminary efficacy of Understanding Social Situations (USS), a new social cognitive intervention that targets higher-level social cognitive skills using methods common to neurocognitive remediation, including drill and practice and hierarchically structured training, which may compensate for the negative effects of cognitive impairment on learning

Targeting of anionic membrane species by lanthanide(III) complexes: towards improved MRI contrast agents for apoptosis

No abstract available

Near-Infrared Light Exposure Triggers ROS to Downregulate Inflammatory Cytokines Induced by SARS-CoV-2 Spike Protein in Human Cell Culture

The leading cause of mortality from SARS-CoV-2 is an exaggerated host immune response, triggering cytokine storms, multiple organ failure and death. Current drug- and vaccine-based therapies are of limited efficacy against novel viral variants. Infrared therapy is a non-invasive and safe method that has proven effective against inflammatory conditions for over 100 years. However, its mechanism of action is poorly understood and has not received widespread acceptance. We herein investigate whether near-infrared (NIR) light exposure in human primary alveolar and macrophage cells could downregulate inflammatory cytokines triggered by the SARS-CoV-2 spike (S) protein or lipopolysaccharide (LPS), and via what underlying mechanism. Our results showed a dramatic reduction in pro-inflammatory cytokines within days of NIR light treatment, while anti-inflammatory cytokines were upregulated. Mechanistically, NIR light stimulated mitochondrial metabolism, induced transient bursts in reactive oxygen species (ROS) and activated antioxidant gene transcription. These, in turn, downregulated ROS and inflammatory cytokines. A causal relationship was shown between the induction of cellular ROS by NIR light exposure and the downregulation of inflammatory cytokines triggered by SARS-CoV-2 S. If confirmed by clinical trials, this method would provide an immediate defense against novel SARS-CoV-2 variants and other inflammatory infectious diseases

Ethnic Differences in Body Fat Deposition and Liver Fat Content in Two UK-Based Cohorts

Objective Differences in the content and distribution of body fat and ectopic lipids may be responsible for ethnic variations in metabolic disease susceptibility. The aim of this study was to examine the ethnic distribution of body fat in two separate UK-based populations. Methods Anthropometry and body composition were assessed in two separate UK cohorts: the Hammersmith cohort and the UK Biobank, both comprising individuals of South Asian descent (SA), individuals of Afro-Caribbean descent (AC), and individuals of European descent (EUR). Regional adipose tissue stores and liver fat were measured by magnetic resonance techniques. Results The Hammersmith cohort (n = 747) had a mean (SD) age of 41.1 (14.5) years (EUR: 374 men, 240 women; SA: 68 men, 22 women; AC: 14 men, 29 women), and the UK Biobank (n = 9,533) had a mean (SD) age of 55.5 (7.5) years (EUR: 4,483 men, 4,873 women; SA: 80 men, 43 women, AC: 31 men, 25 women). Following adjustment for age and BMI, no significant differences in visceral adipose tissue or liver fat were observed between SA and EUR individuals in the either cohort. Conclusions Our data, consistent across two independent UK-based cohorts, present a limited number of ethnic differences in the distribution of body fat depots associated with metabolic disease. These results suggest that the ethnic variation in susceptibility to features of the metabolic syndrome may not arise from differences in body fat

Decisional Informatics for Psychosocial Rehabilitation: A Feasibility Pilot on Tailored and Fluid Treatment Algorithms for Serious Mental Illness

This study introduces a computerized clinical decision-support tool, the Fluid Outpatient Rehabilitation Treatment (FORT), that incorporates individual and ever-evolving patient needs to guide clinicians in developing and updating treatment decisions in real-time. In this proof-of-concept feasibility pilot, FORT was compared against traditional treatment planning using similar behavioral therapies in 52 adults with severe mental illness attending community-based day treatment. At posttreatment and follow-up, group differences and moderate-to-large effect sizes favoring FORT were detected in social function, work readiness, self-esteem, working memory, processing speed, and mental flexibility. Of participants who identified obtaining a General Education Diploma as their goal, 73% in FORT passed the examination compared with 18% in traditional treatment planning. FORT was also associated with higher agency cost-effectiveness and a better average benefit-cost ratio, even when considering diagnosis, baseline symptoms, and education. Although the comparison groups were not completely equivalent, the findings suggest computerized decision support systems that collaborate with human decision-makers to personalize psychiatric rehabilitation and address critical decisions may have a role in improving treatment effectiveness and efficiency

Corrigendum to: “Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis” [J Hepatol (2020) 241-251]

It has come to our attention that there are errors in the Table 2 of the original manuscript “Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis”. The Variance Explained for SNP rs738409 has been incorrectly reported as 0.9. The correct value is 0.29. The amino acid changes for SNPs rs111723834, rs58542926 and rs738409 have been incorrectly reported as A561G, I148M and E167K, respectively. The correct amino acid changes are R561Q, E167K and I148M, respectively. SNP rs4820268 variant type (synonymous) and amino acid change (D521D) have also been corrected. Please see the corrected Table 2 below. These errors have occured during manual editing of the table and do not affect the results and conclusions of this article. The authors would like to apologise for any inconvenience caused

Disparate Functional Responses to β-adrenergic and Ischaemic Challenge in Male and Female Hypertrophic Cardiomyocytes

Cardiac hypertrophy is the most potent cardiovascular risk factor after age, with relative mortality risk greater in women. The cognate issue of whether ischaemia coincident with hypertrophic co-morbidity has differing gender aetiology/outcome has not been addressed. We used a novel polygenic model of hypertrophy to examine male/female cellular stress responses in normal and hypertrophic cardiomyocytes.Centro de Investigaciones Cardiovasculare