28 research outputs found
MicroRNAs in the etiology of colorectal cancer: Pathways and clinical implications
No full textMicroRNAs (miRNAs) are small single-stranded RNAs that repress mRNA translation and trigger mRNA degradation. Of the ∼1900 miRNA-encoding genes present in the human genome, ∼250 miRNAs are reported to have changes in abundance or altered functions in colorectal cancer. Thousands of studies have documented aberrant miRNA levels in colorectal cancer, with some miRNAs reported to actively regulate tumorigenesis. A recurrent phenomenon with miRNAs is their frequent participation in feedback loops, which probably serve to reinforce or magnify biological outcomes to manifest a particular cellular phenotype. Here, we review the roles of oncogenic miRNAs (oncomiRs), tumor suppressive miRNAs (anti-oncomiRs) and miRNA regulators in colorectal cancer. Given their stability in patient-derived samples and ease of detection with standard and novel techniques, we also discuss the potential use of miRNAs as biomarkers in the diagnosis of colorectal cancer and as prognostic indicators of this disease. MiRNAs also represent attractive candidates for targeted therapies because their function can be manipulated through the use of synthetic antagonists and miRNA mimics
PLAGL2 Promotes a Stem Cell Phenotype in Intestinal Epithelial Cells and is Required for a Tumor Phenotype in Colon Cancer Cell Lines
No full textExtensive global movement of multidrug-resistant <em>M. tuberculosis </em>strains revealed by whole-genome analysis
No full textBackground: While the international spread of multidrug-resistant (MDR) Mycobacterium tuberculosis strains is an acknowledged public health threat, a broad and more comprehensive examination of the global spread of MDR-tuberculosis (TB) using whole-genome sequencing has not yet been performed. Methods: In a global dataset of 5310 M. tuberculosis whole-genome sequences isolated from five continents, we performed a phylogenetic analysis to identify and characterise clades of MDR-TB with respect to geographic dispersion. Results: Extensive international dissemination of MDR-TB was observed, with identification of 32 migrant MDR-TB clades with descendants isolated in 17 unique countries. Relatively recent movement of strains from both Beijing and non-Beijing lineages indicated successful global spread of varied genetic backgrounds. Migrant MDR-TB clade members shared relatively recent common ancestry, with a median estimate of divergence of 13-27 years. Migrant extensively drug-resistant (XDR)-TB clades were not observed, although development of XDR-TB within migratory MDR-TB clades was common. Conclusions: Application of genomic techniques to investigate global MDR migration patterns revealed extensive global spread of MDR clades between countries of varying TB burden. Further expansion of genomic studies to incorporate isolates from diverse global settings into a single analysis, as well as data sharing platforms that facilitate genomic data sharing across country lines, may allow for future epidemiological analyses to monitor for international transmission of MDR-TB. In addition, efforts to perform routine whole-genome sequencing on all newly identified M. tuberculosis, like in England, will serve to better our understanding of the transmission dynamics of MDR-TB globally.Pattern Recognition and Bioinformatic
Defective goblet cell exocytosis contributes to murine cystic fibrosis–associated intestinal disease
No full textDeciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: Progress, promise, and challenges
No full textTuberculosis (TB) is a global infectious threat that is intensified by an increasing incidence of highly drug-resistant disease. Whole-genome sequencing (WGS) studies of Mycobacterium tuberculosis, the causative agent of TB, have greatly increased our understanding of this pathogen. Since the first M. tuberculosis genome was published in 1998, WGS has provided a more complete account of the genomic features that cause resistance in populations of M. tuberculosis, has helped to fill gaps in our knowledge of how both classical and new antitubercular drugs work, and has identified specific mutations that allow M. tuberculosis to escape the effects of these drugs. WGS studies have also revealed how resistance evolves both within an individual patient and within patient populations, including the important roles of de novo acquisition of resistance and clonal spread. These findings have informed decisions about which drug-resistance mutations should be included on extended diagnostic panels. From its origins as a basic science technique, WGS of M. tuberculosis is becoming part of the modern clinical microbiology laboratory, promising rapid and improved detection of drug resistance, and detailed and real-time epidemiology of TB outbreaks. We review the successes and highlight the challenges that remain in applying WGS to improve the control of drug-resistant TB through monitoring its evolution and spread, and to inform more rapid and effective diagnostic and therapeutic strategies.Pattern Recognition and Bioinformatic
Reply to Lee and Howden
No full textGreen Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Pattern Recognition and Bioinformatic
Cryptosporidium and Giardia in locally harvested clams in Iqaluit, Nunavut
No full textHigh prevalences of Cryptosporidium and Giardia were recently found in enteric illness patients in the Qikiqtaaluk region of Nunavut, Canada, with a foodborne, waterborne or animal source of parasites suspected. Clams (Mya truncata) are a commonly consumed, culturally important and nutritious country food in Iqaluit; however, shellfish may concentrate protozoan pathogens from contaminated waters. The goal of this work was to investigate clams as a potential source of Cryptosporidium and Giardia infections in residents in Iqaluit, Nunavut. The objectives were to estimate the prevalence and genetically characterize Cryptosporidium and Giardia in locally harvested clams. Clams (n = 404) were collected from Iqaluit harvesters in September 2016. Haemolymph (n = 328) and digestive gland (n = 390) samples were screened for Cryptosporidium and Giardia via PCR, and amplified products were further processed for sequence analyses for definitive confirmation. Giardia DNA was found in haemolymph from 2 clams, while Cryptosporidium was not detected. The two Giardia sequences were identified as zoonotic Giardia enterica assemblage B. The overall prevalence of Giardia in clams near Iqaluit was low (0.6%) compared with other studies in southern Canada and elsewhere. The presence of Giardia DNA in clams suggests human or animal faecal contamination of coastal habitat around Iqaluit in shellfish harvesting waters. Results from this study are intended to inform public health practice and planning in Inuit Nunangat
A modeling framework for characterizing root exudation-driven geochemical dynamics in the Critical Zone
No full textLand use change and intensive agricultural practices have induced significant shifts in the transport and transformation of water, carbon, and nutrients across landscapes. The long-term implications of such changes on soil health and water chemistry remain an open challenge, and the mechanisms that drive changes in solute chemistry and eventually stream water chemistry are not completely understood. Vegetation plays a central role in driving
Critical Zone (CZ) hydrobiogeochemistry through root exudation, the process by which plant roots respond to their environment and release reactive carbon (C) into the soil to influence soil microbial symbionts to their advantage. Although previous studies have demonstrated that such root processes promote soil weathering, there are no existing models capable of describing the interaction of root exudation with temporally-variable processes ranging from mineral dissolution to energy and moisture fluxes in the soil column in a single framework.
The goal of this thesis is to address gaps in the numerical simulation of hydrobiogeochemical dynamics in the shallow subsurface CZ through the development of a modeling framework that links root-microbe-soil-water interactions and feedbacks with above-ground natural and anthropogenic forcings and below-ground influences of soil parent material. This framework was achieved through the development of (1) the root exudation model REWT (Root Exudation in Watershed-scale Transport) which explicitly describes root exudation and associated feedbacks with the soil microbiome; and (2) the model CrunchREWT, which couples REWT with the existing reactive transport model CrunchFlow to incorporate fluid-mineral interactivity, acid/base chemistry, solute complexation, and other geochemical processes to link root-microbe feedbacks to the broader soil environment. These models are driven by a oneway coupling with the existing multi-layer canopy-root ecohydrologic model MLCan, which vertically resolves canopy- and root-system moisture and temperature gradients and fluxes, and plant uptake of moisture and nutrients for various plant species in both natural and intensively managed ecosystems.
We present REWT and CrunchREWT simulations for an intensively managed site in Bondville, Illinois, USA which undergoes corn-corn-soybean rotation. REWT simulations indicate that rates of nitrification and respiration are substantially altered due to the explicit consideration of root exudation. CrunchREWT results show that root-sourced reactive C inputs can lead to the augmentation or reduction of solute concentrations in the soil by several orders of magnitude. Silicate weathering products illustrate episodic leaching patterns, and calcium simulations reveal the development of a stable weathering front consistent with observations. Aluminum concentrations are particularly responsive to geochemical transformations driven by root-sourced reactive C, and analysis of leaching concentration vs leaching flux indicates hysteresis behavior. This work demonstrates the importance of systematically incorporating root exudates into hydrobiogeochemical models and can serve to inform experimental design for shallow subsurface CZ processes.
Although many insights can be gleaned from the simulations presented, several challenges impede our ability to directly compare results with observational data, including the difficulty of procuring the broad array of data necessary to parameterize and validate CrunchREWT. We envision the management-induced reactive zone (MIRZ) flux monitoring system, designed to provide the depth-resolved MIRZ biogeochemical data CrunchREWT requires. We also outline further model improvements that will allow for validation with observational data, including the representation of multi-phase gas diffusion through the soil, tile drain water fluxes and injection of gases in the soil through the tile line, exudation of organic acids, and expansion to a three-dimensional simulation framework.
The work presented here lays the foundation to explore the role of vegetation in soil development and landscape co-evolution. It contributes to a more integrated representation of the interconnected physical, chemical, and biological processes that govern ecosystem functioning.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2023-05-01The student, Susana Roque-Malo, accepted the attached license on 2021-04-16 at 12:03.The student, Susana Roque-Malo, submitted this Dissertation for approval on 2021-04-16 at 12:05.This Dissertation was approved for publication on 2021-04-19 at 15:40.DSpace SAF Submission Ingestion Package generated from Vireo submission #16232 on 2021-09-16 at 20:08:01Made available in DSpace on 2021-09-17T04:04:07Z (GMT). No. of bitstreams: 3
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Mycobacterium tuberculosis Whole Genome Sequences From Southern India Suggest Novel Resistance Mechanisms and the Need for Region-Specific Diagnostics
No full textBackground.India is home to 25% of all tuberculosis cases and the second highest number of multidrug resistant cases worldwide. However, little is known about the genetic diversity and resistance determinants of Indian Mycobacterium tuberculosis, particularly for the primary lineages found in India, lineages 1 and 3.Methods.We whole genome sequenced 223 randomly selected M. tuberculosis strains from 196 patients within the Tiruvallur and Madurai districts of Tamil Nadu in Southern India. Using comparative genomics, we examined genetic diversity, transmission patterns, and evolution of resistance.Results.Genomic analyses revealed (1) prevalence of strains from lineages 1 and 3, (2) recent transmission of strains among patients from the same treatment centers, (3) emergence of drug resistance within patients over time, (4) resistance gained in an order typical of strains from different lineages and geographies, (5) underperformance of known resistance-conferring mutations to explain phenotypic resistance in Indian strains relative to studies focused on other geographies, and (6) the possibility that resistance arose through mutations not previously implicated in resistance, or through infections with multiple strains that confound genotype-based prediction of resistance.Conclusions.In addition to substantially expanding the genomic perspectives of lineages 1 and 3, sequencing and analysis of M. tuberculosis whole genomes from Southern India highlight challenges of infection control and rapid diagnosis of resistant tuberculosis using current technologies. Further studies are needed to fully explore the complement of diversity and resistance determinants within endemic M. tuberculosis populations.Pattern Recognition and Bioinformatic
