Impact of hydroxycarbamide treatment on the whole-blood transcriptome in sickle cell disease.

Hydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF-independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed.

Sex-Dimorphic Analyses Identify Novel and Sex-Specific Genetic Associations in Inflammatory Bowel Disease.

Background: Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

Objective: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in ().

Design: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed.

Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses.

Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.

Background And Aims: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls.

Methods: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis.

Reduced expression of COVID-19 host receptor, is associated with small bowel inflammation, more severe disease, and response to anti-TNF therapy in Crohn's disease.

Angiotensin-Converting Enzyme 2 ( ) has been identified as the host receptor for SARS-coronavirus 2 (SARS-CoV-2) which has infected millions world-wide and likely caused hundreds of thousands of deaths. Utilizing transcriptomic data from four cohorts taken from Crohn's disease (CD) and non-inflammatory bowel disease (IBD) subjects, we observed evidence of increased mRNA in ileum with demographic features that have been associated with poor outcomes in COVID-19 including age and raised BMI. was downregulated in CD compared to controls in independent cohorts.

hnRNP L-mediated RNA switches function as a hypoxia-induced translational regulon.

The GAIT (gamma-interferon-activated inhibitor of translation) complex or miR-297-RISC (RNA-induced silencing complex), together with hnRNP L or hnRNP L-bearing complex, operates an RNA switch in myeloid cells that regulates stress-dependent expression of vascular endothelial growth factor-A (VEGFA). Here, we have shown that hnRNP L directs multiple hypoxia-inducible RNA switches simultaneously and regulates expression of these oncogenic genes in addition to VEGFA. Bioinformatic and polysome profiling-microarray screens have identified DNM1L (Dynamin 1-like) and PHF21A (PHD finger protein 21A) mRNAs as regulated at the translational level by GAIT-dependent, hnRNP L-directed RNA switches.

Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

Background And Aims: Heterogeneity in Crohn's disease [CD] provides a challenge for the development of effective therapies. Our goal was to define a unique molecular signature for severe, refractory CD to enable precision therapy approaches to disease treatment and to facilitate earlier intervention in complicated disease.

Methods: We analysed clinical metadata, genetics, and transcriptomics from uninvolved ileal tissue from CD patients who underwent a single small bowel resection.

A role for BATF3 in T9 differentiation and T-cell-driven mucosal pathologies.

T helper 9 (T9) cells are important for the development of inflammatory and allergic diseases. The T9 transcriptional network converges signals from cytokines and antigen presentation but is incompletely understood. Here, we identified TL1A, a member of the TNF superfamily, as a strong inducer of mouse and human T9 differentiation.

Metabolic origin of the fused aminoacyl-tRNA synthetase, glutamyl-prolyl-tRNA synthetase.

About 1 billion years ago, in a single-celled holozoan ancestor of all animals, a gene fusion of two tRNA synthetases formed the bifunctional enzyme, glutamyl-prolyl-tRNA synthetase (EPRS). We propose here that a confluence of metabolic, biochemical, and environmental factors contributed to the specific fusion of glutamyl- (ERS) and prolyl- (PRS) tRNA synthetases. To test this idea, we developed a mathematical model that centers on the precursor-product relationship of glutamic acid and proline, as well as metabolic constraints on free glutamic acid availability near the time of the fusion event.

Late-Onset Crohn's Disease Is A Subgroup Distinct in Genetic and Behavioral Risk Factors With UC-Like Characteristics.

Background: Age of onset is linked to variations in clinical phenotypes and natural history in Crohn's disease (CD). We aim to define etiologically more homogenous subgroups in CD based on ages of onset.

Methods: We examined the distribution of CD polygenetic risk score (PRS) across ages of diagnosis in a Caucasian cohort of 2344 independent CD patients.

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease.

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling.

Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn's Disease.

Background & Aims: Variants in the tumor necrosis factor superfamily member 15 gene (TNFSF15, also called TL1A) have been associated with risk for inflammatory bowel disease (IBD). TL1A affects expression of multiple cytokines to promote mucosal inflammation. Little is known about the TL1A-response pathways that regulate cytokine expression.

EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice.

Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes to adiposity and ageing.

Computational modeling and analysis of iron release from macrophages.

A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis.

Profilin-1 phosphorylation directs angiocrine expression and glioblastoma progression through HIF-1α accumulation.

The tumour vascular microenvironment supports tumorigenesis not only by supplying oxygen and diffusible nutrients but also by secreting soluble factors that promote tumorigenesis. Here we identify a feedforward mechanism in which endothelial cells (ECs), in response to tumour-derived mediators, release angiocrines driving aberrant vascularization and glioblastoma multiforme (GBM) progression through a hypoxia-independent induction of hypoxia-inducible factor (HIF)-1α. Phosphorylation of profilin-1 (Pfn-1) at Tyr 129 in ECs induces binding to the tumour suppressor protein von Hippel-Lindau (VHL), and prevents VHL-mediated degradation of prolyl-hydroxylated HIF-1α, culminating in HIF-1α accumulation even in normoxia.

The HILDA complex coordinates a conditional switch in the 3'-untranslated region of the VEGFA mRNA.

Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, condition-dependent responses. Here, we elucidate the components and mechanisms driving a protein-directed RNA switch in the 3'UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel HILDA (hypoxia-inducible hnRNP L-DRBP76-hnRNP A2/B1) complex that coordinates a three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia and inflammation.

Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression.

Posttranscriptional regulatory mechanisms superimpose "fine-tuning" control upon "on-off" switches characteristic of gene transcription. We have exploited computational modeling with experimental validation to resolve an anomalous relationship between mRNA expression and protein synthesis. The GAIT (gamma-interferon-activated inhibitor of translation) complex repressed VEGF-A synthesis to a low, constant rate independent of VEGF-A mRNA expression levels.

Laminin-332 cleavage by matriptase alters motility parameters of prostate cancer cells.

Background: Matriptase, a type II transmembrane serine protease, has been linked to initiation and promotion of epidermal carcinogenesis in a murine model, suggesting that deregulation of its role in epithelia contributes to transformation. In human prostate cancer, matriptase expression correlates with progression. It is therefore of interest to determine how matriptase may contribute to epithelial neoplastic progression.

Bimodal analysis reveals a general scaling law governing nondirected and chemotactic cell motility.

Cell motility is a fundamental process with relevance to embryonic development, immune response, and metastasis. Cells move either spontaneously, in a nondirected fashion, or in response to chemotactic signals, in a directed fashion. Even though they are often studied separately, both forms of motility share many complex processes at the molecular and subcellular scale, e.

Human mammary epithelial cells exhibit a bimodal correlated random walk pattern.

Background: Organisms, at scales ranging from unicellular to mammals, have been known to exhibit foraging behavior described by random walks whose segments confirm to Lévy or exponential distributions. For the first time, we present evidence that single cells (mammary epithelial cells) that exist in multi-cellular organisms (humans) follow a bimodal correlated random walk (BCRW).

Methodology/principal Findings: Cellular tracks of MCF-10A pBabe, neuN and neuT random migration on 2-D plastic substrates, analyzed using bimodal analysis, were found to reveal the BCRW pattern.

Bimodal analysis of mammary epithelial cell migration in two dimensions.

Cell migration paths of mammary epithelial cells (expressing different versions of the promigratory tyrosine kinase receptor Her2/Neu) were analyzed within a bimodal framework that is a generalization of the run-and-tumble description applicable to bacterial migration. The mammalian cell trajectories were segregated into two types of alternating modes, namely, the "directional mode" (mode I, the more persistent mode, analogous to the bacterial run phase) and the "re-orientation mode" (mode II, the less persistent mode, analogous to the bacterial tumble phase). Higher resolution (more pixel information, relative to cell size) and smaller sampling intervals (time between images) were found to give a better estimate of the deduced single cell dynamics (such as directional-mode time and turn angle distribution) of the various cell types from the bimodal analysis.