Molecular classification of Crohn's disease reveals two clinically relevant subtypes

The clinical presentation and course of Crohn’s disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes

Alterations to chromatin in intestinal macrophages link IL-10 deficiency to inappropriate inflammatory responses

Intestinal macrophages are uniquely programmed to tolerate exposure to bacteria without mounting potent inflammatory responses. The cytokine IL-10 maintains the macrophage anti-inflammatory response such that loss of IL-10 results in chronic intestinal inflammation. To investigate how IL-10-deficiency alters intestinal macrophage programming and bacterial tolerance, we studied changes in chromatin accessibility in response to bacteria in macrophages from two distinct niches, the intestine and bone-marrow, from both wild-type and IL-10-deficient mice. In both bone-marrow-derived and intestinal macrophages, we identified chromatin accessibility changes associated with bacterial exposure and IL-10-deficiency. Surprisingly, IL-10-deficient intestinal macrophages adopted chromatin and gene expression patterns characteristic of an inflammatory response, even in the absence of bacteria. Further, if IL-10 protein was added to cells that had previously been IL-10-deficient, it could not revert the chromatin landscape to a normal state. Our results demonstrate that IL-10 deficiency results in stable chromatin alterations in macrophages, even in the absence of bacteria. This supports a model where IL-10-deficiency leads to chromatin alterations that contribute to a loss of intestinal macrophage tolerance to bacteria, which is a primary initiating event in chronic intestinal inflammation

Aberrant miR-29 is a predictive feature of severe phenotypes in pediatric Crohn’s disease

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Credit Constraints and the Measurement of Time Preferences

Incentivized experiments are commonly used to estimate marginal rates of intertemporal substitution (MRS) in the lab and in the field in order to make inferences about individual time preferences. This paper considers an integrated model of behavior in which individuals are subject to financial shocks and credit constraints, and take those into account when making experimental choices. The model shows that measured MRS depends on the individual’s effective interest rate which is equal to the relative marginal utility of current and future consumption. Experimental responses should therefore be correlated with other variables that describe the subject’s financial situation, like savings and shocks to income and consumption. We test the model using a new a panel data set from Mali and find evidence for such effects. Our results imply that the relationship between experimentally elicited MRS and time preferences is not straightforward. However, measured MRS can be useful in determining the importance of different types of financial shocks to the household

BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis

Introduction In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice. Conclusion We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis

Increased colonic expression of ACE2 associates with poor prognosis in Crohn’s disease

The host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn's disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course. We examined the expression of colonic ACE2 in 67 adult CD and 14 NIBD control patients using RNA-seq and quantitative (q) RT-PCR. We validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients. Colonic ACE2 expression was significantly higher in a subset of adult CD patients which was defined as the ACE2-high CD subset. IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of CD diagnosis, and a Cox regression analysis found that high ACE2 levels is an independent risk factor for surgery (OR 2.17; 95% CI, 1.10–4.26; p = 0.025). Increased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that can impact CD disease-related outcomes

LET\u27S GET DIRTY! Mini Baja SAE Project

Matthew Suchyna, Matthew Minchen, Seth Britton, Ryan Smoral, Grant Guzek, Adam Glaser, Casey Willer, Evan Shagott, Jerome Allen, Nick Walker, Josh Schaner and Shaun Payne, ENT 422: Machine Design II Faculty Mentor: Professor Jikai Du, Engineering Technology For the Mini Baja team’s Senior Project, the group was tasked with building a Mini Baja car. The vehicle must meet the requirements laid down by the SAE International group, who will be judging our fully finished car based on a strict set of guidelines. The team’s goal was to build a car that passes its rigorous inspection. This means there was much at stake as we built this car. Once the car has been fully built, our team will take it to a competition that is attended to by various teams all across the country. There, we will be judged on how our car performs in a series of obstacle courses, culminating with a final endurance race, going head-to-head against cars from every state, with the winner crowned as champions. This feat is not to be taken lightly, for the competition is fierce, with multiple skilled racers. We strive to be able to put together a car that we can shower with champagne and go down in the annals of Buffalo State engineering history.https://digitalcommons.buffalostate.edu/srcc-sp20-compeng/1019/thumbnail.jp