A Rare Case of Infliximab-Induced Small Vessel Vasculitis With Renal Involvement.

There are few cases in the literature demonstrating vasculitis induced by tumor necrosis factor-α. There exist even fewer cases of systemic inflammation involving the skin, nerves, and kidneys. Here, we present a novel case of a 27-year-old man with Crohn disease refractory to multiple medications, most recently treated with infliximab. He presented with a 3-week history of non-blanching palpable petechial rash involving his bilateral extremities and right upper extremity as well as lesions with black eschar around his ankles. He was found to have refractory cutaneous small vessel vasculitis, nephrotic range proteinuria, and small fiber neuropathy. This case describes the evaluation and treatment of systemic small vessel vasculitis in the setting of infliximab therapy.

What are housekeeping genes?

The concept of "housekeeping gene" has been used for four decades but remains loosely defined. Housekeeping genes are commonly described as "essential for cellular existence regardless of their specific function in the tissue or organism", and "stably expressed irrespective of tissue type, developmental stage, cell cycle state, or external signal". However, experimental support for the tenet that gene essentiality is linked to stable expression across cell types, conditions, and organisms has been limited. Here we use genome-scale functional genomic screens together with bulk and single-cell sequencing technologies to test this link and optimize a quantitative and experimentally validated definition of housekeeping gene. Using the optimized definition, we identify, characterize, and provide as resources, housekeeping gene lists extracted from several human datasets, and 10 other animal species that include primates, chicken, and C. elegans. We find that stably expressed genes are not necessarily essential, and that the individual genes that are essential and stably expressed can considerably differ across organisms; yet the pathways enriched among these genes are conserved. Further, the level of conservation of housekeeping genes across the analyzed organisms captures their taxonomic groups, showing evolutionary relevance for our definition. Therefore, we present a quantitative and experimentally supported definition of housekeeping genes that can contribute to better understanding of their unique biological and evolutionary characteristics.

Ten simple rules for improving communication among scientists.

Communication is a fundamental part of scientific development and methodology. With the advancement of the internet and social networks, communication has become rapid and sometimes overwhelming, especially in science. It is important to provide scientists with useful, effective, and dynamic tools to establish and build a fluid communication framework that allows for scientific advancement. Therefore, in this article, we present advice and recommendations that can help promote and improve science communication while respecting an adequate balance in the degree of commitment toward collaborative work. We have developed 10 rules shown in increasing order of commitment that are grouped into 3 key categories: (1) speak (based on active participation); (2) join (based on joining scientific groups); and (3) assess (based on the analysis and retrospective consideration of the weaknesses and strengths). We include examples and resources that provide actionable strategies for involvement and engagement with science communication, from basic steps to more advanced, introspective, and long-term commitments. Overall, we aim to help spread science from within and encourage and engage scientists to become involved in science communication effectively and dynamically.

Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions.

Plasticity in multicellular organisms involves signaling pathways converting contexts-either natural environmental challenges or laboratory perturbations-into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF-target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16-mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB-the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3 Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name "contextualized transcription."

Dietary serine-microbiota interaction enhances chemotherapeutic toxicity without altering drug conversion.

The gut microbiota metabolizes drugs and alters their efficacy and toxicity. Diet alters drugs, the metabolism of the microbiota, and the host. However, whether diet-triggered metabolic changes in the microbiota can alter drug responses in the host has been largely unexplored. Here we show that dietary thymidine and serine enhance 5-fluoro 2'deoxyuridine (FUdR) toxicity in C. elegans through different microbial mechanisms. Thymidine promotes microbial conversion of the prodrug FUdR into toxic 5-fluorouridine-5'-monophosphate (FUMP), leading to enhanced host death associated with mitochondrial RNA and DNA depletion, and lethal activation of autophagy. By contrast, serine does not alter FUdR metabolism. Instead, serine alters E. coli's 1C-metabolism, reduces the provision of nucleotides to the host, and exacerbates DNA toxicity and host death without mitochondrial RNA or DNA depletion; moreover, autophagy promotes survival in this condition. This work implies that diet-microbe interactions can alter the host response to drugs without altering the drug or the host.

The Ancient Genetic Networks of Obesity: Whole-Animal Automated Screening for Conserved Fat Regulators.

Caenorhabditis elegans is the first and only metazoan model that enables whole-body gene knockdown by simply feeding their standard laboratory diet, E. coli, carrying RNA interference (RNAi)-expressing constructs. The simplicity of the RNAi treatment, small size, and fast reproduction rate of C. elegans allow us to perform whole-animal high-throughput genetic screens in wild-type, mutant, or otherwise genetically modified C. elegans. In addition, more than 65% of C. elegans genes are conserved in mammals including human. In particular, C. elegans metabolic pathways are highly conserved, which supports the study of complex diseases such as obesity in this genetically tractable model system. In this chapter, we present a detailed protocol for automated high-throughput whole-animal RNAi screening to identify the pathways promoting obesity in diet-induced and genetically driven obese C. elegans. We describe an optimized high-content screening protocol to score fat mass and body fat distribution in whole animals at large scale. We provide optimized pipelines to automatically score phenotypes using the open-source CellProfiler platform within the context of supercomputer clusters. Further, we present a guideline to optimize information workflow from the automated microscope to a searchable database. The approaches described here enable unveiling the whole network of gene-gene and gene-environment interactions that define metabolic health or disease status in this proven model of human disease, but similar principles can be applied to other disease models.