Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

Interferon regulatory factors (IRFs) are a family of homologous proteins that regulate the transcription of interferons (IFNs) and IFN-induced gene expression. As such they are important modulating proteins in the Toll-like receptor (TLR) and IFN signaling pathways, which are vital elements of the innate immune system. IRFs have a multi-domain structure, with the N-terminal part acting as a DNA binding domain (DBD) that recognizes a DNA-binding motif similar to the IFN-stimulated response element (ISRE). The C-terminal part contains the IRF-association domain (IAD), with which they can self-associate, bind to IRF family members or interact with other transcription factors. This complex formation is crucial for DNA binding and the commencing of target-gene expression. IRFs bind DNA and exert their activating potential as homo or heterodimers with other IRFs. Moreover, they can form complexes (e.g., with Signal transducers and activators of transcription, STATs) and collaborate with other co-acting transcription factors such as Nuclear factor-κB (NF-κB) and PU.1. In time, more of these IRF co-activating mechanisms have been discovered, which may play a key role in the pathogenesis of many diseases, such as acute and chronic inflammation, autoimmune diseases, and cancer. Detailed knowledge of IRFs structure and activating mechanisms predisposes IRFs as potential targets for inhibition in therapeutic strategies connected to numerous immune system-originated diseases. Until now only indirect IRF modulation has been studied in terms of antiviral response regulation and cancer treatment, using mainly antisense oligonucleotides and siRNA knockdown strategies. However, none of these approaches so far entered clinical trials. Moreover, no direct IRF-inhibitory strategies have been reported. In this review, we summarize current knowledge of the different IRF-mediated transcriptional regulatory mechanisms and how they reflect the diverse functions of IRFs in homeostasis and in TLR and IFN signaling. Moreover, we present IRFs as promising inhibitory targets and propose a novel direct IRF-modulating strategy employing a pipeline approach that combines comparative in silico docking to the IRF-DBD with in vitro validation of IRF inhibition. We hypothesize that our methodology will enable the efficient identification of IRF-specific and pan-IRF inhibitors that can be used for the treatment of IRF-dependent disorders and malignancies

The influence of textile materials on flame resistance ratings of professional uniforms

This study compares the flame speed of different textile materials employed in professional uniforms. Five different garments of aeronauts’ uniforms were analyzed (totaling 200 specimens submitted to flammability tests). Plain weaves and twill weaves composed by 100% CO; 100% PES; 67% PES/33% CO; 50% PES/50% WO; and 55% PES/45%WO were analyzed in the warp and filling directions. The flame speed of each material was determined, and differences in the flame propagation of the fabrics were identified. The lowest flame speed occurred for the material 50% PES/50% WO plain weave and weft direction (0.742 ± 0.140 m/s). The highest flame speed was 3.698 ± 1.806 cm/s for the material 67%PES/33%CO, plain weave and filling direction. Future experiments for reducing the fabric flammability of the uniforms could be related to more closed fabric constructions; mixtures with synthetic fibers to add functionality; changing the direction of the fabric; and changing the weight and torsion of its constituent yarns.São Paulo Research Foundation—FAPESP (“Fundação de Amparo à Pesquisa do Estado de São Paulo”) Grant Number 2016/01331-

Genome-Wide Inhibition of Pro-atherogenic Gene Expression by Multi-STAT Targeting Compounds as a Novel Treatment Strategy of CVDs

Cardiovascular diseases (CVDs), including atherosclerosis, are globally the leading cause of death. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of Signal Transducer and Activator of Transcription (STAT)s. Searches for compounds targeting the pTyr-SH2 interaction area of STAT3, yielded many small molecules, including STATTIC and STX-0119. However, many of these inhibitors do not seem STAT3-specific. We hypothesized that multi-STAT-inhibitors that simultaneously block STAT1, STAT2, and STAT3 activity and pro-inflammatory target gene expression may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple STAT-SH2 models on multi-million compound libraries, we identified the novel multi-STAT inhibitor, C01L_F03. This compound targets the SH2 domain of STAT1, STAT2, and STAT3 with the same affinity and simultaneously blocks their activity and expression of multiple STAT-target genes in HMECs in response to IFNα. The same in silico and in vitro multi-STAT inhibiting capacity was shown for STATTIC and STX-0119. Moreover, C01L_F03, STATTIC and STX-0119 were also able to affect genome-wide interactions between IFNγ and TLR4 by commonly inhibiting pro-inflammatory and pro-atherogenic gene expression directed by cooperative involvement of STATs with IRFs and/or NF-κB. Moreover, we observed that multi-STAT inhibitors could be used to inhibit IFNγ+LPS-induced HMECs migration, leukocyte adhesion to ECs as well as impairment of mesenteric artery contractility. Together, this implicates that application of a multi-STAT inhibitory strategy could provide great promise for the treatment of CVDs

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

astrotoma_94_955

This is the main data matrix file, ready for downstream analyses

README_Astrotoma

README file describing the details of all uploaded dat

Genomic analyses of Northern snakehead (Channa argus) populations in North America

Background The introduction of northern snakehead (Channa argus; Anabantiformes: Channidae) and their subsequent expansion is one of many problematic biological invasions in the United States. This harmful aquatic invasive species has become established in various parts of the eastern United States, including the Potomac River basin, and has recently become established in the Mississippi River basin in Arkansas. Effective management of C. argus and prevention of its further spread depends upon knowledge of current population structure in the United States. Methods Novel methods for invasive species using whole genomic scans provide unprecedented levels of data, which are able to investigate fine scale differences between and within populations of organisms. In this study, we utilize 2b-RAD genomic sequencing to recover 1,007 single-nucleotide polymorphism (SNP) loci from genomic DNA extracted from 165 C. argus individuals: 147 individuals sampled along the East Coast of the United States and 18 individuals sampled throughout Arkansas. Results Analysis of those SNP loci help to resolve existing population structure and recover five genetically distinct populations of C. argus in the United States. Additionally, information from the SNP loci enable us to begin to calculate the long-term effective population size ranges of this harmful aquatic invasive species. We estimate long-term Ne to be 1,840,000–18,400,000 for the Upper Hudson River basin, 4,537,500–45,375,000 for the Lower Hudson River basin, 3,422,500–34,225,000 for the Potomac River basin, 2,715,000–7,150,000 for Philadelphia, and 2,580,000–25,800,000 for Arkansas populations. Discussion and Conclusions This work provides evidence for the presence of more genetic populations than previously estimated and estimates population size, showing the invasive potential of C. argus in the United States. The valuable information gained from this study will allow effective management of the existing populations to avoid expansion and possibly enable future eradication efforts

Astrotoma_cleaned_fasta

This file contains all sample files. All files have be checked for quality, size, and the presence of the restriction enzyme AlfI. Samples are ready for further processing through custom pipelines or through programs such as STACKS

2b-RAD STRUCTURE alignment of Ophionotus victoriae (Meyer)

1,999 bi-allelic SNP loci using Dr. Eli Meyer's (Oregon State University) scripts which can be found at (https://github.com/Eli-Meyer