The endoplasmic reticulum (ER) transmits apoptotic signals in the pancreas during ER stress, implicating stress–mediated apoptosis development of diabetes. P58IPK (DNAJC3) is induced stress and functions as a negative feedback component to inhibit eIF-2α signaling attenuate later phases response. To gain insight into more comprehensive role function, we generated deletion mutant mice that showed gradual onset glucosuria hyperglycemia associated with increasing pancreatic islet cells. Lack...

The preemptive quality control (pQC) pathway protects cells from acute endoplasmic reticulum (ER) stress by attenuating translocation of nascent proteins despite their targeting to translocons at the ER membrane. Here, we investigate hypothesis that DnaJ protein p58(IPK) plays an essential role in this process via HSP70 recruitment cytosolic face for extraction translocationally attenuated chains. Our analyses revealed heightened sensitivity p58-/- was not due impairment pQC or elevated...

Highlights•Drosophila STING (dmSTING) associates with cyclic dinucleotides•Flies knocked down or deleted for dmSTING are more susceptible to Listeria infection•DmSTING functions in mammalian cells and activates NF-κB signaling•DmSTING signals through the IMD pathway stimulates Relish cleavageSummaryThe vertebrate protein STING, an intracellular sensor of dinucleotides, is critical innate immune response induction type I interferon during pathogenic infection. Here, we show that a ortholog...

Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses and the current H1N1 pandemic highlight need for a more detailed understanding virus pathogenesis. To investigate host transcriptional response induced by viruses, we used functional-genomics approach to compare gene expression profiles in lungs from 129S6/SvEv mice infected with either fully reconstructed 1918 (1918) or Vietnam/1203/04 (VN/1203). Although reached similar titers lung caused lethal infections, mean time...

West Nile virus (WNV) is capable of causing severe neurologic disease in both humans and equines, making it a importance human medicine veterinary medicine. No targeted treatments exist for WNV infection either or equines. Infection treated symptomatically through management symptoms like fever seizures. As treatment purely supportive, the response to has focused primarily on methods prevention. To this end, research efforts have yielded several effective vaccines equine use as well numerous...

The World Health Organization estimates that more than half of the world's population is at risk for vector-borne diseases, including arboviruses. Because many arboviruses are mosquito borne, investigation insect immune response will help identify targets to reduce spread Here, we use a genetic screening approach an insulin-like receptor as component arboviral infection. We determine vertebrate insulin reduces West Nile virus (WNV) replication in Drosophila melanogaster well WNV, Zika, and...

Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine whether two primary phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are effective treatments persistent inflammatory pain. In experiment 1, inflammation induced by intraplantar injection Complete Freund's adjuvant (CFA). Then THC (0.0–4.0 mg/kg, i.p.) or CBD (0.0–10 administered twice daily 3 days. On day 4, THC, CBD, vehicle administered,...

ABSTRACT We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment P58 IPK , cellular inhibitor PKR, an interferon-induced kinase targets eukaryotic initiation factor eIF2α. also inhibits PERK, eIF2α is localized in endoplasmic reticulum (ER) and induced during ER stress. The ability to interact with inhibit multiple kinases suggests it a critical regulator both viral translation. In this study, we sought definitively define role infection...

Sleep contributes to cognitive functioning and is sufficient alter brain morphology function. However, mechanisms underlying sleep regulation remain poorly understood. In mammals, tumor necrosis factor-alpha (TNFα) known regulate sleep, cytokine expression may represent an evolutionarily ancient mechanism in regulation. Here we show that the Drosophila TNFα homologue, Eiger, mediates flies. We knockdown of Eiger astrocytes, but not neurons, significantly reduces duration, total...

Cyclobutane pyrimidine dimers (CPDs) are formed in DNA following exposure to ultraviolet (UV) light and mutagenic unless repaired by nucleotide excision repair (NER). It is known that CPD rates vary different genome regions owing transcription-coupled NER differences chromatin accessibility; however, the impact of regional organization on formation remains unclear. Furthermore, nucleosomes modulate UV damage activity, but how these patterns affected overarching domains which located not...

The "Spanish influenza" of 1918 claimed an unprecedented number lives, yet the determinants virulence for this virus are still not fully understood. Here, we used functional genomics and in vitro human lung epithelial cell infection model to define global host transcriptional response eight-gene virus. To better understand role NS1 gene, also evaluated a reassortant containing gene from A/Texas/36/91 (a seasonal isolate influenza virus), as well gene. Genomic analyses revealed that blocked...

There is a need to develop universal vaccine against influenza virus infection avoid developing new formulations of seasonal each year. Many the strategies for target strain-conserved proteins, such as matrix, polymerase, and nucleoproteins, rather than surface hemagglutinin neuraminidase proteins. In addition, non-disease-causing viral vectors are popular choice delivery system antigens. As proof-of-concept, we have designed novel immunogen based on NP backbone containing human T cell...

Insects are not only major vectors of mammalian viruses, but also host to insect-restricted viruses that can potentially be transmitted mammals. While innate immune responses arboviruses well studied, less is known about how cells respond restricted infect invertebrates. Here we demonstrate IIV-6, a DNA virus the family Iridoviridae, able induce type I interferon-dependent antiviral response in cells. Although IIV-6 virus, activated during infection mediated by RIG-I-like receptor (RLR)...

Abstract STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii Gram-negative obligate intracellular bacterium the causative agent zoonotic disease Q fever. The ability C. inhibit host cell death critical factor in development. Previous studies have shown that inhibits apoptosis at early stages infection. However, during late-stages infection, there lysis resulting release...

To support their replication, viruses take advantage of numerous cellular factors and processes. Recent large-scale screens have identified hundreds such factors, yet little is known about how exploit any these. Influenza virus infection post-translationally activates P58IPK, a inhibitor the interferon-induced, dsRNA-activated eIF2α kinase, PKR. Here, we report that P58IPK knockout mice with influenza resulted in increased lung pathology, immune cell apoptosis, PKR activation, mortality....

The innate immune response provides the first line of defense against foreign pathogens by responding to molecules that are a signature pathogenic infection. Certain RNA viruses, such as influenza virus, produce double-stranded an intermediate during replication life cycle, which activates pathogen recognition receptors capable inducing interferon production. By engaging receptors, JAK-STAT pathway and results in positive feedback production, amplifying viral To examine how deficiencies...

The recent global Zika epidemics have revealed the significant threat that mosquito-borne viruses pose. There are currently no effective vaccines or prophylactics to prevent virus (ZIKV) infection. Limiting exposure infected mosquitoes is best way reduce disease incidence. Recent studies focused on targeting mosquito reproduction and immune responses transmission. Previous work has evaluated effect of insulin signaling antiviral JAK/STAT RNAi in vector mosquitoes. Specifically, insulin-fed...

Coxiella burnetii is the causative agent of Q fever, a zoonotic disease that threatens both human and animal health. Due to paucity experimental models, little known about how host factors interface with bacterial components affect pathogenesis. Here, we used Drosophila melanogaster, in conjunction biosafety level 2 (BSL2) Nine Mile phase II (NMII) clone 4 strain C. burnetii, as model investigate implicated infection. We demonstrate adult flies are susceptible NMII infection this strain,...

Mutations in the human carbonic anhydrase IV (hCAIV) have been associated with retinal degeneration an autosomal-dominant form of retinitis pigmentosa (RP17). Prior vitro cell culture studies confirmed that all RP17-associated hCAIV mutations cause protein misfolding, leading to endoplasmic reticulum (ER) stress–induced apoptosis cells expressing mutant proteins. To evaluate physiological impacts these folding mutants other IV–producing tissues, we generated two transgenic mouse lines R219S...

Apoptosis is the primary cause of degeneration in a number neuronal, muscular, and metabolic disorders. These diseases are subject to great deal phenotypic heterogeneity patient populations, primarily due differences genetic variation between individuals. This creates barrier effective diagnosis treatment. Understanding how influences apoptosis could lead development new therapeutics better personalized treatment approaches. In this study, we examine impact natural Drosophila Genetic...