Allatostatin C modulates nociception and immunity in Drosophila.

Bacterial induced inflammatory responses cause pain through direct activation of nociceptive neurons, and the ablation of these neurons leads to increased immune infiltration. In this study, we investigated nociceptive-immune interactions in Drosophila and the role these interactions play during pathogenic bacterial infection. After bacterial infection, we found robust upregulation of ligand-gated ion channels and allatostatin receptors involved in nociception, which potentially leads to hyperalgesia. We further found that Allatostatin-C Receptor 2 (AstC-R2) plays a crucial role in host survival during infection with the pathogenic bacterium Photorhabdus luminescens. Upon examination of immune signaling in AstC-R2 deficient mutants, we demonstrated that Allatostatin-C Receptor 2 specifically inhibits the Immune deficiency pathway, and knockdown of AstC-R2 leads to overproduction of antimicrobial peptides related to this pathway and decreased host survival. This study provides mechanistic insights into the importance of microbe-nociceptor interactions during bacterial challenge. We posit that Allatostatin C is an immunosuppressive substance released by nociceptors or Drosophila hemocytes that dampens IMD signaling in order to either prevent immunopathology or to reduce unnecessary metabolic cost after microbial stimulation. AstC-R2 also acts to dampen thermal nociception in the absence of infection, suggesting an intrinsic neuronal role in mediating these processes during homeostatic conditions. Further examination into the signaling mechanisms by which Allatostatin-C alters immunity and nociception in Drosophila may reveal conserved pathways which can be utilized towards therapeutically targeting inflammatory pain and chronic inflammation

The psychiatric risk gene NT5C2 regulates adenosine monophosphate-activated protein kinase signaling and protein translation in human neural progenitor cells

Background The 5′-nucleotidase, cytosolic II gene (NT5C2, cN-II) is associated with disorders characterized by psychiatric and psychomotor disturbances. Common psychiatric risk alleles at the NT5C2 locus reduce expression of this gene in the fetal and adult brain, but downstream biological risk mechanisms remain elusive. Methods Distribution of the NT5C2 protein in the human dorsolateral prefrontal cortex and cortical human neural progenitor cells (hNPCs) was determined using immunostaining, publicly available expression data, and reverse transcriptase quantitative polymerase chain reaction. Phosphorylation quantification of adenosine monophosphate-activated protein kinase (AMPK) alpha (Thr172) and ribosomal protein S6 (Ser235/Ser236) was performed using Western blotting to infer the degree of activation of AMPK signaling and the rate of protein translation. Knockdowns were induced in hNPCs and Drosophila melanogaster using RNA interference. Transcriptomic profiling of hNPCs was performed using microarrays, and motility behavior was assessed in flies using the climbing assay. Results Expression of NT5C2 was higher during neurodevelopment and was neuronally enriched in the adult human cortex. Knockdown in hNPCs affected AMPK signaling, a major nutrient-sensing mechanism involved in energy homeostasis, and protein translation. Transcriptional changes implicated in protein translation were observed in knockdown hNPCs, and expression changes to genes related to AMPK signaling and protein translation were confirmed using reverse transcriptase quantitative polymerase chain reaction. The knockdown in Drosophila was associated with drastic climbing impairment. Conclusions We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior

Characterization of ERV9 Elements within the Human Genome

Human Endogenous Retroviruses (HERVs) are the genomic remains of ancient retroviruses that infected vertebrate genomes millions of years ago. Over evolutionary time, these proviruses have lost their infectious capacity due to an accumulation of mutations in the coding regions and long terminal repeats (LTRs), and most are believed to be transcriptionally silent in normal human tissue. However, recent evidence has shown several mechanisms by which HERV expression can influence homeostatic processes, including alternative enhancers for protein coding genes, activation of non-coding genomic regions, and expression of retroviral transcripts or proteins. The HERV9 family of endogenous retroviruses is of particular interest because it represents one of the more recent endogenization events, and is thus expected to retain more of its functional capacity than older HERV families. Despite this relatively young evolutionary age, HERV9 has been given relatively little attention compared to other HERV families such as HERV-W and HERV-K (HML-2). Finally, HERV9 and its long terminal repeat, LTR12, has been shown to regulate the activity of certain proapoptotic genes involved in prevention of cancer, specifically TP63 and TNFRSF10B in testicular cancer. In the present work, we identified and detailed the location and genomic context of 190 HERV9 elements in humans. This bioinformatic analysis has led to a characterization of all near-complete HERV9 elements in the human reference genome (hg38), with a report on the genomic and epigenomic context of their insertions throughout the genome and a phylogenetic classification of HERV9 subfamilies. Our exploratory analyses show dynamic connectivities within the HERV9 families. This body of work illustrates the importance of HERV9 elements and possible contributions to human homeostasis and pathogenesis. The goal of our study is to provide an exhaustive reference library for HERV9 to be used in understanding its role in both pathology and cooption throughout human evolution

TiAIN superlattice structured PVD coatings: a new alternative in the machining of aluminium alloys for aerospace and automotive components

A 3 μm thick superlattice structured TiAlN/VN coating has been deposited by the steered cathodic arc/unbalanced magnetron sputtering technique. The coating has been tested in dry high-speed milling of aluminium alloys Al7010-T7651 and AlSi9Cu1 and the performance compared to that of the diamond-like carbon (DLC) coated, TiAlCrYN coated and uncoated tools. In milling the Al7010-T7651 alloy, TiAlN/VN and DLC coated tools showed comparable performance, outperforming TiAlCrYN coated and uncoated tools by a factor of 2.3 and 3.5, respectively. In the case of milling AlSi9Cu1, the DLC coatings failed to produce any lifetime improvement, TiAlCrYN showed 65% longer lifetime thus rendering TiAlN/VN as the best performing coating with 100% longer lifetime compared to that of the uncoated tools. The tests further showed that TiAlN/VN reduces the cutting forces and improves the surface finish. Scanning electron microscopy of the cutting edge carried out after the cutting tests showed that the TiAlN/VN coating significantly reduces metal transfer and built-up edge formation.</p

The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells

Background The 5′-nucleotidase, cytosolic II gene (NT5C2, cN-II) is associated with disorders characterized by psychiatric and psychomotor disturbances. Common psychiatric risk alleles at the NT5C2 locus reduce expression of this gene in the fetal and adult brain, but downstream biological risk mechanisms remain elusive. Methods Distribution of the NT5C2 protein in the human dorsolateral prefrontal cortex and cortical human neural progenitor cells (hNPCs) was determined using immunostaining, publicly available expression data, and reverse transcriptase quantitative polymerase chain reaction. Phosphorylation quantification of adenosine monophosphate-activated protein kinase (AMPK) alpha (Thr172) and ribosomal protein S6 (Ser235/Ser236) was performed using Western blotting to infer the degree of activation of AMPK signaling and the rate of protein translation. Knockdowns were induced in hNPCs and Drosophila melanogaster using RNA interference. Transcriptomic profiling of hNPCs was performed using microarrays, and motility behavior was assessed in flies using the climbing assay. Results Expression of NT5C2 was higher during neurodevelopment and was neuronally enriched in the adult human cortex. Knockdown in hNPCs affected AMPK signaling, a major nutrient-sensing mechanism involved in energy homeostasis, and protein translation. Transcriptional changes implicated in protein translation were observed in knockdown hNPCs, and expression changes to genes related to AMPK signaling and protein translation were confirmed using reverse transcriptase quantitative polymerase chain reaction. The knockdown in Drosophila was associated with drastic climbing impairment. Conclusions We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior