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Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major responder to the pathogenic DNA of viruses and bacteria. Upon DNA binding, cGAS becomes enzymatically active to generate the second messenger cGAMP, leading to activation of inflammatory genes, type I interferon production, autophagy, and cell death. Following genotoxic stress, cGAS can also respond to endogenous DNA, deriving from mitochondria, endogenous retroelements, and chromosomes to affect cellular signaling, secretion, and cell fate decisions. However, under unperturbed conditions, signaling from self-DNA is largely, but not completely, inhibited. Here we review how endogenous DNA is exposed to cGAS, how signaling is attenuated but activated under pathological conditions, and how low-level signaling under unperturbed conditions might prime antipathogenic responses.

In this issue of Blood, Stremenova Spegarova et al report 3 patients with biallelic loss-of-function (LOF) TET2 mutations.(1) These patients suffered from infections, autoimmunity, and lymphoma, demonstrating 3 of the 5 potential phenotypes seen in inborn errors of immunity. TET2 encodes ten-eleven translocation methylcytosine dioxygenase 2 (TET2), 1 of the 3 members of the TET family of epigenetic regulators responsible for converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and subsequent oxidation products in an active DNA demethylation pathway. TET2 is ubiquitous, with particularly strong expression in hematopoietic cells. Somatic LOF TET2 mutations were first reported in patients with myeloproliferative disorders and hematologic cancers over 10 years ago.(2) TET2 haploinsufficiency has also recently been reported in families with myeloid or lymphoid cancers. Intriguingly, some of these patients also presented signs of enhanced monocyte- and macrophage-mediated inflammatory responses, together with atherosclerotic plaque development, which has been associated with increases in NLRP3 inflammasome activation.(3,4) Thus, the tumor suppressor role of TET2 has been extensively documented, especially in myeloid lineages.

Aim:Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD).Patients & methods:One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls.Results:Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect:NPY1R/GALrs4691910/rs1893679,NPY1R/GALrs4691910/rs3136541 andGALR1/GALrs9807208/rs3136541.Conclusion:This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.

Concerns have been raised over the neurotoxicity of triphenyl phosphate (TPP), but there have been few studies of the neurotoxic effects of TPP on mammals and the underlying mechanisms. In this study, weaned male mice (C57/BL6) were used and exposed to 0, 50, or 150 mg/kg TPP daily by oral gavage for 30 days. The blood brain barrier (BBB) permeability of TPP and its metabolite diphenyl phosphate (DPP) in the brain, and TPP induced metabolomic and transcriptomic changes of the brain were investigated. The results showed that TPP and DPP can cross the BBB of mice. Histopathological examination of the brain revealed abnormalities in the hippocampus, cortex and thalamus, and mice treated with high doses showed a potential inflammation in the thalamus and hippocampus. Untargeted metabolomic results revealed that the changed level of glutamic acid, N-acetyl CoA metabolites, and organic acid in the brain of treated mice, suggest that amino acid and lipid metabolism was interfered. RNA-seq data indicated that neuronal transcription processes and cell apoptosis pathway (forkhead box (FOXO), and mitogen-activated protein kinase (MAPK) signaling pathways) were significantly affected by TPP exposure. RT-PCR showed proinflammation cytokine tumor necrosis factor alpha (TNIF-alpha) and interleukin-6 (IL-6)) levels were increased, while antioxidant genes including nuclear factor-E2-related factor 2 (Nrf2), heme oxygenase1 (HO-1) and superoxide dismutase (SOD1) decreased. These results suggest that TPP could cause a degree of neurotoxicity by inducing neuroinflammation and neuronal apoptosis, which are related to oxidative stress. The potential implications for neurophysiology and behavioral regulation cannot be ignored. (C) 2020 Elsevier Ltd. All rights reserved.

Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.

The insect antennal lobe (AL) contains the first synapses of the olfactory system, where olfactory sensory neurons (OSNs) contact second-order projection neurons (PNs). In Drosophila melanogaster, OSNs expressing specific receptor genes send stereotyped projections to one or two of about 50 morphologically defined glomeruli [1-3]. The mechanisms for this precise matching between OSNs and PNs have been studied extensively in D. melanogaster, where development is deterministic and independent of neural activity [4-6]. However, a number of insect lineages, most notably the ants, have receptor gene repertoires many times larger than D. melanogaster and exhibit more structurally complex antennal lobes [7-12]. Moreover, perturbation of OSN function via knockout of the odorant receptor (OR) co-receptor, Orco, results in drastic AL reductions in ants [13, 14], but not in Drosophila [15]. Here, we characterize AL development in the clonal raider ant, Ooceraea biroi. We find that, unlike in Drosophila, ORs and Orco are expressed before the onset of glomerulus formation, and Orco protein is trafficked to developing axon terminals, raising the possibility that ORs play a role during ant AL development. Additionally, ablating ant antennae at the onset of pupation results in AL defects that recapitulate the Orco mutant phenotype. Thus, early loss of functional OSN innervation reveals latent structure in the AL that develops independently of peripheral input, suggesting that the AL is initially pre-patterned and later refined in an OSN-dependent manner. This two-step process might increase developmental flexibility and thereby facilitate the rapid evolution and expansion of the ant chemosensory system.

In 2018, the American Academy of Neurology, the American Congress of Rehabilitation Medicine, and the National Institute on Disability, Independent Living, and Rehabilitation Research published a systematic evidence-based review and an associated practice guideline for improved assessment, treatment, and rehabilitation of patients with disorders of consciousness. Patients with disorders of consciousness include individuals in the vegetative and minimally conscious states, as well as others with covert consciousness and cognitive motor dissociation. These landmark publications (concurrently published in Neurology and Archives of Physical Medicine and Rehabilitation) supplant the 1994 New England Journal of Medicine Multi-Society Task Force report on the vegetative state and the 2002 criteria establishing minimally conscious states. The guideline re-designates the permanent vegetative state as chronic. In our article, we consider the legal and ethical implications of the practice guideline for clinical practice and explain the vulnerability of these patients who suffer from high rates of misdiagnosis, inadequate medical surveillance, undertreatment of pain, inadequate rehabilitation, and segregation in chronic care. We argue that these deficiencies in medical care are inconsistent with our growing appreciation of the dynamic nature of these brain states and an emerging standard of care as articulated by the national guideline. These deficiencies also violate domestic and international disability law. To substantiate this latter claim, we apply disability law to this population, focusing on key Americans with Disabilities Act mandates, the relevance of the 1999 Supreme Court, Olmstead v. L.C., and the utility of Olmstead enforcement actions to integrate the care of these individuals into the medical mainstream. (C) 2020 Mayo Foundation for Medical Education and Research

The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3(+)/CD8(+) (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.

Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1(A) and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4 A cryo-electron microscopy (cryo-EM) structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses, and characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.

Background Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/ kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse. Objectives Determine whether gene variants in the opioid gene system are associated with better or worse treatment response. Methods In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the National Drug Abuse Clinical Trials Network, DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N= 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to each model outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction. Results There were no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions. Conclusions The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.