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The kappa (kappa) opioid receptor/dynorphin system modulates depression-like states and anhedonia, as well adaptations to stress and exposure to drugs of abuse. Several relatively short-acting small molecule kappa-receptor antagonists have been synthesized, and their behavioral profile has been examined under some conditions. The hypothesis of this study is that pharmacological manipulations of the kappa-receptor system will result in changes in ethologically relevant anhedonic-like behaviors in mice. Adult male C57BL/6j mice (n = 6-8) were examined for self-grooming behavior in the splash test (in which robust self-grooming is elicited by spraying the dorsum of the mouse with a sucrose solution). The kappa-agonist salvinorin A (0.56-1.8 mg/kg) produced dose-dependent decreases in self-grooming, a marker of anhedonia. The selectivity, potency, and duration of action of two relatively short-acting kappa-antagonists, LY2444296 [(S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)be nzamide] and LY2795050 [3-chloro-4-(4-(((2S)-2-pyridin-3- ylpyrrolidin-1-yl)methyl) phenoxy)benzamide], were studied for their effectiveness in preventing grooming deficits caused by salvinorin A (1.8 mg/kg). kappa-selective doses of both LY2444296 (0.032-1 mg/kg) and LY2795050 (0.032-0.32 mg/kg) dose- and time-dependently prevented the grooming deficits caused by salvinorin A (1.8 m/kg). We also found that a kappa-selective dose of each of these antagonists decreased immobility in the forced swim test, a common test of anti-anhedonia effects. This study shows that the kappa-receptor system is involved in an ethologically relevant measure of anhedonia, and that kappa-selective doses of these antagonists can produce effects consistent with rapid anti-anhedonia.

Purpose: China recently commenced several pre-exposure prophylaxis (PrEP) projects, but little work has characterized potential users. This study describes awareness of, intention to use, and uptake of PrEP in a sample of men who have sex with men (MSM), a key population experiencing high rates of HIV in China. Methods: Through a cross-sectional survey administered to 708 MSM in four cities, we mapped respondents onto a Motivational PrEP Cascade. We conducted bivariable and multivariable analysis to examine factors associated with progression through the Cascade. Results: Among 45.6% of MSM who were PrEP eligible, 36% were in Contemplation, 9% were in PrEParation, 2% were in PrEP Action and Initiation, and none reached Maintenance and Adherence. We found no association between individual risk factors and progression through the Cascade. In multivariable analysis, friends' positive attitudes toward PrEP, more frequent sexually transmitted infection testing, and higher scores on the perceived PrEP benefits scale were positively associated with entering PrEP Contemplation. Having higher condom use self-efficacy was associated with decreased odds of entering PrEP Contemplation. Having sex with men and women in the past 6 months, having heard of PrEP from medical providers, and knowing a PrEP user were positively associated with entering PrEParation. Conclusion: We found a high proportion of MSM who were PrEP eligible and identified several intervention targets to prepare for PrEP introduction in China: community education to increase accurate knowledge, gain-framed messaging for PrEP and sexual health, and provider trainings to build MSM-competent services that can support shared decision-making for PrEP initiation.

Multiple areas within the reticular activating system (RAS) can hasten awakening from sleep or light planes of anesthesia. However, stimulation in individual sites has shown limited recovery from deep global suppression of brain activity, such as coma. Here we identify a subset of RAS neurons within the anterior portion of nucleus gigantocellularis (aNGC) capable of producing a high degree of awakening represented by a broad high frequency cortical reactivation associated with organized movements and behavioral reactivity to the environment from two different models of deep pharmacologically-induced coma (PIC): isoflurane (1.25%-1.5%) and induced hypoglycemic coma. Activating aNGC neurons triggered awakening by recruiting cholinergic, noradrenergic, and glutamatergic arousal pathways. In summary, we identify an evolutionarily conserved population of RAS neurons, which broadly restore cerebral cortical activation and motor behavior in rodents through the coordinated activation of multiple arousal-promoting circuits.

Pathogenic and other cytoplasmic DNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce inflammation via transcriptional activation by IRF3 and nuclear factor κB (NF-κB), but the functional consequences of exposing cGAS to chromosomes upon mitotic nuclear envelope breakdown are unknown. Here, we show that nucleosomes competitively inhibit DNA-dependent cGAS activation and that the cGAS-STING pathway is not effectively activated during normal mitosis. However, during mitotic arrest, low level cGAS-dependent IRF3 phosphorylation slowly accumulates without triggering inflammation. Phosphorylated IRF3, independently of its DNA-binding domain, stimulates apoptosis through alleviating Bcl-xL-dependent suppression of mitochondrial outer membrane permeabilization. We propose that slow accumulation of phosphorylated IRF3, normally not sufficient for inducing inflammation, can trigger transcription-independent induction of apoptosis upon mitotic aberrations. Accordingly, expression of cGAS and IRF3 in cancer cells makes mouse xenograft tumors responsive to the anti-mitotic agent Taxol. The Cancer Genome Atlas (TCGA) datasets for non-small cell lung cancer patients also suggest an effect of cGAS expression on taxane response

Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues.

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.

The eukaryotic replicative helicase CMG is a closed ring around double-stranded (ds)DNA at origins yet must transition to single-stranded (ss)DNA for helicase action. CMG must also handle repair intermediates, such as reversed forks that lack ssDNA. Here, using correlative single-molecule fluorescence and force microscopy, we show that CMG harbors a ssDNA gate that enables transitions between ss and dsDNA. When coupled to DNA polymerase, CMG remains on ssDNA, but when uncoupled, CMG employs this gate to traverse forked junctions onto dsDNA. Surprisingly, CMG undergoes rapid diffusion on dsDNA and can transition back onto ssDNA to nucleate a functional replisome. The gate-distinct from that between Mcm2/5 used for origin loading-is intrinsic to CMG; however, Mcm10 promotes strand passage by enhancing the affinity of CMG to DNA. This gating process may explain the dsDNA-to-ssDNA transition of CMG at origins and help preserve CMG on dsDNA during fork repair.

Background: Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. Objective: We sought to characterize age-related changes in the AD profile. Methods: We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and >= 61 years). Results: Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b(+) and Fc epsilon RI+, P < .05) decreased with age. T(H)2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T(H)2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = -0.24 and r = -0.23, respectively; P < .05). T(H)22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of T(H)1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and T(H)17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG], P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T(H)2 downregulation (CCL26; r = 0.32, P < .1) and T(H)1 upregulation (IFN-gamma; r = 0.48, P < .01) with age. Conclusion: The adult AD profile varies with age. Although T(H)1/T(H)17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T(H)2/T(H)22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.

Twin CMG complexes are assembled head-to-head around duplex DNA at

Surface proteins are critical for the survival of gram-positive bacteria