CARHSP1 Is Required for Effective Tumor Necrosis Factor Alpha mRNA Stabilization and Localizes to Processing Bodies and Exosomes

Tumor necrosis factor alpha (TNF-α) is a critical mediator of inflammation, and its production is tightly regulated, with control points operating at nearly every step of its biosynthesis. We sought to identify uncharacterized TNF-α 3\u27 untranslated region (3\u27UTR)-interacting proteins utilizing a novel screen, termed the RNA capture assay. We identified CARHSP1, a cold-shock domain-containing protein. Knockdown of CARHSP1 inhibits TNF-α protein production in lipopolysaccharide (LPS)-stimulated cells and reduces the level of TNF-α mRNA in both resting and LPS-stimulated cells. mRNA stability assays demonstrate that CARHSP1 knockdown decreases TNF-α mRNA stability from a half-life (t(1/2)) of 49 min to a t(1/2) of 22 min in LPS-stimulated cells and from a t(1/2) of 29 min to a t(1/2) of 24 min in resting cells. Transfecting CARHSP1 into RAW264.7 cells results in an increase in TNF-α 3\u27UTR luciferase expression in resting cells and CARHSP1 knockdown LPS-stimulated cells. We examined the functional effect of inhibiting Akt, calcineurin, and protein phosphatase 2A and established that inhibition of Akt or calcineurin but not PP2A inhibits CARHSP1 function. Subcellular analysis establishes CARHSP1 as a cytoplasmic protein localizing to processing bodies and exosomes but not on translating mRNAs. We conclude CARHSP1 is a TNF-α mRNA stability enhancer required for effective TNF-α production, demonstrating the importance of both stabilization and destabilization pathways in regulating the TNF-α mRNA half-life

Self-Reported Pain in Male and Female Iraq/Afghanistan-Era Veterans: Associations with Psychiatric Symptoms and Functioning

Objective. To examine pain symptoms and co-occurring psychiatric and functional indices in male and female Iraq/Afghanistan-era veterans. Design. Self-reported data collection and interviews of Iraq/Afghanistan-era veterans who participated in a multisite study of postdeployment mental health. Setting. Veterans were enrolled at one of four participating VA sites. Subjects. Two thousand five hundred eighty-seven male and 662 female Iraq/Afghanistan-era veterans. Methods. Nonparametric Wilcoxon rank tests examined differences in pain scores between male and female veterans. Chi-square tests assessed differences between male and female veterans in the proportion of respondents endorsing moderate to high levels of pain vs no pain. Multilevel regression analyses evaluated the effect of pain on a variety of psychiatric and functional measures. Results. Compared with males, female veterans reported significantly higher mean levels of headache (P \u3c 0.0001), muscle soreness (P \u3c 0.008), and total pain (P \u3c 0.0001), and were more likely to report the highest levels of headache (P \u3c 0.0001) and muscle soreness (P \u3c 0.0039). The presence of pain symptoms in Iraq/Afghanistan-era veterans was positively associated with psychiatric comorbidity and negatively associated with psychosocial functioning. There were no observed gender differences in psychiatric and functional indices when levels of pain were equated. Conclusions. Although female Iraq/Afghanistan-era veterans reported higher levels of pain than male veterans overall, male and female veterans experienced similar levels of psychiatric and functional problems at equivalent levels of reported pain. These findings suggest that pain-associated psychological and functional impacts are comparable and consequential for both male and female veterans

GNAS Codon 201 Mutations.

<p>Representative chromatograms (left) and pyrograms (right) of GNAS wild-type, GNAS R201C, and GNAS R201H mutations detected in colon cancer. Arrows in chromatograms show mutant, heterozygous peaks. Boxed peaks in pyrograms highlight mutant alleles. Percentages indicate allele frequencies calculated from pyrogram peak intensities.</p

GNAS tumors are associated with a villous morphology.

<p>H&E Photomicrograph of a GNAS mutant, villous adenocarcinoma. The tumor has typical villous morphology with protruding papillae containing a fibrovascular core and lined with adenomatous epithelium.</p

Characteristics of GNAS mutant adenomas.

<p>Abbreviations: TVA, tubulovillous adenoma; VA, villous adenom.</p

Motor, emotional, and cognitive empathy in children and adolescents with autism spectrum disorder and conduct disorder

It is unclear which aspects of empathy are shared and which are uniquely affected in autism spectrum disorder (ASD) and conduct disorder (CD) as are the neurobiological correlates of these empathy impairments. The aim of this systematic review is to describe the overlap and specificity of motor, emotional, and cognitive aspects of empathy in children and adolescents with ASD or CD. Motor and cognitive empathy impairments are found in both ASD and CD, yet the specificity seems to differ. In ASD facial mimicry and emotion recognition may be impaired for all basic emotions, whereas in CD this is only the case for negative emotions. Emotional empathy and the role of attention to the eyes therein need further investigation. We hypothesize that impaired motor and cognitive empathy in both disorders are a consequence of lack of attention to the eyes. However, we hypothesize major differences in emotional empathy deficits between ASD and CD, probably due to emotional autonomic and amygdala hyper-responsivity in ASD versus hypo-responsivity in CD, both resulting in lack of attention to the eyes