Dissociable Recruitment of Rostral Anterior Cingulate and Inferior Frontal Cortex in Emotional Response Inhibition

The integrity of decision-making under emotionally evocative circumstances is critical to navigating complex environments, and dysfunctions in these processes may play an important role in the emergence and maintenance of various psychopathologies. The goal of the present study was to examine the spatial and temporal dynamics of neural responses to emotional stimuli and emotion-modulated response inhibition. High-density event-related brain potentials (ERPs) were measured as participants (N=25) performed an emotional Go/NoGo task that required button presses to words of a "target" emotional valence (i.e., positive, negative, neutral) and response inhibition to words of a different "distractor" valence. Using scalp ERP analyses in conjunction with source-localization techniques, we identified distinct neural responses associated with affective salience and affect- modulated response inhibition, respectively. Both earlier (similar to 300 ms) and later (similar to 700 ms) ERP components were enhanced with successful response inhibition to emotional distractors. Only ERPs to target stimuli differentiated affective from neutral cues. Moreover, Source localization analyses revealed right ventral lateral prefrontal cortex (VLPFC) activation in affective response inhibition regardless of emotional valence, whereas rostral anterior cingulate activation (rACC) was potentiated by emotional valence but was not modulated by response inhibition. This dissociation was supported by a significant Region x Trial Type x Emotion interaction, confirming that distinct regional dynamics characterize neural responses to affective valence and affective response-inhibition. The results are discussed in the context of an emerging affective neuroscience literature and implications for understanding psychiatric pathologies characterized by a detrimental susceptibility to emotional cues, with an emphasis on major depressive disorder.Psycholog

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Evidence for a remodelling of DNA-PK upon autophosphorylation from electron microscopy studies

The multi-subunit DNA-dependent protein kinase (DNA-PK), a crucial player in DNA repair by non-homologous end-joining in higher eukaryotes, consists of a catalytic subunit (DNA-PKcs) and the Ku heterodimer. Ku recruits DNA-PKcs to double-strand breaks, where DNA-PK assembles prior to DNA repair. The interaction of DNA-PK with DNA is regulated via autophosphorylation. Recent SAXS data addressed the conformational changes occurring in the purified catalytic subunit upon autophosphorylation. Here, we present the first structural analysis of the effects of autophosphorylation on the trimeric DNA-PK enzyme, performed by electron microscopy and single particle analysis. We observe a considerable degree of heterogeneity in the autophosphorylated material, which we resolved into subpopulations of intact complex, and separate DNA-PKcs and Ku, by using multivariate statistical analysis and multi-reference alignment on a partitioned particle image data set. The proportion of dimeric oligomers was reduced compared to non-phosphorylated complex, and those dimers remaining showed a substantial variation in mutual monomer orientation. Together, our data indicate a substantial remodelling of DNA-PK holo-enzyme upon autophosphorylation, which is crucial to the release of protein factors from a repaired DNA double-strand break

Emergency department spirometric volume and base deficit delineate risk for torso injury in stable patients

BACKGROUND: We sought to determine torso injury rates and sensitivities associated with fluid-positive abdominal ultrasound, metabolic acidosis (increased base deficit and lactate), and impaired pulmonary physiology (decreased spirometric volume and PaO(2)/FiO(2)). METHODS: Level I trauma center prospective pilot and post-pilot study (2000–2001) of stable patients. Increased base deficit was < 0.0 in ethanol-negative and ≤ -3.0 in ethanol-positive patients. Increased lactate was > 2.5 mmol/L in ethanol-negative and ≥ 3.0 mmol/L in ethanol-positive patients. Decreased PaO(2)/FiO(2 )was < 350 and decreased spirometric volume was < 1.8 L. RESULTS: Of 215 patients, 66 (30.7%) had a torso injury (abdominal/pelvic injury n = 35 and/or thoracic injury n = 43). Glasgow Coma Scale score was 14.8 ± 0.5 (13–15). Torso injury rates and sensitivities were: abdominal ultrasound negative and normal base deficit, lactate, PaO(2)/FiO(2), and spirometric volume – 0.0% & 0.0%; normal base deficit and normal spirometric volume – 4.2% & 4.5%; chest/abdominal soft tissue injury – 37.8% & 47.0%; increased lactate – 39.7% & 47.0%; increased base deficit – 41.3% & 75.8%; increased base deficit and/or decreased spirometric volume – 43.8% & 95.5%; decreased PaO(2)/FiO(2 )– 48.9% & 33.3%; positive abdominal ultrasound – 62.5% & 7.6%; decreased spirometric volume – 73.4% & 71.2%; increased base deficit and decreased spirometric volume – 82.9% & 51.5%. CONCLUSIONS: Trauma patients with normal base deficit and spirometric volume are unlikely to have a torso injury. Patients with increased base deficit or lactate, decreased spirometric volume, decreased PaO(2)/FiO(2), or positive FAST have substantial risk for torso injury. Increased base deficit and/or decreased spirometric volume are highly sensitive for torso injury. Base deficit and spirometric volume values are readily available and increase or decrease the suspicion for torso injury

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Linguistic Predictors of Post‐Traumatic Stress Disorder Symptoms Following 11 September 2001

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90077/1/acp1830.pd