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Working memory deficits are linked to irregularities in the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in schizophrenia, effective intervention strategies are lacking. We evaluated the differential efficacy and underlying neuromechanisms of targeting transcranial direct current stimulation (tDCS) at the DLPFC and the PPC with concurrent cognitive performance for working memory in schizophrenia. In a randomized and double-blind clinical trial, sixty clinically stable schizophrenic patients with below-average working memory were randomly assigned to active DLPFC, active PPC, and sham tDCS groups. Two sessions of tDCS during N-back task were delivered daily for five days. The primary outcome was changes in spatial span test scores from baseline to week 1. The secondary outcomes included changes in scores of color delay-estimation task, other cognitive tasks, and mismatch negativity (biomarker of N-methyl-d-aspartate receptor functioning). Compared with the active DLPFC group, the active PPC group demonstrated significantly greater improvement in spatial span test scores ( p  = 0.008, d  = 0.94) and an augmentation in color delay-estimation task capacity at week 1; the latter sustained to week 2. Compared with the sham tDCS group, the active PPC group did not show a significant improvement in spatial span test scores at week 1 and 2; however, significant enhancement was observed in their color delay-estimation task capacity at week 2. Additionally, mismatch negativity amplitude was enhanced, and changes in theta band measures were positively correlated with working memory improvement in the active PPC group, while no such correlations were observed in the active DLPFC group or the sham tDCS group. Our results suggest that tDCS targeting the PPC relative to the DLPFC during concurrent cognitive performance may improve working memory in schizophrenia, meriting further investigation. The improvement in working memory appears to be linked to enhanced N-methyl-d-aspartate receptor functioning.

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H₂O₂) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H₂O₂. Mechanistically, H₂O₂ induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H₂O₂ scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.

While individuals with schizophrenia (SZ) exhibit deficits in social cognition, the specific profile of these deficits across multiple domains and their relationship with clinical symptoms warrants further characterization. This study aimed to systematically assess key social-cognitive domains—theory of mind (ToM), emotion recognition, attributional style, and social perception—and examine their associations with psychopathology in SZ. Sixty-eight individuals with SZ and 68 matched healthy controls (HC) completed a comprehensive battery of social-cognitive measures, including the false-belief task (assessing first- and second-order ToM), the Faux Pas task, the emotional recognition task, the attributional style questionnaire, and the social perception scale. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Compared to HC, individuals with SZ showed significant deficits across all social-cognitive measures. Specifically, the SZ group exhibited deficits in emotion recognition for all negative emotions (fear, anger, sadness, disgust) but not for happiness, and in attributional style for positive but not negative events. Correlation analyses identified a statistically significant inverse relationship between attributional stability for negative events (i.e., the tendency to attribute the causes of negative events to factors that are persistent over time) and PANSS general psychopathology scores (τ = −0.25, P < 0.043). Furthermore, no other social-cognitive domains (ToM, emotion recognition, social perception) showed significant correlations with any PANSS symptom dimensions. Network analysis further characterized second-order ToM as the core deficit, exhibiting the highest strength and centrality within the social-cognitive network, with mediation effects most pronounced for sadness and happiness recognition. These findings highlight second-order ToM as a core deficit in individuals with schizophrenia and suggest that a stable attributional style may be associated with a lower overall burden of general psychopathology. These social-cognitive domains may represent promising targets for future cognitive remediation interventions for people living with schizophrenia.

Cognitive dysfunction is a defining characteristic impairing social functioning in schizophrenia (SZ). N-methyl-D-aspartate receptor (NMDAR) hypofunction may underlie these impairments. This study explored the association between peripheral blood levels of the NMDAR subunits NR1 and NR2 and cognitive improvement in SZ, evaluating their potential as biomarkers for the efficacy of cognitive intervention. This secondary analysis of a randomized controlled trial included 60 clinically stable SZ patients and 30 healthy controls (HCs). Patients received five-day transcranial direct current stimulation (tDCS) during cognitive tasks across three groups: the active dorsolateral prefrontal cortex (DLPFC), the active posterior parietal cortex (PPC), and the sham stimulation group. Cognition was evaluated, and blood samples were collected at baseline, week 1, and week 2. Baseline blood samples were also obtained from HCs. NR1 and NR2 concentrations were quantified using enzyme-linked immunosorbent assay (ELISA). We found that baseline NR1 concentration was significantly lower in the patient group than in HCs, with no NR2 differences observed. Compared to the other two groups, the active PPC group demonstrated significant working memory improvements. In the active PPC group, baseline NR1 and NR2 concentrations were negatively correlated with working memory improvements at week 1. Moreover, changes in NR1 at weeks 1 and 2, and NR2 at week 1, were positively associated with working memory improvements at week 1 in the active PPC group. Peripheral NR1 and NR2 levels may serve as biomarkers for predicting cognitive improvement in SZ, supporting the role of NMDAR dysfunction in SZ-related cognitive deficits.

Both the brain-derived neurotrophic factor (BDNF) valine (Val)/methionine (Met) polymorphism and mismatch negativity (MMN) amplitude are reportedly linked to working memory impairments in schizophrenia. However, there is evident scarcity of research aimed at exploring the relationships among the three factors. In this secondary analysis of a randomized, controlled, double-blind trial, we investigated these relationships. The trial assessed the efficacy of transcranial direct current stimulation for enhancing working memory in clinically stable schizophrenia patients, who were randomly divided into three groups: dorsolateral prefrontal cortex stimulation, posterior parietal cortex stimulation, and sham stimulation groups. Transcranial direct current stimulation was administered concurrently with a working memory task over five days. We assessed the BDNF genotype, MMN amplitude, working memory capacity, and interference control subdomains. These assessments were conducted at baseline with 54 patients and followed up post-intervention with 48 patients. Compared to BDNF Met-carriers, Val homozygotes exhibited fewer positive and general symptoms and increased working memory capacity at baseline. A correlation between MMN amplitude and working memory capacity was noted only in BDNF Val homozygotes. The correlations were significantly different in the two BDNF genotype groups. Furthermore, in the intervention group that showed significant improvement in MMN amplitude, BDNF Val homozygotes exhibited greater enhancement in working memory capacity than Met-carriers. This study provides in vivo evidence for the interaction between MMN and BDNF Val/Met polymorphism for working memory capacity. As MMN has been considered a biomarker of N-methyl-D-aspartate receptor (NMDAR) function, these data shed light on the complex interactions between BDNF and NMDAR in terms of working memory in schizophrenia.

Antibodies to Ebola virus glycoprotein (EBOV GP) represent an important correlate of the vaccine efficiency and infection survival. Both neutralization and some of the Fc-mediated effects are known to contribute the protection conferred by antibodies of various epitope specificities. At the same time, the role of the complement system remains unclear. Here, we compare complement activation by two groups of representative monoclonal antibodies (mAbs) interacting with the glycan cap (GC) or the membrane-proximal external region (MPER) of GP. Binding of GC-specific mAbs to GP induces complement-dependent cytotoxicity (CDC) in the GP-expressing cell line via C3 deposition on GP in contrast to MPER-specific mAbs. In the mouse model of EBOV infection, depletion of the complement system leads to an impairment of protection exerted by one of the GC-specific, but not MPER-specific mAbs. Our data suggest that activation of the complement system represents an important mechanism of antiviral protection by GC antibodies. An analysis of the complement activation by human monoclonal antibodies to Ebola virus glycoprotein suggests the distinct mechanisms for antibodies targeting the glycan cap versus antibodies against the membrane-proximal external region.

Simian varicella virus (SVV) is closely related to human varicella-zoster virus and causes varicella and zoster-like disease in nonhuman primates. In this study, a mini-F replicon was inserted into a SVV cosmid, and infectious SVV was generated by co-transfection of Vero cells with overlapping SVV cosmids. The entire SVV genome, cloned as a bacterial artificial chromosome (BAC), was stably propagated upon serial passage in E. coli . Transfection of pSVV-BAC DNA into Vero cells yielded infectious SVV (rSVV-BAC). The mini-F vector sequences flanked by loxP sites were removed by co-infection of Vero cells with rSVV-BAC and adenovirus expressing Cre -recombinase. Recombinant SVV generated using the SVV-BAC genetic system has similar molecular and in vitro replication properties as wild-type SVV. To demonstrate the utility of this approach, a SVV ORF 10 deletion mutant was created using two-step Red-mediated recombination. The results indicate that SVV ORF 10, which encodes a homolog of the HSV-1 virion VP-16 transactivator protein, is not essential for in vitro replication but is required for optimal replication in cell culture.

Abstract Many robust studies have investigated prepulse inhibition (PPI) in patients with schizophrenia. Recent evidence indicates that PPI may help identify individuals who are at clinical high risk for psychosis (CHR). Selective attention to prepulse stimulus can specifically enhance PPI in healthy subjects; however, this enhancement effect is not observed in patients with schizophrenia. Modified PPI measurement with selective attentional modulation using perceived spatial separation (PSS) condition may be a more robust and sensitive index of PPI impairment in CHR individuals. The current study investigated an improved PSSPPI condition in CHR individuals compared with patients with first-episode schizophrenia (FES) and healthy controls (HC) and evaluated the accuracy of PPI in predicting CHR from HC. We included 53 FESs, 55 CHR individuals, and 53 HCs. CHRs were rated on the Structured Interview for Prodromal Syndromes. The measures of perceived spatial co-location PPI (PSCPPI) and PSSPPI conditions were applied using 60- and 120-ms lead intervals. Compared with HC, the CHR group had lower PSSPPI level (Inter-stimulus interval [ISI] = 60 ms, P < .001; ISI = 120 ms, P < .001). PSSPPI showed an effect size (ES) between CHR and HC (ISI = 60 ms, Cohen’s d = 0.91; ISI = 120 ms, Cohen’s d = 0.98); on PSSPPI using 60-ms lead interval, ES grade increased from CHR to FES. The area under the receiver operating characteristic curve for PSSPPI was greater than that for PSCPPI. CHR individuals showed a PSSPPI deficit similar to FES, with greater ES and sensitivity. PSSPPI appears a promising objective approach for preliminary identification of CHR individuals.