Search

Abstract Intervention for social cognition could be key to improving social functioning in patients with schizophrenia. A first step towards its clinical implementation involves interviewing patients about their subjective difficulties with social cognition as they experience them in the real world. The present study focused on the clinical subtypes classified by the discrepancies between the subjective difficulties in social cognition and actual cognitive impairment. A total of 131 outpatients with schizophrenia and 68 healthy controls were included. Objective measurement of social cognition was performed using a test battery covering four representative domains, and subjective difficulties were determined by a questionnaire covering the same domains. A two-step cluster analysis explored the potential classification of social cognition in patients with schizophrenia. There was little correlation between the objective performance on social cognition tasks and subjective difficulties in social cognition. The analysis yielded three clusters: the low-impact group (low objective impairment and low subjective difficulties), the unaware group (high objective impairment but low subjective difficulties), and the perceptive group (moderate objective impairment and high subjective difficulties). Positive, negative, and general symptoms were more severe in the two groups that showed impaired performance on the social cognition tasks (i.e., the unaware and perceptive groups) than those in the low-impact group. Neurocognition and functional capacity were the lowest in the unaware group, and social functioning was the lowest in the perceptive group. Awareness about the clinical subtypes of social cognition could serve as a guidepost for providing individualized, targeted interventions.

Phylllorhiza punctata von Lendenfeld, 1884 originates from Australia and Coral Triangle, but its occurrence has been reported in the Atlantic Ocean and Mediterranean Sea, so it is necessary to better understand its geographic range. Two specimens were collected in Nagasaki and Kagoshima Prefectures, Japan, and morphological and molecular studies suggest that they are P. punctata. These are the first records of the species in Japan, and it is possible that individuals have been transported to Japan by the Kuroshio Current.

BackgroundSchizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking. ObjectiveThis study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. MethodsForty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest. ResultsCognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P

BackgroundDespite the anticipated efficacy of escitalopram in treating depression and anxiety in individuals with preexisting cardiovascular conditions, persistent concerns regarding its adverse effects have emerged. In this systematic review, we aimed to evaluate the cardiovascular safety profile of escitalopram compared with that of placebo in patients with underlying cardiovascular disease.MethodsWe used a predefined search strategy in PubMed, Cochrane Central Register of Controlled Trials, Embase, International Clinical Trials Registry Platform, and ClinicalTrials.gov to identify studies evaluating adverse cardiovascular reactions to escitalopram in patients with underlying cardiovascular disease. Randomized controlled trials (RCTs) that provided results on cardiovascular safety outcomes were included. Two independent reviewers screened the abstracts and full texts of the individual studies. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach.ResultsThe primary outcomes were the frequency of major adverse cardiovascular events (MACE), QTc prolongation, and discontinuation of study medication. We identified 5 RCTs with 773 participants who met the inclusion criteria. Escitalopram was not associated with significantly increased risk of MACE (risk ratio [RR] = 1.85; 95% confidence interval [CI] 0.80 to 4.26; I2 0%; 5 RCTs; n = 773, moderate certainty of evidence), discontinuation of study medication (RR = 1.03; 95% CI 0.84–1.26; I2 0%; 5 RCTs; n = 773, low certainty of evidence), and QTc prolongation (RR = 1.20; 95% CI 0.76–1.90; I2 0%; 4 RCTs; n = 646, low certainty of evidence).ConclusionEscitalopram does not significantly increase the risk of cardiovascular adverse reactions compared with placebo in patients with underlying cardiovascular disease. However, the presence of wide CIs and the limited number of included studies highlight the need for further studies with larger sample sizes to enhance the precision and reliability of these findings.Systematic review registration: International Prospective Register of Systematic Reviews [CRD42022298181].

Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.

Abstract The monosialodihexosylganglioside, GM3, and its binding to CD169 (Siglec‐1) have been indicated as key factors in the glycoprotein‐independent sequestration of the human immunodeficiency virus‐1 (HIV‐1) in virus‐containing compartments (VCCs) in myeloid cells. Here, lipid‐wrapped polymer nanoparticles (NPs) are applied as a virus‐mimicking model to characterize the effect of core stiffness on NP uptake and intracellular fate triggered by GM3‐CD169 binding in macrophages. GM3‐functionalized lipid‐wrapped NPs are assembled with poly(lactic‐co‐glycolic) acid (PLGA) as well as with low and high molecular weight polylactic acid (PLAlMW and PLAhMW) cores. The NPs have an average diameter of 146 ± 17 nm and comparable surface properties defined by the self‐assembled lipid layer. Due to differences in the glass transition temperature, the Young's modulus (E) differs substantially under physiological conditions between PLGA (EPLGA = 60 ± 32 MPa), PLAlMW (EPLAlMW = 86 ± 25 MPa), and PLAhMW (EPLAhMW = 1.41 ± 0.67 GPa) NPs. Only the stiff GM3‐presenting PLAhMW NPs but not the softer PLGA or PLAlMW NPs avoid a lysosomal pathway and localize in tetraspanin (CD9)‐positive compartments that resemble VCCs. These observations suggest that GM3‐CD169‐induced sequestration of NPs in nonlysosomal compartments is not entirely determined by ligand–receptor interactions but also depends on core stiffness.

Cyclic di-AMP (c-di-AMP) is an important signaling molecule for pneumococci, and as a uniquely prokaryotic product it can be recognized by mammalian cells as a danger signal that triggers innate immunity. Roles of c-di-AMP in directing host responses during pneumococcal infection are only beginning to be defined. We hypothesized that pneumococci with defective c-di-AMP catabolism due to phosphodiesterase deletions could illuminate roles of c-di-AMP in mediating host responses to pneumococcal infection. Pneumococci deficient in phosphodiesterase 2 (Pde2) stimulated a rapid induction of interferon β (IFNβ) expression that was exaggerated in comparison to that induced by wild type (WT) bacteria or bacteria deficient in phosphodiesterase 1. This IFNβ burst was elicited in mouse and human macrophage-like cell lines as well as in primary alveolar macrophages collected from mice with pneumococcal pneumonia. Macrophage hyperactivation by Pde2-deficient pneumococci led to rapid cell death. STING and cGAS were essential for the excessive IFNβ induction, which also required phagocytosis of bacteria and triggered the phosphorylation of IRF3 and IRF7 transcription factors. The select effects of Pde2 deletion were products of a unique role of this enzyme in c-di-AMP catabolism when pneumococci were grown on solid substrate conditions designed to enhance virulence. Because pneumococci with elevated c-di-AMP drive aberrant innate immune responses from macrophages involving hyperactivation of STING, excessive IFNβ expression, and rapid cytotoxicity, we surmise that c-di-AMP is pivotal for directing innate immunity and host-pathogen interactions during pneumococcal pneumonia.

Type I Interferon is thought to be a driving force for immune activation and T cell exhaustion during HIV infection. Here the authors show that intron-containing HIV RNA induces innate immune activation resulting in associated T cell dysfunction.

A hallmark of HIV-1 infection is chronic inflammation, which plays a significant role in disease pathogenesis. Acute HIV infection induces robust inflammatory responses, which are insufficient to prevent or eliminate virus in mucosal tissues. While establishment of viral set-point is coincident with downregulation of acute innate responses, systemic inflammatory responses persist during the course of chronic HIV infection. Since the introduction of combination antiviral therapy (cART), most HIV-1+ individuals can suppress viremia under detection levels for decades. However, chronic immune activation persists and has been postulated to cause HIV associated non-AIDS complications (HANA). Importantly, inflammatory cytokines and activation markers associated with macrophages are strongly and selectively correlated with the incidence of HIV-associated neurocognitive disorder (HAND), cardiovascular dysfunctions (CVD) and other HANA conditions. In this review, we discuss the roles of macrophages in facilitating viral persistence and contributing to generation of persistent inflammatory responses.

Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-containing compartments (VCCs) and disseminated to CD4⁺ T cells, a mechanism of DC-mediated HIV-1 trans-infection. In this study, we describe the mechanism of VCC formation and its role in immune evasion mechanisms of HIV-1. We find HIV-1-induced formation of VCCs is restricted to myeloid cells, and that the cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs and subsequent trans-infection to CD4⁺ T cells. Interestingly, introduction of a di-aromatic endocytic motif in the cytoplasmic tail of CD169 that results in endocytosis of HIV-1 particles, suppressed CD169-mediated HIV-1 trans-infection. Furthermore, super-resolution microscopy revealed close association of CD169 and HIV-1 particles in surface-accessible but deep plasma membrane invaginations. Intriguingly, HIV-1 particles in deep VCCs were inefficiently accessed by anti-gp120 broadly neutralizing antibodies, VRC01 and NIH45-46 G54W, and thus were less susceptible to neutralization. Our study suggests that HIV-1 capture by CD169 can provide virus evasion from both innate (phagocytosis) and adaptive immune responses.

Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC--T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3--CD169 interaction) for DC-dependent HIV dissemination.

Unidentified hydromedusae were collected from Nagasaki and Okinawa prefectures in western Japan. In the present study, taxonomic investigations, including morphological observations, of the unidentified specimens were conducted. The specimens collected from Okinawa had the following morphological characteristics: umbrella spherical; without tentacles; umbrella margin with nematocyst ring from which centripetal, flat, nematocyst-containing bands run meridionally on exumbrella from umbrella margin to umbrella apex; manubrium large, cruciform base, the four perradial corners of mouth margin without oral tentacles; gonads perradial on manubrium wall. Based on these findings, we describe it as a new species, Tregouboviopsis gemmula. Additionally, we performed a detailed morphological examination of the species Tregouboviopsis perradialis. To date, this species has only been reported from the central and northern regions of the South China Sea. This study provides additional information on the morphology and ecology of these two species of Ptilocodiidae, which constitute two new records for Japanese waters. [ABSTRACT FROM AUTHOR]

Four species of the genus Cunina, C. duplicata, C. peregrina, C. globosa and C. octonaria, have been reported from Japanese waters. However, some of species still unidentified. In this study, six specimens of an unidentified Cunina species collected from Kochi, Nagasaki and Okinawa prefectures were examined by morphological observations. The present study reports detailed observations of the morphology of one species newly recorded in Japan: Cunina simplex. This species possesses the following unique morphological characters: four manubrial pouches and four primary tentacles. This study reported C. simplex as the fifth described species from Japan. [ABSTRACT FROM AUTHOR]

Chronic neuroinflammation is observed in HIV1 individuals on suppressive combination antiretroviral therapy (cART) and is thought to cause HIV-associated neurocognitive disorders. We recently reported that expression of HIV intron-containing RNA (icRNA) in productively infected monocyte-derived macrophages induces proinflammatory responses. Microglia, yolk sac-derived brain-resident tissue macrophages, are the primary HIV-1-infected cell type in the central nervous system (CNS). In this study, we tested the hypothesis that persistent expression of HIV icRNA in primary human microglia induces innate immune activation. We established multiple orthogonal primary human microglia-like cell cultures, including peripheral blood monocyte-derived microglia (MDMG) and induced pluripotent stem cell (iPSC)- derived microglia. Unlike MDMG, human iPSC-derived microglia (hiMG), which phenotypically mimic primary CNS microglia, were robustly infected with replicationcompetent HIV-1, and establishment of productive HIV-1 infection and de novo viral gene expression led to proinflammatory cytokine production. Blocking of HIV-1 icRNA expression, but not multiply spliced viral RNA, via either infection with virus expressing a Rev-mutant deficient for HIV icRNA nuclear export or infection in the presence of a small molecule inhibitor of the chromosome region maintenance 1 (CRM1)-mediated viral icRNA nuclear export pathway attenuated induction of innate immune responses. These studies suggest that Rev-CRM1-dependent nuclear export and cytosolic sensing of HIV-1 icRNA induces proinflammatory responses in productively infected microglia. Novel strategies targeting HIV icRNA expression specifically are needed to suppress HIV-induced neuroinflammation. IMPORTANCE Although peripheral viremia can be effectively suppressed with the advent of highly active antiretroviral therapy, a significant portion of HIV1 individuals still suffer from neurocognitive disorders. Despite suppressive therapy, HIV persists in various tissues, including the central nervous system (CNS), leading to chronic inflammation, the chief driver of neurocognitive disorders. While persistent infection has been described in CNS-resident macrophages and microglia, molecular mechanisms of how HIV infection in microglia contributes to neuronal inflammation have remained unclear. In this study, we used multiple primary human microglia-like cellular platforms and demonstrate that HIV-1 intron-containing RNA induces microglial activation and damage. Since current antiretroviral therapy does not suppress HIV-1 transcription, new therapeutics targeting HIV RNA expression may help to treat HIVassociated neurocognitive disorders. [ABSTRACT FROM AUTHOR]

We surveyed the spatial and temporal distribution of Japanese sea nettle jellyfish Chrysaora pacifica in Omura Bay, Japan, using an environmental DNA (eDNA) method. In 2018, the C. pacifica eDNA concentration increased from March-May at all depths. The seasonal pattern of C. pacifica eDNA was consistent with previous reports based on visual observations along the Japanese coast. Thus, the eDNA method might have advantages to follow the seasonal pattern of C. pacifica while being less time-consuming and less laborious compared with traditional methods. The eDNA concentrations tended to reach a maximum near and/or below the pycnocline throughout this study. Therefore, the vertical distribution of C. pacifica medusae may have been restricted by strong pycnocline formation in July and August 2018. However, even with a weak pycnocline, which C. pacifica should be able to swim across, the apparent distribution of C. pacifica eDNA seems to be restricted by the pycnocline. Therefore, the eDNA method cannot, currently, accurately assess the absolute vertical distribution pattern of C. pacifica, especially when a pycnocline is formed. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (NPs) wrapped in a membrane can be utilized as artificial virus nanoparticles (AVNs) that combine the large nonblinking or bleaching optical cross-section of the NP core with the biological surface properties and functionalities provided by a self-assembled lipid membrane. We used these hybrid nanomaterials to test the roles of monosialodihexosylganglioside (GM3) and phosphatidylserine (PS) for a lipid-mediated targeting of virus-containing compartments (VCCs) in macrophages. GM3-presenting AVNs bind to CD169 (Siglec-1)-expressing macrophages, but inclusion of PS in the GM3-containing AVN membrane decreases binding. Molecular dynamics simulations of the AVN membrane and experimental binding studies of CD169 to GM3-presenting AVNs reveal Na+-mediated interactions between GM3 and PS as a potential cause of the antagonistic action on binding by the two negatively charged lipids. GM3-functionalized AVNs with no or low PS content localize to tetherin+, CD9+ VCC in a membrane composition-depending fashion, but increasing amounts of PS in the AVN membrane redirect the NP to lysosomal compartments. Interestingly, this compartmentalization is highly GM3 specific. Even AVNs presenting the related monosialotetrahexosylganglioside (GM1) fail to achieve an accumulation in VCC. AVN localization to VCC was observed for AVN with gold NP core but not for liposomes, suggesting that NP sequestration into VCC has additional requirements beyond ligand (GM3)-receptor (CD169) recognition that are related to the physical properties of the NP core. Our results confirm AVN as a scalable platform for elucidating the mechanisms of lipid-mediated viral entry pathways and for selective intracellular targeting. [ABSTRACT FROM AUTHOR]

HIV-1 acquisition occurs most commonly after sexual contact. To establish infection, HIV-1 must infect cells that support high-level replication, namely CD4+ T cells, which are absent from the outermost genital epithelium. Dendritic cells (DCs), present in mucosal epithelia, potentially facilitate HIV-1 acquisition. We show that vaginal epithelial DCs, termed CD1a+ VEDCs, are unlike other blood- and tissue-derived DCs because they express langerin but not DC-SIGN, and unlike skin-based langerin+ DC subset Langerhans cells (LCs), they do not harbor Birbeck granules. Individuals primarily acquire HIV-1 that utilizes the CCR5 receptor (termed either R5 or R5X4) during heterosexual transmission, and the mechanism for the block against variants that only use the CXCR4 receptor (classified as X4) remains unclear. We show that X4 as compared with R5 HIV-1 shows limited to no replication in CD1a+ VEDCs. This differential replication occurs after fusion, suggesting that receptor usage influences postentry steps in the virus life cycle. Furthermore, CD1a+ VEDCs isolated from HIV-1-infected virologically suppressed women harbor HIV-1 DNA. Thus, CD1a+ VEDCs are potentially infected early during heterosexual transmission and also retain virus during treatment. Understanding the interplay between HIV-1 and CD1a+ VEDCs is important for future prevention and cure strategies. [ABSTRACT FROM AUTHOR]