Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Prenatal immune activation in rats and adult exposure to inescapable shocks reveal sex-dependent effects on fear conditioning that might be relevant for schizophrenia.

Prenatal infection is considered a relevant factor for neurodevelopmental alterations and psychiatric diseases. Administration of bacterial and viral components during pregnancy in rodents results in maternal immune activation (MIA), leading to schizophrenia-like neurochemical and behavioral changes. Despite some evidence for abnormal fear conditioning in schizophrenia, only a few animal studies have focused on this issue. Therefore, we addressed the impact of the administration of the viral mimetic polyI:C to pregnant Long-Evans rats on the adult offspring response to inescapable shocks (IS) and contextual fear conditioning. In males, polyI:C induced a greater endocrine (plasma ACTH) response to IS and both polyI:C and IS enhanced fear conditioning and generalization to a completely different novel environment (hole-board), with no additive effects, probably due to a ceiling effect. In contrast, a modest impact of polyI:C and a lower impact of IS on contextual fear conditioning and generalization was observed in females. Thus, the present results demonstrate that polyI:C dramatically affected fear response to IS in adult males and support the hypothesis that males are more sensitive than females to this treatment. This model might allow to explore neurobiological mechanisms underlying abnormal responsiveness to fear conditioning and stressors in schizophrenia.

Toxoplasma-induced behavior changes - is microbial dysbiosis the missing link?

Toxoplasma gondii (T. gondii) is one of the most successful intracellular protozoa in that it can infect the majority of mammalian cell types during the acute phase of infection. Furthermore, it is able to establish a chronic infection for the host's entire lifespan by developing an encysted parasite form, primarily in the muscles and brain of the host, to avoid the host immune system. The infection affects one third of the world population and poses an increased risk for people with a suppressed immune system. Despite the dormant characteristics of chronic T. gondii infection, there is much evidence suggesting that this infection leads to specific behavior changes in both humans and rodents. Although numerous hypotheses have been put forth, the exact mechanisms underlying these behavior changes have yet to be understood. In recent years, several studies revealed a strong connection between the gut microbiome and the different organ systems that are affected in T. gondii infection. While it is widely studied and accepted that acute T. gondii infection can lead to a dramatic disruption of the host's normal, well-balanced microbial ecosystem (microbial dysbiosis), changes in the gut microbiome during the chronic stage of infection has not been well characterized. This review is intended to briefly inspect the different hypotheses that attempt to explain the behavior changes during T. gondii infection. Furthermore, this review proposes to consider the potential link between gut microbial dysbiosis, and behavior changes in T. gondii infection as a novel way to describe the underlying mechanism.

Amplification of Protein Expression by Self-Amplifying mRNA Delivered in Lipid Nanoparticles Containing a ß-Aminoester Ionizable Lipid Correlates with Reduced Innate Immune Activation.

Self-amplifying mRNA (saRNA) is witnessing increased interest as a platform technology for protein replacement therapy, gene editing, immunotherapy, and vaccination. saRNA can replicate itself inside cells, leading to a higher and more sustained production of the desired protein at a lower dose. Controlling innate immune activation, however, is crucial to suppress unwanted inflammation upon delivery and self-replication of RNA in vivo. In this study, we report on a class of ß-aminoester lipids (ßAELs) synthesized through the Michael addition of an acrylate to diethanolamine, followed by esterification with fatty acids. These lipids possessed one or two ionizable amines, depending on the use of nonionic or amine-containing acrylates. We utilized ßAELs for encapsulating saRNA in lipid nanoparticles (LNPs) and evaluated their transfection efficiency in vitro and in vivo in mice, while comparing them to LNPs containing ALC-0315 as an ionizable lipid reference. Among the tested lipids, OC7, which comprises two unsaturated oleoyl alkyl chains and an ionizable azepanyl motif, emerged as a ßAEL with low cytotoxicity and immunogenicity relative to ALC-0315. Interestingly, saRNA delivered via the OC7 LNP exhibited a distinct in vivo transfection profile. Initially, intramuscular injection of OC7 LNP resulted in low protein expression shortly after administration, followed by a gradual increase over a period of up to 7 days. This pattern is indicative of successful self-amplification of saRNA. In contrast, saRNA delivered via ALC-0315 LNP demonstrated high protein translation initially, which gradually declined over time and lacked the amplification seen with OC7 LNP. We observed that, in contrast to saRNA OC7 LNP, saRNA ALC-0315 LNP induced potent innate immune activation by triggering cytoplasmic RIG-I-like receptors (RLRs), likely due to the highly efficient endosomal membrane rupturing properties of ALC-0315 LNP. Consequently, the massive production of type I interferons quickly hindered the amplification of the saRNA. Our findings highlight the critical role of the choice of ionizable lipid for saRNA formulation in LNPs, particularly in shaping the qualitative profile of protein expression. For applications where minimizing inflammation is desired, the use of ionizable lipids, such as the ßAEL reported in this study, that elicit a low type I interferon response in saRNA LNP is crucial.

CDC25B Is a Prognostic Biomarker Associated With Immune Infiltration and Drug Sensitivity in Hepatocellular Carcinoma.

Cell division cycle 25B (CDC25B), a member of the CDC25 phosphatase family, plays a key role in cell cycle regulation. Studies have suggested its carcinogenic potential in various cancers, but the role of CDC25B in the development of hepatocellular carcinoma (HCC) remains poorly understood. The aim of this study was to clarify the role of CDC25B in HCC using bioinformatics and experiments. CDC25B expression data of HCC cancer tissues and paracancerous normal samples were obtained from The Cancer Gene Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the relationship between CDC25B expression and the prognosis and degree of tumor differentiation of HCC patients was analyzed. CDC25B expression was verified in clinical HCC tissue samples using fluorescence quantitative polymerase chain reaction (q-PCR) and protein immunoblotting (Western blot). Gene set enrichment analysis (GSEA) was used to identify signaling pathways enriched in CDC25B expression, and differential genes (DEGs) were used to screen out coexpressed hub genes and construct protein-protein interaction (PPI) networks. 5-Ethynyl-2'-deoxyuridine (EDU) staining was used to compare the proliferation and differentiation ability of the HCC cell line (HCC-LM3) after knockdown of CDC25B. Finally, we investigated the mutation of CDC25B in HCC and the relationship between CDC25B expression and tumor cell infiltration of lymphocytes and some immune checkpoints as well as drug sensitivity. CDC25B was overexpressed in HCC tissues and correlated with poor prognosis and the degree of tumor differentiation in patients with HCC. The GSEA and PPI networks together revealed significantly upregulated signaling pathways, as well as functions, associated with the development of HCC when CDC25B was overexpressed. The EDU assay demonstrated that the ability of cells to differentiate value addedly was markedly reduced following the downregulation of CDC25B expression in HCC-LM3s. CDC25B was also involved in the formation of the tumor microenvironment (TME) and immune processes in HCC, and the high expression of CDC25B made patients less sensitive to some drugs. CDC25B can be used as a biomarker and immunotherapeutic target for poor prognosis and partial drug sensitivity in HCC, providing new ideas for HCC treatment.

The Role of Parvalbumin Interneurons in Autism Spectrum Disorder.

As an important subtype of GABAergic interneurons, parvalbumin (PV) interneurons play a critical role in regulating cortical circuits and neural networks. Abnormalities in the development or function of PV interneurons have been linked to autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by social and language deficits. In this review, we focus on the abnormalities of PV interneurons in ASD, including quantity and function and discuss the underlying mechanisms of impairments in PV interneurons in the pathology of ASD. Finally, we propose potential therapeutic approaches targeting PV interneurons, such as transplanting MGE progenitor cells and utilizing optogenetic stimulation in the treatment of ASD.

Toward a better understanding of T cell dysregulation in autism: An integrative review.

Autism spectrum disorder (ASD) is a highly heterogeneous disorder characterized by impairments in social, communicative, and restrictive behaviors. Over the past 20 years, research has highlighted the role of the immune system in regulating neurodevelopment and behavior. In ASD, immune abnormalities are frequently observed, such as elevations in pro-inflammatory cytokines, alterations in immune cell frequencies, and dysregulated mechanisms of immune suppression. The adaptive immune system - the branch of the immune system conferring cellular immunity - may be involved in the etiology of ASD. Specifically, dysregulated T cell activity, characterized by altered cellular function and increased cytokine release, presence of inflammatory phenotypes and altered cellular signaling, has been consistently observed in several studies across multiple laboratories and geographic regions. Similarly, mechanisms regulating their activation are also disrupted. T cells at homeostasis coordinate the healthy development of the central nervous system (CNS) during early prenatal and postnatal development, and aid in CNS maintenance into adulthood. Thus, T cell dysregulation may play a role in neurodevelopment and the behavioral and cognitive manifestations observed in ASD. Outside of the CNS, aberrant T cell activity may also be responsible for the increased frequency of immune based conditions in the ASD population, such as allergies, gut inflammation and autoimmunity. In this review, we will discuss the current understanding of T cell biology in ASD and speculate on mechanisms behind their dysregulation. This review also evaluates how aberrant T cell biology affects gastrointestinal issues and behavior in the context of ASD.

CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer.

Poly (ADP-ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high-throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti-tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response is triggered through the induction of the cGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi.

Autophagy activator-loaded bicomponent peptide nanocarriers for phototherapy-triggered immunity enhancement against metastatic breast cancer.

Mild autophagy accompanied with immunogenic cell death (ICD) effect destructs immune-associated antigens, weakening the immune response against tumor growth. To address this dilemma, we develop a peptide-based bicomponent nanocarrier with encapsulation of a cellular hyperautophagy activator (STF-62247) for near-infrared (NIR) photo/immunotherapy to eliminate primary and metastatic breast tumors. The electrostatic-driven nanodrug (PPNPs@STF) with active-targeting and efficient endosomal escape can induce specific ICD effect upon NIR laser irradiation, and trigger autophagy to a mild activation state. Notably, the simultaneously released STF-62247 precisely promotes autophagy to an overactivated state, resulting in autophagic death of tumor cells and further boosting ICD-related antigen presentation. More importantly, the combined photo/immunotherapy of PPNPs@STF not only inhibits tumor cell proliferation, but also promotes dendritic cells (DCs)-associated immune response. In 4 T1 tumor-bearing mice, PPNPs@STF effectively inhibits growth of primary and distant tumors, and suppresses lung metastasis with a minimized side effect. This study provides a hyperautophagy activator-assisted strategy that can enhance ICD-based antitumor immune response for the treatment of metastatic breast cancer.

Pioglitazone attenuates behavioral and electrophysiological dysfunctions induced by two-hit model of schizophrenia in adult rodent offspring.

Maternal infection and stress exposure, especially during childhood and adolescence, have been implicated as risk factors for schizophrenia. Both insults induce an exacerbated inflammatory response, which could mediate disturbance of neurodevelopmental processes and, ultimately, malfunctioning of neural systems observed in this disorder. Thus, anti-inflammatory drugs, such as PPARγ agonists, may potentially be used to prevent the development of schizophrenia. Microglia culture was prepared from the offspring of saline or poly(I:C)-injected mice. The cells were pretreated with pioglitazone and then, stimulated by LPS. Proinflammatory mediators and phagocytic activity were measured. Also, pregnant rats were injected with saline or poly(I:C) on GD17. The offspring were subjected to footshock during adolescence and subsequently injected with pioglitazone or vehicle. At adulthood, behavior and dopaminergic activity were evaluated. Pioglitazone reduced proinflammatory mediators induced by poly(I:C) microglia stimulated by LPS without affecting their decreased phagocytic activity. The PPARγ agonist also prevented the emergence of social and cognitive impairments, as well as attenuated the increased number of spontaneously active dopamine neurons in the VTA, observed in both males and females from poly(I:C) and stress group. Therefore, pioglitazone could potentially prevent the emergence of the schizophrenia-like alterations induced by the two-hit model via reduction of microglial activation.

A Novel Non-Invasive Murine Model of Neonatal Hypoxic-Ischemic Encephalopathy Demonstrates Developmental Delay and Motor Deficits with Activation of Inflammatory Pathways in Monocytes.

Neonatal hypoxic-ischemic encephalopathy (HIE) occurs in 1.5 per 1000 live births, leaving affected children with long-term motor and cognitive deficits. Few animal models of HIE incorporate maternal immune activation (MIA) despite the significant risk MIA poses to HIE incidence and diagnosis. Our non-invasive model of HIE pairs late gestation MIA with postnatal hypoxia. HIE pups exhibited a trend toward smaller overall brain size and delays in the ontogeny of several developmental milestones. In adulthood, HIE animals had reduced strength and gait deficits, but no difference in speed. Surprisingly, HIE animals performed better on the rotarod, an assessment of motor coordination. There was significant upregulation of inflammatory genes in microglia 24 h after hypoxia. Single-cell RNA sequencing (scRNAseq) revealed two microglia subclusters of interest following HIE. Pseudobulk analysis revealed increased microglia motility gene expression and upregulation of epigenetic machinery and neurodevelopmental genes in macrophages following HIE. No sex differences were found in any measures. These results support a two-hit noninvasive model pairing MIA and hypoxia as a model for HIE in humans. This model results in a milder phenotype compared to established HIE models; however, HIE is a clinically heterogeneous injury resulting in a variety of outcomes in humans. The pathways identified in our model of HIE may reveal novel targets for therapy for neonates with HIE.

Autophagy defects at weaning impair complement-dependent synaptic pruning and induce behavior deficits.

Autophagy is crucial for synaptic plasticity and the architecture of dendritic spines. However, the role of autophagy in schizophrenia (SCZ) and the mechanisms through which it affects synaptic function remain unclear. In this study, we identified 995 single nucleotide polymorphisms (SNPs) across 19 autophagy-related genes that are associated with SCZ. Gene Set Enrichment Analysis (GSEA) of data from the Gene Expression Omnibus public database revealed defective autophagy in patients with SCZ. Using a maternal immune activation (MIA) rat model, we observed that autophagy was downregulated during the weaning period, and early-life activation of autophagy with rapamycin restored abnormal behaviors and electrophysiological deficits in adult rats. Additionally, inhibition of autophagy with 3-Methyladenine (3-MA) during the weaning period resulted in aberrant behaviors, abnormal electrophysiology, increased spine density, and reduced microglia-mediated synaptic pruning. Furthermore, 3-MA treatment significantly decreased the expression and synaptosomal content of complement, impaired the recognition of C3b and CR3, indicating that autophagy deficiency disrupts complement-mediated synaptic pruning. Our findings provide evidence for a significant association between SCZ and defective autophagy, highlighting a previously underappreciated role of autophagy in regulating the synaptic and behavioral deficits induced by MIA.

Sex-Specific Behavioral and Molecular Responses to Maternal Lipopolysaccharide-Induced Immune Activation in a Murine Model: Implications for Neurodevelopmental Disorders.

Maternal immune activation (MIA) during pregnancy has been increasingly recognized as a critical factor in the development of neurodevelopmental disorders, with potential sex-specific impacts that are not yet fully understood. In this study, we utilized a murine model to explore the behavioral and molecular consequences of MIA induced by lipopolysaccharide (LPS) administration on embryonic day 12.5. Our findings indicate that male offspring exposed to LPS exhibited significant increases in anxiety-like and depression-like behaviors, while female offspring did not show comparable changes. Molecular analyses revealed alterations in pro-inflammatory cytokine levels and synaptic gene expression in male offspring, suggesting that these molecular disruptions may underlie the observed behavioral differences. These results emphasize the importance of considering sex as a biological variable in studies of neurodevelopmental disorders and highlight the need for further molecular investigations to understand the mechanisms driving these sex-specific outcomes. Our study contributes to the growing evidence that prenatal immune challenges play a pivotal role in the etiology of neurodevelopmental disorders and underscores the potential for sex-specific preventative approaches of MIA.

HIV-1-DNA/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1.

BACKGROUND: Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I. METHODS: Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5' deleted, and 3' deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively. FINDINGS: Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/106 TBP (331-4666)], 17/33 INR [240 (148-589)], and 15/28 IR [144 (15-309)], correlating directly with sCD163, IP-10, GLUT1high cells and glucose uptake, and inversely with the CD4+/CD8+ ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/106 monocytes (7-44)], 8/14 INR [46 (18-67)], and 9/13 IR [9 (7-24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4+/CD8+ ratio. INTERPRETATION: HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR. FUNDING: This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

Changes in the lipidome are associated with immune activation and subclinical vascular disease in youth with HIV in Uganda.

This study examined the changes in the lipidome and associations with immune activation and cardiovascular disease markers in youth living with perinatally acquired HIV (YPHIV). The serum lipidome was measured in ART-treated YPHIV (n=100) and HIV- Ugandan children (n=98) Plasma markers of systemic inflammation, monocyte activation, gut integrity, T cell activation, as well as and common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and 96 weeks. Overall, median age was 12 years,52% were females. Total cholesterol, LDL, and HDL were similar between the groups, however, the concentrations of ceramides, diacylglycerols, free fatty acids, lysophysophatidylcholines and phosphatidylcholines, were higher in YPHIV (P≤0.03). Increases in phosphatidylethanolamine (16:0 and 18:0) correlated with increases in sCD163, OxLDL, CRP, IFAB and PWV in PHIV (r≥0.3). YPHIV, successfully suppressed on ART, have elevated lipid species that are associated with CVD, specificallypalmitic acid (C16:0) and stearic acid (C18:0).

Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study.

Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

Maternal immune activation alters temporal precision of spike generation of CA1 pyramidal neurons by unbalancing GABAergic inhibition intheOffspring.

Infection during pregnancy represents a risk factor for neuropsychiatric disorders associated with neurodevelopmental alterations. A growing body of evidence from rodents and non-human primates shows that maternal inflammation induced by viral or bacterial infections results in several neurobiological alterations in the offspring. These changes may play an important role in the pathophysiology of psychiatric disorders like schizophrenia and autism spectrum disorders, whose clinical features include impairments in cognitive processing and social performance. Such alterations are causally associated with the maternal inflammatory response to infection rather than with the infection itself. Previously, we reported that CA1 pyramidal neurons of mice exposed to MIA exhibit increased excitability accompanied by a reduction in dendritic complexity. However, potential alterations in cellular and synaptic rules that shape the neuronal computational properties of the offspring remain to be determined. In this study, using mice as subjects, we identified a series of cellular and synaptic alterations endured by CA1 pyramidal neurons of the dorsal hippocampus in a lipopolysaccharide-induced maternal immune activation (MIA) model. Our data indicate that MIA reshapes the excitation-inhibition balance by decreasing the perisomatic GABAergic inhibition predominantly mediated by cholecystokinin-expressing Interneurons but not parvalbumin-expressing interneurons impinging on CA1 pyramidal neurons. These alterations yield a dysregulated amplification of the temporal and spatial synaptic integration. In addition, MIA-exposed offspring displayed social and anxiety-like abnormalities. These findings collectively contribute to understanding the cellular and synaptic alterations underlying the behavioral symptoms present in neurodevelopmental disorders associated with MIA.

Integrating Bulk and Single-Cell RNA-Seq Data to Identify Prognostic Features Related to Activated Dendritic Cells in Clear-Cell Renal-Cell Carcinoma.

Dendritic cells (DCs) serve as key regulators in tumor immunity, with activated DCs potentiating antitumor responses through the secretion of pro-inflammatory cytokines and the expression of co-stimulatory molecules. Most current studies focus on the relationship between DC subgroups and clear-cell renal-cell carcinoma (ccRCC), but there is limited research on the connection between DCs and ccRCC from the perspective of immune activation. In this study, activated DC genes were identified in both bulk and single-cell RNA-seq data. A prognostic model related to activated DCs was constructed using univariate, multivariate Cox regression and LASSO regression. The prognostic model was validated in three external validation sets: GSE167573, ICGC, and E-MTAB-1980. The prognostic model consists of five genes, PLCB2, XCR1, IFNG, HLA-DQB2, and SMIM24. The expression of these genes was validated in tissue samples using qRT-PCR. Stratified analysis revealed that the prognostic model was able to better predict outcomes in advanced ccRCC patients. The risk scores were associated with tumor progression, tumor mutation burden, immune cell infiltration, and adverse outcomes of immunotherapy. Notably, there was a strong correlation between the expression of the five genes and the sensitivity to JQ1, a BET inhibitor. Molecular docking indicated high-affinity binding of the proteins encoded by these genes with JQ1. In conclusion, our study reveals the crucial role of activated DCs in ccRCC, offering new insights into predicting immune response, targeted therapy effectiveness, and prognosis for ccRCC patients.

Maternal immune activation upregulates the AU020206-IRFs-STAT1 axis in modulating cytokine production in the brain.

Maternal immune activation (MIA) is reported to increase the risk of psychiatric disorders in the offspring. However, the underlying mechanism remains unclear. Methods: We constructed a MIA mouse model by intraperitoneal injection of LPS into pregnant mice and evaluated the behaviors and gene expression profiles in the brains of the female and male offspring, respectively. Results: We found that the MIA female offspring exhibited increased anxiety and a large number of differentially expressed genes (DEGs) in the brain, which were enriched with candidate gene sets of psychiatric disorders and immune functions. In contrast, the MIA male offspring exhibited no significant abnormal behaviors and only a small number of DEGs that were not enriched with disease genes and immune functions. Therefore, we further pursued the downstream study on the molecular mechanism underlying the increased anxiety in the female offspring. We identified the lncRNA AU020206-IRFs-STAT1-cytokine axis by integrating lncRNA-protein interaction data and TF-promoter interaction data, and verified the axis in vitro and in vivo. Conclusion: This study illustrates that MIA upregulates the AU020206-IRFs-STAT1 axis in controlling the brain immunity linked to abnormal behaviors, providing a basis for understanding the role of MIA in psychiatric disorders.

The rebalancing of the immune system at the maternal-fetal interface ameliorates autism-like behavior in adult offspring.

Maternal immune activation (MIA) is critical for imparting neuropathology and altered behaviors in offspring; however, maternal-fetal immune cell populations have not been thoroughly investigated in MIA-induced autism spectrum disorders (ASDs). Here, we report the single-cell transcriptional landscape of placental cells in both PBS- and poly(I:C)-induced MIA dams. We observed a decrease in regulatory T (Treg) cells but an increase in the M1 macrophage population at the maternal-fetal interface in MIA dams. Based on the Treg-targeting approach, we investigate an immunoregulatory protein, the helminth-derived heat shock protein 90α (Sjp90α), that induces maternal Treg cells and subsequently rescues the autism-like behaviors in adult offspring. Furthermore, in vivo depletion of maternal macrophages attenuates placental inflammatory reaction and reverses behavioral abnormalities in adult offspring. Notably, Sjp90α induces CD4+ T cell differentiation via scavenger receptor A (SR-A) on the macrophage in vitro. Our findings suggest a maternal Treg-targeted approach to alleviate MIA-induced autism-like behavior in adult offspring.