Sex Differences in Personality Disorder and Childhood Maltreatment of Patients with Schizophrenia.

Introduction: Despite numerous studies investigating personality disorder (PD) and childhood maltreatment (CM) characteristics in individuals with schizophrenia (SZ), there remains a scarcity of research focusing on sex differences in PD and CM within large samples of SZ patients. Methods: A total of 592 participants (257 males, 335 females) were consecutively sampled from patients diagnosed with SZ at the psychiatric and psycho-counseling clinics at Shanghai Mental Health Center. PDs were assessed using a self-reported personality diagnostic questionnaire and a structured clinical interview, while CMs were evaluated using the Chinese version of the Child Trauma Questionnaire Short Form. Results: Male patients exhibited a prominent self-reported trait of antisocial PD (t=1.972, p=0.049), while female patients demonstrated a notable emphasis on histrionic PD traits (t=-2.057, p=0.040). Structured interviews for PD diagnoses further indicated a higher comorbidity of schizotypal (χ2=4.805, p=0.028) and schizoid (χ2=6.957, p=0.008) PDs among male patients compared to female patients. Additionally, male patients reported a higher degree (t=2.957, p=0.003) and proportion (χ2=5.277, p=0.022) of experiences of physical abuse in their self-reported CM. Logistic regression analyses highlight distinct factors: higher antisocial PD traits and physical abuse are associated with male patients, while histrionic PD traits and emotional abuse are associated with female patients. Discussion: These findings underscore the importance of recognizing and addressing sex-specific manifestations of personality pathology and the nuanced impact of CM in the clinical management of individuals with SZ. The study advocates for tailored interventions that consider the distinct needs associated with sex differences in both personality traits and CM experiences among SZ patients.

Comparing percutaneous transhepatic papillary balloon dilation with endoscopic retrograde cholangiopancreatography in elderly patients for common bile duct stones: a 3-year retrospective study.

PURPOSE: To assess the safety and effectiveness of PTPBD for CBD stones in the elderly population. METHODS: Patients aged 60 years or older, who underwent PTPBD or ERCP for CBD stones between January 2021 and December 2023, were included in this study and divided into either the PTPBD group or the ERCP group based on the procedure they underwent. Baseline characteristics, intraoperative and postoperative outcomes were collected and analyzed using SPSS 25.0. RESULTS: A total of 145 cases were enrolled in the study. In terms of intraoperative complications, one patient in the ERCP group experienced hemorrhaging, while one patient in the PTPBD group experienced acute pain. However, neither of these patients were in a serious condition and only required observation. Stone removal procedures were successfully conducted in approximately 95% of cases in both the PTPBD and ERCP groups (95.8 and 94.8%, respectively; P > 0.999). ERCP failures were observed in one patient with a previous Billroth II anastomosis and two patients with unconventional anatomy of the esophagus and stomach. There was no statistically significant difference in postoperative complications between the PTPBD group and the ERCP group (P > 0.05). The length of hospital stays did not differ between the PTPBD group and the ERCP group (P = 0.537 > 0.05). CONCLUSION: PTPBD can be used in patients who have complicated anatomical issues that make the ERCP procedure difficult. In comparison, PTPBD is a similarly safe, effective, and minimally invasive technique for extracting CBD stones in elderly patients.

Identifying novel clinical phenotypes of acute respiratory distress syndrome using trajectories of daily fluid balance: a secondary analysis of randomized controlled trials.

BACKGROUND: Previously identified phenotypes of acute respiratory distress syndrome (ARDS) could not reveal the dynamic change of phenotypes over time. We aimed to identify novel clinical phenotypes in ARDS using trajectories of fluid balance, to test whether phenotypes respond differently to different treatment, and to develop a simplified model for phenotype identification. METHODS: FACTT (conservative vs liberal fluid management) trial was classified as a development cohort, joint latent class mixed models (JLCMMs) were employed to identify trajectories of fluid balance. Heterogeneity of treatment effect (HTE) for fluid management strategy across phenotypes was investigated. We also constructed a parsimonious probabilistic model using baseline data to predict the fluid trajectories in the development cohort. The trajectory groups and the probabilistic model were externally validated in EDEN (initial trophic vs full enteral feeding) trial. RESULTS: Using JLCMM, we identified two trajectory groups in the development cohort: Class 1 (n = 758, 76.4% of the cohort) had an early positive fluid balance, but achieved negative fluid balance rapidly, and Class 2 (n = 234, 24.6% of the cohort) was characterized by persistent positive fluid balance. Compared to Class 1 patients, patients in Class 2 had significantly higher 60-day mortality (53.5% vs. 17.8%, p < 0.001), and fewer ventilator-free days (0 vs. 20, p < 0.001). A significant HTE between phenotypes and fluid management strategies was observed in the FACTT. An 8-variables model was derived for phenotype assignment. CONCLUSIONS: We identified and validated two novel clinical trajectories for ARDS patients, with both prognostic and predictive enrichment. The trajectories of ARDS can be identified with simple classifier models.

Cognitive functions following initiation of antipsychotic medication in adolescents and adults at clinical high risk for psychosis: a naturalistic sub group analysis using the MATRICS consensus cognitive battery.

BACKGROUND: The effects of antipsychotic (AP) medications on cognitive functions in individuals at clinical high-risk (CHR) of psychosis are poorly understood. This study compared the effects of AP treatment on cognitive improvement in CHR adolescents and adults. METHODS: A total of 327 CHR participants, with an age range of 13 to 45 years, who underwent baseline neuropsychological assessments and a 1-year clinical follow-up were included. Participants with CHR were categorized into four groups based on their age: adolescents (aged < 18) and adults (aged ≥ 18), as well as their antipsychotic medication status (AP+ or AP-). Therefore, the four groups were defined as Adolescent-AP-, Adolescent-AP+, Adult-AP-, and Adult-AP+. RESULTS: During the follow-up, 231 CHR patients received AP treatment, 94 converted to psychosis, and 161 completed the 1-year follow-up. The Adolescent-AP+ group had more positive symptoms, lower general functions, and cognitive impairments than the Adolescent-AP- group at baseline, but no significant differences were observed among adults. The Adolescent-AP+ group showed a significant increase in the risk of conversion to psychosis (p < 0.001) compared to the Adolescent-AP- group. The Adult-AP+ group showed a decreasing trend in the risk of conversion (p = 0.088) compared to the Adult-AP- group. The Adolescent-AP- group had greater improvement in general functions (p < 0.001), neuropsychological assessment battery mazes (p = 0.025), and brief visuospatial memory test-revised (p = 0.020), as well as a greater decrease in positive symptoms (p < 0.001) at follow-up compared to the Adolescent-AP+ group. No significant differences were observed among adults. CONCLUSIONS: Early use of AP was not associated with a positive effect on cognitive function in CHR adolescents. Instead, the absence of AP treatment was associated with better cognitive recovery, suggesting that AP exposure might not be the preferred choice for cognitive recovery in CHR adolescents, but may be more reasonable for use in adults.

Advancements and Future Directions in Prevention Based on Evaluation for Individuals With Clinical High Risk of Psychosis: Insights From the SHARP Study.

BACKGROUND AND HYPOTHESIS: This review examines the evolution and future prospects of prevention based on evaluation (PBE) for individuals at clinical high risk (CHR) of psychosis, drawing insights from the SHARP (Shanghai At Risk for Psychosis) study. It aims to assess the effectiveness of non-pharmacological interventions in preventing psychosis onset among CHR individuals. STUDY DESIGN: The review provides an overview of the developmental history of the SHARP study and its contributions to understanding the needs of CHR individuals. It explores the limitations of traditional antipsychotic approaches and introduces PBE as a promising framework for intervention. STUDY RESULTS: Three key interventions implemented by the SHARP team are discussed: nutritional supplementation based on niacin skin response blunting, precision transcranial magnetic stimulation targeting cognitive and brain functional abnormalities, and cognitive behavioral therapy for psychotic symptoms addressing symptomatology and impaired insight characteristics. Each intervention is evaluated within the context of PBE, emphasizing the potential for tailored approaches to CHR individuals. CONCLUSIONS: The review highlights the strengths and clinical applications of the discussed interventions, underscoring their potential to revolutionize preventive care for CHR individuals. It also provides insights into future directions for PBE in CHR populations, including efforts to expand evaluation techniques and enhance precision in interventions.

Global diversity of airborne pathogenic bacteria and fungi from wastewater treatment plants.

Wastewater treatment plants (WWTPs) have been recognized as one of the major potential sources of the spread of airborne pathogenic microorganisms under the global pandemic of COVID-19. The differences in research regions, wastewater treatment processes, environmental conditions, and other aspects in the existing case studies have caused some confusion in the understanding of bioaerosol pollution characteristics. In this study, we integrated and analyzed data from field sampling and performed a systematic literature search to determine the abundance of airborne microorganisms in 13 countries and 37 cities across four continents (Asia, Europe, North America, and Africa). We analyzed the concentrations of bioaerosols, the core composition, global diversity, determinants, and potential risks of airborne pathogen communities in WWTPs. Our findings showed that the culturable bioaerosol concentrations of global WWTPs are 102-105 CFU/m3. Three core bacterial pathogens, namely Bacillus, Acinetobacter, and Pseudomonas, as well as two core fungal pathogens, Cladosporium and Aspergillus, were identified in the air across global WWTPs. WWTPs have unique core pathogenic communities and distinct continental divergence. The sources of airborne microorganisms (wastewater) and environmental variables (relative humidity and air contaminants) have impacts on the distribution of airborne pathogens. Potential health risks are associated with the core airborne pathogens in WWTPs. Our study showed the specificity, multifactorial influences, and potential pathogenicity of airborne pathogenic communities in WWTPs. Our findings can improve the understanding of the global diversity and biogeography of airborne pathogens in WWTPs, guiding risk assessment and control strategies for such pathogens. Furthermore, they provide a theoretical basis for safeguarding the health of WWTP workers and ensuring regional ecological security.

Advances in proteomics in diffuse large B­cell lymphoma (Review).

Diffuse large B­cell lymphoma (DLBCL) is the most common pathological type of non­Hodgkin's lymphoma. Although the development of monoclonal antibodies, small­molecule­targeted drugs and novel chemotherapeutic agents, and the increased use of immunotherapy have markedly improved the outcomes of DLBCL, ~40% of patients cannot be cured following the use of standardized first­line treatment. In addition, the specific mechanisms of drug resistance and potential factors associated with a poor prognosis in these patients remain unclear. Proteomics research is used to determine potential associations between changes in DLBCL protein expression levels and different stages of disease occurrence and development. Proteomics may aid in the identification of novel molecular mechanisms and drug resistance mechanisms, through identifying multiple associated proteins and monitoring changes in expression levels. Thus, proteomics research may exhibit potential in the development of therapeutic targets and in improving prognostic evaluation in patients with DLBCL. The present study aimed to review the use of proteomic methods for the investigation of DLBCL, including the mechanisms underlying disease progression and drug resistance in DLBCL, and the function of the tumor microenvironment in lymphoma growth. The present review also demonstrated the potential of proteomic­guided therapeutic strategies for DLBCL and discussed the synergistic benefits of using proteomic methods in DLBCL research.

[3D tumor spheroids promote activation, expansion, and anti-tumor effects of tumor-infiltrating lymphocytes in vitro].

The adoptive immunotherapy mediated by tumor-infiltrating lymphocytes (TILs) has shown definite efficacy against various solid tumors. However, the inefficiency of the conventional method based on in vitro expansion of TILs fails to achieve the cell count and high tumor-killing activity required for therapeutic purposes. This study investigated the effect of 3D tumor spheroids on the activation and expansion of TILs in vitro, aiming to provide a novel approach for the expansion of TILs. We procured TILs and primary tumor cells from surgical samples of lung cancer patients and then compared the impacts of lung cancer cell line NCI-H1975 and primary lung cancer cells cultured under 2D and 3D conditions on the activation, expansion, and anti-tumor activity of TILs. Furthermore, we added the programmed cell death protein 1 (PD-1) antibody into the co-culture of primary tumor cells and TILs within a 3D environment to assess the effects of the antibody on TILs. The results showed that compared with 2D cultured tumor cells, the 3D cultured H1975 cells significantly enhanced the expansion of TILs, increasing the proportion of CD3+/CD8+ cells in TILs to 61.6%. The 3D primary tumor model also enhanced the proportion of CD3+/CD8+ cells in TILs (45.5%, 54.4%), induced apoptosis of tumor epithelial cells and decreased the overall tumor cells survival rate (16.7%) after co-culture. PD-1 antibodies further improved the in vitro expansion capacity of TILs mediated by 3D tumor spheroids, resulting in the proportions of 50.9% and 57.0% for CD3+/CD8+ cells and enhancing the antitumor activity significantly (reducing the overall tumor survival rate to 9.36%). In summary, the use of 3D tumor spheroids significantly promoted the expansion and improved the anti-tumor effect of TILs, and the use of the PD-1 antibody further promoted the expansion and tumor-killing effect of TILs.

Multiple coherent amplitude modes and exciton-phonon coupling in quasi-one-dimensional excitonic insulator Ta2NiSe5.

An excitonic insulator (EI) is an intriguing correlated electronic phase of condensed excitons. Ta2NiSe5 is a model material for investigating condensed excitonic states. Herein, femtosecond pump-probe spectroscopy is used to study the coherent phonon dynamics and associated exciton-phonon coupling in single-crystal Ta2NiSe5. The reflectivity time series consists of exponential decay due to hot carriers and damped oscillations due to the Ag phonon vibration. Given the in-plane anisotropic thermal conductivity of Ta2NiSe5, coherent phonon oscillations are stronger with perpendicular polarization to its quasi-one-dimensional chains. The 1-, 2-, and 4-THz vibration modes show coherent amplitude responses in the EI phase of Ta2NiSe5 with increasing temperature, totally different from those of normal coherent phonons (the 3- and 3.7-THz modes). The amplitude modes at higher frequencies decouple with the EI order parameter at lower temperatures, as supported by theoretical analysis with a model Hamiltonian of the exciton-phonon coupling system. Our work provides valuable insights into the character of the EI order parameter and its coupling to multiple coherent amplitude modes.

Development of a Measurement Device for Micro Gas Flowrate Based on Laminar Flow Element with Micro-Curved Surface.

The laminar flow meter (LFM) boasts several advantages such as no moving parts, a wide range ratio, high measurement accuracy, quick dynamic response, etc., and is a promising technology for micro gas flow measurement. In order to explore the influence of different curvature radii on curved surface gap LFM, three curved structures with different curvature radii were designed. The computational fluid dynamics method is applied to simulate the flow feature of three structures. The simulated velocity cloud and pressure distribution show that the larger the curvature radius, the more stable the flow of gas medium. The relationship between differential pressure and volume flow was obtained through the test within a flow range of 0~540 sccm. Regression analysis revealed that the volume flow measured by the curved surface LFM had a high linear relationship with the differential pressure. Experimental findings indicate that differential pressure of the structure with a curvature radius of 2 mm was greater than that of other two structures (curvature radius of 6 mm and 3 mm) at the same point. This indicates that adding the number of surfaces can effectively increase the pressure loss, so as to obtain a larger range ratio, but will increase the measurement error.

Evolutionary history shapes variation of wood density of tree species across the world.

The effect of evolutionary history on wood density variation may play an important role in shaping variation in wood density, but this has largely not been tested. Using a comprehensive global dataset including 27,297 measurements of wood density from 2621 tree species worldwide, we test the hypothesis that the legacy of evolutionary history plays an important role in driving the variation of wood density among tree species. We assessed phylogenetic signal in different taxonomic (e.g., angiosperms and gymnosperms) and ecological (e.g., tropical, temperate, and boreal) groups of tree species, explored the biogeographical and phylogenetic patterns of wood density, and quantified the relative importance of current environmental factors (e.g., climatic and soil variables) and evolutionary history (i.e., phylogenetic relatedness among species and lineages) in driving global wood density variation. We found that wood density displayed a significant phylogenetic signal. Wood density differed among different biomes and climatic zones, with higher mean values of wood density in relatively drier regions (highest in subtropical desert). Our study revealed that at a global scale, for angiosperms and gymnosperms combined, phylogeny and species (representing the variance explained by taxonomy and not direct explained by long-term evolution process) explained 84.3% and 7.7% of total wood density variation, respectively, whereas current environment explained 2.7% of total wood density variation when phylogeny and species were taken into account. When angiosperms and gymnosperms were considered separately, the three proportions of explained variation are, respectively, 84.2%, 7.5% and 6.7% for angiosperms, and 45.7%, 21.3% and 18.6% for gymnosperms. Our study shows that evolutionary history outpaced current environmental factors in shaping global variation in wood density.

Corrigendum: The central inflammatory regulator IκBζ: induction regulation and physiological functions.

[This corrects the article DOI: 10.3389/fimmu.2023.1188253.].

Threonine dehydrogenase regulates neutrophil homeostasis but not H3K4me3 levels in zebrafish.

l-threonine dehydrogenase (Tdh) is an enzyme that links threonine metabolism to epigenetic modifications and mitochondria biogenesis. In vitro studies show that it is critical for the regulation of trimethylation of histone H3 lysine 4 (H3K4me3) levels and cell fate determination of mouse embryonic stem cells (mESCs). However, whether Tdh regulates a developmental process in vivo and, if it does, whether it also primarily regulates H3K4me3 levels in this process as it does in mESCs, remains elusive. Here, we revealed that, in zebrafish hematopoiesis, tdh is preferentially expressed in neutrophils. Knockout of tdh causes a decrease in neutrophil number and slightly suppresses their acute injury-induced migration, but, unlike the mESCs, the level of H3K4me3 is not evidently reduced in neutrophils sorted from the kidney marrow of adult tdh-null zebrafish. These phenotypes are dependent on the enzymatic activity of Tdh. Importantly, a soluble supplement of nutrients that are able to fuel the acetyl-CoA pool, such as pyruvate, glucose and branched-chain amino acids, is sufficient to rescue the reduction in neutrophils caused by tdh deletion. In summary, our study presents evidence for the functional requirement of Tdh-mediated threonine metabolism in a developmental process in vivo. It also provides an animal model for investigating the nutritional regulation of myelopoiesis and immune response, as well as a useful tool for high-throughput drug/nutrition screening.

Necroptosis contributes to non-alcoholic fatty liver disease pathoetiology with promising diagnostic and therapeutic functions.

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease. However, the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies. Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoetiology and suggest functional therapeutic and diagnostic options. Pyroptosis, ferroptosis, and necroptosis are the main subtypes of non-apoptotic regulated cell deaths (RCDs), each of which represents particular characteristics. Considering the complexity of the findings, the present study aimed to review these types of RCDs and their contribution to NAFLD progression, and subsequently discuss in detail the role of necroptosis in the pathoetiology, diagnosis, and treatment of the disease. The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer, hence it has potential in diagnostic and therapeutic approaches. Nevertheless, further studies are necessary.

A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments.

Cancer models play critical roles in basic cancer research and precision medicine. However, current in vitro cancer models are limited by their inability to mimic the three-dimensional architecture and heterogeneous tumor microenvironments (TME) of in vivo tumors. Here, we develop an innovative patient-specific lung cancer assembloid (LCA) model by using droplet microfluidic technology based on a microinjection strategy. This method enables precise manipulation of clinical microsamples and rapid generation of LCAs with good intra-batch consistency in size and cell composition by evenly encapsulating patient tumor-derived TME cells and lung cancer organoids inside microgels. LCAs recapitulate the inter- and intratumoral heterogeneity, TME cellular diversity, and genomic and transcriptomic landscape of their parental tumors. LCA model could reconstruct the functional heterogeneity of cancer-associated fibroblasts and reflect the influence of TME on drug responses compared to cancer organoids. Notably, LCAs accurately replicate the clinical outcomes of patients, suggesting the potential of the LCA model to predict personalized treatments. Collectively, our studies provide a valuable method for precisely fabricating cancer assembloids and a promising LCA model for cancer research and personalized medicine.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy.

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Legume rhizodeposition promotes nitrogen fixation by soil microbiota under crop diversification.

Biological nitrogen fixation by free-living bacteria and rhizobial symbiosis with legumes plays a key role in sustainable crop production. Here, we study how different crop combinations influence the interaction between peanut plants and their rhizosphere microbiota via metabolite deposition and functional responses of free-living and symbiotic nitrogen-fixing bacteria. Based on a long-term (8 year) diversified cropping field experiment, we find that peanut co-cultured with maize and oilseed rape lead to specific changes in peanut rhizosphere metabolite profiles and bacterial functions and nodulation. Flavonoids and coumarins accumulate due to the activation of phenylpropanoid biosynthesis pathways in peanuts. These changes enhance the growth and nitrogen fixation activity of free-living bacterial isolates, and root nodulation by symbiotic Bradyrhizobium isolates. Peanut plant root metabolites interact with Bradyrhizobium isolates contributing to initiate nodulation. Our findings demonstrate that tailored intercropping could be used to improve soil nitrogen availability through changes in the rhizosphere microbiome and its functions.

Childhood maltreatment and personality disorders in adolescents and adults with psychotic or non-psychotic disorders.

Introduction: While the attention to personality disorders (PD) and childhood maltreatment (CM) has grown in recent years, there remains limited understanding of the prevalence and distinctions of PD and CM in clinical populations of Chinese adolescents in comparison to adults. Methods: A total of 1,417 participants were consecutively sampled from patients diagnosed with either psychotic or non-psychotic disorders in the psychiatric and psycho-counseling clinics at Shanghai Mental Health Center. The participants were categorized into two groups based on their age: adolescents (aged 15-21 years) and adults (aged 22-35 years). PDs were evaluated using a self-reported personality diagnostic questionnaire and a structured clinical interview, while CMs were assessed using the Chinese version of the Child Trauma Questionnaire Short Form. Results: When comparing self-reported PD traits and CM between adolescents and adults, differences emerge. Adolescents, particularly in the psychotic disorder group, exhibit more pronounced schizotypal PD traits (p=0.029), and this pattern extends to non-psychotic disorders (p<0.001). Adolescents in the non-psychotic disorder group also report higher levels of emotional abuse (p=0.014), with a notable trend in physical abuse experiences compared to adults (p=0.057). Furthermore, the most prevalent PDs in the clinical sample are avoidant, borderline, and obsessive-compulsive PDs. Among patients with psychotic disorders, adolescents exhibit higher rates of schizoid, schizotypal, and obsessive-compulsive PDs compared to adults. Logistic regression analyses highlight distinct predictors for psychotic and non-psychotic disorders in adolescents and adults. Discussion: The findings emphasize distinct differences in PDs and CMs between adolescent and adult groups, shedding light on their potential roles in psychotic and non-psychotic disorders.

Association between serum cytokines and timeframe for conversion from clinical high-risk to psychosis.

AIM: Although many studies have explored the link between inflammatory markers and psychosis, there is a paucity of research investigating the temporal progression in individuals at clinical high-risk (CHR) who eventually develop full psychosis. To address this gap, we investigated the correlation between serum cytokine levels and Timeframe for Conversion to Psychosis (TCP) in individuals with CHR. METHODS: We enrolled 53 individuals with CHR who completed a 5-year follow-up with a confirmed conversion to psychosis. Granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-1ß, 2, 6, 8, 10, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF) levels were measured at baseline and 1-year. Correlation and quantile regression analyses were performed. RESULTS: The median TCP duration was 14 months. A significantly shorter TCP was associated with higher levels of TNF-α (P = 0.022) and VEGF (P = 0.016). A negative correlation was observed between TCP and TNF-α level (P = 0.006) and VEGF level (P = 0.04). Quantile regression indicated negative associations between TCP and GM-CSF levels below the 0.5 quantile, IL-10 levels below the 0.3 quantile, IL-2 levels below the 0.25 quantile, IL-6 levels between the 0.65 and 0.75 quantiles, TNF-α levels below the 0.8 quantile, and VEGF levels below the 0.7 quantile. A mixed linear effects model identified significant time effects for IL-10 and IL-2, and significant group effects for changes in IL-2 and TNF-α. CONCLUSIONS: Our findings underscore that a more pronounced baseline inflammatory state is associated with faster progression of psychosis in individuals with CHR. This highlights the importance of considering individual inflammatory profiles during early intervention and of tailoring preventive measures for risk profiles.

Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3.

Oxygen is essential for aerobic organisms, but little is known about its role in antiviral immunity. Here, we report that during responses to viral infection, hypoxic conditions repress antiviral-responsive genes independently of HIF signaling. EGLN1 is identified as a key mediator of the oxygen enhancement of antiviral innate immune responses. Under sufficient oxygen conditions, EGLN1 retains its prolyl hydroxylase activity to catalyze the hydroxylation of IRF3 at proline 10. This modification enhances IRF3 phosphorylation, dimerization and nuclear translocation, leading to subsequent IRF3 activation. Furthermore, mice and zebrafish with Egln1 deletion, treatment with the EGLN inhibitor FG4592, or mice carrying an Irf3 P10A mutation are more susceptible to viral infections. These findings not only reveal a direct link between oxygen and antiviral responses, but also provide insight into the mechanisms by which oxygen regulates innate immunity.