Extracellular matrix hydrogels with fibroblast growth factor 2 containing exosomes for reconstructing skin microstructures.

Decellularized extracellular matrix hydrogel (ECM hydrogel), a natural material derived from normal tissue with unique biocompatibility properties, is widely used for tissue repair. However, there are still problems such as poor biological activity and insufficient antimicrobial property. To overcome these drawbacks, fibroblast growth factor 2 (FGF 2) containing exosome (exoFGF 2) was prepared to increase the biological activity. Furthermore, the antimicrobial capacity of ECM hydrogel was optimised by using copper ions as a ligand-bonded cross-linking agent. The decellularized extracellular matrix hydrogel, intricately cross-linked with copper ions through ligand bonds and loaded with FGF 2 containing exosome (exoFGF 2@ECM/Cu2+ hydrogel), has demonstrated exceptional biocompatibility and antimicrobial properties. In vitro, exoFGF 2@ECM/Cu2+ hydrogel effectively promoted cell proliferation, migration, antioxidant and inhibited bacterial growth. In vivo, the wound area of rat treated with exoFGF 2@ECM/Cu2+ hydrogels were significantly smaller than that of other groups at Day 5 (45.24% ± 3.15%), Day 10 (92.20% ± 2.31%) and Day 15 (95.22% ± 1.28%). Histological examination showed that exoFGF 2@ECM/Cu2+ hydrogels promoted angiogenesis and collagen deposition. Overall, this hydrogel has the potential to inhibit bacterial growth and effectively promote wound healing in a variety of clinical applications.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia.

BACKGROUND: Increasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS). METHODS: The plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC). RESULTS: The plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels. CONCLUSIONS: These results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Cartilage decellularized matrix hydrogel loaded with protocatechualdehyde for targeted epiphycan treatment of osteoarthritis.

Osteoarthritis (OA) is a prevalent chronic disease, characterized by chronic inflammation and cartilage degradation. This study aims to deepen the understanding of OA's pathophysiology and to develop novel therapeutic strategies. Our study underscores the pivotal role of Epiphycan (EPYC) and the IL-17 signaling pathway in OA. EPYC, an essential extracellular matrix constituent, has been found to exhibit a positive correlation with the severity of OA. We have discovered that EPYC modulates the activation of the IL-17 signaling pathway within chondrocytes by regulating the interaction between IL-17A and its receptor, IL-17RA. This regulatory mechanism underscores the intricate interplay between the extracellular matrix and immune signaling in the pathogenesis of OA Another finding of our study is the therapeutic effectiveness of protocatechualdehyde (PAH) in OA. PAH significantly reduces chondrocyte hypertrophy and supports cartilage tissue recovery.by targets EPYC. To reduce the side effects of orally administered PAH and maintain its effective drug concentration, we have developed a decellularized matrix hydrogel loaded with PAH for intra-articular injection. This novel drug delivery system is advantageous in minimizing drug-related side effects and ensuring sustained release PAH within the joint cavity.

History of suicidal behavior and clozapine prescribing among people with schizophrenia in China: a cohort study.

BACKGROUND: Clozapine is an off-label drug used in most countries to prevent suicide in individuals with schizophrenia. However, few studies have reported real-world prescription practices. This study aimed to explore the association between a history of suicidal behavior and clozapine prescribing during eight weeks of hospitalization for individuals with early-stage schizophrenia. METHODS: This observational cohort study used routine health data collected from a mental health hospital in Beijing, China. The study included 1057 inpatients who had schizophrenia onset within 3 years. History of suicidal behavior was coded from reviewing medical notes according to the Columbia Suicide Severity Rating Scale. Information on antipsychotic use during hospitalization was extracted from the prescription records. Time to clozapine use was analyzed using Cox regression models adjusted for sociodemographic and clinical covariates. RESULTS: The prevalence rates of self-harm, suicidal behavior, and suicide attempt were 12.3%, 7.5%, and 5.4%, respectively. A history of self-harm history was positively associated with clozapine uses upon admission (4.1% vs. 0.8%, exact p = 0.009). Among those who had not used clozapine and had no clozapine contraindication, A history of suicidal behavior increased the possibility of switch to clozapine within 56 days after admission (Hazard Ratio[95% CI], 6.09[2.08-17.83]) or during hospitalization (4.18[1.62-10.78]). CONCLUSION: The use of clozapine for early-stage schizophrenia was more frequent among those with suicidal behavior than among those without suicidal behavior in China, although the drug instructions do not label its use for suicide risk.

Serum neuroactive metabolites of the tryptophan pathway in patients with acute phase of affective disorders.

Background: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD). Methods: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale (YMRS) were used to evaluate depressive and manic symptoms at baseline and after 8 weeks of antidepressants, mood stabilizers, some also received antipsychotic medication. Results: The levels of tryptophan (TRP) and kynurenic acid (KYNA) were significantly lower and the ratios of tryptophan/kynurenine (TRP/KYN), 5-hydroxytryptamine/tryptophan (5-HT/TRP), quinolinic acid/kynurenic acid (QUIN/KYNA) were higher in BD-M, BD-D, MDD vs. HC. The levels of QUIN and the ratios of QUIN/KYNA were higher in BD-M than in BD-D, MDD, and HCs. The 5-hydroxyindoleacetic acid (5-HIAA) levels of patients with MDD were significantly higher than those in BD-M and BD-D. Binary logistic regression analysis showed the lower peripheral KYNA, the higher the QUIN level, and the higher the risk of BD-M; the lower peripheral KYNA and the higher KYN/TRP and 5-HT/TRP, the higher the risk of BD-D; and the lower the peripheral KYNA level and the higher the KYN/TRP and 5-HT/TRP, the higher the risk of MDD. Correlation analysis, showing a significant association between tryptophan metabolites and improvement of clinical symptoms, especially depression symptoms. Conclusions: Patients with affective disorders had abnormal tryptophan metabolism, which involved in 5-HT and kynurenine pathway (KP) sub-pathway. Tryptophan metabolites might be potential biomarkers for affective disorders and some metabolites have been associated with remission of depressive symptoms.

Correlation of allostatic load and perceived stress with clinical features in first-episode schizophrenia.

BACKGROUND: Stress plays an important role in the etiology of schizophrenia. However, the mechanisms by which chronic physiological stress and perceived stress relate to the clinical features of schizophrenia may differ. We aimed to elucidate the relationships among chronic physiological stress indexed by allostatic load (AL), perceived stress, and clinical symptoms in individuals with first-episode schizophrenia (FES). METHODS: Individuals with FES (n = 90, mean age = 28.26years old, 49%female) and healthy controls (111, 28.88, 51%) were recruited. We collected data of 13 biological indicators to calculate the AL index, assessed subjective stress with the Perceived Stress Scale-14 (PSS-14), and compared AL and perceived stress between groups. Patients with FES were also evaluated with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS). RESULTS: Individuals with FES had higher AL and PSS score than healthy controls. There were no significant correlations between AL and PSS score in either patients or controls. Among individuals with FES, the AL index was associated with the severity of positive symptoms, while the PSS score was positively associated with CDSS score. Both elevated AL and PSS were correlated with the occurrence of schizophrenia. CONCLUSIONS: Physiological stress, as reflected by AL, may be more related to positive symptoms, while perceived stress appear to be associated with depressive symptoms in individuals with FES. Longitudinal studies are necessary to explore the relationships between interventions for different stressor types and specific clinical outcomes in FES.

Relationship between C-reactive protein and antipsychotics levels in schizophrenic patients infected with COVID-19.

In the context of the COVID-19, inflammation emerges as a prominent characteristic. C-reactive protein (CRP) serves as a commonly employed marker for the evaluation of inflammation. This study aimed to examine the correlation between CRP levels and antipsychotic drug concentrations in patients diagnosed with SCZ during the COVID-19 pandemic. A total of 186 SCZ patients were included in this study, which utilized electronic medical records. The collected data encompassed SCZ diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, respiratory symptoms, and treatments. Laboratory assessments involved the measurement of CRP levels and monitoring of blood drug concentrations. The most prevalent symptoms observed in the patient cohort were fever (59.14%), cough (52.15%), fatigue (45.7%), sore throat (46.24%), runny nose (28.49%), and stuffy nose (25.27%). The levels of CRP during the infection period were significantly higher compared to both the prophase and anaphase of infection (all p < 0.001). The serum levels of clozapine, olanzapine, aripiprazole, quetiapine, and risperidone were elevated during the infection period (all p < 0.001). During the anaphase of infection, patients exhibited higher serum levels of clozapine, olanzapine, and risperidone (all p < 0.001) compared to the infection period, but there was no significant change in serum levels of aripiprazole and quetiapine. Multiple regression analysis revealed a statistically significant positive correlation (P < 0.0001) between CRP and clozapine concentration. In light of the COVID-19 pandemic, it is crucial to adjust the dosage based on drug serum concentration to prevent intoxication or adverse drug reactions.

Immune-Inflammatory Response And Compensatory Immune-Regulatory Reflex Systems And White Matter Integrity in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Low-grade neural and peripheral inflammation are among the proposed pathophysiological mechanisms of schizophrenia. White matter impairment is one of the more consistent findings in schizophrenia but the underlying mechanism remains obscure. Many cerebral white matter components are sensitive to neuroinflammatory conditions that can result in demyelination, altered oligodendrocyte differentiation, and other changes. We tested the hypothesis that altered immune-inflammatory response system (IRS) and compensatory immune-regulatory reflex system (IRS/CIRS) dynamics are associated with reduced white matter integrity in patients with schizophrenia. STUDY DESIGN: Patients with schizophrenia (SCZ, 70M/50F, age = 40.76 ±â€…13.10) and healthy controls (HCs, 38M/27F, age = 37.48 ±â€…12.31) underwent neuroimaging and plasma collection. A panel of cytokines were assessed using enzyme-linked immunosorbent assay. White matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging using a 3-T Prisma MRI scanner. The cytokines were used to generate 3 composite scores: IRS, CIRS, and IRS/CIRS ratio. STUDY RESULTS: The IRS/CIRS ratio in SCZ was significantly higher than that in HCs (P = .009). SCZ had a significantly lower whole-brain white matter average FA (P < .001), and genu of corpus callosum (GCC) was the most affected white matter tract and its FA was significantly associated with IRS/CIRS (r = 0.29, P = .002). FA of GCC was negatively associated with negative symptom scores in SCZ (r = -0.23, P = .016). There was no mediation effect taking FA of GCC as mediator, for that IRS/CIRS was not associated with negative symptom score significantly (P = .217) in SCZ. CONCLUSIONS: Elevated IRS/CIRS might partly account for the severity of negative symptoms through targeting the integrity of GCC.

Role of the immune-kynurenine pathway in treatment-resistant schizophrenia.

BACKGROUND: The immune-inflammatory response system (IRS) and kynurenine pathway (KP) have been implicated in the pathophysiology of schizophrenia. Studies have shown inflammation-related effects on KP metabolism in patients with schizophrenia. This study investigated the relationship between KP metabolites, IRS, and the compensatory immune-regulatory reflex system (CIRS) in patients with treatment-resistant schizophrenia (TRS). METHODS: Patients with (n = 53) and without TRS (n = 47), and healthy controls (HCs, n = 49) were enrolled. We quantified plasma levels of pro-inflammatory cytokines (interleukin [IL]-1ß, IL-2, IL-6, soluble(s)IL-6 receptor, IL-8, IL-12, IL-17, IL-18, interferon-γ, and tumor necrosis factor[TNF]-α) and anti-inflammatory cytokines (IL-1 receptor antagonist, IL-4, IL-10, tumor growth factor [TGF]-ß1, TGF-ß2, soluble (s) IL-2 receptor subunit α, sIL-2 receptor subunit ß, and sTNF-α receptor 1) and calculated the IRS/CIRS ratio. We also tested serum metabolites of the KP, including kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN), along with the QUIN/KYNA ratio. RESULTS: Patients with TRS had significantly higher IRS/CIRS ratio than non-TRS patients (p = 0.002) and HCs (p = 0.007), and significantly lower KYN (p = 0.001) and KYNA (p = 0.01) levels than HCs. Binary logistic regression analysis revealed that a younger age at illness onset (odds ratio [OR] = 0.91, p = 0.02) and a higher IRS/CIRS ratio (OR = 1.22; p = 0.007) were risk factors for patients with TRS. After further adjusted for age of onset, the QUIN/KYNA ratio (ß = 0.97; p = 0.02) significantly moderated the relationship between IRS/CIRS and TRS, showing that in the higher QUIN/KYNA condition, higher IRS/CIRS ratio were significantly and more likely to be associated with patients with TRS (ß = 0.12, z = 3.19, p = 0.001), whereas in the low QUIN/KYNA condition, the association between IRS/CIRS ratio and TRS was weak and insignificant. CONCLUSIONS: The peripheral immune response was imbalanced in TRS and was preferentially directed towards the IRS compared to patients without TRS and healthy controls, which is likely to play a role in neurotoxicity. Additionally, peripheral KP activation was also imbalanced, as evidenced by significantly reduced KYN and KYNA levels in patients with TRS compared to healthy controls, but none of KP metabolisms were significantly difference in non-TRS patients compared to healthy controls. QUIN/KYNA ratio involving to the degree of activation of NMDA receptors, indicated the neurotoxic level of the KP activation. The interaction between IRS/CIRS and QUIN/KYNA ratio was significant in predicting TRS, and our findings suggest a potential role for the immune-kynurenine pathway in TRS pathogenesis.

Correlation of Immune-Inflammatory Response System (IRS)/Compensatory Immune-Regulatory Reflex System (CIRS) with White Matter Integrity in First-Episode Patients with Schizophrenia.

Several studies have reported compromised white matter integrity, and that some inflammatory mediators may underlie this functional dysconnectivity in the brain of patients with schizophrenia. The immune-inflammatory response system and compensatory immune-regulatory reflex system (IRS/CIRS) are novel biomarkers for exploring the role of immune imbalance in the pathophysiological mechanism of schizophrenia. This study aimed to explore the little-known area regarding the composite score of peripheral cytokines, the IRS/CIRS, and its correlation with white matter integrity and the specific microstructures most affected in schizophrenia. First-episode patients with schizophrenia (FEPS, n = 94) and age- and sex-matched healthy controls (HCs, n = 50) were enrolled in this study. Plasma cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA), and psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). The whole brain white matter integrity was measured by fractional anisotropy (FA) from diffusion tensor imaging (DTI) using a 3-T Prisma MRI scanner. The IRS/CIRS in FEPS was significantly higher than that in HCs (p = 1.5 × 10-5) and Cohen's d effect size was d = 0.74. FEPS had a significantly lower whole-brain white matter average FA (p = 0.032), which was negatively associated with IRS/CIRS (p = 0.029, adjusting for age, sex, years of education, BMI, and total intracranial volume), but not in the HCs (p > 0.05). Among the white matter microstructures, only the cortico-spinal tract was significantly correlated with IRS/CIRS in FEPS (r = - 0.543, p = 0.0009). Therefore, elevated IRS/CIRS may affect the white matter in FEPS.

Inhibitory mechanism of quercetin on Alicyclobacillus acidoterrestris.

In this the antibacterial of quercetin against Alicyclobacillus acidoterrestris was evaluated by measuring the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Subsequently, the effect of quercetin on A. acidoterrestris cell membrane was evaluated through scanning electron microscopy (SEM), surface hydrophobicity determination, diacetate fluorescein staining and propidium iodide (PI) staining. Additionally, the effects of quercetin on intracellular macromolecules and cell metabolism were explored by measuring the culture medium protein, bacterial protein and intracellular sodium and potassium adenosine triphosphate (ATP) enzyme activity. The results revealed that quercetin exhibited the MIC and MBC values of 100 ug/mL and 400 ug/mL, respectively, against A. acidoterrestris. The SEM results revealed that quercetin could induce irreversible damage to the cell membrane effectively. Moreover, quercetin could enhance the surface hydrophobicity of A. acidoterrestris. The results of flow cytometry and fluorescence microscopy analyses revealed that quercetin could promote cell damage by altering the cell membrane permeability of A. acidoterrestris, inducing the release of nucleic acid substances from the cells. Furthermore, the determination of protein content in the culture medium, bacterial protein content, and the Na(+)/K(+)-ATPase activity demonstrated that quercetin could reduce the intracellular protein content and impedes protein expression and ATPase synthesis effectively, leading to apoptosis.

Regional Homogeneity in schizophrenia patients with tardive dyskinesia: a resting-state fMRI study.

Neuronal degeneration and apoptosis may play an important role in the pathogenesis of tardive dyskinesia (TD). Previous studies suggested brain structural and functional abnormalities in patients with TD. We investigated changes in cerebral regional homogeneity (ReHo) in patients with TD using resting-state functional magnetic resonance imaging (rs-fMRI). Imaging data were collected from schizophrenia patients with TD (TD group, n=58) and without TD (non-TD group, n=66) and healthy controls (HC group, n=67), processed with SPM, and evaluated at a corrected threshold. Psychopathology and severity of TD were assessed with the Positive and Negative Syndrome Scale (PANSS) and Abnormal Involuntary Movement Scale (AIMS), respectively. Results: TD vs. non-TD group showed significantly higher ReHo in the Left Inferior Semilunar Lobule and Right Fusiform Gyrus and lower ReHo in Left Supramarginal Gyrus, Right Inferior Tempotal Gyrus, and Left Medial Frontal Gyrus. The ReHo value in the Left Inferior Semilunar Lobule was negatively correlated with AIMS upper limbs scores. Conclusions: The findings suggest altered regional neural connectivities in association with TD and may inform research of the etiology and monitor the course of TD in patients with schizophrenia and potentially other psychotic disorders.

Orientational Order in Dense Colloidal Liquids and Glasses.

We construct structural order parameters based on local angular and radial distribution functions in dense colloidal suspensions. All the order parameters show significant correlations to local dynamics in the supercooled and glass regime. In particular, the correlations between the orientational order and dynamical heterogeneity are consistently higher than those between the conventional two-body structural entropy and local dynamics. The structure-dynamics correlations can be explained by a excitation model with the energy barrier depending on local structural order. Our results suggest that in dense disordered packings, local orientational order is higher than translational order, and plays a more important role in determining the dynamics in glassy systems.

CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages.

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility. METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology. RESULTS: FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05). CONCLUSION: Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

A New Contactless Cross-Correlation Velocity Measurement System for Gas-Liquid Two-Phase Flow.

Based on the principle of Contactless Conductivity Detection (CCD), a new contactless cross-correlation velocity measurement system with a three-electrode construction is developed in this work and applied to the contactless velocity measurement of gas-liquid two-phase flow in small channels. To achieve a compact design and to reduce the influence of the slug/bubble deformation and the relative position change on the velocity measurement, an electrode of the upstream sensor is reused as an electrode of the downstream sensor. Meanwhile, a switching unit is introduced to ensure the independence and consistency of the upstream sensor and the downstream sensor. To further improve the synchronization of the upstream sensor and the downstream sensor, fast switching and time compensation are also introduced. Finally, with the obtained upstream and downstream conductance signals, the velocity measurement is achieved by the principle of cross-correlation velocity measurement. To test the measurement performance of the developed system, experiments are carried out on a prototype with a small channel of 2.5 mm. The experimental results show that the compact design (three-electrode construction) is successful, and its measurement performance is satisfactory. The velocity range for the bubble flow is 0.312-0.816 m/s, and the maximum relative error of the flow rate measurement is 4.54%. The velocity range for the slug flow is 0.161 m/s-1.250 m/s, and the maximum relative error of the flow rate measurement is 3.70%.

Changes in Inflammatory Biomarkers in Patients with Schizophrenia: A 3-Year Retrospective Study.

Objective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators. Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors. Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05). Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.

ALKBH5/YTHDF2-mediated m6A modification of circAFF2 enhances radiosensitivity of colorectal cancer by inhibiting Cullin neddylation.

BACKGROUND: Circular RNA (circRNA) and N6-methyladenosine (m6A) play a critical role in tumour occurrence and development, including colorectal cancer (CRC). However, little is known about the interaction between circRNA and m6A in the radiosensitivity of CRC. Here, we investigated the role of a novel m6A-regulated circRNA in CRC. METHODS: Differentially expressed circRNAs from radiosensitive and radioresistant CRC tissues were screened. Modifications of the selected circRNAs were examined by methylated RNA immunoprecipitation assay. Finally, the selected circRNAs were subjected to radiosensitivity assay. RESULTS: We identified that circAFF2 is closely related to both radiosensitivity and m6A in CRC. CircAFF2 was highly expressed in patients with radiosensitive rectal cancer, and patients with high expression of circAFF2 had a better prognosis. In addition, circAFF2 can enhance the radiosensitivity of CRC cells both in vitro and in vivo. The regulation of circAFF2 involves ALKBH5-mediated demethylation, followed by its recognition and degradation via YTHDF2. Rescue experiments revealed that circAFF2 could reverse the radiosensitivity induced by ALKBH5 or YTHDF2. Mechanistically, circAFF2 binds with CAND1, promotes the binding of CAND1 to Cullin1 and inhibits its neddylation, subsequently impacting the radiosensitivity of CRC. CONCLUSION: We identified and characterised circAFF2 as a novel m6A-modified circRNA and validated the ALKBH5/YTHDF2/circAFF2/Cullin-NEDD8 axis as a potential radiotherapy target for CRC.

Short-term antipsychotic treatment response in early-onset, typical-onset, and late-onset first episode schizophrenia.

In schizophrenia, the age at illness onset may reflect genetic loading and predict prognosis. We aimed to compare the pre-treatment symptom profiles and clinical symptom responses to antipsychotic treatment of individuals with late-onset schizophrenia (LOS; onset age: 40-59 years) with individuals with early-onset schizophrenia (EOS; onset age < 18 years) or typical-onset schizophrenia (TOS; onset age: 18-39 years). We conducted an 8-week cohort study in inpatient departments of five mental health hospitals in five cities in China. We included 106 individuals with LOS, 80 with EOS, and 214 with TOS. Their onset of schizophrenia was within three years and the disorders were minimally treated. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate clinical symptoms at baseline and after 8 weeks of antipsychotic treatment. Mixed effect models were used to compare symptom improvement within eight weeks. Antipsychotic therapy reduced all PANSS factor scores in all three groups. LOS had significantly better improvement in PANSS positive factor scores than EOS at week 8 after adjusting for sex, duration of illness, dose equivalents of antipsychotics at baseline, sites as fixed effects, and individuals as random effects. LOS was associated with reduced positive factor scores at week 8 when receiving 1 mg olanzapine dose equivalent per 1 kg body weight compared with EOS or TOS. In conclusion, LOS had better early improvement of positive symptoms than EOS and TOS. Thus, personalized treatment for schizophrenia should consider the age of onset.

Inflammatory disequilibrium and lateral ventricular enlargement in treatment-resistant schizophrenia.

Treatment-resistant schizophrenia (TRS) patient respond poorly to antipsychotics. Inflammatory imbalance involving pro- and anti-inflammatory cytokines may play an important role in the mechanism of antipsychotic-medication response. This study aimed to investigate immune imbalance and how the latter relates to clinical manifestations in patients with TRS. The level of net inflammation was estimated by evaluating the immune-inflammatory response system and compensatory immune-regulatory reflex system (IRS/CIRS) in 52 patients with TRS, 47 with non-TRS, and 56 sex and age matched healthy controls. The immune biomarkers mainly included macrophagic M1, T helper, Th-1, Th-2, Th-17, and T regulatory cytokines and receptors. Plasma cytokine levels were measured using enzyme-linked immunosorbent assay. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Subcortical volumes were quantified using a 3-T Prisma Magnetic Resonance Imaging scanner. The results showed that (1) patients with TRS were characterized by activated pro-inflammatory cytokines and relatively insufficient anti-inflammatory cytokines, with an elevated IRS/CIRS ratio indicating a new homeostatic immune setpoint; (2) IRS/CIRS ratio was positively correlated with larger lateral ventricle volume and higher PANSS score in patients with TRS. Our findings highlighted the inflammatory disequilibrium as a potential pathophysiological process of TRS.

History of suicide attempt associated with amygdala and hippocampus changes among individuals with schizophrenia.

Abnormalities in subcortical brain structures may reflect higher suicide risk in mood disorders, but less is known about its associations for schizophrenia. This cross-sectional imaging study aimed to explore whether the history of suicide attempts was associated with subcortical changes among individuals with schizophrenia. We recruited 44 individuals with schizophrenia and a history of suicide attempts (SZ-SA) and 44 individuals with schizophrenia but without a history of suicide attempts (SZ-NSA) and 44 healthy controls. Linear regression showed that SZ-SA had smaller volumes of the hippocampus (Cohen's d = -0.72), the amygdala (Cohen's d = -0.69), and some nuclei of the amygdala (Cohen's d, -0.57 to -0.72) than SZ-NSA after adjusting for age, sex, illness phase, and intracranial volume. There was no difference in the volume of the subfields of the hippocampus. It suggests the history of suicide attempts is associated with subcortical volume alterations in schizophrenia.