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.

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.

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.

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.

Subcortical structures associated with childhood trauma and perceived stress in schizophrenia.

BACKGROUND: Childhood trauma influences the clinical features of schizophrenia. In this study, we examined how childhood trauma and perceived stress are associated with clinical manifestations and subcortical gray matter volumes (GMVs) in patients with schizophrenia. METHODS: We recruited 127 patients with schizophrenia and 83 healthy controls for assessment of early childhood trauma, perceived stress, and clinical symptoms. With structural brain imaging, we identified the GMVs of subcortical structures and examined the relationships between childhood trauma, perceived stress, clinical symptoms, and subcortical GMVs. RESULTS: Compared to controls, patients with schizophrenia showed higher levels of childhood trauma and perceived stress. Patients with schizophrenia showed significantly smaller amygdala and hippocampus GMVs as well as total cortical GMVs than age-matched controls. Childhood trauma score was significantly correlated with the severity of clinical symptoms, depression, perceived stress, and amygdala GMVs. Perceived stress was significantly correlated with clinical symptoms, depression, and hippocampus and amygdala GMVs. Further, the association between childhood trauma (emotional neglect) and stress coping ability was mediated by right amygdala GMV in patients with schizophrenia. CONCLUSIONS: Patients with schizophrenia had more exposure to early-life trauma and poorer stress coping. Both childhood trauma and perceived stress were associated with smaller amygdala volumes. The relationship between early-life trauma and perceived stress was mediated by right amygdala GMV in patients with schizophrenia. These findings together suggest the long-term effects of childhood trauma on perceived stress and the subcortical volumetric correlates of the effects in schizophrenia.

Circular RNA circ-AGFG1 contributes to esophageal squamous cell carcinoma progression and glutamine catabolism by targeting microRNA-497-5p/solute carrier family 1 member 5 axis.

Circular RNAs (circRNAs) have been shown to play important regulatory roles in human malignancies. However, the role of circRNA ArfGAP with FG repeats 1 (circ-AGFG1) in esophageal squamous cell carcinoma (ESCC) progression and its associated mechanism are still largely undefined. Cell proliferation was analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-ethynyl-2'-deoxyuridine assay. Cell apoptosis was assessed by flow cytometry analysis. Transwell assay and wound healing assay were used to analyze cell invasion and migration abilities. The uptake of glutamine and the production of α-ketoglutarate and glutamate were analyzed using Glutamine Determination Kit, α-ketoglutarate Assay Kit and Glutamate Determination Kit. A xenograft tumor model was used to analyze the biological role of circ-AGFG1 in vivo . The interaction between microRNA-497-5p (miR-497-5p) and circ-AGFG1 or solute carrier family 1 member 5 (SLC1A5) was verified by dual-luciferase reporter assay. Circ-AGFG1 expression was upregulated in ESCC tissues and cell lines. Circ-AGFG1 silencing suppressed the proliferation, migration, invasion and glutaminolysis and triggered the apoptosis of ESCC cells. Circ-AGFG1 knockdown significantly slowed down tumor growth in vivo . Circ-AGFG1 acted as a sponge for miR-497-5p, and miR-497-5p interacted with the 3' untranslated region (3'UTR) of SLC1A5. miR-497-5p silencing largely abolished circ-AGFG1 silencing-induced effects in ESCC cells. miR-497-5p overexpression-mediated influences in ESCC cells were largely reversed by the addition of SLC1A5 expressing plasmid. Circ-AGFG1 could upregulate SLC1A5 expression by sponging miR-497-5p. In summary, circ-AGFG1 acted as an oncogene to elevate the malignant potential and promote the glutamine catabolism of ESCC cells by targeting the miR-497-5p/SLC1A5 axis.

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.

Association of cortical thickness and cognition with schizophrenia treatment resistance.

AIM: Approximately a third of patients with schizophrenia fail to adequately respond to antipsychotic medications, a condition known as treatment resistance (TR). We aimed to assess cognitive and cortical thickness deficits and their relationship to TR in schizophrenia. METHOD: We recruited patients with schizophrenia (n = 127), including patients at treatment initiation (n = 45), treatment-responsive patients (n = 40) and TR patients (n = 42), and healthy controls (n = 83). Clinical symptoms, neurocognitive function, and structural images were assessed. We performed group comparisons, and explored association of cortical thickness and cognition with TR. RESULTS: The TR patients showed significantly more severe clinical symptoms and cognitive impairment relative to the treatment-responsive group. Compared to healthy controls, 56 of 68 brain regions showed significantly reduced cortical thickness in patients with schizophrenia. Reductions in five regions were significantly associated with TR (reduction in TR relative to treatment-responsive patients), i.e. in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cognition deficits were also significantly correlated with cortical thickness in these five regions in patients with schizophrenia. Cortical thickness of the right caudal middle frontal gyrus, superior frontal cortex and pars opercularis of the inferior frontal cortex also significantly mediated effects of cognitive deficits on TR. CONCLUSION: Treatment resistance in schizophrenia was associated with reduced thickness in the right caudal middle frontal gyrus, superior frontal cortex, fusiform gyrus, pars opercularis of the inferior frontal cortex, and supramarginal cortex. Cortical abnormalities further mediate cognitive deficits known to be associated with TR.

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%.

Translating ENIGMA schizophrenia findings using the regional vulnerability index: Association with cognition, symptoms, and disease trajectory.

Patients with schizophrenia have patterns of brain deficits including reduced cortical thickness, subcortical gray matter volumes, and cerebral white matter integrity. We proposed the regional vulnerability index (RVI) to translate the results of Enhancing Neuro Imaging Genetics Meta-Analysis studies to the individual level. We calculated RVIs for cortical, subcortical, and white matter measurements and a multimodality RVI. We evaluated RVI as a measure sensitive to schizophrenia-specific neuroanatomical deficits and symptoms and studied the timeline of deficit formations in: early (≤5 years since diagnosis, N = 45, age = 28.8 ± 8.5); intermediate (6-20 years, N = 30, age 43.3 ± 8.6); and chronic (21+ years, N = 44, age = 52.5 ± 5.2) patients and healthy controls (N = 76, age = 38.6 ± 12.4). All RVIs were significantly elevated in patients compared to controls, with the multimodal RVI showing the largest effect size, followed by cortical, white matter and subcortical RVIs (d = 1.57, 1.23, 1.09, and 0.61, all p < 10-6 ). Multimodal RVI was significantly correlated with multiple cognitive variables including measures of visual learning, working memory and the total score of the MATRICS consensus cognitive battery, and with negative symptoms. The multimodality and white matter RVIs were significantly elevated in the intermediate and chronic versus early diagnosis group, consistent with ongoing progression. Cortical RVI was stable in the three disease-duration groups, suggesting neurodevelopmental origins of cortical deficits. In summary, neuroanatomical deficits in schizophrenia affect the entire brain; the heterochronicity of their appearance indicates both the neurodevelopmental and progressive nature of this illness. These deficit patterns may be useful for early diagnosis and as quantitative targets for more effective treatment strategies aiming to alter these neuroanatomical deficit patterns.

Functional disconnection between subsystems of the default mode network in schizophrenia.

BACKGROUND: A dysfunctional default mode network (DMN) has been reported in patients with schizophrenia. However, the stability of the deficits has not been determined across different stages of the disorder. METHODS: We examined the functional connectivity of the DMN subsystems of 125 patients with first-episode schizophrenia (FES) or recurrent schizophrenia (RES), compared to that of 82 healthy controls. We tested the robustness of the findings in an independent cohort of 158 patients and 39 healthy controls. We performed resting-state functional connectivity analysis, and examined the strength of the connections within and between the three subsystems of the DMN (core, dorsal medial prefrontal cortex [dMPFC], and medial temporal lobe [MTL]). We also analyzed the connectivity correlations to symptoms and illness duration. RESULTS: We found reduced connectivity strength between the core and MTL subsystems in schizophrenia patients compared to controls, with no differences between the FES and RES patient groups; these findings were validated in the second sample. Schizophrenia patients also showed a significant reduction in connectivity within the MTL and between the dMPFC-MTL subsystems, similarly between FES and RES groups. The connectivity strength within the core subsystem was negatively correlated with clinical symptoms in schizophrenia. There was no significant correlation between the DMN subsystem connectivity and illness duration. CONCLUSIONS: DMN subsystem connectivity deficits are present in schizophrenia, and the homochronicity of their appearance indicates the trait-like nature of these alterations. The DMN deficit may be useful for early diagnosis, and MTL dysfunction may be a crucial mechanism underlying schizophrenia.

Elevated salivary kynurenic acid levels related to enlarged choroid plexus and severity of clinical phenotypes in treatment-resistant schizophrenia.

Patients with treatment-resistant schizophrenia (TRS) suffer severe, long-term psychotic symptoms and chronic stress. Salivary kynurenic acid (KYNA) and choroid plexus were evidenced to relate to psychological stress. We hypothesized that TRS patients would have higher salivary KYNA levels than patients who respond to antipsychotics (NTRS) and healthy controls (HC), and increased salivary KYNA levels are associated with clinical phenotypes and choroid plexus volume. A total of 66 HC participants, 53 patients with TRS and 46 with NTRS were enrolled. Salivary KYNA levels were measured by liquid chromatography-tandem mass spectrometry, choroid plexus volume by magnetic resonance imaging, and cognitive functions with the MATRICS Consensus Cognitive Battery. The TRS group had significantly higher salivary KYNA levels than the NTRS group (p = 0.003), who in turn had higher salivary KYNA than HC (p = 0.02). Higher salivary KYNA levels were associated with larger choroid plexus volume (r = 0.48, p = 0.004); lower attention/vigilance (r = -0.44, p = 0.004), verbal learning (r = -0.44, p = 0.004), total MCCB score (r = -0.42, p = 0.005); and a higher total PANSS score (r = 0.48, p = 0.004) in TRS patients. An enlarged choroid plexus also related to worse attention/vigilance (r = -0.39, p = 0.03), verbal learning (r = -0.55, p = 0.001), total MCCB score (r = -0.41, p = 0.02) and clinical symptoms (r = 0.48, p = 0.004) in TRS patients only. We conclude that elevated salivary KYNA levels and associated choroid plexus enlargement are clinically relevant indicators of TRS, with salivary KYNA being particularly valuable as a peripheral marker. Our findings should benefit TRS research and benefit the improvement of personalized treatment.

Genome-wide DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia in the Chinese Han population.

Schizophrenia is a severe neuropsychiatric disorder with core features including hallucinations, delusions, and cognition deficits. Accumulating evidence has implicated abnormal DNA methylation in the development of schizophrenia. However, the mechanisms by which DNA methylation changes alter the risk for schizophrenia remain largely unknown. We recently carried out a DNA methylome study of peripheral blood samples from 469 first-episode patients with schizophrenia and 476 age- and gender-matched healthy controls of Han Chinese origin. Genomic DNA methylation patterns were quantified using an Illumina Infinium Human MethylationEPIC BeadChip. We identified multiple differentially methylated positions (DMPs) and regions between patients and controls. The most significant DMPs were annotated to genes C17orf53, THAP1 and KCNQ4 (KV7.4), with Bonferroni-adjusted P values of [Formula: see text], [Formula: see text], and [Formula: see text], respectively. In particular, KCNQ4 encodes a voltage-gated potassium channel of the KV7 family, which is linked to neuronal excitability. The genes associated with top-ranked DMPs also included many genes involved in nervous system development, such as LIMK2 and TMOD2. Gene ontology analysis of the differentially methylated genes further identified strong enrichment of neuronal networks, including neuron projection extension, axonogenesis and neuron apoptotic process. Finally, we provided evidence that schizophrenia-associated epigenetic alterations co-localize with genetic susceptibility loci. By focusing on first-episode schizophrenia patients, our investigation lends particularly strong support for an important role of DNA methylation in schizophrenia pathogenesis unconfounded by the effects of long-term antipsychotic medication or disease progression. The observed DNA methylation aberrations in schizophrenia patients could potentially provide a valuable resource for identifying diagnostic biomarkers and developing novel therapeutic targets to benefit schizophrenia patients.

Childhood trauma and cognitive deficits in patients with schizophrenia: mediation by orbitofrontal cortex H-shaped sulci volume.

BACKGROUND: A line of evidence has shown that childhood trauma and patterns of H-shaped sulci in the orbitofrontal cortex (OFC) are associated with cognitive deficits in patients with schizophrenia. Studies have also suggested that childhood trauma is associated with OFC volumetrics. This study investigated the interrelationship between childhood trauma, OFC H-shaped sulci volume and cognitive function in patients with first-episode schizophrenia. We hypothesized that OFC H-shaped sulci volume would mediate the relationship between childhood trauma and cognitive function in patients with first-episode schizophrenia. METHODS: We recruited patients with first-episode schizophrenia (n = 63) and healthy controls (n = 48), and quantified OFC H-shaped sulci volumes with 3.0 T high-resolution MRI. We assessed cognitive function and childhood trauma experiences using the MATRICS Consensus Cognitive Battery (MCCB) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Patients with first-episode schizophrenia had smaller left OFC H-shaped sulci volumes, more severe childhood trauma experiences and worse cognitive function than healthy controls. CTQ total score and emotional and physical neglect subscores were negatively correlated with left OFC H-shaped sulci volume. CTQ total score and emotional neglect and sexual abuse subscores were negatively correlated with cognitive function in patients with first-episode schizophrenia. Interestingly, the CTQ total score and physical neglect subscore were positively correlated with cognitive function in healthy controls. Left OFC H-shaped sulci volume played a mediating role in CTQ emotional neglect subscore, CTQ total score and MCCB composite score. LIMITATIONS: The small sample size and retrospective design need to be considered. CONCLUSION: Childhood trauma might contribute to cognitive deficits in patients with first-episode schizophrenia by affecting left OFC H-shaped sulci volume. This finding can help in the design of strategies to improve cognitive function in patients with first-episode schizophrenia.

TGF-ß1 is associated with deficits in cognition and cerebral cortical thickness in first-episode schizophrenia.

BACKGROUND: Evidence indicates that cytokines are associated with cognitive deficits in schizophrenia; however, the underlying brain-behaviour mechanisms remain unclear. We hypothesized that aberrations in brain structural connectivity mediate the cytokine effect in schizophrenia. METHODS: In this study, we recruited patients with first-episode schizophrenia (n = 75, average illness duration 12.3 months, average medication period 0.6 days) and healthy controls (n = 44) of both sexes. We first conducted whole-blood RNA sequencing to detect differentially expressed genes. We also explored transcriptomic data on the dorsal lateral prefrontal cortices (dlPFC) retrieved from the CommonMind Consortium for gene functional clustering; we measured plasma transforming growth factor ß1 (TGF-ß1) levels by enzyme-linked immunosorbent assay; we acquired high-resolution T 1-weighted MRI data on cortical thickness MRI; and we assessed cognitive function using the validated Chinese version of the MATRICS Consensus Cognitive Battery. We compared these parameters in patients with schizophrenia and controls, and analyzed their associations. RESULTS: Patients with schizophrenia had higher TGF-ß1 at both the mRNA level (log2 fold change = 0.24; adjusted p = 0.026) and the protein level (12.85 ± 6.01 µg/mL v. 8.46 ± 5.15 µg/mL, adjusted p < 0.001) compared to controls. Genes coexpressed with TGFB1 in the dlPFC were less abundant in patients with schizophrenia compared to healthy controls. In patients with schizophrenia, TGF-ß1 protein levels were inversely correlated with cortical thickness, especially of the lateral occipital cortex (r = -0.47, adjusted p = 0.001), and with the MATRICS Consensus Cognitive Battery visual learning and memory domain (r = -0.50, adjusted p < 0.001). We found a complete mediation effect of the thickness of the lateral occipital cortex on the negative relationship between TGF-ß1 and visual cognition (p < 0.05). LIMITATIONS: We did not explore the effect of other blood cytokines on neurocognitive performance and cortical thickness. Participants from the CommonMind Consortium did not all have first-episode schizophrenia and they were not all antipsychotic-naive, so we could not exclude an effect of antipsychotics on TGF-ß1 signalling in the dlPFC. The sample size and cross-sectional design of our study were additional limitations. CONCLUSION: These findings highlighted an association between upregulated blood levels of TGF-ß1 and impairments in brain structure and function in schizophrenia.

Computational screening of single transition-metal atoms anchored to g-C9N4 as catalysts for N2 reduction to NH3.

The electrocatalytic nitrogen reduction reaction (NRR) is considered to be the most desirable strategy for ammonia production but still faces many challenges in terms of high activity and high selectivity. Based on density functional theory (DFT) calculations, the catalytic performance of a series of (3d, 4d and 5d series) transition metals atoms (TMs) anchored on a novel graphitic carbon-nitrogen (g-C9N4) monolayer has been systematically investigated. We find that TMs can bind tightly to g-C9N4 and form single-atom catalysts (SACs) with high thermodynamic stability. The four candidates, Nb, Ta, W and Re@g-C9N4, not only exhibit high NRR catalytic activity but also effectively inhibit the competitive HER. Among them, Nb@g-C9N4 is the most promising NRR catalyst with a lowest limiting potential of -0.21 V. The optimal reaction path for Nb, W and Re@g-C9N4 is via the enzymatic mechanism, while Ta@g-C9N4 tends to be through the distal mechanism. In addition, the decomposition potential of the g-C9N4 monolayer is higher than the limiting potential of all four SACs, ensuring the feasibility of the experimental implementation. This work identifies efficient NRR catalysts and provides a feasible screening scheme.

Engineering an oilseed crop for hyper-accumulation of carotenoids in the seeds without using a traditional marker gene.

KEY MESSAGE: Ketocarotenoids were synthesized successfully in Camelina sativa seeds by genetic modification without using a traditional selection marker genes. This method provided an interesting tool for metabolic engineering of seed crops. Camelina sativa (L.) Crantz is an important oil crop with many excellent agronomic traits. This model oil plant has been exploited to accumulate value-added bioproducts using genetic manipulation that depends on antibiotic- or herbicide-based selection marker genes (SMG), one of the major concerns for genetically modified foods. Here we reported metabolic engineering of C. sativa to synthesize red ketocarotenoids that could serve as a reporter to visualize transgenic events without using a traditional SMG. Overexpression of a non-native ß-carotene ketolase gene coupled with three other carotenogenous genes (phytoene synthase, ß-carotene hydroxylase, and Orange) in C. sativa resulted in production of red seeds that were visibly distinguishable from the normal yellow ones. Constitutive expression of the transgenes led to delayed plant development and seed germination. In contrast, seed-specific transformants demonstrated normal growth and seed germination despite the accumulation of up to 70-fold the level of carotenoids in the seeds compared to the controls, including significant amounts of astaxanthin and keto-lutein. As a result, the transgenic seed oils exhibited much higher antioxidant activity. No significant changes were found in the profiles of fatty acids between transgenic and control seeds. This study provided an interesting tool for metabolic engineering of seed crops without using a disputed SMG.

Palovarotene inhibits the NF-κB signalling pathway to prevent heterotopic ossification.

Heterotopic ossification (HO) is a common disease characterized by pain, dysfunction and calcification. The mechanisms underlying HO have not been completely elucidated. Palovarotene, a retinoic acid receptor γ agonist, significantly inhibits the formation of HO in vivo. However, its specific mechanism of action remains unclear. Therefore, we aimed to evaluate the signalling pathways related to the formation of HO as well as the mechanism of palovarotene action. We constructed in vitro and in vivo models of HO. Osteogenic differentiation of bone mesenchymal stem cells (BMSCs) was observed by alizarin red and alkaline phosphatase staining assays in vitro. X-ray and haematoxylin-eosin staining were performed in vivo. Western blots and reverse transcription-polymerase chain reaction were performed to determine the levels of osteogenic- and inflammation-related genes. Immunofluorescence and immunocytochemistry were used to assess the levels of p65, the core molecule of the nuclear factor κ-B (NF-κB) signalling pathway. We demonstrated that, in vitro, under inflammatory stimulation, pathological calcium deposition increased in BMSCs. The levels of osteogenesis- and inflammation-related genes were also upregulated, along with an enhanced expression of p65. Immunofluorescence assays revealed that p65 entered the nucleus, thereby stimulating the downstream effectors of the NF-κB pathway. The above trends were reversed after palovarotene treatment. In conclusion, the NF-κB signalling pathway played an important role in HO, and palovarotene could alleviate HO by blocking the NF-κB cascade. Our results may provide a theoretical basis for palovarotene in the treatment of HO. Further studies on the side effects of palovarotene are warranted in the future.

The mediating effect of brain-derived neurotrophic factor levels on childhood trauma and psychiatric symptoms in patients with first-episode schizophrenia.

BACKGROUND: Previous studies have implicated childhood trauma and abnormal brain-derived neurotrophic factor in the pathogenesis of schizophrenia. Here, we explored whether brain-derived neurotrophic factor levels mediated the relationship between childhood trauma and psychopathological symptoms in patients with first-episode schizophrenia. METHODS: Patients with first-episode schizophrenia (n = 192) and healthy controls (n = 136) were enrolled. Childhood traumatic experiences and psychopathology were assessed by Childhood Trauma Questionnaire and Positive and Negative Syndrome Scale, respectively. Enzyme-linked immunosorbent assay was used to quantify brain-derived neurotrophic factor levels. RESULTS: The patients with first-episode schizophrenia experienced more severe childhood trauma and had lower serum brain-derived neurotrophic factor levels than healthy controls. Emotional abuse and Childhood Trauma Questionnaire total score showed positive correlation with Positive and Negative Syndrome Scale positive, general psychopathological subscore and total score. Emotional neglect showed positive correlation with Positive and Negative Syndrome Scale positive subscore. Physical neglect was positively associated with Positive and Negative Syndrome Scale negative subscore. Emotional neglect and Childhood Trauma Questionnaire total score were negatively correlated with serum brain-derived neurotrophic factor levels. The serum brain-derived neurotrophic factor levels mediated the relationship between both Childhood Trauma Questionnaire total score and Positive and Negative Syndrome Scale total score and negative symptoms in the patients. The brain-derived neurotrophic factor levels also mediated the relationship between emotional neglect and Positive and Negative Syndrome Scale total score in the patients. CONCLUSION: Childhood trauma might contribute to the clinical symptoms of schizophrenia by affecting brain-derived neurotrophic factor levels. Perhaps we can prevent schizophrenia by reducing childhood traumatic experiences.

Developing a Chromochloris zofingiensis Mutant for Enhanced Production of Lutein under CO2 Aeration.

Microalgae are competitive and commercial sources for health-benefit carotenoids. In this study, a Chromochloris zofingiensis mutant (Cz-pkg), which does not shut off its photosystem and stays green upon glucose treatment, was generated and characterized. Cz-pkg was developed by treating the algal cells with a chemical mutagen as N-methyl-N'-nitro-N-nitrosoguanidine and followed by a color-based colony screening approach. Cz-pkg was found to contain a dysfunctional cGMP-dependent protein kinase (PKG). By cultivated with CO2 aeration under mixotrophy, the mutant accumulated lutein up to 31.93 ± 1.91 mg L-1 with a productivity of 10.57 ± 0.73 mg L-1 day-1, which were about 2.5- and 8.5-fold of its mother strain. Besides, the lutein content of Cz-pkg could reach 7.73 ± 0.52 mg g-1 of dry weight, which is much higher than that of marigold flower, the most common commercial source of lutein. Transcriptomic analysis revealed that in the mutant Cz-pkg, most of the genes involved in the biosynthesis of lutein and chlorophylls were not down-regulated upon glucose addition, suggesting that PKG may regulate the metabolisms of photosynthetic pigments. This study demonstrated that Cz-pkg could serve as a promising strain for both lutein production and glucose sensing study.