Hyper-Exponential Stabilization of Neural Networks by Event-Triggered Impulsive Control With Actuation Delay.

This brief studies the hyper-exponential stabilization of neural networks (NNs) by event-triggered impulsive control, where the impulse instants are determined by the event-triggered conditions. In the presence of actuation delay, an event-triggered impulsive control scheme is devised. For reducing the sampling task of continuous detection, a periodic-detection scheme is also introduced. Within these frameworks, the occurrence of Zeno behavior is rigorously precluded, and some criteria are formulated to achieve the stabilization of the system with a hyper-exponential convergence rate. Moreover, a numerical simulation is provided to elucidate the validity of the theoretical findings.

Glutathione and acid dual-responsive bismuth-based nanosensitizer for chemo-mediated cancer sonodynamic therapy.

Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a crucial challenge. In this study, we synthesize and construct a glutathione (GSH) and acid dual-responsive bismuth-based nano-delivery platform (BOD), aiming for sonodynamic enhancement of docetaxel (DTX)-mediated tumor therapy. The bismuth nanomaterial can generate multiple reactive oxygen species under ultrasound stimulation. Furthermore, the loading of DTX to form BOD effectively reduces the toxicity of DTX in the bloodstream, ensuring its cytotoxic effect is predominantly exerted at the tumor site. DTX can be well released in high expression of GSH and acidic tumor microenvironment. Meanwhile, ultrasound can also promote the release of DTX. Results from bothin vitroandin vivoexperiments substantiate that the synergistic therapy involving chemotherapy and sonodynamic therapy significantly inhibits the growth and proliferation of tumor cells. This study provides a favorable paradigm for developing a synergistic tumor treatment platform for tumor microenvironment response and ultrasound-promoted drug release.

Insulin Resistance/Diabetes and Schizophrenia: Potential Shared Genetic Factors and Implications for Better Management of Patients with Schizophrenia.

Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause-effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators.

Contamination and health risks brought by arsenic, lead and cadmium in a water-soil-plant system nearby a non-ferrous metal mining area.

Heavy metal(loid)s contamination prevails in the water-soil-plant system around non-ferrous metal mining areas. The present study aimed to evaluate the heavy metal(loid)s contamination in Nandan Pb-Zn mining area (Guangxi, China). A total of 36 river water samples, 75 paired paddy soil and rice samples, and 128 paired upland soil and plant samples were collected from this area. The concentrations of arsenic (As), lead (Pb), and cadmium (Cd) in these samples were measured. Results showed that the average water quality indexes (WQIs) at the 12 sampling sites along the main river ranged from 41 to 5008, indicating the water qualities decreasing from "Excellent" to "Undrinkable". The WQIs nearby tailings or industrial park were significantly higher than those at the other sites. 34.0% and 64.5% of soil samples exceeded the risk screening values for As and Cd. The Pb and Cd concentrations in all rice samples exceeded the Chinese food safety limits by 18.7% and 82.7%, respectively. Leafy vegetables had a higher concentration of As, Pb, and Cd than other vegetables, exceeding the maximum permissible limits by 14.1%, 61.2%, and 40.0%, respectively. The biological accumulation coefficient (BAC) of Cd was the highest in rice and lettuce leaves. The hazard quotients (HQs) of As and Cd, indicating non-carcinogenic risks, were 4.15 and 1.76 in adult males, and 3.40 and 1.45 in adult females, all higher than the permitted level (1.0). The carcinogenic probabilities of As and Cd from rice and leafy vegetables consumption were all higher than 1 × 10-4. We conclude that metal(loid)s contamination of the water-soil-plant system has posed great non-carcinogenic and carcinogenic risks to the local population.

Validation of a modified Chinese-language version of the Davos Assessment of Cognitive Biases Scale (MCL-DACOBS) in a sample of Chinese patients with schizophrenia.

INTRODUCTION: The Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese-language version of the DACOBS (MCL-DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL-DACOBS. METHODS: Eighteen researchers collaborated to develop the MCL-DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native-English-speaking researcher back-translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL-DACOBS. Forty-two volunteers checked the scale items' comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL-DACOBS used in this study was thus derived from the harmonized English-language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL-DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL-DACOBS was assessed according to the area under the receiver operating characteristic curve. RESULTS: The CFA showed that all items loaded onto factors with loadings >0.400. A two-factor structure showed a good model fit (root mean square error of approximation = .018, Tucker-Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432-0.774). Cronbach's α coefficient and ICC for the MCL-DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability. CONCLUSION: The MCL-DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

Microglia and cognitive impairment in schizophrenia: translating scientific progress into novel therapeutic interventions.

Cognitive impairment is a core clinical feature of schizophrenia, exerting profound adverse effects on social functioning and quality of life in a large proportion of patients with schizophrenia. However, the mechanisms underlying the pathogenesis of schizophrenia-related cognitive impairment are not well understood. Microglia, the primary resident macrophages in the brain, have been shown to play important roles in psychiatric disorders, including schizophrenia. Increasing evidence has revealed excessive microglial activation in cognitive deficits related to a broad range of diseases and medical conditions. Relative to that about age-related cognitive deficits, current knowledge about the roles of microglia in cognitive impairment in neuropsychiatric disorders, such as schizophrenia, is limited, and such research is in its infancy. Thus, we conducted this review of the scientific literature with a focus on the role of microglia in schizophrenia-associated cognitive impairment, aiming to gain insight into the roles of microglial activation in the onset and progression of such impairment and to consider how scientific advances could be translated to preventive and therapeutic interventions. Research has demonstrated that microglia, especially those in the gray matter of the brain, are activated in schizophrenia. Upon activation, microglia release key proinflammatory cytokines and free radicals, which are well-recognized neurotoxic factors contributing to cognitive decline. Thus, we propose that the inhibition of microglial activation holds potential for the prevention and treatment of cognitive deficits in patients with schizophrenia. This review identifies potential targets for the development of new treatment strategies and eventually the improvement of care for these patients. It might also help psychologists and clinical investigators in planning future research.

Low-dose lithium adjunct to quetiapine improves cognitive task performance in mice with MK801-induced long-term cognitive impairment: Evidence from a pilot study.

BACKGROUND: Low-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment. METHODS: The present study used in vivo Ca2+ imaging and a battery of cognitive function assessments to investigate the long-term effects of LD-Li on cognition in mice exposed to repeated injections of MK801. Prefrontal Ca2+ activity was visualized to estimate alterations in neural activity in the model mice. Pre-pulse inhibition (PPI), novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FC) tasks were used to characterize cognitive performance; open field activity (OFA) testing was used to observe psychotic symptoms. Two treatment strategies were tested: LD-Li [250 mg/d human equivalent dose (HED)] adjunct to quetiapine (QTP; 600 mg/d HED); and QTP-monotherapy (mt; 600 mg/d HED). RESULTS: Compared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model. LIMITATIONS: There is no medical consensus regarding lithium use in patients with schizophrenia. CONCLUSION: More pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.

Validation and reliability test of Chinese language patient-reported impact of symptoms in schizophrenia scale.

Background: Patient-reported outcomes, or subjective evaluations directly reflecting the patient's views, feelings, and judgments, are now being used to evaluate the outcomes of care and treatment of people with schizophrenia. In this study, we used an updated tool, the patient-reported impact of symptoms in schizophrenia scale (PRISS), translated into Chinese languages to assess the subjective experiences of schizophrenia patients. Objective: This study aimed to test the psychometrics of the Chinese languages PRISS (CL-PRISS). Method: This study used the Chinese version of PRISS (CL-PRISS), acquired from the harmonized English-language version. A total of 280 patients enrolled in this study were asked to complete the CL-PRISS, the positive and negative syndrome scale (PANSS), and the World Health Organization Disability Assessment Schedule (WHO-DAS). Construct and concurrent validity was tested using the confirmatory factor analysis (CFA) and Spearman correlation coefficient, respectively. The reliability of CL-PRISS was tested using Cronbach's α coefficient and the internal correlation coefficient. Results: Confirmatory factor analysis (CFA) analysis demonstrated three major factors in CL_PRISS: the first factor is productive experiences, the second factor is affective-negative, and the third factor experiences. The factor loadings between items and factors ranged from 0.436 to 0.899 (RMSEA = 0.029, TLI = 0.940, CFI = 0.921). The correlation coefficient between the CL_PRISS and PANSS was 0.845, and between the CL-PRISS and WHO-DAS was 0.886. The ICC of the total CL_PRISS was 0.913, and Cronbach's α was 0.903. Conclusion: The Chinese version of the PRISS (CL_PRISS) can be effectively used for assessing the subjective experience of Chinese patients with schizophrenia.

Low-dose lithium mono- and adjunctive therapies improve MK-801-induced cognitive impairment and schizophrenia-like behavior in mice - Evidence from altered prefrontal lobe Ca2+ activity.

BACKGROUND: Few studies have evaluated lithium either as monotherapy or in combination with anti-psychotic agents to improve cognition in murine models of schizophrenia. METHODS: Visualization of Ca2+ activity in the prefrontal cortex was used to characterize brain neural activity. Novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FCT) tests were used to characterize cognitive performance; while pre-pulse inhibition (PPI), elevated plus maze (EPM) and the open field test (OFT) were used to characterize schizophrenia-like behavior. RESULTS: A 28-day course of low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) improved Ca2+ ratio by 70.10 %, PPI by 69.28 %, NOR by 70.09 %, MWM by 71.28 %, FCT by 68.56 %, EPM by 70.95 % and OFT by 75.23 % compared to the results of positive controls. Unexpectedly, moderate-dose lithium (human equivalent dose of 500 mg/day) used either as monotherapy or as an adjunct with quetiapine worsened Ca2+ activity, PPI, MWM, FCT, EPM, and OPT. LIMITATIONS: Our study cannot explain the contrasting positive and negative effects of low-dose and moderate-dose lithium, respectively, when used either as monotherapies or as adjuncts. Further studies, especially Western blotting, may reveal molecular mechanisms of action. CONCLUSIONS: Low-dose lithium (human equivalent dose of 250 mg/day) combined with moderate-dose quetiapine (human equivalent dose of 600 mg/day) provided the best improvements. Furthermore, benefits persisted for 14 days post-treatment. Our data provide directions for further research of therapeutic alternatives to mitigate schizophrenia-related cognopathy.

Recent advances in stimuli-responsive nano-heterojunctions for tumor therapy.

Stimuli-responsive catalytic therapy based on nano-catalysts has attracted much attention in the field of biomedicine for tumor therapy, due to its excellent and unique properties. However, the complex tumor microenvironment conditions and the rapid charge recombination in the catalyst limit catalytic therapy's effectiveness and further development. Effective heterojunction nanomaterials are constructed to address these problems to improve catalytic performance. Specifically, on the one hand, the band gap of the material is adjusted through the heterojunction structure to promote the charge separation efficiency under exogenous stimulation and further improve the catalytic capacity. On the other hand, the construction of a heterojunction structure can not only preserve the function of the original catalyst but also achieve significantly enhanced synergistic therapy ability. This review summarized the construction and functions of stimuli-responsive heterojunction nanomaterials under the excitation of X-rays, visible-near infrared light, and ultrasound in recent years, and further introduces their application in cancer therapy. Hopefully, the summary of stimuli-responsive heterojunction nanomaterials' applications will help researchers promote the development of nanomaterials in cancer therapy.

Disrupted chromatin architecture in olfactory sensory neurons: looking for the link from COVID-19 infection to anosmia.

We tackle here genomic mechanisms of a rapid onset and recovery from anosmia-a potential diagnostic indicator for early-stage COVID-19 infection. Based on previous observations on how olfactory receptor (OR) gene expression is regulated via chromatin structure in mice, we hypothesized that the disruption of the OR gene expression and, respectively, deficiency of the OR function can be caused by chromatin reorganization taking place upon SARS-CoV-2 infection. We obtained chromatin ensemble reconstructions from COVID-19 patients and control samples using our original computational framework for the whole-genome 3D chromatin ensemble reconstruction. Specifically, we used megabase-scale structural units and effective interactions between them obtained in the Markov State modelling of the Hi-C contact network as an unput in the stochastic embedding procedure of the whole-genome 3D chromatin ensemble reconstruction. We have also developed here a new procedure for analyzing fine structural hierarchy with (sub)TAD-size units in local chromatin regions, which we apply here to parts of chromosomes containing OR genes and corresponding regulatory elements. We observed structural modifications in COVID-19 patients on different levels of chromatin organization, from the alteration of whole genome structure and chromosomal intermingling to reorganization of contacts between chromatin loops at the level of topologically associating domains. While complementary data on known regulatory elements point to potential pathology-associated changes within the overall picture of chromatin alterations, further investigation using additional epigenetic factors mapped on 3D reconstructions with improved resolution will be required for better understanding of anosmia caused by SARS-CoV-2 infection.

Validity and reliability of a Chinese version of the self-evaluation of negative symptoms.

The negative symptoms of schizophrenia can be present at any clinical stage, but evaluating the negative symptoms always remains challenging. To screen the negative symptoms effectively, self-evaluation should be introduced. To date, professional psychiatrists used almost all of the scales available to screen the negative symptoms but could not obtain an accurate outcome. At the same time, an advanced self-assessment scale is needed to accompany the patients' self-feeling-based treatment strategies to understand their feelings about their symptoms. Hence, Chinese self-evaluation of negative symptoms (SNS) should be introduced in China. This study aims to examine the validity and reliability of the Chinese version of SNS. Two hundred patients with schizophrenia were included in this study and were evaluated entirely with the self-assessed negative symptoms by the Chinese version. The correlation analysis was performed between SNS and the Scale for Assessment of Negative Symptoms (SANS) to assess the criterion validity of SNS for screening negative symptoms. Exploratory factor analysis was used to determine the constructive validity of the SNS. Two senior professional psychiatrists were involved in this assessment based on their clinical experience and capability to define the severity of the negative symptoms. Receiver operating characteristic curve (ROC) analysis was performed to assess the cutoff point of SNS. Cronbach's alpha coefficient and intraclass correlation (ICC) coefficient were used to determine the reliability of SNS. We have the following findings: The Chinese version of SNS demonstrated a significant correlation with the SANS (r = .774, p < .05). Exploratory factor analysis demonstrated that the factor loading varies from .442 to .788. ROC analysis demonstrated that at SNS ≥ 8, the patients demonstrated a mild severity of negative symptoms, and at SNS ≥ 15, the patients demonstrated a severe severity of negative symptoms. Subsequently, 9 < SNS < 14 was defined as a moderate severity of negative symptoms. The Cronbach's alpha and ICC coefficients of the Chinese version SNS were .877 and .774, respectively. Our results showed that the acceptable validity and reliability of the Chinese version of SNS confirmed that SNS is an ideal tool for self-assessment of the negative symptoms in patients with schizophrenia.

Protoporphyrin-sensitized degradable bismuth nanoformulations for enhanced sonodynamic oncotherapy.

Decreasing the scavenging capacity of reactive oxygen species (ROS) and enhancing ROS production are the two principal objectives in the development of novel sonosensitizers for sonodynamic therapy (SDT). Herein, we designed a protoporphyrin-sensitized bismuth-based semiconductor (P-NBOF) as a sonosensitizer to generate ROS and synergistically depleted glutathione for enhanced SDT against tumors. The bismuth-based nanomaterial (NBOF) is a wide-bandgap semiconductor. Sensitization by protoporphyrin made it easier to excite electrons under ultrasonic stimulation, and the energy of the lowest unoccupied electron orbital in protoporphyrin was higher than the conduction-band energy of NBOF. Under ultrasound excitation, the excited electrons in the protoporphyrin were injected into the conduction band of the NBOF, increasing its reducing ability leading to the production of more superoxide anion radicals and also helping to increase the charge separation of protoporphyrin leading to the production of more singlet oxygen. Meanwhile, P-NBOF continuously depleted glutathione, which was not only conducive to breaking the redox balance of the tumor microenvironment to enhance the therapeutic efficacy of SDT, but also promoted its degradation and metabolism. The construction of this P-NBOF sonosensitizer thus provided an effective strategy to enhance SDT for tumors. STATEMENT OF SIGNIFICANCE: To enhance the efficacy of sonodynamic tumor therapy, we developed a degradable protoporphyrin-sensitized bismuth-based nano-semiconductor (P-NBOF) by optimizing the band structure and glutathione-depletion ability. Protoporphyrin in P-NBOF under excitation preferentially generates free electrons, which are then injected into the conduction band of NBOF, improving the reducing ability of NBOF and promoting the separation of electron-hole pairs, thereby enhancing the production capacity of reactive oxygen species. Furthermore, P-NBOF can deplete glutathione, reduce the scavenging of reactive oxygen species, and reactivate and amplify the effect of sonodynamic therapy. The construction of the nanotherapeutic platform provides an option for enhancing sonodynamic therapy.

Risk-to-befit ratios of consecutive antidepressants for heavy menstrual bleeding in young women with bipolar disorder or major depressive disorder.

The occurrence of heavy menstrual bleeding (HMB) induced by pharmacological agents has been reported in young adult women. This study aimed to investigate a possible association between the occurrence rates of HMB and different treatment methods such as antidepressant agents alone and in combination with other pharmacological agents. The examined cohort included young women (age 18-35 years, n = 1,949) with bipolar disorder (BP) or major depressive disorder (MDD). Menstruation history for 24 months was recorded and evaluated according to pictorial blood loss assessment charts of HMB. Multivariate analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals. The examined antidepressant agents had varying ORs for patients with BP vs. those with MDD. For example, the ORs of venlafaxine-induced HMB were 5.27 and 4.58 for patients with BP and MDD, respectively; duloxetine-induced HMB, 4.72 and 3.98; mirtazapine-induced HMB, 3.26 and 2.39; fluvoxamine-induced HMB, 3.11 and 2.08; fluoxetine-induced HMB, 2.45 and 1.13; citalopram-induced HMB, 2.03 and 1.25; escitalopram-induced HMB, 1.85 and 1.99; agomelatine-induced HMB, 1.45 and 2.97; paroxetine-induced HMB, 1.19 and 1.75; sertraline-induced HMB, 0.88 and 1.13; reboxetine-induced HMB, 0.45 and 0.45; and bupropion-induced HMB, 0.33 and 0.37, in each case. However, when antidepressant agents were combined with valproate, the OR of HMB greatly increased, with distinct profiles observed for patients with BP vs. those with MDD. For example, the ORs of HMB induced by venlafaxine combined with valproate were 8.48 and 6.70 for patients with BP and MDD, respectively; for duloxetine, 5.40 and 4.40; mirtazapine, 5.67 and 3.73; fluvoxamine, 5.27 and 3.37; fluoxetine, 3.69 and 4.30; citalopram, 5.88 and 3.46; escitalopram, 6.00 and 7.55; agomelatine, 4.26 and 5.65; paroxetine, 5.24 and 3.25; sertraline, 4.97 and 5.11; reboxetine, 3.54 and 2.19; and bupropion, 4.85 and 3.46, in each case. In conclusion, some antidepressant agents exhibited potential risks of inducing HMB. Therefore, a combined prescription of antidepressant agents and valproate should be carefully considered for young women with HMB.

Higher benefit-risk ratio of COVID-19 vaccination in patients with schizophrenia and major depressive disorder versus patients with bipolar disorder when compared to controls.

Patients with major psychiatric disorders (MPD) that include schizophrenia (SCH), bipolar disorder (BP), and major depressive disorder (MDD) are at increased risk for coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccines in MPD patients have not been fully evaluated. This study aimed to investigate adverse events (AEs)/side effects and efficacy of COVID-19 vaccines in MPD patients. This retrospective study included 2034 patients with SCH, BP, or MDD who voluntarily received either BBIBP-CorV or Sinovac COVID-19 vaccines, and 2034 matched healthy controls. The incidence of AEs/side effects and the efficacy of COIVD-19 vaccinations among the two groups were compared. The risk ratio (RR) of side effects in patients with MPD was 0.60 (95% confidence interval [CI]: 0.53-0.68) after the first dose and 0.80 (95% CI: 0.65-0.99) following the second dose, suggesting a significantly lower risk in the MPD group versus healthy controls. The RRs of AEs did not differ between patients and controls. Notably, fully vaccinated patients exhibited a decreased risk of influenza with or without fever compared with controls (RR=0.38, 95% CI: 0.31-0.46; RR=0.23, 95% CI: 0.17-0.30; respectively). Further subgroup comparisons revealed a significantly lower risk of influenza with fever in MDD (RR=0.13, 95% CI: 0.08-0.21) and SCH (RR=0.24, 95% CI: 0.17-0.34) than BP (RR=0.85, 95% CI: 0.69-1.06) compared to controls. We conclude that the benefit-risk ratio of COVID-19 vaccination was more favorable in SCH or MDD versus BP when compared with controls. These data indicate that COVID-19 vaccines are safe and protective in patients with MPD from COVID-19.

Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target.

Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.

Proposed protocol for the investigation of the safety and efficacy of the COVID-19 vaccine for patients with psychosis, with pilot safety findings from a Chinese psychiatrist's self-experiment.

We present a study protocol designed to test the safety and efficacy of the 2019 coronavirus disease (COVID-19) vaccine in patients with major psychotic disease. A secondary objective is to investigate optional vaccination methods for these patients. In a self-experiment, a Chinese psychiatrist examined the safety and efficacy of the COVID-19 vaccine under clinical use of typical antipsychotic agents and sedatives (olanzapine, duloxetine, and diazepam). For patients with extremely drug-resistant conditions, the safety of the COVID-19 vaccine under electroconvulsive therapy was also investigated. The entire study process was recorded on high-definition video. This clinical study protocol is, to our knowledge, the first of its kind. Our findings will shed new light on the protection of patients with psychotic diseases from COVID-19 infection. The protocol was registered at Chinese clinical trial registry (www.chictr.org.cn, ChiCTR2100051297).

Calcium imaging reveals depressive- and manic-phase-specific brain neural activity patterns in a murine model of bipolar disorder: a pilot study.

Brain pathological features during manic/hypomanic and depressive episodes in the same patients with bipolar disorder (BPD) have not been described precisely. The study aimed to investigate depressive and manic-phase-specific brain neural activity patterns of BPD in the same murine model to provide information guiding investigation of the mechanism of phase switching and tailored prevention and treatment for patients with BPD. In vivo two-photon imaging was used to observe brain activity alterations in the depressive and manic phases in the same murine model of BPD. Two-photon imaging showed significantly reduced Ca2+ activity in temporal cortex pyramidal neurons in the depression phase in mice exposed to chronic unpredictable mild stress (CUMS), but not in the manic phase in mice exposed to CUMS and ketamine. Total integrated calcium values correlated significantly with immobility times. Brain Ca2+ hypoactivity was observed in the depression and manic phases in the same mice exposed to CUMS and ketamine relative to naïve controls. The novel object recognition preference ratio correlated negatively with the immobility time in the depression phase and the total distance traveled in the manic phase. With recognition of its limitations, this study revealed brain neural activity impairment indicating that intrinsic emotional network disturbance is a mechanism of BPD and that brain neural activity is associated with cognitive impairment in the depressive and manic phases of this disorder. These findings are consistent with those from macro-imaging studies of patients with BPD. The observed correlation of brain neural activity with the severity of depressive, but not manic, symptoms need to be investigated further.

[Effects of Human Immunodeficiency Virus-positive Mothers Receiving Antiretroviral Therapy to Prevent Mother-to-child Transmission on the Growth and Development of 18-month-old Children in Lingshan County of Guangxi].

Objective To evaluate the effects of antiretroviral therapy(ART)for the prevention of mother-to-child transmission(PMTCT)of acquired immune deficiency syndrome(AIDS)on the growth and development of 18-month-old children born by human immunodeficiency virus(HIV)-positive pregnant women in Lingshan County,Guangxi Zhuang Autonomous Region,and provide scientific evidence for improving the ART medication plan for PMTCT.Methods Lingshan County,ranking the first in the HIV-epidemic counties of Guangxi,was selected as the research site.According to the design of retrospective case-control study,we assigned all the subjects into the case group and the control group:(1)The case group included the HIV-positive pregnant women who had received ART for PMTCT and their HIV-negative infants in Lingshan County from 2010 to 2017.The historical cards and PMTCT data of them were collected from the national PMTCT database.(2)The control group included the healthy pregnant women and their healthy babies born in the Lingshan Maternity and Infant Hospital in 2017,and the children's growth and development data were collected.The stunted growth in children was defined as at least one of the three main indicators of body height,body weight,and head circumference below the normal range.Results The number of HIV-positive mothers and their infants in the case group was 391 and 368,respectively,and 87.21%(341/391)and 95.38%(351/368)of mothers and infants respectively received ART medication.The HIV positive rate,mortality rate,and mother-to-child transmission rate of 18-month-old children were 1.36%(5/368),4.35%(16/368),and 2.01%(5/249),respectively.The incidence of stunted growth of 18-month-old children in the case group and the control group was 42.12%(155/368)and 23.06%(101/438),respectively,with significant difference(χ2=33.520,P<0.001).Conclusion After HIV-positive mothers in Lingshan County of Guangxi received ART for PMTCT,the incidence of growth stunting in 18-month-old children increased.

Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice.

Mild behavioral impairment (MBI), which can include compulsive behavior, is an early sign of Alzheimer's disease (AD), but its underlying neural mechanisms remain unclear. Here, we show that 3-5-month-old APP/PS1 mice display obsessive-compulsive disorder (OCD)-like behavior. The number of parvalbumin-positive (PV) interneurons and level of high gamma (γhigh) oscillation are significantly decreased in the striatum of AD mice. This is accompanied by enhanced ß-γhigh coupling and firing rates of putative striatal projection neurons (SPNs), indicating decorrelation between PV interneurons and SPNs. Local field potentials (LFPs) simultaneously recorded in prefrontal cortex (PFC) and striatum (Str) demonstrate a decrease in γhigh-band coherent activity and spike-field coherence in corticostriatal circuits of APP/PS1 mice. Furthermore, levels of GABAB receptor (GABABR), but not GABAA receptor (GABAAR), and glutamatergic receptors, were markedly reduced, in line with presymptomatic AD-related behavioral changes. These findings suggest that MBI occurs as early as 3-5 months in APP/PS1 mice and that altered corticostriatal synchronization may play a role in mediating the behavioral phenotypes observed.