Multiplex proteomics identifies inflammation-related plasma biomarkers for aging and cardio-metabolic disorders.

BACKGROUND: Cardio-metabolic disorders (CMDs) are common in aging people and are pivotal risk factors for cardiovascular diseases (CVDs). Inflammation is involved in the pathogenesis of CVDs and aging, but the underlying inflammatory molecular phenotypes in CMDs and aging are still unknown. METHOD: We utilized multiple proteomics to detect 368 inflammatory proteins in the plasma of 30 subjects, including healthy young individuals, healthy elderly individuals, and elderly individuals with CMDs, by Proximity Extension Assay technology (PEA, O-link). Protein-protein interaction (PPI) network and functional modules were constructed to explore hub proteins in differentially expressed proteins (DEPs). The correlation between proteins and clinical traits of CMDs was analyzed and diagnostic value for CMDs of proteins was evaluated by ROC curve analysis. RESULT: Our results revealed that there were 161 DEPs (adjusted p < 0.05) in normal aging and EGF was the most differentially expressed hub protein in normal aging. Twenty-eight DEPs were found in elderly individuals with CMDs and MMP1 was the most differentially expressed hub protein in CMDs. After the intersection of DEPs in aging and CMDs, there were 10 overlapping proteins: SHMT1, MVK, EGLN1, SLC39A5, NCF2, CXCL6, IRAK4, REG4, PTPN6, and PRDX5. These proteins were significantly correlated with the level of HDL-C, TG, or FPG in plasma. They were verified to have good diagnostic value for CMDs in aging with an AUC > 0.7. Among these, EGLN1, NCF2, REG4, and SLC39A2 were prominently increased both in normal aging and aging with CMDs. CONCLUSION: Our results could reveal molecular markers for normal aging and CMDs, which need to be further expanded the sample size and to be further investigated to predict their significance for CVDs.

Brain-derived neurotrophic factor gene polymorphism affects cognitive function and neurofilament light chain level in patients with subcortical ischaemic vascular dementia.

Objective: To investigate the effects of brain-derived neurotrophic factor (BDNF) gene polymorphism on cognitive function, neuroimaging and blood biological markers in patients with subcortical ischaemic vascular dementia (SIVD). Methods: A total of 81 patients with SIVD were included. According to their BDNF gene polymorphism, the participants were divided into the Val/Val (n = 26), Val/Met (n = 35), and Met/Met (n = 20) groups. A comprehensive neuropsychological evaluation and multimodal brain MRI scan were performed. MRI markers for small vessel disease were visually rated or quantitatively analysed. Moreover, 52 patients were further evaluated with blood marker assays, including amyloid beta (Aß), phosphorylated tau at threonine-181 (P-tau181), glial fibrillary acidic protein (GFAP), total tau (T-tau) and neurofilament light chain (NfL). Results: There were no significant differences in demographics, disease duration or MRI markers of small vessel disease between the three groups. Compared with the Val/Val and Val/Met groups, the Met/Met group showed worse performance in the verbal fluency test and higher levels of plasma NfL. Conclusion: The rs6265 polymorphism of the BDNF gene is associated with semantic language fluency in patients with SIVD. The Met genotype may be a risk factor for cognitive impairment and neuronal injury.

Neurofilament Light Protein Predicts Disease Progression in Idiopathic REM Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is increasingly recognized as a manifestation preceding the α-synucleinopathies like Parkinson's disease (PD). Neurofilament light chain (NfL) have been reported to be higher in synucleinopathies as a sign of neurodegeneration. OBJECTIVE: To evaluate whether plasma NfL is valuable in reflecting cognitive and motor status in iRBD and PD with a premorbid history of RBD (PDRBD), and predicting disease progression in iRBD. METHODS: Thirty-one patients with iRBD, 30 with PDRBD, and 18 healthy controls were included in the cross-sectional and prospective study. Another cohort from the Parkinson's Progression Markers Initiative (PPMI) dataset was enrolled for verification analysis. All patients received evaluations of cognitive, motor, and autonomic function by a battery of clinical tests at baseline and follow-up. Blood NfL was measured by the Quanterix Simoa HD-1. RESULTS: In our cohort, 26 patients with iRBD completed the follow-up evaluations, among whom eight (30.8%) patients displayed phenoconversion. Baseline plasma NfL cutoff value of 22.93 pg/mL performed best in distinguishing the iRBD converters from non-converters (sensitivity: 75.0%, specificity: 83.3%, area under the curve: 0.84). Cognitive and motor function were significantly correlated with NfL levels in PDRBD (correlation coefficients: -0.379, 0.399; respectively). Higher baseline NfL levels in iRBD were significantly associated with higher risks for cognitive, motor, autonomic function progression, and phenoconversion at follow-up (hazard ratios: 1.069, 1.065, 1.170, 1.065; respectively). The findings were supported by the PPMI dataset. CONCLUSION: Plasma NfL is valuable in reflecting disease severity of PDRBD and predicting disease progression and phenoconversion in iRBD.

Reference intervals for plasma amyloid-ß, total tau, and phosphorylated tau181 in healthy elderly Chinese individuals without cognitive impairment.

BACKGROUND: Plasma amyloid-ß (Aß) peptides and tau proteins are promising biomarkers of Alzheimer's disease (AD), not only for predicting Aß and tau pathology but also for differentiating AD from other neurodegenerative diseases. However, reference intervals for plasma biomarkers of AD in healthy elderly Chinese individuals have not yet been established. METHODS: Biomarkers of AD were measured using single-molecule array (Simoa) assays in plasma samples from 193 healthy, cognitively unimpaired Chinese individuals aged 50-89 years. The 95% reference intervals for plasma Aß42, Aß40, t-tau, p-tau181, and derived ratios were calculated by using log-transformed parametric methods. RESULTS: Plasma Aß42, Aß40, and p-tau181 levels were positively correlated with age, while the Aß42/Aß40 ratio was negatively correlated with age. The 95% reference intervals for plasma Aß42 and Aß40 were 2.72-11.09 pg/mL and 61.4-303.9 pg/mL, respectively, and the 95% reference intervals for plasma t-tau and p-tau181 were 0.20-3.12 pg/mL and 0.49-3.29 pg/mL, respectively. The 95% reference intervals for the Aß42/Aß40 ratio, p-tau181/t-tau ratio, and p-tau181/Aß42 ratio were 0.022-0.064, 0.38-6.34, and 0.05-0.55, respectively. CONCLUSION: Reference intervals for plasma biomarkers of AD may assist clinicians in making accurate clinical decisions.

Plasma Neurofilament Light Chain Predicts Mortality and Long-Term Neurological Outcomes in Patients with Intracerebral Hemorrhage.

Patients with intracerebral hemorrhage (ICH) often suffer from heterogeneous long-term neurological deficits, such as cognitive decline. Our ability to measure secondary brain injury to predict the long-term outcomes of these patients is limited. We investigated whether the blood neurofilament light chain (NfL) can monitor brain injury and predict long-term outcomes in patients with ICH. We enrolled 300 patients with first-episode ICH within 24 h recruited in the Chinese Cerebral Hemorrhage Mechanisms and Intervention study cohort from January 2019 to June 2020. Patients were prospectively followed up for 12 months. Blood samples were collected from 153 healthy participants. Plasma NfL levels determined using a single-molecule array revealed a biphasic increase in plasma NfL in ICH patients compared to healthy controls, with the first peak at around 24 h and a second elevation from day 7 through day 14 post-ICH. Plasma NfL levels were positively correlated with hemorrhage volume, National Institute of Health Stroke Scale, and Glasgow Coma Scale scores of ICH patients. Higher NfL concentration within 72 h after ictus was independently associated with 6- and 12-month worsened functional outcomes (modified Rankin Scale ≥ 3) and higher all-cause mortality. Magnetic resonance imaging and cognitive function evaluation were available for 26 patients at 6 months post-ICH, and NfL levels measured 7 days post-ictus correlated with decreased white matter fiber integrity and poor cognitive function at 6 months after stroke. These findings suggest that blood NfL is a sensitive marker for monitoring axonal injury post-ICH and can predict long-term functional ability and survival.

Supported photocatalyst for Cr (VI) conversion and removal of organic pollutants.

The photocatalytic property of available semiconductor catalysts still suffers from some urgent problems, such as the high excitation energy, easy agglomeration of powders, or weak recycling property. Therefore, developing novel visible light-supported catalysts and catalyst loading have aroused great attention recently. In this work, a novel Ag3PO4/BiVO4/MWCNTs@Cotton functional fabric was prepared by introducing Ag3PO4 as a plasma resonance photocatalyst and MWCNTs with cotton as composite substrates. Not only did the introduction of Ag3PO4 and MWCNTs effectively strengthen the application ability of BiVO4, but also inhibited the recombination of carriers, and promoted the transport of carriers according to spectroscopic and electrochemical tests. Degradation tests remained that Ag3PO4/BiVO4/MWCNTs @cotton retained the high photocatalytic efficiency of the powder catalyst, along with the degradation degree of active blue KN-R (50mg/L) as well as Cr (VI) (20mg/L) could reach more than 90% within 120 min. What's more, the functional fabric has gained excellent performance in degrading pollutants for 5 cycles. Meanwhile, the prepared BiVO4 is consistent with the band structure and electron density calculated theoretically by the GGA-PBE function. Free radical trapping and scavenging experiments exhibited that functional fabrics could produce active substances such as h+,·O2-, and·OH, among which the first two are the main active substances in the reaction. To sum up, this study is an effective attempt based on the existing problems of photocatalysts together with providing some study directions for the development of photocatalytic technology in the future.

Transgenerational male reproductive effect of prenatal arsenic exposure: abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse.

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. We treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that F0 transient exposure to arsenic can cause decreased sperm quality and histological abnormalities in the F1 and F3. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly increased in both F1 and F3. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

Longitudinal treatment responsiveness on plasma neurofilament light chain and glial fibrillary acidic protein levels in neuromyelitis optica spectrum disorder.

BACKGROUND: Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood. OBJECTIVE: To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD. METHODS: pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab (n = 29), rituximab (n = 23), oral prednisone (n = 16), and oral azathioprine or mycophenolate mofetil (n = 4). RESULTS: NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2-39.3) versus 11.5 (7.0-23.3) pg/mL; p = 0.001; pGFAP, 149.7 (88.6-406.5) versus 68.7 (59.4-80.8) pg/mL; p < 0.001). Multivariable regression analyses indicated that baseline pNfL concentration was associated with age (p = 0.017), Expanded Disability Status Scale (EDSS) score (p = 0.002), and recent relapses (p < 0.001). Baseline pGFAP concentration was also associated with EDSS (p < 0.001) and recent relapses (p < 0.001). Compared with prednisone, tocilizumab and rituximab significantly reduced pNfL [tocilizumab, exp(ß), 0.65; 95% confidence interval (CI), 0.56-0.75; p < 0.001; rituximab, exp(ß), 0.79; 95% CI = 0.68-0.93; p = 0.005] and pGFAP levels [tocilizumab, exp(ß), 0.64; 95% CI, 0.51-0.80; p < 0.001; rituximab, exp(ß), 0.77; 95% CI, 0.61-0.98; p = 0.041] at the end of the study. The pNfL levels in the tocilizumab and rituximab groups were reduced to those of HCs [tocilizumab, 8.5 (7.06-17.90) pg/mL; p = 0.426; rituximab, 14.0 (9.94-21.80) pg/mL; p = 0.216]. However, the pGFAP levels did not decrease to those of HCs in NMOSD patients at the end of study [tocilizumab, 88.9 (63.4-131.8) pg/mL; p = 0.012; rituximab, 141.7 (90.8-192.7) pg/mL; p < 0.001]. CONCLUSION: pNfL and pGFAP may serve as biomarkers for NMOSD disease activity and treatment effects.

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains.

The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.

Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders.

OBJECTIVE: Disease-modifying drugs (DMDs) may alter the immune status and thus increase the susceptibility to coronavirus disease 2019 (COVID-19) in patients with MS or neuromyelitis optica spectrum disorders (NMOSD). However, evidence supporting this notion is currently lacking. In this study, we conducted a survey on the risk of COVID-19 in patients with MS and NMOSD. METHODS: The survey was conducted through the Chinese Medical Network for Neuroinflammation. Patients in 10 MS centers from 8 cities including Wuhan were included. Information about MS and NMOSD disease duration and the usage of DMDs were collected. Data of suspected cases of COVID-19 were obtained from hospital visits, questionnaires, and patient self-reporting. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was confirmed through clinical evaluation by a panel of experts in conjunction with chest CT and viral RNA detection. RESULTS: Eight hundred eighty-two of 1,804 (48.89%) patients with MS and 2,129 of 3,060 (69.58%) patients with NMOSD were receiving DMDs. There were no alterations in the patients' DMD regimen during January 15, 2020, to March 15, 2020, the 3-month period. None of the patients with MS treated with DMDs had COVID-19. However, 2 patients with relapsing NMOSD were diagnosed with COVID-19-related pneumonia. After treatment, both patients recovered from pneumonia and neither patient experienced new attacks due to predisposing SARS-CoV-2 infection in the following 2 months. CONCLUSIONS: No increased risk of COVID-19 infection was observed in patients with MS or NMOSD, irrespective of whether these patients received DMDs. A battery of stringent preventive measures adopted by neurologists to reduce COVID-19 infection in these patients may have contributed to low risk of COVID-19 infection.

Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study.

BACKGROUND: Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission, but the incidence of MG in China is unknown. We conducted the first nationwide study to determine the incidence and mortality rates of MG in all age groups at the national level in China. METHODS: This national population-based registry study is based on the database of the Hospital Quality Monitoring System of National Health Commission, which covers 1665 hospitals providing myasthenia gravis care in 31 provinces and municipalities across China. 94,638 hospital admissions for 59,243 myasthenia gravis patients were identified from January 1st, 2016 to December 31st, 2018. Myasthenia gravis was identified by ICD-10 codes (G70). Incidence of myasthenia gravis was stratified by age, sex, and province. FINDINGS: Of 59,243 patients, 30,503 individuals with myasthenia gravis were newly diagnosed. Age and sex adjusted incidence of myasthenia gravis was 0.68 per 100,000 person-years, with highest in the age group of 70-74 years. The incidence in females was 0.76 per 100,000 and 0.60 per 100,000 in males. The admission mortality rate was 14.69‰. Respiratory failure was the leading cause of death in patients with myasthenic crisis. There were 14,840 patients with thymomas, encompassing 14,636 (26.5%) adults and 204 (7.1%) juveniles. 9453 (63.7%) patients with thymomas underwent thymomectomy. The median length of hospital stay was 8 days (interquartile range (IQR) 4 to 15 days) with median hospitalization cost $1037 (IQR $493 to $2925). The Basic Medical Insurance was the most common payment method, covering 67.4% of patients. INTERPRETATION: The age and sex adjusted incidence of MG was 0.68 per 100,000 person-years in China. The admission mortality rate was 14.69‰. Most cases of new onset MG occurred in the seventh decade of life. FUNDING: National Science Foundation of China (91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing.

Maternal exposure to TCDD during gestation advanced sensory-motor development, but induced impairments of spatial learning and memory in adult male rat offspring.

2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) is an endocrine disrupting chemical (EDC) with high persistency. Even a low amount can pass the placental barrier during gestational exposure. Exposure to TCDD exposure can impair the development of the nervous system in children, leading to impaired learning ability in later-life. But the changes in neurobehavioral developments in infancy and childhood caused by TCDD are unknown. Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8-14 (GD 8-14) as the prenatal TCDD exposure model. In the offspring, early neurobehavioral development was assessed at postnatal day 5 (PND5) and eye-opening was monitored from PND10 onwards. Adult male offspring was tested by Morris Water Maze for spatial memory and learning ability evaluation. Hippocampus Nissl's staining and astrocyte GFAP immunohistochemistry were used to evaluate the activity of astrocytes. The results of the behavioral tests showed that gestational TCDD exposure induced premature motor activity and earlier eyes-opening, but lead to serious deficits of spatial memory and learning ability in the adult male offspring. Morphology and number of neurons in the hippocampus CA1 region was not affected, while the activity of astrocytes in the same region was significantly reduced. These data indicate that perinatal TCDD exposure induced premature neurobehavioral development but impaired the spatial learning and memory in adult male rat offspring. The decreased activity of astrocytes in the hippocampus may play a role in these adverse effects.

Association between VEGF-460T/C gene polymorphism and clinical outcomes of nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a critical role in the development, metastasis, and recurrence of tumors. This study aims to determine the correlation of single-nucleotide polymorphisms in the VEGF gene with the prognosis of nasopharyngeal carcinoma (NPC). The VEGF -460T/C gene polymorphisms in the genomic DNA of the blood samples of 338 patients with NPC were investigated through polymerase chain reaction and direct DNA sequencing. Results showed a significant association between the -460C-allele carriers and the aggressive forms of NPC as defined by stages N2-3 (odds ratio =1.820, 95% confidence interval [CI]: 1.118-2.962, P=0.015). Furthermore, the VEGF -460T/C polymorphism was significantly associated with 3-year overall survival (OS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) (T/C + C/C vs T/T: 3-year OS 78.8% vs 95.1%, P=0.003; 3-year DMFS 80.2% vs 90.6%, P=0.036; 3-year PFS 73.9% vs 86.7%, P=0.042) but was not associated with the local recurrence-free survival (LRFS) of the patients. The multivariate analysis indicated that the VEGF -460C-allele carrier was an independent significant prognostic factor for OS (hazard ratio [HR] 4.096, 95% CI: 1.333-12.591, P=0.014). N classification was an independent significant prognostic factor for DMFS in patients with locoregionally advanced NPC (HR 3.674, 95% CI: 1.144-11.792, P=0.029). However, neoadjuvant chemotherapy (NACT) followed by concurrent chemoradiotherapy (CCRT) was not superior to CCRT alone in terms of the 3-year OS, LRFS, DMFS, and PFS of patients with VEGF -460T/C polymorphism. In conclusion, the VEGF -460T/C gene polymorphism may negatively affect the clinical outcomes of patients with NPC and may be considered a potential prognostic factor for this disease.

Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity.

Catechol-O-methyltransferase (COMT) modulates dopamine levels in the prefrontal cortex. The human gene contains a polymorphism (Val158Met) that alters enzyme activity and influences PFC function. It has also been linked with cognition and anxiety, but the findings are mixed. We therefore developed a novel mouse model of altered COMT activity. The human Met allele was introduced into the native mouse COMT gene to produce COMT-Met mice, which were compared with their wild-type littermates. The model proved highly specific: COMT-Met mice had reductions in COMT abundance and activity, compared with wild-type mice, explicitly in the absence of off-target changes in the expression of other genes. Despite robust alterations in dopamine metabolism, we found only subtle changes on certain cognitive tasks under baseline conditions (eg, increased spatial novelty preference in COMT-Met mice vs wild-type mice). However, genotype differences emerged after administration of the COMT inhibitor tolcapone: performance of wild-type mice, but not COMT-Met mice, was improved on the 5-choice serial reaction time task after tolcapone administration. There were no changes in anxiety-related behaviors in the tests that we used. Our findings are convergent with human studies of the Val158Met polymorphism, and suggest that COMT's effects are most prominent when the dopamine system is challenged. Finally, they demonstrate the importance of considering COMT genotype when examining the therapeutic potential of COMT inhibitors.

Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model.

UNLABELLED: Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory-inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development. SIGNIFICANCE STATEMENT: Schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory-inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia.

KCNH2-3.1 expression impairs cognition and alters neuronal function in a model of molecular pathology associated with schizophrenia.

Overexpression in humans of KCNH2-3.1, which encodes a primate-specific and brain-selective isoform of the human ether-a-go-go-related potassium channel, is associated with impaired cognition, inefficient neural processing and schizophrenia. Here, we describe a new mouse model that incorporates the KCNH2-3.1 molecular phenotype. KCNH2-3.1 transgenic mice are viable and display normal sensorimotor behaviors. However, they show alterations in neuronal structure and microcircuit function in the hippocampus and prefrontal cortex, areas affected in schizophrenia. Specifically, in slice preparations from the CA1 region of the hippocampus, KCNH2-3.1 transgenic mice have fewer mature dendrites and impaired theta burst stimulation long-term potentiation. Abnormal neuronal firing patterns characteristic of the fast deactivation kinetics of the KCNH2-3.1 isoform were also observed in prefrontal cortex. Transgenic mice showed significant deficits in a hippocampal-dependent object location task and a prefrontal cortex-dependent T-maze working memory task. Interestingly, the hippocampal-dependent alterations were not present in juvenile transgenic mice, suggesting a developmental trajectory to the phenotype. Suppressing KCNH2-3.1 expression in adult mice rescues both the behavioral and physiological phenotypes. These data provide insight into the mechanism of association of KCNH2-3.1 with variation in human cognition and neuronal physiology and may explain its role in schizophrenia.

Ancestral TCDD exposure promotes epigenetic transgenerational inheritance of imprinted gene Igf2: Methylation status and DNMTs.

Ancestral TCDD exposure could induce epigenetic transgenerational phenotypes, which may be mediated in part by imprinted gene inheritance. The aim of our study was to evaluate the transgenerational effects of ancestral TCDD exposure on the imprinted gene insulin-like growth factor-2 (Igf2) in rat somatic tissue. TCDD was administered daily by oral gavage to groups of F0 pregnant SD rats at dose levels of 0 (control), 200 or 800 ng/kg bw during gestation day 8-14. Animal transgenerational model of ancestral exposure to TCDD was carefully built, avoiding sibling inbreeding. Hepatic Igf2 expression of the TCDD male progeny was decreased concomitantly with hepatic damage and increased activities of serum hepatic enzymes both in the F1 and F3 generation. Imprinted Control Region (ICR) of Igf2 manifested a hypermethylated pattern, whereas methylation status in the Differentially Methylated Region 2 (DMR2) showed a hypomethylated manner in the F1 generation. These epigenetic alterations in these two regions maintained similar trends in the F3 generation. Meanwhile, the expressions of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) changed in a non-monotonic manner both in the F1 and F3 generation. This study provides evidence that ancestral TCDD exposure may promote epigenetic transgenerational alterations of imprinted gene Igf2 in adult somatic tissue.

Psychological distress and dyslipidemia in chinese police officers: a 4-year follow-up study in Tianjin, China.

OBJECTIVE: This study aimed at investigating whether psychological distress in police officers was associated with dyslipidemia. METHODS: A survey was conducted to examine the psychological distress among 5867 police officers in Tianjin, China, from 2007 to 2011. Psychological distress was measured using the Symptom Check List-90-Revised. Cox proportional hazard regression was used to calculate the hazard ratios (HR) of the incidence of dyslipidemia predicted by psychological distress. RESULTS: Among the 3300 participants without dyslipidemia at baseline (2567 with dyslipidemia), 60.5% (n = 1829) developed incident dyslipidemia 2.61 years (median) later. The adjusted HR was 1.15 (95% confidence interval, 1.05 to 1.26) after the adjustment of police classifications and other variables. The adjusted HR for police officers in charge of traffic control was 1.30 (95% confidence interval, 1.09 to 1.56). CONCLUSIONS: Further investigations for associations of psychological factors with dyslipidemia and cardiovascular diseases are needed.

Levels of PCDDs, PCDFs and dl-PCBs in the blood of childbearing-aged women living in the vicinity of a chemical plant in Tianjin: a primary study.

Several studies have suggested that maternal exposure to Polychlorinated dibenzo-p-dioxins (PCDDs), poly-chlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (PCBs) may affect foetal growth and infant development. The aim of our study was to determine whether the childbearing-aged residents living near a chemical plant have a greater exposure risk. Concentrations of 17 PCDD/Fs congeners and 12 non-ortho and mono-ortho dioxin-like PCBs were measured using HRGC-HRMS in the blood of 30 non-occupational childbearing-aged women living near a chemical plant (Dagu) that had been producing chlorinated pesticides from 1958 to 2004. The factors that influenced the body burden were investigated based on responses to a questionnaire. Levels of PCDD/Fs+PCBs were in the range of 16.43-155.29pg WHO 2005-TEQg(-1) lipid. PCDDs and PCDFs contributed 56.72% and 34.44%, respectively, to the total TEQ value. Total WHO-TEQ was approximately tenfold higher in the participants living in the vicinity of the plant (distance: 1.52±0.148km) than in the groups living farther away (distance: 4.93±1.124km). A negative correlation between total WHO-TEQ and distance to Dagu was observed by multiple linear regression models. The data provide basic information for monitoring dioxin-like chemicals in the district and for the future study of the relationship between POPs and pregnancy outcomes.