Network-based protein-protein interaction prediction method maps perturbations of cancer interactome.

The perturbations of protein-protein interactions (PPIs) were found to be the main cause of cancer. Previous PPI prediction methods which were trained with non-disease general PPI data were not compatible to map the PPI network in cancer. Therefore, we established a novel cancer specific PPI prediction method dubbed NECARE, which was based on relational graph convolutional network (R-GCN) with knowledge-based features. It achieved the best performance with a Matthews correlation coefficient (MCC) = 0.84±0.03 and an F1 = 91±2% compared with other methods. With NECARE, we mapped the cancer interactome atlas and revealed that the perturbations of PPIs were enriched on 1362 genes, which were named cancer hub genes. Those genes were found to over-represent with mutations occurring at protein-macromolecules binding interfaces. Furthermore, over 56% of cancer treatment-related genes belonged to hub genes and they were significantly related to the prognosis of 32 types of cancers. Finally, by coimmunoprecipitation, we confirmed that the NECARE prediction method was highly reliable with a 90% accuracy. Overall, we provided the novel network-based cancer protein-protein interaction prediction method and mapped the perturbation of cancer interactome. NECARE is available at: https://github.com/JiajunQiu/NECARE.

NDUFA4 promotes the progression of head and neck paraganglioma by inhibiting ferroptosis.

NDUFA4 is a component of respiratory chain-oxidative phosphorylation pathway. NDUFA4 is highly expressed in tumor tissues, but little is known about the function of NDUFA4 in head and neck paraganglioma (HNPGL). We examined NDUFA4 expression in tissues from 10 HNPGL patients and 6 controls using qRT-PCR and Western blotting. NDUFA4 knockdown PGL-626 cells were established by using lentivirus infection and puromycin screening. Cell viability, ATP production, lipid reactive oxygen species, and mitochondrial membrane potential assays were performed to investigate the ferroptotic effects in NDUFA4 deficiency HNPGL cancer cells. Xenograft mouse model was created to detect the synergetic antitumor action between NDUFA4 deficiency and Metformin. NDUFA4 was upregulated in tumor tissues of HNPGL patients. NDUFA4 knockdown impaired the assembly of mitochondrial respiratory chain complexes and decreased the production of ATP and reduced cancer cell viability. Mechanistically, NDUFA4 knockdown increased cell ferroptosis, which further promoted Metformin-induced ferroptosis in PGL-626 cells. Therefore, NDUFA4 deficiency enhanced Metformin-mediated inhibition of the HNPGL progression in mice. In conclusion, NDUFA4 promotes the progression of HNPGL, and NDUFA4 knockdown enhances Metformin-mediated inhibition of the HNPGL progression in a mouse model.

Gastrodin synergistically increases migration of interleukin-13 receptor α2 chimeric antigen receptor T cell to the brain against glioblastoma multiforme: A preclinical study.

Therapy with chimeric antigen receptor T (CAR-T) cells involves using reformative T lymphocytes that have three domains, antigen recognition, transmembrane, and costimulating to achieve the therapeutic purpose. CAR-T therapy on malignant hematologic has been successful; however, its effectiveness in patients with solid tumors is still limited. Few studies exist confirming the efficacy of natural products on the function of CAR-T cells. The purpose of this study is to assess the effect of gastrodin (GAS) on CAR-T cells that target interleukin-13 receptor α2 antigen (IL-13Rα2 CAR-T) in the brain against glioblastoma multiforme. Migration of IL-13Rα2 CAR-T was evaluated using the Transwell assay. The effects of GAS on IL-13Rα2 CAR-T cells were assessed both in vitro and situ glioblastoma models. The cytoskeleton was stained with Fluorescein 5-isothiocyanate (FITC)-phalloidin. Cytokines expression in cells was determined by flow cytometry and ELISA assay. Western blotting was used to detect the S1P1 expression, and quantitative PCR assay was used to determine the IL-13Rα2 gene level. GAS increased the migratory and destructive capacity of IL-13Rα2 CAR-T cells with no effect on cytokine release. By increasing the expression of S1P1, GAS encouraged the entry of CAR-T cells into the brain and bone marrow. Transcriptomic analysis revealed that genes related to skeletal migration such as add2 and gng8 showed increased expression in GAS-treated CAR-T cells. We found that GAS synergistically improves the mobility of IL-13Rα2 CAR-T, enhancing their ability to recognize the tumor antigen of glioblastoma, which could be advantageous for the application of CAR-T for the treatment of solid tumors.

YTHDF1 Attenuates TBI-Induced Brain-Gut Axis Dysfunction in Mice.

The brain-gut axis (BGA) is a significant bidirectional communication pathway between the brain and gut. Traumatic brain injury (TBI) induced neurotoxicity and neuroinflammation can affect gut functions through BGA. N6-methyladenosine (m6A), as the most popular posttranscriptional modification of eukaryotic mRNA, has recently been identified as playing important roles in both the brain and gut. However, whether m6A RNA methylation modification is involved in TBI-induced BGA dysfunction is not clear. Here, we showed that YTHDF1 knockout reduced histopathological lesions and decreased the levels of apoptosis, inflammation, and oedema proteins in brain and gut tissues in mice after TBI. We also found that YTHDF1 knockout improved fungal mycobiome abundance and probiotic (particularly Akkermansia) colonization in mice at 3 days post-CCI. Then, we identified the differentially expressed genes (DEGs) in the cortex between YTHDF1-knockout and WT mice. These genes were primarily enriched in the regulation of neurotransmitter-related neuronal signalling pathways, inflammatory signalling pathways, and apoptotic signalling pathways. This study reveals that the ITGA6-mediated cell adhesion molecule signalling pathway may be the key feature of m6A regulation in TBI-induced BGA dysfunction. Our results suggest that YTHDF1 knockout could attenuate TBI-induced BGA dysfunction.

HDAC1 expression is positively correlated with NADPH oxidase 4-mediated oxidative stress in a mouse model of traumatic brain injury.

Accumulating evidence has demonstrated that histone deacetylase 1 (HDAC1) expression is statistically correlated with the severity of traumatic brain injury (TBI). However, the specific role of HDAC1 in the occurrence and development of TBI remains unclear. The lateral fluid percussion injury (LFPI) was used to conduct TBI mouse model in C57BL/6J and C57BL/6J-Hdac1em1cyagen mice. Western blot and qRT-PCR were performed to estimate the expression of HDAC1 and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in brain tissues. Modified neurological severity score (mNSS) and brain water content were analyzed to detect the neurological deficit. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were used to detect the oxidative stress. Oxidative stresses, HDAC1, and NOX4 expression were upregulated in the lesioned cortices tissues after TBI. HDAC1 protein expression was positively correlated with the NOX4 in TBI mouse. Hdac1 knockout attenuated brain edema and neurological dysfunction caused by TBI in mice. Hdac1 knockout inhibited the expressions of NOX4 induced by TBI and attenuated TBI-induced oxidative stress. HDAC1 expression is positively correlated with to NOX4-mediated oxidative stress in a TBI mouse model.NEW & NOTEWORTHY Traumatic brain injury causes increased oxidative stresses, histone deacetylase 1, and nicotinamide adenine dinucleotide phosphate oxidase 4 expression. Hdac1 knockout could attenuate the brain damage caused by traumatic brain injury. The results suggest that histone deacetylase 1 may be a therapeutic target for the treatment of traumatic brain injury.

GJA1-20K Enhances Mitochondria Transfer from Astrocytes to Neurons via Cx43-TnTs After Traumatic Brain Injury.

Astrocytes are crucial in neural protection after traumatic brain injury (TBI), a global health problem causing severe brain tissue damage. Astrocytic connexin 43 (Cx43), encoded by GJA1 gene, has been demonstrated to facilitate the protection of astrocytes to neural damage with unclear mechanisms. This study aims to explore the role of GJA1-20K/Cx43 axis in the astrocyte-neuron interaction after TBI and the underlying mechanisms. Primarily cultured cortical neurons isolated from embryonic C57BL/6 mice were treated by compressed nitrogen-oxygen mixed gas to simulate TBI-like damage in vitro. The transwell astrocyte-neuron co-culture system were constructed to recapitulate the interaction between the two cell types. Quantitative PCR was applied to analyze mRNA level of target genes. Western blot and immunofluorescence were conducted to detect target proteins expression. GJA1-20K overexpression significantly down-regulated the expression of phosphorylated Cx43 (p-Cx43) without affecting the total Cx43 protein level. Besides, GJA1-20K overexpression obviously enhanced the dendrite length, as well as the expression levels of function and synthesis-related factors of mitochondria in damaged neurons. GJA1-20K up-regulated functional Cx43 expression in astrocytes, which promoted mitochondria transmission from astrocytes to neurons which might be responsible to the protection of astrocyte to neurons after TBI-like damage in vitro.

MicroRNA-550a-3-5p controls the brain metastasis of lung cancer by directly targeting YAP1.

BACKGROUND: This study aimed to explore the potential regulatory mechanisms of brain metastasis and to identify novel underlying targets of lung cancer with brain metastasis. METHODS: Exosomes were isolated from the plasma of lung cancer patients with or without brain metastasis and low or high metastatic lung cancer cells, and small RNA from plasma-derived exosomes were sequenced. Differentially expressed miRNAs (DE-miRNAs) were identified. Human brain microvascular endothelial cells (HBMECs) were transfected with miR-550a-3-5p mimics or inhibitors and exosomes. Cell viability, migration, and apoptosis/cycle were determined using Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. Western blotting was used to measure the expression of the associated proteins. Finally, a dual-luciferase reporter gene assay was performed to confirm the miR-550a-3-5p target. RESULTS: Transmission electron microscopy, NanoSight, and western blotting showed that exosomes were successfully isolated and cell-derived exosomes could be taken up by HBMECs. Sequencing identified 22 DE-miRNAs which were enriched in the MAPK, chemokine, PPAR, and Wnt signaling pathways. MiR-550a-3-5p was significantly enriched in brain metastatic exosomes. Cellular experiments showed that miR-550a-3-5p and exosome enrichment significantly inhibited cell viability and migration, promoted apoptosis, and regulated the cell cycle of HBMECs compared with the controls (P < 0.05). Compared with the controls, high levels of both miR-550a-3-5p and exosomes markedly upregulated cleaved-PARP expression, but downregulated the expression of pRB, CDK6, YAP1, CTGF, and CYR61 (P < 0.05). Finally, YAP1 was confirmed to bind directly to miR-550a-3-5p. CONCLUSION: Our results indicate that miR-550a-3-5p and YAP1 may be novel potential targets for controlling brain metastasis.

An in vitro and in vivo study of the role of long non-coding RNA-HOST2 in the proliferation, migration, and invasion of human glioma cells.

Gliomas are the most commonly occurring primary malignant brain tumors in the central nervous system of adults. They are rarely curable and the prognosis for high grade gliomas is generally poor. Recently, long non-coding RNA (lncRNA) human ovarian cancer-specific transcript 2 (HOST2) has been reported to be expressed at high levels in human ovarian cancer, involving tumorigenesis. However, little is still known about whether and how HOST2 regulates glioma development and progression. Therefore, this study aims to investigate the role of HOST2 in human glioma cells. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to determine the expression of lncRNA HOST2, let-7b, and PBX3 in human glioma cells. Cultured human glioma cells were treated with siRNA (si)-lncRNA HOST2, let-7b mimic, si-lncRNA HOST2 + let-7b inhibitor, and si-PBX3. Parameters including cell viability, colony formation, cell migration, and cell invasion were detected by cell counting kit-8 assay, colony formation assay, scratch test, and Transwell assay respectively to determine the effects of down-regulated HOST2 on glioma cells. Tumor formation in nude mice was evaluated by subcutaneous tumor formation experiment. Results showed that HOST2 and PBX3 were highly expressed in glioma tissue whereas let-7b was expressed at much lower levels. In response to treatment with si-lncRNA HOST2, si-PBX3, and let-7b mimic, glioma cell lines exhibited decreased cell viability, suppressed cell migration, invasion, and reduced colony formation of glioma cells. This was accompanied by an attenuated tumor formation with smaller volume and weight in nude mice, suggesting that down-regulated HOST2 could inhibit the tumorigenicity of glioma cells. Lastly, we found that lncRNA HOST2 was highly expressed in glioma tissues and its down-regulation could inhibit the growth and invasion of glioma cells. © 2018 IUBMB Life, 71(1):93-104, 2019.

3-Aminobenzamide protects against cerebral artery injury and inflammation in rats with intracranial aneurysms.

This study aimed to investigate the treatment effects and molecular mechanism of 3-aminobenzamide (3-AB) on intracranial aneurysms (IA). The IA model was established in male Sprague-Dawley (SD) rats and sham group was set up without ligation. The rats were intraperitoneally injected with normal saline in sham and model control groups and 10 mg/kg, 20 mg/kg and 40 mg/kg 3-AB for low, middle and high 3-AB groups for 3 months, respectively. The rates in and blood pressures of caudal artery were measured and anterior cerebral artery and olfactory artery were stained with hematoxylin and eosin (HE) for morphology observation. Besides, the effects of 3-AB on inflammatory cells, macrophages, neutrophils and T cells, were evaluated using immunohistochemistry. Gene expressions of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65 were measured using qRT-PCR and the protein levels of TLR4, PARP-1 and p-p65 were evaluated using western blotting. Blood pressures of rats in 3-AB treatment groups were decreased in a dose-dependent manner. The damage of cerebral artery wall was alleviated and the inflammatory cells (macrophages, neutrophils and T cells) were reduced to some extent in 3-AB high-dose groups. The gene expression of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65, as well as the protein expression of TLR4, PARP-1 and p-p65 in 3-AB treatment groups were decreased in a dose-dependent manner (P < 0.01).3-AB exhibited therapeutic effects on IA through inhibiting the secretions of inflammatory cytokines and MMPs.

Metabolite differences between glutamate carboxypeptidase II gene knockout mice and their wild-type littermates after traumatic brain injury: a 7-tesla 1H-MRS study.

BACKGROUND: Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate-induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis. RESULTS: Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p < 0.05). T2 MR data and brain water-content analysis demonstrated that the extent of cortical edema and brain swelling was less in KO than in WT mice after TBI (p < 0.05). CONCLUSION: Using two non-invasive methods, 1H-MRS and T2 MR imaging, as well as in vitro brain-water content measurements, we demonstrated that the mechanism underlying the neuroprotective effects of GCP II-KO against brain swelling in TBI involves changes in glutamate and N-acetylaspartate levels. This knowledge may contribute towards the development of therapeutic strategies for TBI.

Astaxanthin protects astrocytes against trauma-induced apoptosis through inhibition of NKCC1 expression via the NF-κB signaling pathway.

BACKGROUND: Astaxanthin (ATX) is a carotenoid pigment with pleiotropic pharmacological properties that is seen as a possible drug for treating cerebral ischemic injury and subarachnoid hemorrhage. Na+-K+-2Cl- co-transporter-1 (NKCC1), an intrinsic membrane protein expressed by many cell types, is activated by various insults, leading to the formation of cell swelling and brain edema. We previously established that ATX attenuated brain edema and improved neurological outcomes by modulating NKCC1 expression after traumatic brain injury in mice. This paper explored the molecular mechanism of ATX-mediated inhibition of NKCC1 utilizing an in vitro astrocyte stretch injury model. RESULTS: Stretch injury in cultured astrocytes lowered cell viability time-dependently, which was substantially reducing by pretreating with ATX (50 µmol/L). Stretch injury increased Bax level and cleaved caspase-3 activity, and decreased Bcl-2 level and pro-caspase 3 activity, resulting in the apoptosis of astrocytes. Additionally, stretch injury substantially raised the gene and protein expressions of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α and prompted the expression and nuclear translocation of NF-κB. Pretreatment with ATX remarkably prevented the trauma-induced initiation of NF-κB, expressions of pro-inflammatory cytokines, and cell apoptosis. Moreover, stretch injury markedly elevated the gene and protein expression of NKCC1, which was partly blocked by co-treatment with ATX (50 µmol/L) or an NF-κB inhibitor (PDTC, 10 µmol/L). Cleaved caspase-3 activity was partially reduced by PDTC (10 µmol/L) or an NKCC1 inhibitor (bumetanide, 50 µmol/L). CONCLUSIONS: ATX attenuates apoptosis after stretch injury in cultured astrocytes by inhibiting NKCC1 expression, and it acts by reducing the expression of NF-κB-mediated pro-inflammatory factors.

Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumatic brain injury in mice.

BACKGROUND: Astaxanthin is a carotenoid pigment that possesses potent antioxidative, anti-inflammatory, antitumor, and immunomodulatory activities. Previous studies have demonstrated that astaxanthin displays potential neuroprotective properties for the treatment of central nervous system diseases, such as ischemic brain injury and subarachnoid hemorrhage. This study explored whether astaxanthin is neuroprotective and ameliorates neurological deficits following traumatic brain injury (TBI). RESULTS: Our results showed that, following CCI, treatment with astaxanthin compared to vehicle ameliorated neurologic dysfunctions after day 3 and alleviated cerebral edema and Evans blue extravasation at 24 h (p < 0.05). Astaxanthin treatment decreased AQP4 and NKCC1 mRNA levels in a dose-dependent manner at 24 h. AQP4 and NKCC1 protein expressions in the peri-contusional cortex were significantly reduced by astaxanthin at 24 h (p < 0.05). Furthermore, we also found that bumetanide (BU), an inhibitor of NKCC1, inhibited trauma-induced AQP4 upregulation (p < 0.05). CONCLUSIONS: Our data suggest that astaxanthin reduces TBI-related injury in brain tissue by ameliorating AQP4/NKCC1-mediated cerebral edema and that NKCC1 contributes to the upregulation of AQP4 after TBI.

Glutamate carboxypeptidase II gene knockout attenuates oxidative stress and cortical apoptosis after traumatic brain injury.

BACKGROUND: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system. RESULTS: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice. CONCLUSIONS: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

Cerebral blood perfusion changes in amputees with myoelectric hands after rehabilitation: a SPECT computer-aided analysis.

BACKGROUND: Rehabilitation, which is essential for amputees with myoelectric hands, can improve the quality of daily life by remodeling the neuron network. In our study, we aim to develop a cerebral blood perfusion (CBF) single-photon emission computed tomography computer-aided (SPECT-CA) detection scheme to automatically locate the brain's activated regions after rehabilitation. RESULTS: Five participants without forearms (three male, two female, mean age 51 ± 12.89 years, two missing the right side, and three missing the left side) were included in our study. In the clinical assessment, all of the participants received higher scores after training. The results of the SPM analysis indicated that CBF in the precentral gyrus, postcentral gyrus, frontal lobe, temporal lobe and cerebellum was significantly different among the five participants (P < 0.05). Moreover, SPECT-CA showed that the activated brain areas mainly included the precentral gyrus, postcentral gyrus, cerebellum and extensive cerebral cortex. CONCLUSION: Our study demonstrated that the CBF SPECT-CA method can detect the brain blood perfusion changes induced by rehabilitation with high sensitivity and accuracy. This method has great potential for locating the remodeled neuron regions of amputees with myoelectric hands after rehabilitation.

Endoscopic Fenestration of Twenty-Six Patients With Middle Fossa Arachnoid Cyst.

Middle fossa arachnoid cyst (MFAC) is the most common kind of arachnoid cyst. The objective of this study was to assess the efficacy of endoscopic fenestration for MFACs. The authors report 26 patients of MFAC with variety symptoms such as macrocrania, epilepsy, headache, and development delay. The authors performed surgery with a neuroendoscope to drain and fenestrate the cyst to obtain nearby cystocisternal communications under general anesthesia. All of the 26 patients had a successful fenestration, most of them had an improvement of at least 1 of their pretreatment symptoms with the substantial reduction of the cyst postoperatively. The authors conclude that endoscopic fenestration may be an acceptable and minimally invasive option for the management of symptomatic MFACs.

Endoscopic Versus Microscopic Approach in Pituitary Surgery.

The objective of this study is to compare the efficacy and complications of endoscopic and microscopic transsphenoidal surgery in the treatment of pituitary adenomas. A total of 105 follow-up cases including 60 in endoscopic surgery and 45 in microscopic surgery were treated in our hospital between January 2012 and November 2014. The endoscopic approach had a higher rate of gross tumor removal (81.7% versus 62.2%, P < 0.05) as well as a lower rate of postoperative complications (18.3% versus 35.6%, P < 0.05) than that in the microscopic group. There was no significant difference in the rates of visual improvement and cerebrospinal fluid leak between endoscopic group and microscopic group (P > 0.05). The length of the operation was longer (175 ±â€Š25 minutes versus 110 ±â€Š17 minutes, P < 0.05) but the postoperative hospital stay was significantly shorter (5.1 ±â€Š0.7 versus 7.8 ±â€Š0.8 days, P < 0.05) for the endoscopic surgery group compared with microscopic surgery group. Endoscopic approach provides a wide surgical field and broad lateral vision making easier distinction of tumor tissue. The results of this study support the safety and short-term efficacy of endoscopic pituitary surgery.

Feasibility of Simple Linear Measurements to Determine Ventricular Enlargement in Patients With Idiopathic Normal Pressure Hydrocephalus.

OBJECTIVE: To evaluate the feasibility and reproducibility of linear measurements for determining ventricular enlargement in patients with idiopathic normal pressure hydrocephalus (iNPH) and their correlation to ventricular volume (VV). METHODS: Preoperative brain computed tomography scans were retrospectively evaluated in 36 patients with iNPH. The quantitative markers of Evan index (EI), VV, frontal and occipital horn ratio (FOR), modified cella media index (mCMI), third ventricular width (TVW), temporal horn width (TPH), frontal horn width (FHW), and callosal angle (CA) at the posterior commissure (PC) were independently measured by a neurosurgeon and a radiologist. Intraclass correlation coefficients were calculated to establish inter-rater agreement among the 2 investigators. Pearson correlation coefficients were used to assess the relationship of each linear measurement with total VV. RESULTS: The overall inter-rater agreement among investigators was almost perfect for EI, VV, FOR, mCMI, TVW, substantial for FHW and moderate for TPH, and CA at PC. Pearson correlation coefficients showed excellent correlation between mCMI and VV. Moderate correlation was found between the VV and FHW, TVW, FOR, EI, and CA at PC. Fair correlation was found between the VV and TPH. CONCLUSION: Simple linear measurements could serve as effective alternative to volumetric analysis to determine ventricular size in patients with iNPH. The quantitative marker of mCMI is more reasonable and accurate than EI, FOR, and other simple linear measurements.

Associations of rare nicotinic cholinergic receptor gene variants to nicotine and alcohol dependence.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes. © 2016 Wiley Periodicals, Inc.

Mice lacking glutamate carboxypeptidase II develop normally, but are less susceptible to traumatic brain injury.

Glutamate carboxypeptidase II (GCPII) is a transmembrane zinc metallopeptidase found mainly in the nervous system, prostate and small intestine. In the nervous system, glia-bound GCPII mediates the hydrolysis of the neurotransmitter N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate. Inhibition of GCPII has been shown to attenuate excitotoxicity associated with enhanced glutamate transmission under pathological conditions. However, different strains of mice lacking the GCPII gene are reported to exhibit striking phenotypic differences. In this study, a GCPII gene knockout (KO) strategy involved removing exons 3-5 of GCPII. This generated a new GCPII KO mice line with no overt differences in standard neurological behavior compared to their wild-type (WT) littermates. However, GCPII KO mice were significantly less susceptible to moderate traumatic brain injury (TBI). GCPII gene KO significantly lessened neuronal degeneration and astrocyte damage in the CA2 and CA3 regions of the hippocampus 24 h after moderate TBI. In addition, GCPII gene KO reduced TBI-induced deficits in long-term spatial learning/memory tested in the Morris water maze and motor balance tested via beam walking. Knockout of the GCPII gene is not embryonic lethal and affords histopathological protection with improved long-term behavioral outcomes after TBI, a result that further validates GCPII as a target for drug development consistent with results from studies using GCPII peptidase inhibitors.

A New Genomewide Association Meta-Analysis of Alcohol Dependence.

BACKGROUND: Conventional meta-analysis based on genetic markers may be less powerful for heterogeneous samples. In this study, we introduced a new meta-analysis for 4 genomewide association studies on alcohol dependence that integrated the information of putative causal variants. METHODS: A total of 12,481 subjects in 4 independent cohorts were analyzed, including 1 European American cohort (1,409 cases with alcohol dependence and 1,518 controls), 1 European Australian cohort (a total of 6,438 family subjects with 1,645 probands), 1 African American cohort from SAGE + COGA (681 cases and 508 controls), and 1 African American cohort from Yale (1,429 cases and 498 controls). The genomewide association analysis was conducted for each cohort, and then, a new meta-analysis was performed to derive the combined p-values. cis-Acting expression of quantitative locus (cis-eQTL) analysis of each risk variant in human tissues and RNA expression analysis of each risk gene in rat brain served as functional validation. RESULTS: In meta-analysis of European American and European Australian cohorts, we found 10 top-ranked single nucleotide polymorphisms (SNPs) (p < 10(-6) ) that were associated with alcohol dependence. They included 6 at SERINC2 (3.1 × 10(-8) ≤ p ≤ 9.6 × 10(-8) ), 1 at STK40 (p = 1.3 × 10(-7) ), 2 at KIAA0040 (3.3 × 10(-7) ≤ p ≤ 5.2 × 10(-7) ), and 1 at IPO11 (p = 6.9 × 10(-7) ). In meta-analysis of 2 African American cohorts, we found 2 top-ranked SNPs including 1 at SLC6A11 (p = 2.7 × 10(-7) ) and 1 at CBLN2 (p = 7.4 × 10(-7) ). In meta-analysis of all 4 cohorts, we found 2 top-ranked SNPs in PTP4A1-PHF3 locus (6.0 × 10(-7) ≤ p ≤ 7.2 × 10(-7) ). In an African American cohort only, we found 1 top-ranked SNP at PLD1 (p = 8.3 × 10(-7) ; OR = 1.56). Many risk SNPs had positive cis-eQTL signals, and all these risk genes except KIAA0040 were found to express in both rat and mouse brains. CONCLUSIONS: We found multiple genes that were significantly or suggestively associated with alcohol dependence. They are among the most appropriate for follow-up as contributors to risk for alcohol dependence.