Caffeine is one of the most extensively consumed stimulants in the world and has been suggested to induce wakefulness by antagonizing the function of the adenosine A2A receptor. Therefore, we investigated the effects of chronic caffeine consumption on learning and memory in the REM sleep-deprived rats.Male Wistar rats (n = 50), were randomly assigned into 5 groups: Control (C), Caffeine (Cf), Pedestal Control (PC), Sleep Deprivation (SD), Sleep Deprivation and Caffeine (SD + Cf). Sleep deprivation procedure was applied as the flower-pot technique. SD and SD + Cf groups were deprived for 18 hours in a day for 21 days. Caffeine was administered daily in drinking water (0.3 g⁄L) for 5 weeks. For evaluated learning and memory function, Morris Water Maze Test (MWM) was used. Fluidigm Access Array was used for Grin2a, Grin2b, BDNF, cdk5/cdk5r1, CaMKIIa genes expression in the hippocampus. Distance moved and escape latency were decreased through trial days (p<0.05). However, there is no significant difference between groups for time spent in targeted quadrant during probe test for memory performance. Grin2a up-regulation was found in Cf and SD+Cf (p<0.05), and cdk5r1 increased in Cf and PC control (p<0.05). Also, BDNF up-regulation was found in PC group. Grin2b, Cdk5, CaMKIIa expression levels were not changed significantly. We showed chronic caffeine altered some of the hippocampal genes without changing learning and memory in REM sleep deprived rats. Chronic consumption of caffeine caused up-regulation in Grin2a that subunit of NMDA receptor. We supposed that chronic caffeine consumption maintained arousal without affecting learning and memory performance.

Lead acts as an antagonist of the N-methyl-d-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in lead-induced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells ( p < 0.001) compared with lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls ( p < 0.001), and we found a trend of decreasing GRIN2A level with an increase in blood lead level ( p < 0.001). In addition, we found a significant association between rs2650429 CT and TT genotypes and risk of lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01-2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity.

Objective: The aim of this study was to comprehensively explore the relationship between genetic variations within GRIN2A, GRIN2B, GRIK1, GRIK4, GRID2, and ADHD. Method: Genotyping was performed with the Sequenom MassARRAY system in a two-stage case-control study. ADHD symptoms were assessed using the Swanson, Nolan, and Pelham version IV scale and the Integrated Visual and Auditory Continuous Performance Test. In silico analysis was performed with website resources. Results: GRID2 rs1385405 showed a significant association with ADHD risk in the codominant model (OR = 2.208, 95% CI = [1.387, 3.515]) in the first stage and in the codominant model (OR = 1.874, 95% CI = [1.225, 2.869]) and recessive model (OR = 1.906, 95% CI = [1.265, 2.873]) in the second stage and related to inattention and hyperactivity symptom. In addition, rs1385405 disturbed the activity of exonic splicing enhancer and mediated GRID2 gene expression in the frontal cortex. Conclusion: our data provided evidence for the participation of GRID2 variants in conferring the risk of ADHD.

Epileptic encephalopathies with continuous spike-and-waves during sleep (CSWS) are characterized by cognitive or language impairment, and are occasionally associated with pathogenic variants of the GRIN2A gene. In these disorders, speech dysfunction could be either related to cerebral dysfunction caused by the GRIN2A deleterious variant or intense interictal epileptic activity. Here, we present a patient with apraxia of speech, clearly linked to severity of epilepsy, carrying a GRIN2A variant. A 6-year-old boy developed acute regression of expressive language following epileptic seizures, leading to complete mutism, at which time EEG revealed CSWS. MEG showed bilateral superior parietal and opercular independent CSWS onsets and PET with fluorodeoxyglucose demonstrated significant increase in relative glucose metabolism in bilateral superior parietal regions. Corticosteroids induced a regression of CSWS together with impressive improvement in speech abilities. This case supports the hypothesis of a triggering role for epileptic discharges in speech deterioration observed in children carrying a deleterious variant of GRIN2A. When classic antiepileptic drugs fail to control epileptic activity, corticosteroids should be considered. Multimodal functional neuroimaging suggests a role for opercular and superior parietal areas in acquired epileptic opercular syndrome. [Published with video sequences on www.epilepticdisorders.com].

Speech and language development may be impaired in all forms of epilepsy involving specialized functional areas in the dominant cerebral hemisphere and their connections. The concept of epilepsy-aphasia clinical spectrum was recently proposed, but the notion of aphasia is quite conditional here as many of these patients demonstrate disorders of speech and language development from their infancy. Those forms of epilepsy are considered as continuum from the most severe Landau-Kleffner syndrome (LKS) and epilepsy with continuous spike-and-wave during sleep (CSWS) (also indicating as electrical status epilepticus during sleep - ESES) to intermediate epilepsy-aphasia disorders (with incomplete correspondence to diagnostic criteria of LKS and epilepsy with CSWS). The mild end of the spectrum is represented by benign childhood epilepsy with centrotemporal spikes (rolandic), which is often associated with speech and language disorders. The importance of genetic factors is discussed, including mutations in SRPX2, GRIN2A and other genes. The perspectives of individualized pharmacotherapy in epilepsy, co-morbid with neurodevelopmental disorders or impairments of speech and language development, are depending on the progress in genetic studies. In the new generation of antiepileptic drugs the positive influence on neuroplasticity mechanisms and higher cerebral functions are supposed for levetiracetam.

Purpose: Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.

Methods: From 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.

Results: In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.

Conclusions: Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Keywords: EGFR; T790M; circulating cell-free DNA (cfDNA); lung cancer; third-generation EGFR TKI declarations.

Activity-dependent plasticity in NMDA receptor-containing synapses can be regulated by phosphorylation of serines and tyrosines in the C-terminal domain of the receptor subunits by various kinases. We have previously identified S1291/S1312 as important sites for PKC phosphorylation; while Y1292/Y1312 are the sites indirectly phosphorylated by PKC via Src kinase. In the oocyte expression system, mutation of those Serine sites to Alanine (that cannot be phosphorylated) in the GluN2A subunit, resulted in a decreased PKC stimulated current enhancement through the receptors compared to wild-type NMDA receptors. To investigate the behavioral and physiological significance of those PKC-mediated phosphorylation sites in vivo, the Grin2a∆PKC mouse expressing GluN2A with four mutated amino acids: S1291A, S1312A, Y1292F and Y1387F was generated using homologous recombination. The Grin2a∆PKC mice exhibit reduced anxiety in the open field test, light dark emergence test, and elevated plus maze. The mutant mice show reduced alternation in a Y maze spontaneous alternation task and a in a non-reinforced T maze alternation task. Interestingly, when the mutant mice were exposed to novel environments, there was no increase in context-induced Fos levels in hippocampal CA1 and CA3 compared to home-cage Fos levels, while the Fos increased in the WT mice in CA1, CA3 and DG. When the SC-CA1 synapses in slices from mutant mice were stimulated using a theta-burst protocol, there was no impairment in LTP. Overall, these results suggest that at least one of those PKC-mediated phosphorylation sites regulates NMDAR-mediated signaling that modulates anxiety.

Background: Neurogranin (Ng), encoded by the schizophrenia risk gene NRGN, is a calmodulin-binding protein enriched in the postsynaptic compartments, and its expression is reduced in the postmortem brains of patients with schizophrenia. Experience-dependent translation of Ng is critical for encoding contextual memory, and Ng regulates developmental plasticity in the primary visual cortex during the critical period. However, the overall impact of Ng on the neuronal signaling that regulates synaptic plasticity is unknown.

Methods: Altered Ng expression was achieved via virus-mediated gene manipulation in mice. The effect on long-term potentiation (LTP) was accessed using spike timing-dependent plasticity protocols. Quantitative phosphoproteomics analyses led to discoveries in significant phosphorylated targets. An identified candidate was examined with high-throughput planar patch clamp and was validated with pharmacological manipulation.

Results: Ng bidirectionally modulated LTP in the hippocampus. Decreasing Ng levels significantly affected the phosphorylation pattern of postsynaptic density proteins, including glutamate receptors, GTPases, kinases, RNA binding proteins, selective ion channels, and ionic transporters, some of which highlighted clusters of schizophrenia- and autism-related genes. Hypophosphorylation of NMDA receptor subunit Grin2A, one significant phosphorylated target, resulted in accelerated decay of NMDA receptor currents. Blocking protein phosphatase PP2B activity rescued the accelerated NMDA receptor current decay and the impairment of LTP mediated by Ng knockdown, implicating the requirement of synaptic PP2B activity for the deficits.

Conclusions: Altered Ng levels affect the phosphorylation landscape of neuronal proteins. PP2B activity is required for mediating the deficit in synaptic plasticity caused by decreasing Ng levels, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.

Melanoma holds a leading position in the mortality from skin tumors. Standard treatment of metastatic melanoma allows tumor remission to be achieved only in a small subset of patients. Studies on melanoma molecular pathogenesis led to the identification of several causative genetic events and, consequently, to the development of novel targeted drugs. More than a half of melanomas contain amine acid substitutions in serine-threonine kinase BRAF. Clinical trials involving specific BRAF inhibitors--vemurafenib and dabrafenib--demonstrated high efficacy of these agents towards BRAF-mutated melanoma. MEK inhibitors may show activity against both BRAF--and NRAS-driven tumors. Mucosal and acral melanomas frequently contain mutation in KIT receptor and can be successfully treated by imatinib. There are novel therapeutic monoclonal antibodies targeted against immunosuppressive molecules CTLA4, PD-1 and PD-L1. In some instances these drugs allow to obtain exceptionally prolonged responses. Whole genome sequencing led to the identification of new melanoma genes, e.g. GRIN2A, TRRAP, PREX2, RAC1, STK19, PPP6C, etc. Molecular testing, especially BRAF mutation analysis, has become a mandatory part of melanoma diagnosis. Nevertheless, despite the revolution in melanoma treatment, the prevention of excessive ultraviolet exposure, cancer awareness and early diagnosis remain the main tools for the management of this disease.

The effects of different forms of monosaccharides on the brain remain unclear, though neuropsychiatric disorders undergo changes in glucose metabolism. This study assessed cell viability responses to five commonly consumed monosaccharides-D-ribose (RIB), D-glucose, D-mannose (MAN), D-xylose and L-arabinose-in cultured neuro-2a cells. Markedly decreased cell viability was observed in cells treated with RIB and MAN. We then showed that high-dose administration of RIB induced depressive- and anxiety-like behavior as well as spatial memory impairment in mice, while high-dose administration of MAN induced anxiety-like behavior and spatial memory impairment only. Moreover, significant pathological changes were observed in the hippocampus of high-dose RIB-treated mice by hematoxylin-eosin staining. Association analysis of the metabolome and transcriptome suggested that the anxiety-like behavior and spatial memory impairment induced by RIB and MAN may be attributed to the changes in four metabolites and 81 genes in the hippocampus, which is involved in amino acid metabolism and serotonin transport. In addition, combined with previous genome-wide association studies on depression, a correlation was found between the levels of Tnni3k and Tbx1 in the hippocampus and RIB induced depressive-like behavior. Finally, metabolite-gene network, qRT-PCR and western blot analysis showed that the insulin-POMC-MEK-TCF7L2 and MAPK-CREB-GRIN2A-CaMKII signaling pathways were respectively associated with RIB and MAN induced depressive/anxiety-like behavior and spatial memory impairment. Our findings clarified our understanding of the biological mechanisms underlying RIB and MAN induced depressive/anxiety-like behavior and spatial memory impairment in mice and highlighted the deleterious effects of high-dose RIB and MAN as long-term energy sources.

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that shares many similarities with spontaneously occurring hemangiosarcoma (HSA) in dogs and cats. To investigate the genetic suitability of HSA as a model for AS, we sequenced ∼1000 cancer genes in 41 cases of HSA and matched germline tissue: 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of HSA to AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs and both species show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrates many important parallels to AS and provides hope that future studies on these cancers will benefit of all three species.

Keywords: Cat; Comparative genomics; Dog; Hemangiosarcoma; Skin; Visceral.

Background: This study aims to explore the prognostic values of CT83 and CT83-related genes in lung adenocarcinoma (LUAD).

Methods: We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC patients (Affymetrix Human Genome U133 Plus 2.0 Array) from TCGA and GEO databases. According to the median expression of CT83, the TCGA samples were divided into high and low expression groups, and differential expression analysis between them was performed. Functional enrichment analysis of differential expression genes (DEGs) was conducted. Univariate Cox regression analysis and LASSO Cox regression analysis were performed to screen the optimal prognostic DEGs. Then we established the prognostic model. A Nomogram model was constructed to predict the overall survival (OS) probability of LUAD patients.

Results: CT83 expression was significantly correlated to the prognosis of LUAD patients. A total of 59 DEGs were identified, and a predictive model was constructed based on six optimal CT83-related DEGs, including CPS1, RHOV, TNNT1, FAM83A, IGF2BP1, and GRIN2A, could effectively predict the prognosis of LUAD patients. The nomogram could reliably predict the OS of LUAD patients. Moreover, the six important immune checkpoints (CTLA4, PD1, IDO1, TDO2, LAG3, and TIGIT) were closely correlated with the Risk Score, which was also differentially expressed between the LUAD samples with high and low-Risk Scores, suggesting that the poor prognosis of LUAD patients with high-Risk Score might be due to the immunosuppressive microenvironments.

Conclusion: A prognostic model based on six optimal CT83 related genes could effectively predict the prognosis of LUAD patients.

Keywords: CT83; Risk Score; biomaker; lung adenocarcinoma; overall survival; prognostic.

Elite rugby league and union have some of the highest reported rates of concussion (mild traumatic brain injury) in professional sport due in part to their full-contact high-velocity collision-based nature. Currently, concussions are the most commonly reported match injury during the tackle for both the ball carrier and the tackler (8-28 concussions per 1000 player match hours) and reports exist of reduced cognitive function and long-term health consequences that can end a playing career and produce continued ill health. Concussion is a complex phenotype, influenced by environmental factors and an individual's genetic predisposition. This article reviews concussion incidence within elite rugby and addresses the biomechanics and pathophysiology of concussion and how genetic predisposition may influence incidence, severity and outcome. Associations have been reported between a variety of genetic variants and traumatic brain injury. However, little effort has been devoted to the study of genetic associations with concussion within elite rugby players. Due to a growing understanding of the molecular characteristics underpinning the pathophysiology of concussion, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose from this review that several genetic variants within or near candidate genes of interest, namely <i>APOE</i>, <i>MAPT</i>, <i>IL6R</i>, <i>COMT</i>, <i>SLC6A4</i>, <i>5-HTTLPR</i>, <i>DRD2</i>, <i>DRD4</i>, <i>ANKK1</i>, <i>BDNF</i> and <i><em>GRIN2A</em></i>, warrant further study within elite rugby and other sports involving high-velocity collisions.

Keywords: concussion; genomics; mild traumatic brain injury; polymorphisms; rugby.

We report a 2.5-year-old Turkish boy who first presented with nystagmus, lack of eye contact, and hypotonia at 2 months of age and developed refractory seizures when 6 months old. Extensive metabolic tests and imaging being noncontributory, whole-exome sequencing was carried out which revealed a heterozygote NM_001134407.2:C.3299A>G (p.Glu1100Gly) novel mutation in GRIN2A gene. Topiramate was started and seizures were rapidly brought under control. GRIN2A mutations may result in altered GluN2A membrane trafficking and response to glutamate. This report illustrates the clinical variability of GRIN2A mutations according to the age of onset of symptoms and suggests considering mutations in this gene in cases of global developmental delay, refractory epilepsy, and nystagmus.

Keywords: Epilepsy; GRIN2A; neurodevelopmental delay; nystagmus; whole-exome sequencing.

The aim of this study was to investigate the effects of ethyl acetate extract from Coreopsis tinctoria (EACC) on learning and memory impairment in d-galactose-induced aging mice and the underlying molecular mechanism. The composition of EACC was analyzed by UPLC-MS, and the targets and pathways of EACC to improve learning and memory impairment were predicted and analyzed by the network pharmacology method. A mouse aging model was established by subcutaneous injection of d-galactose in mice, and EACC and piracetam were given to the model mice by gavage to observe their behavioral changes and changes in their SOD and GSH-Px activities in MDA contents in their peripheral blood serum and in the contents of Glu and GABA in their brain tissues. Then the hippocampus of the three mice selected from each of the MOD group and EACC-H group was separated for RT-qPCR assay. The results of the animal experiments showed that EACC could improve the learning and memory impairment of model mice by affecting the level of oxidative stress enzymes in serum and the content of neurotransmitters in the brain tissue. The results of network pharmacology analysis showed that the EACC components corresponded to 74 learning and memory-related targets, of which 13 were enriched in the long-term potentiation pathway. The results of RT-qPCR showed that 12 of the 13 detected targets were consistent with the predicted targets, and 9 of them were located in the NMDA receptor-related pathway of the long-term potentiation process and the pathway played an important regulatory role. It is believed that EACC could improve the learning and memory impairment of d-galactose-induced aging mice by acting on the nine targets Grin1, Grin2a, Camk2a, Camk2b, Kras, Raf1, Mapk1, Mapk3 and Creb to affect the NMDA receptor-related pathway of long-term potentiation.

In recent years, intracellular signal transduction via RAS-RAF-MEK-ERK has been successfully targeted in new treatment approaches for melanoma using small molecule inhibitors against activated BRAF (V600E mutation) and activated MEK1/2. Also mutated c-KIT has been identified as a promising target. Meanwhile, evidence has been provided that combinations between BRAF inhibitors and MEK1/2 inhibitors are more promising than single-agent treatments. Moreover, new treatment algorithms favor sequential treatment using BRAF inhibitors and newly developed immunotherapies targeting common T lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1). In depth molecular analyses have uncovered new mechanisms of treatment resistance and recurrence, which may impact on future treatment decisions. Moreover, next-generation sequencing data have shown that recurrent lesions harbor specific genetic aberrations. At the same time, high throughput sequencing studies of melanoma unraveled a series of new treatment candidates for future treatment approaches such as ERBB4, GRIN2A, GRM3, and RAC1. More recent bioinformatic technologies provided genetic evidence for extensive tumor heterogeneity and tumor clonality of solid tumors, which might also be of relevance for melanoma. However, these technologies have not yet been applied to this tumor. In this review, an overview on the genetic basis of current treatment of melanoma, treatment resistance and recurrences including new treatment perspectives based on recent high-throughput sequencing data is provided. Moreover, future aspects of individualized treatment based on each patient's individual mutational landscape are discussed.

OBJECTIVE

To detect potential mutations of the glutamate receptor subunit (GRIN2A) gene and delineate the clinical-genetic characteristics of patients with epilepsy-aphasia spectrum (EAS) disorders.

METHODS

One hundred twenty two patients with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), benign childhood epilepsy with centrotemporal spikes (BECT) and BECT variants were recruited. Potential mutations of the GRIN2A gene were screened with Sanger sequencing. And clinical-genetic characteristics for all patients were analyzed.

RESULTS

The patients have included 9 LKS, 26 CSWS, 42 BECT variants and 45 BECT. The mean age of onset of seizure or aphasia was 5 years old (10 months to 11 years). Mutation screening has detected 4 possible pathogenic missense mutations including c.2278G>A (p.G760S), c.4153G>T (p.D1385Y), c.1364G>A (p.C455Y) and c.691T>C (p.C231R) in four unrelated probands, which comprised one case with LKS and three with BECT variants. The mutation rate was 11.1% (1/9) for LKS and 7.2% (3/42) for BECT variants. No GRIN2A mutation was found in the 26 patients with CSWS and 45 patients with BECT. Among the 122 probands, 25 (20.5%) patients without a GRIN2A mutation had a positive family history of febrile seizures or epilepsy.

CONCLUSIONS

GRIN2A mutation do exist in EAS patients, but with a relatively low rate. A proportion of EAS patients without a GRIN2A mutation have a positive family history, which suggested a complex mechanism for EAS.

Objective: This study aimed to investigate the regulatory effects of repressor element-1 silencing transcription factor (REST) on the glutamate receptors and immediate early genes (IEGs) in the SH-SY5Y cells.

Methods: The genes regulated by REST were screened by bioinformatics between AD patients and the control group. Then, SH-SY5Y cells were treated with 10 μM Aβ or REST siRNA/cDNA, and the expressions of synaptic genes and IEGs were detected. Moreover, the protein expression of synaptophysin and PSD-95 was detected by Western blotting in the primary mouse hippocampal neurons.

Results: Firstly, 464 differentially expressed genes regulated by REST were identified between Alzheimer's disease (AD) patients and controls, and REST was closely related to the glutamatergic synapses and long-term potentiation. GRIA1, GRIN2A, GRIN1, and ARC showed significant variations with the changes of REST. Moreover, the loss of REST reduced the expression of synaptophysin and PSD-95, which was related to synaptic plasticity.

Conclusion: REST maintains synaptic plasticity by affecting both glutamate receptors and IEGs, and the imbalance between neural excitation and inhibition mediated by REST compromises neural function, contributing to cognitive impairment.

Keywords: immediate early genes; repressor element-1 silencing transcription factor; synaptic genes; synaptic plasticity.

Body surface area (BSA) is an important trait used for many clinical purposes. People's BSA may vary due to genetic background, race, and different lifestyle factors (such as walking, exercise, reading, smoking, transportation, etc.). GWAS of BSA was conducted on 5,324 subjects of four ethnic populations of European-American, African-American, Hispanic-American, and Chinese-American from the Multi-Ethnic Study of Atherocloris (MESA) data using unconditional and conditional full genetic models. In this study, fifteen SNPs were identified (Experiment-wise PEW < 1×10-5) using unconditional full genetic model, of which thirteen SNPs had individual genetic effects and seven SNPs were involved in four pairs of epistasis interactions. Seven single SNPs and eight pairs of epistasis SNPs were additionally identified using exercise, smoking, and transportation cofactor-conditional models. By comparing association analysis results from unconditional and cofactor conditional models, we observed three different scenarios: (i) genetic effects of several SNPs did not affected by cofactors, e.g., additive effect of gene CREB5 (a≙ -0.013 for T/T and 0.013 for G/G, -Log10 PEW = 8.240) did not change in the cofactor models; (ii) genetic effects of several SNPs affected by cofactors, e.g., the genetic additive effect (a≙ 0.012 for A/A and -0.012 for G/G, -Log10 PEW = 7.185) of SNP of the gene GRIN2A was not significant in transportation cofactor model; and (iii) genetic effects of several SNPs suppressed by cofactors, e.g., additive (a≙ -0.018 for G/G and 0.018 for C/C, -Log10 PEW = 19.737) and dominance (d≙ -0.038 for G/C, -Log10 PEW = 27.734) effects of SNP of gene ERBB4 was identified using only transportation cofactor model. Gene ontology analysis showed that several genes are related to the metabolic pathway of calcium compounds, coronary artery disease, type-2 Diabetes, Alzheimer disease, childhood obesity, sleeping duration, Parkinson disease, and cancer. This study revealed that lifestyle cofactors could contribute, suppress, increase or decrease the genetic effects of BSA associated genes.

Angiosarcoma (AS) is a highly aggressive tumor of blood and lymphatic vessels in humans that carries a poor prognosis. The rarity of AS, together with its heterogeneous nature, and locations (skin, breast, visceral organs and deep soft tissues), makes understanding the pathogenesis of AS challenging. Dogs and cats spontaneously develop hemangiosarcoma (HSA), an aggressive tumor that shares many histopathological and clinical similarities to AS. To investigate the genetic suitability of spontaneously occurring HSA as a model for AS, we sequenced ∼1,000 cancer genes in 41 cases of HSA and matched germline tissue; 15 canine visceral HSAs, 13 canine skin HSAs and 13 feline skin HSAs. Analysis of visceral HSAs from dogs presenting with concurrent splenic and cardiac neoplasms showed that the tumors were not independent primaries, consistent with the highly metastatic nature of HSA. Comparison of canine and feline HSA to human AS revealed that several driver genes were recurrently mutated in both species, such as TP53, PIK3CA, ATRX, GRIN2A and LRP1B. In the germlines, by focusing specifically on canine and feline orthologs of human AS risk genes, we identified several candidate pathogenic variants. Similar to AS, a UV mutational signature was found in a subset of canine cutaneous HSAs. Furthermore, both AS and canine HSA show differing mutational profiles between tissue sites. Our characterization of canine and feline HSA demonstrate many important parallels to AS and provides hope that future studies on these cancers will benefit patients of all three species.

Keywords: Cat; Comparative genomics; Dog; Hemangiosarcoma; Skin; Visceral.

Purpose: Our purpose was to describe the phenotypic features and test for association of genes GRIN2A, RBFOX1 and RBFOX3 with rolandic epilepsy in patients from Colombia.

Methods: Thirty patients were enrolled. A structured interview was applied. In addition, saliva samples were collected from the patients and their parents. One polymorphism in each of GRIN2A, RBFOX1 and RBFOX3 genes was tested.

Results: The average age at onset was 5.3 years. Almost half the sample presented prolonged seizures (>5 minutes); although the majority of the patients presented their seizures only while asleep, over a quarter presented them only while awake. The most frequent comorbidity was the presence of symptoms compatible with attention-deficit hyperactivity disorder (ADHD). Personal history of febrile seizures and parasomnias were equally frequent (20%). Family history of any type of epilepsy was reported in 80% of the patients, followed by migraine (73.3%) and poor academic performance (63.3%). About half the sample reported sleepwalking in parents or sibs. Most patients had received pharmacologic treatment. We found no association of rolandic epilepsy with the single nucleotide polymorphisms tested.

Conclusions: Our rolandic epilepsy cohort presents clinical features clearly different from other cohorts. For instance, age at onset is much earlier in our set of patients, and personal and family history of febrile seizures as well as parasomnias are highly prevalent in our sample. No association of rolandic epilepsy with variants at the 3 genes tested was found. This lack of association may reflect the high genetic heterogeneity of the epilepsies.

Keywords: Colombia; Rolandic epilepsy; clinical features; comorbidities; genetic association.

There are a number of familial focal epilepsy syndromes, each with distinct clinical characteristics. Here, we review the epilepsy phenotypes and the genetic architecture of these syndromes. Using an illustrative clinical case, we describe the important steps in making a diagnosis and ordering appropriate genetic tests. Our discussion on the genetics of the familial focal epilepsies will provide a framework for interpreting the results of genetic testing, and allow us to apply this information to patient management.

Keywords: DEPDC5; GRIN2A; LGI1; familial focal epilepsy; focal epilepsy genetics; mTOR.

Background: Exposure to Poly I:C in pregnant rats has been reported to cause schizophrenia-like behaviours and abnormal neurotransmissions in adult, particularly male, offspring. However, what is less well understood are the effects of maternal Poly I:C exposure on adolescent behaviors and neurotransmission in female juvenile rats.

Methods: Female adolescent Poly I:C offspring were constructed by treating with 5 mg/kg Poly I:C on timed pregnant rats (GD 15). A battery of behavioral tests were conducted during postnatal day (PD) 35-60. Neurotransmitter receptors and inflammation markers in brain regions were evaluated by RT-qPCR on PD 60.

Results: Open field, elevated plus maze, and forced swimming tests revealed that prenatal Poly I:C exposure led to elevated anxiety-like and depression-like behaviors in female adolescent offspring. Deficits in pre-pulse inhibition and social interaction were also observed. However, the Poly I:C rats had better performance than the controls in the novel object recognition memory test which demonstrated a behavioral phenotype with improved cognitive function. Prenatal Poly I:C exposure caused brain region-specific elevation of the P2X7 receptor- and NF-κB-NLRP3-IL-1β inflammatory signalling in female juvenile rats. Prenatal Poly I:C exposure decreased expression of GABAA receptor subunits Gabrb3 in the PFC, and Gabrb1 and dopamine D2 (Drd2) in the hippocampus, but increased NMDA receptor subunit Grin2a in the PFC, 5-HT2A in the hippocampus, and Gabrb3 and Drd2 in the NAc.

Conclusions: Prenatal Poly I:C challenge causes behavioral deficits and brain-specific neurotransmission changes via elevated neuroinflammation responses in female adolescent offspring rats.

Keywords: adolescent; behavior; female offspring; inflammation marker; maternal immune activation; neurotransmitter receptor.