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1. The interictal mesial temporal lobe epilepsy network

   https://doi.org/10.1111/epi.13959  

   Karunakaran, Suganya ; Rollo, Matthew J. ; Kim, Kamin ; Johnson, Jessica A. ; Kalamangalam, Giridhar P. ; Aazhang, Behnaam ; Tandon, Nitin ( December 2017 , Epilepsia)

   Identification of patient‐specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network.

   Intracranial recordings from 10 medically refractoryMTLEpatients were analyzed. In each patient, hour‐long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150‐millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize theMTLEnetwork at group level.

   We generated the first graph of connectivity across a cohort ofMTLEpatients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians.

   Apart from identifying interictal measures that can model patient‐specific epileptogenic networks, we also produce a group map of network connectivity from a cohort ofMTLEpatients.

    

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2. Diagnostic implications of genetic copy number variation in epilepsy plus

   https://doi.org/10.1111/epi.14683  

   Coppola, Antonietta ; Cellini, Elena ; Stamberger, Hannah ; Saarentaus, Elmo ; Cetica, Valentina ; Lal, Dennis ; Djémié, Tania ; Bartnik‐Glaska, Magdalena ; Ceulemans, Berten ; Helen Cross, J. ; et al ( March 2019 , Epilepsia)

   Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution ofCNVs to epilepsies from sizeable populations are not available.

   We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array basedCNVdata. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features.CNVclassification was conducted using a systematic filtering workflow adapted to epilepsy.

   Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomalCNVclassified as pathogenic; 19 individuals (1.7%) carried at least one autosomalCNVclassified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenicCNV. We identifiedCNVs covering recently reported (HNRNPU)or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenicCNVcarriers to those of noncarriers of pathogenicCNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenicCNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68;P = 2.34 × 10⁻⁹). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency ofCNVs.

   The use of a specifically adapted workflow enabled identification of pathogenic autosomalCNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenicCNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm includingCNVdetection. Collaborative large‐scaleCNVreanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

    

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3. Binge‐eating disorder with and without lifetime anorexia nervosa: A comparison of sociodemographic and clinical features

   https://doi.org/10.1002/eat.23858  

   Pawar, Pratiksha S. ; Thornton, Laura M. ; Flatt, Rachael E. ; Sanzari, Christina M. ; Carrino, Emily A. ; Tregarthen, Jenna P. ; Argue, Stuart ; Bulik, Cynthia M. ; Watson, Hunna J. ( November 2022 , International Journal of Eating Disorders)

   To compare individuals who have experienced binge‐eating disorder (BED) and anorexia nervosa (AN) (BED AN+) to those who have experienced BED and not AN (BED AN–).

   Participants (N = 898) met criteria for lifetime BED and reported current binge eating. Approximately 14% had a lifetime diagnosis of AN. Analyses compared BED AN+ and BED AN– on sociodemographic variables and clinical history.

   The presence of lifetimeANwas associated with more severe eating disorder symptoms, including earlier onset, more frequent, more chronic, and more types of eating disorder behaviors over the lifetime, as well as a higher lifetime prevalence of bulimia nervosa (BN). Participants with lifetimeANreported being more likely to have received treatments forBEDorBN, had significantly lower minimum, current, and maximumBMIs, had more severe general anxiety, and were significantly more likely to be younger and female. In the full sample, the lifetime prevalence of unhealthy weight control behaviors was high and treatment utilization was low, despite an average 15‐year history since symptom onset. Gastrointestinal disorders and comorbid anxiety, depression, and attention‐deficit/hyperactivity disorder symptoms were prevalent.

   Individuals fared poorly on a wide array of domains, yet those with lifetimeANfared considerably more poorly. All patients withBEDshould be screened for mental health and gastrointestinal comorbidities and offered referral and treatment options.

   Individuals experiencing binge‐eating disorder have severe symptomology, but those who have experienced binge‐eating disorder and anorexia nervosa fare even more poorly. Our study emphasizes that patients with binge‐eating disorder would benefit from being screened for mental health and gastrointestinal comorbidities, and clinicians should consider history of unhealthy weight control behaviors to inform treatment and relapse prevention.

    

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4. Cellular and behavioral effects of altered NaV1.2 sodium channel ion permeability in Scn2a K1422E mice

   https://doi.org/10.1093/hmg/ddac087  

   Echevarria-Cooper, Dennis M. ; Hawkins, Nicole A. ; Misra, Sunita N. ; Huffman, Alexandra M. ; Thaxton, Tyler ; Thompson, Christopher H. ; Ben-Shalom, Roy ; Nelson, Andrew D. ; Lipkin, Anna M. ; George Jr, Alfred L. ; et al ( April 2022 , Human Molecular Genetics)

   Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure–function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.

    

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5. Double‐stranded RNA targeting calmodulin reveals a potential target for pest management of Nilaparvata lugens

   https://doi.org/10.1002/ps.4865  

   Wang, Weixia ; Wan, Pinjun ; Lai, Fengxiang ; Zhu, Tingheng ; Fu, Qiang ( March 2018 , Pest Management Science)

   Calmodulin (CaM) is an essential protein in cellular activity and plays important roles in many processes in insect development. RNA interference (RNAi) has been hypothesized to be a promising method for pest control. CaM is a good candidate for RNAi target. However, the sequence and function of CaM inNilaparvata lugensare unknown. Furthermore, the double‐stranded RNA (dsRNA) target to CaM gene in pest control is still unavailable.

   In the present study, two alternatively spliced variants ofCaMtranscripts, designatedNlCaM1andNlCaM2, were cloned fromN. lugens. The two cDNA sequences exhibited 100% identity to each other in the open reading frame (ORF), and only differed in the 3′ untranslated region (UTR).NlCaMincludingNlCaM1andNlCaM2mRNA was detectable in all developmental stages and tissues ofN. lugens, with significantly increased expression in the salivary glands. Knockdown ofNlCaMexpression by RNAi with different dsRNAs led to an inability to molt properly, increased mortality, which ranged from 49.7 to 92.5%, impacted development of the ovaries and led to female infertility. There were no significant reductions in the transcript levels of vitellogenin and its receptor or in the total vitellogenin protein level relative to the control group. However, a significant reduction in vitellogenin protein was detected in ovaries injected with dsNlCaM. In addition, a specific dsRNA ofNlCaMfor control ofN. lugenswas designed and tested.

   NlCaMplays important roles mainly in nymph development and uptake of vitellogenin by ovaries in vitellogenesis inN. lugens. dsRNA derived from the less conserved 3′‐UTR ofNlCaMshows great potential for RNAi‐basedN. lugensmanagement. © 2018 Society of Chemical Industry

    

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