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Connexin 43 peptidic medicine for glioblastoma stem cells
Sheng, Zhi (Elsevier, 2021-02-01)
Dear reviewers: Responses to common reviewer critiques about infant neuroimaging studies
Korom, Marta; Camacho, M. Catalina; Filippi, Courtney A.; Licandro, Roxane; Moore, Lucille A.; Dufford, Alexander; Zöllei, Lilla; Graham, Alice M.; Spann, Marisa; Howell, Brittany R.; Shultz, Sarah; Scheinost, Dustin (Elsevier, 2022-02-01)
The field of adult neuroimaging relies on well-established principles in research design, imaging sequences, processing pipelines, as well as safety and data collection protocols. The field of infant magnetic resonance imaging, by comparison, is a young field with tremendous scientific potential but continuously evolving standards. The present article aims to initiate a constructive dialog between researchers who grapple with the challenges and inherent limitations of a nascent field and reviewers who evaluate their work. We address 20 questions that researchers commonly receive from research ethics boards, grant, and manuscript reviewers related to infant neuroimaging data collection, safety protocols, study planning, imaging sequences, decisions related to software and hardware, and data processing and sharing, while acknowledging both the accomplishments of the field and areas of much needed future advancements. This article reflects the cumulative knowledge of experts in the FIT'NG community and can act as a resource for both researchers and reviewers alike seeking a deeper understanding of the standards and tradeoffs involved in infant neuroimaging.
Fasting and postprandial trimethylamine N-oxide in sedentary and endurance-trained males following a short-term high-fat diet
Steele, Cortney N.; Baugh, Mary Elizabeth; Griffin, Laura E.; Neilson, Andrew P.; Davy, Brenda M.; Hulver, Matthew W.; Davy, Kevin P. (Wiley, 2021-08-01)
Gut bacteria release trimethylamine (TMA) from dietary substrates. TMA is absorbed and is subsequently oxidized in the liver to produce trimethylamine N-oxide (TMAO). Plasma TMAO levels are positively correlated with risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). High-fat diet (HFD) consumption has been reported to increase fasting and postprandial TMAO in sedentary individuals. However, whether the increase in TMAO with consumption of an HFD is observed in endurance-trained males is unknown. Healthy, sedentary (n = 17), and endurance-trained (n = 7) males consumed a 10-day eucaloric diet comprised of 55% carbohydrate, 30% total fat, and <10% saturated fat prior to baseline testing. Blood samples were obtained in a fasted state and for a 4-hour high-fat challenge (HFC) meal at baseline and then again following 5-day HFD (30% carbohydrate, 55% total fat, and 25% saturated fat). Plasma TMAO and TMA-moiety (choline, betaine, L-carnitine) concentrations were measured using isocratic ultraperformance liquid chromatography-tandem mass spectrometry. Age (23 ±3 vs. 22 ± 2 years) and body mass index (23.0 ± 3.0 vs. 23.5 ± 2.1 kg/m2) were similar (both p > 0.05) in the sedentary and endurance-trained group, respectively. VO2max was significantly higher in the endurance-trained compared with sedentary males (56.7 ± 8.2 vs. 39.9 ± 6.0 ml/kg/min). Neither the HFC nor the HFD evoked a detectable change in plasma TMAO (p > 0.05) in either group. Future studies are needed to identify the effects of endurance training on TMAO production.
Glioma-induced peritumoral hyperexcitability in a pediatric glioma model
Chaunsali, Lata; Tewari, Bhanu P.; Gallucci, Allison; Thompson, Emily G.; Savoia, Andrew; Feld, Noah; Campbell, Susan L. (Wiley, 2020-10-01)
Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma-related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient-derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons.
Maltreatment and brain development: The effects of abuse and neglect on longitudinal trajectories of neural activation during risk processing and cognitive control
Kim-Spoon, Jungmeen; Herd, Toria; Brieant, Alexis; Peviani, Kristin; Deater-Deckard, Kirby; Lauharatanahirun, Nina; Lee, Jacob; Casas, Brooks (Elsevier, 2021-04-01)
The profound effects of child maltreatment on brain functioning have been documented. Yet, little is known about whether distinct maltreatment experiences are differentially related to underlying neural processes of risky decision making: valuation and control. Using conditional growth curve modeling, we compared a cumulative approach versus a dimensional approach (relative effects of abuse and neglect) to examine the link between child maltreatment and brain development. The sample included 167 adolescents (13–14 years at Time 1, 53 % male), assessed annually four times. Risk processing was assessed by blood-oxygen-level-dependent responses (BOLD) during a lottery choice task, and cognitive control by BOLD responses during the Multi-Source Interference Task. Cumulative maltreatment effects on insula and dorsolateral anterior cingulate cortex (dACC) activation during risk processing were not significant. However, neglect (but not abuse) was associated with slower developmental increases in insula and dACC activation. In contrast, cumulative maltreatment effects on fronto-parietal activation during cognitive control were significant, and abuse (but not neglect) was associated with steeper developmental decreases in fronto-parietal activation. The results suggest neglect effects on detrimental neurodevelopment of the valuation system and abuse effects on accelerated neurodevelopment of the control system, highlighting differential effects of distinct neglect versus abuse adverse experiences on neurodevelopment.
Processes linking socioeconomic disadvantage and neural correlates of cognitive control in adolescence
Brieant, Alexis; Herd, Toria; Deater-Deckard, Kirby; Lee, Jacob; Casas, Brooks; Kim-Spoon, Jungmeen (Elsevier, 2021-04-01)
Socioeconomic status (SES) is broadly associated with self-regulatory abilities across childhood and adolescence. However, there is limited understanding of the mechanisms underlying this association, especially during adolescence when individuals are particularly sensitive to environmental influences. The current study tested perceived stress, household chaos, parent cognitive control, and parent-adolescent relationship quality as potential proximal mediators of the association between family SES and neural correlates of cognitive control. A sample of 167 adolescents and their primary caregivers participated in a longitudinal study across four years. SES was indexed by caregivers’ education and income-to-needs ratio at Time 1. At Time 2, adolescents reported on their perceived stress, household chaos, and relationship with parents, and parents completed a cognitive control task. Two years later, adolescents completed the same cognitive control task while blood-oxygenation-level-dependent (BOLD) response was monitored with functional magnetic resonance imaging (fMRI). A parallel mediation model indicated that parent cognitive control, but not other proximal factors, explained the relation between SES and adolescents’ activation in the middle frontal gyrus during a cognitive control task. The results suggest potential targets for intervention and prevention efforts that may positively alter neurocognitive outcomes related to socioeconomic disadvantage.
Survival of a male patient harboring CASK Arg27Ter mutation to adolescence
Mukherjee, Konark; Patel, Paras A.; Rajan, Deepa S.; LaConte, Leslie E. W.; Srivastava, Sarika (Wiley, 2020-07-21)
Background: CASK is an X-linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age. Methods: Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively. Results: Trio-WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N-terminus of the protein. The 17-years, and 11-month-old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto-cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state. Conclusion: This case study is the first to report survival of a male patient carrying a CASK loss-of-function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations.
Triangulating abuse liability assessment for flavoured cigar products using physiological, behavioural economic and subjective assessments: a within-subjects clinical laboratory protocol
Wall, Catherine S.; Bono, Rose S.; Lester, Rebecca C.; Hoetger, Cosima; Lipato, Thokozeni; Guy, Mignonne C.; Eissenberg, Thomas E.; Bickel, Warren K.; Barnes, Andrew J.; Cobb, Caroline O. (BMJ, 2018-10-01)
Introduction In the USA, Food and Drug Administration regulations prohibit the sale of flavoured cigarettes, with menthol being the exception. However, the manufacture, advertisement and sale of flavoured cigar products are permitted. Such flavourings influence positive perceptions of tobacco products and are linked to increased use. Flavourings may mask the taste of tobacco and enhance smoke inhalation, influencing toxicant exposure and abuse liability among novice tobacco users. Using clinical laboratory methods, this study investigates how flavour availability affects measures of abuse liability in young adult cigarette smokers. The specific aims are to evaluate the effect of cigar flavours on nicotine exposure, and behavioural and subjective measures of abuse liability. Methods and analyses Participants (projected n=25) are healthy smokers of five or more cigarettes per day over the past 3 months, 18-25 years old, naive to cigar use (lifetime use of 50 or fewer cigar products and no more than 10 cigars smoked in the past 30 days) and without a desire to quit cigarette smoking in the next 30 days. Participants complete five laboratory sessions in a Latin square design with either their own brand cigarette or a session-specific Black & Mild cigar differing in flavour (apple, cream, original and wine). Participants are single-blinded to cigar flavours. Each session consists of two 10-puff smoking bouts (30 s interpuff interval) separated by 1 hour. Primary outcomes include saliva nicotine concentration, behavioural economic task performance and response to various questionnaire items assessing subjective effects predictive of abuse liability. Differences in outcomes across own brand cigarette and flavoured cigar conditions will be tested using linear mixed models. Ethics and dissemination The Virginia Commonwealth University Institutional Review Board approved the study (VCU IRB: HM20007848). Dissemination channels for study findings include scientific journals, scientific meetings, and policy briefs.

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