Reversibility and Improved Hydrogen Release of Magnesium Borohydride

Desorption and subsequent rehydrogenation of Mg(BH_4)_2 with and without 5 mol % TiF_3 and ScCl_3 have been investigated. Temperature programmed desorption (TPD) experiments revealed a significant increase in the rate of desorption as well as the weight percentage of hydrogen released with additives upon heating to 300 °C. Stable Mg(B_xH_y)_n intermediates were formed at 300 °C, whereas MgB_2 was the major product when heated to 600 °C. These samples were then rehydrogenated and subsequently characterized with powder X-ray diffraction (pXRD), Raman, and NMR spectroscopy. We confirmed significant conversion of MgB_2 to fully hydrogenated Mg(BH_4)_2 for the sample with and without additives. TPD and NMR studies revealed that the additives have a significant effect on the reaction pathway during both dehydrogenation and rehydrogenation reactions. This work suggests that the use of additives may provide a valid pathway for improving intrinsic hydrogen storage properties of magnesium borohydride

Fluoroscopic Surrogate for Pharyngeal Strength: The Pharyngeal Constriction Ratio (PCR)

The pharyngeal constriction ratio (PCR), derived directly from videofluoroscopy without the need for manometry, requires validation as a surrogate for pharyngeal strength. A correlation of −0.70 was previously identified between PCR and pharyngeal clearing pressures (PP) on separate fluoroscopic and manometric studies. As PP increases, PCR decreases. The objective of the current study was to evaluate the correlation between PCR and PP in 25 patients undergoing simultaneous fluoroscopy and pharyngeal manometry. The effect of the manometric catheter on PCR was also investigated. The correlation between the PCR and averaged pharyngeal clearing pressures was −0.72 (p < 0.001). All patients with a PCR > 0.25 had a PP < 60 mmHg. PCR did not differ significantly as a consequence of the manometric catheter. Results suggest the utility of an objective fluoroscopic measure in assessing pharyngeal strength when manometry may not be available or possible

Methylomic trajectories across human fetal brain development

Open access articleEpigenetic processes play a key role in orchestrating transcriptional regulation during development. The importance of DNA methylation in fetal brain development is highlighted by the dynamic expression of de novo DNA methyltransferases during the perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenome during fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNA methylation at ∼ 400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to 184 d post-conception. We identified highly significant changes in DNA methylation across fetal brain development at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sites associated with developmental changes in DNA methylation during fetal brain development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across brain development. Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated loci associated with fetal age that are significantly enriched for genes involved in neurodevelopmental processes. This is, to our knowledge, the most extensive study of DNA methylation across human fetal brain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity.MRCUniversity of Exeter Medical SchoolWellcome Trus

Posterior cricoid region fluoroscopic findings: the posterior cricoid plication.

The region posterior to the cricoid cartilage is challenging to assess fluoroscopically. The purpose of this investigation is to critically evaluate the posterior cricoid (PC) region on fluoroscopy and describe patterns of common findings. This was a case control study. All fluoroscopic swallowing studies performed between June 16, 2009, and February 9, 2010, were reviewed for features seen in the PC region. These findings were categorized into distinct patterns and compared to fluoroscopic studies performed in a cohort of normal volunteers. Two hundred patient studies and 149 healthy volunteer studies were reviewed. The mean age of the referred patient cohort and the volunteer cohort was 57&nbsp;years (±19) and 61&nbsp;years (±16), respectively (p&nbsp;&gt;&nbsp;0.05). The patient cohort was 53% male and the control cohort was 56% female (p&nbsp;&gt;&nbsp;0.05). Four groups were identified. Pharyngoesophageal webs were seen in 7% (10/149) of controls and 14% (28/200) of patients (p&nbsp;=&nbsp;0.03). A PC arch impression was seen in 16% of patients (32/200) and controls (24/149) (p&nbsp;=&nbsp;1). A PC plication was demonstrated in 23% (34/149) of controls and 30% (60/200) of patients (p&nbsp;=&nbsp;0.13). No distinctive PC region findings were seen in 54% (81/149) of controls and 42% (84/200) of referred patients (p&nbsp;=&nbsp;0.02). Four patients (2%) had both a web and a PC plication. Four categories of PC region findings were identified (unremarkable PC region, web, PC arch impression, and PC plication). Both patients referred for swallowing studies and healthy volunteers demonstrated esophageal webs, PC arch impressions, and PC plications. Only webs were more common in patients than in control subjects (p&nbsp;=&nbsp;0.03). The PC impression and PC plication are likely to represent normal variants that may be identified on fluoroscopic swallow studies

Alcohol, Self-regulation, and Partner Physical Aggression: Actor-Partner Effects over a Three Year Time Frame

The question of how individual differences related to self-regulation interact with alcohol use patterns to predict intimate partner aggression (IPA) is examined. We hypothesized that excessive drinking will be related to partner aggression among those who have low self-regulation. In addition, we explored the extent to which differences in self-regulation in one partner may moderate the relationship between alcohol use and partner aggression. A sample of married or cohabitating community couples (N = 280) ages 18–45 was recruited according to their classification into four drinking groups: heavy drinking in both partners (n = 79), husband only (n = 80), wife only (n = 41), by neither (n = 80), and interviewed annually for 3 years. IPA, drinking, and scores on measures of negative affect, self-control, and Executive Cognitive Functioning (ECF) were assessed for both members of the couple. The Actor Partner Interdependence Model (APIM) was used to analyze longitudinal models predicting the occurrence of IPA from baseline alcohol use, negative affect, self-control and ECF. Actor self-control interacted with partner self-control such that IPA was most probable when both were low in self-control. Contrary to prediction, actors high in alcohol use and also high on self-control were more likely to engage in IPA. Partner alcohol use was predictive of actor IPA when the partner was also high in negative affect. Low partner ECF was associated with more actor IPA. These findings suggest that self-regulatory factors within both members of a couple can interact with alcohol use patterns to increase the risk for relationship aggression

Kids, Adolescents, and Young Adult Cancer Study—A Methodologic Approach in Cancer Epidemiology Research

Advances have been made in treatment and outcomes for pediatric cancer. However adolescents and young adults (AYAs) with cancer have not experienced similar relative improvements. We undertook a study to develop the methodology necessary for epidemiologic cancer research in these age groups. Our goal was to create the Kids, Adolescents, and Young Adults Cancer (KAYAC) project to create a resource to address research questions relevant to this population. We used a combination of clinic and population-based ascertainment to enroll 111 cases aged 0–39 for this methodology development study. The largest groups of cancer types enrolled include: breast cancer, leukemia, lymphoma, and melanoma. The overall participation rate is 69.8% and varies by age and tumor type. The study included patients, mothers, and fathers. The methods used to establish this resource are described, and the values of the resource in studies of childhood and young adult cancer are outlined

Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.

Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p&lt;0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR&lt;0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p&lt;0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p&lt;0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies

Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p ≤ 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required

The Warburg Effect Dictates the Mechanism of Butyrate-Mediated Histone Acetylation and Cell Proliferation

Widespread changes in gene expression drive tumorigenesis, yet our knowledge of how aberrant epigenomic and transcriptome profiles arise in cancer cells is poorly understood. Here, we demonstrate that metabolic transformation plays an important role. Butyrate is the primary energy source of normal colonocytes and is metabolized to acetyl-CoA, which was shown to be important not only for energetics but also for HAT activity. Due to the Warburg effect, cancerous colonocytes rely on glucose as their primary energy source so butyrate accumulated and functioned as an HDAC inhibitor. Although both mechanisms increased histone acetylation, different target genes were upregulated. Consequently, butyrate stimulated the proliferation of normal colonocytes and cancerous colonocytes when the Warburg effect was prevented from occurring, whereas it inhibited the proliferation of cancerous colonocytes undergoing the Warburg effect. These findings link a common metabolite to epigenetic mechanisms that are differentially utilized by normal and cancerous cells because of their inherent metabolic differences