Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

Background: Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. Methods: We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). Results: Chd8 V986/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8 V986/+ mutant mice at 1 year of age. Pup survival was reduced in wild-Type x Chd8 V986/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8 V986/+ mice and then equalized relative to wild-Type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8 V986/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression. Limitations: It is unclear whether the transcriptional changes observed with age in Chd8 V986/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. Conclusions: Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8 V986/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8 V986/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice

Evaluation of sesamum gum as an excipient in matrix tablets

In developing countries modern medicines are often beyond the affordability of the majority of the population. This is due to the reliance on expensive imported raw materials despite the abundance of natural resources which could provide an equivalent or even an improved function. The aim of this study was to investigate the potential of sesamum gum (SG) extracted from the leaves of Sesamum radiatum (readily cultivated in sub-Saharan Africa) as a matrix former. Directly compressed matrix tablets were prepared from the extract and compared with similar matrices of HPMC (K4M) using theophylline as a model water soluble drug. The compaction, swelling, erosion and drug release from the matrices were studied in deionized water, 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using USP apparatus II. The data from the swelling, erosion and drug release studies were also fitted into the respective mathematical models. Results showed that the matrices underwent a combination of swelling and erosion, with the swelling action being controlled by the rate of hydration in the medium. SG also controlled the release of theophylline similar to the HPMC and therefore may have use as an alternative excipient in regions where Sesamum radiatum can be easily cultivated

Search for long-lived doubly charged Higgs bosons in p(p)over-bar collisions at root s=1.96 TeV

We present a search for long-lived doubly charged Higgs bosons (H+/-+/-), with signatures of high ionization energy loss and muonlike penetration. We use 292 pb(-1) of data collected in p (p) over bar collisions at root s=1.96 TeV by the CDF II detector at the Fermilab Tevatron. Observing no evidence of long-lived doubly charged particle production, we exclude H-L(+/-+/-) and H-R(+/-+/-) bosons with masses below 133 GeV/c(2) and 109 GeV/c(2), respectively. In the degenerate case we exclude H+/-+/- mass below 146 GeV/c(2). All limits are quoted at the 95% confidence level