A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized ...by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.
This study investigated gut microbiota composition along with food, host, and microbial derived metabolites in the colon and systemic circulation of healthy mice following dietary rice bran and ...fermented rice bran intake. Adult male BALB/c mice were fed a control diet or one of two experimental diets containing 10% w/w rice bran fermented by Bifidobacterium longum or 10% w/w non-fermented rice bran for 15 weeks. Metabolomics was performed on the study diets (food), the murine colon and whole blood. These were analysed in concert with 16S rRNA amplicon sequencing of faeces, caecum, and colon microbiomes. Principal components analysis of murine microbiota composition displayed marked separation between control and experimental diets, and between faecal and tissue (caecum and colon) microbiomes. Colon and caecal microbiomes in both experimental diet groups showed enrichment of Roseburia, Lachnospiraceae, and Clostridiales related amplicon sequence variants compared to control. Bacterial composition was largely similar between experimental diets. Metabolite profiling revealed 530 small molecules comprising of 39% amino acids and 21% lipids that had differential abundances across food, colon, and blood matrices, and statistically significant between the control, rice bran, and fermented rice bran groups. The amino acid metabolite, N-delta-acetylornithine, was notably increased by B. longum rice bran fermentation when compared to non-fermented rice bran in food, colon, and blood. These findings support that dietary intake of rice bran fermented with B. longum modulates multiple metabolic pathways important to the gut and overall health.
ABSTRACT We present a new, publicly available set of Los Alamos OPLIB opacity tables for the elements hydrogen through zinc. Our tables are computed using the Los Alamos ATOMIC opacity and plasma ...modeling code, and make use of atomic structure calculations that use fine-structure detail for all the elements considered. Our equation of state model, known as ChemEOS, is based on the minimization of free energy in a chemical picture and appears to be a reasonable and robust approach to determining atomic state populations over a wide range of temperatures and densities. In this paper we discuss in detail the calculations that we have performed for the 30 elements considered, and present some comparisons of our monochromatic opacities with measurements and other opacity codes. We also use our new opacity tables in solar modeling calculations and compare and contrast such modeling with previous work.
Glucagon and glucagon-like peptide-1 (GLP-1) are evolutionarily related anorectic hormones. Glucagon also increases energy expenditure. The combination of glucagon and GLP-1 could cause weight loss ...through a simultaneous reduction in food intake and increased energy expenditure. However, the effect of combined administration of glucagon and GLP-1 on food intake and neuronal activation has not previously been studied. Furthermore, the effect of glucagon on neuronal activation in appetite regulating centres has not been assessed. Characterisation of the effects of glucagon when administered singly and in combination with GLP-1 on neuronal activation will be important for determining the mechanism of action of related potential antiobesity therapies.
To investigate the effects of peripherally administered GLP-1 and glucagon on food intake, neuronal activation and blood glucose in mice when administered individually and in combination.
Food intake, blood glucose and c-fos expression in the hypothalamus, amygdala and brainstem were measured in response to GLP-1 and glucagon, alone and in combination.
Peripherally administered GLP-1 and glucagon decreased food intake and increased c-fos expression in the brainstem and amygdala. Doses of GLP-1 and glucagon that individually did not significantly affect feeding, in combination were anorectic and stimulated neuronal activation in the area postrema (AP) and central nucleus of the amygdala. Combined administration of GLP-1 and glucagon prevented the acute hyperglycemic effect of glucagon alone.
Anorectic doses of glucagon and GLP-1 induced similar patterns of c-fos expression. Combined administration of low dose GLP-1 and glucagon inhibited food intake and induced c-fos expression in the AP and amygdala. The combination of both hormones may offer the opportunity to utilise the beneficial effects of reduced food intake and increased energy expenditure, and may therefore be a potential treatment for obesity.
In cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG ...dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific.
Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing.
mQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation.
Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.
Over the past ten years there has been a resurgence of interest in the coordination chemistry of lanthanide complexes in aqueous solution. Parker et al highlight the complexation chemistry of ...lanthanide ions in aqueous solution.
BACKGROUND AND AIMS: The extent to which the carbohydrate source–sink ratio influences the time of veraison of different Vitis vinifera L. cultivars was studied for Sauvignon Blanc and Pinot Noir. ...The aims were to: (i) determine how changing the leaf area: fruit mass (LA : FM) ratio shortly after fruitset alters the timing of veraison; (ii) establish the relative importance of adjusting the vine yield or the leaf area on the timing of veraison; and (iii) evaluate the relative effect on the timing of veraison, leaf area and yield parameters of the two cultivars at similar LA : FM ratios. METHODS AND RESULTS: Four cane, vertical shoot positioned trained vines were trimmed shortly after fruitset to retain six or 12 leaves per shoot and thinned by removing 0, 50 or 75% of the bunches. The timing of veraison was assessed by colour change for Pinot Noir, berry softness for Sauvignon Blanc and the day at which a mean of 8°Brix was reached for both cultivars. Manipulating leaf area had a greater effect on the date of veraison than crop removal, which had no effect, except when vines were trimmed to six leaves. Sauvignon Blanc was always later than Pinot Noir for the time to reach 8°Brix at all LA : FM ratio manipulations. CONCLUSIONS: Restricting potential carbohydrate sources post‐flowering delayed veraison, while removing crop had less influence. SIGNIFICANCE OF THE STUDY: Reduced leaf area can delay the time of veraison, which could counter the earlier timing that could occur from climate change or warmer than average seasons. Conversely, increased leaf area could enable target soluble solids to be achieved in cooler seasons.
Summary
This study reported the effects of enzymatic hydrolysis treatments on the physiochemical properties of beef bone extract using endo‐ and exoproteases. Each enzyme hydrolysis kinetics were ...studied using Michaelis–Menten model, and the ideal E/S ratio obtained for Protamex® (P), bromelain (B) and Flavourzyme® (F) was found to be 1.10%, 1.60% and 4.70% w/w, respectively. Seven hydrolysates were produced from single (P, B, F), simultaneous (P + F, B + F) and sequential (P > F, B > F) treatments, where bone extract hydrolysed by Flavourzyme® exhibited highest DH and proportion of low molecular weight (Mw) peptides (<5000 Da) in single treatment. When Flavourzyme® was used with Protamex® or bromelain in simultaneous or sequential treatments, no significant differences in Mw distribution, exposed SH content, SS content and viscosity were evident compared with Flavourzyme® only. This indicated that without the addition of other enzymes, Flavourzyme® was capable of increasing the proportion of low Mw peptides and reduce viscosity.
Three types of endo‐ and exoproteases were used to hydrolyse beef bone extract at different hydrolysis treatments (i.e. single, simultaneous and sequential). Results shown that enzymatic hydrolysis reduced the viscosities of beef bone hydrolysates by cutting the high molecular peptides into small fragments.
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