Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

A feminist new materialist experiment: exploring what else gets produced through encounters with children’s news media

In this paper we are concerned to grapple with the ways in which real world issues directly impact children’s lives, and ask what else gets produced through encounters with children’s global news media specifically within the contexts of the UK and Norway. Our aim is to experiment with worldling practices as a means to open up generative possibilities to encounter and reconfigure difficult knowledges. We take two contemporary events: the 2017 Grenfell Tower fire tragedy in London, and the 2018 Marjory Stoneman high school shooting massacre in Florida, as a means to attend to ways in which affects are materialised across multiple times and spaces. News reports of these harrowing events, alongside what they produced, in terms of child activism, racism and toxic masculinity, provided a catalyst for a feminist new materialist experiment in generating other knowledges through material-affective-embodied encounters. Newspapers, glue, sticky tape, string, torches, bags and a cartridge for a firearm undertook important work within a speculative workshop, where a small number of early childhood researchers came together to be open to multiple and experimental ways of (k)not-knowing in order to formulate collectively shared problems. Following Manning (2016) we recognise that to avoid getting stuck in familiar ways of thinking and doing we need to undertake research differently. We wondered how might the re-materialisation of these events (through objects, artefacts, sounds and images) shift our thinking about childhood in other directions. We dwell upon the affective work that these high-profile news events perform, and how they might become rearticulated through affective encounters with materiality. Attending to how these events worked on us involves staying with the trouble (Haraway, 2016) as it becomes reignited, mutated and amplified across time and in different contexts. Our goal is to generate other possibilities that seek to reconfigure the ‘image of the child’. By resisting comforts of recognition, reflection and identification we reach beyond what we think we know about how children are in the world, and instead argue for their entanglement with difficult knowledges through, ours and their, world-making practices

World Spinors - Construction and Some Applications

The existence of a topological double-covering for the $GL(n,R)$ and diffeomorphism groups is reviewed. These groups do not have finite-dimensional faithful representations. An explicit construction and the classification of all $\bar{SL}(n,R)$, $n=3,4$ unitary irreducible representations is presented. Infinite-component spinorial and tensorial $\bar{SL}(4,R)$ fields, "manifields", are introduced. Particle content of the ladder manifields, as given by the $\bar{SL}(3,R)$ "little" group is determined. The manifields are lifted to the corresponding world spinorial and tensorial manifields by making use of generalized infinite-component frame fields. World manifields transform w.r.t. corresponding $\bar{Diff}(4,R)$ representations, that are constructed explicitly.Comment: 19 pages, Te

Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: role of epigenetic adaptation.

Sufficient quantity and quality of skeletal muscle is required to maintain lifespan and healthspan into older age. The concept of skeletal muscle programming/memory has been suggested to contribute to accelerated muscle decline in the elderly in association with early life stress such as fetal malnutrition. Further, muscle cells in vitro appear to remember the in vivo environments from which they are derived (e.g. cancer, obesity, type II diabetes, physical inactivity and nutrient restriction). Tumour-necrosis factor alpha (TNF-α) is a pleiotropic cytokine that is chronically elevated in sarcopenia and cancer cachexia. Higher TNF-α levels are strongly correlated with muscle loss, reduced strength and therefore morbidity and earlier mortality. We have extensively shown that TNF-α impairs regenerative capacity in mouse and human muscle derived stem cells [Meadows et al. (J Cell Physiol 183(3):330-337, 2000); Foulstone et al. (J Cell Physiol 189(2):207-215, 2001); Foulstone et al. (Exp Cell Res 294(1):223-235, 2004); Stewart et al. (J Cell Physiol 198(2):237-247, 2004); Al-Shanti et al. (Growth factors (Chur, Switzerland) 26(2):61-73, 2008); Saini et al. (Growth factors (Chur, Switzerland) 26(5):239-253, 2008); Sharples et al. (J Cell Physiol 225(1):240-250, 2010)]. We have also recently established an epigenetically mediated mechanism (SIRT1-histone deacetylase) regulating survival of myoblasts in the presence of TNF-α [Saini et al. (Exp Physiol 97(3):400-418, 2012)]. We therefore wished to extend this work in relation to muscle memory of catabolic stimuli and the potential underlying epigenetic modulation of muscle loss. To enable this aim; C2C12 myoblasts were cultured in the absence or presence of early TNF-α (early proliferative lifespan) followed by 30 population doublings in the absence of TNF-α, prior to the induction of differentiation in low serum media (LSM) in the absence or presence of late TNF-α (late proliferative lifespan). The cells that received an early plus late lifespan dose of TNF-α exhibited reduced morphological (myotube number) and biochemical (creatine kinase activity) differentiation vs. control cells that underwent the same number of proliferative divisions but only a later life encounter with TNF-α. This suggested that muscle cells had a morphological memory of the acute early lifespan TNF-α encounter. Importantly, methylation of myoD CpG islands were increased in the early TNF-α cells, 30 population doublings later, suggesting that even after an acute encounter with TNF-α, the cells have the capability of retaining elevated methylation for at least 30 cellular divisions. Despite these fascinating findings, there were no further increases in myoD methylation or changes in its gene expression when these cells were exposed to a later TNF-α dose suggesting that this was not directly responsible for the decline in differentiation observed. In conclusion, data suggest that elevated myoD methylation is retained throughout muscle cells proliferative lifespan as result of early life TNF-α treatment and has implications for the epigenetic control of muscle loss

Segregating the Distinct Effects of Sedentary Behavior and Physical Activity on Older Adults' Cardiovascular Profile: Part 2-Isotemporal Substitution Approach.

The aim of the study was to provide an isotemporal substitution model to predict how changes in physical behavior may affect the cardiovascular parameters (CVPs) of older adults. Methods: Participants wore a thigh-mounted accelerometer for 7 days. Phenotype of the carotid, brachial, and popliteal artery was conducted using ultrasound. Isotemporal substitution was used to simulate the degree to which replacing 1 hour of physical behavior with another would affect CVP. Results: Substitution of sedentary behavior with Standing and sporadic moderate- to vigorous-intensity physical activity (MVPA accumulated in bouts <10 min) would reduce resting heart rate [−6.20 beats per minute (−12.1 to −0.22) and −3.72 beats per minute (−7.01 to −0.44), respectively]. Substitution of sedentary behavior with light-intensity physical activity would reduce carotid artery diameter [−0.54 mm (−1.00 to −0.07)]. Substitution of Standing with sporadic MVPA would increase popliteal artery diameter [1.31 mm (0.11 to 2.51)]. Conclusions: Our modeling suggests that an accumulation of MVPA bouts that are shorter than the recommended 10-minute minimum may still improve CVP, with lower intensity physical activity also influencing CVP. Our findings are a promising avenue for lifestyle interventions in older adults to reduce the aging effects on CVP for those who cannot engage or sustain sufficient MVPA

L-glutamine improves skeletal muscle cell differentiation and prevents myotube atrophy after cytokine (TNF-α) stress via reduced p38 MAPK signal transduction

Tumour Necrosis Factor- Alpha (TNF-α) is chronically elevated in conditions where skeletal muscle loss occurs. As L-glutamine can dampen the effects of inflamed environments, we investigated the role of L-glutamine in both differentiating C2C12 myoblasts and existing myotubes in the absence/presence of TNF-α (20 ng.ml−1) ± L-glutamine (20 mM).TNF-α reduced the proportion of cells in G1 phase, as well as biochemical (CK activity) and morphological differentiation (myotube number), with corresponding reductions in transcript expression of: Myogenin, Igf-I and Igfbp5. Furthermore, when administered to mature myotubes, TNF-α induced myotube loss and atrophy underpinned by reductions in Myogenin, Igf-I, Igfbp2 and glutamine synthetase and parallel increases in Fox03, Cfos, p53 and Bid gene expression. Investigation of signaling activity suggested that Akt and ERK1/2 were unchanged, JNK increased (non-significantly) whereas P38 MAPK substantially and significantly increased in both myoblasts and myotubes in the presence of TNF-α. Importantly, 20 mM L-glutamine reduced p38 MAPK activity in TNF-α conditions back to control levels, with a corresponding rescue of myoblast differentiation and a reversal of atrophy in myotubes. L-glutamine resulted in upregulation of genes associated with growth and survival including; Myogenin, Igf-Ir, Myhc2 & 7, Tnfsfr1b, Adra1d and restored atrophic gene expression of Fox03 back to baseline in TNF-α conditions. In conclusion, L-glutamine supplementation rescued suppressed muscle cell differentiation and prevented myotube atrophy in an inflamed environment via regulation of p38 MAPK. L-glutamine administration could represent an important therapeutic strategy for reducing muscle loss in catabolic diseases and inflamed ageing. This article is protected by copyright. All rights reserve

Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study

Type 1 diabetes is the product of a complex interplay between genetic susceptibility and exposure to environmental factors. Existing bacterial profiling studies focus on people who are most at risk at the time of diagnosis; there are limited data on the gut microbiota of people with long-standing Type 1 diabetes. This study compared the gut microbiota of patients with Type 1 diabetes and good glycaemic control and high levels of physical-fitness with that of matched controls without diabetes.Ten males with Type 1 diabetes and ten matched controls without diabetes were recruited; groups were matched for gender, age, BMI, peak oxygen uptake (VO2max ), and exercise habits. Stool samples were analysed using next-generation sequencing of the 16S rRNA gene to obtain bacterial profiles from each individual. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was implemented to predict the functional content of the bacterial operational taxonomic units.Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were typically the most abundant members of the community in both patients with Type 1 diabetes and controls, and were present in every sample in the cohort. Each bacterial profile was relatively individual and no significant difference was reported between the bacterial profiles or the Shannon diversity indices of Type 1 diabetes compared with controls. The functional profiles were more conserved and the Type 1 diabetes group were comparable with the control group.We show that both gut microbiota and resulting functional bacterial profiles from patients with long-standing Type 1 diabetes in good glycaemic control and high physical fitness levels are comparable with those of matched people without diabetes. This article is protected by copyright. All rights reserved

Coprecipitation of 14C and Sr with carbonate precipitates: The importance of reaction kinetics and recrystallization pathways

This study investigated the simultaneous removal of Sr2+ and 14CO32- from an alkaline (pH >12) Ca(OH)2 solution by the precipitation of calcium carbonate. Initial Ca2+:CO32- ratios ranged from 10:1 to 10:100 (mM: mM). Maximum removal of 14C and Sr2+ both occurred in the system containing 10 mM Ca2+ and 1 mM CO32- (99.7% and 98.6% removal, respectively). A kinetic model is provided that describes 14C and Sr removal in terms of mineral dissolution & precipitation reactions. The removal of 14C was achieved during the depletion of the initial TIC in solution, and was subsequently significantly affected by recrystallization of a calcite precipitate from an elongate to isotropic morphology. This liberated >46% of the 14C back to solution. Sr2+ removal occurred as Ca2+ became depleted in solution and was not significantly affected by the recrystallization process. This reaction could form the basis for low cost remediation scheme for 90Sr and 14C in radioactively contaminated waters (<$0.25 reagent cost per m3 treated)

Impact of socioeconomic deprivation on rate and cause of death in severe mental illness

Background: Socioeconomic status has important associations with disease-specific mortality in the general population. Although individuals with Severe Mental Illnesses (SMI) experience significant premature mortality, the relationship between socioeconomic status and mortality in this group remains under investigated.&lt;p&gt;&lt;/p&gt; Aims: To assess the impact of socioeconomic status on rate and cause of death in individuals with SMI (schizophrenia and bipolar disorder) relative to the local (Glasgow) and wider (Scottish) populations.&lt;p&gt;&lt;/p&gt; Methods: Cause and age of death during 2006-2010 inclusive for individuals with schizophrenia or bipolar disorder registered on the Glasgow Psychosis Clinical Information System (PsyCIS) were obtained by linkage to the Scottish General Register Office (GRO). Rate and cause of death by socioeconomic status, measured by Scottish Index of Multiple Deprivation (SIMD), were compared to the Glasgow and Scottish populations.&lt;p&gt;&lt;/p&gt; Results: Death rates were higher in people with SMI across all socioeconomic quintiles compared to the Glasgow and Scottish populations, and persisted when suicide was excluded. Differences were largest in the most deprived quintile (794.6 per 10,000 population vs. 274.7 and 252.4 for Glasgow and Scotland respectively). Cause of death varied by socioeconomic status. For those living in the most deprived quintile, higher drug-related deaths occurred in those with SMI compared to local Glasgow and wider Scottish population rates (12.3% vs. 5.9%, p = &#60;0.001 and 5.1% p = 0.002 respectively). A lower proportion of deaths due to cancer in those with SMI living in the most deprived quintile were also observed, relative to the local Glasgow and wider Scottish populations (12.3% vs. 25.1% p = 0.013 and 26.3% p = &#60;0.001). The proportion of suicides was significantly higher in those with SMI living in the more affluent quintiles relative to Glasgow and Scotland (54.6% vs. 5.8%, p = &#60;0.001 and 5.5%, p = &#60;0.001). Discussion and conclusions: Excess mortality in those with SMI occurred across all socioeconomic quintiles compared to the Glasgow and Scottish populations but was most marked in the most deprived quintiles when suicide was excluded as a cause of death. Further work assessing the impact of socioeconomic status on specific causes of premature mortality in SMI is needed