Glioma cells influence the migration of neuralized mouse embryonic stem cells in vivo [abstract]

Abstract only availableOf the 200,000 brain tumors diagnosed in the United States each year, approximately 23% of them are glioblastomas (Brain Tumor Society 2004). These aggressive tumors spread rapidly and are resistant to standard treatment, and the average survival rate of patients diagnosed with glioblastomas is approximately one year. Current research suggests there is great potential for neural stem cells (NSCs) to be used as a delivery vehicle for therapeutic agents against tumors. Studies have shown NSCs have an innate attraction to tumors and other inflammatory diseases of the brain. This NSC pathotropism is due in part to inflammatory signals, angiogenesis, reactive astrocytosis, and tumor cytokines (M&uumlller, et al. 2006). By harnessing their natural tropism, NSCs engineered with chemotherapeutic properties can be used to track and target tumors for destruction. To demonstrate the therapeutic potential of NSCs as a transplantable, therapeutic delivery system, we are investigating the in vivo migratory behavior and cellular fate of neuralized mouse embryonic stem cells (mESCs) in the presence of glioma cells. In this study, neuralized mESCs and SF767 human glioblastoma cells were injected into opposite hemispheres of the mouse cortex, and frozen sections of the brain tissue were examined to determine the extent of mESC migration and survival. After 3 days in vivo, co-localization of tumor and neuralized mESCs was evident in multiple sections. Previously, we have seen co-localization of neuralized mESCs and tumor cells on organotypic mouse brain slices after approximately one week of migration. NSC migration to tumor cells in vivo lends support to current efforts to use stem cells as a therapeutic deliver system. Furthermore, the neuralized mESCs' proximity to the tumor cells will allow for the specific delivery of chemotherapeutic agents to tumor sites. Expanding our knowledge of fundamental characteristics and behaviors of neural stem cells will facilitate the development of novel and effective stem cell therapies for glioblastomas

Electric vehicles as distribution grid batteries:a reality check

Abstract The current transition towards electric mobility implies that a significant portion of electricity is drawn by and stored in the electric vehicle’s (EV) batteries. Vehicle-to-grid (V2G) technologies can potentially give distribution system operators access to such energy to provide ancillary services, while remunerating the vehicle owners for their availability to participate. Although the benefits of stabilization and grid efficiency improvements are clear, is it appealing and lucrative for the vehicle owners to participate in such services? In this work, we answer this question by modelling the V2G system and performing economic projections of the possible benefits for EV owners. In particular, we present a novel way of parametrizing the electric vehicle driving profile and the V2G energy transfer to compute battery degradation costs. A profit model is developed to evaluate the profit earned by the vehicle owners offering their batteries. The profit is estimated on the basis of the owner’s inclination to buy and sell energy from the grid based on the electricity price. Using data of the German electricity market, we estimate a profit of 662 €/EV/Year for a vehicle with 100 kWh capacity, 95% battery round trip efficiency and driving 52 km per day. The remuneration is meaningful and can have the potential to encourage EV owners to participate in V2G service

Vitamin D prescribing in children in UK primary care practices:a population-based cohort study

OBJECTIVE: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016. DESIGN: Population-based cohort study. SETTING: UK general practice health records from The Health Improvement Network. PARTICIPANTS: Children aged 0 to 17 years who were registered with their general practices for at least 3 months. OUTCOME MEASURES: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed. RESULTS: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually. CONCLUSIONS: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs

Feasibility of a multiparametric MRI protocol for imaging biomarkers associated with neoadjuvant radiotherapy for soft tissue sarcoma

OBJECTIVE: Soft tissue sarcoma (STS) is a rare malignancy with a 5 year overall survival rate of 55%. Neoadjuvant radiotherapy is commonly used in preparation for surgery, but methods to assess early response are lacking despite pathological response at surgery being predictive of overall survival, local recurrence and distant metastasis. Multiparametric MR imaging (mpMRI) is used to assess response in a variety of tumours but lacks a robust, standardised method. The overall aim of this study was to develop a feasible imaging protocol to identify imaging biomarkers for further investigation. METHODS: 15 patients with biopsy-confirmed STS suitable for pre-operative radiotherapy and radical surgery were imaged throughout treatment. The mpMRI protocol included anatomical, diffusion-weighted and dynamic contrast-enhanced imaging, giving estimates of apparent diffusion coefficient (ADC) and the area under the enhancement curve at 60 s (iAUC(60)). Histological analysis of resected tumours included detection of CD31, Ki67, hypoxia inducible factor and calculation of a hypoxia score. RESULTS: There was a significant reduction in T1 at visit 2 and in ADC at visit 3. Significant associations were found between hypoxia and pre-treatment iAUC(60), pre-treatment ADC and mid-treatment iAUC(60). There was also statistically significant association between mid-treatment ADC and Ki67. CONCLUSION: This work showed that mpMRI throughout treatment is feasible in patients with STS having neoadjuvant radiotherapy. The relationships between imaging parameters, tissue biomarkers and clinical outcomes warrant further investigation. ADVANCES IN KNOWLEDGE: mpMRI-based biomarkers have good correlation with STS tumour biology and are potentially of use for evaluation of radiotherapy response

Cell–substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime

The Scar/WAVE complex is the principal catalyst of pseudopod and lamellipod formation. Here we show that Scar/WAVE’s proline-rich domain is polyphosphorylated after the complex is activated. Blocking Scar/WAVE activation stops phosphorylation in both Dictyostelium and mammalian cells, implying that phosphorylation modulates pseudopods after they have been formed, rather than controlling whether they are initiated. Unexpectedly, phosphorylation is not promoted by chemotactic signaling but is greatly stimulated by cell:substrate adhesion and diminished when cells deadhere. Phosphorylation-deficient or phosphomimetic Scar/WAVE mutants are both normally functional and rescue the phenotype of knockout cells, demonstrating that phosphorylation is dispensable for activation and actin regulation. However, pseudopods and patches of phosphorylation-deficient Scar/WAVE last substantially longer in mutants, altering the dynamics and size of pseudopods and lamellipods and thus changing migration speed. Scar/WAVE phosphorylation does not require ERK2 in Dictyostelium or mammalian cells. However, the MAPKKK homologue SepA contributes substantially—sepA mutants have less steady-state phosphorylation, which does not increase in response to adhesion. The mutants also behave similarly to cells expressing phosphorylation-deficient Scar, with longer-lived pseudopods and patches of Scar recruitment. We conclude that pseudopod engagement with substratum is more important than extracellular signals at regulating Scar/WAVE’s activity and that phosphorylation acts as a pseudopod timer by promoting Scar/WAVE turnover

Developmental cues and persistent neurogenic potential within an in vitro neural niche

<p>Abstract</p> <p>Background</p> <p>Neurogenesis, the production of neural cell-types from neural stem cells (NSCs), occurs during development as well as within select regions of the adult brain. NSCs in the adult subependymal zone (SEZ) exist in a well-categorized niche microenvironment established by surrounding cells and their molecular products. The components of this niche maintain the NSCs and their definitive properties, including the ability to self-renew and multipotency (neuronal and glial differentiation).</p> <p>Results</p> <p>We describe a model <it>in vitro </it>NSC niche, derived from embryonic stem cells, that produces many of the cells and products of the developing subventricular zone (SVZ) and adult SEZ NSC niche. We demonstrate a possible role for apoptosis and for components of the extracellular matrix in the maintenance of the NSC population within our niche cultures. We characterize expression of genes relevant to NSC self-renewal and the process of neurogenesis and compare these findings to gene expression produced by an established neural-induction protocol employing retinoic acid.</p> <p>Conclusions</p> <p>The <it>in vitro </it>NSC niche shows an identity that is distinct from the neurally induced embryonic cells that were used to derive it. Molecular and cellular components found in our <it>in vitro </it>NSC niche include NSCs, neural progeny, and ECM components and their receptors. Establishment of the <it>in vitro </it>NSC niche occurs in conjunction with apoptosis. Applications of this culture system range from studies of signaling events fundamental to niche formation and maintenance as well as development of unique NSC transplant platforms to treat disease or injury.</p

Unveiling Dark Matter free-streaming at the smallest scales with high redshift Lyman-alpha forest

This study introduces novel constraints on the free-streaming of thermal relic warm dark matter (WDM) from Lyman-$\alpha$ forest flux power spectra. Our analysis utilises a high-resolution, high-redshift sample of quasar spectra observed using the HIRES and UVES spectrographs ($z=4.2-5.0$). We employ a Bayesian inference framework and a simulation-based likelihood that encompasses various parameters including the free-streaming of dark matter, cosmological parameters, the thermal history of the intergalactic medium, and inhomogeneous reionization, to establish lower limits on the mass of a thermal relic WDM particle of $5.7\;\mathrm{keV}$ (at 95\% C.L.). This result surpasses previous limits from the Lyman-$\alpha$ forest through reduction of the measured uncertainties due to a larger statistical sample and by measuring clustering to smaller scales ($k_{\rm max}=0.2\;\mathrm{km^{-1}\,s}$). The approximately two-fold improvement due to the expanded statistical sample suggests that the effectiveness of Lyman-$\alpha$ forest constraints on WDM models at high redshifts are limited by the availability of high-quality quasar spectra. Restricting the analysis to comparable scales and thermal history priors as in prior studies ($k_{\rm max}<0.1\;\mathrm{km^{-1}\,s}$) lowers the bound on the WDM mass to $4.1\;\mathrm{keV}$. As the precision of the measurements increases, it becomes crucial to examine the instrumental and modelling systematics. On the modelling front, we argue that the impact of the thermal history uncertainty on the WDM particle mass constraint has diminished due to improved independent observations. At the smallest scales, the primary source of modeling systematic arises from the structure in the peculiar velocity of the intergalactic medium and inhomogeneous reionization.Comment: 22 pages, 14 figures, 2 tables; submitte