XAV939-mediated ARTD activity inhibition in human MB cell lines

Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD-5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients

Ignitor: Physics and Progress Towards Ignition

Thermonuclear ignition condition for deuterium-tritium plasmas can be achieved in compact, high magnetic field devices such as Ignitor. The main scientific goals, the underlying physics basis, and the most relevant engineering solutions of this experiment are described. Burning plasma conditions can be reached either with ohmic heating only or with small amount of auxiliary power in the form of ICRH waves, and this condition can be sustained for a time considerably longer than all the relevant plasma time scales. In the reference operating scenario, no transport barriers are present, and the resulting thermal loads on the plasma facing component are estimated to be rather modest, thanks to the high edge density and low edge temperature that ensure an effective intrinsic radiating mantle in elongated limiter configurations. Enhanced confinement regimes can also be obtained in configurations with double X-points near the first wall

Structural approaches to modeling the impact of climate change and adaptation technologies on crop yields and food security

Article purchasedAchieving and maintaining global food security is challenged by changes in population, income, and climate, among other drivers. Assessing these threats and weighing possible solutions requires a robust multidisciplinary approach. One such approach integrates biophysical modeling with economic modeling to explore the combined effects of climate stresses and future socioeconomic trends, thus providing a more accurate picture of how agriculture and the food system may be affected in the coming decades. We review and analyze the literature on this structural approach and present a case study that follows this methodology, explicitly modeling drought and heat tolerant crop varieties. We show that yield gains from adoption of these varieties differ by technology and region, but are generally comparable in scale to (and thus able to offset) adverse effects of climate change. However, yield increases over the projection period are dominated by the effects of growth in population, income, and general productivity, highlighting the importance of joint assessment of biophysical and socioeconomic drivers to better understand climate impacts and responses

Different renal phenotypes in related adult males with Fabry disease with the same classic genotype

BACKGROUND: Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation. METHODS: A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia. RESULTS: The DBS revealed absent leukocyte \u3b1-Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuria and proteinuria were absent. The brain MRI showed ischemic lesions and a diffuse focus of gliosis in the white matter, while the echocardiogram showed a left ventricular hypertrophy. The renal biopsy performed in the case index showed a massive deposition of zebra bodies. By a familiar investigation, it was recognized that his brother (Patient 2) died 2 years before from sudden death syndrome at the age of 49. He had suffered sporadic and undiagnosed pain at the extremities, a prior cataract, bilateral neurosensorial hearing loss and left ventricular hypertrophy on Echocardiogram. His previous laboratory examinations revealed a normal serum creatinine and the absence of proteinuria. Pedigree analysis of the brothers revealed a high disease burden among family members, with an affected cousin (Patient 3) who progressed early to end-stage renal disease (ESRD) that required renal transplantation. CONCLUSIONS: Here we describe the clinical history of three adult male members of the same family with the same genotype who manifested different presentation and progression of the disease, particularly concerning the renal involvement

Mesenchymal stem cells in renal function recovery after acute kidney injury. Use of a differentiating agent in a rat model.

Acute kidney injury (AKI) is a major health care condition with limited current treatment options. Within this context, stem cells may provide a clinical approach for AKI. Moreover, a synthetic compound previously developed, hyaluronan monoesters with butyric acid (HB), able to induce metanephric differentiation, formation of capillary-like structures, and secretion of angiogenic cytokines, was tested in vitro. Thereafter, we investigated the effects of human mesenchymal stem cells from fetal membranes (FMhMSCs), both treated and untreated with HB, after induction of ischemic AKI in a rat model. At reperfusion following 45-min clamping of renal pedicles, each rat was randomly assigned to one of four groups: CTR, PBS, MSC, and MSC-HB. Renal function at 1, 3, 5, and 7 days was assessed. Histological samples were analyzed by light and electron microscopy and renal injury was graded. Cytokine analysis on serum samples was performed. FMhMSCs induced an accelerated renal functional recovery, demonstrated by biochemical parameters and confirmed by histology showing that histopathological alterations associated with ischemic injury were less severe in cell-treated kidneys. HB-treated rats showed a minor degree of inflammation, both at cytokine and TEM analyses. Better functional and morphological recovery were not associated to stem cells' regenerative processes, but possibly suggest paracrine effects on microenvironment that induce retrieval of renal damaged tissues. These results suggest that FMhMSCs could be useful in the treatment of AKI and the utilization of synthetic compounds could enhance the recovery induction ability of cells

Climate change adaptation in agriculture: Ex ante analysis of promising and alternative crop technologies using DSSAT and IMPACT

Achieving and maintaining global food security is challenged by changes in population, income, and climate, among other drivers. Assessing these challenges and possible solutions over the coming decades requires a rigorous multidisciplinary approach. To answer this challenge, the International Food Policy Research Institute (IFPRI) has developed a system of linked simulation models of global agriculture to do long-run scenario analysis of the effects of climate change and various adaptation strategies. This system includes the core International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT), which is linked to water models (global hydrology, water basin management, and water stress on crops) and crop simulation models. The Global Futures and Strategic Foresight program, a CGIAR initiative led by IFPRI in collaboration with other CGIAR research centers, is working to improve these tools and conducting ex ante assessments of promising technologies, investments, and policies under alternative global futures. Baseline projections from IMPACT set the foundation with the latest outlook on long-term trends in food demand and agricultural production based on projected changes in population, income, technology, and climate. On top of the baseline, scenarios are developed for assessing the impacts of promising climate-adapted technologies for maize, wheat, rice, potatoes, sorghum, groundnut, and cassava on yields, area, production, trade, and prices in 2050 at a variety of scales. Yield gains from adoption of the selected technologies vary by technology and region, but are found to be generally comparable in scale to (and thus able to offset) the adverse effects of climate change under a high-emissions representative concentration pathway (RCP 8.5). Even more important in this long-term climate change scenario are effects of growth in population, income, and investments in overall technological change, highlighting the importance of linked assessment of biophysical and socioeconomic drivers to better understand climate impacts and responses. For all crops in the selected countries, climate change impacts are negative with the baseline technology. All new technologies have beneficial effects on yields under climate change, with combined traits (drought and heat tolerance) showing the greatest benefi

ITA-MNGIE: an Italian regional and national survey for mitochondrial neuro-gastro-intestinal encephalomyopathy

Mitochondrial neuro-gastro-intestinal encephalomyopathy (MNGIE) is a rare and unavoidably fatal disease due to mutations in thymidine phosphorylase (TP). Clinically it is characterized by gastrointestinal dysfunction, malnutrition/cachexia and neurological manifestations. MNGIE diagnosis remains a challenge mainly because of the complexity and rarity of the disease. Thus, our purposes were to promote a better knowledge of the disease in Emilia-Romagna region (ERR) by creating an accurate and dedicated network; to establish the minimal prevalence of MNGIE in Italy starting from ERR. Blood TP activity level was used as screening test to direct candidates to complete diagnostic work-up. During the study period of 1 year, only 10/71 units of ERR recruited 14 candidates. Their screening did not show TP activity changes. An Italian patient not resident in ERR was actually proved to have MNGIE. At the end of study in Italy there were nine cases of MNGIE; thus, the Italian prevalence of the disease is ~0.15/1,000,000 as a gross estimation. Our study confirms that MNGIE diagnosis is a difficult process which reflects the rarity of the disease and, as a result, a low level of awareness among specialists and physicians. Having available novel therapeutic options (e.g., allogenic hematopoietic stem cell transplantation and, more recently, liver transplantation) and an easy screening test, an early diagnosis should be sought before tissue damage occurs irreversibly