Impaired Translesion Synthesis in Xeroderma Pigmentosum Variant Extracts

Xeroderma pigmentosum variant (XPV) cells are characterized by a cellular defect in the ability to synthesize intact daughter DNA strands on damaged templates. Molecular mechanisms that facilitate replication fork progression on damaged DNA in normal cells are not well defined. In this study, we used single-stranded plasmid molecules containing a single N-2-acetylaminofluorene (AAF) adduct to analyze translesion synthesis (TLS) catalyzed by extracts of either normal or XPV primary skin fibroblasts. In one of the substrates, the single AAF adduct was located at the 3' end of a run of three guanines that was previously shown to induce deletion of one G by a slippage mechanism. Primer extension reactions performed by normal cellular extracts from four different individuals produced the same distinct pattern of TLS, with over 80% of the products resulting from the elongation of a slipped intermediate and the remaining 20% resulting from a nonslipped intermediate. In contrast, with cellular extracts from five different XPV patients, the TLS reaction was strongly reduced, yielding only low amounts of TLS via the nonslipped intermediate. With our second substrate, in which the AAF adduct was located at the first G in the run, thus preventing slippage from occurring, we confirmed that normal extracts were able to perform TLS 10-fold more efficiently than XPV extracts. These data demonstrate unequivocally that the defect in XPV cells resides in translesion synthesis independently of the slippage proces

Interactive Generation of Time-Evolving Snow-Covered Landscaped with Avalanches

We introduce a novel method for interactive generation of visually consistent, snow-covered landscapes and provide control of their dynamic evolution over time. Our main contribution is the real-time phenomenological simulation of avalanches and other user-guided events, such as tracks left by Nordic skiing, which can be applied to interactively sculpt the landscape. The terrain is modeled as a height field with additional layers for stable, compacted, unstable, and powdery snow, which behave in combination as a semi-viscous fluid. We incorporate the impact of several phenomena, including sunlight, temperature, prevailing wind direction, and skiing activities. The snow evolution includes snow-melt and snow-drift, which affect stability of the snow mass and the probability of avalanches. A user can shape landscapes and their evolution either with a variety of interactive brushes, or by prescribing events along a winter season time-line. Our optimized GPU-implementation allows interactive updates of snow type and depth across a large (10×10km) terrain, including real-time avalanches, making this suitable for visual assets in computer games. We evaluate our method through perceptual comparison against exiting methods and real snow-depth data

Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death

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Difficulties in the revaccination program of hematopoietic stem cell transplantation recipients

ABSTRACT Hematopoietic stem cell transplant (HSCT) recipients should be routinely revaccinated after transplantation. We evaluated the difficulties met in the revaccination program and how a prospective and tailored follow-up could help to overcome these obstacles. HSCT recipients (n=122) were prospectively followed up and categorized into Group 1 (n=72), recipients who had already started the revaccination program, and Group 2 (n=50), recipients starting their vaccines. Whenever a difficulty was reported, interventions and subsequent evaluations were performed. Reported problems were related to patient compliance, HSCT center and/or vaccination center. Problems related to patient compliance were less frequent than those related to HSCT center modifications of previous recommendations, or to errors made by the vaccination center. The main gap found was vaccination delays (81.9%). Advisory intervention was needed in 64% and 46% of Group 1 and Group 2, respectively (p=0.05), and was partially successful in around 70% of the cases. Total resolution was achieved in more than 35% in both groups. Improvements are needed in the Brazilian vaccination program for HSCT recipients to assure a complete and updated revaccination schedule. HSCT centers should assign nurses and transplant infectious disease specialist physicians to organize the revaccination schedule and to monitor the program development

Prevalence of Clinical and Neuroimaging Markers in Cerebral Amyloid Angiopathy: A Systematic Review and Meta-Analysis

BACKGROUND: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. METHODS: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I2 statistics. RESULTS: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%-60%]; I2=93%), cortical superficial siderosis (49% [95% CI, 38%-59%]; I2=95%), dementia or mild cognitive impairment (50% [95% CI, 35%-65%]; I2=97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%-61%]; I2=98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%-67%]; I2=97%), lacunar infarcts (30% [95% CI, 25%-36%]; I2=78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%-67%]; I2=88%) and basal ganglia (21% [95% CI, 2%-51%]; I2=98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%-65%]; I2=91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01-2.46]; I2=47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P=0.03) and transient focal neurological episodes (57% versus 17%; P=0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. CONCLUSIONS: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings

Sustained release of TGF-β1 from biodegradable microparticles prepared by a new green process in CO2 medium

The aim of this work was to encapsulate transforming growth factor b1 (TGF-b1) into PLGA microparticles for regenerative medicine applications. TGF-b1 was firstly precipitated to ensure its stability during subsequent encapsulation within microparticles. A novel emulsification/extraction process in CO2 medium under mild conditions of pressure and temperature was used to encapsulate the protein. Interestingly, non-volatile injectable solvents, isosorbide dimethyl ether (DMI) and glycofurol (GF), were employed to precipitate the protein and to dissolve the polymer. Good encapsulation efficiency was obtained with preserved bioactivity of the protein. The microparticles were characterized in terms of size and zeta potential. In addition, the morphology and surface properties were determined using scanning electron microscopy (SEM) and atomic force microscopy (AFM) respectively. In vitro release study of the protein from microparticles was presented to assess the capacity of these systems to control the protein release. Moreover, cytotoxicity study was performed and showed an excellent cytocompatibility of the obtained microparticles. Thus, we described an effective and original process for TGF-b1 encapsulation into PLGA microparticles. The obtained polymeric carriers could be used in many biomedical applications and were more specifically developed for cartilage regeneration

Volatile and glycosidically bound composition of Loureiro and Alvarinho wines

Composition of Loureiro and Alvarinho wines from the Vinhos Verdes region, respecting free volatile compounds as well as glycosidically bound aroma precursors, was exhaustively determined by GC-MS after adsorption on XAD-2 resin. On the whole, were identified and quantified 120 volatile compounds in the free fraction and 77 glycosidically bound compounds, belonging to C6-compounds, alcohols, fatty acids ethyl esters, esters of organic acids, acetates, monoterpenic alcohols, monoterpenic oxides and diols, C13-norisoprenoids, volatile phenols, volatile fatty acids and carbonyl compounds. Globally, the wines of the two cultivars present similar composition on volatiles. However, respecting varietal compounds, Loureiro wines are richer than Alvarinho ones with regard to C6-compounds and monoterpenic compounds, occurring the opposite for volatile phenols. It was also demonstrate that wines of both varieties may benefit the aroma reserve, present as glycoconjugates, as it is susceptible of being technologically explored. Linalool, Ho-trienol, α-terpineol, contributing with fruity and floral notes, and β-damascenone mostly for Alvarinho, confering tropical fruit notes, are the varietal compounds which may particularly influence the aroma of these wines. Respecting fermentative compounds, Alvarinho is also particularly rich in fatty acids ethyl esters related to lipid metabolism and acetates of fusel alcohols, which can provide it a fruity character; Loureiro contains higher levels of esters of organic acids and 2-phenylethanol, conferring fruity and floral notes. Sensory analysis agree with chemical analyses showing a pronounced tree and tropical fruit character for Alvarinho wines while Loureiro wines present more intense citrus fruit notes.Centre of Biological Engineering of Universidade do Minho; Estação Vitivinícola Amândio Galhano (EVAG); Solar de Serrade; EVAG; Comissão de Viticultura da Região dos Vinhos Verdes

The effects of financialisation and financial development on investment: Evidence from firm-level data in Europe

In this paper we estimate the effects of financialization on physical investment in selected western European countries using panel data based on the balance-sheets of publicly listed non-financial companies (NFCs) supplied by Worldscope for the period 1995-2015. We find robust evidence of an adverse effect of both financial payments (interests and dividends) and financial incomes on investment in fixed assets by the NFCs. This finding is robust for both the pool of all Western European firms and single country estimations. The negative impacts of financial incomes are non-linear with respect to the companies’ size: financial incomes crowd-out investment in large companies, and have a positive effect on the investment of only small, relatively more credit-constrained companies. Moreover, we find that a higher degree of financial development is associated with a stronger negative effect of financial incomes on companies’ investment. This finding challenges the common wisdom on ‘finance-growth nexus’. Our findings support the ‘financialization thesis’ that the increasing orientation of the non-financial sector towards financial activities is ultimately leading to lower physical investment, hence to stagnant or fragile growth, as well as long term stagnation in productivity

Design, data management, and population baseline characteristics of the PERFORM magnetic resonance imaging project

Quantitative information from magnetic resonance imaging (MRI) may substantiate clinical findings and provide additional insight into the mechanism of clinical interventions in therapeutic stroke trials. The PERFORM study is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke. We report on the design of an exploratory longitudinal MRI follow-up study that was performed in a subgroup of the PERFORM trial. An international multi-centre longitudinal follow-up MRI study was designed for different MR systems employing safety and efficacy readouts: new T2 lesions, new DWI lesions, whole brain volume change, hippocampal volume change, changes in tissue microstructure as depicted by mean diffusivity and fractional anisotropy, vessel patency on MR angiography, and the presence of and development of new microbleeds. A total of 1,056 patients (men and women ≥55 years) were included. The data analysis included 3D reformation, image registration of different contrasts, tissue segmentation, and automated lesion detection. This large international multi-centre study demonstrates how new MRI readouts can be used to provide key information on the evolution of cerebral tissue lesions and within the macrovasculature after atherothrombotic stroke in a large sample of patients