Path integral Monte Carlo simulations for rigid rotors and their application to water

In this work the path integral formulation for rigid rotors, proposed by M\"user and Berne [Phys. Rev. Lett. {\bf 77}, 2638 (1996)], is described in detail. It is shown how this formulation can be used to perform Monte Carlo simulations of water. Our numerical results show that whereas some properties of water can be accurately reproduced using classical simulations with an empirical potential which, implicitly, includes quantum effects, other properties can only be described quantitatively when quantum effects are explicitly incorporated. In particular, quantum effects are extremely relevant when it comes to describing the equation of state of the ice phases at low temperatures, the structure of the ices at low temperatures, and the heat capacity of both liquid water and the ice phases. They also play a minor role in the relative stability of the ice phases.Comment: to appear in Molecular Physics (2011

Child-OIDP index in Brazil: Cross-cultural adaptation and validation

Background: Oral health-related quality of life (OHRQoL) measures are being increasingly used to introduce dimensions excluded by normative measures. Consequently, there is a need for an index which evaluates children's OHRQoL validated for Brazilian population, useful for oral health needs assessments and for the evaluation of oral health programs, services and technologies. The aim of this study was to do a cross-cultural adaptation of the Child Oral Impacts on Daily Performances (Child-OIDP) index, and assess its reliability and validity for application among Brazilian children between the ages of eleven and fourteen. Methods: For cross-cultural adaptation, a translation/back-translation method integrated with expert panel reviews was applied. A total of 342 students from four public schools took part of the study. Results: Overall, 80.7% of the sample reported at least one oral impact in the last three months. Cronbach's alpha was 0.63, the weighted kappa 0.76, and the intraclass correlation coefficient (ICC) 0.79. The index had a significant association with self-reported health measurements (self-rated oral health, satisfaction with oral health, perceived dental treatment needs, self-rated general health; all p < 0.01). Conclusion: It was concluded that the Child-OIDP index is a measure of oral health-related quality of life that can be applied to Brazilian children

Combined Effects of Dewatering, Composting and Pelleting to Valorize and Delocalize Livestock Manure, Improving Agricultural Sustainability

An agronomic strategy to mitigate climate change impact can be the build-up of soil organic carbon. Among agronomic management approaches, the administration of organic fertilizers like livestock manure represents an eective strategy to increase soil organic carbon. However, livestock manure usually contains a high amount of water, reducing its sustainable delocalization and impacting on greenhouse gas emissions and nutrient leaching. Furthermore, the possible presence of weed seeds and harmful microorganisms could reduce the agronomic value of the manure. To overcome these issues, the combined eects of dewatering, composting and pelleting were investigated on livestock manure to produce sustainable organic fertilizers. Our results showed that composting and pelleting can represent a feasible and sustainable solution to reduce the potential risks related to the presence of weed seeds and harmful bacteria, concentrating nutrients and allowing a sustainable valorization and delocalization of the livestock manure. In addition, the processed manures were assessed as fertilizers in the growing medium (GM), displaying an increase in water retention and nutrient availability and a decrease of GM temperature and weed seed emergences. However, further study is needed to validate, both in open field and greenhouse productions, the eects of the proposed fertilizers in real cropping systems

Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.

BACKGROUND: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence. METHODS: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity. RESULTS: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+ and CD8+ responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+ double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants. CONCLUSIONS: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse

STARE DECISIS, INTEGRIDADE E SEGURANÇA JURIDICAL: REFLEXÕES CRÍTICAS A PARTIR DA APROXIMAÇÃO DOS SISTEMAS DO COMMON LAW E CIVIL LAW

O estudo objetiva analisar o novo modo de interpretar e aplicar o Direito instaurado a partir da centralidade dos direitos humanos e fundamentais na segunda metade do século XX, que levou à preponderância do Poder Judiciário nas decisões políticas e morais do Estado, fazendo-o assumir o papel de judge-made-law, tradicional nos sistemas de common law.  Pretende-se examinar as possibilidades de previsibilidade e de segurança jurídica no common law, que tem maior proximidade com o processo de construção do direito. Por essa razão, o trabalho aproxima os sistemas de civil law e common law no âmbito da Jurisdição constitucional, especialmente no controle material de constitucionalidade realizado com base nos direitos humanos ou fundamentais. Propugna pela utilização da doutrina do stare decisis, que, por sua vez, é compatível com o modelo do direito como integridade de Dworkin para a garantia de segurança jurídica, previsibilidade e estabilidade das decisões judiciais na sociedade contemporânea. Para realizar tal reflexão, a tese está dividida em duas partes, uma voltada à fundamentação e outra, à proposição. A primeira parte do trabalho discorre historicamente sobre os sistemas de civil law e common law. Constata que a Revolução de Direitos Humanos e a Judicialização da Política constituem causas da expansão do judicial review em diversos países. Aponta que a fundamentalidade material dos direitos humanos tem conteúdo moral e serve de parâmetro para o judicial review em ambos os sistemas, estejam eles expressos, implícitos ou não escritos em um documento constitucional. Na segunda parte, estuda-se a doutrina dos precedentes vinculantes, bem como suas características e hipóteses de superação. A partir da leitura do “direito como integridade” de Dworkin, pode-se concluir que é factível a adoção da doutrina do stare decisis que aplique o princípio da integridade na decisão judicial no âmbito  da Jurisdição Constitucional brasileira, o que garantirá coerência, estabilidade, previsibilidade e segurança jurídica em relação a suas decisões.Palavras-chave: Civil Law e Common Law. Judicialização da Política. Sociedade Contemporânea. Constitucionalismo Brasileiro. Direitos Humanos. Integridade. Segurança Jurídica

Calcium-sensing receptor antagonist NPS 2143 restores amyloid precursor protein physiological non-amyloidogenic processing in A\u3b2-exposed adult human astrocytes

Physiological non-amyloidogenic processing (NAP) of amyloid precursor holoprotein (hAPP) by \u3b1-secretases (e.g., ADAM10) extracellularly sheds neurotrophic/neuroprotective soluble (s)APP\u3b1 and precludes amyloid-\u3b2 peptides (A\u3b2s) production via \u3b2-secretase amyloidogenic processing (AP). Evidence exists that A\u3b2s interact with calcium-sensing receptors (CaSRs) in human astrocytes and neurons, driving the overrelease of toxic A\u3b242/A\u3b242-os (oligomers), which is completely blocked by CaSR antagonist (calcilytic) NPS 2143. Here, we investigated the mechanisms underlying NPS 2143 beneficial effects in human astrocytes. Moreover, because Alzheimer's disease (AD) involves neuroinflammation, we examined whether NPS 2143 remained beneficial when both fibrillary (f)A\u3b225-35 and a microglial cytokine mixture (CMT) were present. Thus, hAPP NAP prevailed over AP in untreated astrocytes, which extracellularly shed all synthesized sAPP\u3b1 while secreting basal A\u3b240/42 amounts. Conversely, fA\u3b225-35 alone dramatically reduced sAPP\u3b1 extracellular shedding while driving A\u3b242/A\u3b242-os oversecretion that CMT accelerated but not increased, despite a concurring hAPP overexpression. NPS 2143 promoted hAPP and ADAM10 translocation to the plasma membrane, thereby restoring sAPP\u3b1 extracellular shedding and fully suppressing any A\u3b242/A\u3b242-os oversecretion, but left hAPP expression unaffected. Therefore, as anti-AD therapeutics calcilytics support neuronal viability by safeguarding astrocytes neurotrophic/neuroprotective sAPP\u3b1 shedding, suppressing neurons and astrocytes A\u3b242/A\u3b242-os build-up/secretion, and remaining effective even under AD-typical neuroinflammatory conditions

Socioeconomic inequalities in health among Swedish adolescents - adding the subjective perspective

Abstract Background Socioeconomic inequalities in adolescent health predict future inequalities in adult health. Subjective measures of socioeconomic status (SES) may contribute with an increased understanding of these inequalities. The aim of this study was to investigate socioeconomic health inequalities using both a subjective and an objective measure of SES among Swedish adolescents. Method Cross-sectional HBSC-data from 2002 to 2014 was used with a total sample of 23,088 adolescents aged 11–15 years. Three measures of self-rated health (dependent variables) were assessed: multiple health complaints, life satisfaction and health perception. SES was measured objectively by the Family Affluence Scale (FAS) and subjectively by “perceived family wealth” (independent variables). The trend for health inequalities was investigated descriptively with independent t-tests and the relationship between independent and dependent variables was investigated with multiple logistic regression analysis. Gender, age and survey year was considered as possible confounders. Results Subjective SES was more strongly related to health outcomes than the objective measure (FAS). Also, the relation between FAS and health was weakened and even reversed (for multiple health complaints) when subjective SES was tested simultaneously in regression models (FAS OR: 1.03, CI: 1.00;1.06 and subjective SES OR: 0.66, CI: 0.63;0.68). Conclusions The level of socioeconomic inequalities in adolescent health varied depending on which measure that was used to define SES. When focusing on adolescents, the subjective appraisals of SES is important to consider because they seem to provide a stronger tool for identifying inequalities in health for this group. This finding is important for policy makers to consider given the persistence of health inequalities in Sweden and other high-income countries

Calcium-sensing receptors of human neural cells play crucial roles in Alzheimer's disease

In aged subjects, late-onset Alzheimer's disease (LOAD) starts in the lateral entorhinal allocortex where a failure of clearance mechanisms triggers an accumulation of neurotoxic amyloid-\u3b242 oligomers (A\u3b242-os). In neurons and astrocytes, A\u3b242-os enhance the transcription of A\u3b2 precursor protein (APP) and \u3b2-secretase/BACE1 genes. Thus, by acting together with \u3b3-secretase, the surpluses of APP and BACE1 amplify the endogenous production of A\u3b242-os which pile up, damage mitochondria, and are oversecreted. At the plasmalemma, exogenous A\u3b242-os bind neurons' and astrocytes' calcium-sensing receptors (CaSRs) activating a set of intracellular signaling pathways which upkeep A\u3b242-os intracellular accumulation and oversecretion by hindering A\u3b242-os proteolysis. In addition, A\u3b242-os accumulating in the extracellular milieu spread and reach mounting numbers of adjacent and remoter teams of neurons and astrocytes which in turn are recruited, again via A\u3b242-os\u2022CaSR-governed mechanisms, to produce and release additional A\u3b242-os amounts. This relentless self-sustaining mechanism drives AD progression toward upper cortical areas. Later on accumulating A\u3b242-os elicit the advent of hyperphosphorylated (p)-Tau oligomers which acting together with A\u3b242-os and other glial neurotoxins cooperatively destroy wider and wider cognition-related cortical areas. In parallel, A\u3b242-os\u2022CaSR signals also elicit an excess production and secretion of nitric oxide and vascular endothelial growth factor-A from astrocytes, of A\u3b242-os and myelin basic protein from oligodendrocytes, and of proinflammatory cytokines, nitric oxide and (likely) A\u3b242-os from microglia. Activated astrocytes and microglia survive the toxic onslaught, whereas neurons and oligodendrocytes increasingly die. However, we have shown that highly selective allosteric CaSR antagonists (calcilytics), like NPS 2143 and NPS 89626, efficiently suppress all the neurotoxic effects A\u3b242-os\u2022CaSR signaling drives in cultured cortical untransformed human neurons and astrocytes. In fact, calcilytics increase A\u3b242 proteolysis and discontinue the oversecretion of A\u3b242-os, nitric oxide, and vascular endothelial growth factor-A from both astrocytes and neurons. Seemingly, calcilytics would also benefit the other types of glial cells and cerebrovascular cells otherwise damaged by the effects of A\u3b242-os\u2022CaSR signaling. Thus, given at amnestic minor cognitive impairment (aMCI) or initial symptomatic stages, calcilytics could prevent or terminate the propagation of LOAD neuropathology and preserve human neurons' viability and hence patients' cognitive abilities