Constraint methods for determining pathways and free energy of activated processes

Activated processes from chemical reactions up to conformational transitions of large biomolecules are hampered by barriers which are overcome only by the input of some free energy of activation. Hence, the characteristic and rate-determining barrier regions are not sufficiently sampled by usual simulation techniques. Constraints on a reaction coordinate r have turned out to be a suitable means to explore difficult pathways without changing potential function, energy or temperature. For a dense sequence of values of r, the corresponding sequence of simulations provides a pathway for the process. As only one coordinate among thousands is fixed during each simulation, the pathway essentially reflects the system's internal dynamics. From mean forces the free energy profile can be calculated to obtain reaction rates and insight in the reaction mechanism. In the last decade, theoretical tools and computing capacity have been developed to a degree where simulations give impressive qualitative insight in the processes at quantitative agreement with experiments. Here, we give an introduction to reaction pathways and coordinates, and develop the theory of free energy as the potential of mean force. We clarify the connection between mean force and constraint force which is the central quantity evaluated, and discuss the mass metric tensor correction. Well-behaved coordinates without tensor correction are considered. We discuss the theoretical background and practical implementation on the example of the reaction coordinate of targeted molecular dynamics simulation. Finally, we compare applications of constraint methods and other techniques developed for the same purpose, and discuss the limits of the approach

BRCA1 associated protein 1 (BAP1) expression in pleural diffuse malignant mesothelioma: A comparative cytological and histological analyses on 50 patients

International audienceINTRODUCTION: Diffuse malignant mesothelioma (MMD) is a rare disease. The diagnosis is difficult and needs an antibody panel. The tumor suppressor gene BRCA1 associated protein 1 (BAP1) is involved in several cancers, including MMD. Loss of BAP1 expression is correlated with BAP1 somatic or constitutional genetic defects. Our work assesses the value of integrating BAP1 in the panel of antibodies used for the diagnosis of MMD. MATERIALS AND METHODS: Immunohistochemical techniques were performed on cytological and histological specimens of MMD and adenocarcinoma pleural metastasis. RESULTS: Of the 26 patients with MMD and the 24 patients with adenocarcinoma pleural metastasis, loss of BAP1 expression was observed in 11 (48%) and one adenocarcinoma (6%) on cytological specimens and in 12 MMD (48%) and in one adenocarcinoma (5%) on biopsy specimens. The concordance between immunocytochemistry and immunohistochemistry was 100%. The specificity of BAP1 was 100% on cytological and biopsy specimen for the diagnosis of malignancy in case of mesothelial proliferation. DISCUSSION AND CONCLUSION: Loss of BAP1 expression is an indicator of MMD in a context of mesothelial proliferation. This immunohistochemistry could be integrated in the panel of immunostaining used for MMD diagnosis, either on histological or cytological samples. Furthermore, loss of BAP1 expression guides the patient to an oncology genetic counseling in order to eliminate a MMD developed as part of a constitutional genetic defec

Necessidades especiais de escolares com diabetes mellitus tipo 1 identificadas por familiares Special needs of students with diabetes mellitus type 1 identified by relatives

É um desafio atender aos alunos, em suas diversas necessidades especiais. Diferentemente das deficiências, há poucas pesquisas no Brasil sobre estudantes com doenças crônicas e suas especificidades, na escola. O objetivo do presente estudo foi identificar as necessidades especiais de escolares com diabetes mellitus tipo 1. Participaram 37 familiares de escolares em tratamento ambulatorial de uma faculdade paulista, por meio de entrevista semiestruturada, gravada em áudio e transcrita para análise. Os resultados mostraram que todos comunicaram a escola a respeito da doença do filho, mas, mesmo assim, 29,7% relatam dificuldade de inclusão ou acesso à escola, como desconhecimento do professor para o controle do diabetes, merenda escolar inadequada, preconceito dos colegas e da diretora ou vergonha por parte do aluno. As faltas ocorrem com 70,3% dos alunos, principalmente devido às consultas médicas. Necessidades especiais foram identificadas por 32,4%, incluindo a alimentação, o desempenho escolar e a necessidade de profissionais da escola mais bem informados sobre a doença. Além disso, 72,9% referem algum tipo de apoio para enfrentar o diabetes, principalmente de profissionais de saúde. Dos familiares, 51,3% apresentam sugestões para um melhor desenvolvimento do filho na escola, incluindo alimentação escolar adequada e melhor preparo da escola para lidar com o diabetes, como palestras e treinamento aos professores. Sugerimos a aproximação entre a escola e a área da saúde, porém, o primeiro passo para a integração intersetorial é identificar as necessidades desses alunos com doenças crônicas, como foi possível com este trabalho, ao enfocar o diabetes mellitus e suas repercussões escolares.<br>Catering to students according to their various special needs is a challenge. As opposed to the field of disability, there is little research in Brazil on students with chronic diseases and their specific needs at school. The purpose of this study was to identify the special needs of children with diabetes mellitus type 1. The participants were 37 family members of students in treatment in an outpatient center at a state of São Paulo medical school. A semi-structured interview was carried, which was audio recorded and transcribed for analysis. The results showed that all participants informed the school informed about their child's condition, however 29,7% reported that inclusion or access to school was difficult, due to the teacher being uninformed about diabetes control, inadequate school lunches, and preconceptions of peers and school supervisor, or the student's embarrassment. Absenteeism occurred among 70,3% of the students, mainly due to doctor appointments. Special needs were identified by 32,4%, including meals, performance in school tasks and the need to better inform school professionals about the condition. Furthermore, 72,9% reported some kind of support to cope with diabetes had been provided, mainly by health professionals. In order to improve their child's development at school 51,3% presented suggestions such as including appropriate school meals, better preparation of school for dealing with diabetes, i.e. lectures and training for teachers. Our suggestion is that there should be a closer relationship between the school and health services, but the first step towards intersector integration is to identify the needs of students with chronic diseases, such as this study showed, by focusing on diabetes mellitus and its impact on the school

Measurement of Acoustic Attenuation in South Pole Ice

Using the South Pole Acoustic Test Setup (SPATS) and a retrievable transmitter deployed in holes drilled for the IceCube experiment, we have measured the attenuation of acoustic signals by South Pole ice at depths between 190 m and 500 m. Three data sets, using different acoustic sources, have been analyzed and give consistent results. The method with the smallest systematic uncertainties yields an amplitude attenuation coefficient alpha = 3.20 \pm 0.57 km^(-1) between 10 and 30 kHz, considerably larger than previous theoretical estimates. Expressed as an attenuation length, the analyses give a consistent result for lambda = 1/alpha of ~1/300 m with 20% uncertainty. No significant depth or frequency dependence has been found.Comment: 17 pages, 12 figures, published in Astroparticle Physics, 201

Background studies for acoustic neutrino detection at the South Pole

The detection of acoustic signals from ultra-high energy neutrino interactions is a promising method to measure the tiny flux of cosmogenic neutrinos expected on Earth. The energy threshold for this process depends strongly on the absolute noise level in the target material. The South Pole Acoustic Test Setup (SPATS), deployed in the upper part of four boreholes of the IceCube Neutrino Observatory, has monitored the noise in Antarctic ice at the geographic South Pole for more than two years down to 500 m depth. The noise is very stable and Gaussian distributed. Lacking an in-situ calibration up to now, laboratory measurements have been used to estimate the absolute noise level in the 10 to 50 kHz frequency range to be smaller than 20 mPa. Using a threshold trigger, sensors of the South Pole Acoustic Test Setup registered acoustic pulse-like events in the IceCube detector volume and its vicinity. Acoustic signals from refreezing IceCube holes and from anthropogenic sources have been used to localize acoustic events. Monte Carlo simulations of sound propagating from the established sources to the SPATS sensors have allowed to check corresponding model expectations. An upper limit on the neutrino flux at energies $E_\nu > 10^{11}$ GeV is derived from acoustic data taken over eight months.Comment: 17 pages, 14 figure

Search for neutrino-induced cascades with five years of AMANDA data

We report on the search for electromagnetic and hadronic showers ("cascades") produced by a diffuse flux of extraterrestrial neutrinos in the AMANDA neutrino telescope. Data for this analysis were recorded during 1001 days of detector livetime in the years 2000-2004. The observed event rates are consistent with the background expectation from atmospheric neutrinos and muons. An upper limit is derived for the diffuse flux of neutrinos of all flavors assuming a flavor ratio of νe:νμ: ντ = 1:1:1 at the detection site. The all-flavor flux of neutrinos with an energy spectrum Φ ∝ E-2 is less than 5.0 × 10-7 GeV s-1 sr-1 cm-2 at a 90% C.L. Here, 90% of the simulated signal would fall within the energy range 40 TeV to 9 PeV. We discuss flux limits in the context of several specific models of extraterrestrial and prompt atmospheric neutrino production. © 2010 Elsevier B.V. All rights reserved.0SCOPUS: ar.jinfo:eu-repo/semantics/publishe