Anomalous Rotational Relaxation: A Fractional Fokker-Planck Equation Approach

In this study we obtained analytically relaxation function in terms of rotational correlation functions based on Brownian motion for complex disordered systems in a stochastic framework. We found out that rotational relaxation function has a fractional form for complex disordered systems, which indicates relaxation has non-exponential character obeys to Kohlrausch-William-Watts law, following the Mittag-Leffler decay.Comment: Revtex4, 9 pages. Paper was revised. References adde

Detailed phytochemical analysis of high- and low artemisinin-producing chemotypes of Artemisia annua

Chemical derivatives of artemisinin, a sesquiterpene lactone produced by Artemisia annua, are the active ingredient in the most effective treatment for malaria. Comprehensive phytochemical analysis of two contrasting chemotypes of A. annua resulted in the characterization of over 80 natural products by NMR, more than 20 of which are novel and described here for the first time. Analysis of high- and low-artemisinin producing (HAP and LAP) chemotypes of A. annua confirmed the latter to have a low level of DBR2 (artemisinic aldehyde Δ11(13) reductase) gene expression. Here we show that the LAP chemotype accumulates high levels of artemisinic acid, arteannuin B, epi-deoxyarteannuin B and other amorpha-4,11-diene derived sesquiterpenes which are unsaturated at the 11,13-position. By contrast, the HAP chemotype is rich in sesquiterpenes saturated at the 11,13-position (dihydroartemisinic acid, artemisinin and dihydro-epi-deoxyarteannunin B), which is consistent with higher expression levels of DBR2, and also with the presence of a HAP-chemotype version of CYP71AV1 (amorpha-4,11-diene C-12 oxidase). Our results indicate that the conversion steps from artemisinic acid to arteannuin B, epi-deoxyarteannuin B and artemisitene in the LAP chemotype are non-enzymatic and parallel the non-enzymatic conversion of DHAA to artemisinin and dihyro-epi-deoxyarteannuin B in the HAP chemotype. Interestingly, artemisinic acid in the LAP chemotype preferentially converts to arteannuin B rather than the endoperoxide bridge containing artemisitene. In contrast, in the HAP chemotype, DHAA preferentially converts to artemisinin. Broader metabolomic and transcriptomic profiling revealed significantly different terpenoid profiles and related terpenoid gene expression in these two morphologically distinct chemotypes

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

Proteomic analysis of Artemisia annua – towards elucidating the biosynthetic pathways of the antimalarial pro-drug artemisinin

Background: MS-based proteomics was applied to the analysis of the medicinal plant Artemisia annua, exploiting a recently published contig sequence database (Graham et al. (2010) Science 327, 328–331) and other genomic and proteomic sequence databases for comparison. A. annua is the predominant natural source of artemisinin, the precursor for artemisinin-based combination therapies (ACTs), which are the WHO-recommended treatment for P. falciparum malaria. Results: The comparison of various databases containing A. annua sequences (NCBInr/viridiplantae, UniProt/ viridiplantae, UniProt/A. annua, an A. annua trichome Trinity contig database, the above contig database and another A. annua EST database) revealed significant differences in respect of their suitability for proteomic analysis, showing that an organism-specific database that has undergone extensive curation, leading to longer contig sequences, can greatly increase the number of true positive protein identifications, while reducing the number of false positives. Compared to previously published data an order-of-magnitude more proteins have been identified from trichome-enriched A. annua samples, including proteins which are known to be involved in the biosynthesis of artemisinin, as well as other highly abundant proteins, which suggest additional enzymatic processes occurring within the trichomes that are important for the biosynthesis of artemisinin. Conclusions: The newly gained information allows for the possibility of an enzymatic pathway, utilizing peroxidases, for the less well understood final stages of artemisinin’s biosynthesis, as an alternative to the known non-enzymatic in vitro conversion of dihydroartemisinic acid to artemisinin. Data are available via ProteomeXchange with identifier PXD000703

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care

Prediction of Ideas Number During a Brainstorming Session

International audienceIn this paper, we present an approach allowing the prediction of ideas number during a brainstorming session. This prediction is based on two dynamic models of brainstorming, the non-cognitive and the cognitive models proposed by Brown and Paulus (Small Group Res 27(1):91–114, 1996). These models describe for each participant, the evolution of ideas number over time, and are formalized by differential equations. Through solution functions of these models, we propose to calculate the number of ideas of each participant on any time intervals and thus in the future (called prediction). To be able to compute solution functions, it is necessary to determine the parameters of these models. In our approach, we use optimization model for model parameters calculation in which solution functions are approximated by numerical methods. We developed two generic optimization models, one based on Euler’s and the other on the fourth order Runge–Kutta’s numerical methods for the solving of differential equations, and we apply them to the non-cognitive and respectively to the cognitive models. Through some feasibility tests, we show the adequacy of the proposed approach to our prediction context

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table

The action of a multidisciplinary team in the nutritional care of critically ill patients

Hospitalized patients may have special nutrient requirements imposed by a combination of malnutrition and enhanced utilization of nutrients resulting from the disease process. Nutritional support, mainly during critical stages of disease, should be provided safely and effectively. Several studies have evaluated the paper of a multidisciplinary team in the administration of a nutritional therapy. Individually, the majority of these studies are underpowered to evaluate an effect on the quality of nutritional care. With the objective to identify problems inherent to the supply of nutritional support to hospitalized patients and verify the impact of the actions of a multidisciplinary team on the quality of these procedures, we analysed articles that have been published between 1980 and 2004 about the role of the action of multidisciplinary teams in the care and nutritional outcome of hospitalized patients, especially those undergoing intensive care. The terms used for the search were: multidisciplinary team, nutritional support, parenteral nutrition, enteral feeding, critically ill, intensive care unit, critically ill child. Of 130 studies, intially identified, just 24 were selected, of which 14 compared the standard of nutritional therapy with and without the presence of a multidisciplinary team. The inadequate supply of nutrients, infection and metabolic complications and the excessive use of parenteral nutrition were the main problems detected in the supply of nutritional support to hospitalized patients. In the comparative studies, the presence of the multidisciplinary team improved the pattern of nutritional support, and reduced the incidence of complications and the costs.Pacientes hospitalizados podem ter necessidades nutricionais especiais em função da desnutrição e dos desequilíbrios metabólicos impostos pelas doenças. A terapia nutricional, principalmente nos estágios críticos das enfermidades, deve ser administrada de modo seguro e eficaz. Vários estudos têm avaliado o papel da equipe multidisciplinar na administração da terapia nutricional. Com o objetivo de identificar os problemas inerentes à administração da terapia nutricional em pacientes hospitalizados e verificar o impacto da atuação de uma equipe multidisciplinar na qualidade dos procedimentos, foi realizada uma revisão que analisou artigos publicados entre 1980 e 2004 sobre o papel da atuação de equipes multidisciplinares no cuidado e na evolução nutricional de pacientes hospitalizados, principalmente os que se encontravam sob cuidados intensivos. Os termos utilizados na pesquisa foram: multidisciplinary team, nutritional support, parente-ral nutrition, enteral feeding, critically ill, intensive care unit,critically ill child. Dos 130 estudos inicialmente identificados, foram selecionados 24, dos quais 14 compararam o padrão de terapia nutricional com e sem a presença da equipe multidisciplinar. Os principais problemas detectados na administração de terapia nutricional em pacientes hospitalizados foram a oferta inadequada de nutrientes, as complicações infecciosas e metabólicas e o uso excessivo de nutrição parenteral. Nos estudos comparativos, a presença da equipe multidisciplinar melhorou o padrão de oferta nutricional, reduziu a incidência de complicações e os custos.Universidade Federal de São Paulo (UNIFESP) Departamento de PediatriaHospital São Paulo Unidade de Cuidados Intensivos PediátricosHospital São Paulo Equipe Multidisciplinar de Terapia NutricionalUNIFESP, Depto. de PediatriaHospital São Paulo Unidade de Cuidados Intensivos PediátricosHospital São Paulo Equipe Multidisciplinar de Terapia NutricionalSciEL

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE