A control flow prototype for a dose recommending device for chronic myeloid leukemia patients

In this paper we present a prototype of a control flow for an a posteriori drug dose adaptation for Chronic Myelogenous Leukemia (CML) patients. The control flow is modeled using Timed Automata extended with Tasks (TAT) model. The feedback loop of the control flow includes the decision-making process for drug dose adaptation. This is based on the outputs of the body response model represented by the Support Vector Machine (SVM) algorithm for drug concentration prediction. The decision is further checked for conformity with the dose level rules of a medical guideline. We also have developed an automatic code synthesizer for the icycom platform as an extension of the TIMES tool.

Sistema de monitorització Open Source: projecte d'empresa per Computer Technology Catalunya

L’objectiu del projecte consisteix en l’estudi, simulació i implantació d’un conjunt d’aplicacions que permeten tenir un control sobre possibles problemes que puguin succeir a la nostra xarxa. Aquest projecte és la solució als problemes de detecció d’errors en el funcionament de les infraestructures de networking de les que disposen els nostres clients.

Some personal views on the control of schistosomiasis mansoni

Our views are based, on a recent study of a district of Uniao dos Palmares (Alagoas). Although being a very compact community (32 city blocks holding two thousand families), transmission is very uneven, the geometric mean egg counts in the various blocks ranging between extremes of 96 and 1920. (Results do not correlate with the availability of domestic water supply). We thus are led to conclude that: (a) transmission is primarily peridomestic, resulting from pollution of open ditches and other collections of water; (b) control of transmission can be done on a selective basis, requiring quite medest investments. Given the inefficacy of population-based chemotherapy, when used alone, the author insists that this alternative cannot any longer be overlooked. He also regrets the emphasis placed upon vaccine development; allegations that this would, at any rate, prevent severe morbidity can be dismissed, since-whatever the cause-morbidity due to schistosomiasis has been rapidly declining in Northeast Brazil.

Mechanical external work and recovery at preferred walking speed in obese subjects

PURPOSE: The aim of this study was to compare the mechanical external work (per kg) and pendular energy transduction at preferred walking speed (PWS) in obese versus normal body mass subjects to investigate whether obese adults adopt energy conserving gait mechanics. METHODS: The mechanical external work (Wext) and the fraction of mechanical energy recovered by the pendular mechanism (Rstep) were computed using kinematic data acquired by an optoelectronic system and were compared in 30 obese (OG; body mass index [BMI] = 39.6 +/- 0.6 kg m(-2); 29.5 +/- 1.3 yr) and 19 normal body mass adults (NG; BMI = 21.4 +/- 0.5 kg m(-2); 31.2 +/- 1.2 yr) walking at PWS. RESULTS: PWS was significantly lower in OG (1.18 +/- 0.02 m s(-1)) than in NG (1.33 +/- 0.02 m s(-1); P <or= 0.001). There was no significant difference in Wext per unit mass between groups (OG: 0.36 +/- 0.03 J kg(-1) m(-1); NG: 0.31 +/- 0.02 J kg(-1) m(-1); P = 0.12). Rstep was significantly lower in OG (68.4% +/- 2.0%) compared with NG (74.4% +/- 1.0%; P = 0.01). In OG only, Wext per unit mass was positively correlated with PWS (r = 0.57; P < 0.001). CONCLUSION: Obese adults do not appear to alter their gait to improve pendular energy transduction and may select slower PWS to reduce mechanical and metabolic work.

Predictive and distributed routing balancing (PR-DRB): high speed interconnection networks

Current parallel applications running on clusters require the use of an interconnection network to perform communications among all computing nodes available. Imbalance of communications can produce network congestion, reducing throughput and increasing latency, degrading the overall system performance. On the other hand, parallel applications running on these networks posses representative stages which allow their characterization, as well as repetitive behavior that can be identified on the basis of this characterization. This work presents the Predictive and Distributed Routing Balancing (PR-DRB), a new method developed to gradually control network congestion, based on paths expansion, traffic distribution and effective traffic load, in order to maintain low latency values. PR-DRB monitors messages latencies on intermediate routers, makes decisions about alternative paths and record communication pattern information encountered during congestion situation. Based on the concept of applications repetitiveness, best solution recorded are reapplied when saved communication pattern re-appears. Traffic congestion experiments were conducted in order to evaluate the performance of the method, and improvements were observed.

A molecular framework for light and gibberellin control of cell elongation.

Cell elongation during seedling development is antagonistically regulated by light and gibberellins (GAs). Light induces photomorphogenesis, leading to inhibition of hypocotyl growth, whereas GAs promote etiolated growth, characterized by increased hypocotyl elongation. The mechanism underlying this antagonistic interaction remains unclear. Here we report on the central role of the Arabidopsis thaliana nuclear transcription factor PIF4 (encoded by PHYTOCHROME INTERACTING FACTOR 4) in the positive control of genes mediating cell elongation and show that this factor is negatively regulated by the light photoreceptor phyB (ref. 4) and by DELLA proteins that have a key repressor function in GA signalling. Our results demonstrate that PIF4 is destabilized by phyB in the light and that DELLAs block PIF4 transcriptional activity by binding the DNA-recognition domain of this factor. We show that GAs abrogate such repression by promoting DELLA destabilization, and therefore cause a concomitant accumulation of free PIF4 in the nucleus. Consistent with this model, intermediate hypocotyl lengths were observed in transgenic plants over-accumulating both DELLAs and PIF4. Destabilization of this factor by phyB, together with its inactivation by DELLAs, constitutes a protein interaction framework that explains how plants integrate both light and GA signals to optimize growth and development in response to changing environments.

Cruciferous vegetables and cancer risk in a network of case-control studies.

Background Cruciferous vegetables have been suggested to protect against various cancers, though the issue is open to discussion. To further understand their role, we analyzed data from a network of case-control studies conducted in Italy and Switzerland. Patients and methods The studies included a total of 1468 cancers of the oral cavity/pharynx, 505 of the esophagus, 230 of the stomach, 2390 of the colorectum, 185 of the liver, 326 of the pancreas, 852 of the larynx, 3034 of the breast, 367 of the endometrium, 1031 of the ovary, 1294 of the prostate, 767 of the kidney, and 11 492 controls. All cancers were incident, histologically confirmed; controls were subjects admitted to the same network of hospitals as cases for a wide spectrum of acute nonneoplastic conditions. Results The multivariate odds ratio (OR) for consumption of cruciferous vegetables at least once a week as compared with no/occasional consumption was significantly reduced for cancer of the oral cavity/pharynx (OR = 0.83), esophagus (OR = 0.72), colorectum (OR = 0.83), breast (OR = 0.83), and kidney (OR = 0.68). The OR was below unity, but not significant, for stomach (OR = 0.90), liver (OR = 0.72), pancreatic (OR = 0.90), laryngeal (OR = 0.84), endometrial (OR = 0.93), ovarian (OR = 0.91), and prostate (OR = 0.87) cancer. Conclusion This large series of studies provides additional evidence of a favorable effect of cruciferous vegetables on several common cancers.

Connexin implication in the control of the murine beta-cell mass.

Diabetes develops when the insulin needs of peripheral cells exceed the availability or action of the hormone. This situation results from the death of most beta-cells in type 1 diabetes, and from an inability of the beta-cell mass to adapt to increasing insulin needs in type 2 and gestational diabetes. We analyzed several lines of transgenic mice and showed that connexins (Cxs), the transmembrane proteins that form gap junctions, are implicated in the modulation of the beta-cell mass. Specifically, we found that the native Cx36 does not alter islet size or insulin content, whereas the Cx43 isoform increases both parameters, and Cx32 has a similar effect only when combined with GH. These findings open interesting perspectives for the in vitro and in vivo regulation of the beta-cell mass.

Selecting control genes for RT-QPCR using public microarray data.

Background: Gene expression analysis has emerged as a major biological research area, with real-time quantitative reverse transcription PCR (RT-QPCR) being one of the most accurate and widely used techniques for expression profiling of selected genes. In order to obtain results that are comparable across assays, a stable normalization strategy is required. In general, the normalization of PCR measurements between different samples uses one to several control genes (e. g. housekeeping genes), from which a baseline reference level is constructed. Thus, the choice of the control genes is of utmost importance, yet there is not a generally accepted standard technique for screening a large number of candidates and identifying the best ones. Results: We propose a novel approach for scoring and ranking candidate genes for their suitability as control genes. Our approach relies on publicly available microarray data and allows the combination of multiple data sets originating from different platforms and/or representing different pathologies. The use of microarray data allows the screening of tens of thousands of genes, producing very comprehensive lists of candidates. We also provide two lists of candidate control genes: one which is breast cancer-specific and one with more general applicability. Two genes from the breast cancer list which had not been previously used as control genes are identified and validated by RT-QPCR. Open source R functions are available at http://www.isrec.isb-sib.ch/similar to vpopovic/research/ Conclusion: We proposed a new method for identifying candidate control genes for RT-QPCR which was able to rank thousands of genes according to some predefined suitability criteria and we applied it to the case of breast cancer. We also empirically showed that translating the results from microarray to PCR platform was achievable.

Plasma membrane cyclic nucleotide gated calcium channels control land plant thermal sensing and acquired thermotolerance.

Typically at dawn on a hot summer day, land plants need precise molecular thermometers to sense harmless increments in the ambient temperature to induce a timely heat shock response (HSR) and accumulate protective heat shock proteins in anticipation of harmful temperatures at mid-day. Here, we found that the cyclic nucleotide gated calcium channel (CNGC) CNGCb gene from Physcomitrella patens and its Arabidopsis thaliana ortholog CNGC2, encode a component of cyclic nucleotide gated Ca(2+) channels that act as the primary thermosensors of land plant cells. Disruption of CNGCb or CNGC2 produced a hyper-thermosensitive phenotype, giving rise to an HSR and acquired thermotolerance at significantly milder heat-priming treatments than in wild-type plants. In an aequorin-expressing moss, CNGCb loss-of-function caused a hyper-thermoresponsive Ca(2+) influx and altered Ca(2+) signaling. Patch clamp recordings on moss protoplasts showed the presence of three distinct thermoresponsive Ca(2+) channels in wild-type cells. Deletion of CNGCb led to a total absence of one and increased the open probability of the remaining two thermoresponsive Ca(2+) channels. Thus, CNGC2 and CNGCb are expected to form heteromeric Ca(2+) channels with other related CNGCs. These channels in the plasma membrane respond to increments in the ambient temperature by triggering an optimal HSR, leading to the onset of plant acquired thermotolerance.

Access of extracellular cations to their binding sites in Na,K-ATPase: role of the second extracellular loop of the alpha subunit.

Na,K-ATPase, the main active transport system for monovalent cations in animal cells, is responsible for maintaining Na(+) and K(+) gradients across the plasma membrane. During its transport cycle it binds three cytoplasmic Na(+) ions and releases them on the extracellular side of the membrane, and then binds two extracellular K(+) ions and releases them into the cytoplasm. The fourth, fifth, and sixth transmembrane helices of the alpha subunit of Na,K-ATPase are known to be involved in Na(+) and K(+) binding sites, but the gating mechanisms that control the access of these ions to their binding sites are not yet fully understood. We have focused on the second extracellular loop linking transmembrane segments 3 and 4 and attempted to determine its role in gating. We replaced 13 residues of this loop in the rat alpha1 subunit, from E314 to G326, by cysteine, and then studied the function of these mutants using electrophysiological techniques. We analyzed the results using a structural model obtained by homology with SERCA, and ab initio calculations for the second extracellular loop. Four mutants were markedly modified by the sulfhydryl reagent MTSET, and we investigated them in detail. The substituted cysteines were more readily accessible to MTSET in the E1 conformation for the Y315C, W317C, and I322C mutants. Mutations or derivatization of the substituted cysteines in the second extracellular loop resulted in major increases in the apparent affinity for extracellular K(+), and this was associated with a reduction in the maximum activity. The changes produced by the E314C mutation were reversed by MTSET treatment. In the W317C and I322C mutants, MTSET also induced a moderate shift of the E1/E2 equilibrium towards the E1(Na) conformation under Na/Na exchange conditions. These findings indicate that the second extracellular loop must be functionally linked to the gating mechanism that controls the access of K(+) to its binding site.

Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock.

Recent evidence has emerged that peroxisome proliferator-activated receptor alpha (PPARalpha), which is largely involved in lipid metabolism, can play an important role in connecting circadian biology and metabolism. In the present study, we investigated the mechanisms by which PPARalpha influences the pacemakers acting in the central clock located in the suprachiasmatic nucleus and in the peripheral oscillator of the liver. We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. We further demonstrate that fenofibrate induces circadian rhythm of clock gene expression in cell culture and up-regulates hepatic bmal1 in vivo. Together, these results provide evidence for an additional regulatory feedback loop involving BMAL1 and PPARalpha in peripheral clocks.

Use of Sensors in the Treatment and Follow-up of Patients with Diabetes Mellitus

Glucose control is the cornerstone of Diabetes Mellitus (DM) treatment. Although self-regulation using capillary glycemia (SRCG) still remains the best procedure in clinical practice, continuous glucose monitoring systems (CGM) offer the possibility of continuous and dynamic assessment of interstitial glucose concentration. CGM systems have the potential to improve glycemic control while decreasing the incidence of hypoglycemia but the efficiency, compared with SRCG, is still debated. CGM systems have the greatest potential value in patients with hypoglycemic unawareness and in controlling daily fluctuations in blood glucose. The implementation of continuous monitoring in the standard clinical setting has not yet been established but a new generation of open and close loop subcutaneous insulin infusion devices are emerging making insulin treatment and glycemic control more reliable.

Assessing key safety concerns of a Wolbachia-based strategy to control dengue transmission by Aedes mosquitoes

Mosquito-borne diseases such as dengue fever, chikungunya or malaria affect millions of people each year and control solutions are urgently needed. An international research program is currently being developed that relies on the introduction of the bacterial endosymbiont Wolbachia pipientis into Aedes aegypti to control dengue transmission. In order to prepare for open-field testing releases of Wolbachia-infected mosquitoes, an intensive social research and community engagement program was undertaken in Cairns, Northern Australia. The most common concern expressed by the diverse range of community members and stakeholders surveyed was the necessity of assuring the safety of the proposed approach for humans, animals and the environment. To address these concerns a series of safety experiments were undertaken. We report in this paper on the experimental data obtained, discuss the limitations of experimental risk assessment and focus on the necessity of including community concerns in scientific research.