3,197 research outputs found
Computational Perspectives into Plasmepsins Structure—Function Relationship: Implications to Inhibitors Design
The development of efficient and selective antimalariais remains a challenge for the pharmaceutical industry. The aspartic proteases plasmepsins, whose inhibition leads to parasite death, are classified as targets for the design of potent drugs. Combinatorial synthesis is currently being used to generate inhibitor libraries for these enzymes, and together with computational methodologies have been demonstrated capable for the selection of lead compounds. The high structural flexibility of plasmepsins, revealed by their X-ray structures and molecular dynamics simulations, made even more complicated the prediction of putative binding modes, and therefore, the use of common computational tools, like docking and free-energy calculations. In this review, we revised the computational strategies utilized so far, for the structure-function relationship studies concerning the plasmepsin family, with special focus on the recent advances in the improvement of the linear interaction estimation (LIE) method, which is one of the most successful methodologies in the evaluation of plasmepsin-inhibitor binding affinity
Situs ambiguous and absence of the inferior vena cava: an extremely rare cause of femoral hemodialysis catheter dysfunction
Hemodialysis catheter dysfunction (CDys) has been defined by Kidney Disease utcomes Quality Initiative (K/DOQI) guidelines as “failure to maintain an extracorporeal
blood flow sufficient to perform hemodialysis without significantly lengthening
the hemodialysis treatment” [1], influencing stage 5 chronic kidney disease (CKD)
patients’ morbidity and mortality [2]. Among the causes of CDys, those occurring within
the first 2 weeks of placement are defined as early dysfunction commonly resulting from
mechanical problems, which include inadequate positioning, kinking, or constriction,
while late dysfunction usually results from thrombus formation [1]. However, this case
report demonstrates that one must also consider other causes of CDys.info:eu-repo/semantics/publishedVersio
Assessment of a mattress with phase change materials using a thermal and perception test
Mattresses composed by phase change materials (PCMs) may improve the thermoregulation of the human body. The aim of the study was to analyze the thermoregulatory efficiency of a PCMs and a conventional mattresses via the evaluation of the skin temperature, thermal comfort and thermal perception. Twenty participants lay on a PCMs and a conventional mattress for 20 minutes in each mattress on the same day. Skin temperature of the back of the participants and temperature of the sheet of the mattresses were measured before and immediately after lying on each mattress. Thermal comfort and thermal perception were also reported during the last minute of the lying test. The PCMs mattress resulted in a lower increase in skin temperature (0.3 - 1.0°C, p=0.002 and ES=1.4) and a greater increase of the sheet temperature (0.2 - 1.6°C, p=0.02 and ES=0.8). No differences in thermal comfort and thermal perception were observed between mattresses (p>0.05 and ES<0.8). The analysis of the superficial temperature (skin, sheet) was an adequate tool to identify differences in the thermoregulatory efficiency of different mattresses. The use of PCMs in mattresses improved the heat dissipation of the human body during lying in a proportion between 2.7% and 25.6%. However, the thermoregulatory differences were not big enough to alter the thermal comfort and thermal perception of the participants after 20 minutes of test.SIThe contribution of two of the authors were funded with doctoral fellowships (FPU) from the Spanish Ministry of Education. Thanks are given to all participants who volunteered for this study. We also acknowledge D. Oscar Calvo (AITEX – Textile Research Institute) for their collaboration and support in the stud
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A TRAF2 binding independent region of TNFR2 is responsibl for TRAF2 depletion and enhancement of cytotoxicity driven b TNFR1
Tumor Necrosis Factor (TNF) interacts with two receptors known as TNFR1 and TNFR2. TNFR1 activation may result in either cell proliferation or cell death. TNFR2 activates Nuclear Factor-kappaB (NF-kB) and c-Jun N-terminal kinase (JNK) which lead to transcriptional activation of genes related to cell proliferation and survival. This depends on the binding of TNF Receptor Associated Factor 2 (TRAF2) to the receptor. TNFR2 also induces TRAF2 degradation. In this work we have investigated the structural features of TNFR2 responsible for inducing TRAF2 degradation and have studied the biological consequences of this activity. We show that when TNFR1 and TNFR2 are co-expressed, TRAF2 depletion leads to an enhanced TNFR1 cytotoxicity which correlates with the inhibition of NF-kB. NF-kB activation and TRAF2 degradation depend of different regions of the receptor since TNFR2 mutants at amino acids 343-349 fail to induce TRAF2 degradation and have lost their ability to enhance TNFR1-mediated cell death but are still able to activate NF-kB. Moreover, whereas NF-kB activation requires TRAF2 binding to the receptor, TRAF2 degradation appears independent of TRAF2 binding. Thus, TNFR2 mutants unable to bind TRAF2 are still able to induce its degradation and to enhance TNFR1-mediated cytotoxicity. To test further this receptor crosstalk we have developed a system stably expressing in cells carrying only endogenous TNFR1 the chimeric receptor RANK-TNFR2, formed by the extracellular region of RANK (Receptor activator of NF-kB) and the intracellular region of TNFR2.This has made possible to study independently the signals triggered by TNFR1 and TNFR2. In these cells TNFR1 is selectively activated by soluble TNF (sTNF) while RANK-TNFR2 is selectively activated by RANKL. Treatment of these cells with sTNF and RANKL leads to an enhanced cytotoxicity
THE EFFECT OF WARM-UP ON SPRINTING KINEMATICS
The purpose of this study was to verify the effects of warm-up on kinematic variables during short distance repeated sprints. Twenty-two college students randomly performed 2 x 30-m running time-trials after warm-up or with no warm-up, in different days. Performance (time-trial) and biomechanical (step length and step frequency) were assessed during both repeated trials. Performance was 0.5% faster after warm-up in the first 30-m time-trial (p = 0.03, d = 0.44), but without differences on step length and frequency. The second sprint was not different between conditions, but it was better than the first sprint in the no warm-up condition. This condition also led to higher changes between the first and second sprint. Thus, the warm-up is suggested to improve maximal running performances and maintaining kinematics more similar throughout the sprints
Crossing the phantom divide in an interacting generalized Chaplygin gas
Unified generalized Chaplygin gas models assuming an interaction between dark
energy and dark matter fluids have been previously proposed. Following these
ideas, we consider a particular relation between dark densities, which allows
the possibility of a time varying equation of state for dark energy that
crosses the phantom divide at a recent epoch. Moreover, these densities decay
during all the evolution of the Universe, avoiding a Big Rip. We find also a
scaling solution, i.e. these densities are asymptotically proportional in the
future, which contributes to the solution of the coincidence problem.Comment: Improved version, 10 pages, 4 figures, References adde
Calculation methods of Radon-222 radiological activity for NORM plant with ventilation
A procedure is proposed to determine the radiological activity of air present in the working area of a NORM (Naturally-Occurring Radioactive Materials) plant. This NORM plant is located in the United Arab Emirates and is dedicated to the recycling of material and equipment used in oil extraction facilities. Substantial quantities of NORM waste will be present inside the enclosed plant facilities and will exhale significant amounts of Radon-222 into the working environment. The continued inhalation of this gas and its progeny has been shown to cause lung cancer. In order to reduce the concentration level of the aforementioned gas to an acceptable regulatory value, the best solution is by means of mechanical ventilation. The two calculation methods used to analysis the relationship between the ventilation rate and the degree of radioactive contamination are considered. The first being ventilation by perfect dilution, commonly employed in industrial environments with radiological contamination. The second method of analysis is by means of a CFD (Computational Fluid Dynamics) which permits a more precise calculation of the required fresh air quantity and spatial concentrations. Validation was carried out in a small experimental plant space, obtaining results reasonable approximate to those predicted by the computational analysis. The similarities and differences between the respective calculation methods and their respective fields of application are analyzed. It is concluded that for lower air change rates, less than five air changes per hour, the CFD analysis is the most appropriate method. By contrast, when using a higher rate of outside air changes in the plant, the perfect dilution method should be sufficient enough to control the presence of radon and its progeny. Both calculation methods consider the activity of radon and the activity of the most significant radioisotopes of its progeny
Air diffusion system design in large assembly halls. Case study of the Congress of Deputies parliament building, Madrid, Spain
The paper describes and analyses the air distribution solution adopted in the refurbishment of the Spanish Congress of Deputies assembly hall. A new approach is proposed for the design of displacement ventilation systems. The system performance is methodically validated both with laboratory tests, computational fluid dynamics analysis and experimental field measurements related to the environmental performance of the built environment. In assembly halls, microclimate and displacement ventilation systems, which supply air by means of floor mounted outlets, have been shown to perform adequately. In this case study floor air supply is not feasible. The solution adapted uses parapet mounted diffusers, using a confluent jet flow parallel to the floor plane above the occupied area. All the tools used to analyse the performance of this system showed that the admixing overhead supply, with ceiling return, and flowing parallel to and above the occupied zone is drawn back into the occupied zone, creating a plume effect similar to that of floor mounted displacement outlets. Thus, this confirms that the displacement effect can be accomplished using a high induction turbulent overhead supply with ceiling return. Therefore supplying air directly into the occupied zone, at or near to floor level, is not a prerequisite to achieve the desired displacement effect. This report concludes that, using the correct design parameters, as set out in this paper, the displacement ventilation effect is independent of the plane of air supply. The conclusions suggest that accepted criteria for the definition and design of displacement systems should be redefined
SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer
Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers
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