329 research outputs found
A teaching proposal on electrostatics based on the history of science through the reading of historical texts and argumentative discussions
Researches on electrostaticsâ conceptions found that students have ideas and conceptions that disagree with the scientific models and that might explain studentsâ learning difficulties. To favour the change of studentâs ideas and
conceptions, a teaching sequence that relies on a historical study of electrostatics is proposed. It begins with an exploration of electrostatics phenomena that students would do with everyday materials. About these phenomena they must draw their own explanations that will be shared and discussed in the class. The teacher will collect and summarize the ideas and explanations which are nearer the history of science. A brief history of electrostatics is introduced then, and some texts from scientists are used in an activity role-play-debate type in which the âsupporters of a single fluidâ and âsupporters of two fluidsâ have to present arguments for their model and/or against the other model to explain the phenomena observed in the exploration phase. In the following, students will read texts related to science applications, the main aim of this activity is to relate electrostatics phenomena with current electricity. The first text explains how Franklin understood the nature of the lightning and the lightning rod and the second is a chapter of a roman about
one historical episode situated in the Barcelona of the XVIII Century. Students will use the historical models of one and of two fluids to explain these two phenomena, and will compare them with the scientific explanation of the âacceptedâ science of nowadays introduced by the teacher. With this type of teaching proposal, conceptual aspect of electrostatics will be learnt, but also the students will learn about the nature and history of science and culture, as well as about the practice of argumentation
C-hypergroupoids obtained by special binary relations
AbstractIn this paper we deal with the partial or non-partial C-hypergroupoids which are associated with special binary relations defined on H, such as Reflexive, Symmetric, Cyclic and Transitive. Basic properties are investigated and various characterizations are given. The main tool to study the previous special classes of hypergroupoids is the fundamental relation ÎČâ (i.e. the smallest equivalence relation such that the quotient of a hypergroupoid (partial or not) is a groupoid (partial or not)
Translation-Dependent Mechanisms Lead to PML Upregulation and Mediate Oncogenic K-RAS-Induced Cellular Senescence
Expression of oncogenic K-RAS in primary cells elicits oncogene-induced cellular senescence (OIS), a form of growth arrest that potently opposes tumourigenesis. This effect has been largely attributed to transcriptional mechanisms that depend on the p53 tumour suppressor protein. The PML tumour suppressor was initially identified as a component of the oncoprotein of acute promyelocytic leukaemia (APL). PML, a critical OIS mediator, is upregulated by oncogenic K-RAS in vivo and in vitro. We demonstrate here that oncogenic K-RAS induces PML protein upregulation by activating the RAS/MEK1/mTOR/eIF4E pathway even in the absence of p53. Under these circumstances, PML mRNA is selectively associated to polysomes. Importantly, we find that the PML 5âČ untranslated mRNA region plays a key role in mediating PML protein upregulation and that its presence is essential for an efficient OIS response. These findings demonstrate that upregulation of PML translation plays a central role in oncogenic K-RAS-induced OIS. Thus, selective translation initiation plays a critical role in tumour suppression with important therapeutic implications for the treatment of solid tumours and APL
Mesenchymal/Stromal Gene Expression Signature Relates to Basal-Like Breast Cancers, Identifies Bone Metastasis and Predicts Resistance to Therapies
BACKGROUND:
Mounting clinical and experimental evidence suggests that the shift of carcinomas towards a mesenchymal phenotype is a common paradigm for both resistance to therapy and tumor recurrence. However, the mesenchymalization of carcinomas has not yet entered clinical practice as a crucial diagnostic paradigm.
METHODOLOGY/PRINCIPAL FINDINGS:
By integrating in silico and in vitro studies with our epithelial and mesenchymal tumor models, we compare herein crucial molecular pathways of previously described carcinoma-derived mesenchymal tumor cells (A17) with that of both carcinomas and other mesenchymal phenotypes, such as mesenchymal stem cells (MSCs), breast stroma, and various types of sarcomas. We identified three mesenchymal/stromal-signatures which A17 cells shares with MSCs and breast stroma. By using a recently developed computational approach with publicly available microarray data, we show that these signatures: 1) significantly relates to basal-like breast cancer subtypes; 2) significantly relates to bone metastasis; 3) are up-regulated after hormonal treatment; 4) predict resistance to neoadjuvant therapies.
CONCLUSIONS/SIGNIFICANCE:
Our results demonstrate that mesenchymalization is an intrinsic property of the most aggressive tumors and it relates to therapy resistance as well as bone metastasis
Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach
Pharmacophore searches that include anchors, fragments
contributing above average to receptor binding, combined with
one-step syntheses are a powerful approach for the fast
discovery of novel bioactive molecules. Here, we are presenting
a pipeline for the rapid and efficient discovery of aspartyl
protease inhibitors. First, we hypothesized that hydrazine could
be a multi-valent warhead to interact with the active site Asp
carboxylic acids. We incorporated the hydrazine anchor in a
multicomponent reaction and created a large virtual library of
hydrazine derivatives synthetically accessible in one-step. Next,
we performed anchor-based pharmacophore screening of the
libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an
enzyme activity assay and the binding mode confirmed by
several soaked crystal structures supporting the validity of the
hypothesis and approach. The herein reported pipeline of tools
will be of general value for the rapid generation of receptor
binders beyond Asp proteases
Human transcriptome response after Mediterranean diet consumption
Trabajo presentado en el IV Congress of International Society of Nutrigenetics/Nutrigenomics ISNN, celebrado en Pamplona (España) del 18 al 20 de noviembre de 2010.[Introduction]: Despite the benefits associated with healthy diets, data on the mechanisms by which these benefits are promoted are scarce. Our aim was to explore the global transcriptomic response of biological pathways related to cardiovascular disease associated with traditional Mediterranean diet (TMD) intervention.[Methods]: The PREDIMED study is a large on-going, parallel, multicentre, randomized, controlled trial aimed at assessing the TMD effect on primary cardiovascular prevention. High cardiovascular risk participants were recruited and assigned to one of the following interventions: 1) TMD plus virgin olive oil (VOO); 2) TMD plus mixed nuts; or 3) low-fat diet (control group). In a sub sample of 30 volunteers of the PREDIMED-Barcelona Sur Centre, gene expression changes in peripheral mononuclear cells, after 3 months of intervention, were assessed by microarray analysis (Affymetrix) in which about 30,000 individual human genes were included. Crude and adjusted models for data analyses were performed separately in two different centres. PearsonÂŽs correlation coefficients for log2ratio (post-intervention/pre-intervention value) and T-statistics were greater than 0.97. Gene ontology analyses were performed by Bioingenuity Software on genes with T-statistics â„1.5 or â„-1.5 after interventions.[Results]: Analyses of canonical pathways related with cardiovascular risk highlighted that: 1) MUFA versus PUFA rich diets (MUFA/PUFA ratio >3.5; TMD plus VOO and Low-fat) promoted changes in clusters of genes associated with cytokine and nuclear receptor signaling; and 2) TMD plus VOO promoted changes in blood pressure related pathways. In agreement with this, the greatest decrease in systolic and diastolic blood pressure levels were observed after TMD
plus VOO diet.[Conclusions]: One of the mechanisms by which MUFA rich diets, and particularly a TMD rich in virgin olive oil, can exert their health benefits is through an enhancement of the global transcriptomic response in pathways related with cardiovascular risk
The Antioxidant Potential of the Mediterranean Diet in Patients at High Cardiovascular Risk: An In-Depth Review of the PREDIMED
Cardiovascular disease (CVD) is the leading global cause of death. Diet is known to be important in the prevention of CVD. The PREDIMED trial tested a relatively low-fat diet versus a high-fat Mediterranean diet (MedDiet) for the primary prevention of CVD. The resulting reduction of the CV composite outcome resulted in a paradigm shift in CV nutrition. Though many dietary factors likely contributed to this effect, this review focuses on the influence of the MedDiet on endogenous antioxidant systems and the effect of dietary polyphenols. Subgroup analysis of the PREDIMED trial revealed increased endogenous antioxidant and decreased pro-oxidant activity in the MedDiet groups. Moreover, higher polyphenol intake was associated with lower incidence of the primary outcome, overall mortality, blood pressure, inflammatory biomarkers, onset of new-onset type 2 diabetes mellitus (T2DM), and obesity. This suggests that polyphenols likely contributed to the lower incidence of the primary event in the MedDiet groups. In this article, we summarize the potential benefits of polyphenols found in the MedDiet, specifically the PREDIMED cohort. We also discuss the need for further research to confirm and expand the findings of the PREDIMED in a non-Mediterranean population and to determine the exact mechanisms of action of polyphenols
Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS-mutant cancer.
KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun N-terminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patient-derived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer
Screening for pre-eclampsia by maternal factors and biomarkers at 11-13âweeks' gestation
Objective:
To examine the performance of screening for early-, preterm- and term-preeclampsia (PE) at 11 13 weeksâ gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PLGF) and serum pregnancy associated plasma protein A (PAPP A).
Methods
The data for this study were derived from three previously reported prospective non intervention screening studies at 11+0 â 13+6 weeksâ gestation in a combined total of 61,174 singleton pregnancies, including 1,770 (2.9%) that developed PE. Bayes theorem was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiple of the median (MoM) values to derive the p patient specific risks of delivery with PE at <37 weeksâ gestation. The performance of such screening was estimated.
Results In pregnancies that develop ed PE , compared to those without PE, the MoM values of UtA-PI and MAP were increased and PAPP A and PLGF were decreased and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PLGF predicted 90% of early PE, 75% of preterm PE and 4 1 % of term PE, at screen positive rate of 10%; inclusion of PAPP A did not improve the performance of screening The performance of screening depended on the racial origin of the women; in screening by a combination of maternal factors, MAP, UtA-PI and PLGF and use of the risk cut off of 1 in 10 0 for PE at <37 weeks in Caucasian women, the screen positive rate was 10% and detection rates for early --, preterm and term PE were 88%, 69% and 40%, respectively. With the same
method of screening and risk cut off in women of Afro Caribbean racial origin, the screen positive rate was 34% and detection rates for early --, preterm and term PE were 100%,
92% and 75%, respectively.
Conclusion
Screening by maternal factors and biomarkers at 11-13 weeksâ gestation can identify a high proportion of pregnancies that develop early- and preterm-PE
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