Novel micropatterns mechanically control fibrotic reactions at the surface of silicone implants.

Over the past decade, various implantable devices have been developed to treat diseases that were previously difficult to manage such diabetes, chronic pain, and neurodegenerative disorders. However, translation of these novel technologies into clinical practice is often difficult because fibrotic encapsulation and/or rejection impairs device function after body implantation. Ideally, cells of the host tissue should perceive the surface of the implant being similar to the normal extracellular matrix. Here, we developed an innovative approach to provide implant surfaces with adhesive protein micropatterns. The patterns were designed to promote adhesion of fibroblasts and macrophages by simultaneously suppressing fibrogenic activation of both cell types. In a rat model, subcutaneously implanted silicone pads provided with the novel micropatterns caused 6-fold lower formation of inflammatory giant cells compared with clinical grade, uncoated, or collagen-coated silicone implants. We further show that micropatterning of implants resulted in 2-3-fold reduced numbers of pro-fibrotic myofibroblast by inhibiting their mechanical activation. Our novel approach allows controlled cell attachment to implant surfaces, representing a critical advance for enhanced biointegration of implantable medical devices.

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

CCL8 and the Immune Control of Cytomegalovirus in Organ Transplant Recipients.

Monitoring of cytomegalovirus cell-mediated immunity is a promising tool for the refinement of preventative and therapeutic strategies posttransplantation. Typically, the interferon-γ response to T cell stimulation is measured. We evaluated a broad range of cytokine and chemokines to better characterize the ex vivo host-response to CMV peptide stimulation. In a cohort of CMV viremic organ transplant recipients, chemokine expression-specifically CCL8 (AUC 0.849 95% CI 0.721-0.978; p = 0.003) and CXCL10 (AUC 0.841, 95% CI 0.707-0.974; p = 0.004)-was associated with control of viral replication. In a second cohort of transplant recipients at high-risk for CMV, the presence of a polymorphism in the CCL8 promoter conferred an increased risk of viral replication after discontinuation of antiviral prophylaxis (logrank hazard ratio 3.6; 95% CI 2.077-51.88). Using cell-sorting experiments, we determined that the primary cell type producing CCL8 in response to CMV peptide stimulation was the monocyte fraction. Finally, in vitro experiments using standard immunosuppressive agents demonstrated a dose-dependent reduction in CCL8 production. Chemokines appear to be important elements of the cell-mediated response to CMV infection posttransplant, as here suggested for CCL8, and translation of this knowledge may allow for the tailoring and improvement of preventative strategies.

Los enfoques de aprendizaje en estudiantes universitarios Catalanes mediante el approaches and study skills inventory for students (ASSIST) = Learning Approaches of Catalan University Students Measured with the Approaches and Study Skills Inventory for Students (ASSIST)

The aim of this study is to measure the psychometric properties of a Catalan translation of the Approaches and Study Skills Inventory for Students (ASSIST), and to analyse the different learning styles used by university students, considering the influence of gender and type of studies. The instrument was administered to 834 students at the University of Girona. The results showed that most students interviewed had a deep approach to learning, although the analysis by gender showed that females tended to use a more strategic approach, while males used a deep approach predominantly. As to whether the type of studies influenced learning styles, a prevalence of deep approach was found among Science and Technology students, while a more strategic approach was found among Humanities and Education students

Quality of life after pulmonary embolism, validation of the French version of the PEmb-QoL questionnaire

Background: The PEmb-QoL is a validated 40-item questionnaire to quantify health-related quality of life in patients having experienced pulmonary embolism (PE). It covers six health dimensions: frequency of complaints, activities of daily living limitations, work-related problems, social limitations, intensity of complaints, and emotional complaints. Originally developed in Dutch and English, we sought to prospectively validate the psychometric properties of a French version of the PEmb-QoL. Methods: We performed a forward and backward translation of the English version of the PEmb-QoL into French. French-speaking consecutive adult patients with an acute, objectively confirmed PE admitted to the emergency department of a Swiss university hospital between 08/2009 and 09/2011 were recruited telephonically. We used standard psychometric tests and criteria to evaluate the acceptability, reliability, and validity of the French version of the PEmb-QoL. We also performed an exploratory factor analysis. Results: Overall, 102 patients were enrolled in the study. The French version of the PEmb-QoL showed good reliability (internal consistency, item-total and inter-item correlations), reproducibility (test-retest reliability), and validity (convergent, discriminant) in French-speaking patients with PE. The exploratory factor analysis suggested three underlying dimensions: limitations in daily activity (items 4b-m, 5a-d), symptoms (items 1a-h and 7), and emotional complaints (items 9a-f and j). Conclusion: We successfully validated the French version of the PEmb-QoL questionnaire in patients with PE. Our results show that the PEmb-QoL is a valuable tool for assessing health-related quality of life after PE in French-speaking patients.

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver.

Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5'-UTR (TISU) motif. The increased translation efficiency of 5'-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.

Swiss family physicians' perceptions and attitudes towards knowledge translation practices.

BACKGROUND: Several studies have been performed to understand the way family physicians apply knowledge from medical research in practice. However, very little is known concerning family physicians in Switzerland. In an environment in which information constantly accumulates, it is crucial to identify the major sources of scientific information that are used by family physicians to keep their medical knowledge up to date and barriers to use these sources. Our main objective was to examine medical knowledge translation (KT) practices of Swiss family physicians. METHODS: The population consisted of French- and German-speaking private practice physicians specialised in family medicine. We conducted four interviews and three focus groups (n = 25). The interview guides of the semi-structured interviews and focus groups focused on (a) ways and means used by physicians to keep updated with information relevant to clinical practice; (b) how they consider their role in translating knowledge into practice; (c) potential barriers to KT; (d) solutions proposed by physicians for effective KT. RESULTS: Family physicians find themselves rather ambivalent about the translation of knowledge based on scientific literature, but generally express much interest in KT. They often feel overwhelmed by "information floods" and perceive clinical practice guidelines and other supports to be of limited usefulness for their practice. They often combine various formal and informal information sources to keep their knowledge up to date. Swiss family physicians report considering themselves as artisans, caring for patients with complex needs. CONCLUSION: Improved performance of KT initiatives in family medicine should be tailored to actual needs and based on high quality evidence-based sources.

Traducción de fragmentos humorísticos de dos videojuegos

En este trabajo se estudia la relación entre el humor y el mundo de la localización de videojuegos mediante el análisis de las diferentes técnicas de traducción utilizadas en la traducción oficial de dos fragmentos de los videojuegos Portal (2007) y Portal 2(2011) respectivamente. De este modo, por una parte, el trabajo profundiza en el mundo de la localización de videojuegos centrándose en diferentes aspectos relacionados como la interfaz, los componentes que forman un videojuego y los tipos, modelos y procesos de localización existentes y, por la otra, se centra en cómo traducir referencias humorísticas en este ámbito de la traducción especializada. Para poner en práctica todo lo analizado, se realiza una traducción de los fragmentos de Portal y de Portal 2 seleccionados con tal de comparar las soluciones que hemos ofrecido con las que aparecen en los productos oficiales.

A Write-Based Solver for SAT Modulo the Theory of Arrays

The extensional theory of arrays is one of the most important ones for applications of SAT Modulo Theories (SMT) to hardware and software verification. Here we present a new T-solver for arrays in the context of the DPLL(T) approach to SMT. The main characteristics of our solver are: (i) no translation of writes into reads is needed, (ii) there is no axiom instantiation, and (iii) the T-solver interacts with the Boolean engine by asking to split on equality literals between indices. As far as we know, this is the first accurate description of an array solver integrated in a state-of-the-art SMT solver and, unlike most state-of-the-art solvers, it is not based on a lazy instantiation of the array axioms. Moreover, it is very competitive in practice, specially on problems that require heavy reasoning on array literals

Early Modern Persian, Urdu, and English Historiography and the Imagination of Islamic India under British Rule

This paper analyses the early modern transformations of South Asian literary cultures through the production of historiography in Persian, English, and Urdu. In the 18th-19th centuries, South Asian communities experienced and participated in a major restructuring of the languages of the subcontinent. Urdu and English were institutionalized as governmental languages and utilized in new literary productions as Persian was gradually marginalized from the centre of literary and governmental polities. Three interrelated colonial policies reshaped the historical consciousness of South Asia and Britain: the production of new Persian histories commissioned under British patronage, the initiation of Urdu historiography through the translation of Persian and English histories, and the construction of the British history of India written in English. This article explores the historical and social dynamics of these events and situates the origins and evolution of the colonial historiographical project. Major works discussed are the Tārīkh-i Bangālah of Salīm Allāh Munshī (fl. 1763), James Mill's (1773-1836) The History of British India first published in 1817, Mīr Sher ʿAlī Afsos' the Ārāʾish-i mahfil, as well as the production of original Urdu histories such as Muḥammad Zakāʾ-Allāh's (1832-1910) the Tārīkh-i Hindustān.

The natural history of type II odontoid fractures in the elderly population. A retrospective study over a 14 years period.

Odontoid fractures are the most common cervical fractures in the adult population. They represent 9 to 18 % of all cervical fractures and the type II is the most common. The incidence of neurologic deficits (ND) in odontoid fractures varies between 3 to 25%. A recent study showed that patients with ND had a mortality rate increased by 4.72 times and a complication rate higher of 1.18 times. The most common complication in patients with ND was respiratory distress8. Surprisingly, although type II odontoid fractures are frequent cervical fractures, their natural history has been poorly described. Surgery for odontoid fractures is well described. However, there are so far guidelines based on class II and class III evidence only regarding indications for surgery and regarding surgical techniques. The class II guidelines recommend to consider surgical stabilization and fusion for type II odontoid in patients over 50 years of age. The class III recommendations are to first manage non-displaced odontoid type II fracture with external immobilization and that translation of 5mm or more is associated with a high rate of non- union with the conservative treatment and should be treated surgically.

Neuropeptide Y at the cellular level – Studies on PreproNPY L7P Polymorphism and the Mitochondrial Form of NPY

Neuropeptide Y (NPY) is a widely expressed neurotransmitter in the central and peripheral nervous systems. Thymidine 1128 to cytocine substitution in the signal sequence of the preproNPY results in a single amino acid change where leucine is changed to proline. This L7P change leads to a conformational change of the signal sequence which can have an effect on the intracellular processing of NPY. The L7P polymorphism was originally associated with higher total and LDL cholesterol levels in obese subjects. It has also been associated with several other physiological and pathophysiological responses such as atherosclerosis and T2 diabetes. However, the changes on the cellular level due to the preproNPY signal sequence L7P polymorphism were not known. The aims of the current thesis were to study the effects of the [p.L7]+[p.L7] and the [p.L7]+[p.P7] genotypes in primary cultured and genotyped human umbilical vein endothelial cells (HUVEC), in neuroblastoma (SK-N-BE(2)) cells and in fibroblast (CHO-K1) cells. Also, the putative effects of the L7P polymorphism on proliferation, apoptosis and LDL and nitric oxide metabolism were investigated. In the course of the studies a fragment of NPY targeted to mitochondria was found. With the putative mitochondrial NPY fragment the aim was to study the translational preferences and the mobility of the protein. The intracellular distribution of NPY between the [p.L7]+[p.L7] and the [p.L7]+[p.P7] genotypes was found to be different. NPY immunoreactivity was prominent in the [p.L7]+[p.P7] cells while the proNPY immunoreactivity was prominent in the [p.L7]+[p.L7] genotype cells. In the proliferation experiments there was a difference in the [p.L7]+[p.L7] genotype cells between early and late passage (aged) cells; the proliferation was raised in the aged cells. NPY increased the growth of the cells with the [p.L7]+[p.P7] genotype. Apoptosis did not seem to differ between the genotypes, but in the aged cells with the [p.L7]+[p.L7] genotype, LDL uptake was found to be elevated. Furthermore, the genotype seemed to have a strong effect on the nitric oxide metabolism. The results indicated that the mobility of NPY protein inside the cells was increased within the P7 containing constructs. The existence of the mitochondria targeted NPY fragment was verified, and translational preferences were proved to be due to the origin of the cells. Cell of neuronal origin preferred the translation of mature NPY (NPY1-36) when compared to the non neuronal cells that translated both, NPY and the mitochondrial fragment of NPY. The mobility of the mitochondrial fragment was found to be minimal. The functionality of the mitochondrial NPY fragment remains to be investigated. L7P polymorphism in the preproNPY causes a series of intracellular changes. These changes may contribute to the state of cellular senescence, vascular tone and lead to endothelial dysfunction and even to increased susceptibility to diseases, like atherosclerosis and T2 diabetes.

Otra mirada al tema del cambio de escala: los nuevos espacios de comercio, ocio y turismo = Another look at the theme of the change of scale: new spaces in commerce, leisure and tourism

The technological advances and new organisation of the economy together with a change in ideas in consumer habits andlifestyle that have happened in the last 25 years have placed us in a new state of capitalism. The spatial translation of thisnew state has been immediate and implies among other changes the overcoming of the concept of scale. Commercialspaces and those of leisure and tourism offer us an unbeatable opportunity of exemplifying these changes because they arethe most effected by the new postmodern tendencies

The Art & Science of Learning Design

We live in an era defined by a wealth of open and readily available information, and the accelerated evolution of social, mobile and creative technologies. The provision of knowledge, once a primary role of educators, is now devolved to an immense web of free and readily accessible sources. Consequently, educators need to redefine their role not just ¿from sage on the stage to guide on the side¿ but, as more and more voices insist, as ¿designers for learning¿.The call for such a repositioning of educators is heard from leaders in the field of technology-enhanced learning (TEL) and resonates well with the growing culture of design-based research in Education. However, it is still struggling to find a foothold in educational practice. We contend that the root causes of this discrepancy are the lack of articulation of design practices and methods, along with a shortage of tools and representations to support such practices, a lack of a culture of teacher-as-designer among practitioners, and insufficient theoretical development.The Art and Science of Learning Design (ASLD) explores the frameworks, methods, and tools available for teachers, technologists and researchers interested in designing for learning Learning Design theories arising from findings of research are explored, drawing upon research and practitioner experiences. It then surveys current trends in the practices, methods, and methodologies of Learning Design. Highlighting the translation of theory into practice, this book showcases some of the latest tools that support the learning design process itself.

Analysis of the nucleotide sequence of the coat protein and 3'-untranslated region of two Brazilian Potato virus Y isolates

Two Brazilian Potato virus Y (PVY) isolates were biologically characterized as necrotic (PVY-NBR) and common (PVY-OBR) based upon symptoms on test plants. Additional characterization was performed by sequencing a cDNA corresponding to the 3' terminal region of the viral genome. The sequence consisted of 195 nucleotides (nt) coding part of the nuclear inclusion body b (NIb) gene, 804 nt of the coat protein (CP) gene, and 328 nt (PVY-OBR) or 326 nt (PVY-NBR) of the 3'-untranslated region (UTR). Translation of the sequence resulted in one single open reading frame with part of the NIb and a CP of 267 amino acids. The two isolates shared 95.1% similarity in the CP amino acid sequence. The CP and the 3'-UTR sequence of the Brazilian isolates were compared to those of other PVY isolates previously reported and unrooted phylogenetic trees were constructed. The trees revealed a separation of two distinct clusters, one comprising most of the common strains and the other comprising the necrotic strains. PVY-OBR was clustered in the common group and PVY-NBR in the necrotic one.