Éditorial

Introduction L’adoption de la Convention Européenne du Paysages (CEP) en 2000 constitue un événement clef dans la prise en compte des paysages au niveau européen. À ce jour, trente‐huit pays ont ratifié la Convention adoptée sous l’égide du Conseil de l’Europe. En spécifiant que le paysage est une composante essentielle du cadre de vie des Européens, la convention s’inscrit avant toute chose dans une dimension territoriale. Par ailleurs, un fondement fort de la CEP réside dans la particularit..

Blood and Marrow Transplant Clinical Trials Network Toxicity Committee Consensus Summary: Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation

AbstractThe syndrome of microangiopathic hemolysis associated with renal failure, neurologic impairment, or both is a recognized complication of hematopoietic stem cell transplantation. This entity is often called hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP), yet it is clear that the pathophysiology of transplant-associated HUS/TTP is different from that of classic HUS or TTP. Furthermore, the incidence of this syndrome varies from 0.5% to 76% in different transplant series, primarily because of the lack of a uniform definition. The toxicity committee of the Blood and Marrow Transplant Clinical Trials Network has reviewed the current literature on transplant-related HUS/TTP and recommends that it be henceforth renamed posttransplantation thrombotic microangiopathy (TMA). An operational definition for TMA based on the presence of microangiopathic hemolysis and renal and/or neurologic dysfunction is proposed. The primary intervention after diagnosis of TMA should be withdrawal of calcineurin inhibitors. Plasma exchange, although frequently used in this condition, has not been proven to be effective. In the absence of definitive trials, plasma exchange cannot be considered a standard of care for TMA. It is hoped that these positions will improve the identification and reporting of this devastating complication after hematopoietic stem cell transplantation and facilitate future clinical studies for its prevention and treatment

Exploring Shared Memory Protocols in FLASH

ABSTRACT The goal of this project was to improve the performance of large scientific and engineering applications through collaborative hardware and software mechanisms to manage the memory hierarchy of non-uniform memory access time (NUMA) shared-memory machines, as well as their component individual processors. In spite of the programming advantages of shared-memory platforms, obtaining good performance for large scientific and engineering applications on such machines can be challenging. Because communication between processors is managed implicitly by the hardware, rather than expressed by the programmer, application performance may suffer from unintended communication – communication that the programmer did not consider when developing his/her application. In this project, we developed and evaluated a collection of hardware, compiler, languages and performance monitoring tools to obtain high performance on scientific and engineering applications on NUMA platforms by managing communication through alternative coherence mechanisms. Alternative coherence mechanisms have often been discussed as a means for reducing unintended communication, although architecture implementations of such mechanisms are quite rare. This report describes an actual implementation of a set of coherence protocols that support coherent, non-coherent and write-update accesses for a CC-NUMA shared-memory architecture, the Stanford FLASH machine. Such an approach has the advantages of using alternative coherence only where it is beneficial, and also provides an evolutionary migration path for improving application performance. We present data on two computations, RandomAccess from the HPC Challenge benchmarks and a forward solver derived from LS-DYNA, showing the performance advantages of the alternative coherence mechanisms. For RandomAccess, the non-coherent and write-update versions can outperform the coherent version by factors of 5 and 2.5, respectively. In LS-DYNA, we obtain improvements of 18% on average using the non-coherent version. We also present data on the SpecOMP benchmarks, showing that the protocols have a modest overhead of less than 3% in applications where the alternative mechanisms are not needed. In addition to the selective coherence studies on the FLASH machine, in the last six months of this project ISI performed research on compiler technology for the transactional memory (TM) programming model being developed at Stanford. As part of this research ISI developed a compiler that recognizes transactional memory “pragmas” and automatically generates parallel code for the TM programming mode

Structural and Functional Characterization of Sulfonium Carbon-Oxygen Hydrogen Bonding in the Deoxyamino Sugar Methyltransferase TyIM1

The N-methyltransferase TylM1 from Streptomyces fradiae catalyzes the final step in the biosynthesis of the deoxyamino sugar mycaminose, a substituent of the antibiotic tylosin. The high-resolution crystal structure of TylM1 bound to the methyl donor S-adenosylmethionine (AdoMet) illustrates a network of carbon-oxygen (CH•••O) hydrogen bonds between the substrate’s sulfonium cation and residues within the active site. These interactions include hydrogen bonds between the methyl and methylene groups of the AdoMet sulfonium cation and the hydroxyl groups of Tyr14 and Ser120 in the enzyme. To examine the functions of these interactions, we generated Tyr14 to phenylalanine (Y14F) and Ser120 to alanine (S120A)mutations to selectively ablate the CH•••O hydrogen bonding to AdoMet. The TylM1 S120A mutant exhibited a modest decrease in the catalytic efficiency relative to wild type (WT) enzyme, whereas the Y14F mutation resulted in an approximately 30-fold decrease in catalytic efficiency. In contrast, site-specific substitution of Tyr14 by the noncanonical amino acid p-aminophenylalanine partially restored activity comparable to the WT enzyme. Correlatively, quantum mechanical calculations of the activation barrier energies of WT TylM1 and the Tyr14 mutants suggest that substitutions which abrogate hydrogen bonding with the AdoMet methyl group impair methyl transfer. Together, these results offer insights into roles of CH•••O hydrogen bonding in modulating the catalytic efficiency of TylM1

Did giraffe cardiovascular evolution solve the problem of heart failure with preserved ejection fraction?

The evolved adaptations of other species can be a source of insight for novel biomedical innovation. Limitations of traditional animal models for the study of some pathologies are fueling efforts to find new approaches to biomedical investigation. One emerging approach recognizes the evolved adaptations in other species as possible solutions to human pathology. The giraffe heart, for example, appears resistant to pathology related to heart failure with preserved ejection fraction (HFpEF)-a leading form of hypertension-associated cardiovascular disease in humans. Here, we postulate that the physiological pressure-induced left ventricular thickening in giraffes does not result in the pathological cardiovascular changes observed in humans with hypertension. The mechanisms underlying this cardiovascular adaptation to high blood pressure in the giraffe may be a bioinspired roadmap for preventive and therapeutic strategies for human HFpEF

Practice Patterns and Preferences Among Hematopoietic Cell Transplantation Clinicians

Hematopoietic cell transplantation can cure many high-risk diseases but is associated with complexity, cost, and risk. Several areas in transplantation practice were identified in the 2014 Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium (BMT CTN SOSS) as high priorities for further study. We developed a survey for hematopoietic cell transplantation clinicians to identify current practices in BMT CTN SOSS priority areas and to understand, more generally, the variation in approach to transplantation and estimation of transplantation benefit in current medical practice. Of 1439 transplantation clinicians surveyed, 305 responded (20% response rate). Clinicians were well represented by age, experience, geography, and size of practice. We found that several techniques identified in the BMT CTN SOSS, such as maintenance therapy for acute myeloid leukemia or myelodysplastic syndromes after allogeneic transplantation, were already being utilized in practice on and off study, with higher rates of use in higher-volume centers. There was significant variation among clinicians in use of transplantation technologies and approaches to common transplantation scenarios. Appraisals of risks and benefits of transplantation appeared to converge upon similar estimates despite the presentation of different hypothetical scenarios. These results suggest overall equipoise in several BMT CTN SOSS high-priority areas and support the need for better data to inform clinical practice