Common variants associated with plasma triglycerides and risk for coronary artery disease.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Genetic variation in LIN28B is associated with the timing of puberty.

The timing of puberty is highly variable. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing, as the first genetic determinant regulating the timing of human pubertal growth and development.

[Archives de la Parole]. , Pombada Songs / [Sir George Grierson], éd. ; Linguistic survey of India ; [Tyampa Pombada et Venku], voix

[Traditions. Asie. Inde. Province de Madras [i.e. Chennai]. Région de Kanara]

闢釋氏諸妄 Pi shi shi zhu wang.

Contre les erreurs du bouddhisme. Par Xu Guang qi, de Wu song. 16 feuillets (8 sections). Catalogus librorum 22 (Bi wang).

Computing infinite plans for LTL goals using a classical planner

Classical planning has been notably successful in synthesizing finite plans to achieve states where propositional goals hold. In the last few years, classical planning has also been extended to incorporate temporally extended goals, expressed in temporal logics such as LTL, to impose restrictions on the state sequences generated by finite plans. In this work, we take the next step and consider the computation of infinite plans for achieving arbitrary LTL goals. We show that infinite plans can also be obtained efficiently by calling a classical planner once over a classical planning encoding that represents and extends the composition of the planningdomain and the B¨uchi automaton representingthe goal. This compilation scheme has been implemented and a number of experiments are reported.

Metaphyseal chondromatosis combined with D-2-hydroxyglutaric aciduria in four patients.

We report four patients who presented with a severe form of metaphyseal chondromatosis in association with D-2-hydroxyglutaric aciduria (D-2-HGA). All patients showed splaying columns of irregular ossification defects with bulbous metaphyses of the long tubular bones, as well as remarkable involvement of the short tubular and flat bones. The vertebral bodies revealed platyspondyly with irregular, stippled endplates. D-2-HGA has been described as a neurometabolic disorder manifesting a broad range of impairment in mental and motor development. Although hydroxyglutaric acid was excreted in high amounts in the urine of all four patients described herein, no significant neurologic abnormalities were evident. This unusual combination of characteristic skeletal and metabolic abnormalities has rarely been reported. Thus, our report will facilitate the recognition of this distinctive entity, and we suggest that a urine organic acid screening be obtained in patients who present with generalized enchondromatosis.

The role of territory choice mate choice and arrival date on breeding success in the Savi's warbler (Locustella luscinioides)

We investigated how territory quality, settlement date and morphometry affected several components of yearly breeding success of a Swiss population of Savi's Warblers Locustella luscinioides. Territories occupied by males differed from unoccupied sites of similar size and location by having higher and denser reeds, a more extensive straw litter, and a thicker cover of dead sedge leaves. Territories with these characteristics were the ones first chosen by males upon spring arrival. These males, however, did not differ in morphometry from those that arrived later. Availability of suitable nesting sites; rather than food availability, appears to be an important choice criterion for territories. Early arriving males had higher breeding success than late males because of a higher mating success and more successful clutches. The positive correlation between male breeding success and territory quality was thus mediated through their common dependence on occupancy date. Female breeding success decreased with the date of first-clutch laying, mainly because late-nesting females fledged fewer broods. Breeding success in either sex did not correlate with morphometry. Our results provide clear support for territory choice by males, but not for mate or territory choice by females, and show the crucial role played by individual settlement date on many aspects of the breeding cycle of both sexes. We propose a lottery model of mate choice. arriving females obtain the best available territories even without choosing mates or territories; since males occupy territories sequentially and in order of decreasing quality, the few unpaired males available at any moment also occupy the best available territories.

Defining the critical hurdles in cancer immunotherapy.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

Time-resolved lanthanide luminescence for lab-on-a-chip detection of biomarkers on cancerous tissues.

PDMS-based microfluidic devices combined with lanthanide-based immunocomplexes have been successfully tested for the multiplex detection of biomarkers on cancerous tissues, revealing an enhanced sensitivity compared to classical organic dyes.

Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

Sibling rivalry and vocal negotiation in the barn owl Tyto alba

Chez les animaux, les jeunes dépendant des parents durant leur développement sont en compétition pour obtenir la nourriture, qu'ils quémandent par des cris et postures ostentatoires et se disputent physiquement. Les frères et soeurs n'ont pas la même compétitivité, en particulier s'ils diffèrent en âge, et leur niveau de faim fluctue dans le temps. Comme dans tout type de compétition, chacun doit ajuster son investissement aux rivaux, c'est à dire aux besoins et comportements de ses frères et soeurs. Dans le contexte de la famille, selon la théorie de sélection de parentèle, les jeunes bénéficient de leur survie mutuelle et donc de la propagation de la part de gènes qu'ils ont en commun. L'hypothèse de la « négociation frères-soeurs » prédit que, sous certaines conditions, les jeunes négocient entre eux la nourriture, ce qui réduit les coûts de compétition et permet de favoriser les frères et soeurs les plus affamés. La littérature actuelle se focalise sur les signaux de quémande entre enfants et parents et les interactions compétitives frères-soeurs sont étudiées principalement au sein de paires, alors que les nichées ou portées en comprennent souvent de nombreux. Cette thèse vise à mieux comprendre comment et jusqu'à quel point plusieurs jeunes ajustent mutuellement leurs signaux de besoin. C'est une question importante, étant donné que cela influence la répartition de nourriture entre eux, donc la résolution du conflit qui les oppose et à terme leur valeur évolutive. Le modèle d'étude est la chouette effraie (Tyto alba), chez laquelle jusqu'à neufs poussins émettent des milliers de cris chacun par nuit. Ils négocieraient entre eux la prochaine proie indivisible rapportée au nid avant que les parents ne reviennent : un poussin affamé crie plus qu'un autre moins affamé, ce qui dissuade ce dernier de crier en retour et par la suite de quémander la nourriture aux parents. L'investissement optimal correspondrait donc à écarter son frère en permanence vu que l'arrivée des parents est imprévisible, mais à moindre coût. Dans un premier axe, nous avons exploré au sein de dyades les mécanismes acoustiques permettant aux poussins de doser leur effort vocal durant les heures de compétition où ils sont laissés seuls au nid. Nous avons trouvé que les poussins évitent de crier simultanément, ce qui optimiserait la discrimination du nombre et de la durée de leurs cris, lesquels reflètent de façon honnête leur niveau de faim et donc leur motivation. L'alternance des cris paraît particulièrement adaptée au fait que les poussins se fient à des variations temporelles subtiles dans le rythme et la durée de leurs vocalisations pour prendre la parole. En particulier, allonger ses cris tout en criant moins dissuade efficacement le rival de répondre, ce qui permet de monopoliser la parole dans de longs « monologues ». Ces règles seraient universelles puisqu'elles ne dépendent pas de la séniorité, de la faim, ni de la parenté et les poussins répondent à un playback de façon similaire à un vrai frère. Tous ces résultats apportent la première preuve expérimentale que les juvéniles communiquent de façon honnête sur leurs besoins, ajustent activement le rythme de leurs cris et utilisent des composantes multiples de leurs vocalisations d'une façon qui réduit le coût de la compétition. De plus, il s'agit de la première démonstration que des règles de conversation régissent de longs échanges vocaux chez les animaux de façon comparable aux règles basiques observées chez l'Homme. Dans un second axe, nous avons exploré les stratégies comportementales que les poussins adoptent pour rivaliser avec plusieurs frères et soeurs, par le biais d'expériences de playback. Nous avons trouvé que les poussins mémorisent des asymétries de compétitivité entre deux individus qui dialoguent et répondent plus agressivement au moins compétitif une fois qu'ils sont confrontés à chacun isolément. Dans la même ligne, quand ils entendent un nombre variable d'individus criant à un taux variable, les poussins investissent le plus contre des rivaux moins nombreux et moins motivés. En accord avec les prédictions des modèles théoriques, les poussins de chouette effraie escaladent donc les conflits pour lesquels leur chance de gagner contrebalance le plus l'énergie dépensée. Nous révélons ainsi que 1) les jeunes frères et soeurs 'espionnent' les interactions de leurs rivaux pour évaluer leur compétitivité relative, ce qui est sans doute moins coûteux qu'une confrontation directe avec chacun, et 2) dosent leur investissement vocal en fonction du nombre de rivaux actuellement en compétition et de leur motivation de façon concomitante. Ces résultats montrent que les interactions entre frères et soeurs au nid reposent sur des mécanismes similaires à ceux observés, mais encore de façon anecdotique, chez les adultes non apparentés qui se disputent les territoires et partenaires sexuels. Cette thèse souligne donc combien il est crucial de considérer dorénavant la famille comme un réseau de communication à part entière pour mieux comprendre comment les jeunes résolvent les conflits autour du partage des ressources parentales. Plus généralement, elle révèle l'importance de la dynamique temporelle des vocalisations dans les conflits et la communication des animaux. A la lumière de nos résultats, la chouette effraie apparaît comme un modèle clé pour de futures recherches sur la résolution des conflits et la communication acoustique. - In species with parental care, offspring contest priority access to food by begging through conspicuous postures and vocalisations and by physically jockeying. Siblings differ in their competitiveness, especially in the case of age and size hierarchies, and their hunger level fluctuates in time. As in competition in general, each individual should adjust its investment to opponents that is to say to its siblings' needs and behaviours. In the particular context of family, according to kin selection theory, siblings derive extra fitness benefits from their mutual survival and hence the spreading of the genes they share. The "sibling negotiation" predicts that, under certain conditions, young would negotiate among them priority access to food, which reduces competition costs and enables promoting the most hungry siblings. To date, the literature focuses on signals of need between parents and offspring and competitive interactions (in particular among siblings) are mostly studied within pairwise interactions, yet they commonly involve more numerous rivals. This PhD aims at better understanding how and the extent to which several young siblings compete through signalling. This is important since this influences how food is allocated among them, thus the outcome of sibling rivalry and ultimately their fitness. I use the barn owl (Tyto alba) as a model, in which the one to nine nestlings emit a simple noisy call thousands of times per night. Thereby, they would negotiate among them priority access to the indivisible food next delivered prior to parents' feeding visits. A hungry nestling emits more calls than a less hungry sibling, which deters it to call in return and ultimately beg food at parents. The optimal investment thus corresponds to constantly deterring the rival to compete, given that parents' arrival is unpredictable, but at the lowest costs. In the first axis of my thesis, we explored within dyads the acoustic mechanisms by which owlets dose vocal effort when competing during the hours they are left alone. We found that owlets avoid overlapping each other's calls. This would enhance the discrimination of both call number and duration, which honestly reflect individuals' hunger level and hence motivation to compete. Such antiphony seems best adapted to the fact that siblings actually use subtle temporal variations in the rhythm and duration of their calls to take or give their turn. Owlets alternate monologs, in which lengthening calls efficiently deters the rival to respond while reducing call number. Such rules depend neither on seniority, hunger level nor kinship since nestlings responded similarly to a live sibling and an unrelated playback individual. Taken together, these findings provide the first experimental proof that dependent young honestly communicate about their need, actively adjust the timing of their calls and use multicomponent signals in a way that reduces vocal costs. Moreover, this is the first demonstration of conversational rules underlying animal long-lasting vocal exchanges comparable to the basic turn-taking signals observed in humans. In the second axis, we focused on the behavioural strategies owlets adopt to compete with more than one sibling, using playback experiments. We found that singleton bystanders memorised competitive asymmetries between two playback individuals dialoguing and responded more aggressively to the submissive one once they later faced each of both alone. Moreover, when hearing a varying number of nestlings calling at varying rates, owlets vocally invested the most towards fewer and less motivated rivals. In line with predictions from models on conflict settlement, barn owls thus escalate contests in which their chance of winning best counterbalances the energy spent. These results reveal that young socially eavesdrop on their siblings' interactions to assess their relative competitiveness at likely lower costs than direct confrontation, and dose vocal effort relative to both their number and motivation. This shows that young siblings' interactions imply mechanisms similar to those observed, yet still anecdotally, in unrelated adults that contest mates and territories. This PhD therefore highlights how crucial it is to further consider family as a communication network to better understand how siblings resolve conflicts over the share of parental resources. More generally, it provides important insights into the role of the temporal dynamics of signalling during animal contests and communication. In the light of our findings, the barn owl emerges as a key model for future research on conflict resolution and acoustic communication in animals.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Ethics Outside, Within, or Beyond OR Models

Since ethical concerns are calling for more attention within Operational Research, we present three approaches to combine Operational Research models with ethics. Our intention is to clarify the trade-offs faced by the OR community, in particular the tension between the scientific legitimacy of OR models (ethics outside OR models) and the integration of ethics within models (ethics within OR models). Presenting and discussing an approach that combines OR models with the process of OR (ethics beyond OR models), we suggest rigorous ways to express the relation between ethics and OR models. As our work is exploratory, we are trying to avoid a dogmatic attitude and call for further research. We argue that there are interesting avenues for research at the theoretical, methodological and applied levels and that the OR community can contribute to an innovative, constructive and responsible social dialogue about its ethics.

Why bystanders decline telephone cardiac resuscitation advice.

OBJECTIVES: The aim of this study was to evaluate the rate and reason for refusal of telephone-based cardiopulmonary resuscitation (CPR) instruction by bystanders after the implementation of the dispatch center's systematic telephone CPR protocol. METHODS: Over a 15-month period the authors prospectively collected all case records from the emergency medical services (EMS) dispatch center when CPR had been proposed to the bystander calling in and recorded the reason for declining or not performing that the bystander spontaneously mentioned. All pediatric and adult traumatic and nontraumatic cases were included. Situations when resuscitation had been spontaneously initiated by bystanders were excluded. RESULTS: During the study period, dispatchers proposed CPR on 264 occasions: 232 adult nontraumatic cases, 17 adult traumatic cases, and 15 pediatric (traumatic and nontraumatic) cases. The proposal was accepted in 163 cases (61.7%, 95% confidence interval [CI] = 54.6% to 66.5%), and CPR was eventually performed in 134 cases (51%, 95% CI = 43.2% to 55.3%). In 35 of the cases where resuscitation was not carried out, the condition of the patient or conditions at the scene made this decision medically appropriate. Of the remaining 95 cases, 55 were due to physical limitations of the caller, and 33 were due to emotional distress. CONCLUSIONS: The telephone CPR acceptance rate of 62% in this study is comparable to those of other similar studies. Because bystanders' physical condition is one of the keys to success, the rate may not improve as the population ages.

Ethics outside, within or beyond OR models

Since ethical concerns are calling for more attention within OperationalResearch, we present three approaches to combine Operational Researchmodels with ethics. Our intention is to clarify the trade-offs faced bythe OR community, in particular the tension between the scientificlegitimacy of OR models (ethics outside OR models) and the integrationof ethics within models (ethics within OR models). Presenting anddiscussing an approach that combines OR models with the process of OR(ethics beyond OR models), we suggest rigorous ways to express the relationbetween ethics and OR models. As our work is exploratory, we are trying toavoid a dogmatic attitude and call for further research. We argue thatthere are interesting avenues for research at the theoretical,methodological and applied levels and that the OR community can contributeto an innovative, constructive and responsible social dialogue about itsethics.