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We single out the role of fully coherent induced gluon radiation on light hadron production in p-A collisions. The effect has an interesting color structure, as the induced radiation depends on the global color charge of the partonic subprocess final state. Baseline predictions for light hadron nuclear suppression in p-Pb collisions at the LHC are provided, taking into account only the effect of fully coherent energy loss, which proves of the same order of magnitude as gluon shadowing or saturation. This underlines the need to include fully coherent energy loss in phenomenological studies of hadron production in p-A collisions.

Introduction: In this paper, we studied the effect over time of agomelatine, an antidepressant drug administered in patient with major depressive disorder, through item response theory (IRT), taking into account a strong placebo effect and missing not at random. We also assessed the informativeness of the HAMD-17 scale's item., Materials and Methods: The data includes five phase III clinical trials sponsored by Servier Institute, totalling 1549 patients followed during a maximum of 1 year. At each observation, individual scores for the 17 items of the HAMD scale were recorded. The probability for each score was modelled with IRT. A non-linear mixed effects model was used to describe the evolution of the disease and was coupled with a time to event model to predict dropout. Clinical trial simulations were then used to compare placebo and active treatment. Informativeness of each item was evaluated using the Fisher information theory., Results: The best model combined an IRT model, a longitudinal model for underlying depression which describes the remission and then a possible relapse, and a hazard model for dropout depending on the evolution from baseline. The drug effect was best modelled as an effect on the remission and the relapse phases. The median predicted drop in HAMD between baseline and 6 weeks was 8.8 (90% PI, 8.3-9.2) when on placebo and 13.1 (90% PI, 12.8-13.4) when treated. Nine items were found to be the most informative., Conclusion: The IRT framework allowed to characterise the evolution of depression with time and estimate the effect of agomelatine, as well as the link between symptoms and disease.

Aim: The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose., Methods: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration-time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose., Results: The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V d /F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V d /F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg., Conclusion: This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose-dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children >30 kg, suggesting an eventual dose adjustment during adolescence., Clinical Trial Identifier: This study is part of the STIPOP study (EUDRACT number: 2007-001784-30).

Pangolins, considered the most-trafficked mammals on Earth, are rapidly heading to extinction. Eight extant species of these African and Asian scale-bodied anteaters are commonly recognized, but their evolutionary relationships remain largely unexplored. Here, we present the most comprehensive phylogenetic assessment of pangolins, based on genetic variation of complete mitogenomes and 9 nuclear genes. We confirm deep divergence among Asian and African pangolins occurring not later than the Oligocene-Miocene boundary ca. 23 million years ago (Ma) (95% HPD = 18.7-27.2), limited fossil evidence suggesting dispersals from Europe. We recognize 3 genera including Manis (Asian pangolins), Smutsia (large African pangolins), and Phataginus (small African pangolins), which first diversified in the Middle-Upper Miocene (9.8-13.3 Ma) through a period of gradual cooling coinciding with a worldwide taxonomic diversification among mammals. Based on large mitogenomic distances among the 3 genera (18.3-22.8%) and numerous (18) morphological traits unique to Phataginus, we propose the subfamily Phatagininae subfam. nov. to designate small African pangolins. In contrast with the morphological-based literature, our results establish that the thick-tailed pangolin (Manis crassicaudata) is sister-species of the Sunda (Manis javanica) and Palawan (Manis culionensis) pangolins. Mitogenomic phylogenetic delineations supported additional pangolin species subdivisions (n = 13), including 6 African common pangolin (Phataginus tricuspis) lineages, but these patterns were not fully supported by our multi-locus approach. Finally, we identified more than 5000 informative mitogenomic sites and diagnostic variation from 5 nuclear genes among all species and lineages of pangolins, providing an important resource for further research and for effectively tracing the worldwide pangolin trade.

Arboreal locomotion imposes selective pressures that may affect the evolution of the locomotor apparatus. The limbs have to be mobile to reach across discontinuities, yet at the same time need to be forceful to move against gravity during climbing. However, as intermediaries between the arboreal and terrestrial environment, semi-arboreal mammals appear not extremely specialized and, thus, anatomical adaptations may be less evident than expected for arboreal climbers. Here, we present quantitative data on the muscle anatomy of the forelimbs (N = 14) of two closely related species of Mustelidae and relate the findings to their locomotor habits. The arboreal pine marten (Martes martes) and the more terrestrial stone marten (Martes foina) are the most similar sympatric carnivores in Europe, but distinctly differ in habitat selection and locomotor mode. Via dissections muscle architectural variables including muscle mass, pennation angle, and fiber length were measured and the physiological cross-sectional area and maximum isometric force were estimated for each muscle. The results reveal that the force-generating capacity of the limb flexor and retractor muscles and the excursion capability of the adductor muscles are greater in the pine marten compared to the stone marten. Since the two sympatric martens are very similar in terms of overall appearance, body size, intra-limb proportions, phylogenetic relationships and predation behavior, the differences in forelimb musculature are interpreted to reflect the greater climbing ability of the pine marten. The functional properties appear to facilitate locomotion in a three-dimensionally complex arboreal environment. Anat Rec, 301:449-472, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

The Plio-Pleistocene evolution of Equus and the subsequent domestication of horses and donkeys remains poorly understood, due to the lack of phenotypic markers capable of tracing this evolutionary process in the palaeontological/archaeological record. Using images from 345 specimens, encompassing 15 extant taxa of equids, we quantified the occlusal enamel folding pattern in four mandibular cheek teeth with a single geometric morphometric protocol. We initially investigated the protocol accuracy by assigning each tooth to its correct anatomical position and taxonomic group. We then contrasted the phylogenetic signal present in each tooth shape with an exome-wide phylogeny from 10 extant equine species. We estimated the strength of the phylogenetic signal using a Brownian motion model of evolution with multivariate K statistic, and mapped the dental shape along the molecular phylogeny using an approach based on squared-change parsimony. We found clear evidence for the relevance of dental phenotypes to accurately discriminate all modern members of the genus Equus and capture their phylogenetic relationships. These results are valuable for both palaeontologists and zooarchaeologists exploring the spatial and temporal dynamics of the evolutionary history of the horse family, up to the latest domestication trajectories of horses and donkeys., Competing Interests: The authors have no competing interests.

The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma PK exposure parameters were calculated in children using plasma PK profiles. In order to assess the PK/PD relationship in children, an adult PK/PD model was used. The relationship between blood and plasma concentrations was described using linear mixed effect models. Two and one-compartment models best described parent and metabolite dispositions. Weight effects were fixed to the allometric values of ¾ on clearance (CL) and 1 on volume. A maturation function was added on metabolite formation clearance (CL PM ) reflecting enzyme maturation. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose. The PK/PD relationship in adult patients is conserved in children.

The main objective was to help design a paediatric study for ivabradine, a compound already marketed in adults, focusing on: the paediatric formulation evaluation, the doses to be administered, the sampling design and the sampling technique. A secondary objective was to perform a comparison of the prediction of ivabradine pharmacokinetics (PK) in children using a physiologically-based pharmacokinetic (PBPK) approach and allometric scaling of a population pharmacokinetic (PPK) model. A study was conducted in order to assess the relative bioavailability (Frel) of the paediatric formulation and a similar Frel was observed between the paediatric formulation and the adult marketed tablet. PBPK modelling was used to predict initial doses to be administered in the paediatric study and to select the most appropriate sample time collections. The dried blood spot technique was recommended in the clinical trial in children. Simulations obtained by both the PBPK approach and allometric scaling of a PPK model were compared a posteriori to the paediatric study observations. Both PPK and PBPK approaches allowed an adequate prediction of the PK of ivabradine and its metabolite in children.

Whether or not evolutionary lineages in general show a tendency to increase in body size has often been discussed. This tendency has been dubbed "Cope's rule" but because Cope never hypothesized it, we suggest renaming it after Depéret, who formulated it clearly in 1907. Depéret's rule has traditionally been studied using fossil data, but more recently a number of studies have used present-day species. While several paleontological studies of Cenozoic placental mammals have found support for increasing body size, most studies of extant placentals have failed to detect such a trend. Here, we present a method to combine information from present-day species with fossil data in a Bayesian phylogenetic framework. We apply the method to body mass estimates of a large number of extant and extinct mammal species, and find strong support for Depéret's rule. The tendency for size increase appears to be driven not by evolution toward larger size in established species, but by processes related to the emergence of new species. Our analysis shows that complementary data from extant and extinct species can greatly improve inference of macroevolutionary processes., (© The Author(s) 2015. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.)

Inferences of function and ecology in extinct taxa have long been a subject of interest because it is fundamental to understand the evolutionary history of species. In this study, we use a quantitative approach to investigate the locomotor behaviour of Simocyon batalleri, a key taxon related to the ailurid family. To do so, we use 3D surface geometric morphometric approaches on the three long bones of the forelimb of an extant reference sample. Next, we test the locomotor strategy of S. batalleri using a leave-one-out cross-validated linear discriminant analysis. Our results show that S. batalleri is included in the morphospace of the living species of musteloids. However, each bone of the forelimb appears to show a different functional signal suggesting that inferring the lifestyle or locomotor behaviour of fossils can be difficult and dependent on the bone investigated. This highlights the importance of studying, where possible, a maximum of skeletal elements to be able to make robust inferences on the lifestyle of extinct species. Finally, our results suggest that S. batalleri may be more arboreal than previously suggested.

Convergence in morphology can result from evolutionary adaptations in species living in environments with similar selective pressures. Here, we investigate whether the shape of the forelimb long bones has converged in environments imposing similar functional constraints, using musteloid carnivores as a model. The limbs of quadrupeds are subjected to many factors that may influence their shape. They need to support body mass without collapsing or breaking, yet at the same time resist the stresses and strains induced by locomotion. This likely imposes strong constraints on their morphology. Our geometric morphometric analyses show that locomotion, body mass and phylogeny all influence the shape of the forelimb. Furthermore, we find a remarkable convergence between: (i) aquatic and semi-fossorial species, both displaying a robust forelimb, with a shape that improves stability and load transfer in response to the physical resistance imposed by the locomotor environment; and (ii) aquatic and arboreal/semi-arboreal species, with both groups displaying a broad capitulum. This augments the degree of pronation/supination, an important feature for climbing as well as grasping and manipulation ability, behaviors common to aquatic and arboreal species. In summary, our results highlight how musteloids with different locomotor ecologies show differences in the anatomy of their forelimb bones. Yet, functional demands for limb movement through dense media also result in convergence in forelimb long-bone shape between diverse groups, for example, otters and badgers., (© 2015 Anatomical Society.)

Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The forelimb forms a functional unit that allows a variety of behaviours and needs to be mobile, yet at the same time stable. Both mobility and stability are controlled, amongst others, at the level of the elbow joint. This joint is composed of the humero-ulnar articulation, mainly involved during parasagittal movements; and the radio-ulnar articulation, mainly allowing rotation. In contrast, the humero-radial articulation allows both movements of flexion-extension and rotation. Here, we study the morphological integration between each bone of the forelimb at the level of the entire arm, as well as at the elbow joint, in musteloid carnivorans. To do so, we quantitatively test shape co-variation using surface 3D geometric morphometric data. Our results show that morphological integration is stronger for bones that form functional units. Different results are obtained depending on the level of investigation: for the entire arm, results show a greater degree of shape co-variation between long bones of the lower arm than between the humerus and either bone of the lower arm. Thus, at this level the functional unit of the lower arm is comprised of the radius and ulna, permitting rotational movements of the lower arm. At the level of the elbow, results display a stronger shape co-variation between bones allowing flexion and stability (humerus and ulna) than between bones allowing mobility (ulna and radius and humerus and radius). Thus, the critical functional unit appears to be the articulation between the humerus and ulna providing the stability of the joint., (© 2014 Anatomical Society.)

The effects of energy loss in cold nuclear matter on J/ψ suppression in p-A collisions are studied. A simple model based on first principles and depending on a single free parameter is able to reproduce J/ψ suppression data at large x(F) and at various center-of-mass energies. These results strongly support energy loss as a dominant effect in quarkonium suppression. They also give some hint on its hadroproduction mechanism suggesting color neutralization to happen on long time scales. Predictions for J/ψ and Υ suppression in p-Pb collisions at the LHC are made.

The recovery at Shi'bat Dihya 1 (SD1) of a dense Middle Paleolithic human occupation dated to 55 ka BP sheds new light on the role of the Arabian Peninsula at the time of the alleged expansion of modern humans out of Africa. SD1 is part of a complex of Middle Paleolithic sites cut by the Wadi Surdud and interstratified within an alluvial sedimentary basin in the foothills that connect the Yemeni highlands with the Tihama coastal plain. A number of environmental proxies indicate arid conditions throughout a sequence that extends between 63 and 42 ka BP. The lithic industry is geared toward the production of a variety of end products: blades, pointed blades, pointed flakes and Levallois-like flakes with long unmodified cutting edges, made from locally available rhyolite. The occasional exploitation of other local raw materials, that fulfill distinct complementary needs, highlights the multi-functional nature of the occupation. The slightly younger Shi'bat Dihya 2 (SD2) site is characterized by a less elaborate production of flakes, together with some elements (blades and pointed flakes) similar to those found at SD1, and may indicate a cultural continuity between the two sites. The technological behaviors of the SD1 toolmakers present similarities with those documented from a number of nearly contemporaneous assemblages from southern Arabia, the Levant, the Horn of Africa and North Africa. However, they do not directly conform to any of the techno-complexes typical of the late Middle Paleolithic or late Middle Stone Age from these regions. This period would have witnessed the development of local Middle Paleolithic traditions in the Arabian Peninsula, which suggests more complex settlement dynamics and possible population interactions than commonly inferred by the current models of modern human expansion out of Africa., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent fossil discoveries have demonstrated that Africa and Asia were epicentres for the origin and/or early diversification of the major living primate lineages, including both anthropoids (monkeys, apes and humans) and crown strepsirhine primates (lemurs, lorises and galagos). Competing hypotheses favouring either an African or Asian origin for anthropoids rank among the most hotly contested issues in paleoprimatology. The Afrocentric model for anthropoid origins rests heavily on the >45 Myr old fossil Algeripithecus minutus from Algeria, which is widely acknowledged to be one of the oldest known anthropoids. However, the phylogenetic position of Algeripithecus with respect to other primates has been tenuous because of the highly fragmentary fossils that have documented this primate until now. Recently recovered and more nearly complete fossils of Algeripithecus and contemporaneous relatives reveal that they are not anthropoids. New data support the idea that Algeripithecus and its sister genus Azibius are the earliest offshoots of an Afro-Arabian strepsirhine clade that embraces extant toothcombed primates and their fossil relatives. Azibius exhibits anatomical evidence for nocturnality. Algeripithecus has a long, thin and forwardly inclined lower canine alveolus, a feature that is entirely compatible with the long and procumbent lower canine included in the toothcomb of crown strepsirhines. These results strengthen an ancient African origin for crown strepsirhines and, in turn, strongly challenge the role of Africa as the ancestral homeland for anthropoids.

Previous morphological and isotopic studies indicate that Late Pleistocene cave bear (Ursus spelaeus) diet ranged from mostly vegetarian to omnivory or even carnivory. However, such analyses do not provide information on seasonal diets, and only provide an average record of diet. A dental microwear analysis of 43 young and adult individuals demonstrate that, during the predormancy period, cave bears from Goyet (Late Pleistocene, Belgium) were not strictly herbivorous, but had a mixed diet composed of hard items (e.g., possibly bone), invertebrates (e.g., insects), meat (ungulates, small vertebrates), and/or plant matter (hard mast, seeds, herbaceous vegetations, and fruits). Therefore, our results indicate that cave bears at Goyet were generalist omnivores during the predormancy period, which is consistent with current data on the dietary ecology of extant bears during this season. These data also raise questions about the ecological role and causes of the extinction of cave bears.

We report on the oldest fox (Canidae) ever found in Africa. It is dated to 7 Ma based on the degree of evolution of the whole fauna. It belongs to a new species. Its overall size and some morphological characteristics distinguish the Chadian specimen from all the other foxes. The presence of Vulpes and of the genus Eucyon in slightly younger African locality, as well as in southwestern Europe in the late Miocene, may indicate that canids migrated in Europe from Africa through a trans-Mediterranean route.

Both the giant panda (Ailuropoda melanoleuca) and the red panda (Ailurus fulgens) possess a 'false-thumb', actually an enlarged radial sesamoid bone, which contributes to the gripping action of the hand. These species are not closely related, however, as one is an ursid and the other an ailurid, so the fact that they share this adaptation implies a remarkable convergence. We studied the functional anatomy of this structure in the red panda, comparing it with existing descriptions of the grasping mechanism in both pandas. Previous interpretations of the radial sesamoid in Ailurus as a rod-like structure without direct articulation to the wrist bones are inaccurate. There are various important differences between the red panda and the giant panda. In the former, the lesser development of the radial sesamoid, its connection with the flexor retinaculum, the presence of an insertion of the muscle abductor pollicis longus in the first metacarpal, which enhances its supinatory action, and the presence of a muscle flexor brevis digitorum manus point to thin-branch climbing features serving as an exaptation to the more recent role of the red panda hand in the manipulation of bamboo.

The "false thumb" of pandas is a carpal bone, the radial sesamoid, which has been enlarged and functions as an opposable thumb. If the giant panda (Ailuropoda melanoleuca) and the red panda (Ailurus fulgens) are not closely related, their sharing of this adaptation implies a remarkable convergence. The discovery of previously unknown postcranial remains of a Miocene red panda relative, Simocyon batalleri, from the Spanish site of Batallones-1 (Madrid), now shows that this animal had a false thumb. The radial sesamoid of S. batalleri shows similarities with that of the red panda, which supports a sister-group relationship and indicates independent evolution in both pandas. The fossils from Batallones-1 reveal S. batalleri as a puma-sized, semiarboreal carnivore with a moderately hypercarnivore diet. These data suggest that the false thumbs of S. batalleri and Ailurus fulgens were probably inherited from a primitive member of the red panda family (Ailuridae), which lacked the red panda's specializations for herbivory but shared its arboreal adaptations. Thus, it seems that, whereas the false thumb of the giant panda probably evolved for manipulating bamboo, the false thumbs of the red panda and of S. batalleri more likely evolved as an aid for arboreal locomotion, with the red panda secondarily developing its ability for item manipulation and thus producing one of the most dramatic cases of convergence among vertebrates.

We report on the earliest modern mongooses of Africa, from the late Miocene (ca. 7 Ma) of the hominid locality TM 266, Toros-Menalla, Chad. The material is based on fragmentary dentitions of three individuals. The main diagnostic feature of the Chadian species is the great development of the shear in the carnassials, which distinguishes the Chadian specimens from all extant herpestids except Herpestes and Galerella. In comparison with most extinct and extant Herpestes, the species from Toros-Menalla differs by a markedly smaller size and, depending on the species, relatively more elongated carnassials, more transversely elongated M1 and more reduced p4. On the basis of a great morphological similarity and the absence of significant differences, we assign our material to Galerella sanguinea; the Chadian finding therefore represents the earliest appearance of an extant species of Herpestidae. This record ties the first appearance of the genus to a minimum age of ca. 7 Ma, which is consistent with the estimated divergence date of 11.4 Ma known from the literature for the species of Galerella.