Structure of a Pheromone Receptor-Associated MHC Molecule with an Open and Empty Groove

Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide–binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I–binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8–10-mer class I–binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC–binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs

Imagerie dans le cathétérisme des cardiopathies congénitales : place de l’échocardiographie 3D transthoracique

RésuméL’échocardiographie 3D transthoracique a longtemps été freinée dans son développement en raison de conditions techniques d’acquisition compliquées et de qualité d’images médiocres. L’avènement des sondes matricielles permet au 3D en devenant temps réel d’entrer dans la pratique clinique courante. Si la voie œsophagienne a permis au 3D de trouver ses lettres de noblesses par ses descriptions anatomiques uniques des valves et des septa, l’échocardiographie transthoracique peut désormais se décliner en modes 2D, Doppler et 3D. Ses applications dans la cardiologie congénitale et pédiatrique sont multiples : description anatomique précise des défauts septaux auriculaires et ventriculaires, classification des bicuspidies aortiques et analyse du mécanisme de sténose. Ainsi, l’échocardiographie 3D permet-elle de sélectionner de façon non invasive les patients, de guider et de juger du résultat d’un cathétérisme interventionnel. L’imagerie 3D est un excellent moyen de communication entre l’imageur et le cardiologue interventionnel mais aussi de délivrer des informations claires au patient et à la famille avant et après un cathétérisme.SummaryThree-dimensional echocardiography has improved dramatically due to technical advances in probe design and computer processing. The introduction of real time 3D echocardiography has led to its use in everyday clinical practice. Congenital heart disease demands a detailed understanding of the spatial relationships of cardiac structures to plan treatment. The introduction of new transthoracic 3D probes has extended the applications to real-time guidance of catheter procedures. Prominent among the cardiac lesions which have been studied are: atrial septal defects, ventricular septal defects and stenotic bicuspid aortic valves. Its values should be decisive in many congenital cardiac lesions requiring interventional catheterisation. 3D echocardiography is an easy way to communicate to the patient and its family about the pathology

Structure of a Pheromone Receptor-Associated MHC Molecule with an Open and Empty Groove

Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide–binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I–binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8–10-mer class I–binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC–binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.Molecular and Cellular Biolog

Galanin neurons in the medial preoptic area govern parental behavior

Mice display robust, stereotyped behaviors toward pups: virgin males typically attack pups, while virgin females and sexually experienced males and females display parental care. We show here that virgin males genetically impaired in vomeronasal sensing do not attack pups and are parental. Further, we uncover a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation activated during mating. Genetic ablation of MPOA galanin neurons results in dramatic impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression and induces pup grooming. Thus, MPOA galanin neurons emerge as an essential regulatory node of male and female parenting behavior and other social responses. These results provide an entry point to a circuit-level dissection of parental behavior and its modulation by social experience

Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: A European consensus statement

Rasmussen encephalitis (RE) is a rare but severe immune-mediated brain disorder leading to unilateral hemispheric atrophy, associated progressive neurological dysfunction and intractable seizures. Recent data on the pathogenesis of the disease, its clinical and paraclinical presentation, and therapeutic approaches are summarized. Based on these data, we propose formal diagnostic criteria and a therapeutic pathway for the management of RE patient

Specific Mesenchymal/Epithelial Induction of Olfactory Receptor, Vomeronasal, and Gonadotropin-Releasing Hormone (GnRH) Neurons

We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs), and gonadotropin-releasing hormone (GnRH) neurons, the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions specify the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons.Molecular and Cellular Biolog

Probing deeper into the risks of slips, trips and falls for an ageing rail passenger population: applying a systems approach

In this study, the authors report the findings from a study of the contributory factors leading to slips, trips and falls (STFs) amongst elderly passengers at train stations and how these are likely to change in the future over the medium to long term (the period 2035–2050). Their data draws on: stakeholder interviews with rail personnel and elderly passengers; a set of station observations carried out across the UK; and, a survey of the views of station managers. The findings point to a set of 22 contributory factors covering aspects of organisational, station environment and passenger (individual) influence on STFs. Amongst the factors which most concern station managers at the present and over the next few decades are: rushing behaviour on train platforms; the consumption of alcohol by passengers; aspects of station design (e.g. flooring); and, training for station staff as regard the risks of STFs. The authors summarise their findings in the form of a systems model which highlights priorities with regard to STFs in terms of all of the stakeholders taking part in the study. A final section discusses a set of issues which might form the basis for a future agenda for research and practice in this area

Modeling organic aerosol concentrations and properties during winter 2014 in the northwestern Mediterranean region

Organic aerosols are measured at a remote site (Ersa) on the cape of Corsica in the northwestern Mediterranean basin during the winter campaign of 2014 of the CHemistry and AeRosols Mediterranean EXperiment (CharMEx), when high organic concentrations from anthropogenic origins are observed. This work aims to represent the observed organic aerosol concentrations and properties (oxidation state) using the air-quality model Polyphemus with a surrogate approach for secondary organic aerosol (SOA) formation. Because intermediate and semi-volatile organic compounds (I/S-VOCs) are the main precursors of SOAs at Ersa during winter 2014, different parameterizations to represent the emission and aging of I/S-VOCs were implemented in the chemistry-transport model of Polyphemus (different volatility distribution emissions and single-step oxidation vs multi-step oxidation within a volatility basis set – VBS – framework, inclusion of non-traditional volatile organic compounds – NTVOCs). Simulations using the different parameterizations are compared to each other and to the measurements (concentration and oxidation state). The highly observed organic concentrations are well reproduced in all the parameterizations. They are slightly underestimated in most parameterizations. The volatility distribution at emissions influences the concentrations more strongly than the choice of the parameterization that may be used for aging (single-step oxidation vs multi-step oxidation), stressing the importance of an accurate characterization of emissions. Assuming the volatility distribution of sectors other than residential heating to be the same as residential heating may lead to a strong underestimation of organic concentrations. The observed organic oxidation and oxygenation states are strongly underestimated in all simulations, even when multigenerational aging of I/S-VOCs from all sectors is modeled. This suggests that uncertainties in the emissions and aging of I/S-VOC emissions remain to be elucidated, with a potential role of formation of organic nitrate and low-volatility highly oxygenated organic molecules.</p