Epistasis between the MHC and the RCAα block in primary Sjögren syndrome

ObjectiveThe RCA alpha block (Regulators of Complement Activation, 1q32) contains critical complement regulatory genes such as CR1 and MCP. This study examined RCA alpha block haplotype associations with both disease susceptibility and diversification of the anti-Ro/La autoantibody response in primary Sjögren syndrome (pSS).Methods115 patients with pSS and 98 controls were included in the study. 93 of 109 (85%) of the patients with pSS were seropositive for Ro/La autoantibodies. The Genomic Matching Technique (GMT) was used to define RCA alpha block ancestral haplotypes (AH).ResultsRCA alpha block haplotypes, AH1 and AH3, were both associated with autoantibody-positive pSS (p = 0.0003). Autoantibody associations with both HLA DR3 and DR15 have been previously defined. There was an epistatic interaction (p = 0.023) between RCA alpha AH1 and HLA DR3, and this genotypic combination was present in 48% of autoantibody-positive patients with pSS compared with 8% of controls. This epistasis is most simply attributable to an interaction between C4 and its receptor, CR1, encoded within the RCA alpha block. Both DR3 and a relative C4 deficiency are carried on the major histocompatibility complex 8.1 ancestral haplotype. Only four of 92 (4%) autoantibody-positive patients with pSS did not carry any risk RCA alpha or HLA haplotype, compared with 36 of 96 (38%) controls, and there were differences in haplotype frequencies within autoantibody subsets of pSS.ConclusionsNormal population variation in the RCA alpha block, in addition to the major histocompatibility complex, contributes genetic susceptibility to systemic autoimmune disease and the autoantibody response. This finding provides evidence for the role of regulation of complement activation in disease pathogenesis.S. Lester, C. McLure, J. Williamson, P. Bardy, M. Rischmueller, R. L. Dawkin

Moving in unison after perceptual interruption

Humans interact in groups through various perception and action channels. The continuity of interaction despite a transient loss of perceptual contact often exists and contributes to goal achievement. Here, we study the dynamics of this continuity, in two experiments involving groups of participants (N= 7) synchronizing their movements in space and in time. We show that behavioural unison can be maintained after perceptual contact has been lost, for about 7s. Agent similarity and spatial configuration in the group modulated synchronization performance, differently so when perceptual interaction was present or when it was memorized. Modelling these data through a network of oscillators enabled us to clarify the double origin of this memory effect, of individual and social nature. These results shed new light into why humans continue to move in unison after perceptual interruption, and are consequential for a wide variety of applications at work, in art and in sport

A transcriptional switch controls sex determination in <i>Plasmodium falciparum</i>

Sexual reproduction and meiotic sex are deeply rooted in the eukaryotic tree of life, but mechanisms determining sex or mating types are extremely varied and are only well characterized in a few model organisms(1). In malaria parasites, sexual reproduction coincides with transmission to the vector host. Sex determination is non-genetic, with each haploid parasite capable of producing either a male or a female gametocyte in the human host(2). The hierarchy of events and molecular mechanisms that trigger sex determination and maintenance of sexual identity are yet to be elucidated. Here we show that the male development 1 (md1) gene is both necessary and sufficient for male fate determination in the human malaria parasite Plasmodium falciparum. We show that Md1 has a dual function stemming from two separate domains: in sex determination through its N terminus and in male development from its conserved C-terminal LOTUS/OST-HTH domain. We further identify a bistable switch at the md1 locus, which is coupled with sex determination and ensures that the male-determining gene is not expressed in the female lineage. We describe one of only a few known non-genetic mechanisms of sex determination in a eukaryote and highlight Md1 as a potential target for interventions that block malaria transmission

Record RF performance of standard 90 nm CMOS technology

We have optimized 3 key RF devices realized in standard logic 90 nm CMOS technology and report a record performance in terms of n-MOS maximum oscillation frequency f/sub max/ (280 GHz), varactor tuning range and varactor and inductor quality factor

Fertilité des sols: conclusions du rapport sur l'état des sols de France

Les sols constituent une ressource naturelle non renouvelable. Leurs usages et leur devenir représentent un enjeu collectif majeur, tant pour les activités agricoles ou sylvicoles que pour la préservation de la qualité de notre environnement. Après dix ans de travaux, le Groupement d’Intérêt Scientifique sur les sols, le Gis Sol, a dressé le premier bilan scientifiquement quantifié de l’état des sols de France métropolitaine et d’Outre-mer dans un rapport sur l’état des sols de France publié en 2011. Ce rapport relève des points positifs mais également un certain nombre de préoccupations du point de vue de la fertilité. Les sols agricoles ne présentent pas d’évolution mesurable de leur acidité, ce quiindique une bonne gestion du pH à l’échelle nationale. Le rapport fait en revanche état de teneurs en phosphore relativement faibles pour de nombreux sols, et à l’inverse de situations d’excédents très préoccupantes en raison de son impact sur la qualité des eaux et l’eutrophisation des milieux. Il pose ainsi la question de la durabilité à long terme du système agricole actuel et celle d’une meilleure valorisation des effluents d’élevage. D’assez nombreuses situations pourraient également être susceptibles de provoquer des carences en oligo-éléments pour des cultures exigeantes. Enfin, une inquiétude majeure concerne la progression de l’artificialisation des sols, qui s’est accélérée durant la dernière décennie et occasionne des pertes importantes de sols agricoles.Soils are a non-renewable, natural resource. Their uses and their future represent, therefore, a collective issue for agricultural and forestry production, as well as for the preservation of our environment. After ten years of work, the “Groupement d’intérêt scientifique sur les sols”, the Gis Sol (Soils Scientific Interest Group) has presented the first appraisal of soil quality in mainland France and its overseas territories in a report on the state of the soils in France published in 2011. This appraisal shows evidence for positive points but also highlights some concerns regarding soil fertility. Agricultural soils do not show a measurable change in their acidity, thus indicating an efficient management of pH at a national level. On the other hand, the report shows relatively low phosphorus levels for numerous soils, and inversely situations of structural excess which remain very worrying due to its impact on water quality and on the eutrophication of the environments. It also raises the questionsof the long-term sustainability of current cultivation systems and of a better treatment of effluents from livestock farming. Numerous situations also seem to be incompatible, for certain oligo-elements, with demanding cultures. At last, a major concern is the development of soil sealing, which has accelerated over the last decade and is responsible for the loss of large areas of agricultural soils

Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.

Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1-40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients

Identification and Characterization of the Unique N-Linked Glycan Common to the Flagellins and S-layer Glycoprotein of Methanococcus voltae*

The flagellum of Methanococcus voltae is composed of four structural flagellin proteins FlaA, FlaB1, FlaB2, and FlaB3. These proteins possess a total of 15 potential N-linked sequons (NX(S/T)) and show a mass shift on an SDS-polyacrylamide gel indicating significant post-translational modification. We describe here the structural characterization of the flagellin glycan from M. voltae using mass spectrometry to examine the proteolytic digests of the flagellin proteins in combination with NMR analysis of the purified glycan using a sensitive, cryogenically cooled probe. Nano-liquid chromatography-tandem mass spectrometry analysis of the proteolytic digests of the flagellin proteins revealed that they are post-translationally modified with a novel N-linked trisaccharide of mass 779 Da that is composed of three sugar residues with masses of 318, 258, and 203 Da, respectively. In every instance the glycan is attached to the peptide through the asparagine residue of a typical N-linked sequon. The glycan modification has been observed on 14 of the 15 sequon sites present on the four flagellin structural proteins. The novel glycan structure elucidated by NMR analysis was shown to be a trisaccharide composed of beta-ManpNAcA6Thr-(1-4)-beta-Glc-pNAc3NAcA-(1-3)-beta-GlcpNAc linked to Asn. In addition, the same trisaccharide was identified on a tryptic peptide of the S-layer protein from this organism implicating a common N-linked glycosylation pathway

Influence of facial feedback and mind perception during a cooperative human-robot task in schizophrenia

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Rapid progress in the area of humanoid robots offers tremendous possibilities for investigating and improving social competences in people with social deficits, but remains yet unexplored in schizophrenia. In this study, we examined the influence of social feedbacks elicited by a humanoid robot on motor coordination during a human-robot interaction. Twenty-two schizophrenia patients and twenty-two matched healthy controls underwent a collaborative motor synchrony task with the iCub humanoid robot. Results revealed that positive social feedback had a facilitatory effect on motor coordination in the control participants compared to non-social positive feedback. This facilitatory effect was not present in schizophrenia patients, whose social-motor coordination was similarly impaired in social and non-social feedback conditions. Furthermore, patients’ cognitive flexibility impairment and antipsychotic dosing were negatively correlated with patients’ ability to synchronize hand movements with iCub. Overall, our findings reveal that patients have marked difficulties to exploit facial social cues elicited by a humanoid robot to modulate their motor coordination during human-robot interaction, partly accounted for by cognitive deficits and medication. This study opens new perspectives for comprehension of social deficits in this mental disorder.This experiment was supported by a grant from the European Union’s Seventh Framework Program (FP7 ICT 2011 Call 9) under grant agreement n FP7-ICT-600610 ALTEREGO

Expanding and Collapsing Scalar Field Thin Shell

This paper deals with the dynamics of scalar field thin shell in the Reissner-Nordstr$\ddot{o}$m geometry. The Israel junction conditions between Reissner-Nordstr$\ddot{o}$m spacetimes are derived, which lead to the equation of motion of scalar field shell and Klien-Gordon equation. These equations are solved numerically by taking scalar field model with the quadratic scalar potential. It is found that solution represents the expanding and collapsing scalar field shell. For the better understanding of this problem, we investigate the case of massless scalar field (by taking the scalar field potential zero). Also, we evaluate the scalar field potential when $p$ is an explicit function of $R$. We conclude that both massless as well as massive scalar field shell can expand to infinity at constant rate or collapse to zero size forming a curvature singularity or bounce under suitable conditions.Comment: 15 pages, 11 figure

Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation

AIMS: To investigate the effects of cardiac resynchronization therapy (CRT) on survival in heart failure (HF) patients with permanent atrial fibrillation (AF) and the role of atrio-ventricular junction (AVJ) ablation in these patients. METHODS AND RESULTS: Data from 1285 consecutive patients implanted with CRT devices are presented: 1042 patients were in sinus rhythm (SR) and 243 (19%) in AF. Rate control in AF was achieved by either ablating the AVJ in 118 patients (AVJ-abl) or prescribing negative chronotropic drugs (AF-Drugs). Compared with SR, patients with AF were significantly older, more likely to be non-ischaemic, with higher ejection fraction, shorter QRS duration, and less often received ICD back-up. During a median follow-up of 34 months, 170/1042 patients in SR and 39/243 in AF died (mortality: 8.4 and 8.9 per 100 person-year, respectively). Adjusted hazard ratios were similar for all-cause and cardiac mortality [0.9 (0.57-1.42), P = 0.64 and 1.00 (0.60-1.66) P = 0.99, respectively]. Among AF patients, only 11/118 AVJ-abl patients died vs. 28/125 AF-Drugs patients (mortality: 4.3 and 15.2 per 100 person-year, respectively, P < 0.001). Adjusted hazard ratios of AVJ-abl vs. AF-Drugs was 0.26 [95% confidence interval (CI) 0.09-0.73, P = 0.010] for all-cause mortality, 0.31 (95% CI 0.10-0.99, P = 0.048) for cardiac mortality, and 0.15 (95% CI 0.03-0.70, P = 0.016) for HF mortality. CONCLUSION: Patients with HF and AF treated with CRT have similar mortality compared with patients in SR. In AF, AVJ ablation in addition to CRT significantly improves overall survival compared with CRT alone, primarily by reducing HF death