Height estimates for Killing graphs

The paper aims at proving global height estimates for Killing graphs defined over a complete manifold with nonempty boundary. To this end, we first point out how the geometric analysis on a Killing graph is naturally related to a weighted manifold structure, where the weight is defined in terms of the length of the Killing vector field. According to this viewpoint, we introduce some potential theory on weighted manifolds with boundary and we prove a weighted volume estimate for intrinsic balls on the Killing graph. Finally, using these tools, we provide the desired estimate for the weighted height in the assumption that the Killing graph has constant weighted mean curvature and the weighted geometry of the ambient space is suitably controlled.Comment: 26 pages. Final version. To appear on Journal of Geometric Analysi

What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Mega-analysis methods in ENIGMA: the experience of the generalized anxiety disorder working group

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA‐Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega‐analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between‐country transfer of subject‐level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega‐analyses

Respiratory insufficiency in desminopathy patients caused by introduction of proline residues in desmin c-terminal alpha-helical segment.

Mutations in desmin gene have been identified in patients with cardiac and skeletal myopathy characterized by intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates. We characterized two new desminopathy families with unusual features of adult-onset, slowly progressive, diffuse skeletal myopathy and respiratory insufficiency. Progressive reduction of respiratory muscle strength became clinically detectable between the 3rd and the 8th years of illness and led to recurrent chest infections and death in one of the patients. Novel mutations, A357P and L370P, predicted to introduce proline residue into a highly conserved alpha-helical region of desmin, were identified. Proline is known to disrupt the alpha-helix. In addition, the A357P mutation distorts a unique stutter sequence that is considered to be critically important for proper filament assembly. Functional assessment in two cell-lines, one of which does and the other of which does not constitutively produce type III intermediate filaments, demonstrated the inability of mutant desmin carrying either the A357P or the L370P mutation to polymerize and form an intracellular filamentous network. The results of this study indicate that respiratory insufficiency is an intrinsic feature of disease associated with specific desmin mutations; in some patients, respiratory weakness may present as a dominant clinical manifestation and a major cause of disability and death

Some non-stability results for geometric Paneitz–Branson type equations

International audienceLet (M, g) be a compact riemannian manifold of dimension n ≥ 5. We consider two Paneitz-Branson type equations with general coefficients ∆ 2 g u − div g (A g du) + hu = |u| 2 * −2−ε u on M, (E1) and ∆ 2 g u − div g ((A g + εB g)du) + hu = |u| 2 * −2 u on M, (E2) where A g and B g are smooth symmetric (2, 0)-tensors, h ∈ C ∞ (M), 2 * = 2n n − 4 and ε is a small positive parameter. Under suitable assumptions , we construct solutions u ε to (??) and (??) which blow up at one point of the manifold when ε tends to 0. In particular, we extend the result of Deng and Pistoia 2011 (to the case where A g is the one defined in the Paneitz operator) and the result of Pistoia and Vaira 2013 (to the case n = 8 and (M, g) locally conformally flat)

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt.

Comment in : Fusion of field studies and the laboratory solves a puzzle in antimalarial resistance. [Proc Natl Acad Sci U S A. 2015]International audienceIn regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance

Preorogenic Folds and Syn-Orogenic Basement Tilts in an Inverted Hyperextended Margin: The Northern Pyrenees Case Study

International audienceThe Chaînons Béarnais (CB, North Pyrenean Zone) resulted from the Cenozoic contractional reactivation of the salt tectonics-bearing, hyperextended margin that initiated at the Europe-Iberia transition during the Early Cretaceous. In this tectonic scenario, assessing the relative contribution of extension and contraction to the present-day structure is crucial to reconstruct the hyperextended margin geometry and to quantify the subsequent shortening. This study undertakes this issue by defining the relationship between folding and two bedding-independent references: peak temperature isotherms and paleomagnetic data. Isotherms were reconstructed from 76 new measurements of Raman spectroscopy on carbonaceous materials (RSCM) and indicate temperatures at the time of peak metamorphism in the CB (110-85 Ma, end of extension). They are shallowly to moderately northwards dipping and cut across most of the folds deforming the Mesozoic units. Paleomagnetic data from 29 sites evidence a widespread remagnetization carried by pyrrhotite that was probably blocked during the early Paleogene (before the onset of continental collision) and postdated folding in the CB. Abnormal inclinations in this remagnetization suggest syn-collision tilts up to 60°to the north in the back limb of the Axial Zone. Based on the presented data set, we propose that the folding of the cover above the evaporitic décollement was almost fully completed by the end of the Cretaceous extension, with~85-100% of the dip of fold limbs being acquired before the remagnetization time. Cenozoic contraction reactivated the extensional faults in the shallow basement as top-to-the-S thrusts, leading to the passive transport and northwards tilting of the folded cover