Existence of conformal metrics with constant QQ-curvature

Given a compact four dimensional manifold, we prove existence of conformal metrics with constant $Q$-curvature under generic assumptions. The problem amounts to solving a fourth-order nonlinear elliptic equation with variational structure. Since the corresponding Euler functional is in general unbounded from above and from below, we employ topological methods and minimax schemes, jointly with a compactness result by the second author.Comment: 36 pages, revised version. To appear in Annals of Mathematic

Rapid determination of HLA B*07 ligands from the West Nile virus NY99 genome.

Defined T cell epitopes for West Nile (WN) virus may be useful for developing subunit vaccines against WN virus infection and diagnostic reagents to detect WN virus-specific immune response. We applied a bioinformatics (EpiMatrix) approach to search the WN virus NY99 genome for HLA B*07 restricted cytotoxic T cell (CTL) epitopes. Ninety-five of 3,433 WN virus peptides scored above a predetermined cutoff, suggesting that these would be likely to bind to HLA B*07 and would also be likely candidate CTL epitopes. Compared with other methods for genome mapping, derivation of these ligands was rapid and inexpensive. Major histocompatibility complex ligands identified by this method may be used to screen T cells from WN virus-exposed persons for cell-mediated response to WN virus or to develop diagnostic reagents for immunopathogenesis studies and epidemiologic surveillance

H_c_3 for a thin-film superconductor with a ferromagnetic dot

We investigate the effect of a ferromagnetic dot on a thin-film superconductor. We use a real-space method to solve the linearized Ginzburg-Landau equation in order to find the upper critical field, H_c_3. We show that H_c_3 is crucially dependent on dot composition and geometry, and may be significantly greater than H_c_2. H_c_3 is maximally enhanced when (1) the dot saturation magnetization is large, (2) the ratio of dot thickness to dot diameter is of order one, and (3) the dot thickness is large

Arrival of Paleo-Indians to the Southern Cone of South America: New Clues from Mitogenomes

With analyses of entire mitogenomes, studies of Native American mitochondrial DNA (mtDNA) variation have entered the final phase of phylogenetic refinement: the dissection of the founding haplogroups into clades that arose in America during and after human arrival and spread. Ages and geographic distributions of these clades could provide novel clues on the colonization processes of the different regions of the double continent. As for the Southern Cone of South America, this approach has recently allowed the identification of two local clades (D1g and D1j) whose age estimates agree with the dating of the earliest archaeological sites in South America, indicating that Paleo-Indians might have reached that region from Beringia in less than 2000 years. In this study, we sequenced 46 mitogenomes belonging to two additional clades, termed B2i2 (former B2l) and C1b13, which were recently identified on the basis of mtDNA control-region data and whose geographical distributions appear to be restricted to Chile and Argentina. We confirm that their mutational motifs most likely arose in the Southern Cone region. However, the age estimate for B2i2 and C1b13 (11–13,000 years) appears to be younger than those of other local clades. The difference could reflect the different evolutionary origins of the distinct South American-specific sub-haplogroups, with some being already present, at different times and locations, at the very front of the expansion wave in South America, and others originating later in situ, when the tribalization process had already begun. A delayed origin of a few thousand years in one of the locally derived populations, possibly in the central part of Chile, would have limited the geographical and ethnic diffusion of B2i2 and explain the present-day occurrence that appears to be mainly confined to the Tehuelche and Araucanian-speaking grou

Type I interferonopathy due to a homozygous loss-of-inhibitory-function mutation in STAT2

International audiencePurpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling

Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Forensic age diagnostics by magnetic resonance imaging of the proximal humeral epiphysis

The most commonly used radiological method for age estimation of living individuals is X-ray. Computed tomography is not commonly used due to high radiation exposure, which raises ethical concerns. This problem can be solved with the use of magnetic resonance imaging (MRI), which avoids the use of ionizing radiation. The purpose of the present study was to evaluate the utility of MRI analysis of the proximal humeral epiphyses for forensic age estimations of living individuals. In this study, 395 left proximal humeral epiphyses (patient age 12-30years) were evaluated with fast-spin-echo proton density-weighted image (FSE PD) sequences in a coronal oblique orientation on shoulder MRI images. A five-stage scoring system was used following the method of Dedouit et al. The intra- and interobserver reliabilities assessed using Cohen's kappa statistic were =0.818 and =0.798, respectively. According to this study, stage five first appeared at 20 and 21years of age in males and females, respectively. These results are not directly comparable to any other published study due to the lack of MRI data on proximal humeral head development. These findings may provide valuable information for legally important age thresholds using shoulder MRI. The current study demonstrates that MRI of the proximal humerus can support forensic age estimation. Further research is needed to establish a standardized protocol that can be applied worldwide

Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery

Update of variants identified in the pancreatic β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.This article is freely available via Open Access. Click on the publisher URL to access it via the publisher's site.P30 DK020595/NH/NIH HHS/United States K23 DK094866/NH/NIH HHS/United States R03 DK103096/NH/NIH HHS/United States 1-11-CT-41/American Diabetes Association/International R01 DK104942/DK/NIDDK NIH HHS/United States WT_/Wellcome Trust/United Kingdom WT098395/Z/12/Z/WT_/Wellcome Trust/United Kingdom UL1 TR000430/NH/NIH HHS/United States P30 DK020595/DK/NIDDK NIH HHS/United States UL1 TR000430/TR/NCATS NIH HHS/United States 1-17-JDF-008/American Diabetes Association/International 105636/Z/14/Z/WT_/Wellcome Trust/United Kingdom 110675/European Association for the Study of Diabetes-Novo Nordisk/International 16/0005407/DUK_/Diabetes UK/United Kingdom R01 DK104942/NH/NIH HHS/United States R03 DK103096/DK/NIDDK NIH HHS/United States K23 DK094866/DK/NIDDK NIH HHS/United Statespublished version, accepted version (12 month embargo), submitted versio

Svestka's Research: Then and Now

Zdenek Svestka's research work influenced many fields of solar physics, especially in the area of flare research. In this article I take five of the areas that particularly interested him and assess them in a "then and now" style. His insights in each case were quite sound, although of course in the modern era we have learned things that he could not readily have envisioned. His own views about his research life have been published recently in this journal, to which he contributed so much, and his memoir contains much additional scientific and personal information (Svestka, 2010).Comment: Invited review for "Solar and Stellar Flares," a conference in honour of Prof. Zden\v{e}k \v{S}vestka, Prague, June 23-27, 2014. This is a contribution to a Topical Issue in Solar Physics, based on the presentations at this meeting (Editors Lyndsay Fletcher and Petr Heinzel