Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes

Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts

Genome Sequences of Poaceae-Associated Gemycirularviruses from the Pacific Ocean Island of Tonga

We sampled and analyzed 43 Poaceae plants from the Pacific Ocean island of Tonga for the presence of circular DNA viruses. From these samples, we recovered three gemycircularvirus genomes, which share >99% identity, from Brachiaria deflexa (n 2) and sugarcane (n 1). These genomes share<61% genome-wide identity with other gemycircularvirus sequences in public databases

The pseudogap: friend or foe of high Tc?

Although nineteen years have passed since the discovery of high temperature superconductivity, there is still no consensus on its physical origin. This is in large part because of a lack of understanding of the state of matter out of which the superconductivity arises. In optimally and underdoped materials, this state exhibits a pseudogap at temperatures large compared to the superconducting transition temperature. Although discovered only three years after the pioneering work of Bednorz and Muller, the physical origin of this pseudogap behavior and whether it constitutes a distinct phase of matter is still shrouded in mystery. In the summer of 2004, a band of physicists gathered for five weeks at the Aspen Center for Physics to discuss the pseudogap. In this perspective, we would like to summarize some of the results presented there and discuss its importance in the context of strongly correlated electron systems.Comment: expanded version, 20 pages, 11 figures, to be published, Advances in Physic

miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity

Stationary Black Holes: Uniqueness and Beyond

The spectrum of known black-hole solutions to the stationary Einstein equations has been steadily increasing, sometimes in unexpected ways. In particular, it has turned out that not all black-hole-equilibrium configurations are characterized by their mass, angular momentum and global charges. Moreover, the high degree of symmetry displayed by vacuum and electro-vacuum black-hole spacetimes ceases to exist in self-gravitating non-linear field theories. This text aims to review some developments in the subject and to discuss them in light of the uniqueness theorem for the Einstein-Maxwell system.Comment: Major update of the original version by Markus Heusler from 1998. Piotr T. Chru\'sciel and Jo\~ao Lopes Costa succeeded to this review's authorship. Significantly restructured and updated all sections; changes are too numerous to be usefully described here. The number of references increased from 186 to 32

Cardiovascular Dynamics in Crocodylus porosus Breathing Air and During Voluntary Aerobic Dives

Pressure records from the heart and outflow vessels of the heart of Crocodylus porosus resolve previously conflicting results, showing that left aortic filling via the foramen of Panizza may occur during both cardiac diastole and systole. Filling of the left aorta during diastole, identified by the asynchrony and comparative shape of pressure events in the left and right aortae, is reconciled more easily with the anatomy, which suggests that the foramen would be occluded by opening of the pocket valves at the base of the right aorta during systole. Filling during systole, indicated when pressure traces in the left and right aortae could be superimposed, was associated with lower systemic pressures, which may occur at the end of a voluntary aerobic dive or can be induced by lowering water temperature or during a long forced dive. To explain this flexibility, we propose that the foramen of Panizza is of variable calibre. The presence of a 'right-left' shunt, in which increased right ventricular pressure leads to blood being diverted from the lungs and exiting the right ventricle via the left aorta, was found to be a frequent though not obligate correlate of voluntary aerobic dives. This contrasts with the previous concept of the shunt as a correlate of diving bradycardia. The magnitude of the shunt is difficult to assess but is likely to be relatively small. This information has allowed some new insights into the functional significance of the complex anatomy of the crocodilian heart and major blood vessels

Assessing the efficiency of mother-to-child HIV prevention in low- and middle-income countries using data envelopment analysis

AIDS is one of the most significant health care problems worldwide. Due to the difficulty and costs involved in treating HIV, preventing infection is of paramount importance in controlling the AIDS epidemic. The main purpose of this paper is to explore the potential of using Data Envelopment Analysis (DEA) to establish international comparisons on the efficiency of implementation of HIV prevention programmes. To do this we use data from 52 low- and middle-income countries regarding the prevention of mother-to-child transmission of HIV. Our results indicate that there is a remarkable variation in the efficiency of prevention services across nations, suggesting that a better use of resources could lead to more and improved services, and ultimately, prevent the infection of thousands of children. These results also demonstrate the potential strategic role of DEA for the efficient and effective planning of scarce resources to fight the epidemic

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

Life Satisfaction and Sense of Coherence of Breast Cancer Survivors Compared to Women with Mental Depression, Arterial Hypertension and Healthy Controls

The purpose of the study was to compare the life satisfaction (LS) and sense of coherence (SOC) of women recovering from breast cancer (BC) to LS and SOC of women with depression or hypertension and of healthy controls. Finnish Health and Social Support (HeSSup) follow-up survey data in 2003 was linked with national health registries. BC patients were followed up for mortality until the end of 2012. The statistical computations were carried out with SAS (R). There were no significant differences in LS and SOC between the groups with BC, arterial hypertension or healthy controls. Women recovering from BC are as satisfied with their life as healthy controls, and their perceived LS is better and SOC is stronger compared to women with depression. SOC correlated positively (r(2) = 0.36, p <0.001) with LS. However, more studies on determinants of the LS are needed for designing and organizing health care services for BC survivors.Peer reviewe