Multiplex ligation-dependent probe amplification (MLPA) analysis is an effective tool for the detection of novel intragenic PLA2G6 mutations: Implications for molecular diagnosis

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects 85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencin

Future Contingents and the Logic of Temporal Omniscience

At least since Aristotle’s famous 'sea-battle' passages in On Interpretation 9, some substantial minority of philosophers has been attracted to the doctrine of the open future--the doctrine that future contingent statements are not true. But, prima facie, such views seem inconsistent with the following intuition: if something has happened, then (looking back) it was the case that it would happen. How can it be that, looking forwards, it isn’t true that there will be a sea battle, while also being true that, looking backwards, it was the case that there would be a sea battle? This tension forms, in large part, what might be called the problem of future contingents. A dominant trend in temporal logic and semantic theorizing about future contingents seeks to validate both intuitions. Theorists in this tradition--including some interpretations of Aristotle, but paradigmatically, Thomason (1970), as well as more recent developments in Belnap, et. al (2001) and MacFarlane (2003, 2014)--have argued that the apparent tension between the intuitions is in fact merely apparent. In short, such theorists seek to maintain both of the following two theses: (i) the open future: Future contingents are not true, and (ii) retro-closure: From the fact that something is true, it follows that it was the case that it would be true. It is well-known that reflection on the problem of future contingents has in many ways been inspired by importantly parallel issues regarding divine foreknowledge and indeterminism. In this paper, we take up this perspective, and ask what accepting both the open future and retro-closure predicts about omniscience. When we theorize about a perfect knower, we are theorizing about what an ideal agent ought to believe. Our contention is that there isn’t an acceptable view of ideally rational belief given the assumptions of the open future and retro-closure, and thus this casts doubt on the conjunction of those assumptions

HST Snaphot Study of Variable Stars in Globular Clusters: Inner Region of NGC 6441

[Abridged] We present the results of a Hubble Space Telescope snapshot program to survey the inner region of the globular cluster NGC 6441 for its variable stars. A total of 57 variable stars was found including 38 RR Lyrae stars, 6 Population II Cepheids, and 12 long period variables. Of the RR Lyrae stars observed in this survey, 26 are pulsating in the fundamental mode with a mean period of 0.753d and 12 are first-overtone mode pulsators with a mean period of 0.365d. These values match up very well with those found in ground-based surveys. Combining all the available data for NGC 6441, we find mean periods of 0.759d and 0.375d for the RRab and RRc stars, respectively. We also find that the RR Lyrae in this survey are located in the same regions of a period-amplitude diagram as those found in ground-based surveys. Although NGC 6441 is a metal-rich globular cluster, its RR Lyrae more closely resemble those in Oosterhoff type II globular clusters. However, even compared to typical Oosterhoff type II systems, the mean period of its RRab stars is unusually long. We also derived I-band period-luminosity relations for the RR Lyrae stars. Of the six Population II Cepheids, five are of W Virginis type and one is a BL Herculis variable stars. This makes NGC 6441, along with NGC 6388, the most metal-rich globular cluster known to contain these types of variable stars. Another variable, V118, may also be a Population II Cepheid given its long period and its separation in magnitude from the RR Lyrae stars. We argue that there does not appear to be a change in the period-luminosity relation slope between the BL Herculis and W Virginis stars, but that a change of slope does occur when the RV Tauri stars are added to the period-luminosity relation.Comment: 28 pages, including 9 figures and 8 tables, emulateapj5/apjfonts style. Accepted by the Astronomical Journal. Approximate publication date September 2003. We recommend the interested reader to download the preprint with full-resolution figures, which can be found at http://www.astro.puc.cl/~mcatelan/Pritzl.zi

Supervised Exercise Intervention and Overall Activity in CKD.

Introduction: Patients are often instructed to engage in multiple weekly sessions of exercise to increase physical activity. We aimed to determine whether assignment to a supervised exercise regimen increases overall weekly activity in individuals with chronic kidney disease (CKD). Methods: We performed a secondary analysis of a pilot randomized 2 × 2 factorial design trial examining the effects of diet and exercise (10%-15% reduction in caloric intake, 3 supervised exercise sessions/wk, combined diet restriction/exercise, and control). Activity was measured as counts detected by accelerometer. Counts data were collected on all days for which an accelerometer was worn at baseline, month 2, and month 4 follow-up. The primary outcome was a relative change from baseline in log-transformed counts/min. Generalized estimating equations were used to compare the primary outcome in individuals in the exercise group and the nonexercise group. Results: We examined 111 individuals randomized to aerobic exercise or usual activity (n = 48 in the exercise group and n = 44 controls). The mean age was 57 years, 42% were female, and 28% were black. Median overall adherence over all time was 73%. Median (25th, 75th percentile) counts/min over nonsupervised exercise days at months 2 and 4 were 237.5 (6.5, 444.4) for controls and 250.9 (7.7, 529.8) for the exercise group ( Conclusion: Engaging in a supervised exercise program does not increase overall weekly physical activity in individuals with stage 3 to 4 CKD

Visceral adiposity is associated with metabolic profiles predictive of type 2 diabetes and myocardial infarction

Background: Visceral fat (VF) increases risk for cardiometabolic disease (CMD), the leading cause of morbidity and mortality. Variations in the circulating metabolome predict the risk for CMD but whether or not this is related to VF is unknown. Further, CMD is now also present in adolescents, and the relationships between VF, circulating metabolome, and CMD may vary between adolescents and adults. Methods: With an aim to add understanding to the metabolic variations in visceral obesity, we tested associations between VF, measured directly with magnetic resonance imaging, and 228 fasting serum metabolomic measures, quantified with nuclear magnetic resonance spectroscopy, in 507 adults (36-65 years) and 938 adolescents (12-18 years). We further utilized data from published studies to estimate similarities between VF and CMD-associated metabolic profiles. Results: Here we show that VF, independently of body mass index (BMI) or subcutaneous fat, is associated with triglyceride-rich lipoproteins, fatty acids, and inflammation in both adults and adolescents, whereas the associations with amino acids, glucose, and intermediary metabolites are significant in adults only. BMI-adjusted metabolomic profile of VF resembles those predicting type 2 diabetes in adults (R 2 = 0.88) and adolescents (R 2 = 0.70), and myocardial infarction in adults (R 2 = 0.59) and adolescents (R 2 = 0.40); this is not the case for ischemic stroke (adults: R 2 = 0.05, adolescents: R 2 = 0.08). Conclusions: Visceral adiposity is associated with metabolomic profiles predictive of type 2 diabetes and myocardial infarction even in normal-weight individuals and already in adolescence. Targeting factors contributing to the emergence and maintenance of these profiles might ameliorate their cumulative effects on cardiometabolic health

Leprosy at the edge of Europe-Biomolecular, isotopic and osteoarchaeological findings from medieval Ireland

Relatively little is known of leprosy in Medieval Ireland; as an island located at the far west of Europe it has the potential to provide interesting insights in relation to the historical epidemiology of the disease. To this end the study focuses on five cases of probable leprosy identified in human skeletal remains excavated from inhumation burials. Three of the individuals derived from the cemetery of St Michael Le Pole, Golden Lane, Dublin, while single examples were also identified from Ardreigh, Co. Kildare, and St Patrick's Church, Armoy, Co. Antrim. The individuals were radiocarbon dated and examined biomolecularly for evidence of either of the causative pathogens, M. leprae or M. lepromatosis. Oxygen and strontium isotopes were measured in tooth enamel and rib samples to determine where the individuals had spent their formative years and to ascertain if they had undertaken any recent migrations. We detected M. leprae DNA in the three Golden Lane cases but not in the probable cases from either Ardreigh Co. Kildare or Armoy, Co. Antrim. M. lepromatosis was not detected in any of the burals. DNA preservation was sufficiently robust to allow genotyping of M. leprae strains in two of the Golden Lane burials, SkCXCV (12-13th century) and SkCCXXX (11-13th century). These strains were found to belong on different lineages of the M. leprae phylogenetic tree, namely branches 3 and 2 respectively. Whole genome sequencing was also attempted on these two isolates with a view to gaining further information but poor genome coverage precluded phylogenetic analysis. Data from the biomolecular study was combined with osteological, isotopic and radiocarbon dating to provide a comprehensive and multidisciplinary study of the Irish cases. Strontium and oxygen isotopic analysis indicate that two of the individuals from Golden Lane (SkCXLVIII (10-11th century) and SkCXCV) were of Scandinavian origin, while SkCCXXX may have spent his childhood in the north of Ireland or central Britain. We propose that the Vikings were responsible for introducing leprosy to Ireland. This work adds to our knowledge of the likely origins of leprosy in Medieval Ireland and will hopefully stimulate further research into the history and spread of this ancient disease across the world.</p

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P &lt; 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes