The correlation potential of magnetic susceptibility and outcrop gamma-ray logs at Tournaisian-Viséan boundary sections in western Europe

We have measured five deep-water carbonate and carbonate-siliciclastic sections at the Tournaisian-Visean (Tn/V) boundary in western Europe, using petrophysical outcrop logging techniques (gamma-ray spectrometry /GRS/ and magnetic susceptibility /MS/). The aim was to trace correlatable log patterns across the flanks of the London-Brabant Massif from eastern Ireland to western Germany. Both GRS and MS logging proved useful for long-distance (up to similar to 1000 km) correlation. The log patterns can be interpreted in terms of sea-level fluctuations. A late Tournaisian regression, a sequence boundary at the Tn/V boundary, early Visean lowstand systems tract and an overlying transgressive to regressive succession can be identified from the GRS and MS logs. The Tn/V sequence boundary can be correlated with exposure features and karstic surfaces in the up-dip shallow-water settings at the boundary between sequence 4 and 5 of Hance et al. (2001, 2002). This indicates that sea-level fluctuations around the Tn/V boundary were synchronous and traceable on the flanks of the London-Brabant Massif. The GRS-based logging has a greater correlation potential than MS as it can be applied in a broad spectrum of facies and depositional settings. In certain sections, the MS signal shows an increasing trend during transgression and a decreasing during regression, which is opposite to the MS paradigm from shallow-water carbonate platform settings. These trends are assumed to result from landward/basinward facies shifts of low-productivity carbonate ramp systems. Lowstand shedding of carbonate tempestites and turbidites results in low MS values while during sea-level rise the ramp systems backstep, developing retrograding facies successions in their distal parts, which are associated with upward-increasing MS values

Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies

The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with nine multiplex PCR reactions. This kit produced 571 amplicons covering 37 genes associated with tubulopathies followed by massive parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, 384 index patients and 16 siblings were assessed. Most common clinical diagnoses were 174 patients with Bartter/Gitelman syndrome and 76 with distal renal tubular acidosis. A total of 269 different variants were identified in 27 genes, of which 95 variants were considered likely, 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 of the index patients. Genetic testing changed the clinical diagnosis in 16 cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic etiology in known disease genes. Thus, genetic testing helped establish a definitive diagnosis in almost two-thirds of patients thereby informing prognosis, management and genetic counseling

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Sleep-spindle detection: crowdsourcing and evaluating performance of experts, non-experts and automated methods

Sleep spindles are discrete, intermittent patterns of brain activity observed in human electroencephalographic data. Increasingly, these oscillations are of biological and clinical interest because of their role in development, learning and neurological disorders. We used an Internet interface to crowdsource spindle identification by human experts and non-experts, and we compared their performance with that of automated detection algorithms in data from middle- to older-aged subjects from the general population. We also refined methods for forming group consensus and evaluating the performance of event detectors in physiological data such as electroencephalographic recordings from polysomnography. Compared to the expert group consensus gold standard, the highest performance was by individual experts and the non-expert group consensus, followed by automated spindle detectors. This analysis showed that crowdsourcing the scoring of sleep data is an efficient method to collect large data sets, even for difficult tasks such as spindle identification. Further refinements to spindle detection algorithms are needed for middle- to older-aged subjects

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.</p

Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound.

BACKGROUND: The risk of stroke and the long-term prognosis of recurrent strokes in young patients with patent foramen ovale (PFO) are not well known. For this reason, the treatment of these patients remains empirical. An alternative treatment to prolonged antithrombotic therapy may be surgical closure of the PFO. METHODS: Thirty patients (20 men and 10 women) with stroke and PFO were prospectively selected among 138 patients with stroke and PFO for a study of surgical closure of PFO at our center. Eligible patients were &amp;lt; 60 years old, had negative results of a systematic search for another cause of stroke (first criterion), and met two of the four following criteria: (1) recurrent clinical cerebrovascular events or multiple ischemic lesions on brain MR, (2) PFO associated with an atrial septal aneurysm, (3) &amp;gt; 50 microbubbles counted in the left atrium on contrast transesophageal echocardiography (TEE), and (4) Valsalva maneuver or cough preceding the stroke. Patients selected in this manner for surgery were considered to be a subgroup with a higher risk of stroke recurrence. RESULTS: All patients had a direct suture of PFO while under cardiopulmonary bypass without recorded early or delayed significant complication. All patients underwent a new brain MRI and TEE simultaneous with transcranial Doppler ultrasonography after contrast injection at 8 +/- 3 months after surgery. After a mean follow-up of 2 years without antithrombotic treatment, no recurrent cerebrovascular event (stroke or transient ischemic attack [TIA]) and no new lesion on MRI had developed. Postoperative contrast TEE and transcranial Doppler ultrasonography showed that two patients had residual interatrial right-to-left shunting, although much smaller than before surgery, associated with single versus double continuous suture. CONCLUSIONS: Our study of 30 selected stroke patients with surgical suture of PFO showed a stroke recurrence rate of 0% and no significant complication. Residual right-to-left shunting may be avoided by double continuous suture of the PFO. In the absence of controlled studies to guide individual therapeutic decisions, our findings show that PFO closure can be done safely and may be considered to avoid recurrence in selected patients with long life expectancy and presumed paradoxic embolism

Global time scale and regional stratigraphic reference scales of Central and West Europe, East Europe, Tethys, South China, and North America as used in the Devonian-Carboniferous-Permian Correlation Chart 2003 (DCP 2003)

The boundaries of the Devonian, Carboniferous, and Permian stages of the Global Stratigraphic Reference Scale (abbreviated to Global Stratigraphic Scale-GSS) are described in relation to the biostratigraphic and/or lithostratigraphic units of the Regional Stratigraphic Reference Scales (abbreviated to Regional Stratigraphic Scales-RSS) of Central and West Europe, East Europe, Tethys, South China (eastern Tethys), and North America. In their type regions the boundaries of GSS units rarely coincide with those of homonymous RSS units. Moreover, the definitions of some RSS units have changed several times over the last decades, and subsequent misunderstanding of the stratigraphical significance of these changes has often introduced errors into proposed global correlation charts. The stratigraphic framework proposed in our global Devonian-Carboniferous-Permian Correlation Chart 2003 [DCP 2003 (Devonian-Carboniferous-Permian Correlation Chart 2003, Menning, M., Schneider, J. W., Alekseev, A. S., Amon, E. O., Becker, G., von Bitter, P. H., Boardman, D. R., Bogoslovskaya, M., Braun, A., Brocke, R., Chernykh, V., Chuvashov, B. I., Clayton, G., Dusar, M., Davydov, V. I., Dybova-Jachowicz, S., Forke, H. C., Gibling, M., Gilmour, E. H., Goretzki, J., Grunt, T. A., Hance, L., Heckel, P. H., Izokh, N. G., Jansen, U., Jin Y.-G., Jones, P., Käding, K.-Ch., Kerp, H., Kiersnowski, H., Klets, A., Klug, Ch., Korn, D., Kossovaya, O., Kotlyar, G. V., Kozur, H. W., Laveine, J.-P., Martens, Th., Nemyrovska, T. I., Nigmadganov, A. I., Paech, H.-J., Peryt, T. M., Rohn, R., Roscher, M., Rubidge, B., Schiappa, T. A., Schindler, E., Skompski, S., Ueno, K., Utting, J., Vdovenko, M. V., Villa, E., Voigt, S., Wahlman, G. P., Wardlaw, B. R., Warrington, G., Weddige, K., Werneburg, R., Weyer, D., Wilde, V., Winkler Prins, C. F., Work, D. M., 2004). Abschlußkolloquium DFG-Schwerpunktprogramm 1054: Evolution des Systems Erde während des jüngeren Paläozoikums im Spiegel der Sedimentgeochemie. Abstracts Univ. Erlangen, Germany, 2004, p. 43.] (herein abbreviated to DCP 2003, and cited as DCP, 2003 in references) is an attempt to reduce these errors. The DCP 2003 is the stratigraphic base for Project 1054 of the Deutsche Forschungsgemeinschaft (DFG) "The evolution of the Late Palaeozoic in the light of sedimentary geochemistry". This composite time scale has been carefully balanced, as far as data allows, to remove unnecessary, artificial compression and expansion of time intervals, biozonations and depositional events. The ages selected in DCP 2003 are markedly different to those in the Geologic Time Scale 1989 [GTS 1989 (Harland, W.B., Armstrong, R.L., Cox, A.V., Craig, L.E., Smith, A.G., Smith, D.G., 1990). A geologic time scale 1989. Cambridge Univ. Press, Cambridge.; Harland, W.B., Armstrong, R.L., Cox, A.V., Craig, L.E., Smith, A.G., Smith, D.G., 1990. A geologic time scale 1989. Cambridge Univ. Press, Cambridge, pp. 1-263.] and in Gradstein and Ogg [Gradstein, F.M., Ogg, J., 1996. A Phanerozoic time scale. Episodes 19 (1/2), 3-4, insert.), whereas they are closer to those of the Geologic Time Scale 2004 [GTS 2004; Gradstein, F.M., Ogg, J.G., Smith, A.G., 2004. A Geologic Time Scale 2004. Cambridge Univ. Press, Cambridge, pp. 1-589.]. Mostly, the ages are rounded to the nearest 0.5 Ma in order to avoid estimates of questionable accuracy, whereas ages of 0.1 Ma in the GTS 2004 and their error bars of ± 0.4 Ma to ± 2.8 Ma for the Devonian to Permian stage boundaries suggest an improved accuracy. In contrast, in the DCP 2003 questionable ages and positions of stratigraphic boundaries are marked by arrows