Comparing call-based versus subunit-based methods for categorizing Norwegian killer whale, Orcinus orca, vocalizations

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Animal Behaviour 81 (2011): 377-386, doi:10.1016/j.anbehav.2010.09.020.Students of animal communication face significant challenges when deciding how to categorise calls into subunits, calls, and call series. Here, we use algorithms designed to parse human speech to test different approaches for categorising calls of killer whales. Killer whale vocalisations have traditionally been categorised by humans into discrete call types. These calls often contain internal spectral shifts, periods of silence, and synchronously produced low and high frequency components, suggesting that they may be composed of subunits. We describe and compare three different approaches for modelling Norwegian killer whale calls. The first method considered the whole call as the basic unit of analysis. Inspired by human speech processing techniques, the second and third methods represented the calls in terms of subunits. Subunits may provide a more parsimonious approach to modelling the vocal stream since (1) there were fewer subunits than call types; (2) nearly 75% of all call types shared at least one subunit. We show that contour traces from stereotyped Norwegian killer whale calls yielded similar automatic classification performance using either whole calls or subunits. We also demonstrate that subunits derived from Norwegian stereotyped calls were detected in some Norwegian variable (non-stereotyped) calls as well as the stereotyped calls of other killer whale populations. Further work is required to test whether killer whales use subunits to generate and categorize their vocal repertoire.The undergraduate students were supported by the Massachusetts Institute of Technology Undergraduate Research Opportunities Program office and the Ocean Life Institute (OLI) at the Woods Hole Oceanographic Institution (WHOI). Field work was financed by the OLI, National Geographic Society and WWF Sweden. A. D. Shapiro was funded by a National Defense Science and Engineering Graduate Fellowship and the WHOI Academic Programs Office

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy

Objective:To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology.Methods:We collected molecular and clinical data from several diagnostic and research cohorts. Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes.Results:We identified heterozygous de novo GRIN1 mutations in 14 individuals and reviewed the phenotypes of all 9 previously reported patients. These 23 individuals presented with a distinct phenotype of profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, hyperkinetic movement disorder, oculogyric crises, cortical blindness, generalized cerebral atrophy, and epilepsy. Mutations cluster within transmembrane segments and result in loss of channel function of varying severity with a dominant-negative effect. In addition, we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families.Conclusions:De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1-associated disorders.Johannes R. Lemke (32EP30_136042/1) and Peter De Jonghe (G.A.136.11.N and FWO/ESF-ECRP) received financial support within the EuroEPINOMICS-RES network (www.euroepinomics.org) within the Eurocores framework of the European Science Foundation (ESF). Saskia Biskup and Henrike Heyne received financial support from the German Federal Ministry for Education and Research (BMBF IonNeurONet: 01 GM1105A and FKZ: 01EO1501). Katia Hardies is a PhD fellow of the Institute for Science and Technology (IWT) Flanders. Ingo Helbig was supported by intramural funds of the University of Kiel, by a grant from the German Research Foundation (HE5415/3-1) within the EuroEPINOMICS framework of the European Science Foundation, and additional grants of the German Research Foundation (DFG, HE5415/5-1, HE 5415/6-1), German Ministry for Education and Research (01DH12033, MAR 10/012), and grant by the German chapter of the International League against Epilepsy (DGfE). The project also received infrastructural support through the Institute of Clinical Molecular Biology in Kiel, supported in part by DFG Cluster of Excellence "Inflammation at Interfaces" and "Future Ocean." The project was also supported by the popgen 2.0 network (P2N) through a grant from the German Ministry for Education and Research (01EY1103) and by the International Coordination Action (ICA) grant G0E8614N. Christel Depienne, Caroline Nava, and Delphine Heron received financial support for exome analyses by the Centre National de Genotypage (CNG, Evry, France)

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as path

Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

A. Palotie on työryhmän jäsen.Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.Peer reviewe

Swiss interdisciplinary guidance on good practices for acute and complicated diabetic foot syndromes

BACKGROUND Diabetic foot syndromes (DFS) usually have negative outcomes for patients characterised by multiple comorbidities and frailty. In Switzerland, we need a nationwide "quality of care" programme consisting of evidence-based, practical guidance for primary care providers, together with the implementation of a multidisciplinary care system for DFS. METHODS Elaboration of interprofessional and comprehensive Swiss practical guidance for the timely management of acute DFS. This guidance will not replace existing recommendations, but will be complementary to them. Before nationwide implementation, three Swiss pilot sites will test the guidance in collaboration with local interprofessional foot-care centres. RESULTS Under the umbrella of QualiCCare, and endorsed by the professional societies involved, twenty experts from all relevant professions issued four protocols for various aspects of DFS between March 2018 and January 2020. In addition, they defined criteria for triage and treatment in primary care, as well as the timely referral of patients with DFS to interprofessional foot-care centres. We propose a framework for multidisciplinary, specialised foot-care networks, and interprofessional foot-care centres. The piloting of the proposed concepts is underway. All documents are available on the website www.qualiccare.ch. CONCLUSIONS We provide evidence-based tools for Swiss primary care providers and specialists, and increase the accessibility for patients to specialised and timely care of DFS

Glucose and carbachol generate 1,2-diacylglycerols by different mechanisms in pancreatic islets.

Diacylglycerols (DAG) modulate secretory responses by the activation of protein kinase C. Early changes in DAG formation induced by the muscarinic receptor agonist carbachol were compared to those caused by the nutrient secretagogue glucose in pancreatic islets. Turnover rates of DAG were investigated in radiolabeling experiments, whereas changes in total mass and fatty acid composition of DAG were assessed by gas-liquid chromatography. When islet lipids were labeled to steady state in tissue culture with [3H]glycerol, carbachol induced a rapid (10 s) and sustained increase of [3H]DAG generation. In contrast, glucose stimulation failed to increase [3H]glycerol containing DAG, and this was probably due to the isotopic dilution of the label secondary to enhanced glycolysis. This was substantiated by following the transfer of 14C from glucose into DAG. Within 1 min of acute exposure of islets to D-[U-14C]-glucose at stimulatory concentrations, DAG labeling increased fivefold representing up to 2% of total glucose usage. Similar stimulation of 14C incorporation into other neutral lipids and inositol phospholipids was observed, suggesting the enhanced de novo synthesis of phosphatidic acid, the common precursor for DAG, and inositol phospholipids from glycolytic intermediates. Transfer of 14C from glucose was not stimulated by agents such as carbachol and exogenous phospholipase C that act primarily on inositol phospholipid breakdown. The total mass of islet DAG was increased by 60% after both carbachol and glucose stimulation. However, analysis of the fatty acid composition of carbachol-generated DAG revealed at the early time point (10 s) a prevalent stearoyl-arachidonoyl configuration similar to that reported for inositol phospholipids. This pattern shifted to a DAG enriched in palmitic acid at a later time point. Glucose-stimulated islets displayed a predominance of palmitic acid containing DAG, indicating increased de novo synthesis of the putative second messenger rather than its formation by inositol phospholipid hydrolysis. Indeed, steady-state labeling of these phospholipids with [3H]inositol confirmed this idea since only carbachol caused detectable inositol phospholipid hydrolysis. Thus, although protein kinase C may be activated by both carbachol and glucose, the two secretagogues generate diacylglycerols through different mechanisms

Management of diabetic foot infections in the light of recent literature and new international guidelines

Introduction: In May 2019 the International Working Group on the Diabetic Foot (IWGDF) launched their quadrennially updated guidelines on the management of diabetic foot infections (DFIs). Concomitantly, the number of new publications regarding DFI increased.Areas covered: The IWGDF committee developed and addressed key questions and produced evidence-based recommendations related to diagnosing and treating DFIs. This narrative review provides an overview of this new guideline and also of other recently published literature in the field of DFIs.Expert opinion: The 2019 IWGDF guidelines provide an authoritative, international, evidence-based approach to diagnosing and treating DFIs. The 27 recommendations are supported by systematic reviews of both diagnosis and interventions. Our review of this guideline, along with other recent publications in the field, allows us to offer state-of-the-art guidance for caring for these difficult infections. As the evidence base for management of DFIs remains suboptimal, we need further research to improve the management of DFIs