Conditional Spike Transmission Mediated by Electrical Coupling Ensures Millisecond Precision-Correlated Activity among Interneurons In Vivo

Many GABAergic interneurons are electrically coupled and in vitro can display correlated activity with millisecond precision. However, the mechanisms underlying correlated activity between interneurons in vivo are unknown. Using dual patch-clamp recordings in vivo, we reveal that in the presence of spontaneous background synaptic activity, electrically coupled cerebellar Golgi cells exhibit robust millisecond precision-correlated activity which is enhanced by sensory stimulation. This precisely correlated activity results from the cooperative action of two mechanisms. First, electrical coupling ensures slow subthreshold membrane potential correlations by equalizing membrane potential fluctuations, such that coupled neurons tend to approach action potential threshold together. Second, fast spike-triggered spikelets transmitted through gap junctions conditionally trigger postjunctional spikes, depending on both neurons being close to threshold. Electrical coupling therefore controls the temporal precision and degree of both spontaneous and sensory-evoked correlated activity between interneurons, by the cooperative effects of shared synaptic depolarization and spikelet transmission

Bayesian optimization of the PC algorithm for learning Gaussian Bayesian networks

The PC algorithm is a popular method for learning the structure of Gaussian Bayesian networks. It carries out statistical tests to determine absent edges in the network. It is hence governed by two parameters: (i) The type of test, and (ii) its significance level. These parameters are usually set to values recommended by an expert. Nevertheless, such an approach can suffer from human bias, leading to suboptimal reconstruction results. In this paper we consider a more principled approach for choosing these parameters in an automatic way. For this we optimize a reconstruction score evaluated on a set of different Gaussian Bayesian networks. This objective is expensive to evaluate and lacks a closed-form expression, which means that Bayesian optimization (BO) is a natural choice. BO methods use a model to guide the search and are hence able to exploit smoothness properties of the objective surface. We show that the parameters found by a BO method outperform those found by a random search strategy and the expert recommendation. Importantly, we have found that an often overlooked statistical test provides the best over-all reconstruction results

Characteristics of global naturopathic education, regulation, and practice frameworks: results from an international survey.

BackgroundThis descriptive study provides the first examination of global naturopathic education, regulation and practice frameworks that have potential to constrain or assist professional formation and integration in global health systems. Despite increasing public use, a significant workforce, and World Health Organization calls for national policy development to support integration of services, existent frameworks as potential barriers to integration have not been examined.MethodsThis cross-sectional survey utilized purposive sampling of 65 naturopathic organisations (educational institutions, professional associations, and regulatory bodies) from 29 countries. Organizational representatives completed an on-line survey, conducted between Nov 2016 - Aug 2019. Frequencies and cross-tabulation statistics were analyzed using SPSSv.25. Qualitative responses were hand-coded and thematically analysed where appropriate.ResultsSixty-five of 228 naturopathic organizations completed the survey (29% response rate) from 29 of 46 countries (63% country response rate). Most education programs (68%) were delivered via a national framework. Higher education qualifications (60%) predominated. Organizations influential in education were professional associations (75.4%), particularly where naturopathy was unregulated, and accreditation bodies (41.5%) and regulatory boards (33.8%) where regulated. Full access to controlled acts, and to health insurance rebates were more commonly reported where regulated. Attitude of decision-makers, opinions of other health professions and existing legislation were perceived to most impact regulation, which was globally heterogeneous.ConclusionEducation and regulation of the naturopathic profession has significant heterogeneity, even in the face of global calls for consistent regulation that recognizes naturopathy as a medical system. Standards are highest and consistency more apparent in countries with regulatory frameworks

Quality of life and clinical characteristics of self-improving congenital ichthyosis within the disease spectrum of autosomal recessive congenital ichthyosis

Background Autosomal-recessive congenital ichthyosis (ARCI) is a heterogeneous group of ichthyoses presenting at birth. Self-improving congenital ichthyosis (SICI) is a subtype of ARCI and is diagnosed when skin condition improves remarkably (within years) after birth. So far, there are sparse data on SICI and quality of life (QoL) in this ARCI subtype. This study aims to further delineate the clinical spectrum of SICI as a rather unique subtype of ARCI. Objectives This prospective study included 78 patients (median age: 15 years) with ARCI who were subdivided in SICI (n = 18) and non-SICI patients (nSICI, n = 60) by their ARCI phenotype. Methods Quality of life (QoL) was assessed using the (Children's) Dermatology Life Quality Index. Statistical analysis was performed with chi-squared and t-Tests. Results The genetically confirmed SICI patients presented causative mutations in the following genes: ALOXE3 (8/16; 50.0%), ALOX12B (6/16; 37.5%), PNPLA1 (1/16; 6.3%) and CYP4F22 (1/16; 6.3%). Hypo-/anhidrosis and insufficient vitamin D levels (<30 ng/mL) were often seen in SICI patients. Brachydactyly (a shortening of the 4th and 5th fingers) was statistically more frequent in SICI (P = 0.023) than in nSICI patients. A kink of the ear's helix was seen in half of the SICI patients and tends to occur more frequently in patients with ALOX12B mutations (P = 0.005). QoL was less impaired in patients under the age of 16, regardless of ARCI type. Conclusions SICI is an underestimated, milder clinical variant of ARCI including distinct features such as brachydactyly and kinking of the ears. Clinical experts should be aware of these features when seeing neonates with a collodion membrane. SICI patients should be regularly checked for clinical parameters such as hypo-/anhidrosis or vitamin D levels and monitored for changes in quality of life

Nucleobindin-1 regulates ECM degradation by promoting intra-Golgi trafficking of MMPs.

Matrix metalloproteinases (MMPs) degrade several ECM components and are crucial modulators of cell invasion and tissue organization. Although much has been reported about their function in remodeling ECM in health and disease, their trafficking across the Golgi apparatus remains poorly understood. Here we report that the cis-Golgi protein nucleobindin-1 (NUCB1) is critical for MMP2 and MT1-MMP trafficking along the Golgi apparatus. This process is Ca2+-dependent and is required for invasive MDA-MB-231 cell migration as well as for gelatin degradation in primary human macrophages. Our findings emphasize the importance of NUCB1 as an essential component of MMP transport and its overall impact on ECM remodeling. © 2020 Pacheco-Fernandez et al

A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis

Epidermolytic hyperkeratosis (EHK) is a blistering skin disease inherited as an autosomal-dominant trait. The disease is caused by genetic defects of the epidermal keratin K1 or K10, leading to an impaired tonofilament network of differentiating epidermal cells. Here, we describe for the first time a kindred with recessive inheritance of EHK. Sequence analysis revealed a homozygous nonsense mutation of the KRT10 gene in the affected family members, leading to a premature termination codon (p.Q434X), whereas the clinically unaffected consanguineous parents were both heterozygous carriers of the mutation. Semi-quantitative RT-PCR and western blot analysis demonstrated degradation of the KRT10 transcript, resulting in complete absence of keratin K10 protein in the epidermis and cultured keratinocytes of homozygous patients. This K10 null mutation leads to a severe phenotype, clinically resembling autosomal-dominant EHK, but differing in form and distribution of keratin aggregates on ultrastructural analysis. Strong induction of the wound-healing keratins K6, K16 and K17 was found in the suprabasal epidermis, which are not able to compensate for the lack of keratin 10. We demonstrate that a recessive mutation in KRT10 leading to a complete human K10 knockout can cause EHK. Identification of the heterogeneity of this disorder has a major impact for the accurate genetic counseling of patients and their families and also has implications for gene-therapy approaches

A novel class of microRNA-recognition elements that function only within open reading frames.

MicroRNAs (miRNAs) are well known to target 3' untranslated regions (3' UTRs) in mRNAs, thereby silencing gene expression at the post-transcriptional level. Multiple reports have also indicated the ability of miRNAs to target protein-coding sequences (CDS); however, miRNAs have been generally believed to function through similar mechanisms regardless of the locations of their sites of action. Here, we report a class of miRNA-recognition elements (MREs) that function exclusively in CDS regions. Through functional and mechanistic characterization of these 'unusual' MREs, we demonstrate that CDS-targeted miRNAs require extensive base-pairing at the 3' side rather than the 5' seed; cause gene silencing in an Argonaute-dependent but GW182-independent manner; and repress translation by inducing transient ribosome stalling instead of mRNA destabilization. These findings reveal distinct mechanisms and functional consequences of miRNAs that target CDS versus the 3' UTR and suggest that CDS-targeted miRNAs may use a translational quality-control-related mechanism to regulate translation in mammalian cells

Descriptions, truth value intuitions, and questions

International audienceSince the famous debate between Russell (Mind 14: 479–493, 1905, Mind 66: 385–389, 1957) and Strawson (Mind 59: 320–344, 1950; Introduction to logical theory, 1952; Theoria, 30: 96–118, 1964) linguistic intuitions about truth values have been considered notoriously unreliable as a guide to the semantics of definite descriptions. As a result, most existing semantic analyses of definites leave a large number of intuitions unexplained. In this paper, I explore the nature of the relationship between truth value intuitions and non-referring definites. Inspired by comments in Strawson (Introduction to logical theory, 1964), I argue that given certain systematic considerations, one can provide a structured explanation of conflicting intuitions. I show that the intuitions of falsity, which proponents of a Russellian analysis often appeal to, result from evaluating sentences in relation to specific questions in context. This is shown by developing a method for predicting when sentences containing non-referring definites elicit intuitions of falsity. My proposed analysis draws importantly on Roberts (in: Yoon & Kathol (eds.) OSU working papers in Linguistics: vol. 49: Papers in Semantics 1998; in: Horn & Ward (eds.) Handbook of pragmatics, 2004) and recent research in the semantics and pragmatics of focus

Standardized and reproducible measurement of decision-making in mice

Progress in science requires standardized assays whose results can be readily shared, compared, and reproduced across laboratories. Reproducibility, however, has been a concern in neuroscience, particularly for measurements of mouse behavior. Here we show that a standardized task to probe decision-making in mice produces reproducible results across multiple laboratories. We designed a task for head-fixed mice that combines established assays of perceptual and value-based decision making, and we standardized training protocol and experimental hardware, software, and procedures. We trained 140 mice across seven laboratories in three countries, and we collected 5 million mouse choices into a publicly available database. Learning speed was variable across mice and laboratories, but once training was complete there were no significant differences in behavior across laboratories. Mice in different laboratories adopted similar reliance on visual stimuli, on past successes and failures, and on estimates of stimulus prior probability to guide their choices. These results reveal that a complex mouse behavior can be successfully reproduced across multiple laboratories. They establish a standard for reproducible rodent behavior, and provide an unprecedented dataset and open-access tools to study decision-making in mice. More generally, they indicate a path towards achieving reproducibility in neuroscience through collaborative open-science approaches

Measurement of Angular Distributions and R= sigma_L/sigma_T in Diffractive Electroproduction of rho^0 Mesons

Production and decay angular distributions were extracted from measurements of exclusive electroproduction of the rho^0(770) meson over a range in the virtual photon negative four-momentum squared 0.5< Q^2 <4 GeV^2 and the photon-nucleon invariant mass range 3.8< W <6.5 GeV. The experiment was performed with the HERMES spectrometer, using a longitudinally polarized positron beam and a ^3He gas target internal to the HERA e^{+-} storage ring. The event sample combines rho^0 mesons produced incoherently off individual nucleons and coherently off the nucleus as a whole. The distributions in one production angle and two angles describing the rho^0 -> pi+ pi- decay yielded measurements of eight elements of the spin-density matrix, including one that had not been measured before. The results are consistent with the dominance of helicity-conserving amplitudes and natural parity exchange. The improved precision achieved at 47 GeV, reveals evidence for an energy dependence in the ratio R of the longitudinal to transverse cross sections at constant Q^2.Comment: 15 pages, 15 embedded figures, LaTeX for SVJour(epj) document class Revision: Fig. 15 corrected, recent data added to Figs. 10,12,14,15; minor changes to tex