Review article

In eukaryotic cells, the trans-Golgi network (TGN) serves as a platform for secretory cargo sorting and trafficking. In recent years, it has become evident that a complex network of lipid-lipid and lipid-protein interactions contributes to these key functions. This review addresses the role of lipids at the TGN with a particular emphasis on sphingolipids and diacylglycerol. We further highlight how these lipids couple secretory cargo sorting and trafficking for spatiotemporal coordination of protein transport to the plasma membrane

Testican-1, an inhibitor of pro-MMP-2 activation, is expressed in cartilage

SummaryObjectiveRecently, testican-1 has been described to be an inhibitor of MT1-MMP and MT3-MMP mediated pro-MMP-2 activation. As MT1-MMP mediated pro-MMP-2 activation is of significance for cartilage destruction in osteoarthritis, we studied the expression and localization of testican-1 in human articular cartilage.MethodsCartilage samples from the medial and lateral tibia plateau were obtained from osteoarthritic patients who underwent joint replacements, and were graded histomorphologically by Mankin score. Testican-1 expression was assessed in RNA isolated directly from cartilage as well as in freshly isolated chondrocytes by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantified by real-time RT-PCR. Testican-1 protein was localized by immunohistochemistry in human osteoarthritic cartilage samples, in human fetal knee joint, and in knees from mice.ResultsTestican-1 mRNA could be detected in cartilage and in freshly isolated chondrocytes both from moderately and from severely damaged osteoarthritic cartilage. In the same donor, expression in chondrocytes from more severely affected regions was decreased compared with chondrocytes from less affected regions. By immunolocalization, testican-1 protein could be detected in chondrocytes predominantly of the superficial and transitional zones. Matrix staining in these zones was greatly reduced in samples from more severely affected osteoarthritic cartilage. A similar distribution was found in the articular cartilage of knees from 7-week-old mice. In addition to articular cartilage, testican-1 was also present in growth plate cartilage.ConclusionsTestican-1 is a component of cartilage, both of the joint and of the growth plate. Given its activity as an inhibitor of MT1-MMP mediated pro-MMP-2 activation, it is reasonable to speculate that it participates in the regulation of matrix turnover in cartilage

Do riverine barriers, history or introgression shape the genetic structuring of a common shrew (Sorex araneus) population?

The common shrew (Sorex araneus) is subdivided into numerous chromosome races. The Valais and Cordon chromosome races meet and hybridize at a mountain river in Les Houches (French Alps). Significant genetic structuring was recently reported among populations found on the Valais side of this hybrid zone. In this paper, a phylogenetic analysis and partial Mantel tests are used to investigate the patterns and causes of this structuring. A total of 185 shrews were trapped at 12 localities. All individuals were typed for nine microsatellite loci. Although several mountain rivers are found in the study area, riverine barriers do not have a significant influence on gene flow. Partial Mantel tests show that our result is caused by the influence of the hybrid zone with the Cordon race. The geographical patterns of this structuring are discussed in the context of the contact zone, which appears to extend up to a group of two rivers. The glacier they originate from is known to have cut the Arve valley as recently as 1818. The recent history of this glacier, its moraine and possibly rivers, may therefore be linked to the history of this hybrid zone

Nomenclature for the chromosomes of the common shrew (Sorex araneus)

A G-band composite karyotype has been prepared for the common shrew (Sorex araneus Linnaeus, 1758). This includes multiple cut-outs of each chromosome arm (in different stages of contraction) derived from chromosome spreads prepared by a variety of methods by the different authors. The important features of each chromosome arm are described. The nomenclature for the chromosome arms follows that of Halkka et al. (1974) as clarified by Fredga, Nawrin (1977) and subsequent authors, i.e. italicised letters of the alphabet are used with a as the largest chromosome arm. Different authors have used a variety of methods to describe the karyotype of (a) individuals and (b) the pattern of variation within populations. Also, definitions of chromosomal ‘race’ differ. We suggest a standardised scheme for the description of individuals, populations and chromosomal race

Bayesian Network Structure Learning with Permutation Tests

In literature there are several studies on the performance of Bayesian network structure learning algorithms. The focus of these studies is almost always the heuristics the learning algorithms are based on, i.e. the maximisation algorithms (in score-based algorithms) or the techniques for learning the dependencies of each variable (in constraint-based algorithms). In this paper we investigate how the use of permutation tests instead of parametric ones affects the performance of Bayesian network structure learning from discrete data. Shrinkage tests are also covered to provide a broad overview of the techniques developed in current literature.Comment: 13 pages, 4 figures. Presented at the Conference 'Statistics for Complex Problems', Padova, June 15, 201

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

Tailored parameter optimization methods for ordinary differential equation models with steady-state constraints

Background: Ordinary differential equation (ODE) models are widely used to describe (bio-)chemical and biological processes. To enhance the predictive power of these models, their unknown parameters are estimated from experimental data. These experimental data are mostly collected in perturbation experiments, in which the processes are pushed out of steady state by applying a stimulus. The information that the initial condition is a steady state of the unperturbed process provides valuable information, as it restricts the dynamics of the process and thereby the parameters. However, implementing steady-state constraints in the optimization often results in convergence problems. Results: In this manuscript, we propose two new methods for solving optimization problems with steady-state constraints. The first method exploits ideas from optimization algorithms on manifolds and introduces a retraction operator, essentially reducing the dimension of the optimization problem. The second method is based on the continuous analogue of the optimization problem. This continuous analogue is an ODE whose equilibrium points are the optima of the constrained optimization problem. This equivalence enables the use of adaptive numerical methods for solving optimization problems with steady-state constraints. Both methods are tailored to the problem structure and exploit the local geometry of the steady-state manifold and its stability properties. A parameterization of the steady-state manifold is not required. The efficiency and reliability of the proposed methods is evaluated using one toy example and two applications. The first application example uses published data while the second uses a novel dataset for Raf/MEK/ERK signaling. The proposed methods demonstrated better convergence properties than state-of-the-art methods employed in systems and computational biology. Furthermore, the average computation time per converged start is significantly lower. In addition to the theoretical results, the analysis of the dataset for Raf/MEK/ERK signaling provides novel biological insights regarding the existence of feedback regulation. Conclusion: Many optimization problems considered in systems and computational biology are subject to steady-state constraints. While most optimization methods have convergence problems if these steady-state constraints are highly nonlinear, the methods presented recover the convergence properties of optimizers which can exploit an analytical expression for the parameter-dependent steady state. This renders them an excellent alternative to methods which are currently employed in systems and computational biology

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

Accuracy of B(E2; 0+ -> 2+) transition rates from intermediate-energy Coulomb excitation experiments

The method of intermediate-energy Coulomb excitation has been widely used to determine absolute B(E2; 0+ -> 2+) quadrupole excitation strengths in exotic nuclei with even numbers of protons and neutrons. Transition rates measured with intermediate-energy Coulomb excitation are compared to their respective adopted values and for the example of 26Mg to the B(E2; 0+ -> 2+) values obtained with a variety of standard methods. Intermediate-energy Coulomb excitation is found to have an accuracy comparable to those of long-established experimental techniques.Comment: to be published in Phys. Rev.