Cataract, the opacity of the eye lens, is an age-onset pathology that affects nearly 50To monitor the heat and Here we focused on the effects of this structural transition on the The Dynamic light scattering (DLS) (24) provides information on the aggregation kinetics and on the clusters dimension and evolution as the aggregation proceeds. DLS measurements were performed during aggregation by using a commercial computer-interfaced scattering instruments ALV/SLS-5000 system from ALV, Langen, Germany, equipped with a To determine Where we assumed The complete distribution of decay rates can also be recovered by introducing from the relation The recovery of the A key to the understanding of proteins aggregation is the behavior of the energy of interaction between two approaching particles. It has been demonstrated that for a wide variety of proteins, this can be understood within the Derjaguin-Landau-Verwey-Overbeek (DLVO) model Clusters formed in the RLCA regime show an extremely high mass polydispersity, described by a power law, up to a cutoff mass To characterize the extent of the aggregation process, we performed dynamic light scattering experiments by measuring the time evolution of the intensity weighted average hydrodynamic radius of the clusters, After an initial, fast, increase of The first increase of Fits of Eq.9 to experimental data allow to recover  process . The valAll the aggregations, carried out at different temperatures, show the same behavior. The initially formed basic aggregation units aggregate forming fractal clusters, accordingly to an RLCA process characterized by a temperature dependent rate constant (i.e. higher is the temperature faster is the aggregation rate). The size of basic aggregation units,instead, is independent on temperature with an average value of By decreasing temperature below fication  and the aller  . At timeTherefore above and below A closer look of Supramolecular structure of crystallins substantially varies both in lenses of different vertebrate species and in various parts of the same lens Here we monitor changes in the At all the temperatures investigated supramolecular aggregation of The radius of the HMW is The aggregation rate, instead, undergoes to an overall abrupt change when crossing Therefore, the change in tertiary structure occurring at the endothermic phase transition at Lens crystallin is particularly recessive to deleterious effects from elecromagnetic radiations that are known to be a potential risk factor for cataract and other eyes diseases. Indeed, its aqueous content favors radiation absorption and the very weak vascularization makes difficult to stand fast temperature increases In this context, the natural self-protective mechanism that we report preserves the lens from premature opacification throughout the lifespan of the organism


Cognitive and information processing deficits are core features and important sources of disability in schizophrenia. Our understanding of the neural substrates of these deficits remains incomplete, in large part because the complexity of impairments in schizophrenia makes the identification of specific deficits very challenging. Vision science presents unique opportunities in this regard: many years of basic research have led to detailed characterization of relationships between structure and function in the early visual system and have produced sophisticated methods to quantify visual perception and characterize its neural substrates. We present a selective review of research that illustrates the opportunities for discovery provided by visual studies in schizophrenia. We highlight work that has been particularly effective in applying vision science methods to identify specific neural abnormalities underlying information processing deficits in schizophrenia. In addition, we describe studies that have utilized psychophysical experimental designs that mitigate generalized deficit confounds, thereby revealing specific visual impairments in schizophrenia. These studies contribute to accumulating evidence that early visual cortex is a useful experimental system for the study of local cortical circuit abnormalities in schizophrenia. The high degree of similarity across neocortical areas of neuronal subtypes and their patterns of connectivity suggests that insights obtained from the study of early visual cortex may be applicable to other brain regions. We conclude with a discussion of future studies that combine vision science and neuroimaging methods. These studies have the potential to address pressing questions in schizophrenia, including the dissociation of local circuit deficits vs. impairments in feedback modulation by cognitive processes such as spatial attention and working memory, and the relative contributions of glutamatergic and GABAergic deficits. Schizophrenia is one of the most perplexing and important mysteries in modern medicine. This condition is associated with significant impairments across diverse functional domains, usually conferring to the affected individual a lifetime of disability and the need for long-term treatment. The prevalence of schizophrenia is nearly 1% of the general population, and it constitutes one of the largest public health burdens of any condition .Research in schizophrenia has examined a wide variety of processes that have implicated abnormalities at various levels of the visual system, from the retina  due to spatial and/or temporal proximity of a behaviorally irrelevant stimulus (mask) Figure . As exteWhile abnormalities in a variety of types of masking have been documented in schizophrenia, the best studied is backward masking. In backward masking, a mask is presented a fraction of a second after target onset. It is thought that two processes, interruption and integration, can contribute to visual masking and that these processes involve distinct neural mechanisms. Masking by interruption occurs after the target representation has already been formed and is based on interference with higher-level, feedback processes that underlie conscious perception of the target  Figure , represeOSSS has been measured perceptually with contrast discrimination thresholds for center stimuli in different surround orientations. Relative to a no-surround condition, healthy control subjects showed larger increases in contrast discrimination thresholds  than patients with schizophrenia, and this group difference was selective for the parallel orientation condition , a cortical area with neurons containing oculomotor signals. A model derived from detailed anatomical and physiological studies of early visual cortical area V1 was used to generate neuronal and connectivity parameters that were then applied to FEF, quantitatively accounting for responses of FEF neurons and FEF-dependent oculomotor behaviors in macaque  and parvocellular (P)  provides a highly controlled measure of feedback modulation of visual cortical activity by spatial attention in schizophrenia. The use of fMRI or other neurophysiological techniques uniquely allow measurement of responses to a stimulus when it is being ignored. Analogous measures of the impact of unattended stimuli are very difficult to obtain with behavioral methods, because requiring a subject to make a behavioral response to a stimulus necessarily requires the allocation of some attentional resources  to that stimulus.Finally, combining spatial attention manipulations with OSSS is likely to provide insights regarding the causes of reduced OSSS in schizophrenia at the local cortical circuit level. For grating stimuli, the neural substrates of surround suppression are thought to include feedback projections from higher-order visual cortical areas to area V1 (Angelucci and Bressloff, While contributions from multiple disciplines and experimental approaches will likely be required to overcome the formidable challenges in elucidating the neural mechanisms of cognitive and information processing deficits in schizophrenia, the study of the visual system has a number of distinct advantages in this area. This review has highlighted some of the most productive lines of research within the rapidly growing body of literature on visual processing in schizophrenia, illustrating the diversity of visual processes that have been studied as well as the sophisticated methods available in the vision sciences. We also discussed several key factors that make the visual system such an appealing model system for the discovery of neural mechanisms. The convergence of the well-developed body of knowledge in structure-function relationships in the visual system, the conservation of the functional architecture across species, the preservation of basic local circuit architecture across neocortical regions, and the availability of quantitative methods to control for generalized deficits allow for inferences at a level of detail and specificity that is usually impossible in other neural systems. In the near future, the combination of vision science paradigms with modern neuroimaging methods may allow us to test some of the most compelling hypotheses on the neural origins of cognitive and information processing deficits in schizophrenia.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The synthesis, design and simulation of chemical processes, in particular thermal separation processes is today carried out by solving the resulting balance equations of a mathematical model of the considered unit operation or the whole chemical plant using sophisticated commercial process simulation software.E-models and equations of state were developed. These models allow the prediction of the phase equilibrium behavior of multicomponent systems using binary experimental data only.The reliability and correctness of the simulation results is mainly influenced by the reliability and correctness of the thermophysical property parameters used for the pure compounds and their mixtures. For the description of the required phase equilibria GHowever, since the number of experimental binary data is limited, these methods often cannot be applied. Therefore in particular for process development reliable predictive models with a large range of applicability are most important.With the help of the worldwide largest factual data bank (Dortmund Data Bank (DDB)) for pure component properties, phase equilibria and excess properties, in the last 35 years powerful group contribution methods  have been developed in my research group. By combination of cubic equations of state with the group contribution concept, now even the phase equilibrium behavior with supercritical compounds can be predicted. At the same time other important properties  can directly be predicted. With the development of an adequate electrolyte model  the equation of state approach was even extended to systems with strong electrolytes. Today ideal predictive thermodynamic tools are available, which can be used in combination with factual data banks for the development of chemical processes.In the lecture the status of the factual data bank and the different predictive models will be shown. Furthermore important applications of industrial interest of the predictive thermodynamic models and the Dortmund Data Bank will be presented.


In 2009, the Department of Health asked the MRC and MHRA to identify major obstacles to non-commercial clinical trials research in the UK and suggest remedial actions. Risk-proportionality in trial management and monitoring was identified as a key area and a sub-group formed to:• Develop a process to facilitate the agreement of key stakeholders on the level of risk associated with a clinical trial of an investigational medicinal product (CTIMP).• Identify how risk-adapted approaches for CTIMPs can be achieved within the current regulatory framework.• Develop guidance on risk assessment and the risk-proportionate management of clinical trials.The resulting guidance focuses on the risks inherent in a trial protocol which impact on participant safety and rights, and the reliability of the results. A two-part assessment is suggested: 1) a simple IMP risk categorisation based on marketing status and standard medical care, and 2) assessment of the trial design, population and procedures to identify specific areas of vulnerability.The first part, IMP risk category, has implications for simplifications of initiation and conduct of a CTIMP that may be possible within the current regulatory framework. Possible risk-adaptations include: the need for competent authority authorisation; content of the Clinical Trials Authorisation (CTA) application; IMP management; safety surveillance; trial documentation; and GCP Inspection. The risks associated with the IMP also determine trial procedures for monitoring participant safety.The second part of the risk assessment addresses other aspects of clinical trial design and methods: safety risks from clinical procedures; risks related to participant rights; and risks to the reliability of trial results. It is designed to help trialists identify potential vulnerabilities and to prepare tailored trial management and monitoring plans to minimise risks which may be reviewed and modified throughout the life of a trial.The IMP risk category and safety monitoring plan may be submitted to the MHRA with the CTA application to ensure that there is shared understanding on this key aspect of a trial. We hope that the entire risk assessment and associated plans will provide the basis for a common understanding of stakeholders of the risks for that trial, and facilitate a risk-proportionate approach to trial activities.The guidance is available on the MHRA and NETSCC websites.


The recent focus on the potential link between periodontal and cardiovascular disease (PD and CVD) is part of the larger renewed interest on the role of infection and inflammation in the etiology of atherosclerosis and its clinical manifestations. Periodontal Disease is an inflammatory process affecting the periodontium, the tissue that surrounds and supports the teeth. The process usually starts with an inflammatory process of the gum (gingivitis) but it may progress with an extensive involvement of the gum, as well as the periodontal ligament and the bone surrounding the teeth resulting in substantial bone loss. Periodontal disease is a common oral pathological condition in the adult age and represents the leading cause of tooth loss. PD prevalence increases with age and there are estimates that up to 49,000,000 Americans may suffer from some form of gum disease. The gingival plaque associated with PD is colonized by a number of gram-positive and gram-negative bacteria that have been shown to affect the initiation and development of PD and have been associated with the potential etiological role of PD in CVD and other chronic conditions. A potential etiological link between PD and CVD may have important public health implications as both the exposure (PD) and the outcomes (CVD) are highly prevalent in industrialized societies. In situations in which both the exposure and the outcome are highly prevalent even modest associations, like those observed in the studies reporting on the link between PD and CVD outcomes, may have relevance. There are not definite data on the effect of periodontal treatment on CVD clinical outcomes (either in primary or secondary prevention) however it should be pointed out that the limited (both in terms of numbers and study design) experimental evidence in humans suggests a possible beneficial effect of periodontal treatment of indices of functional and structural vascular health. The recent focus on the potential link between periodontal and cardiovascular disease (PD and CVD) is part of the larger renewed interest on the role of infection and inflammation in the etiology of atherosclerosis and its clinical manifestations. In this review, we will describe the potential mechanisms that have been identified and review the evidence from observational and intervention studies.Periodontal Disease is an inflammatory process affecting the periodontium, the tissue that surrounds and supports the teeth. The process usually starts with an inflammatory process of the gum (gingivitis) but it may progress with an extensive involvement of the gum, as well as the periodontal ligament and the bone surrounding the teeth resulting in substantial bone loss. Periodontal disease is a common oral pathological condition in the adult age and represents the leading cause of tooth loss. PD prevalence increases with age and there are estimates that up to 49,000,000 Americans may suffer from some form of gum disease.A hallmark of PD is the presence of bacteria in the gingival plaque  that characterizes the periodontal pathological process. The oral cavity is colonized by hundreds of bacteria, most of which have no clear pathological effects; however the gingival plaque associated with PD is colonized by a number of gram-positive and gram-negative bacteria that have been shown to affect the initiation and development of PD and have been associated with the potential etiological role of PD in CVD and other chronic conditions.A number of mechanisms have been hypothesized to explain the potential pathological role of periodontal disease in cardiovascular disease etiology. These include: a) potential direct mechanisms on the vessel wall and the atherosclerotic plaque and b) indirect mechanisms.This hypothesis assumes that bacteria or their products access the vessel wall (endothelium) directly, through the blood stream, and affect either the formation of the plaque and/or its evolution. In support of this hypothesis a number of studies have shown evidence of presence of viable oral bacteria or their genetic material in atheromatous plaque samples from different vascular beds.6Indirect mechanisms through which PD can affect CVD include the potential effects on a number of classical CVD risk factors like total and LDL serum cholesterol, blood pressure, glucose metabolism and platelet aggregation. A number of observational studies have shown significant associations between PD and serum total cholesterol14Substantial efforts have been dedicated to investigate the role of inflammation and its biomarkers in the link between PD and CVD.As previously indicated hallmarks of PD are the presence of bacteria and the local inflammatory process.An additional mechanism that has been hypothesized to play a role in the link between PD and CVD is molecular mimicry.The measurements of Periodontal disease/health that have been utilized to date vary substantially, and include: general measurements of oral health, crude measurements of self-reported missing teeth, standardized measurements of gingival detachment , radiographic measurements of bone loss and more recently measurements of bacterial infection. The interpretation of the literature is complicated by the lack of an agreement on a clear definition of PD in the scientific community. In general there is consistency in findings across studies using different indices of PD and the studies that have used more detailed measurements of exposures have, in general, showed stronger association between PD and CVD outcomes.Different outcomes have been investigated and include both clinical outcomes  as well as non-invasive measurements of subclinical atherosclerosis [i.e. carotid intima media thickness (IMT) and endothelial dysfunction].In addition to these disease related outcomes a number of studies  have investigated the relationship between PD and a wide array of cellular and plasma markers of inflammation .The evidence to date relating PD to clinical outcomes is based solely on observational studies. These studies include clinical comparisons of selected samples, retrospective (case-control) and longitudinal epidemiological studies.A total of approximately sixty studies have focused on cardiac outcomes  and provided quantitative assessment of risk. The majority but not all these studies show a significant association between PD and these clinical outcomes. Many of the studies presented multivariate adjusted estimates indicating that the relationship may be independent from the potential confounding effect of socio-economic factors, life style habits like smoking and other important covariates. This association has been consistently found in studies from different parts of the world and in both men and women. The evidence in women is much more limited but a study that focused on both sexes provided evidence for a potentially higher risk of MI in women compared to men.22Several reviews have indicated an overall significant association between PD and coronary outcomes, two more recent systematic reviews indicated that relative risk estimates ranged from a 24% to a 34% increased risk and that these estimates were consistent across the various methods to ascertain both PD and coronary events.24The amount of articles reporting on the link between PD and cerebrovascular outcomes are more limited but, as for coronary outcomes, the overall evidence is in support of a positive association. The evidence appears to be stronger for studies with more detailed measures of PD and to be present for both fatal and non fatal events.26A number of studies have investigated the relationship between structural [carotid intima media thickness (IMT)] and functional measurements of vascular health and PD. The most convincing evidence regarding structural changes comes from epidemiological studies showing a significant cross-sectional association between periodontitis and carotid IMT in multivariate analyses.31Functional measurements of vascular health have been the focus of several studies, in general small clinical samples, all have shown a significant positive association between PD and vascular health .34Smoking is an important risk factor for both PD and CVD. The strong association between smoking and these two conditions has raised concern over the true nature of the observed association between PD and CVD outcomes. Some, in fact had argued that because of the strong co-linearity among these three variables it is basically impossible to address the independent nature of the relationship between PD and CVD through multivariate adjustment .No studies to date have been published investigating the role of periodontal treatment on clinical outcomes.Several intervention studies have been conducted to investigate the effect of various periodontal treatments on either biomarkers of inflammation and vascular health.The studies with a randomized design and using a control group do not demonstrate consistent effects of periodontal intervention on inflammatory markers, in particular CRP.Few studies have been conducted to ascertain the effect of PD on a number of indicators of functional vascular health, these includes three small clinical studies (without placebo group) and a randomized controlled trial.44A potential etiological link between PD and CVD may have important public health implications as both the exposure (PD) and the outcomes (CVD) are highly prevalent in industrialized societies. In situations in which both the exposure and the outcome are highly prevalent even modest associations, like those observed in the studies reporting on the link between PD and CVD outcomes, may have relevance.significant, consistent across different study designs and settings, specific to the hypothesized outcome based on postulated mechanisms, longitudinal studies have confirmed the temporal relationship between exposure and outcomes, elegant mechanisms have been hypothesized and confirmed to show the plausibility of the association that is coherent with the results of the laboratory evidence. Unfortunately we are missing, what is considered by many the strongest of the criteria i.e. definite evidence that the outcome can be altered (prevented or treated) by intervening on the exposure. As previously indicated, we have no definite data on the effect of periodontal treatment on CVD clinical outcomes (either in primary or secondary prevention) however it should be pointed out that the limited (both in terms of numbers and study design) experimental evidence in humans suggests a possible beneficial effect of periodontal treatment of indices of functional and structural vascular health. These same studies however have raised concerns regarding the role of inflammation and its markers as an important link between PD and CVD; in particular, the role of CRP has been called to question by the available experimental evidence.If we consider the criteria for establishing the cause-effect relationship of an observed association, we can conclude that the observed association between PD and CVD outcomes satisfies most of these criteria. In particular, studies  to date have shown the association to be The link between PD and CVD is worth investigating because of its potential public health implications, the evidence to data has been shown to fulfill most of the criteria established for determining a cause-effect relationship. The observed association appears to be independent from the potential confounding role of important covariates ; studies need to be conducted to better understand the pathophysiological links between PD and CVD and this improved knowledge regarding the pathways should guide the design of specific intervention studies aimed at providing definite proof that we can, through periodontal treatment, affect CVD clinical outcomes.


Recent experiments reveal both passive subdiffusion of various nanoparticles and anomalous active transport of such particles by molecular motors in the molecularly crowded environment of living biological cells. Passive and active microrheology reveals that the origin of this anomalous dynamics is due to the viscoelasticity of the intracellular fluid. How do molecular motors perform in such a highly viscous, dissipative environment? Can we explain the observed co-existence of the anomalous transport of relatively large particles of 100 to 500 nm in size by kinesin motors with the normal transport of smaller particles by the same molecular motors? What is the efficiency of molecular motors in the anomalous transport regime? Here we answer these seemingly conflicting questions and consistently explain experimental findings in a generalization of the well-known continuous diffusion model for molecular motors with two conformational states in which viscoelastic effects are included. After the publication of Albert Einstein’s theory of Brownian motion in 1905 The intracellular fluid (cytosol) of biological cells is a superdense same motors in the same cell? Which role is played by the size of the cargo, and what determines the precise behavior of such active transport and its efficiency? These are the questions we answer in this article.What happens to the active motion of particles in the cytosol which are driven by molecular motors A well-established physical approach to anomalous transport phenomena is based on the intrinsic viscoelasticity We study the interplay of the viscoelastic environment of the cytosol with the action of a molecular motor and its cargo. A well-established model of Brownian motors of the kinesin family is based on the continuous diffusion of a Brownian particle in a potential landscape, which randomly fluctuates in time between two realizations, Within the power-stroke idealization, the maximal mean velocity of the motor due to the fluctuations between the potentials Both the motor and its cargo are subjected to friction and random thermal forces from the environment. For normal viscous Stokes friction, the frictional drag force is The above ratchet model is appropriate to describe the motor dynamics at dilute solvent conditions in vitro. Our focus here is different, as we want to study the motor action in living cells, where the following experimental facts have been established: Even in the absence of cargo the effective friction coefficient for the motor is enhanced by a factor of 100 to 1000 in the cytosol compared with the one in water Methods for details. On the basis of this theoretically and experimentally well-founded approach the results herein were obtained from numerical analysis.Methods) and The first major surprise is that even carrying large cargo particles like magnetic endosomes with radius about 300 nm our model motor can operate by an almost perfect power stroke mechanism in the normal transport regime, as demonstrated in Indeed, when we decrease the potential amplitude by Depending on the cargo size and the binding potential amplitude the transport can become more normal and thermodynamically highly efficient even for a large turnover frequency, as ven for  . Still, For vanishing loading force We proposed a simple basic model which reconciles experimental observations of both normal and anomalous transport by highly processive molecular motors in biological cells. Our model presents an immediate generalization of a well-known two-state model of normally diffusing molecular motors by accounting for the viscoelastic properties of the intracellular fluid. It not only explains how molecular motors may still operate by a power-stroke like mechanism while carrying a large cargo which subdiffuses when left alone, but also why and how an anomalous transport regime emerges for even larger cargo. It is crucial for this explanation that viscoelastic subdiffusion and anomalous transport possess finite moments of residence times in any finite spatial domain. Thus, there exist time scales for sliding down towards the potential minimum within one period of the flashing ratchet potential, for the escape to another potential well, and for the mean turnover time of the potential flashes. When the time scales are well separated, the transport is normal. However, when the sliding time scale starts to interfere with the turnover time, or the interwell potential barrier is lowered so that backsteps can occur, the transport becomes anomalous. These qualitative basic features are expected to survive in more complex models of molecular motors operating in viscoelastic environments.Specifically, we showed that transport by molecular motors becomes anomalous for large cargo particles with large fractional friction coefficient Our research provokes a number of follow-up questions. Thus, what happens if we relaxed the assumption of a rigid motor-cargo linker molecule? In that case, the large subdiffusing cargo is elastically coupled to a molecular motor, that possibly still operates normally in the absence of cargo. We are currently investigating this generalization for realistic spring constants of the linker. However, qualitatively the results remain very similar. Another question is prompted by the experimental results in Ref. Our model presents a good starting point for future research and further generalizations. Understanding how molecular motors perform in the viscoelastic cytosol of living cells despite the subdiffusion of the free cargo is compelling. Our findings open new vistas to the old problem of intracellular trafficking, reconciling seemingly conflicting results for the motor-cargo dynamics under different conditions. Finally, our results will be of crucial importance for the design of new technologies of motor-driven particles and drug delivery in the crowded cytosol of cells. We are confident that our findings will prompt a series of new experiments on the dynamics of molecular motors under realistic conditions in living cells.The numerical approach to integrate the generalized Langevin The rate constants The power exponent of anomalous diffusion was fixed to


RLS) method of feature subset selection was checked for high-dimensional and mixed type (genetic and phenotypic) clinical data of patients with end-stage renal disease. The RLS method allowed for substantial reduction of the dimensionality through omitting redundant features while maintaining the linear separability of data sets of patients with high and low levels of an inflammatory biomarker. The synergy between genetic and phenotypic features in differentiation between these two subgroups was demonstrated.Identification of risk factors in patients with a particular disease can be analyzed in clinical data sets by using feature selection procedures of pattern recognition and data mining methods. The applicability of the relaxed linear separability ( Statistical models for analysis of risk factors for a disease or clinical complications, a main focus of medical research, require that the number of patients is larger than the number of variables (factors) to ensure that the statistical significance of the results can be appropriately established. In practice, most studies assess only the influence of each variable separately rather than the combined importance of a set of variables; the former oversimplistic but yet prevailing approach ignores the possibility of interactions between variables or between groups of variables Medical data sets collected today often have a large number of variables for a relatively low number of patients. This may happen for genetic data sets, where the number of variables  can be thousand times greater than the number of patients. Statistical methods are not fully justified in this situation Feature selection methods are used to reduce feature space dimensionality by neglecting features  that are irrelevant or redundant for the considered problem. Feature selection is a basic step in the complex processes of pattern recognition, data mining and decision making The feature subset resulting from feature selection procedure should allow building a model on the basis of available learning data sets that can be applied for new problems. In the context of designing such prognostic models, the feature subset selection procedures are expected to produce high prediction accuracy.relaxed linear separability (RLS) method of feature selection for the analysis of data on clinical and genetic factors related to inflammation. These data were obtained from the so called malnutrition, inflammation and atherosclerosis (MIA) cohort of incident dialysis patients with end-stage renal disease CRP, above median) and non-inflamed patients (as defined by a CRP below median). Then, genetic and phenotypic  risk factors that may be associated with the plasma CRP levels were identified by exploring the linear separability of the high and low CRP patient groups. Particular attention was paid in this work to study the complementary role of genetic and phenotypic feature subsets in differentiation between inflamed and non-inflamed patients.We apply here the RLS method on the given clinical data set: 1) ReliefF, based on feature ranking procedure proposed by Kononenko Relief algorithm Correlation-based Feature Subset Selection - Sequential Forward algorithm (CFS-SF) Multiple Support Vector Machine Recursive Feature Elimination (mSVM-RFE) Minimum Redundancy Maximum Relevance (MRMR) algorithm CPL method and four other frequently used classification methods (RF (Random Forests) KNN  SVM (Support Vector Machines) NBC (Naive Bayes Classifier) Four benchmarking feature selection algorithms were selected for the comparisons with relaxed linear separability (RLS) method as applied in the present study is provided in A detailed description of the RLS method of feature subset selection is linked to the basic concept of linear separability. The linear separability means possibility of two learning sets separationby a hyperplane perceptron criterion functionconvex and piecewise-linear (CPL) criterion functions The perceptron criterion function was modified by adding a regularization component for the purpose of the feature subset selection task Lasso regressionLasso and the RLS methods is in the types of the basic criterion functions. The basic criterion function used in the Lasso method is that of the least squared method, whereas the perceptron criterion function and the modified criterion function are used in the RLS method. This difference effects the computational techniques used to minimize the criterion functions. The modified criterion function, similarly to the perceptron criterion function, is convex and piecewise-linear (CPL). The basis exchange algorithms allow the identification of the minimum of each of these CPL criterion functions The RLS) method of feature subset selection is based on minimization of the modified perceptron criterion function and allows for successive reduction of unnecessary features while preserving the linear separability of the learning sets by increasing the cost parameter in the modified criterion function. The stop criterion for discarding the unnecessary features was based on the cross-validation error (CVE) rate (defined as the average fraction of wrongly classified elements) estimated by the leave-one-out method.The , which allows to correctly distinguish with 100% accuracy two leaning sets composed of 46 cancer and 51 non-cancer patients.The evaluation of the RLS method of feature subset selection involves generation of the sequence of the reduced feature subspaces The RLS method. One of the selected algorithms, ReliefF, is based on feature ranking procedure proposed by Kononenko Relief algorithm ReliefF searches for the nearest objects from different classes and weighs features according to how well they differentiate these objects. The second one is a subset search algorithm denoted as CFS-SF  CFS-SF algorithm is based on a correlation measure which evaluates the goodness of a given feature subset by assessing the predictive ability of each feature in the subset and a low degree of correlation between features in the subset. These two feature selection algorithms are considered as “the state of the art” tools for feature selection mSVM-RFE, is a relatively new idea. It is an extension of the SVM-RFE algorithm (Support Vector Machine Recursive Feature Elimination). The SVM-RFE is an iterative procedure that works backward from an initial set of features. At each round it fits a simple linear SVM, ranks the features based on their weights in the SVM solution, and eliminates the feature with the lowest weight SVM-RFE (mSVM-RFE) extends this idea by using resampling techniques at each iteration to stabilize the feature rankings MRMR (Minimum Redundancy - Maximum Relevance) Four benchmarking feature selection algorithms were chosen for an experimental comparison with the CPL method, were applied:To compare feature selection algorithms and to evaluate the selected feature subspaces, four frequently used classification methods, beside the Weka's implementation Weka's implementation of ReliefF and CFS-SF was used also for the feature selection and cross validation evaluation of designed classifiers. The R implementation of mSVM-RFE was used (SVM-RFE package) MRMR was obtained with the help of the code provided by its author CPL classifiers based on the search for optimal separating hyperplane CPL criterion functions RLS method of feature selection The four first classifiers (1) were designed by using ane  see  through MIA cohort CRP levels  and the set CRP levels . Each patient SNPs) or deletions/insertions). The index) of a patient Two learning sets ce.impute procedure of dprep package of the R programming language was used for the substitution of missing values.These cohort and feature sets were selected from a larger data set and included only those patients for whom at least CRP levels in the feature subspaces CRP levels.During exploration of this database, the computations were performed in feature subspaces Three basic feature spaces RLS procedure of feature selection was carried out in each of the basic feature spaces (2) separately.The The apparent error rate AE) and the cross-validation error (CVE) in feature subspaces phenotypic space CVE) equal to factors) of the components of the optimal weight vector The apparent error rate  which is in turn linked to inflammation nutrition . It is well established that an abnormal nutritional status with protein-energy wasting in this patient population is strongly linked to inflammation hormonal status or metabolism ; in general, relations between these features and inflammation have been described previously, but the relation with plasma calcium is not expected. Finally, high age and smoking are factors which are associated with inflammation.Whereas the list of phenotypic features in general appears to be biologically plausible, the ranking of the strength of the association as expressed by the value of the factor coefficient genetic space AE is equal to zero. Moreover, the linear separability was preserved during feature reduction from Feature selection from the eparable .phenotypic and genetic space phenotypic  features and genotypes. The minimal value of the average cross-validation error rate was low: The process of feature selection from the combined phenotypic space genetic space phenotypic and genetic factors (features) resulted in a marked reduction of the CVE error rate to phenotypic and genetic factors are not independent and play complementary roles in describing the inflammatory status of the patients in the MIA cohort.The minimal cross validation error rate in the ce  was  , and the it was  . Combiniconfusion matricesleave-one-out procedure for the phenotypic and genetic features are presented in RLS method of feature selection.The The optimal parameters scatter diagram (diagnostic map) showed in phenotypic fraction) was obtained by transformation (3) applied for phenotypic features that constitute the optimal feature subspaces phenotypic and genetic space genetic fraction) of the diagram was obtained by transformation (3) applied for genetic features The above transformation described by diagnostic map showed in diagnostic map as the point CRP patients, then we infer that the new patient is inflamed. If most of the CRP patients, then we infer that the new patient is not inflamed. Similar schemes of decision support are called the K-nearest neighbours (KNN) in the pattern recognition or as the Case Based Reasoning (CBR) scheme The similarity measureprecedents  from the learning sets . Such scheme of the decision support based on the diagnostic maps has been used successfully in the medical diagnosis support system HeparThe transformation of the multidimensional feature vectors RLS selection method and CPL classifier applied in our study was compared to other selection methods and classifiers (see Section “Alternative methods for feature selection and classification”) using the error rate (fraction of misclassified objects from the test set), CVE, evaluated in the cross-validation (leave-one-out) procedure CFS-FS and mSVM-RFE alongside with RLS select an optimal subset of features and their prediction power can be assessed using different classifiers. In contrast, ReliefF and MRMR methods are ranking procedures and od not provide any intrinsic criteria for selection of any optimal subset of features. Such criterion need to be chosen separately. For the purpose of comparison of all these methods, the optimal sets of features for ReliefF and MRMR were determined for each classifier separately as those with minimal CVE for the applied classifier. Thus, the optimal set (and number) of features for these two methods can vary with the choice of classifier , one can easily reduce further the number of features selected by RLS method as it can be seen in SVM and/or CPL yielded the lowest errors when combined with RLS or CFS-FS selection methods. ReliefF method worked also well with RF and KNN classifiers. The errors related to the application of mSVM-RFE were similar to those related to ReliefF and CFS-FS methods . ReliefF and MRMR  needed between a few and a few tens of minutes (depending on the applied classifier). The computation time of the RLS method was of the order of tens of minutes. The mSVM-RFE method had the computation time of about 20 hours. It should be stressed that the relatively long computation time of the RLS, mSVM-RFE, ReliefF and MRMR methods was caused mainly by repeated computation in the framework of the cross-validation procedure used by these methods.Among the four applied feature selection methods, RLS) method is that it may identify directly and efficiently a subset of related features that influences the outcome and that it assesses the combined effect of these features as prognostic factors. This characteristic of the approach presented here is clearly visible in the dataset of phenotypic features with minimal cross validation error rate, CRP in plasma, the clinical biomarker used here for discrimination of inflamed and non-inflamed patients.Feature selection is an integral - but often implicit - component in statistical analyses. An explicit systematic feature selection process is of value for identifying features that are important for prediction, and for analysis on how these features are related, and furthermore it provides a framework for selecting a subset of relevant features for use in model construction. The most common approach for feature selection in clinical and epidemiological research is based so far on evaluation of the impact of single features RLS method of feature selection is based on the minimization of the criterion function CPL criterion function The AE) estimator  risk factors that are associated with inflammation was implemented using a clinical database of patients with chronic kidney disease. A few important properties of the computation results obtained from this cohort can be pointed out. The results show, among others, the scale of the bias of the apparent error  the number of cases and features, and 2) the repetition of calculations for the cross-validation method. The actual computing time for personal computer implementations was in the order of tens of minutes, and was longer than for some alternative methods (see Results), but all the computational times were reasonably short for the current research purpose. However, the computation time may be a limitation of the phenotypic, genetic, combined) showed that the combined phenotypic and genetic subspace can provide a very low CVE error rate of The comparison between the optimal feature subspaces rate of  . Such a rate of  . NeverthAppendix S1RLS method of feature selection.Mathematical foundations of the (PDF)Click here for additional data file.


All of the isolates segregated into seven highly significant clades that correspond to the known geographical clades: in particular the two new isolates from northern Albania clustered significantly within the Europe 1 clade. Our phylogeographical reconstruction suggests that the global CCHFV clades originated about one thousand years ago from a common ancestor probably located in Africa. The virus then spread to Asia in the XV century and entered Europe on at least two occasions: the first in the early 1800s, when a still circulating but less or non-pathogenic virus emerged in Greece and Turkey, and the second in the early 1900s, when a pathogenic CCHFV strain began to spread in eastern Europe. The most probable location for the origin of this European clade 1 was Russia, but Turkey played a central role in spreading the virus throughout Europe. Given the close proximity of the infected areas, our data suggest that the movement of wild and domestic ungulates from endemic areas was probably the main cause of the dissemination of the virus in eastern Europe. Crimean-Congo hemorrhagic fever (CCHF) is a zoonosis mainly transmitted by ticks that causes severe hemorrhagic fever and has a mortality rate of 5-60%. The first outbreak of CCHF occurred in the Crimean peninsula in 1944-45 and it has recently emerged in the Balkans and eastern Mediterranean. In order to reconstruct the origin and pathway of the worldwide dispersion of the virus at global and regional (eastern European) level, we investigated the phylogeography of the infection by analysing 121 publicly available CCHFV S gene sequences including two recently characterised Albanian isolates. The spatial and temporal phylogeny was reconstructed using a Bayesian Markov chain Monte Carlo approach, which estimated a mean evolutionary rate of 2.96 x 10 Bunyaviridae, genus Nairovirus. It is an enveloped virus with a negative-sense single stranded RNA genome consisting of one small (S), one medium (M) and one large segment (L) that respectively encode the viral nucleocapsid (N), the membrane glycoprotein precursor (GPC), and RNA-dependent RNA polymerase (L) proteins , but the extensive geographical intermixing of the three African clades and the relatively small number of African isolates available prevented us from reaching any more precise conclusions. In our reconstruction, CCHFV left Africa in the second half of the XVII century, reached the Middle East, and then dispersed in two directions in the early XIX century to form the two Asian clades: one spreading in Iran and Pakistan, and the second in China and central Asia . The virus therefore originally spread in an eastward direction to the Middle East and south-east Asia, crossing an area with a constant presence of CCHF susceptible species and the Himalayan mountains as a barrier to natural dispersion. It has recently been speculated that pathogens spread along the Eurasian ruminant route, as in the cases of foot-and-mouth disease ,40 and RTwo highly divergent CCHFV strains entered Europe on at least two occasions: the first in the early 1800s , and the second in the first decades of the XX century, when a more pathogenic strain caused human outbreaks in eastern Europe until recently. In our phylogeographical reconstruction, the most probable location of the MRCA of this European clade 1 was Russia, which suggests that this was the gateway through which genotype 4 CCHFV entered Europe in the early 1900s. This partially conflicts with previous findings  suggestiA recent study  has suggIn our reconstruction, the virus spread from Turkey to the Balkans, reaching Kosovo in the 1990s and Albania in the last decade. It is possible to hypothesise that the main cause of its dispersion through eastern Europe was the movement of wild and domestic ungulates carrying infected ticks, although outbreaks of CCHFV infection in South Africa have been associated with the passive transportation of infected ticks by birds , and thepeste-des-petits ruminants [Turkey has one of the largest ruminant populations in Europe and the Middle East, and witnesses the movement of large and small ruminants for breeding, transhumance (within and across its borders), slaughter and import/export. The main direction of the flow is from neighboring countries such as Russia and Iran  and the uminants . Moreoveuminants , and couThe currently used methods of phylogeographical reconstruction are inherently limited by the availability of sample locations and the numbers of isolates at each location. The sensitivity test performed in this study (which suggested that sampling frequencies had little impact on the root location) cannot exclude the influence of unsampled locations. Nevertheless, the analysed data set included all of the sequences with a known sampling location and year that were available in public databases at the time the study began. In particular, the scarcity of sequences from Bulgaria prevented us from fully clarifying the country’s role in disseminating the infection. Bulgarian Thrace and Thrace as a whole  is a high-risk zone for the cross-border spread of animal infectious diseases, as has recently been reported in the case of outbreaks of foot-and-mouth disease in Bulgaria and Greece close to the Turkish border . MoreoveThe findings of this study indicate that continuous surveillance of the CCHF epidemic in Turkey and the entire Thracian area may be very important for monitoring and predicting future CCHF outbreaks in the Balkans.Figure S1Evaluation of the impact of sampling heterogeneity on the phylogeographic reconstruction. The figure shows the root state probability as a function of the location sample size. Randomisation analysis of the tip-localities throughout the MCMC analysis revealed a low level of correlation between the number of taxa per locality and the root-location probability.(PPTX)Click here for additional data file.Figure S2Likelihood map of the 121 CCHFV S gene sequences. Each dot represents the likelihoods of the three possible unrooted trees per quartet randomly selected from the data set: the dots near the corners and sides respectively represent tree-like (fully resolved phylogenies in which one tree is clearly better than the others) and network-like phylogenetic signals (three regions in which it is not possible to decide between two topologies). The central area of the map represents a star-like signal . The numbers indicate the percentage of dots in the centre of the triangle.(JPG)Click here for additional data file.Figure S3Maximum likelihood tree of the 121 CCHFV S gene sequences. The numbers on the branches represent bootstrap values . The previously described viral genotypes [enotypes  have bee(JPG)Click here for additional data file.Table S1Accession numbers and characteristics of the CCHFV sequences used in the study.(DOCX)Click here for additional data file.


The paradigm of the ‘pyramid of need’ and the relatively high per unit cost of telehealth has led to its use being targeted at supporting those ‘high-risk’ patients who it is widely believed account for a significant proportion of unplanned admissions. However, close examination of the frequency distribution of such admissions shows that the number of patients repeatedly admitted is low. This may explain why the dramatic reductions in rates of unplanned admissions reported by many telehealth projects have had little impact on the total number of unplanned admissions and thus healthcare costs.Interactive Voice Response (IVR) reduces the costs of telehealth dramatically, is effective in capturing indicators of decreased well-being and, as the dialogue is symptom based, helps patients self-manage their condition. Low cost and the ubiquity of the telephone (mobile or landline) suggest that this technology is an economically and culturally acceptable means of screening large populations of patients.


Electrophorus electricus. Although the original species description indicated that this fin was a composite of the caudal fin plus the elongate anal fin characteristic of other genera of the Gymnotiformes, subsequent researchers proposed that the posterior region of the fin was formed by the extension of the anal fin posteriorly to the tip of the tail, thereby forming a “false caudal fin.” Examination of ontogenetic series of the genus reveal that Electrophorus possesses a true caudal fin formed of a terminal centrum, hypural plate and a low number of caudal-fin rays. The confluence of the two fins is proposed as an additional autapomorphy for the genus. Under all alternative proposed hypotheses of relationships within the order Gymnotiformes, the presence of a caudal fin in Electrophorus optimized as being independent of the occurence of the morphologically equivalent structure in the Apteronotidae. Possible functional advantages to the presence of a caudal fin in the genus are discussed.Alternative hypotheses had been advanced as to the components forming the elongate fin coursing along the ventral margin of much of the body and tail from behind the abdominal region to the posterior margin of the tail in the Electric Eel,  Hypopygus minissimusElectrophorus electricusThe order Gymnotiformes includes 33 genera and more than 200 extant species of Neotropical electric fishes plus one fossil form from the Late Miocene of Bolivia Electrophorus is unique within the Gymnotiformes in having a third form of discharge of up to 600 volts used for hunting and self-defense Arguably one of the most noteworthy characteristics of all gymnotiforms is their ability to produce electric organ discharges (EODs) which serve dual purposes - communication and exploration of the surrounding environment. Two alternative forms of such discharges occur among these electric fishes: pulse EODs (via myogenic organs) and wave EODs (via myogenic or neurogenic organs). Electrophorus was erected by Gill Gymnotus electricus Linnaeus Electrophorus has a broad distribution in low- and mid-elevation settings across the vast expanse encompassed by the Amazon and Orinoco basins and additionally through the river systems of northern Brazil and the Guianas between the mouths of those two major drainages ElectrophorusElectrophorus also has a highly vascularized oral respiratory organ with multiple folds that greatly increase its surface area Various autapomorphies unique within the Ostariophysi distinguish Electrophorus. Linnaeus Gymnotus electricus (the Electrophorus electricus of this paper) was posteriorly continuous with the rays of the caudal-fin, i.e., the caudal fin is present. Subsequent authors ascribed to the alternative concept of the absence of a caudal fin in the genus. Intriguingly, the details of the unusual tail along the ventral and posterior margins of the body in Electrophorus have not been the subject of analysis to evaluate the two alternative hypotheses – that the fin at the posterior of the tail is a true caudal fin versus that the terminal portion of the elongate fin in the genus is a posterior extension of the anal fin to form a false caudal fin. We herein address that question and evaluate the results within the context of the divergent hypotheses of intraordinal phylogenetic relationships in the Gymnotiformes.Alternative hypotheses have been advanced concerning the components of the elongate fin coursing along the ventral surface of the body and tail of Specimens were examined at, or borrowed from, the following institutions: AMNH, American Museum of Natural History, New York; AUM, Auburn University Museum, Auburn; ANSP, Academy of Natural Sciences of Drexel University, Philadelphia; FMNH, Field Museum of Natural History, Chicago; INHS, Illinois Natural History Survey, Champaign; KU, University of Kansas, Lawrence; MBUCV, Museo de Biologia de la Universidad Central de Venezuela, Caracas; MCZ, Museum of Comparative Zoology, Harvard University, Cambridge; MNRJ, Museu Nacional, Rio de Janeiro; MPEG, Museu Paraense Emílio Goeldi, Belém; MZUSP, Museu de Zoologia da Universidade de São Paulo, São Paulo; UF, Florida Museum of Natural History, Gainesville; NRM, Swedish Museum of Natural History, Stockholm; and USNM, National Museum of Natural History, Smithsonian Institution, Washington. The abbreviation TL in the text  = total length. Caudal fin skeletal morphology was assessed via radiographs and specimens cleared and counterstained for bone and cartilage following the procedure of Taylor & Van Dyke Gymnotus electricus had “Pinna caudali obtufiffima anali annexa” . Information in that account indicated that his statement was most likely derived from a detailed description and illustration of a specimen of the species by Gronovius G. electricus. This concept of conjoined anal and caudal fins in what was later termed Electrophorus electricus (hereafter Electrophorus) then vanished without comment from the scientific literature for more than 200 years. The alternative accepted scenario was that the anal fin extended posteriorly to the end of tail in Electrophorus and formed what has been termed a false caudal fin Electrophorus was a false, rather than true, caudal fin may have been, in part, based on the absence of the caudal fin in Gymnotus, a genus showing a number of derived characters with Electrophorus, with those two genera now forming the Gymnotidae. Comments as to a possible contrary arrangement were limited to remarks by Meunier & Kirschbaum Well over two centuries ago, Linnaeus Electrophorus as an alternative to the prevailing concept of an elongate anal fin extending posteriorly to the terminus of the tail. Soon thereafter Meunier & Kirschbaum Electrophorus.Meunier & Kirschbaum Electrophorus proved informative as to this question. Presence of a ventral embryological fin fold in individuals of Electrophorus shorter than approximately 85 mm TL gives a false first impression of a continuous anal-caudal fin during the early stages of the development in the genus. In actuality the anal-fin rays terminate well anterior to the posterior limit of the fin fold in specimens of less than this length. Larvae of Electrophorus of approximately 19 mm TL have anal-fin rays as evidenced by Alcian blue staining plus non-staining rays apparent in transmitted light limited to the anterior one-half of the fin fold that extends the length of the tail. Specimens at that size possess a cartilage body at the posterior end of the tail as evidenced in transmitted light without, however, any obvious associated caudal-fin rays. Conversely, fin rays are apparent at the posterior end of the tail in a circa 26 mm TL whole specimen, but with the retention of a distinct gap along the ventral margin of the tail between the posterior most apparent anal-fin ray and the ventral most caudal-fin ray. This condition is comparable to that found in adults of all species of the Apteronotidae , than all members of the Apteronotidae and the hypural complex of Electrophorus remains incompletely ossified to at least circa 300 mm TL.Overall morphology of the complex formed by the terminal centrum and the posterior plate of onotidae ; the oneonotidae . One notElectrophorus and the Apteronotidae due to the reduced nature of the elements in these taxa versus the condition in other lineages in the Otophysi; for example basal members of the Siluriformes, the sister group to the Gymnotiformes. A parhypural plus six separate hypurals Olivaichthys viedmensis  was composed of the compound centrum  followed posteriorly by a hypural plate (the “hp” of that study); a form of the caudal-fin skeleton comparable with that present in adults of Electrophorus other than for two features. The hypural plate in Orthosternarchus is cartilaginous and disjunct from the terminal centrum whereas in adult specimens of Electrophorus the hypural plate and terminal centum are both ossified and broadly conjoined  a joining of the two fins at least, in part, as a result of the increase in the number of ventral procurrent rays with a consequent anterior extension of the caudal fin towards the anal fin; versus 2) the posterior extension of the anal fin to contact an unelaborated caudal fin . The anteroventral most ray of the caudal fin serves as an appropriate landmark for the anterior limit of that fin versus the conjoined anal fin. This ray is readily distinguished from the terminal anal-fin ray via the lack of the associated proximal pterygiophore characteristic of anal-fin rays. Additionally, the anteroventral ray of the caudal fin is most often associated with the hypural plate , whePhreatobius which has 11 to 26 ventral procurrent rays Gymnallabes in which there are at least five ventral procurrent rays extending forward to meet an posteriorly extended anal fin . This condition is characterized by the immediate proximity of the posterior most anal-fin ray as evidenced by an associated proximal pterygiophore with the ventral most caudal-fin ray; the condition found in  complex . Elsewhe complex . The PloElectrophorus, information on the number of caudal-fin rays for that genus was not included in prior phylogenetic analyses. Within the Apteronotidae, the only other group in the order with a caudal fin, the number of rays ranges from five to 30 with the basal clades, such as that formed by Orthosternarchus plus Sternarchorhamphus, possessing five to nine rays and the other genera in the family 10 to 30 rays  and hypural plate (hp) is restricted in the Gymnotiformes to members of the Apteronotidae, the most speciose family in the order Electrophorus separated from the Apteronotidae within the Gymnotiformes by three nodes. Given the phylogenetic distance between the Apteronotidae and Electrophorus, the most parsimonious explanation for the distribution of a caudal fin in the two lineages involves retention of the caudal fin in the basal Apteronotidae, the loss of the fin in the ancestor of the remainder of the order, and a reacquisition of the fin in Electrophorus. This involves fewer evolutionary steps than the perhaps intuitively more appealing hypothesis of multiple loses of the fin in the Sternopygidae, the ancestor of the Hypopomidae plus Rhamphichthyidae, plus Gymnotus in the Gymnotidae  is the sister group to all other families in the Gymnotiformes was advanced based on morphological mnotidae . The molElectrophorus plus Gymnotus) as the sister clade to the remainder of the order Electrophorus. Within this phylogenetic scheme, the presence of a caudal fin in those taxa again optimizes as separate events, with two alternative equally parsimonious explanations. Under one, the presence of the caudal fin in the Apteronotidae and Electrophorus represents separate acquisitions post the presumed loss of the complex in the ancestor of the Gymnotiformes. The second scheme involves the loss of the fin in Gymnotus (the sister group to Electrophorus) in the Gymnotidae and in the ancestor of the Rhamphichthyidae, Hypopomidae, Sternopygidae and Apteronotidae and the reacquistion of the fin in the Apteronotidae  being the sister of the remainder of the Gymnotiformes  or acquisition of the fin in a clade sister to the remainder of the order and a secondary presence of the caudal complex in another lineage. The alternatives mirror each other with the presence of a true caudal fin in families  and the tiformes .Absence of the caudal fin is common to many components of the Gymnotiformes, but overall is limited to relatively few groups within the Teleostei; a not unexpected situation in so far as the caudal fin provides the majority, or a significant portion, of the propulsive force to the fish along with contributing to steering functions. A universal lack of the pelvic fin across Neotropical electric fishes in addition to the general absence of the caudal fin is also noteworthy. Although the pelvic fins are not a major factor in propulsion across fishes, they contribute to fine movement control. Offsetting the loss of these two fins across the Gymnotiformes is a dramatic lengthening of the anal fin and increased fine motor control of propulsive movements within the fin. Depending on the taxon, the gymnotiform anal fin commences anteriorly within the region between the vertical through the orbit to the posterior limit of the abdominal cavity and continues caudally to varying positions along, or at the end of, the tail . Gymnarchus also swims with a largely rigid body and propels itself via sinusoidal movements along an elongate median fin; the propulsive fin in that genus being, however, the dorsal rather than anal fin yielding an amiiform swimming mode Sinusoidal movements along this elongate anal fin among species of the Gymnotiformes provide the primary propulsive mechanism for the distinctive anterior and posterior movements of these fishes and in conjunction with the pectoral fin, critical fine scale control of such movements Electrophorus versus absent in its sister group, Gymnotus. A potential functional difference underlying this variation may be the rigid body posture in life of species of Gymnotus with sinusoidal movements along the anal fin generating the primary propulsive force Electrophorus demonstrates two alternative swimming modes. The first of these is the straight alignment of the body during obligate gulping of air and in the detection, location and shocking of prey items. This is the body orientation general across the Gymnotiformes, e.g., Electrophorus is additionally able to use sinusoidal or anguilliform movements along the length of the entire body to supplement the waves of movements along the anal fin during capture of prey and rapid forward motion. During this swimming mode, the posterior portion of the body undergoes pronounced side-to-side movements; a situation in which a caudal fin would increase the anterior propulsive force and thereby be functionally advantageous as is the case with other groups of fishes using anguilliform swimming modes. Taxa of the Apteronotidae which also have caudal fins lack, however, anal-caudal fin conjunction and is there no indication of alternative swimming modes in the family.The Gymnotidae is unique within the Gymnotiformes in demonstrating intrafamilial variation in the presence versus absence of the caudal fin, with the fin present in List S1List of specimens of Electrophorus and outgroups examined in this study.(DOC)Click here for additional data file.


Spinal cord injury disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. The most important reason for such permanent functional deficits is the failure of injured axons to regenerate after injury. In principle, the functional recovery could be achieved by two forms of axonal regrowth: the regeneration of lesioned axons which will reconnect with their original targets and the sprouting of spared axons that form new circuits and compensate for the lost function. Our recent studies reveal the activity of the mammalian target of rapamycin (mTOR) pathway, a major regulator of new protein synthesis, as a critical determinant of axon regrowth in the adult retinal ganglion neurons Injury to the mammalian adult central nervous system (CNS) often results in functional deficits, largely owing to the limited regenerative and repairing capabilities. In the case of spinal cord injury, the disruption of axonal tracts that convey ascending sensory and descending motor information could lead to pronounced and persistent sensorimotor dysfunctions in the body parts below the lesion sites. Although partial spontaneous functional recovery occurs in the patients and animal models at the neonatal stages, this declines in the adult. Presumably, rebuilding the functional circuits may result from two types of axon regrowth: ① true regenerative growth of injured axons and ② compensatory sprouting from spared fibers. While regenerative growth occurs rarely in the adult CNS, compensatory sprouting of the same or different types of axons may form new circuits across the lesion sites and compensate for the function lost as the result of injury. Thus, ideal repair strategies could be to promote these two different forms of axon regrowth for optimal functional recovery.In contrast to robust axon growth during development, both regenerative growth and compensatory sprouting in the adult CNS are very limited and abortive. Many studies in the past decades have been largely focused on characterizing environmental inhibitory molecules in the adult CNSA potentially useful approach to understand the intrinsic mechanisms of axon regeneration is to study how robust axon growth in immature neurons during development is achieved. Many of these studies involve neurotrophin-dependent axon growth of peripheral neurons. For example, by using specific chemical inhibitors, Liu and Sniderin vivo is unclear.Despite the progress made in axon growth during development, little is known about what accounts for the transition from the rapid growth mode of immature neurons into the poor growth mode of mature neurons in the CNS. Several potential players have been implicated, such as development-dependent decline of neuronal cAMP levelsFig. 1, ref. 19-21). It catalyzes the conversion from phosphatidylinositol  trisphosphate (PIP3) to phosphatidylinositol  bisphosphate (PIP2) and antagonizes the effects of PI3K. Thus, inactivation of PTEN results in the accumulation of PIP3 and subsequently the activation of the Akt. A well characterized downstream event of PTEN deletion and Akt activation is the activation of mTOR, which is a central regulator of cap-dependent protein translation initiation and cell growthDevelopment-dependent decline of axon growth ability is reminiscent of cell size control in almost any cell type: active growth during development followed by ceased growth upon the completion of development result in a normally fixed size for individual cell types. Extensive studies in the fields of developmental biology and cancer biology have identified a number of genes critical for regulating cellular growth and many of these are tumor suppressor genes. Because many of these growth-control molecules are expressed in the adult neurons, we hypothesized that the mechanisms preventing individual cell types from over-growth might also play a role in suppressing the axon growth ability of adult neurons. To test this, we utilized an optic nerve crush model to examine the regeneration of axons from RGCs in different mutant mice with the deletion of individual growth control genes in the RGCs. By analyzing more than 10 different conditional deletion mouse lines, we found that deletion of PTEN promotes both the survival of axotomized RGCs and the robust regeneration of injured optic nerve fibers


The firing rate model in the form of nonlinear integrodifferential equations can characterize spatiotemporal patterns of a continuum neural field. These patterns are associated with a wide range of neurobiological phenomena, such as persistent activity and propagating waves in neural networks.To understand the substrates of neural circuitry that supports the localized stationary patterns, we study the existence of multi-bump pulse solutions of an integral equation that is the equilibrium equation of the firing rate model. If the integral coupling function, which describes the spatial connection among the network of neurons, is even and its positive half solves a second order linear ordinary differential equation (ODE), then the multi-bump pulse solutions of the integral equation are homoclinic solutions of a reversible fourth order ODE. It was known previously that the corresponding ODEs are conservative for a class of oscillatory and decaying coupling functions . We show


The realization of injury to large motor neurons is embedded within contextual reference to the parallel pathways of apoptosis and necrosis of system-patterned evolution. A widespread loss of cell components occurs intracellularly and involves a reactive participation to a neuroinflammation that potentially is immunologically definable. In such terms, sporadic and hereditary forms of amyotrophic sclerosis are paralleled by the components of a reactive nature that involve the aggregation of proteins and conformational misfolding on the one hand and a powerful oxidative degradation that overwhelms the proteasome clearance mechanisms. In such terms, global participation is only one aspect of a disorder realization that induces the development of the defining systems of modulation and of injury that involves the systems of consequence as demonstrated by the overwhelming immaturity of the molecular variants of mutated superoxide dismutase. It is further to such processes of neuroinflammatory consequence that the immune system is integral to the reactive involvement of neurons as patterns of disease recognition and as the system biology of prevalent voluntarily motor character. It is highly significant to recognize various inflammatory states in the nervous system as prototype variability in phenotype expression and as incremental progression in pathogenesis. In fact a determining definition of amyotrophic lateral sclerosis is an incremental phenotype modulation within the pathways of the consequential loss and depletion of motor cell components in the first instance. Neuroinflammation proves a pattern of the contextual spread of such pathogenic progression in the realization of end-stage injury states involving neurons and neuronal networks. Amyotrophic lateral sclerosis (ALS) is manifested by an array of the large neuronal cell loss of motor type as further constituted by a toxic gain of the function of superoxide dismutase in a small percentage of the patients. The evolutionary course of the disease is further constituted by a series of progressive changes that affect clinically both sporadic and hereditary forms of motor neuronal loss . In suchDisease pattern is recognizable in terms of ongoing changes in neuronal cells that comprises a noncell autonomous involvement implicating glial cells ranging from astrocytic glutamate production and microglial reactivity. Nuclear factor-kappaB downregulation in neuronal nuclei in ALS might promote the loss of neuroprotection or else be associated with nuclear loss .The developmental consequences of injury in this disorder are further evidenced by the appearance of defects in axonal transport and in the phosphorylation of light and heavy forms of neurofilament, by the appearance of aggregation or inclusion bodies and also by such structures as hyaline bodies consisting of mutant superoxide dismutase, skein inclusions, Bunina bodies, and at times discrepancy in the evolutionary course when correlated with specific missense mutations of superoxide dismutase gene.The overall dynamics of this heterogeneous group of disorders complicate a derivational body of consequences that results, in the overwhelming majority of cases, in respiratory failure after some 2-3 years of disease course. The skeletal muscle atrophy is a realization of the central nervous system involvement that evolves as an apparent consequence to lesions in motor supplying neuronal axons and to abnormalities in eventual neuromuscular junctions supplying these muscles. Disease-driven changes in ATP-binding cassette drug efflux transporters in the CNS interfere with effective ALS pharmacotherapies [A network basis for the disease is recognizable in terms of evolutionary dynamics in the face of injury to a systemic series of structural components throughout the entire complex of motor neuronal supply to skeletal muscle. In such manner, patterns of involvement are realized dimensions of network participation in the delineation of progressive kinetics in skeletal muscle atrophy.The disease recognition patterns of involvement are reflected in the systemic response of neurons to endoplasmic reticulum stress and cytosol saturation by mutant superoxide dismutase in some 20% of the hereditary cases of amyotrophic lateral sclerosis. In such manner, oxidative stress is a recognized component pathway with indices referable to such stress response to a primary injury to neurons. It is in such capacity of attempted containment of the cellular stress that the progression of this disorder proves the true dimensional dynamics of pathogenesis in neuronal cell loss. Oligoclonal bands in the CSF of patients with ALS may be associated with gene mutations . FurtherMicroglia become transformed and neurotoxic in end-stage disease ALS .Aggregation of immature forms of superoxide dismutase and the mechanics of cytosol-nuclear abnormalities of the exchange and transport of antioxidants also are referable to the dimensions of a recognition pattern signature of disease involvement that attests to the overall dynamics of neuronal cell death pathways .Lipid and DNA oxidation correlate with the systems of the aggregation of inclusion bodies as further attested by the oxidation of the superoxide dismutase itself. It is further to ongoing developmental outlines of disease reappraisal that amyotrophic lateral sclerosis is indeed a response pattern of consequence within the contextual reproducible pathways of ongoing aberrant intracellular transport mechanics. Neuroinflammation proves a response to neuronal dysfunction and death and response manipulation might alter disease progression . An esseThe concept of the renewal of the immune response arises in terms of a recurring system of parallel pathways that may especially target the central nervous system. It is with regard to an extensive repertoire of conditioning and reconditioning manoeuvres that the overall dimensionality of targeting provokes a reappraisal of current processes that prove dominant in further injuring the brain in patients with acquired immunodeficiency syndrome . A critiIt is further to be realized that the systems of the involvement of inflammatory reactivity are borne out by a system organ that is participant in provoking systemic by-products as defined by multiple organs such as the reactive spleen and lymph nodes.Such panorama of participating components in AIDS encephalitis is a truly derived phenomenon and also a real originator of further aberrant responsiveness as evidenced by a wide diversity of possible opportunistic infections seen clinically in patients with AIDS.It is within the developmentally aberrant severity of the inflammatory response within the central nervous system that the realization of tissue injury proves a progressive phenomenon of self-sustaining participation in injuring further the native neural tissues . The sigB cells and antibodies are implicated in at least a subset of patients with multiple sclerosis and are related to the production of oligoclonal bands. The CNS also locally produces antibodies .The extreme variability of pathologic events both in patients with AIDS encephalitis and also in patients with different biologic substrate in evolving multiple sclerosis proves a serial representation of multimodal realizations that provoke an immune participation that results in a further augment in the inflammatory response. Lipid metabolism and vascular pathology are both implicated in multiple sclerosis .In such manner, the provocation of a targeting inflammatory process is determined and also determines in its turn an alternating but self-sustaining realization of tissue injury that spans the dimensional conditions in AIDS encephalitis or multiple sclerosis. It is further to a serial reconstruction of various forms of injury to neural tissues that the by-product of significant injury is the main criteria in the evidential proposition of inflammatory and immune system induction to further tissue injury . OxidatiThe distinctive cell subpopulations of the involvement of the central nervous system are real component of a confined series of pathways of an organ such as the brain that proves not immune privileged . Thus, pThe constitutive evidence for a further increment in disease activity is borne out by developmental innate immune response and as further signified by the injury to multiple tissue components .The multifocality of injury to the CNS is an integration of evidential pathways of the reconstruction of the injurious events themselves in various modes of the further promotion of such pathways as directed microglial response and as participating vascularity and as also gliosis and subsequent aberrant immune- and inflammatory-mediated responses . HIV treFurther to the significant emergence of tissue injury, the parameters of dimensional involvement in CNS inflammation are dramatically reconstituted in terms of the realization of new, targeted responses to other foci of directed involvement. It is significant to consider the overall dimensions of realization in terms of the participation of the overall self-augmenting or positive feedback loops in CNS inflammatory states .Dual participation of the immune and the inflammatory pathways proves integrative, especially with an increasing severity of these responses towards further foci of neural injury. The dimensions of further cooperative participation are mutually self-identifying motives in the significant emergence to necrotic foci of neural tissue. Microglia express various Pattern Recognition Receptors to identify viral signatures called Pathogen Associated Molecular Patterns to which microglia respond by producing inflammatory mediators .In terms of such ongoing pathway culmination, the persistence of an integrative response is paradoxically self-generating as realized also by the intermittent relapses in multiple sclerosis patients or in the recurrent attacks of opportunistic infection in AIDS patients.Neuroinflammation is a potentially constitutive mode of pathogenesis in various neurodegenerative disorders such as amyotrophic lateral sclerosis that evolves as an apparent primary neuronal cell loss within the additional contexts of the parallel evolution of apoptosis and necrosis of the neurons .In such manner, a beneficial incremental change attests to the possible limitation of injury that is partly contributed to by glial cells such as astrocytes and by microglial reactivity.The corresponding pathologic spread in amyotrophic lateral sclerosis of a putative agent is analogous to dynamics of involvement in prion disease in terms of aggregation that corresponds to mechanics of neuronal cell loss in these disorders. The innate immune response is a recognized component pattern of involvement in a disease process such as neurodegeneration whereby also inclusion bodies are the consequences of attested intracellular stress mechanics.Disease recognition patterns as network involvement primarily indicate system participation in pathogenic progression and also as incremental definition of inflammatory pathways. In such terms, the distribution of motor neuron loss indicates a predilection for neurons in reference to such indices as the large size of the cells and as further spread involvement within the neuronal motor systems .Toxic gain of function of mutant superoxide dismutase indicates a realization that is deferentially distributed due to modes of action independent of enzymatic function. In such manner, the promotional realization of evidential pathways includes derived neuronal lesions that arise as neuroinflammatory foci and as distributional realization for the further spread of the neuronal cell loss. Composite idealization is dimensionally ensured as a significant pattern formulation in disease signature definition. It is in view of comparable indices as parameters of evolution that disease progression permits and also enhances susceptibility to stress-induced injury to individual neurons within motor system pathways.Blood brain barrier breakdown leads to a neuroinflammation and oxidative stress .Distributional markers as models of injury indicate a proximate series of changes that account in turn for the oxidative series of modulated lesions within the patterns of the evolutionary progression of the disease. Hereditary motor neuronal lesions prove a susceptibility series of a heightened nature and are formulated by the network reactivity of neuronal subsets.System biology is a source of potential realization in amyotrophic lateral sclerosis that persistently constitutes the determined involvement of systems of the progression of a disease process that is rapid and incrementally realized as a loss of large motor neurons. It is further to such considerations that the outline parameters of overall index involvement include the definition of patterns of disease definition within the distributional reality of the motor neuronal system as a whole.The overactivity parameters of oxidative stress somehow include a toxic gain of function that involves systems of repair or compensation, on the one hand, and also serial modulation of recoverability as system dimensions of the disease entity. It is in terms of such evolutionary course that the further outline of lesion characterization permits the distribution of significant lesions beyond simple oxidative stress.The sporadic form of amyotrophic lateral sclerosis includes oxidative stress in its own right but as definable beyond mutations of the superoxide dismutase enzyme. It is with regard to further neuroinflammatory injury that the immune system appears as a common referential series of pathways in its own right that defines the nature of characterized neuronal cell loss.Neuroinflammation pathogenically links such diverse conditions such as amyotrophic lateral sclerosis, AIDS encephalitis, and multiple sclerosis with the marked activation of astrocytes and microglia and the production of proinflammatory agonists. Upregulation of endothelial adhesion molecules and downgrading of tight junction proteins facilitate in particular CNS the ingress of T lymphocytes .In such manner, parametric indices allow for the emergence of overall dimensions as important determinants in the characterization of the progressive course of a disorder that is primarily depletive but also reactive. Neuroinflammation, hence, is constitutionally a superimposed series of gains in toxicity that overcome recoverability parameters on the part of individual neurons as integrated signature networks of pattern recognition.Significant overall dimensions of inclusion allow for the distribution of lesions within the intracellular compartment in modes of aggregation and precipitation as evidenced by forms of mutated superoxide dismutase that lack in particular the Zn ion or of the disulfide bonds. It is further to a compromising realization of immature metabolic phenotype that mitochondrial damage precipitates apoptotic cell death and also other metabolic phenotypes of the realized destabilization of the proteasomal system in misfolded protein clearance. With reference to misfolded moieties of protein aggregation it is significant to recognize the reactive constitution of the motor system disorders within the context of further progression of the neuronal cell loss.Various aspects of the biology of neuronal cell loss permit the global evolution of injury that complicates patterns of potential recoverability in the face of evolutionary system participation. Allowance for participation is significant in terms of further modulation of the lesion that accommodates indices of determining pathogenic influence. Neuroinflammation is a powerfully effective series of revision pathways that incorporate the subsequent realization of the evolutionary patterns of an incremental nature. In terms of serial conformation and as evidential system patterns, the biology of amyotrophic lateral sclerosis consists of an inflammatory reactivity in the face of the serial reconstitution of inflammatory and immune pathways that incrementally challenge the neuronal viability issues. Such processes implicate the significant modification of phenotype as evidential systems of systemic requirement. It is with regard to system pathways that the conclusive phenomenon of neuronal cell death indicates the deliberate termination of system determination.In overall terms, the required pathogenic course dynamics in neuronal cell loss participate as systems of over-riding reactivity. Significant signature recognition patterns of pathogenic progression are potentially implicated in amyotrophic lateral sclerosis. Such incremental indices would indicate the overwhelming systemic central nervous system involvement as predominant neuroinflammatory indices of activity and reactivity.


Power underpins relationships between different actors in health systems and is exercised  directly by way of coercion and inducement, or indirectly by controlling the ideas and environments that influence other actors to make decisions. Increasingly, abuse and misuse of power have been implicated as key determinants of poor health systems performance in low-income contexts. However the ephemeral nature of power makes it a difficult subject to study, as do the political connotations of such analysis.We present case studies from three separate research projects conducted in varied settings in India. The studies draw from bottom up theories of policy implementation analysis, which help to locate intangible themes such as power in real life events and processes.i) A qualitative analysis of implementation of global guidelines for HIV testing in five cities ii) A policy analysis of factors influencing the performance of regulatory institutions for health care, in two states iii) A health systems ethnography exploring the decision-making processes of doctors working in remote rural areas in Chhattisgarh state All three studies utilized qualitative research methodology, including in-depth interviews and document review, and the ‘interpretive’ approach of analysis to understand the experiences of health systems actors.i) The analysis of implementation of global guidelines for HIV testing revealed that doctors widely resisted pressures to follow the guidelines, yet could rarely play a role in influencing policy change. A combination of this paradoxical balance of power, conflicts between different actors’  interpretation of policies, and lack of avenues for the exchange of ideas, contribute to the rift between written policies and field level practices.ii) The second study describes how public institutions for health care regulation have been subjected to ‘capture’ by medical professional groups that are represented in these institutions. The performance of core functions of these regulatory bodies is frequently subverted or obstructed by the forces embedded within, with the objective of protecting or serving specific vested interests.iii) The final case study highlights how doctors performing crucial roles in providing health care in remote rural areas face adversity not only from poor working and living conditions, but also in the form of unsupportive administrative structures, unaccountable promotion and transfer policies, and poor access to continued education.These three studies present a heterogeneous picture of the power of medical professionals in the context of national health systems. While medical professionals continue to hold sway over key administrative and regulatory institutions, this power tends to be directed to the protection of pecuniary and petty political interests, rather than to the upliftment of medical practice. Even as rural doctors struggle to perform under the yoke of unjust administrations, there is evidence that doctors in cities may also be powerless to influence the policies that guide the norms of their practice.societal reforms favouring justice and equity, for improving health systems performance. More evidence on the sociology of health systems is called for, as India moves towards sweeping health sector reforms.The case studies collectively highlight the crucial role of medical professional power and interests in influencing health systems performance in India, and also demonstrate that a closer appreciation of doctors’ vulnerabilities is necessary in order to confront the problem of medical dominance. At the same time they draw attention to the embeddedness of health systems in society – societal norms, structures and balances of power – and consequently of the necessity of Author declares that he has no conflict of interest.The author declares that the research studies on which this paper is based were funded by the Aga Khan Foundation and University of London (study 1); the Nossal Institute, University of Melbourne (study 2); the World Health Organization and the Government of India  (study 3).