Biomaterials’ structural characteristics and the addition of osteoinductors influence the osteointegration capacity of bone substitutes. This study aims to identify the characteristics of porous and resorbable bone substitutes that influence new bone formation. An Internet search for studies reporting new bone formation rates in bone defects filled with porous and resorbable substitutes was performed in duplicate using the PubMed, Web of Science, Scielo, and University of São Paulo Digital Library databases. Metaphyseal or calvarial bone defects 4 to 10 mm in diameter from various animal models were selected. New bone formation rates were collected from the histomorphometry or micro-CT data. The following variables were analyzed: animal model, bone region, defect diameter, follow-up time after implantation, basic substitute material, osteoinductor addition, pore size and porosity. Of 3,266 initially identified articles, 15 articles describing 32 experimental groups met the inclusion criteria. There were no differences between the groups in the experimental model characteristics, except for the follow-up time, which showed a very weak to moderate correlation with the rate of new bone formation. In terms of the biomaterial and structural characteristics, only porosity showed a significant influence on the rate of new bone formation. Higher porosity is related to higher new bone formation rates. The influence of other characteristics could not be identified, possibly due to the large variety of experimental models and methodologies used to estimate new bone formation rates. We suggest the inclusion of standard control groups in future experimental studies to compare biomaterials. The use of autografts for the treatment of bone defects has well-known restrictions, including limited availability and donor site morbidity A large number of new materials and material combinations have been developed. Structural characteristics have also been improved. The presence of pores significantly increases the osteointegration capacity, whereas solid biomaterials tend to form a fibrosis layer on the surface Comparing the many combinations of materials is a demanding task, and the use of many different analysis methods makes comparisons even more challenging. Computed microtomography (micro-CT) and histomorphometry (HMM) have frequently been used to quantify new bone formation (NBF) in bone defects created in animal models and inside the porous biomaterial The aim of this study was to identify the chemical and structural characteristics that influence the capacity of new bone formation of porous and absorbable bone substitutes implanted in animal models using a systematic review.in vivo studies affects the capacity of new bone formation using micro-CT or HMM quantifications.A systematic review was performed to evaluate how specific characteristics of porous and absorbable bone substitutes used to fill bone defects in experimental An electronic search was independently performed by two researchers (MJEP and MAS) between July 2014 and February 2015 without restrictions on the publication date. The following databases were used: PubMed, Web of Science, Scielo, and Theses and Dissertations of the University of São Paulo Digital Library. Only articles written in English or Portuguese were selected. The following search term combinations were used: (bone substitute AND porous) OR (bone substitute AND cancellous) OR (bone substitute AND spongy) OR (bone substitute AND pore) OR (cement AND porous) OR (cement AND cancellous) OR (cement AND spongy) OR (cement AND pore) OR (bone cement AND porous) OR (bone cement AND cancellous) OR (bone cement AND spongy) OR (bone cement AND pore).Two researchers (MJEP and MAS) independently performed the article selection based on the eligibility criteria by reading the titles, summaries or full text, according to the search strategy . ConsensThe experimental groups of each article that met eligibility criteria were analyzed independently; therefore, each article could have more than one group.Inclusion criteria:in vivo studies in animal models;Experimental, Orificial defects, 4.0 mm to 10.0 mm in diameter, produced by curettage or drilling of holes;Implantation of porous and resorbable bone substitutes in the form of premolded blocks or cement with a clear description of the composition, porosity and pore size;NBF indicated as a rate according to HMM or micro-CT data.Exclusion criteria:in vitro studies;Clinical trials, implantation in humans or Insufficient description of the substitute characteristics, methodology or results;Non-porous or non-absorbable substitutes;Presentation in granular form. This form was excluded due to interference with the porosity and pore size of the substitute.The end point variable was the rate of new bone formation (NBF), which was based on the histomorphometry (HMM) or micro-CT analysis data. The remaining dependent variables were as follows: animal model, bone region of the defect, diameter of the defect (in mm), follow-up time after implantation (in weeks), substitute basic material , osteoinductor addition (fibroblast growth factor (FGF), BMP or bone marrow mesenchymal stem cells (BMSCs)), maximum pore size and porosity.The NBF rates are described as the means, maximum and minimum values. The categorical variables and maximum defect size were grouped and compared using the Kruskal-Wallis test. The defect size, follow-up time and porosity were correlated to NBR using the Spearman’s correlation coefficient. PASW software version 17  was used for the data analysis and the level of significance was set as 5%.The initial search identified 3,266 studies. p=0.446) and micro-CT analysis . NBR showed a moderate correlation to the follow-up time in the HMM analysis  but a weak correlation in the micro-CT analysis . NBF was significantly influenced by porosity . In both analysis methods, no significant differences were found when the NBF means were grouped according to the animal model and bone region . The basporosity .The search for bone substitutes is a contemporary and relevant subject A large number of materials have been developed and tested, separately or combined, to increase the capacity of new bone formation. This continuous and effervescent development hinders the classification of these materials The influence of the other chemical and structural characteristics of the biomaterials had to be very large to be detected in such a heterogeneous sample. For this reason, it was not possible to identify differences in the capacity of new bone formation by comparing the different groups of experimental animals, the sizes and locations of bone defects, the association with osteoinducers and the pore sizes. The follow-up time presented a weak to moderate correlation to NBF, depending on the analysis method (HMM or micro-CT). However, the porosity presented significant differences, suggesting that this parameter has a strong impact on the NBF rate.Despite the large number, few studies could be included due to the significant variation in the presentation of the bone substitutes and experimental models. In addition, the NBF assessment method varied greatly, making comparison unsuitable. In this review, we used the two most cited methods, which, according to some articles, do not present comparable values but are related Although a substantial effort has been made by the scientific community in recent years to improve bone substitutes, some skepticism still exists regarding the effectiveness of the currently available biomaterials to cure critical size bone defects This review demonstrates that the lack of standardization of NBF analyses has hampered the comparison of the various types of porous and absorbable bone substitutes. Even when limiting the evaluation to two types of quantitative analyses for NBF, it was not possible to obtain accurate results. A better description of the analyzed region of interest (ROI) by each method could offer more precise data interpretation, and consequently, a more consistent comparison with other similar studies. Additionally, the inclusion of standard control groups with autografts or a commonly used substitute would allow the calibration of the results and the comparison of many different study groups.We conclude that porosity has a high impact on NBF rates and that the current lack of standardized analysis methods and the broad variety of experimental models makes identifying the chemical and structural characteristics that provide a greater capacity for NBF almost impossible. We suggest that standard control groups should always be used to allow for a better comparison of the results.Paulo MJ and dos Santos MA conducted the electronic search and data collection. Cimatti B and Gava NF reviewed the electronic search and data collection. Riberto M revised the manuscript and conducted the data analysis. Engel EE wrote the manuscript, reviewed the data analysis and supervised the study.


The cyanobacterial phylum exhibits enormous metabolic diversity with respect to morphology, lifestyle and habitat. As yet, however, research has mostly focused on few model strains and cyanobacterial diversity is insufficiently understood. In this respect, the increasing availability of fully sequenced bacterial genomes opens new and unprecedented opportunities to investigate the genetic inventory of organisms in the context of their pan-genome. Here, we seek understand cyanobacterial diversity using a comparative genome analysis of 77 fully sequenced and assembled cyanobacterial genomes. We use phylogenetic profiling to analyze the co-occurrence of clusters of likely ortholog genes (CLOGs) and reveal novel functional associations between CLOGs that are not captured by co-localization of genes. Going beyond pair-wise co-occurrences, we propose a network approach that allows us to identify modules of co-occurring CLOGs. The extracted modules exhibit a high degree of functional coherence and reveal known as well as previously unknown functional associations. We argue that the high functional coherence observed for the modules is a consequence of the similar-yet-diverse nature of cyanobacteria. Our approach highlights the importance of a multi-strain analysis to understand gene functions and environmental adaptations, with implications beyond the cyanobacterial phylum. The analysis is augmented with a simple toolbox that facilitates further analysis to investigate the co-occurrence neighborhood of specific CLOGs of interest.Cyanobacteria are a monophyletic phylogenetic group of global importance and have received considerable attention as potential host organisms for the renewable synthesis of chemical bulk products from atmospheric CO 2. As yet, however, research has mostly focussed on a small number of model strains and the genetic inventory of the cyanobacterial phylum is still insufficiently understood. The rapidly increasing availability of fully sequenced cyanobacterial genomes opens new and unprecendented possibilities to study the diversity of cyanobacterial strain in the context of the cyanobacterial pan-genome. Here, we seek to understand the genetic inventory of individual cyanobacterial strains based on the hypothesis that genes that are functionally related also co-occur within the genomes of different strains. We confirm this hypothesis by in depth analysis of co-occurrence that goes beyond pair-wise co-occurrences. We show that co-occurrence does not imply co-localization on the genome. Our work provides a novel approach to infer gene function and highlights the importance of a multi-strain analysis, with implications beyond the analysis of the cyanobacterial phylum.Cyanobacteria are photoautotrophic prokaryotes of global importance and offer great potential as host organisms for the renewable synthesis of chemical bulk products, including biofuels, from atmospheric CO Cyanobacteria are photosynthetic prokaryotes of global importance and recently gained renewed interest as a resource for natural products , 2 and aEscherichia coli genomes .The PDF file enlists all 78 chromosome and 136 plasmids considered in this study. The GenBank accession ID links every sequence to the according entry in the GenBank database of the National Center for Biotechnology Information (NCBI) [(PDF)Click here for additional data file.S4 TableProchlorococcus are annotated with the water depth at which the according strain was found, and their adaptation to high light (HL) or low light (LL). If not noted otherwise, data regarding the structural section was extracted from [In this table, we provide genomic and growth information for each strain including natural habitat, morphology , numberted from , while ited from .(PDF)Click here for additional data file.


The rise of autonomous systems operating close to humans imposes new challenges in terms of robustness and precision on the estimation and control algorithms. Approaches based on nonlinear optimization, such as moving horizon estimation, have been shown to improve the accuracy of the estimated solution compared to traditional filter techniques. This paper introduces an optimization-based framework for multi-sensor fusion following a moving horizon scheme. The framework is applied to the often occurring estimation problem of motion tracking by fusing measurements of a global navigation satellite system receiver and an inertial measurement unit. The resulting algorithm is used to estimate position, velocity, and orientation of a maneuvering airplane and is evaluated against an accurate reference trajectory. A detailed study of the influence of the horizon length on the quality of the solution is presented and evaluated against filter-like and batch solutions of the problem. The versatile configuration possibilities of the framework are finally used to analyze the estimated solutions at different evaluation times exposing a nearly linear behavior of the sensor fusion problem. Besides the future of self-driving cars, autonomous drones will soon take over tasks in transportation, agriculture, maintenance, surveillance or energy generation. The first prototypes have already proven to be feasible and have successfully delivered small sized goods, simplified inspection processes in rough terrain or harvested wind energy at previously unreachable altitudes. These recent developments allow the prediction of an increasing number of uavs applications  and model predictive control (mpc) are promising strategies that use numerical optimization methods over a window of data to increase stability and accuracy of the system’s motion. Mpc has been successfully applied to challenging control problems with nonlinear dynamics and difficult environment conditions [mhe which has already been used for decades to estimate the state of nonlinear chemical processes [Unditions ,2,3. Therocesses  or more rocesses . The comrocesses ,7 that nKalman filter (kf) algorithm [extended Kalman filter (ekf) and unscented Kalman filter (ukf). To achieve high estimation accuracy, kf-based algorithms require, in practice, a procedure to tune the filter parameters, which is, for complex systems, non-trivial yet crucial. To overcome this problem, adaptive methods have been proposed [To estimate the motion of a system exposing a high degree of freedom with high accuracy, it often becomes necessary to fuse information from different sensors. Sensor fusion is a well known strategy to reduce the impact of measurement errors on the state estimate  and estilgorithm  and its proposed ,11; howeproposed . Typicalmhe approach, extending [global navigation satellite system (gnss) receiver measuring position and an inertial measurement unit (imu) measuring linear acceleration and angular velocity. The measurement data is used to estimate the 3D-pose and velocity of a maneuvering object, such as an aircraft or satellite. There are several methods to integrate the inertial data and gnss, such as loosely coupled and tightly coupled integration. The integration is typically achieved by adapting a nonlinear kf [kfs represent a further option for the sensor fusion problem [In this paper, we present an optimization-based sensor fusion framework for state estimation following an xtending . The frainear kf ,15,16. B problem .imus for which sensor errors introduce a drift that needs to be compensated for by using different measurement updates such as those given by vision based sensors [gnss receivers. The resulting sensor fusion problem for inertial navigation has been addressed using traditional and advanced approaches for Kalman filtering [imu, is strongly coupled to the motions of the system. Therefore, a unique solution to the estimation problem cannot be guaranteed [mhe formulations for sensor fusion in the context of inertial navigation have been published in the recent past and have been shown to outperform traditional ekf approaches for the integration of gnss and imu [imu parameters [The sensor fusion problem discussed in this paper arises from the use of consumer-grade  sensors  or gnss iltering ,19. The aranteed . By consaranteed . Several and imu ,23 and orameters . DespiteThis paper is organized as follows. First, in mhe state estimator.gnss sensor in the earth-centered, earth-fixed (ecef) frame and often expressed in latitude, longitude, altitude (lla). The measurements are transformed to a locally-fixed and non-moving frame L following the east, north, up (enu) convention with its origin located at a reference location. Since the transformation between global and local frame is constant over time, the measurements are converted to the local frame in a preprocessing step. The measurements of the imu are obtained in the sensor coordinate frame S, which is moving with respect to the local frame L. Throughout this document, the notation The sensor fusion problem contains measured and estimated quantities expressed in several coordinate frames see . The posordinary differential equations (odes) of the navigational states are defined byS-frame to the L-frame expressed in the S-frame drives the ode of the orientation, which is parametrized by a unit quaternion S and L-frame. The ⊙ operator is introducedode Equations =vgnss receiver and an imu which are both rigidly attached to the moving system. The described sensor models relate the measured quantities to the state and control variables defined accordingly in Equations (The sensors used for this estimation problem are a single quations  and 4)..gnss recimu combines a three-axis accelerometer and a three-axis gyroscope in a single package. The sensors can be based on different principles that define implicitly the accuracy of the sensor. Due to the advances in micro-electro-mechanical system (mems) technology, the sensor modules can be produced very cost efficiently on a single silicon chip. The mems accelerometer and gyroscope are modeled in this paper using an additive bias term An e sensor . These bvariance . To inclimu at sampling rate imu data is integrated between two consecutive measurements of the slowest sensor, which is, in this specific problem, the gnss receiver, and expressed as motion increments [imu measurements in terms of state and control variables:L frame and The inertial quantities acceleration crements . The incEquation . The folgnss receiver is used to retrieve position measurements based on pseudo ranges estimated from satellite signals. The interested reader is referred to [gnss receiver has an output frequency between L frame as described before in gnss measurements directly to the state gnss receiver and strongly depends on the signal and ambient conditions.A erred to  for moregnss and imu, we first define the components of the cost function, the implicit integration method using direct collocation, and the necessary equality constraints.To define the optimization problem for the nonlinear sensor fusion of imu (7) and gnss (8) at time The cost function of the optimal estimation problem is defined by the squared weighted sum of residuals between the estimated output variables D at Gauss–Radau collocation points ode of the system D equality constraints for each time interval We use a direct collocation approach to embed the integration of the nonlinear dynamics inside the optimization problem. Direct collocation is a strategy known from the field of direct optimal control  that is nts τ∈RD . Hence, The discretization of the state trajectory Equation .As described in ode of an orientation as defined in Equation (The components of the optimization problem introduced in ),u(t)),Zqxj+Nimu and gEquation . The gnsimu [fibre optic gyro (fog) with lower measurement noise compared to the consumer-grade mems gyroscopes used for estimation. Furthermore accurate gnss receivers were used in a differentialgps (dgps) configuration allowing for very precise positioning with errors below imu  uses a tapproach .S of the imu was aligned with the body frame of the aircraft, which implies that no further transformations were required to retrieve physically meaningful output for the navigation states defined in Equation  and itsN, the estimation is repeated for different values N directly defines the number of measurements mhe optimization problem, where D defines implicitly the number of collocation variables used for the integration of the navigation states and is set to To analyze the estimation accuracy depending on the horizon length quations  and 4)..N, the emhe estimator output follows the reference trajectory and no major differences are observable. The plots reveal, however, that the estimation results recover faster from an incorrect initialization with longer horizons and that, in general, larger horizons show an improved tracking behavior of the reference trajectory. The evolution of the standard deviations of position, velocity, and orientation for the evaluated horizons is plotted in j = 1,..., J of total length J, the lagged solution can be compared to fixed-lag smoothing, maximizing the probability of p(xj-N|yj1:), whereas the real-time solution corresponds to filtering approach estimating p(xj|yj1:). For completeness, we remind readers that a typical batch processing approach estimates p(xj0:|yJ1:). Even though both real-time and lagged solutions contain more measurement data with increasing horizons, there are differences in their interpretation. Both estimators contain an approximation of the past that is defined by the arrival cost Ac(xj) in Equation  with increasing horizons can only be observed for the lagged solution. The accuracy of the lagged solution converges towards the solution of the batch estimator (dotted lines), which can be interpreted as a locally optimal solution since all measurement data is contained in the optimization problem, allowing the removal of start-up effects due to the initialization of the algorithm.A comparison between real-time and lagged solutions for different horizon lengths is given in z-direction. The batch solution confirms this large error of gnss receiver, used in the reference setup, operates on the gnss receiver as used for estimation.In terms of error quantities, we observe relatively large rmses for the position estimate, ranging up to x- and y-directions become observable and the values converge to their corresponding steady state.The orientation estimate reveals error reductions for roll mhe solution (solid lines) achieves major rmse improvements in position, velocity, and orientation with an increasing horizon length N. The real-time solution does hardly improve by considering a bigger horizon in comparison to the filter solution, where Coming back to imum number of one iteration [kf-like algorithm where only a single linearization of the system is calculated. Analyzing the solution in The nearly linear behavior of the regarded problem is further proven by restricting the optimization algorithm to a maxteration . This comhe approach for multi-sensor fusion allows a mathematically elegant formulation in a single optimization problem where cost functions and constraints are recursively adapted with the availability of new measurement data. We introduced the modules of the framework by applying it to the commonly known sensor fusion problem of gnss receiver and imu and evaluated the accuracy of the solution on a real flight dataset in comparison to an accurate reference trajectory for different horizon lengths The presented mhe is suggested to improve consistently the accuracy of the estimates at the price of a higher computational cost. In general, it can be said that if applications allow for a time-lagged estimate, the results will be more accurate considering larger horizons. This makes the time-lagged implementation of a mhe-based estimator a versatile approach for systems with slow dynamics and represents an alternative for memory-restrictive offline processing. For real-time critical applications which are governed by nearly linear equations, the accuracy of the state estimates does hardly benefit from the nonlinear optimization approach resulting in a comparable accuracy to filter solutions. The nearly linear behavior of the specific sensor fusion problem was confirmed by evaluating an ekf-like configuration of the mhe estimator using a real-time iteration scheme [imu and gnss receiver can be considered a linear estimation problem when conditioned on orientation, i.e., the optimization problem reduces to linear system if the orientation trajectory is known a priori.These findings coincide with relevant research , where mn scheme  with a smhe, and batch solutions by adapting the horizon length N. The modular structure contains several key features which we aim to exploit in further research. By encoding the system dynamics in a single set of odes, the framework can be adjusted to consider more complex system kinematics in a straightforward manner. Additional measurement updates from further sensors can be included by manipulation of the cost function of the optimization problem. When increasing the number of sensors, the calculation of a common time-grid becomes nontrivial. The presented framework is prepared to account for asynchronous measurements by estimating time-continuous state trajectories using a direct collocation approach. The adaptivity of a mhe-based approach for sensor fusion is one major advantage compared to traditional filter schemes and combined with efficient numerical solvers mhe is likely to be beneficial for many challenging applications.The presented optimization-based framework for sensor fusion allows a seamless and detailed evaluation of filter, ultra-wideband (uwb), time of flight (tof) or camera sensors, the sensor models become strongly nonlinear. Therefore an mhe approach with the appropriate optimization strategy is expected to improve the real-time estimates as well. For the future, we plan to extend the presented sensor fusion approach of gnss and imu to include the full calibration of the sensors, which will increase the nonlinearity of the optimization problem and mhe is expected to outperform conventional filter techniques. The identification of parameters like scale factors, misalignment or time delays will improve the accuracy when using uncalibrated consumer-grade sensors.The problem of motion tracking does not classify as nearly-linear problem in the general case. By considering measurements of relative distance sensors, such as


Overall Abstract: While drugs that target the dopaminergic and glutamatergic neurotransmitter systems have been extensively investigated as treatments for psychosis, there has been increasing attention in recent years on the endocannabinoid system as a therapeutic target. The CB1 receptor, the main central cannabinoid receptor is ubiquitous and modulates the function of several neurotransmitters, including dopamine and glutamate. A growing body of evidence suggests that psychosis is associated with alterations in the endocannabinoid system, independent of exposure to cannabis.The CB1 receptor is the main molecular target for delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis. THC is responsible for the psychotogenic effects of cannabis, and is a partial agonist at the CB1 receptor. On the other hand, Cannabidiol (CBD), the second major constituent of cannabis is a non-psychoactive compound that may have an inverse agonist/antagonist effect at CB1 receptors, in addition to a range of other possible mechanisms of action. Interest in the therapeutic potential of CBD stemmed from evidence that it has broadly opposite effects to that of THC, at both the neural and the behavioural level in healthy individuals. Consistent with these results independent evidence that CBD has antipsychotic and anxiolytic properties in patients with mental health disorders has been accumulating. The absence of significant adverse effects associated with CBD, is a critical advantage in relation to the treatment of patients in the various stages of psychosis. Given its tolerability profile, CBD is a treatment of particular interest not just in those with chronic psychosis as in schizophrenia, but also in those in the earlier stages of psychosis. However, published evidence regarding the therapeutic efficacy of CBD as a treatment in psychosis has been limited except a small randomized clinical trial (RCT) some years ago . Furthermore, the mechanisms that may underlie the beneficial effects of CBD are unclear.This symposium will bring together state of the art evidence regarding the efficacy of CBD in the different stages of psychosis – from those at clinical high-risk (CHR), through early psychosis to chronic schizophrenia. Furthermore, data from animal and human studies will be presented to give an understanding of the potential mechanisms that may underlie the therapeutic effects of CBD.The first speaker (Prof Crippa) will set the scene by presenting evidence regarding the different potential mechanisms of action that may underlie the antipsychotic effect of CBD.The second speaker (Prof McGuire) will present the results of a 6-week placebo-controlled RCT demonstrating the efficacy of CBD as an add-on to existing antipsychotic treatment in schizophrenia.The third speaker (Dr. Ranganathan) will present the results from an ongoing, placebo-controlled RCT using an within-subject, crossover design to show the effects of 4-week CBD treatment on psychotic symptoms, cognition and electrophysiological markers in patients with established psychosis.Finally, the fourth speaker (Dr. Bhattacharyya) will present the results from a recently completed proof-of-concept study demonstrating the efficacy of short-term CBD treatment on symptoms and distress in CHR patients as well as on neurocognitive substrates implicated in the CHR state.Evidence presented here will be discussed by Prof D’Souza, who is an internationally recognized expert in cannabinoid pharmacology and experimental therapeutics development.


Mitochondria are the “power plants” of eukaryotic cells involved cellular energy metabolism and lead the generation of most of the cellular “energy currency” adenosine triphosphate (ATP). In addition, they have other crucial functions including the control of programmed cell death, iron/sulfur cluster biogenesis and copper and calcium homeostasis. Mitochondrial dysfunction is deleterious and leads to degeneration, disease and aging. A number of individual pathways are active in keeping mitochondria functional over longer periods of time and thereby have a strong impact on lifespan. These mitochondrial quality control (mtQC) pathways occur at different molecular and cellular levels and are all limited in their capacity. They do not all work at the same time. Some of them are induced when others fail. Currently, the underlying molecular interaction of pathways and their regulation is only initially elucidated.Podospora anserina is an experimental aging model in which different mtQC pathways have been shown to influence aging and lifespan [P. anserina wild type aging [lifespan , 2, 3. Flifespan . Anotherpe aging , 6.PaSod3) in which the mitochondrial superoxide dismutase (PaSOD3) was ablated  autophagy, the non-selective degradation of cytoplasmic portions by autophagy is induced.In a further study, another component of the mtQC system was investigated Figure , right, xtension . Again, PaSod3 mutant mitochondrial function does not result from a total block of a specific pathway . As long as the damage remains low, efficient remodeling of damaged mitochondria is sufficient to compensate the impaired function. In the ∆PaClpXP mutants induction of mitophagy is not the adequate response. In these mutants the whole mitochondrial energy metabolism is affected due to the function of the CLPXP complex to adapt the energy metabolism in response to the cellular needs and not in removal of damaged proteins. Ablation of this complex therefore leads to the deregulation of the mitochondrial metabolism and a subsequent adaptation via the induction of general autophagy (Figure PaClpXP mutants appears wild-type-like, and strongly depends on functional autophagy machinery. The induction of general autophagy in ∆PaClpXP mutants thus resembles a situation after nutrient starvation. The molecular details involved in the induction of this response remain to be unraveled.The data of the two studies identify a flexible context-dependent autophagic response and the induction of different forms of autophagy. In the ∆y Figure . CellulaOverall, from recent analysis of the role of different mtQC pathways revealed unexpected and counter-intuitive results that identifies crosstalks between different pathways and revealed a context-dependent differential induction of different forms of autophagy. Impairments in individual mtQC pathways do not always result in the induction of mitophagy although in these cases mitochondria are affected in their function. The induced mitochondrial autophagic responses depend on the kind and level of mitochondrial impairments Figure . Organis


This case report documents the clinical approach adopted for three upper incisors with horizontal root fracture in the middle or cervical third. The proposed procedures involved maintaining pulp vitality and periodontal stability of the fractured teeth with 13 years of follow-up. Root fractures mainly affect the maxillary central incisors, followed by the maxillary lateral incisors; the rate of occurrence of root fractures is 0.5 to 7% . The mosA horizontal root fracture is diagnosed by clinical and radiographic examinations . ClinicaTreatment consists of repositioning the crown fragment, stabilizing it with a fixed retainer followed by splinting to the adjacent teeth, and preserving pulp vitality and the type of repair around the fracture . The desThis case report describes the occurrence of horizontal root fractures in the middle and cervical third of incisors that presented pulp vitality after 13 years of follow-up .The patient was a 23-year-old woman who visited a dentoalveolar trauma clinic six months after a fall. The patient remembered being referred to a hospital and receiving initial care after the accident. An intraoral examination revealed the presence of rigid splint involving the maxillary incisors and canines. The left maxillary lateral incisor had a temporary crown made of composite resin without an intra-canal retainer; the other three maxillary incisors had crowns that were otherwise healthy. Radiographic examination revealed complete root formation in the involved teeth, a root fracture in the cervical third of the right maxillary lateral incisor , and a fDuring a second visit, the patient underwent endodontic treatment in the right maxillary lateral incisor to allow for the installation of a root canal seal and for prosthetic rehabilitation of the crown. During the first six months, monthly radiographic and clinical controls of all the involved teeth were performed. Dental splint was maintained for 12 months because of the right maxillary lateral incisor fracture. At the time of splint removal, the teeth did not show increased mobility. The maxillary central incisors and right maxillary lateral incisor showed positive responses to pulp sensitivity tests. Annual controls were performed until 2009. Because the patient did not attend the scheduled controls in the following years, the subsequent follow-up was possible only in February 2016. Clinical examination revealed normal soft and hard tissues, and a positive response to pulp sensitivity tests. Periapical radiographs  and a coThe tomographic image suggested repairing of the maxillary central incisors with deposition of mineralized tissue between the fragments . The rigThe distance between the fragments and the level of horizontal root fracture directly interfere with the treatment outcome. The determination of these parameters involves interpretation of the radiographic image, which allows classification of the fractures as follows: cervical, middle, or apical .The adoption of CT as a diagnostic aid adds much greater complexity to fracture classification. The comparison between radiographic and tomographic images of teeth with root fractures showed no agreement in the level of fractures. In the et al. (Pulp vitality is better preserved in teeth that have undergone horizontal fractures than in teeth with dislocations and without root fractures. The rapet al.  evaluateThe prognosis for middle third fractures is more favorable, and in about 86% of cases, it is possible to maintain the responsiveness of the affected teeth to pulp sensitivity tests . The diaThe recommended duration of follow-up for cases of root fractures is currently at least five years . The repAlthough the present case suggests 13 years of stability, clinical and radiographic success, routine follow-ups are still required. Periodontal problems resulting from poor hygiene can trigger cervical resorption in teeth with root fractures similar to those observed.


Nanoparticles made of noble metals, such as gold and silver, have a great potential to be effectively employed for wound management. The nano-size of such particles provides an opportunity to enlarge the contacting area, which results in more effective anti-bacterial action and faster wound repair. It must be noted that the shape of noble nanoparticles might play a crucial role in the manifestation of their anti-microbial properties. The modern state of technology allows fabrication of the nanoparticles with the desired shape and physical properties. In order to provide efficacy and close contact with the wound, the noble nanoparticles can be incorporated into a special matrix made of a cryogel (based on polymethyl methacrylate). This combination might serve as a foundation for developing completely new types of wound dressing.We have developed a few methods for synthesizing gold and silver nanoparticles of different shapes and sizes. After fabrication of metallic nanoparticles, they were characterized by using Tunneling Electron Microscopy (TEM) and Malvern Zetasizer system in order to determine the average population size and consistency. The silver nanoparticles was synthesized using sodium borohydride reduction of silver nitrate. The synthesis of gold nanoparticles was conducted by using the Turkevich method.We have developed a synthetic cryogel based on polyacrylamide (by cryogelation reaction) at several temperatures. At the second step, we developed a method for conjugating fabricated gold and silver nanoparticles to the surface (or pores) of cryogel through covalent bonds so they can provide antibacterial action within the wound. By following the developed protocol, we were able to obtain an approximate cryogel layer (1 cm thickness) with embedded gold and silver nanoparticles. This conjugate was analyzed and confirmed using Scanning Electron Microscopy (SEM) and TEM.The obtained results indicate the feasibility of the fabrication of a novel type of wound dressing. At the next step, we are planning to elucidate the bio-compatibility of the combination of cryogel and nanoparticles. Moreover, anti-bacterial properties of this new type of wound dressing will be analyzed.


The purpose of this article is to determine if telehealth-delivered speech-language pathology interventions are as effective as traditional in-person delivery for primary school-age children with speech and/or language difficulties. A systematic review was conducted (in accordance with PRISMA guidelines) using five databases, two journals and reference lists. Titles and abstracts were screened for inclusion, with relevant studies reviewed in full-text. Initial searches identified 132 articles. Following exclusion of non-relevant studies, seven articles remained for inclusion. Results revealed both telehealth and in-person participants made significant and similar improvements when treatment effects were measured through five of the six outcome measures. Findings showed there is limited but promising evidence to support telehealth for delivering speech-language pathology intervention services to school-age children. Whilst this is encouraging, particularly for rural children where in-person services are limited, more rigorous study designs are required to support the efficacy of telehealth for this population. In Australia, over 17% of children are considered to be vulnerable (<10th percentile) or at-risk (10–25th percentile) for developing impairments in language and literacy . AnotherRegardless of location, speech and language skills are a strong predictor of success in education, social participation, and employment. Children with communication difficulties progress more slowly in reading and writing and experience increased bullying and poorer peer relationships . Speech As a solution to the inequity of access to SLP services in rural areas, some practices/practitioners have begun to make use of an innovative service delivery approach, commonly referred to as telehealth . This teTelehealth-delivered SLP services have previously been investigated in reviews regarding a number of practice areas and populations. Although these previously conducted reviews included studies targeting the paediatric population, the number of studies investigated was minimal and the focus was primarily on the application of telehealth in SLP with the adult population. These reviews suggest positive results. However, service delivery models and intervention techniques used with children typically differ from those used with adults, as the focus with children tends to be on achieving developmental milestones, as opposed to a rehabilitative approach that is commonly used with adults . It can The potentially detrimental effects of communication difficulties on a child’s education and social participation increase the importance of alleviating these where possible, regardless of where the child resides. It is therefore important to focus on this specific population to determine whether telehealth service delivery may be a viable alternative to in-person intervention in locations where this service is not readily available. However, no review to date has focused specifically on evaluating the telehealth studies undertaken with children. Thus, this systematic review evaluated the present literature to determine if telehealth-delivered SLP interventions are as effective as traditional in-person delivery for primary school-age children with speech and/or language difficulties.To address this study’s aim, a systematic review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines . The PRIA systematic literature search was undertaken using the PubMed, CINAHL, Scopus, ERIC and SpeechBITE databases. Additional manual searches in two highly relevant journals, the International Journal of Speech-Language Pathology and the International Journal of Telerehabilitation, were also conducted, in order to locate more recent versions of journals that may not yet have been transferred into the databases. Systematic search strategies were adhered to using the following search string:  AND (speech pathology OR speech-language pathology OR speech therapy) AND (child OR paediatric). In addition, citations and references within identified articles were searched for further studies relevant to the review. The authors corresponded with experts in the field to ensure all relevant studies were included within the review.The studies identified through the systematic searches were included in the review if they reported studies of speech and language intervention delivered through telehealth to primary school-age children (4–12 years) across various settings , provided treatment outcome data on intervention effectiveness and did not describe special client populations . The year of publication was not restricted, ensuring all available evidence was identified, but the search was limited to articles written in English. Papers were included on speech intervention (speech sound production and intelligibility) and language intervention (receptive and expressive language). Articles describing voice, fluency, pragmatics, literacy or special client populations were excluded to focus on primary speech and language disorders.All articles identified from the initial searches were reviewed and duplicates were removed. The title and abstracts of the articles were screened for inclusion by all authors, with the remaining articles reviewed in full text and the exclusion criteria applied. In the case of disparities between the authors’ judgments regarding suitability, they consulted to achieve agreement. Data from the included studies were extracted using a standard table developed specifically for this review refer to . The artThe initial database and reference list searches conducted during November and December 2016 yielded a total of 120 unique articles. During the initial screening, 68 articles were excluded on title and another 33 articles were eliminated on abstract. The remaining 19 articles were reviewed in full-text. The full-length review excluded a further 12 articles, because they: (1) did not describe speech and language intervention via telehealth with the majority of participants between 4 and 12 years of age, and/or (2) did not provide outcome data on intervention effectiveness. From this selection process, seven articles were retained for the final systematic review. The review process is detailed in the flow chart in The seven included studies focused on telehealth-delivered speech and language intervention with primary school-age children. Two of the included studies were randomised controlled trials (level of evidence II)  and anotThe majority of the studies (71%) focused only on primary school-age children between the ages of 4 and 12 years . HoweverThree papers reported the use of commercial videoconferencing systems  designedFive of the seven included studies investigated the application of both speech sound and language intervention through telehealth . The remTwo studies conducted only traditional speech sound intervention (Van Riper approach to articulation intervention) through both telehealth and in-person delivery models. The participants in the study conducted by An examination of a combination of speech sound and language interventions was conducted in five of the seven studies. The duration of intervention varied between studies. Participants in the study by Further differences between the studies focussing on both speech and language intervention related to whether or not the treatment sessions were provided on an individual basis or in a group setting. An individual format was adopted in three of the studies , howeverThe intervention provided varied depending on the selected targets. Two studies selected intervention targets based on the participant’s IEP goals and objectives , whereasThe included studies examined the efficacy of telehealth intervention using various outcome measures. Six different outcome measures were investigated: the Goldman Fristoe Test of Articulation – second edition (GFTA-2); Functional Communication Measures (FCMs); goal achievement; informal probes; comparison of pre-intervention baselines with post-intervention production levels; and change reported on quarterly progress reports.Three studies utilised pre- and post-intervention testing with the GFTA-2 to compare telehealth to in-person delivered intervention . Each ofTwo studies measured outcomes through Functional Communication Measures (FCMs), which are used as a measure of progress in the ASHA K-12 Schools National Outcomes Measurement System (NOMS) database . This daThe results of these two studies demonstrate conflicting findings; however, neither of the studies conducted statistical analyses of the results and thus the significance of the percentage differences between the two intervention conditions is unknown. The limitations evident in both studies could also likely have introduced confounding factors, which may have affected the results. For instance, one study had a considerable difference in the sample size for the two conditions and did not randomly allocate participants, but instead selected the telehealth participants from a pilot project already being conducted . The selTwo studies  used goaThe second study evaluated goal completion against a set criterion , with thExamination of progress using informal probes was conducted in one study . The parTwo studies used the comparison of pre-intervention baselines with post-intervention production levels as an outcome measure . The anaThe results reported on participants’ quarterly progress reports were used as outcome measures for two studies . In the The difference in the results for the number of IEP goals achieved between the intervention conditions in these studies can be explained by a disproportionate number of IEP objectives being targeted in the two intervention conditions and across the first  and second treatment period . A larger number of total IEP objectives were targeted in the telehealth group across the two treatment periods.Four studies reported satisfaction data through the provision of surveys . High leThe present review investigated the efficacy of telehealth-delivered SLP services when compared to traditional in-person delivery for primary school-age children with speech and/or language difficulties. Evidence was collated through a systematic review of the available telehealth literature. Overall, the findings of the review showed that there is some evidence to support the use of telehealth when delivering SLP intervention services to school-age children. However, it also demonstrated that the amount of research into speech and language intervention for children via the telehealth service delivery model is limited and of variable quality, as the included studies span across the levels of evidence according to the National Health and Medical Research Council (NHMRC) .A total of six different types of outcome measures were used to investigate the efficacy of telehealth intervention, therefore creating difficulty in directly comparing the studies. The design of the three studies using the goal achievement and informal probe outcome measures did not allow direct comparison between the telehealth and in-person intervention conditions, as the study designs only evaluated the telehealth-delivered intervention, without comparing it to the traditional in-person model . HoweverThe remaining reviewed studies directly compared the telehealth and in-person intervention conditions using four different outcome measures. There was convincing evidence in the literature suggesting that speech sound intervention delivered through telehealth to primary school-age children was just as effective as in-person intervention when measured through the GFTA-2 . ParticiPositive results were also identified in the studies that used the comparison of pre-intervention baselines and post-intervention production levels to measure outcomes, with both studies indicating that progress was achieved regardless of the treatment modality .Despite these positive results, the two studies that examined telehealth-delivered speech and language intervention and used the FCMs as their outcome measure identified contradictory results. For the intelligibility and speech sound production measures, Both speech sound and language interventions were implemented as part of the seven studies included in the review. However, of these reviewed studies, there appeared to be a stronger focus on speech sound intervention, with two studies primarily aiming to assess this range of practice area through telehealth. The remaining five studies investigated the application of both speech sound and language intervention through telehealth, however two focused more heavily on speech than on language, as a greater number of speech goals were targeted in one study  and moreThe uptake of the use of telehealth by speech-language pathologists has been influenced by the need to address the inequity of access to services experienced by Australia’s rural population . TeleheaInterestingly, all of the reviewed studies utilised real-time videoconferencing facilities, allowing the clinician and client to visualise each other. This finding is consistent with results from previous reviews , indicatReports that videoconferencing facilities do effectively support real-time interactions between clinicians, clients and families, are consistent with parent, student, and staff satisfaction data that was collected as part of four of the seven studies included in this review . SatisfaOverall, the findings from the seven reviewed studies revealed that telehealth is a promising method for treating children with speech and/or language difficulties. However, in spite of this interesting finding, a number of methodological issues limit the quality of the results. The conclusions found in the literature on the effectiveness of telehealth-delivered intervention are dependent on the selected outcome measure. Outcomes for telehealth were more consistently positive when standardised assessments, such as the GFTA-2, were used for the pre- and post-intervention testing. The literature also revealed considerable variation in the intensity of therapy, with some studies claiming significant improvement after only a small number of sessions (6) were delivered fortnightly , whereasThe current systematic review also has some limitations that require consideration. Firstly, although two studies included a very small number of participants outside the set age criteria, the primary school-age population was the focus of the review. Therefore, studies which included a large number of children outside this age range were excluded due to the differences in attention span and behaviour between age groups . Whilst The current review aimed to determine if telehealth-delivered SLP interventions are as effective as traditional in-person delivery for primary school-age children with speech and language difficulties. The reviewed research was limited and of variable quality, however, the evidence presented showed that telehealth is a promising service delivery method for delivering speech and language intervention services to this population. This alternative service delivery model has the potential to improve access to SLP services for children living in geographically remote areas, reducing travel time and alleviating the detrimental effects of communication difficulties on education, social participation and employment. Although some initial positive findings have been published, there is a need for further research using more rigorous study designs to further investigate the efficacy of telehealth-delivered speech and language intervention.


Reconstruction of the neck following a burn injury poses a significant challenge to reconstructive burn surgeons. Here, we report a case of successful application of pre-expanded occipito-dorsal flaps in the reconstruction of postburn scars and contractures in the neck. The patient was a 10-year-old boy who sustained scars and contractures secondary to a burn injury 4 years ago. “Super-thin” flaps were obtained through pre-expansion in the occipito-dorsal area and then transferred to the recipient site. This approach resulted in an esthetic satisfaction and a significant functional improvement, thereby having significant clinical implications in the reconstruction of soft tissue damage secondary to burn injuries in the neck. Post-burn deformities or scar contractures in the head and neck region impact the victim more significantly than those in the other parts of the body, because of both functional and esthetic reasons. Reconstruction of this region poses a significant clinical challenge to burn surgeons. Currently, a variety of techniques are available to burn reconstructive surgeons, among which transfer of expanded microvascular flaps has perhaps become the most favored option worldwide. This tecTransfer of “super-thin” flaps expanded from the occipital, clavicular, or pectoral area has been previously described as an alternative approach to minimize the risk of complications associated with the conventional reconstruction techniques.  Here we A 10-year-old boy presented to our unit with significant scars, keloids, and contractures in his anterior chest and neck that were formed secondary to burn injuries 4 years ago [Figure Given severe hypertrophic scars in his pectoral and supraclavicular areas resulting from the original burn injury, the occipito-dorsal area was the only available and appropriate donor site of local autologous skin for neck reconstruction. Accordingly, bilateral pre-expansion of occipito-dorsal flaps was conducted. Under general anaesthesia in the prone position, the shape of the flap was designed in a way to match the recipient site and the occipital arteries were identified and marked on the skin using a portable Doppler ultrasound machine Figure . Tissue Two revision procedures were performed; the first one to address the dog ears in the posterior cervical region and the second one to remove excess adipose tissue by liposuction. As shown in Figure Tissue expansion is an effective method for replacing scarred tissue secondary to burn insult. Being increasingly applied in reconstruction of the head and neck, this technique enables generation of flaps with a good cosmetic color match and reliable vascularity of an axial or random pattern.The occipito-cervico-dorsal flap that is based on a descending branch of the occipital artery and arises close to the junction of rectus capitis and trapezius has been described previously. In this In general, our unit prefers using expanded supraclavicular or pectoral skin whenever available, since it allows for vertical transfer rather than pedicle rotation. However, pectoral and supraclavicular skin was heavily scarred due to the original burn injury in the patient reported in this paper, and occipito-dorsal flap was the only source of local autologous skin for neck reconstruction. To avoid possible failure of the distal flap associated with aggressive thinning, we adopted a delayed liposculpture approach. Additionally, we utilized tissue expansion that might have conditioned the flap vasculature, thus increasing the chance of a successful outcome. It would be our interest to evaluate the possibility and benefits of using a central skin bridge to ensure the expander pockets remain separate in future.In summary, this case report suggests that pre-expanded occipito-dorsal flap is worth considering when supraclavicular skin is not available for neck reconstruction. Although the skin on the back may be thick in some individuals and thus impose a limitation to the application of this flap, flap thinning using liposuction technique may be an effective solution. Nevertheless, patients should be counseled on the risks of tissue expansion and skin necrosis.


The aim of this study was to assess the dimensionality of YFHS-Swe and identify possible unique factors in the evaluation of youth-friendliness. YFHS-Swe was answered by 1110 youths aged 16 to 25 years visiting youth clinics in Northern Sweden. Thirteen factors were identified by exploratory factor analysis and except for one factor they all proved to fit well and have good reliability when assessed by the confirmatory factor analysis. The YFHS-Swe proved to be credible and suitable for assessing youth-friendliness of differentiated health services in Sweden. With cultural and linguistic adaptations, it can be used in similar settings internationally. Ensuring that health services are youth-friendly is important because it increases the utilization of these services and thus promotes better health behaviours.,2 HealthYouth aged 13–25 years accounts for around 15% of the Swedish population. An increWorldwide, Sweden has one of the most consolidated examples of differentiated services for youth, called youth clinics. A few youth clinics began during the early 1970s and worked mainly with health promotion. After the new abortion legislation in 1975, more clinics opened and worked on the prevention of unplanned pregnancies. Sexually transmitted infection (STI) prevention programs, especially for HIV and chlamydia, were implemented in youth clinics in the early 1980s. Later, in 1988, youth clinics were organized under the Swedish society of youth centres (FSUM), where national guidelines were developed to ensure youth-friendly health services in line with the WHO recommendations. These guidelines emphasized a holistic approach to youth and stressed the role of youth clinics as a gateway to other health services in regard to all health complaints; sexual, social, psychological or physical. In orderIn order to assess the youth-friendliness of this differentiated health service, an adapted Swedish version of the YFHS WHO+ questionnaire (YFHS-Swe) was validated. YFHS-Swe proved to have good internal homogeneity and consistency over time in test–retest reliability. However,Despite the importance of youth-friendliness, the credibility of its few assessment tools are not well studied. The aim of this article was to assess the dimensionality of the YFHS-Swe to assure its quality and reliability and to identify possible factors that might be of importance for policy making. This will contribute to the credibility of this tool in assessing youth-friendliness of differentiated health services in Sweden. In addition, describing the process of the factor analysis, it might be helpful to researchers and practitioners aiming to validate similar tools.During the period from September 2016 to February 2017, the YFHS-Swe questionnaire was applied in 20 youth clinics in four counties in Northern Sweden. A total number of 1110 eligible participants aged 16 to 25 answered the questionnaire after their visit to the clinics.WHO divides youth-friendliness of health services into five dimensions: accessibility; acceptability; equity; appropriateness; and effectiveness. The YFHSPrincipal component analysis (PCA) was first used to assess dimensionality and to identify the factors that explain the items in each domain. Varimax rotation was used to simplify the interpretation of the results. Factors were retained based on Kaiser’s criterion, parallel analysis of Horn  and thorConfirmatory factor analysis (CFA) was performed to assess the quality of the factors identified by PCA. CFA also allows for each item to have its unique variance as the items cannot be entirely explained by their factors. The method of quasi maximum likelihood estimation with robust standard error (ml vce(robust)) was used, as normality could not be assumed. The method of maximum likelihood with missing value was used in privacy factor as this factor contains a question that is only answered by some of participants. To increase the validity of the models, an interaction between the error terms of the items was included when suggested by the modification indices and was conceptually reasonable. A satisfactory level of standardized root mean squared residual (SRMR) of less than 0.08  and a ρ All 13 factors were predicted from their CFA models, which allows the share meaning of items to be obtained. The predicted variables were standardized and divided into quintiles in order to visually display the factors and present them to the clinics.Our sample consists of 90.7% females, 86.2% heterosexual and 94% Sweden-born participants. Due to the unequal access to health services among youth in Sweden, we think that this sample reflects the real users of youth clinics in Sweden.Fourteen items were omitted to secure clearer unidimensional factors. The decision was based on statistical indications, conceptual reasoning, or indications that the youths misinterpreted the questions. .Thirteen factors were retained from the original seven domains: ability to get contact; access to sexual and reproductive health service; access to psychosocial health services; parental support of sexual and reproductive health services; parental support of psychosocial health services; equity with diverse concerns; equity with legal concerns; fear of exposure; respect; privacy and confidentiality; no judgement; quality of consultation; and quality of facility . These fOur results suggest that the original seven domains of YFHS-Swe cannot capture all the dimensions of youth-friendliness and these 13 identified factors might be of an importance in assessing the friendliness of differentiated youth services. The robust process we followed and the large sample size of this study increase the credibility of these results.[On the other hand, the low number of males and immigrants in our sample might make our results unrepresentative of the Swedish youth population. However, the aim of the instrument was to assess the perception of youth-friendliness among those who have visited the youth clinics, not among youth in general. Another limitation could be that we only surveyed the four sparsely populated northern counties, which might not represent youth clinics in other parts of Sweden. Future research could embrace a nationwide perspective including clinics from different parts of Sweden and focus on the underrepresented groups.YFHS-Swe proved to be credible and suitable for the Swedish context. We therefore can recommend the usage of this questionnaire to assess youth-friendliness nationally and, with some cultural and linguistic adaptations, in other differentiated youth health services internationally. The identified factors might be of an importance to capture different dimensions of youth-friendliness.Click here for additional data file.


The effect of a mutation on the organism often depends on what other mutations are already present in its genome. Geneticists refer to such mutational interactions as epistasis. Pairwise epistatic effects have been recognized for over a century, and their evolutionary implications have received theoretical attention for nearly as long. However, pairwise epistatic interactions themselves can vary with genomic background. This is called higher-order epistasis, and its consequences for evolution are much less well understood. Here, we assess the influence that higher-order epistasis has on the topography of 16 published, biological fitness landscapes. We find that on average, their effects on fitness landscape declines with order, and suggest that notable exceptions to this trend may deserve experimental scrutiny. We conclude by highlighting opportunities for further theoretical and experimental work dissecting the influence that epistasis of all orders has on fitness landscape topography and on the efficiency of evolution by natural selection.The online version of this article (10.1007/s10955-018-1975-3) contains supplementary material, which is available to authorized users. One of the more evocative pictures of biological evolution is that of a population climbing the fitness landscape , 44. ThiWhile several distinct framings of the fitness landscape have been suggested , here weThe most obviously interesting topographic feature of the fitness landscape is the number of maxima, a point already recognized by Wright . Two . This counting reflects the isomorphism between any fitness landscape and its corresponding suite of epistatic terms   and the mentclass2pt{minimThe consideration of the combinatorics of the problem is closely related to the Fourier spectrum of a fitness landscape , 57, namNevertheless, declining average epistatic effects notwithstanding we find many examples of specific epistatic terms with anomalously large explanatory effects in many of the datasets examined here . We suggest that these may reflect important mechanistic interactions among those particular mutations in the underlying biology of the system, thus representing potentially fruitful entry points for the molecular biologist .Our observation that the influence of epistatic terms on naturally occurring fitness landscapes declines with epistatic order raises the question of how epistatic terms influence the efficiency of natural selection. We lack a complete theoretical understanding of this connection.One well-developed result concerns the influence of epistasis on the selective accessibility of mutational trajectories to high fitness genotypes. First, sign epistasis means that the sign of the fitness effect of a mutation varies with genetic background , and it Moreover, pairwise epistasis has long been understood to influence not just the selective accessibility of high fitness genotypes but also the pace at which natural selection both increases the frequency of beneficial mutations  and at In addition, we have only quantitatively examined the sequence of epistatic orders sorted by explanatory power Fig. c. Thus, Finally, we note that the Fourier–Walsh framework employed here depends on the availability of combinatorially complete datasets. But the experimental demands of this approach grow exponentially with the number of mutations examined. This fact sharply limits the scalability of analytic pipelines like ours. Recently, theoretical progress has been made in the analysis of less-than-complete datasets , 12, 13,Supplementary material 1 (pdf 1923 KB)Below is the link to the electronic supplementary material.


Traumatic brain injury (TBI) is a major health concern worldwide. Laboratory studies utilizing animal models of TBI are essential for addressing pathological mechanisms of brain injury and development of innovative treatments. Over the past 75 years, pioneering head injury researchers have devised and tested a number of fluid percussive methods to reproduce the concussive clinical syndrome in animals. The fluid-percussion brain injury technique has evolved from early investigations that applied a generalized loading of the brain to more recent computer-controlled systems. Of the many preclinical TBI models, the fluid-percussion technique is one of the most extensively characterized and widely used models. Some of the most important advances involved the development of the Stalhammer device to produce concussion in cats and the later characterization of this device for application in rodents. The goal of this historical review is to provide readers with an appreciation for the time and effort expended by the pioneering researchers who have led to today’s state of the art fluid-percussion animal models of TBI. Traumatic brain injury (TBI) is a major health concern worldwide , 2. In tExperimental models of TBI apply various forms of mechanical energy to the brain with a goal of replicating in animals the neurological syndromes, biological responses, and pathophysiology observed in human closed head TBI. Thus, animal models provide a means of rigorously studying clinical pathological states of TBI in a scientifically controlled manner in a laboratory setting. Over the years, animal models of TBI have employed numerous techniques applied to various species in attempts to reproduce multiple aspects of human TBI. Techniques include rapid acceleration or rotation of the head , impact The earliest application of a fluid-percussion technique involved striking a fluid-filled column secured to the exposed dura of an animal. Denny-Brown and Russell attempted to produce a generalized loading to the brain rather than a focal injury by applying a localized pressure pulse to the exposed dura of cats . They caThe Richmond group at the Medical College of Virginia, led by Becker, Povlishock, and Hayes further modified the Stalhammar device and applied fluid percussion to the midline of the cat brain through an 18-mm diameter craniectomy , 30, 31.The next major advance in the fluid-percussion technique was Dixon’s development of midline fluid percussion in the rat. The impetus for developing a rat model of TBI was the goal to expand laboratory TBI model endpoints to behavioral assessment of outcome. The choice of the rat took advantage of the rich history in the field of psychology that made extensive use of behavioral analysis in this species. Dixon’s landmark study characterized the pathophysiological, histopathological, neurological, and behavioral responses to a range of injury severities in the rat . Dixon’sper diem costs of maintenance.The development of the rat fluid-percussion model also afforded several other advantages including genetic homogeneity, ethical considerations of moving away from the use of companion animals to those lower on the phylogenetic scale, ease of procurement, and availability through a network of professional vendors. Furthermore, there were practical and financial advantages of using a species that required less vivarium space, afforded ease of handling, and reduced financial burdens of procurement and lower Perhaps the main advantage of moving to a rat model of TBI was to make feasible and practical, testing of dose–response pharmacological interventions that require behavioral assessment of large numbers of subjects. The first such dose–response pharmacological intervention study administered scopolamine to examine muscarinic cholinergic receptor involvement in transient behavioral suppression (traumatic unconsciousness) and physiological responses to TBI . That stAn extremely important alteration to the central rat fluid-percussion model, instituted by McIntosh, moved the craniectomy position from the vertex to a lateral  site . The intThis innovative lateral rat fluid-percussion model provided several advantages over the central/midline model. First, rupture of the sagittal sinus underlying the central craniectomy, which could occur during surgery or upon percussive impact, was completely avoided, resulting in reduced blood loss and preservation of proper venous blood outflow from the brain. Second, the lateral model produced consistent cortical and hippocampal neuronal cell death compared to the central model. The gross pathology was always localized to the hemisphere ipsilateral to the fluid pulse, providing a relatively less injured, contralateral hemisphere useful for certain control comparisons. However, numerous studies have since demonstrated that the contralateral hemisphere sustains pathological neurochemical perturbations , 59 and Finally, the lateral fluid-percussion orientation appears to produce less direct brain stem compression allowing for application of higher fluid-percussion forces with lower mortality than central fluid percussion . CompareN-methyl-d-aspartate type glutamate receptor, demonstrated class I evidence  for improving disability rating scale scores in the chronic phase of TBI , as originally performed by McIntosh et al. . Over thWhile there are many benefits associated with the use of rodent models of TBI, there are also arguments for the use of higher order animals to better characterize the relevant pathobiology of human TBI. The use of multiple species is encouraged to address fully the complex pathobiological processes ongoing in human TBI . The lisA German group led by Bauer characterized a severe lateral fluid-percussion model over the right parietal cortex in juvenile pigs (6 weeks old mixed German domestic breed), which reliably produced secondary elevations in ICP accompanied by patterns of diffuse brain damage . More reThe robust proliferation of genetically altered mice has provided opportunity to more precisely focus mechanistic studies on pathological processes. Following the lead of the Penn group who adapted the controlled cortical impact for mice , CarboneSeveral different fluid-percussion devices have been developed since the inception of the Richmond device in the 1980s. The Dragonfly fluid-percussion device, used primarily by Shima’s group in Japan, applies the same basic principle of a closed hydraulic system as the Richmond device, but differs with smaller dimensions and stainless steel construction in place of Plexiglas™ , 83. FadThere are a number of important parameters to consider when utilizing the fluid-percussion technique regardless of the subject species. Craniectomy location  produces unique pathological responses , 50. RelFrom the early 1940s through the 1970s, pioneering head injury researchers developed and tested a number of fluid percussive methods to reproduce the concussive clinical syndrome in laboratory animals. By today’s standards, the work of these early pioneers in the field of Neurotrauma appear somewhat crude. However, it was their ingenuity and determination that laid the foundation for the level of sophistication found in today’s animal models of TBI using well-characterized and controlled devices and procedures such as fluid percussion and controlled cortical impact. The early fluid-percussion studies in cats provided a benchmark standard in the 1980s, producing groundbreaking studies of the mammalian response to brain trauma. The early cat fluid-percussion studies contributed greatly to our understanding of the brains response to head injury ranging from cerebral vascular alterations to traumatic disruption of consciousness. The development and characterization of rat fluid-percussion injury in the mid to late 1980s provided an important leap forward making possible behavioral outcome evaluations and a practical means of performing large scale studies of experimental therapeutics. Fluid percussion was later adapted for use in larger (pigs) and smaller animals (mice), providing means of studying TBI in gyrencephalic and genetically altered animals. The historical perspective of this brief review will hopefully provide appreciation for the effort, determination, and ingenuity expended by pioneering researchers who have led to today’s state of the art fluid-percussion animal models of TBI.BL wrote and edited the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In order to assess the capacity of neurological patients to process syntactic features unique to Korean, such as the heavy dependence of parsing on syntactic morphemes rather than the word order in a sentence, the Korean Syntactic Comprehension Test (KSCT) was newly developed. To examine the correlation between lesion locations and the test performance, we did voxel-based lesion-symptom mapping (VLSM) analysis in a group of 39 patients with ischemic stroke. As a result, KSCT scores of the aphasic patients were significantly lower than those of 18 normal subjects. Within the patient group, VLSM analysis showed significant association between lower KSCT performance and the lesions mainly located in left perisylvian area and anterior temporal lobe. The KSCT results were also closely correlated with the results of two subtests in the Korean version-the Western Aphasia Battery. We conclude therefore that brain localization of syntactic comprehension in Korean native speakers is similar to that in other language speakers, despite the unique features of the Korean syntax, and that the KSCT will be of diagnostic value in assessing left fronto-temporal functions in Korean patients.


The mechanistic events of female infertility have been investigated for over 50 years and despite progress many causes of infertility remain elusive. However, over half of idiopathic infertility issues have been attributed to a defective ovarian tissue responsible for the maintenance of a conceptus, the corpus luteum (CL). Many CL defects are attributed, in part, to abnormal vascularization (angiogenesis), which occurs primarily during the developmental stage of the luteal lifespan. A few well-established angiogenic growth promotants have been implicated in luteal angiogenic processes but the mechanisms of the process are still under investigation. Recent evidence supports a role for the adipokine hormone leptin as a probable component in the angiogenic and developmental processes of a CL. Leptin expression is present during the developmental and maturation stages of the luteal lifespan and stimulates the expression of angiogenic hormones in the CL. Induced leptin deficient CL have a higher occurrence of abnormal, underdeveloped gross morphology and an increase in the number of large diameter vessels and large luteal cells. Leptin replacement therapy in leptin deficient CL accelerates tissue development, increasing overall tissue mass and forming a structure that resembled a mature CL during the early stages of development. Collectively, the evidence supports the supposition that leptin is involved in the angiogenic and developmental processes of luteal tissue. The corpus luteum (CL) is an important ovarian tissue that secretes progesterone, a steroid hormone essential for the maintenance of pregnancy in mammals. It exhibits tumorigenic growth properties during the developmental process, doubling in size and cell number every 60-70 h . In ordeIn 2014, Wiles et al.  reported


Microarrays covers research where microarrays are applied to address complex biological questions. This new open access journal publishes articles where novel applications or state-of-the art technology developments in the field are reported. In addition, novel methods or data analysis algorithms are under the scope of Microarrays. This journal will serve as a platform for fast and efficient sharing of data within this large user community. As one of the first microarray users in Europe back in 1996, I am proud to serve as Editor-in-Chief and I believe we have assembled a highly proficient Editorial Board, responsible for a fair and fast peer-review of articles. The first generations of commercial microarrays introduced in the mid-nineties suffered mainly from sensitivity and reproducibility due to poor production technologies. In the early days of the technology, the first microarrays had probe sets complementary to about 120 genes and about 30 transcripts were measured in routine experiments. However, it became clear that further reduction of the feature size would ultimately allow integration of entire genomes, which is the case today. In addition, array production and sample preparation methods underwent significant improvements resulting in robust and indispensable tools for routine applications in biomedical research [In parallel microarray technologies for the genome wide analysis of single-nucleotide polymorphisms (SNPs) , copy nuRecently exceptionally efficient deep sequencing technologies became available at highly competitive prices. Measuring clone frequencies in bead libraries has the potential to replace or complement chip based fluorescence based transcript imaging in the future. One advantage of this approach is the possibility to detect any genomic transcript of an organism, provided the genome is available. Today many aspects of next-generation sequencing (NGS) remain to be solved. Although data generation can be fast, depending on the technology, the data analysis and processing have currently no user friendly solution, especially when multiple samples and conditions are part of the experiment. In addition, sample preparation is complex and certainly a source for artifacts which is reminiscent to the early days of microarray technology. Finally, the poor concordance of chip based transcript profiling experiments and NGS is inadequately understood in the research community . In summMicroarrays and encourage submissions of interesting papers. We also welcome suggestions regarding the scope and content of the journal.We welcome you to


Neutrophil extracellular traps (NETs) are formed by activated neutrophils during the process of NETosis in which the nuclear material is released into extracellular space, including DNA molecules, citrullinated histones, and neutrophil granule enzymes, such as elastase. This material forms networks that are able not only to physically entrap bacteria but also to provide elevated concentration of bactericidal components. Over the last years, it has become clear that NETs can also be formed under numerous sterile inflammatory conditions, i.e., thrombosis, cancer, SLE, atherosclerosis, and diabetes.We reviewed studies published until July 2016 to find possible associations between elevated cell-free DNA levels in dialyzed patients and the process of NETosis and its consequences.The process of NETosis, its elevated activation, or impaired clearance provides the link between clinical conditions and elevated levels of cell-free DNA found in plasma after the hemodialytic procedure which itself is able to activate neutrophils via platelets and ROS formation. NETs stimulate thrombosis and endothelial damage, and their formation may contribute to the development of spectrum of comorbidities described in dialyzed patients.The study of plasma cell-free DNA levels together with markers of NETosis could contribute to the evaluation of the influence of hemodialysis on the immune system of patients. The fact that neutrophils can form extracellular traps (neutrophil extracellular traps—NETs) containing DNA to kill bacteria was first observed and described in 2004 by Brinkmann and colleagues . The terSince the discoveries, the process of NETosis has been explored in greater detail. It has been found that it can be activated not only by bacterial infection but also under sterile conditions associated with thrombosis, cancer, atherosclerosis, and diabetes . The firWe studied the cell-free DNA (cfDNA) levels in plasma in HD patients before and after a hemodialysis session . In accoIn present minireview, our attempt is to summarize what is recently known about the NETosis generally and about the connection between this process; hemodialysis and comorbidities in HD patients with the goal to stimulate intensive research of this interesting phenomenon with multiple potential clinical applications not exclusively for HD patients.NETosis is described as a new type of a programmed cell death following the multi-step highly coordinated scenario based on histone citrullination, chromatin decondensation, migration of elastase and other neutrophil granule enzymes into the nucleus, disintegration of nuclear membranes, and the release of neutrophil extracellular traps (NETs) containing DNA, citrullinated histones, and enzymes of neutrophil granules into extracellular space. NETs are characterized by specific ultrastructure. They are formed by chromatin filaments having 15–17 nm in diameter .Extracellular Traps formation) has been proposed to denote this process [Different types of cell death are usually defined by morphological criteria Table  21]. Re. Re21].  process .Table 1C® Green which label DNA but do not enter intact cells [The methods allowing the quantification of NETosis-specific markers are elaborated and the first reports concerning their use appeared , 24. UnfThe molecular mechanisms activating the process of NETosis are not fully understood. It is clear that the ROS play one of the most important roles in this event. The best inducer of NEtosis in vitro is phorbol 12-myristate 13-acetate (PMA) which belongs to strong inducers of ROS generation . ROS areMPO gene [During the first hour after activation of NETosis, the nucleus loses its lobules, the membranes of nuclear envelope separate, and later, they form vesicles, chromatin decondenses, and the neutrophil granules disintegrate. Then, nucleoplasm and cytoplasm merge, cytoplasmic membrane is broken, and the content of the cell is released into extracellular space to form the NET . EnzymesMPO gene . The enzMPO gene –33. The MPO gene , becauseMPO gene .vital NETosis in contrast to the above-mentioned process of suicidal NETosis [The modification of the process of NETosis which does not lead to the cell death has also been described. This process is referred as  NETosis . Vital N NETosis –38. Amon NETosis –38.ROS-dependent formation of NETs from mitochondrial DNA but not nuclear DNA by viable neutrophils has also been observed . NeutropAntimicrobial activity of NETs was explored widely. The fact that NETs avoid the dissemination of bacteria in the body has been proven in experiments employing artificial bacterial infection of animals and their treatment with DNases . The stuNETs with their complex composition may be considered as typical representatives of alarmins. Alarmins were defined as molecules providing a danger signal associated not only with infections but also with tissue damage. According to the definition , alarminIn vitro, the NETs are degraded by the addition of DNase 1 [The clearance of NETs is not fully understood.  DNase 1 , 45. It  DNase 1 , 46. Imp DNase 1 .The levels of cell-free DNA (cfDNA) were studied before the start and after the completion of a hemodialysis procedure. Irrespective of the type of hemodialysis membrane, the mutually confirming results were obtained by independent studies –16. All Tovbin et al.  regardedJeong da Wun et al.  studied In the opposite way, cfDNA in plasma of HD patients may stimulate the production of IL-6 as demonstrated in an experimental study by Atamaniuk et al. . The resThe researchers measured NET formation markers, including DNA-histone complexes and cfDNA, neutrophil elastase, and IL-6 in HD patients and investigated their potential as predictors of cardiovascular risk and mortality. They also focused on the exploration of the role of uremic toxins with regard to their potential to stimulate the production of DNA-histone complexes and cfDNA in peripheral neutrophils from normal volunteers. This study provided the evidence that uremic toxins induce DNA-histone complex formation and the elevated levels of cfDNA in an in vitro experiment. The levels of DNA-histone complexes were evaluated as a significant independent predictor of major adverse cardiovascular events (MACE) in HD patients.The DNA-histone complexes were regarded as markers of NET formation associated with inflammatory conditions in this study. Inflammatory status of studied HD patients was confirmed by elevated levels of inflammatory cytokine IL-6.In our study , we deteNETosis in peritoneal cavity in the response to the treatment by peritoneal dialysis has not been studied yet. It seems that the research focused on this problem could provide new interesting insights into the complex regulatory network associated with biocompatibility of PD solutions.The elevated levels of NET formation or their persistence have been demonstrated in clinical disorders which frequently occur in HD patients—cardiovascular diseases, including atherosclerosis and thrombosis , diabeteCardiovascular disease belongs to the major causes of morbidity and mortality in HD patients with end-stage renal disease . It has The complex role of NETosis in pathogenesis of atherosclerosis has been partially elucidated. Cholesterol crystals activate the release of NETs, which are able to stimulate macrophages to release the cytokines. In this manner, the immune cell recruitment into atherotic plaques is intensified . NETosisExacerbated NETosis is known as factor complicating wound healing in diabetic patients . The higNETs were detected in affected kidneys in patients with SLE , in autoIn rheumatoid arthritis, the autoantibodies to a citrullinated protein fillagrin are detected. Many patients also express the autoantibodies to histones. Therefore, it is reasonable to suppose that the NETosis is also involved in the pathogenesis of this disease .The study of the roles of NETosis in cancerogenesis represents an exciting newly emerging topic with many practical implications. It has been reviewed in detail by Cools-Lartigue et al. . NeutropThe interconnections among processes of NETosis activation and clearance, clinical conditions, and known laboratory and clinical outcomes are schematically presented in Fig. It seems that cfDNA if regarded in association with other markers of NETosis may become from an analyte of unknown meaning to an important marker providing not only the information about the reaction of patient’s immune response to hemodialysis. In the group of HD patients studied by us previously, we found rarely the individuals in which plasma cfDNA levels decreased due the process of hemodialysis , 47. It The response to the hemodialytic procedure quantified as elevation of NETosis should be taken into account in the treatment of patients according to the severity of their comorbidities especially diabetes, cardiovascular, and autoimmune diseases.Further studies focused on the elucidation of mechanisms of NET clearance, and the possible therapeutic interventions allowing the regulation of this process are needed. It is necessary to keep in mind that NETosis functions as a double-edged sword—the balance between correct immune system performance and the potential damaging effects of exacerbated NETosis should be achieved in HD patients with different comorbidities.The first attempts in this direction have been made. The physiological consequences of NETosis blocking began to be studied , 74. TheElevated plasma levels of cell-free DNA after a hemodialysis procedure may be activated by NETosis which occurs as a consequence of activation of neutrophils during the process of hemodialysis.NETs play crucial roles in pathogenesis of numerous comorbidities of HD patients, such as diabetes, cardiovascular and autoimmune diseases.Better understanding of NETs formation, clearance, and inter-individual differences in this processes is needed for the development of proper diagnostic and therapeutic approaches.The study of plasma cell-free DNA levels together with markers of NETosis could also contribute to evaluation of the influence of hemodialysis on patient’s immune system and to the prediction and management of clinical outcomes with regard to patient’s comorbidities.