Non-invasive ablation and hyperthermia treatments of abdominal organs using High Intensity Focused Ultrasound (HIFU) still impose severe challenges. Especially for liver and kidney treatments, the target motion and accessibility over the entire respiratory cycle make the application of HIFU difficult. To allow for a safe, effective, and efficient treatment, detailed planning and monitoring of the intervention is needed. Current general-purpose physics simulation software cannot fulfill the real-time requirements of the therapy-monitoring application. Our goal is to improve this by numerical simulation to allow for fast and accurate treatment planning and real-time detection of motion-induced risks during HIFU-therapy.We developed a method to numerically simulate HIFU using patient-specific motion information in real time. The bio-heat equation describing the temperature distribution in the patient is mathematically transformed to a static reference anatomy. The numerical solution can then be performed in the reference anatomy on a static computational domain. Patient-specific respiratory motion information is provided by an abdominal motion model that can be fed with sparse tracking data in the clinical setting. The respiratory motion is modelled allowing sliding motion of the inner organs along the abdominal wall.Motion information is fed into the simulation by an unstructured moving point cloud. On top of this point cloud a tetrahedral mesh is build to interpolate the motion information. The mesh is split at the abdominal wall into individually moving parts to allow the sliding motion of the liver along the abdominal wall. The numerical simulation thereby resolves the sliding boundary and allows the prediction of the temperature rise also in the beam path between transducer and target. Fast US beam steering is simulated using ultrasound pressure field pre-computations for key states over the respiratory cycle. Any remaining location mismatch between closest pre-computation and actual target location is compensated using an additional transformation. The numerical simulation method is integrated into a HIFU-therapy planning tool. Based on image data the target volume, anatomical and risk structures are defined. Treatment planning is then performed guided by direct feedback from the numerical simulation including respiratory motion of the domain. Using the feedback from the simulation, the user can manually optimize transducer and target location and HIFU parameters.The method accounts for patient-specific anatomy and motion information in real time. Sliding motion of the inner organs along the abdominal wall is accounted for by the simulation. The transformation to the static reference frame results in an accurate scheme for long simulation durations. The developed method can be a possible important building block for HIFU-therapy planning and conduction in moving organs.


The access of high-technology medicines in Russia is restricted for such reasons as pricing and reimbursement policy, medical indications and many others. Most difficulties are presented in children because of a lack of clinical data about effectiveness and safety.The objective of the study was to evaluate acceptability, affordability and availability of high technology medicines and provide the practical recommendations for optimization of their access in Russia ).A retrospective non-interventional study of JIA patients  for assessment of clinical and economical effectiveness of biologics and disease-modifying therapy[Availability: six biologics  were available for patients with JIA in Russia. Two of them (Infliximab and Rituximab) were used off-label. Affordability: direct medical costs for therapy including biologics were nine times higher than for disease-modifying drugs. Price nAcceptability: expert survey has shown that there is a very long patient journey for administration of biologics for advanced forms of JIA in patients with proved disability. There is a restriction of access to biologics on a regional level.There is an improvement of affordability of high-technology medicines in Russia thanks to development of the methods of health technology assessment.


To our knowledge, the use of point-of-care ultrasound for detecting a fish bone in the cervical esophagus has never previously been reported in the English literature.We herein report the case of the accidental ingestion of a fish bone which was detected in the cervical esophagus by means of point-of-care ultrasound. A-70-year-old woman presented at the emergency department of our hospital with odynophagia in the neck after eating a slice of grunt (a type of fish) simmered in broth. Prior to this presentation she had already undergone direct laryngoscopy without any fish bone being identified at an otorhinolaryngology clinic. Point-of-care ultrasound was thereafter performed. As a result, a linear and hyperechoic structure was thus identified in the cervical esophagus. The structure did not seem to penetrate the wall of the esophagus. Computed tomography confirmed the same finding without any penetration. An endoscopic examination revealed a fish bone stuck in the cervical esophagus. The bone measured 17 mm in length, and was safely removed under endoscopic guidance. Subsequently the patient demonstrated a good recovery without any complications.We describe the identification of a fish bone in the cervical esophagus using point-of-care ultrasound. Point-of-care ultrasound may therefore be a useful modality for both detecting the presence of fish bones in the cervical esophagus and also for confirming the existence of any complications.The study was conducted in accordance with the ethical standards dictated by applicable law. Informed consent was obtained from each owner to enrolment in the study and to the inclusion in this article of information that could potentially lead to their identification.


Men who have sex with men (MSM) are at increased risk of HIV and other STI infections in Nigeria. This is because MSM are afraid to seek medical help because the healthcare workers in various facilities are afraid of the consequences if they provide services for MSM citing the law as a reason not to intervene. MSM in northern states of Nigeria are facing double-jeopardy because the few international partners working in MSM in Nigeria are pulling out of these volatile areas because of the fear of attacks by the Boko Haram and the Nigerian law enforcement agencies.The intervention was conducted to promote affordable and sustainable HIV care and treatment for MSM in Nigeria.This intervention was conducted in the Boko Haram ravaged cities of Kano and Maiduguri (North-East Nigeria). Twenty MSM-key influencers from the two cities were identified and trained on HIV counselling and testing, caregivers, case managers and on initiation process for ARV treatment for new HIV+MSM as well as ethical considerations.The mean age of the key influencers was 24 years +/−SD. Each of the trained 20 key influencers reached 20 MSM-peer with condom promotion, HCT, referral to identified MSM-community health centers and follow-up/caregiving within the space of one month. The project was able to reach 400 MSM in the two cities. 89% of the peers consented to HCT. HIV prevalence among the participants was at 18%. The project recorded ARV-successful referral to healthcare facilities for the respondents that tested positive. The key influencers have been following up for ARV-adherence.Use of community members should be promoted for sustainability and ownership. It also helps in eradicating socio-cultural barrier to HIV intervention for MSM. Moreover, this proves to be one of the safest and affordable methods of reaching MSM in Nigeria in this ugly time of legalization of homophobia in the country's constitution.


This article studies the viscous flow and heat transfer over a plane horizontal surface stretched non-linearly in two lateral directions. Appropriate wall conditions characterizing the non-linear variation in the velocity and temperature of the sheet are employed for the first time. A new set of similarity variables is introduced to reduce the boundary layer equations into self-similar forms. The velocity and temperature distributions are determined by two methods, namely (i) optimal homotopy analysis method (OHAM) and (ii) fourth-fifth-order Runge-Kutta integration based shooting technique. The analytic and numerical solutions are compared and these are found in excellent agreement. Influences of embedded parameters on momentum and thermal boundary layers are sketched and discussed. The fundamental problem of two-dimensional flow due to stretching plane surface, initially discussed by Crane The literature cited above deals only with the case of either linearly or exponentially driven velocity of the sheet. Vajravelu To our knowledge, the three-dimensional flow due to non-linearly stretching sheet has not been yet reported. It is obvious that three-dimensional flows can be appropriate in giving more clear physical insights of the real world problem when compared with the two-dimensional flows. The present work is therefore undertaken to fill such a void. The study also assumes that the temperature across the sheet is non-linearly distributed. Introducing a new set of similarity variables the boundary layer equations are first reduced into self-similar forms and then solved both analytically and numerically. It is pertinent to mention that computation of either approximate analytic or numerical solutions of the boundary layer equations governing the flow and heat transfer is often challenging  and (12) in Eq. (11), one obtainsvely see . The verThe non-linear differential and the auxiliary linear operators are selected as belowIf By Taylor's series expansion one obtainsmth-order deformation equations corresponding to Eqs. (7)–(10) are as belowSubstituting In order to determine the optimal values of Minimize of the software MATHEMATICA (see Liao Such kind of error has been considered in other works st order ODEs by substituting Eqs. (7)–(9) subject to the boundary conditions (10) have been solved numerically by shooting method with fifth order Runge-Kutta integration procedure. First, we reduce the original ODEs into a system of 1and the corresponding initial conditions areSuitable values of the unknown initial conditions th-order OHAM solutions for temperature This section contains the physical interpretations of the behavior of the interesting parameters entering into the problem. We compare the 15For the first time, the flow and heat transfer over a plane surface stretched non-linearly in two lateral directions have been investigated. The simulation in this study assumes that the temperature across the sheet is non-linearly distributed. Both analytic and numerical solutions are obtained and found in excellent agreement. Following are the major results of this study.I. It is seen that shear stress at the wall increase when the stretching rates ratio is increased. The entrainment velocity is negative, representing a downward flow in the vertical direction, which is a consequence of the bi-directional stretching sheet.II. The increased intensity of the cold fluid at the ambient towards the stretching sheet with an increase in stretching rates ratio III. The temperature decreases and thermal boundary layer thins when the power-law index IV. The results for the case of two-dimensional and axisymmetric flows can be obtained as special cases of present study when


Despite more than a century of dedicated research, the etiology and pathogenesis of AIS remain unclear. By definition, 'idiopathic' implies an unknown cause. Nevertheless, many abnormalities concomitant to AIS have been described, often with the suggestion that these abnormalities are related to etio-pathogenesis. Insight in the concomitant abnormalities may assist in improving the understanding of the etiological pathways of AIS. For understanding of the etiology of adolescent idiopathic scoliosis (AIS), this systematic review gives as complete an overview as possible of abnormalities that have been implicated to be concomitant with AIS.Original studies comparing untreated AIS patients with healthy adolescents on abnormalities other than the deformity of the spine were retrieved from PubMed and Embase. We followed PRISMA guidelines and to quantify the relationship between each abnormality and AIS we used a best-evidence-syntheses for relating risk-of-bias to consistency of effect sizes.We identified 88 relevant citations, forty-seven carried high risk-of-bias and twenty studies did not report quantitative data in a sufficient manner. The remaining twenty-one publications failed to report data from before initiation of the deformity and blind assessments. These cross-sectional studies provided data on fourteen abnormalities concomitant to AIS. With our best-evidence-syntheses we were unable to find both strong evidence and a consistent pattern of occurrence for AIS and any of these abnormalities. From moderate risk-of-bias studies a relatively consistent pattern of occurrence for AIS and impaired gait control  and decreased bone mineral density  was found. For nine abnormalities a consistent pattern of occurrence with AIS was found, but the evidence for these was weak.Based on the available literature, strong evidence is lacking for a consistent pattern of occurrence of AIS and any abnormality. In addition, abnormalities were never studied before the onset of the deformity. The relevance for understanding the multifactorial etiology of AIS is very limited.


Spontaneous activity as recorded by fMRI has often been used to infer active connections  in the human brain through correlations of activity measures. Some serious questions have been raised about the interpretation of these correlations, which are often apparent only on time scales of tens of seconds. Confirmation of correlations in measures of activity on shorter time-scales closer to those of neural activity would be very desirable.Numerous mechanisms have been proposed for various rhythms but in the past half-century little consensus has been reached on the mechanism of any major rhythm. The recent development of high-throughput imaging methods enable us for the first time to rigorously and quantitatively test ideas about the dynamics of brain rhythms.We have generated high-resolution data on neural activity over most of one hemisphere of mouse cortex by voltage-sensitive dyes, in both anesthetized and awake animals. In previous work  we have Our results suggest that similar methods can be used with data generated by the new high-throughput technologies anticipated by the BRAIN initiative, to understand communication between brain regions at time scales of neural computation.


There is not any evidence of previous publications about the matter in our country.To observe if a sample of 4The students completed a questionnaire before and after a 2-hour practical lesson about ultrasound. The surveys were divided in three parts: a) questions about theoretical and practical knowledge about ultrasound using a 5-point Likert scale of perceived importance ; b) list of structures and pathologies that the students were able to detect by using the ultrasound; c) open-ended questions and comments. The statisitics are presented as percent means or proportions with p-values from t-testing.Significant improvements in knowledge about ultrasound were observed, comparing the pre- and post-practical tests (the number of structures and pathologies detected increased). The intervention also increased their perceived importance of this diagnostic tool.The students increased their level of knowledge about ultrasound, as well as the level of the perceived importance of its use in medical practice. It would be interesting to conduct more educational sessions on this diagnostic tool, including the introduction of ultrasound in different subjects, including anatomy and physiology during the pre-clinical years of training, in our country as it is done in other countries.


The evaluation of innovation from early to late phase studies requires appropriate selection and reporting of outcomes. These are well defined for pharmaceutical interventions, but much less well considered for non-pharmaceutical interventions such as surgery. We report a new method - an evolution review - to understand and document the evolution of outcomes reported at each stage of evaluation of novel surgery from first in human to pragmatic multi-centre RCTs.A search strategy identified all search terms for precursors and derivatives of a novel surgical intervention and was run in Embase and Medline. Abstracts with primary data were included and ordered chronologically, sequentially numbered and then grouped by year. We identified the year of publication of the first-in-human study and used that year to begin the sampling. Three publications were sampled from each year after randomly ordering. An additional sample equal in size to the previous sample was randomly sampled from the remainder. This methodology was chosen as the initial sample ensured representation of each year studied and the second sample added weight to years where there was a higher frequency of studies published.This new methodology - which we have termed an ‘evolution review’ - aims to use this information to inform guidelines for outcome reporting during the evolution of surgical interventions.


There are two errors in the RP-1164 row and Nucleotide Change and Protein Change columns of


The Stimulus-Response (S-R) theory and Tolman's Cognitive Theory of behavior control both issued from behaviorism in the early 20th century still provide a relevant general framework to account for animal reward-based adaptive behavior. In this paper, we propose a new paradigm for representing and implementing both the cognitive strategy and the S-R habit strategy within a unitary coding frame. Based on a parallel learning of both strategies, the model explains how the fast learning cognitive strategy can supervise and accelerate the slow learning S-R habit strategy; and also how. In late learning stages, the habit strategy can overcome the cognitive. This parallel representation is inspired by the cortico-basal functional loops  and the The implementation of S-R habit strategy is based on a neural modified version of the classical Q-learning and is based on the model of , emulatiThe model exploits this speed difference in its parallel learning. The fast acquisition of the cognitive map allows the robot to quickly choose correct paths to the goal, and thus the time convergence of the Q-learning algorithm is optimized. The cooperation is based on the biasing of the selected transition by the cognitive map and the Q-learning in parallel (see Figure


There is an error in the fifth sentence of the Abstract. The correct sentence is: In total, 288 up-regulated DEGs and 106 down-regulated DEGs were identified.There is an error in the third sentence of the Results section under the heading “GO and pathway enrichment analyses of DEGs.” The correct sentence is: Specifically, the DEG distribution in the pathway of Metabolism of xenobiotics by cytochrome P450 was shown in Fig 2.


Stem cells are undifferentiated cells with the ability to self-renew and the potential to differentiate into all body cell types. Stem cells follow a developmental genetic program and are able to respond to alterations in the environment through various signaling pathways. The mechanisms that control these processes involve the activation of transcription followed by a series of post-transcriptional events. These post-transcriptional steps are mediated by the interaction of RNA-binding proteins (RBPs) with defined subpopulations of RNAs creating a regulatory gene network. Characterizing these RNA-protein networks is essential to understanding the regulatory mechanisms underlying the control of stem cell fate. Ribonomics is the combination of classical biochemical purification protocols with the high-throughput identification of transcripts applied to the functional characterization of RNA-protein complexes. Here, we describe the different approaches that can be used in a ribonomic approach and how they have contributed to understanding the function of several RBPs with central roles in stem cell biology. Stem cells are undifferentiated cells that are found in multicellular organisms both throughout embryonic development and in adult tissues. These cells have the ability to self-renew and the potential to differentiate into all body cell types. This plasticity makes stem cells especially attractive for use in cell therapies.Embryonic stem cells respond to and follow a developmental genetic program that is triggered by a complex cascade of regulatory molecules. Adult stem cells remain in small amounts in adult tissues, where they are responsible for tissue repair and homeostasis  method involves the fusion of a double-tag either at the amino or carboxy terminus of the protein followed by transfection of the studied cell type Figure . In vivoRNA targets of RBPs have been identified by immunoprecipitation assays, followed by genomic analysis using microarrays, known as RIP-Chip (RNA ImmunoPrecipitation and microchip hybridization), or more recently using next-generation sequencing methods, RIP-Seq Figure  Tenenba, 2014. TOne major unwanted output of these techniques is the co-purification of non-specific and usually abundant transcripts. To isolate only specific transcripts that are bound by RBPs, different strategies have been developed to improve the RIP analysis. The refinement of this technique involves the cross-linking of RNA-protein complexes prior to purification (CLIP) Figure . UltraviTo map the binding site, RNA is digested up to a length of ~50 nt, reverse transcribed after RNA adapter ligation, and amplified to prior sequencing. One limitation is represented by the low efficiency of crosslinking using UV light. PAR-CLIP (PhotoActivatable Ribonucleoside-enhanced CrossLinking and ImmunoPrecipitation)  protein is essential for the maintenance of viable stem cells. This protein is expressed in human embryonic stem cells, where the population of associated mRNAs was identified  is responsible for fragile X syndrome. FMRP contains multiple domains that directly interact with RNA  mechanisms with alternative splicing regulation. In mouse embryonic stem cells, a stringent purification method was used when iCLIP libraries were generated by sequential Flag and HA tag immunoprecipitation . The Musashi proteins are found in stem and progenitor cells and are overexpressed in several cancer cells, with a well-defined role in the regulation of the undifferentiated state. A pulldown assay (RNA bind and seq) using RNA from mouse neural stem cells identified the population of MSI1-bound transcripts  proteins are mRNA regulators with a conserved role in the maintenance of mitotic division, resulting in the self-renewal of stem cells  of their respective transcriptomes  (Galgano et al., Our group was able to identify approximately 300 putative PUM2 targets in adipose-derived stem cells using RIP-Chip Figures  Shiguno. CellulaIn another study from our group, we evaluated the total RNAs and polysome-associated mRNAs in adipose-derived stem cells using polysome profiling (Spangenberg et al., The identification of which RNAs are associated with post-transcriptional regulatory proteins and the genetic network that they form is important to understand the essential steps in stem cell differentiation and the mechanisms that are responsible for the maintenance of the undifferentiated state. The combination of affinity purification methods and large-scale identification of transcripts, plus the development of powerful bioinformatics tools will lead to a systematic characterization of these networks. Though much effort has been devoted to this challenge, there is still much work in the future that is needed to understand the complex mechanisms underlying post-transcriptional regulation.The authors contributed equally to write the mini review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Exposure to the trauma memory is the common denominator of most evidence-based interventions for posttraumatic stress disorder (PTSD). Although exposure-based therapies aim to change associative learning networks and negative cognitions related to the trauma memory, emotional interactions between patient and therapist have not been thoroughly considered in past evaluations of exposure-based therapy. This work focuses on recent discoveries of the mirror-neuron system and the theory of embodied simulation (ES). These conceptualizations may add a new perspective to our understanding of change processes in exposure-based treatments for PTSD patients. It is proposed that during exposure to trauma memories, emotional responses of the patient are transferred to the therapist through ES and then mirrored back to the patient in a modulated way. This process helps to alleviate the patient's sense of loneliness and enhances his or her ability to exert control over painful, trauma-related emotional responses. ES processes may enhance the integration of clinical insights originating in psychoanalytic theories—such as holding, containment, projective identification, and emotional attunement—with cognitive behavioral theories of learning processes in the alleviation of painful emotional responses aroused by trauma memories. These processes are demonstrated through a clinical vignette from an exposure-based therapy with a trauma survivor. Possible clinical implications for the importance of face-to-face relationships during exposure-based therapy are discussed. Exposure to the memory of the traumatic event is the common denominator of most evidence-based interventions for posttraumatic stress disorder (PTSD) and is included in the guidelines for the treatment of PTSD set by the International Society for Traumatic Stress Studies and by the Veterans Health Administration and Department of Defense  emotions are shared thus creating a sense of “we-ness” in the therapy; and 2) emotions are modulated in a way that simultaneously reduces fear as well as enhances regulation of a wider range of feelings. The interpersonal aspects of exposure therapy, as discussed above, may require an additional skill set for the therapist to further enhance the practice of exposure in psychotherapy for PTSD.


Increasingly, health policy-makers and managers all over the world look for alternative forms of organisation and governance in order to add more value and quality to their health systems. In recent years, the central government in England mandated several cross-sector health initiatives based on collaborative governance arrangements. However, there is little empirical evidence that examines local implementation responses to such centrally-mandated collaborations.Data from the national study of Health Innovation and Education Clusters (HIECs) are used to provide the first comprehensive empirical evidence about the implementation of collaborative governance arrangements in cross-sector health networks in England. The study employed a mixed-methods approach, integrating both quantitative and qualitative data from a national survey of the entire population of HIEC directors , a group discussion with 7 HIEC directors, and 15 in-depth interviews with HIEC directors and chairs.The study provides a description and analysis of local implementation responses to the central government mandate to establish HIECs. The latter exemplify cross-sector health networks characterized by a vague mandate with the provision of a small amount of new resources. Our findings indicate that in the case of HIECs such a mandate resulted in the creation of rather fluid and informal partnerships, which over the period of three years made partial-to-full progress on governance activities and, in most cases, did not manage to become self-sustaining without government funding.This study has produced valuable insights into the implementation responses in HIECs and possibly other cross-sector collaborations characterised by a vague mandate with the provision of a small amount of new resources. There is little evidence that local dominant coalitions appropriated the central HIEC mandate to their own ends. On the other hand, there is evidence of interpretation and implementation of the central mandate by HIEC leaders to serve their local needs. These findings augur well for Academic Health Science Networks, which pick up the mantle of large-scale, cross-sector collaborations for health and innovation. This study also highlights that a supportive policy environment and sufficient time would be crucial to the successful implementation of new cross-sector health collaborations.


Selenium (Se) is an important trace element for human physiology. It has anti-inflammatory, anti-neoplastic and anti-aging properties and protects from oxidative stress . It is pLow concentrations of Se were shown in patients with Graves' disease . Higher The influence of Se on goitrogenesis and carcinogenesis in the thyroid gland is still unclear. The data on effect of low Se levels in patients with goiter and thyroid nodules are divergent ,10. In vConclusive results about the undisputable role of Se in the treatment of thyroid related diseases, including hyperthyroidism or thyroid orbitopathy, on a wider scale are still unavailable and further research is both required and recommended.


With the launch of our journal, we aim to fill this gap and provide a forum for interdisciplinary research articles that specifically address computational approaches in drug-design and multi-scale analysis of bioactive substances from the cellular up to behavioral level.


Femtosecond X-ray irradiation of solids excites energetic photoelectrons that thermalize on a timescale of a few hundred femtoseconds. The thermalized electrons exchange energy with the lattice and heat it up. Experiments with X-ray free-electron lasers have unveiled so far the details of the electronic thermalization. In this work we show that the data on transient optical reflectivity measured in GaAs irradiated with femtosecond X-ray pulses can be used to follow electron-lattice relaxation up to a few tens of picoseconds. With a dedicated theoretical framework, we explain the so far unexplained reflectivity overshooting as a result of band-gap shrinking. We also obtain predictions for a timescale of electron-lattice thermalization, initiated by conduction band electrons in the temperature regime of a few eVs. The conduction and valence band carriers were then strongly non-isothermal. The presented scheme is of general applicability and can stimulate further studies of relaxation within X-ray excited narrow band-gap semiconductors. Intense ultrashort radiation available at the free-electron-laser (FEL) facilities all over the world12346810111213However, this experimental scheme also opens possibilities to extract information about the physical processes following the relaxation of the laser-excited materials. Similar techniques have been used in two-color experiments with optical lasers to extract information on the electron-phonon coupling coefficient1617In this study we revisit the results of the experiments measuring the transient optical reflectivity in GaAs irradiated with femtosecond pulses of soft and hard X-ray radiation8Electronic excitation and relaxation processes following the FEL irradiation of solids are well understood2324However, thermalization between the valence and conduction band may take longer time than the carrier thermalization within the conduction band. The relation between these two timescales depends on the ratio of the effective masses of holes and electrons. In GaAs holes are almost Already after the appearance of first photoelectrons within the conduction band, the energy exchange between free carriers and lattice starts. In semiconductors the timescale of this process In this work we show that the experimental data on the transient reflectivity allow to follow in time the relaxation of FEL excited GaAs on timescales up to a few tens of picoseconds. We follow the ideas from the optical measurements described in refs 17Our proposed theoretical framework uses rate equations to describe the evolution of electron distribution as a function of time. The rate equations are coupled with the two-temperature modelet al.et al.In experiments with X-ray FELs8Both experiments observed a centeracteristic shape of transient reflectivity curve, ectivity . These cectivity . In whatWith our modeling tool we performed simulations of the transient reflectivity changes within GaAs for the experimental conditions as described in refs First, we estimated the final electron-hole density after FEL irradiation, knowing the pulse fluence and the photoabsorption cross section at a given photon energy. We then followed the increase of the electron-hole density until the maximal density was reached. Such behaviour is typical for FEL irradiated semiconductors as described, e.g., in24After the maximal electron-hole density is reached, the system starts to relax. Electron-lattice thermalization and electron-hole recombination are the predominant relaxation channels. In GaAs the latter one contributes less significantly, as the typical recombination timescales are of the order of The extended Drude model including the interband contribution is used to calculate the transient reflectivity change from the dielectric function, where The average electron collision time Rate equations describe the changes of electron-hole density due to ionization and recombination processes. Heat capacities of the free-electron gas from ref.  . Plots  show theThe ultrafast drop and rise of optical reflectivity is due to the production of electron-hole pairs in the irradiated semiconductors as described in ref. et al. that lead to an overcritical electron density. However, at the pulse fluences close and larger than the one leading to the critical electron density, the minimum of The theoretical calculations shown in At a 400 nm probe-pulse the interband absorption coefficient is about 100 times larger than at 800 nm2121As we have discussed above, the centeracteristic time of the overshooting directly follows the timescale of the band-gap shrinking. The experimental data on reflectivity change can then be used to determine the electron-lattice thermalization time. Experimental studies of electron-phonon coupling and electron-lattice thermalization time have been extensively performed in metals1541424344171848493843515253545657N is the number of the available experimental points. The values of thermalization time and electron temperature presented in Here, we apply our model to the experimental data to extract information on the electron-lattice thermalization time in GaAs. In et al.) at the pulse fluence of 2 are The values of The estimated electron temperature at the end of the electron thermalization .


The structure of synaptic connectivity plays an important role in information processing and dynamics of neuronal microcircuits. Previous work has shown that cortical microcircuits contain non-random features of the network structure , and thaA subpopulation of connected hubs can be analyzed using common mean-field methods. This analysis reveals two stable fixed points of the spiking activity, one at a low firing rate and another one at a high firing rate.We first model a single layer of a column of rodent barrel cortex. The subpopulation of connected hubs switches between the two fixed points and generates up-state/down-state oscillations (see Figure


The concept of specificity of exercise prescription and training is a longstanding and widely accepted foundation of the exercise sciences. Simply, the principle holds that training adaptations are achieved relative to the stimulus applied. That is, the manipulation of training variables  directly influences the acute training stimulus, and so the long-term adaptive response (Young et al., one-size-fits-all approach to post-exercise recovery is likely to contribute to contrasting reports of the efficacy of many techniques. While these concerns could indicate the need for greater understanding of the mechanistic demands of specific exercise tasks and post-exercise recovery protocols so to be suitably matched, they are of great consequence in applied settings where maladaptation may be the result of inappropriate recovery practices (Kenttä and Hassmén, Despite the emphasis that is placed on specificity in the application of the desired training stimulus, it is noteworthy that this concept receives less attention within the post-exercise recovery literature. Indeed, most recovery strategies are intended to treat only symptoms of exercise-induced muscle damage by blunting inflammatory responses associated with disturbances to the structural integrity of the exercised musculature (Minett and Duffield, The research narrative surrounding post-exercise cooling for recovery reflects this point. A derivative of the use of ice as a therapeutic treatment of soft tissue injuries, the proposed benefits of acute cooling interventions on recovery after exercise relate to peripheral vasoconstriction centralizing blood volume away from exercised musculature (Bleakley and Davison, Irrespective of whether post-exercise cooling benefits recovery through the treatment of exercise-induced muscle damage or through other means, the specificity of administration of this intervention becomes key. Most pertinent, changes in circulatory dynamics and muscle metabolism as a result of post-exercise cooling (Vaile et al., The topic of post-exercise recovery from training has been the focus of recent attention in both narrative (e.g., Nédélec et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This data article presents the differences observed between the myristoylated and non-myristoylated forms of the neuronal calcium sensor protein, neurocalcin delta (NCALD). Analysis of the myristoylated and non-myristoylated versions of the protein by mass spectrometry provided difference in mass values consistent with addition of myristoyl group. In the presence of calcium, mobility retardation was observed upon electrophoresis of the protein in native gels. The retardation was dose-dependent and was exhibited by both the myristoylated and non-myristoylated forms of the protein. Value of the data•The relevance of myristoylation to the biological functions of Neuronal Calcium Sensor (NCS) proteins remains to be elucidated.•Data is presented on the myristoylated and non-myristoylated forms of NCALD assessed by calcium-induced mobility shift assay.•The calcium-induced mobility shift assay may be useful in assessing the contribution of myristoylation and other post-translational modifications to response of all NCS proteins to calcium.1Bacterially expressed NCALD was purified in its myristoylated and non-myristoylated forms independently. Mass spectrometric analyses was carried out to determine the mass of each form and to determine if the myristoylated form also contained the non-myristoylated form. A table of the mass values of the two forms is provided, along with those documented in an earlier report by other investigators. Based on the analyses, there is little non-myristoylated NCALD in the myristoylated preparations. The two preparations were subjected to electrophoresis in native gels in the presence of incremental concentrations of calcium. A dose-dependent mobility retardation is observed with both forms. However, the myristoylated form exhibits a greater amplitude and increased sensitivity to change in calcium concentrations.2E. coli ER2566 as described in N-Myristoyl Transferase were used and myristic acid was supplemented. Cells without the transferase were used to generate the non-myristoylated form; the supplementation was also skipped. Cells were collected 2.5 h after induction, sonicated and the protein was purified on phenyl sepharose columns as described previously NCALD was expressed in −) or myristoylated (Myr+) NCALD. Protein was incubated in the presence of indicated concentration of calcium using calibration buffers and electrophoresed in native gels as described Mobility Retardation of NCALD (and other NCS proteins) in native gels has been documented. The retardation was directly dependent on the concentration of calcium. In order to determine if myristoylation of NCALD was essential for the calcium-dependent mobility shift, analyses were carried out with the non-myristoylated (Myr


The original article "Cost-Effectiveness of High, Moderate and Low-Dose Statins in thePrevention of Vascular Events in the Brazilian Public Health System" published in theJanuary 2015 issue of the Brazilian Archives of Cardiology , was published in the Portuguese version as "Effectiveness of High,Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian PublicHealth System". A correction was made in the Portuguese version.


It is generally acknowledged that the 17-segment AHA model provides a suitable approximation for mapping the results of X-ray angiography onto myocardial anatomy in a consistent way in the absence of a more exact method. In practice, coronary anatomy varies from patient to patient which is acknowledged as the main limitation of the AHA model. The aim of this study was to establish whether the generation of a patient-specific coronary artery to perfusion segment map improved diagnosis of myocardial ischaemia.In this retrospective sub-study with the data from the CE-MARC trial  an 18-patient sample was selected where the image quality of the magnetic resonance angiography (MRA) data allowed for a reliable manual coronary tree annotation. Mediated spatiotemporal registration was used to compute the deformation fields between the MRA and perfusion data. The deformation fields were applied to the annotated coronary trees in order to warp them into the spatiotemporal coordinate space of the corresponding perfusion series. Three patient-specific coronary supply territories  were computed on the basis of the physical proximity of the major coronary arteries to the epicardial surface of the basal, medial and apical slices in the given perfusion series. Quantitative perfusion analysis using Fermi-constrained deconvolution was performed after manual motion correction and contour delineation in the perfusion series. Myocardial perfusion reserve (MPR) ratios were calculated from the ratio of stress to rest myocardial blood flow (MBF) estimates. A comparison between the diagnoses made using the AHA map and the patient-specific map was performed for each of the 18 patients. The presence of myocardial ischaemia was assessed using the consensus diagnosis of invasive, quantitative X-ray angiography and myocardial Single Photon Computed Tomography (SPECT) imaging.The patient-specific territories were markedly different from the AHA Figure . For a tThe use of patient-specific blood supply territories derived from the actual coronary anatomy has the potential of enhancing the diagnostic accuracy of quantitative perfusion analysis by providing a mechanism for computing perfusion parameters for the artery-specific regions of the myocardium. An improvement on the allocation of coronary artery to myocardial region over the AHA recommendation has been shown.This work was funded by the Top Achiever Doctoral scholarship awarded by the Tertiary Education Commission of New Zealand.


Intracranial branch atheromatous disease is a type of ischemic stroke that is caused by narrowing or occlusion of the orifice of the penetrating artery by atheromatous plaque. Pontine branch atheromatous disease is usually diagnosed using indirect findings such as the extension of a lesion to the basal surface of the pons because of the difficulty of demonstrating plaque in the basilar artery.A 72-year-old Japanese man developed sudden dysarthria and left hemiparesis, and his symptoms deteriorated thereafter. Brain magnetic resonance imaging revealed an acute infarction in the territory of the right paramedian pontine artery extending to the basal surface. Non-contrast-enhanced three-dimensional fast spin-echo T1 imaging with variable flip angles and three-dimensional fast imaging with steady-state acquisition revealed a plaque in the dorsal wall of the basilar artery that spread to the origin of the paramedian pontine artery that branched toward the infarction. Although antithrombotic agents were started, the left hemiparesis got worse and became flaccid on the following day.This is the first report to confirm the pathological basis of branch atheromatous disease by three-dimensional images using the new modalities of 3-Tesla magnetic resonance imaging. The use of these techniques will foster better understanding of the clinicopathological mechanisms of branch atheromatous disease. Intracranial branch atheromatous disease (BAD) is a type of ischemic stroke that is caused by narrowing or occlusion of the orifice of the penetrating artery by atheromatous plaque. Pontine BAD is usually diagnosed using indirect magnetic resonance imaging (MRI) findings such as the extension of a lesion to the basal surface of the pons. Here we report a case of pontine BAD diagnosed directly by the radiographic demonstration of BAD pathophysiology using 3-Tesla MRI.A 72-year-old Japanese man with hypertension, diabetes mellitus, and dyslipidemia presented with sudden left hemiparesis in the early afternoon. He developed dysarthria and choked on food and drink in the evening. By the next morning, the left hemiparesis had progressed and he could not stand up. He was taken by ambulance and admitted to our hospital; on admission a neurological examination revealed dysarthria and left hemiparesis involving his face, arm, and leg. MRI  revealed an acute infarction in the territory of the right paramedian pontine artery (PPA) extending to the basal surface Figure A. MR angCaplan described BAD as cerebral infarction caused by narrowing or occlusion of the mouth of the branching artery by an atheromatous process that is different from lipohyalinosis causing lacunar infarction . RecentlCube T1 is a volumetric imaging technique with isotropic voxels that enables reformation of black-blood images into any plane and allows detection of atherosclerotic plaques with high resolution. In addition, we depicted the outer contour of the PPA using 3D-FIESTA, which detects small amounts of fluid based on the long T2 relaxation. These new reconstructive modalities of MRI clearly and three-dimensionally demonstrated the presence of atherosclerotic plaque in the major artery at the origin of the penetrating artery, which is the pathological basis of BAD.We reported the case of a patient with a typical clinical course of BAD and demonstrated the pathological basis of BAD using 3-Tesla Cube T1 and 3D-FIESTA MRI techniques. At present, the recognition of BAD is insufficient and the use of these high-resolution MRI modalities will foster better understanding of the clinicopathological mechanisms of BAD.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Pre-eclampsia is a major cause of maternal and fetal mortality in pregnancy. The identification of genetic variants which predispose to pre-eclampsia demands large DNA collections from affected mothers and babies and controls, with reliable supporting phenotypic data. The InterPregGen study has assembled a consortium of researchers from Europe, Central Asia and South America with the aim of elucidating the genetic architecture of pre-eclampsia. The MoBa collection is playing a vital role in this collaborative venture, which has the potential to provide new insights into the causes of pre-eclampsia, and provide a rational basis for novel approaches to prevention and treatment. The InterPregGen consortium, a multinational collaboration between research groups from Europe, Central Asia and South America, is seeking to identify genetic factors which predispose to pre-eclampsia, a quest which has proved challenging to investigators from around the world for decades. Pre-eclampsia is the most serious of the hypertensive disorders of pregnancy, with an incidence ranging from 2-5% of pregnancies in Western Europe and North America to as high as 18% in parts of Africa . Exact fth week of gestation; these are manifestations of widespread vascular endothelial dysfunction. It is possible that this is a common end point to diverse pathogenetic mechanisms, but the two-stage theory is a useful model, supported by observational and experimental evidence [The clinical features of pre-eclampsia are maternal hypertension and proteinuria developing after the 20evidence . In the evidence . For theEpidemiological studies over the past five decades have provided robust and consistent support for the clinical observation that pre-eclampsia runs in families. First degree relatives of affected women have a 2- to 3-fold increase in risk of pre-eclampsia -10. FurtThese observations justify the search for genetic variants in mothers and babies which confer susceptibility to pre-eclampsia. Genetic studies offer an important advantage in the identification of novel pathogenetic mechanisms in diseases of pregnancy, as they circumvent the practical and ethical challenges of obtaining suitable maternal and fetal tissue early in pregnancy, when trophoblastic invasion of maternal tissues occurs; investigation of genetic variation in mother and offspring can be conducted on DNA obtained at any time. Furthermore, in a disorder such as pre-eclampsia with a rapidly progressive pathophysiology it is often difficult to distinguish between causal factors and secondary phenomena resulting from disease processes. Genetic variation which proves to be associated with disease is guaranteed to predate the disease process.Genome-wide linkage studies of pre-eclampsia, analysing families with two or more affected women from Australasia, Iceland, Finland and Holland, have each identified loci which appear to show linkage with pre-eclampsia in their populations, but these results have not been independently replicated -18. ManyA major cause of the lack of success in identifying susceptibility genes has been the limited statistical power of the majority of studies performed to date. It is now apparent that many common genetic variants which predispose to complex disorders have individually small effect sizes. These variants are therefore difficult to detect by linkage analysis but can be detected with much higher power using genetic association study designs . InteresThe InterPregGen consortium was formed to address these deficiencies, aiming firstly to include a sufficiently large number of subjects with rigorously defined pre-eclampsia to provide adequate statistical power for association studies to detect genetic variants with small effect sizes; secondly, to use genome-wide association screening (GWAS) to scan both the maternal and fetal genomes for variants that predispose to pre-eclampsia. Also, the majority of larger published genetic studies in pre-eclampsia have been conducted in women of European ancestry, where the incidence of pre-eclampsia is amongst the lowest in the world. Therefore a further objective of the InterPregGen study was the inclusion of populations from different ethnic backgrounds in Europe, Central Asia and South America.InterPregGen is making use of several large biobanked DNA collections for studies of pre-eclampsia in Western Europe. These include the Norwegian Mother and Child Cohort Study (MoBa) ,25; the th week of gestation [The diagnosis of pre-eclampsia is based on an international definition, requiring new-onset hypertension , associated with proteinuria (≥ 300 mg/L) after the 20estation . RecruitThe majority of control subjects are women with no history of hypertension (blood pressure <140/90 mm Hg) recruited during pregnancy. For Icelandic and UK subjects control data is provided by extensive existing GWAS data from population cohorts of respectively 36000 and 6000 individuals. Population control data have been used successfully for the identification of genetic associations with many complex disorders ; providiAll participants in the study have provided informed consent for the use of their samples, or those of their babies, in genetic studies. Approval for use of the samples and associated clinical data has been obtained from Research Ethics Committees in their country of origin, and over-arching approval for the InterPregGen study has been provided by the University of Nottingham Research Ethics Committee.The study is using genome-wide association screening as the primary strategy for discovery of genetic variants which are associated with pre-eclampsia. The principles of GWAS have been well-described elsewhere : case anTo maximise the statistical power of the study in a cost-effective way, InterPregGen is making use of GWAS data generated in the course of earlier studies in maternal and control samples from Iceland, the UK and Colombia. Additional GWAS is being undertaken using Illumina genome-wide arrays on offspring of pre-eclamptic pregnancies from Iceland and the UK, and also on newly collected maternal-fetal cases and controls from Central Asia. GWAS data is therefore available from a total of 7600 maternal cases and 4000 fetal cases .−8 is applied for genome-wide significance . For each study population with GWAS genotypes from pre-eclamptic mother-baby pairs, SNPs are also tested for evidence that maternal-fetal genotype interaction increases susceptibility to pre-eclampsia. Allelic odds ratios (OR) provided for each population by logistic regression analysis are combined in a meta-analysis to generate an overall OR for each SNP. The selection of SNPs for subsequent replication genotyping is based on the results of meta-analysis, with priority given to those with the lowest p-values. To adjust for the multiple statistical tests conducted in the course of GWAS, a meta-analytic p-value below 5×10nce  effects. The approach for examining parent-of-origin effects in Icelandic data will differ, due to the richness of existing Icelandic whole-genome data, providing two independent approaches to test for imprinting effects. Through whole-genome sequencing of Icelandic individuals, long-range haplotype phasing and parental-origin determination the deCODE dataset provides complete information of the parental-origin of each allele, without additional genotyping of paternal samples.We anticipate that the research effort will identify functional DNA variants, or their proxies, which pre-dispose to pre-eclampsia and its complications, leading to enhanced understanding of the underlying disease process. InterPregGen will explore the potential for translating this information into clinical benefits through risk-profiling and the development of novel predictive markers. Currently the prediction of women at high risk of pre-eclampsia depends on clinical criteria, including the identification of risk factors at antenatal booking . These iMoBa is a unique collection of samples and data gathered prospectively at the time of pregnancy. For researchers into the genetics of complex disorders of pregnancy such as pre-eclampsia MoBa offers the advantages of a searchable database of reliable clinical information which can be used to identify cases and controls which fulfil the inclusion criteria of the study with a high degree of confidence. The well-managed biobanking facility ensures that DNA of dependable quality is available for genotyping studies from large numbers of cases and controls, a vital requirement for adequately powered genetic association studies. In contrast to many case-control collections, MoBa includes data and DNA samples from the partners and babies of pregnant women, which will enable InterPregGen to explore both maternal and fetal genomes, the interactions between maternal and fetal gene variants, and the contribution of paternal genes to pre-eclampsia. The biobanking expertise of MoBa partners in the InterPregGen study is proving invaluable in the discussion of ethical policies, and in the development of procedures for the newly formed biobanks in Uzbekistan and Kazakhstan.The identification of genetic factors which predispose to pre-eclampsia is a large undertaking, in which MoBa has a key role. InterPregGen is conducting the largest ever genome-wide association screen of maternal and fetal genes and their interactions in this disorder, and is also the first with adequate power to investigate the role of genetic imprinting (parent-of-origin effect). The ability to compare the genetic architecture of pre-eclampsia in subjects from three continents may give insights into the source of variation in the frequency of the condition across different ethnic groups. The prospects are good for novel findings which will ultimately translate into a better understanding and management of a condition which remains one of the major killers of pregnant women and their babies throughout the world.


We launched the special research topic of cortico-cortical communication dynamics to invite contributions that would cast light on such evolution of spatio-temporal action potential and membrane potential dynamics in the cerebral cortex.A considerable number of axons from neurons in one cortical area end up on other cortical areas. When one neuron in one cortical area sends an action potential to target neurons in other cortical areas, this is a realization of a cortico-cortical communication. Sensory perception, thinking, and planning of a specific behavior, all rely on the evolution of cortico-cortical communications. The action potentials change the membrane potentials in the target neurons and, in turn, may excite these neurons to produce action potentials and complex patterns of excitation and inhibition in in vivo experimental data from animals accounting for specific aspects of cortico-cortical communication dynamics.The contributions were theoretical models, human EEG, and MEG data and data-driven models, and in vitro experiment, Branco et al. (2+ influx when their depolarization progresses toward the soma, than when depolarization progresses away from the soma. Kiebel and Friston (in vivo. In vivo, the neurons and their dendrites are in a high conductance state (Destexhe et al., In a recent o et al.  show tha Friston  construc Friston  if the sAs pointed out in a critical review of cortico-cortical communication dynamics, there are many obstacles precluding the tracing the ms by ms evolution of the spatio-temporal dynamics of the cortex (Roland et al., Facing the obstacles of tracing the spatio-temporal dynamics of cortico-cortical communications at the cellular scale, many scientists choose to study membrane electrical activity at the scale of large neuron populations, and from EEG and MEG signals try to infer putative routes of communication. Banerjee et al.  discuss At the mesoscopic scale one can observe changes in the membrane potentials with voltage sensitive dyes, local field potentials and combine this with recordings of action potentials from a few neurons or single neurons in experimental animals. Harvey and Roland  demonstrIf one wants to understand how the cerebral cortex works one must be able to trace the evolution of the spatio-temporal transmission of action potentials and membrane conductances down to the cellular scale. As the critical review concludes, this is not possible yet. Assume that a full connectome of the mouse cerebral cortex exists (Bohland et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multi-parameter gene expression assays (MPA) to aid selection of chemotherapy in hormone-sensitive early breast cancer have not been prospectively validated. This field of personalised medicine is rapidly evolving. There is currently no “best test”. OPTIMA is an adaptive trial of MPA-based chemotherapy assignment in a largely node-positive breast cancer population.OPTIMA prelim, the feasibility phase, recruited 302 patients to establish acceptability of the trial to patients and clinicians and evaluate the performance of MPAs to identify a suitable test(s) to be used in the main efficacy trial. Ethical approval was also gained for an additional 200 patient roll through before the opening of the main trial. The logistics of this design and practicalities of rolling through will be discussed. Whilst this design was efficient and minimises bureaucracy, the delays encountered with this type of design stem from the need to produce pilot results quickly and for funding bodies to make quick decisions about the feasibility of the main trial.The success of OPTIMA not only relies on the integration of a multi-disciplinary team of methodologists, clinical experts and patients at all stages of the trial, but on its adaptive design. The complexities of using such methodology and decision-making to roll forward into a main trial are challenging but provide the most efficient use of patients and costs.Project funded by the NIHR HTA Programme (10/34/01). Views expressed are those of the authors and not those of the HTA programme, NIHR, NHS or the DoH.


The short allelic variant has been shown to reduce 5-HTT transcription resulting in diminished 5-HTT levels and reduced serotonin (5-HTT) reuptake into human platelets. We speculate the possibility of altered hormone levels (Melatonin and Serotonin) in individuals with ASD.Autism Spectrum Disorder (ASD) is a developmental disorder that affects the behavior and social communication of the child. In India, awareness about Autism coupled with shortage of skilled professionals poses severe constraints in management of children with ASD. There arises a need to explore the avenues of alternate therapy in the form of Group Therapy. A 44-bp insertion/deletion polymorphism in the promoter region of the serotonin receptor gene As per earlier reports an association between 5-HTT gene polymorphism and autism has been indicated. Recent evidences from clinical and neuroscience research suggests an approach based on yogic principles and meditative tools is worth experimenting in children with autism.The same could be addressed in ASD individuals to ameliorate the drastic effect of these hormones on ASD individuals.5-HTT) is to be analyzed to correlate the endocrine findings.A single group pre-/ post- test study design was employed. With the aid of a social and behavioral assessment scale for ASD, fifteen children with ASD between the age group of 7 - 14 years were evaluated for assessing the effect of the Vedic Chants Intervention Program recruited from special schools in and around Chennai. Chanting of select Sanskrit Mantras by an experienced meditator were given as an auditory stimulus in a closed room to the children for a period of 20 min daily at a fixed time. Alterations in the endocrine profile (Melatonin and Serotonin) were measured using ELISA Kits. Polymorphism in serotonin transporter (Study shows that there is a difference in the pre & post-test mean achievement scores due to the Vedic Chants Intervention Program. Some of the qualitative changes observed by the special educators were a reduction in the hyper activity, self-biting and other common traits of ASD like head nodding, hand flapping etc. This reflected in their class room sitting as well. Some of the children were remembering certain lines of the mantras and imitating the sound ‘Om’ and responding to the ‘Namaste’ gesture. Most of the children including those with ADHD sat throughout the entire session. The endocrine profile of the subjects was altered.The auditory stimulus has the potential to provoke the cognitive abilities of the children. Vedic Chants therapy might be one of the efficient Group therapies for the management of children with ASD.


Part of the innate host defense against microbial infection is nutritional restriction of access to sources of host nutrients  that is ER-derived and evades lysosomal fusion   results in varying degrees of failure in intra-vacuolar proliferation and attenuation in the mouse model of Legionnaires' disease  family of membrane proteins (Cedernaes et al., in vivo is essential for our understanding of host-microbe interaction, and nutrient retrieval strategies by intracellular pathogens are potential targets for therapy.Remarkably, pyruvate or citrate supplementation is as effective as amino acids in rescuing the intra-vacuolar growth defect of the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We will report the design and performance of a MR-compatible SPECT system that utilizes a dual-FOV aperture design for microscopic SPECT imaging of small animals inside an pre-existing MR scanner. The MRC-SPECT-DF system consists of a full ring of high resolution CdTe detectors and an aperture that consists of dual-FOV aperture system design that has two sets of aperture rings along the axis, one providing a large FOV and the other one allowing an ultrahigh resolution microscopic imaging of a selected target region in the object. The switching between apertures does not require mechanical shifting of either the aperture or the CdTe detector ring. This is critical for integrating the SPECT system with the MR scanner, and minimizing the interference between both sub-system while operation.


Being the first second messenger described  is a second messenger of paramount biological importance, involved in the regulation of a significant number of cellular functions To our belief, this aim has been successfully fulfilled. The present collection of articles highlights, in a representative (but certainly not exhaustive) way, the research activity and emerging concepts in the field, while it also reveals the therapeutic potential that targeted pharmacological manipulation of intracellular cAMP levels could exert on a number of pathological conditions. We organized the papers of this Research Topic/e-Book into three sections (A–C).Frontiers in the role of cAMP in cellular function, homeostasis and disease”) opens with a very informative review article on the reciprocal regulation between cAMP signaling and the ubiquitin-proteasome system, as well as its relevance to certain human diseases . A more focused perspective on the importance of cAMP in cardiac physiology and pathophysiology is presented by the review article of Boularan and Gales and the mini review article of Froese and Nikolaev; both articles provide an up-to-date account of recent developments in the field and should be considered by readers as complementary to each other. Later in section A, readers will discover an elegant mini review on the role of cAMP signaling in neural plasticity, learning and memory (Lee), that summarizes findings generated by research on the fruit fly Drosophila melanogaster and briefly highlights implications of this signaling pathway to potential therapeutic applications. Section A concludes with an original article on the role of cAMP signaling in human trophoblast fusion , and with a perspective article on the spatiotemporal regulation of cAMP signaling in blood platelets .The first section  includes an informative review article on state-of-the-art methodologies which can be utilized toward the study of cAMP-mediated signal transduction via G-protein coupled receptors , as well as two excellent review articles on the pharmacological manipulation of intracellular cAMP levels through interference of the molecular interactions between the A-kinase anchoring proteins and other signaling protein intermediates . This section also accommodates a contribution by Röck et al. with an original research article in which analysis of protein kinase A (PKA) dynamics following the integration of patient mutations into its catalytic (PKAc) and regulatory (RIa) subunits is presented. The section is completed with two analytical review articles that present recent developments in the utilization of genetically encoded tools for cAMP measurement in health and disease .The second section  is introduced with a perspective article on the role of patients' sex toward a more targeted (cAMP pathway-regulated) therapeutic approach to brain tumors , followed by two original research articles on the role of cAMP signaling in the context of hematological malignancies and the potential therapeutic applications that could arise through its pharmacological manipulation . The current Research Topic / e-Book is concluded with a well-written review article on cAMP signaling in trypanosomatids that provides an overview of the complex functions of cAMP in these protozoan parasites, as well as a fine perspective on how potential targets for the trypanosomatid-specific cAMP pathway could provide efficient therapeutics for serious human diseases such as the sleeping sickness and other trypanosomatid-induced pathological entities .The third section (C: “The recruited articles cover multiple aspects of the ongoing research in the cAMP field and allow an appreciation of the difficult task ahead in fully-understanding the complexity of this ubiquitous signaling cascade and taming it to develop efficient therapeutic applications. Hopefully, readers will consider this collection of papers as a small step toward these goals.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


It is currently one of the most active areas of research in diagnostic imaging. The characterisation of an incidental renal lesion can be difficult. In particular, the differentiation of an oncocytoma from other solid renal lesions such as renal cell carcinoma (RCC) represents a diagnostic challenge. We describe the detection of an incidental renal oncocytoma in a 79-year gentleman who underwent a re-staging


Sensitivity to temporal contingencies appears early in life and plays a key role in the ontogeny of socio-cognitive abilities in humans  quantifying how interactions with the environment and others have a causal role at the intra-individual level and non-additive consequences at the inter-individual level, and (2) deciphering the different factors of coupling across neural, behavioral and cultural scales. A last challenge is to embrace the ongoing change of paradigm that shall bridge the gap between the lived and the observed experience of social coordination in ecological contexts. Taken together, integrating first-, second- and third-person perspectives is a required move to accurately study natural human coordination phenomena.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The generation of engineered tissues and organs has entered into the clinical practice in response to the chronic lack of organ donors. In particular, for the skeletal and cardiac muscles the translational potential of tissue engineering approaches has clearly been shown, even though the construction of these tissues lags behind others given the hierarchical, highly organized architecture of striated muscles. Failure of the cardiac tissue leads to cardiovascular diseases, which are the leading cause of death in the developed world  structures able to induce stem cell differentiation and which may be used in pre-clinical and clinical studies.Of the two bio-artificial systems described, one is a silicon chamber system for the generation of skeletal muscle constructs described by Snyman et al. . This inin vivo implantation. Pagliari et al.  from skeletal muscle. Perniconi et al.  demonstrThe same authors also contributed a review article on the usefulness of the MAS as a scaffolding platform able to re-create the natural structure of the muscle. MAS is naturally embedded with active native molecules which remain active after the decellularization process and help the implanted proto-tissue to integrate in the host organ. Tissue-derived ECM helps in structuring niches rich in adhesive and signaling molecules supporting stem cells self-renewal and differentiation  applies. In this case the muscle should be replaced by devices able to re-establish the function of the musculature and which preserve force transmission and continuity of the architecture within the host tissues. Hence, Cittadella Vigodarzere and Mantero  describeA clinical example of the latter is described in an interesting review discussing the importance of angiogenesis and the pro-angiogenic and pro-myogenic effects of the vascular endothelial growth factor (VEGF)/VEGF receptor pathway as a therapeutic strategy to cure muscle weakness and cardiomyopathy in Duchenne muscular dystrophy (DMD) patients .Apart from the structures of ECM and vasculature, also growth factors, cytokines, pleiotropic signaling pathways, and cell-specific regulators play an important role in the differentiation and self-renewal of cardiac as well as skeletal muscle stem cells. Pagliari et al.  describeThis book provides a comprehensive up-to-date review on cardiac and skeletal muscle tissue engineering and highlights the several elements which have to be taken into consideration when engineering a functional proto-tissue.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There are errors in the Results, PEST-NLS and yEVenus-NLS when expressed by the constitutive promoter ADH1 .There is an error in the penultimate sentence of the third paragraph of the “Construction of Yeast Gateway Vectors for One-step Gene Assembly” subsection of the Results. The correct sentence is: We compared the fluorescence produced by yEVenus-Cln2There is an error in There is an error in


The main challenge for understanding motion processing in the visual system is that local motion signals do not accurately represent the direction of the whole object. This is known as the "aperture problem". The small receptive fields of individual neurons can only measure motion components orthogonal to their preferred direction. Neuro-physiological studies show that neurons in brain area MT (V5) have a major role in dealing with this problem . We deveThe model contains two levels of rate-based neuron. The first level is a model of V1 with two sets of neurons: complex neurons and hyper-complex end-stopped neurons. End-stopped neurons respond to the end-points of the stimulus , thereby representing an unambiguous estimation of the direction of motion . The resExcitatory recurrent connections between integration neurons propagate end-stopped information from the object terminators. As each spatial location contains neurons selective to different directions, inhibitory connections are added between the neurons such that there will be only one neuron active at each spatial location. Long-range inhibitory connections are also added between more distant MT neurons selective to other directions. Segmentation neurons send inhibitory connections to integration neurons to prevent the propagation of motion signals outside the border of the input stimulus. Inhibitory connections between segmentation neurons are defined based on center-surround interactions; this suppresses activity when the motion signals in the center and surround are in the same directions; ensuring that their activity will not prevent the propagation of motion signals when there is no discontinuity.The results of simulations show that the activity of V1 neurons along the edges is much stronger than the activity of the neurons at the end-points. Activation of end-stopped neurons in V1 suppresses ambiguous motion signals along the edges of the stimulus. Therefore, unambiguous information at the end-points wins the competition over the neurons with ambiguous motion signals. The final output of the model shows that MT neurons achieve an accurate estimation of motion using the information provided by the end-stopped neurons.We developed a model of MT neurons for motion perception based on the available neuro-physiological data. These neurons receive their input from neurons in V1. The results show the successful function of these neurons in the perception of motion of a single moving bar. In this model, we also investigated the role of end-stopped neurons in overcoming the aperture problem. The results suggest that MT neurons are not able to solve the aperture problem without the vital role played by end-stopped cells.


Kangaroo mother care has been highlighted as an effective intervention package to address high neonatal mortality pertaining to preterm births and low birth weight. However, KMC uptake and service coverage have not progressed well in many countries. The aim of this case study was to understand the institutionalisation processes of facility-based KMC services in three Asian countries  and the reasons for the slow uptake of KMC in these countries.Three main data sources were available: background documents providing insight in the state of implementation of KMC in the three countries; visits to a selection of health facilities to gauge their progress with KMC implementation; and data from interviews and meetings with key stakeholders.The establishment of KMC services at individual facilities began many years before official prioritisation for scale-up. Three major themes were identified: pioneers of facility-based KMC; patterns of KMC knowledge and skills dissemination; and uptake and expansion of KMC services in relation to global trends and national policies.Pioneers of facility-based KMC were introduced to the concept in the 1990s and established the practice in a few individual tertiary or teaching hospitals, without further spread. A training method beneficial to the initial establishment of KMC services in a country was to send institutional health-professional teams to learn abroad, notably in Colombia. Further in-country cascading took place afterwards and still later on KMC was integrated into newborn and obstetric care programs.The patchy uptake and expansion of KMC services took place in three phases aligned with global trends of the time: the pioneer phase with individual champions while the global focus was on child survival (1998–2006); the newborn-care phase (2007–2012); and lastly the current phase where small babies are also included in action plans.This paper illustrates the complexities of implementing a new healthcare intervention. Although preterm care is currently in the limelight, clear and concerted country-led KMC scale-up strategies with associated operational plans and budgets are essential for successful scale-up. Babies with a birth weight of <2500 g are the most vulnerable newborns at higher risk of mortality , 2. Low Three-quarters of deaths from preterm birth complications are preventable without intensive care units . AccordiKangaroo mother care is a ‘total health-care strategy’ , which iBorn Too Soon report ’ ’ ) and of phasis]’ ) should Responses in the bottleneck investigation that was part of the Every Newborn Action Plan included the absence of an investment plan for scale-up of KMC, with no funding allocation to KMC implementation, resulting in high dependency on external funding . In all The focus of this study was limited to the provision of facility-based KMC services. It is acknowledged that almost half the preterm babies in middle- and low-income countries are born at home . AlthougThis paper illustrated the complexities of the implementation of a new healthcare intervention. Professional resistance and the lack of political priority for newborn and LBW care within the political and healthcare structures at the time when early adopters introduced KMC into their health facilities explain why the vast majority of institutions were left behind. Only now that KMC has been included in the global health agenda as one of the key interventions for the reduction of newborn morbidity and mortality can we expect the majority to follow suit. However, this expectation might not materialise without a country-led clear and concerted KMC scale-up strategy with an associated operational plan and budget.Enabling mothers and their families to practice kangaroo mother care entails a complex interplay between health-system requirements, organisational culture, human behaviour and community networks. Scaling up KMC is not an easy process and it takes time for services to become institutionalised and integrated into the total newborn care package. Leadership reflecting an understanding of the necessity of prioritising the provision of facility-based KMC services and good governance at all levels throughout the implementation process is essential. Scale-up processes should be driven by strategies to ensure appropriate quality of care.


The dynamics of intense twin beams in pump-depleted parametric down-conversion is studied. A generalized parametric approximation is suggested to solve the quantum model. Its comparison with a semiclassical model valid for larger twin-beam intensities confirms its applicability. The experimentally observed maxima in the spectral and spatial intensity auto- and cross- correlation functions depending on pump power are explained in terms of different speeds of the (back-) flow of energy between the individual down-converted modes and the corresponding pump modes. This effect is also responsible for the gradual replacement of the initial exponential growth of the down-converted fields by the linear one. Furthermore, it forms a minimum in the curve giving the effective number of twin-beam modes. These effects manifest a tight relation between the twin-beam coherence and its internal structure, as clearly visible in the model. Multiple maxima in the intensity correlation functions originating in the oscillations of energy flow between the pump and down-converted modes are theoretically predicted. Nowadays, parametric down-conversion (PDC) describing three mutually interacting optical fields68910141518192022We note that the model developed here for twin beams may be useful also for other three-mode nonlinear interactions found, e.g., in acousto-opticsIn the process of PDC, pump, signal and idler fields mutually interact in a nonlinear medium with an effective nonlinear susceptibility λ giving the quantum probability amplitudes of finding a given paired mode in the state are obtained  proportional to the squared product In a classical nonlinear problem. The Schmidt decomposition provides the signal and idler modes in pairs in which they share a common Schmidt coefficient λ. As a consequence, the signal and idler field amplitudes (expressed in photon numbers) belonging to one pair are the same. Using this symmetry, the classical counterpart of the Heisenberg equations written for mean values of the symmetrically-ordered signal To include the quantum statistical character of the signal and idler fields in multi-thermal PDC, we first propose The solution of defining We note that the second term on the r.h.s. of a semiclassical model (SCM) that preserves the overall energy. In this model, we build the operator solution from the classical one written in To verify the validity of GPA, we develop in parallel We recall that P for which an exponential growth of the number N of emitted photon pairs is observedN slows down as the pump power P increases and finally a linear increase is reached  become completely depleted and begin to take their energy back from the signal and idler modes with whose they share the common modes’ triplets. This reflects the most important feature of the nonlinear dynamics of individual modes’ triplets in PDC: the larger the mode’s incident pump power, the faster the nonlinear dynamics of the corresponding triplet. Detailed insight into the dynamics is provided in P forming an increasing succession. For high powers P, the pump modes with the largest Schmidt coefficients λ  are completely depleted inside the crystal and they even take some energy back from their signal and idler modes contrary to the rest of pump modes (with lower Schmidt coefficients λ), which are only losing their energy during the propagation in the crystal. This results in the slower-than-exponential growth of the signal- and idler-field intensities. The observed nearly-linear character of this growth is a consequence of the large number of modes with different evolution that constitute the TWB  crystal cut for a nearly collinear spectrally degenerate type-I interaction  of spatial and spectral coherence accompanied by a decrease (increase) of the number of modes observed in different regimes of pump powers. The comparison of the results with the experimental data and with the results of semiclassical model confirms the validity of the suggested μm wide (FWHM) at the lowest pump power. A half-wave plate followed by a polarizing-cube beam splitter was used to change the pump power. Phase-matching in the crystal for frequency degenerate down-converted beams was reached in a slightly non-collinear configuration. The down-converted light was collected by a lens with 60-mm focal length and then focused in the plane of the vertical slit of an imaging spectrometer . The angularly dispersed far-field radiation was recorded, shot by shot, by a synchronized EMCCD camera  operated at full-frame resolution . We note that for the detection of intense TWBs EMCCD cameras are more convenient compared to iCCD cameras, which have been often exploited in this area383940The experimentThe intensity auto- and cross-correlation functions characterizing the TWB coherence are obtained as correlation coefficients between a single pixel (In 12), ,  standsThe number of TWB modes in the radial direction was determined by the Fedorov ratioHow to cite this article: Peřina, J. et al. Internal dynamics of intense twin beams and their coherence. Sci. Rep.6, 22320; doi: 10.1038/srep22320 (2016).


EGFR gene.Multiplex ligation-dependent probe amplification (MLPA) is a multiplex copy number analysis method that is routinely used to identify large mutations in many clinical and research labs. One of the most important drawbacks of the standard MLPA setup is a complicated, and therefore expensive, procedure of generating long MLPA probes. This drawback substantially limits the applicability of MLPA to those genomic regions for which ready-to-use commercial kits are available. Here we present a simple protocol for designing MLPA probe sets that are composed entirely of short oligonucleotide half-probes generated through chemical synthesis. As an example, we present the design and generation of an MLPA assay for parallel copy number and small-mutation analysis of the


Solar magnetism displays a host of variational timescales of which the enigmatic 11-year sunspot cycle is most prominent. Recent work has demonstrated that the sunspot cycle can be explained in terms of the intra- and extra-hemispheric interaction between the overlapping activity bands of the 22-year magnetic polarity cycle. Those activity bands appear to be driven by the rotation of the Sun's deep interior. Here we deduce that activity band interaction can qualitatively explain the ‘Gnevyshev Gap'—a well-established feature of flare and sunspot occurrence. Strong quasi-annual variability in the number of flares, coronal mass ejections, the radiative and particulate environment of the heliosphere is also observed. We infer that this secondary variability is driven by surges of magnetism from the activity bands. Understanding the formation, interaction and instability of these activity bands will considerably improve forecast capability in space weather and solar activity over a range of timescales. The origins of the Sun's periodic activity, such as sunspot cycles, are poorly understood. McIntosh et al. posit that the rotational forcing of the activity bands comprising the 22-year magnetic cycle undergoes shorter-term variations, driving magnetic flux surges that impact solar output on those timescales. The obvious hemispheric asymmetry of the solar atmosphere over the past several years 2009–2014) has generated a significant amount of interest in the heliophysics community4 has genet al.et al.McIntosh Rotating atmospheres, like that of the Earth and the giant planets of our solar system, often exhibit shorter-timescale global-scale phenomena such as Kelvin and Rossby waves47Variations of significantly shorter period than the canonical 11-year) envelope of solar variability are visible in the Sun's flaring activity . The fig9-year envStudying the last solar cycle in more detail, 13We see that the peaks in the total sunspot number have corresponding peaks in the CME rate. The surges in the daily sunspot number can be as large as 30% and they can lead to a 100% increase in the daily CME rate. The same strong correspondence is visible for the flare rate. The relationship between the disk-integrated CME rate and the hemispheric rates of sunspot and flare formation highlight a critical property in disk-integrated quantities—they will typically exhibit shorter period variations than hemispherically resolved ones. The phase offset between the two hemispheres will determine the resulting ‘hybrid' period observed. In this case, we see that marked increases in surface magnetism lead to a profound increase in the rate of eruptive phenomena.−2—equivalent to the variation over the whole solar cycle . The seasonal variation of the latter modulates the visible area of the solar diskThese periodic changes in the morphology of the coronal (and heliospheric) magnetic field can be inferred from Magnetic fields on smaller spatial scales than coronal holes and sunspots display similar periodicities to their larger brethren throughout the solar cycle. 225The physical origin of these strong quasi-periodic surges in the Sun's magnetism is not known. However, their effect on the outer solar atmosphere and on the geospace environment is profound. Their existence has been documented extensively since the start of the space-age. For example, strong quasi-periodicities that are longer than the Sun's rotation rate have been amply documented in the literature for sunspot areas29et al.As we have noted above, it is unlikely that a strong modulation in the number of sunspots can be easily explained by processes in the near-surface layers of the Sun. However, considering a spatio-temporal decomposition of solar surface magnetismet al.We infer that the interaction of the oppositely signed, long-lived activity bands in each hemisphere as discussed by McIntosh In addition to the decadal envelope of solar activity, there is a clear, strong, variability of the magnetic flux in each solar hemisphere of approximately 1  year. We propose that the process at the root of the short-term propagating pattern shown in 910112526272829So, what are the poleward-propagating excursions seen in et al.et al. indicate that there are global-scale waves and instabilities that propagate in the shear layer known as the tachocline38One possible explanation follows from the deliberations of Howe What could these perturbations to the magneto-convective system be? The Earth's mantle, ocean and thermosphere/stratosphere exhibit global-scale waves that are driven by the rotation of the planet at shear interfaces, or Rossby waves4042To summarize, we have inferred that the interaction of the activity bands belonging to the Sun's relentless 22-year magnetic polarity cycle shape the decadal-scale variability of solar activity1The growing dependence of our civilization on technology susceptible to space weather should motivate investigations into the rotational forcing of the Sun's deep convection zone by the radiative zone. Specifically, challenging simulations of activity band formation, intra- and extra-hemispheric activity band interaction and the zoo of rotational-gravity-buoyancy waves that interact with those activity bands are required. These factors appear to be key drivers of solar variability on decadal and annual timescales. A better understanding of the processes responsible for modulating the decadal variability and the (quasi-)annual ‘seasons' of solar activity will yield a significantly increased forecast skill for solar activity in parallel with continued observational monitoring.Using the Morlet wavelet as a model representation of the oscillatory signals observed, we construct the wavelet power spectra of each timeseries. In the most general sense a wavelet power spectrum can be thought of as an image that indicates the strength and the duration that an oscillation of a particular period is present in the timeseries. It is a particularly powerful tool for the analysis of timeseries that exhibit mixed periods and quasi-periodicities as is often the case in many solar phenomena.For the wavelet power spectra shown in N up to the next-higher power of two—this limits any edge effects and speeds up the Fourier transform at the core of the computation.The cross-hatched areas in the wavelet power spectrum define the ‘cone of influence.' The interpretation of the cone of influence is relatively straightforward—the signal in the cross-hatched area may not be entirely reliable because of the influence of edge effects of the timeseries. Because these are finite-length timeseries, errors will occur at the beginning and end of the wavelet power spectrum, as the Fourier transform used in the Wavelet method assumes that the data are cyclichttp://virtualsolar.org) data archives.The data used in this paper are openly available from the NGDC, SOHO, SDO and the Virtual Solar Observatory .Supplementary Figures 1-3


Inverse synthetic aperture radar (ISAR) imaging of a maneuvering target is a challenging task in the field of radar signal processing. The azimuth echo can be characterized as a multi-component polynomial phase signal (PPS) after the translational compensation, and the high quality ISAR images can be obtained by the parameters estimation of it combined with the Range-Instantaneous-Doppler (RID) technique. In this paper, a novel parameters estimation algorithm of the multi-component PPS with order three  based on the modified discrete polynomial-phase transform (MDPT) is proposed, and the corresponding new ISAR imaging algorithm is presented consequently. This algorithm is efficient and accurate to generate a focused ISAR image, and the results of real data demonstrate the effectiveness of it. In this paper, a novel algorithm for the parameters estimation of multi-component CPS by the MDPT method is proposed. This algorithm has better performance than the traditional DPT algorithm in the case of similar amplitudes of each component. Then, the corresponding ISAR imaging algorithm based on MDPT is presented. The ISAR imaging results of real data demonstrate the validity of the novel algorithm proposed in this paper.


The establishment of the Cancer Drugs Fund (CDF), which removed the necessity for cost-effectiveness as a criterion for drugs access and expedited access to non-NICE appraised drugs, has significantly changed prescribing of cancer drugs for terminally ill cancer patients in the NHS. Neither clinicians nor the public have a preference for spending money on cancer over other disease states. The most effective and efficient way to spend resource within cancer care is hotly debated.Audio-recorded, semi-structured interviews with oncology and palliative care consultants (n=16) took place in the South West region (March-October 2013). Transcripts were analyzed iteratively using constant comparison to identify and understand common themes. Matrices were developed to explore and compare derived themes and highlight dissonant views.The complex dynamic of personal, familial, media and political influence on palliative chemotherapy decision-making were described by participants. Decision-making around palliative chemotherapies was improved by the CDF according to all oncology participants. The main benefit of the CDF was thought to be access to treatments not previously available to patients. However, the improved availability of high cost drugs caused conflict for clinicians reconciling the apparent benefits for the patient and the cost for the population. The disadvantages of the CDF included a potential reduction in clinician discretion in chemotherapy decision-making since the National CDF Cohort List and a delay in advanced care planning conversations. The appropriateness of ‘weighting’ the value of life more at the end of life (as defined by NICE) was felt to be artificial by 5/6 palliative care and 5/10 oncology consultants. The majority of consultants described an uncomfortable compromise between the importance of that time to some individuals offset by the lessened quality of life for the majority (13/16). Professional opinion clashed most over the role of Multi-Disciplinary Team meetings (MDTs) in accessing CDF drugs. MDTs were felt to be a cause for delay and ‘a tick-box’ exercise (oncologists) and a missed opportunity for patient advocacy .Clinicians indicated that they mostly approved of the CDF in enabling patient access to new palliative chemotherapy. However; clinicians sometimes struggled with judging the balance between potential gains and losses in length and quality of life for individual patients and the level of financial cost incurred by the NHS. The views of patients accessing drugs through the CDF are currently being sought in order to improve understanding of the impact of the CDF.