The biomimetic flow at different scales has been discussed at length. The need of looking into the biological surfaces and morphologies and both geometrical and physical similarities to imitate the technological products and processes has been emphasized. The complex fluid flow and heat transfer problems, the fluid-interface and the physics involved at multiscale and macro-, meso-, micro- and nano-scales have been discussed. The flow and heat transfer simulation is done by various CFD solvers including Navier-Stokes and energy equations, lattice Boltzmann method and molecular dynamics method. Combined continuum-molecular dynamics method is also reviewed. Human knowledge is getting enriched from the four billion years' worth of R & D in the natural world of plants and animals and other lower level living creatures and microorganisms, which have evolved through the ages to nicely adapt to the environment. Man has now drawn his attention to soil creatures like earthworms, dung beetle, sea animals like shark and plants and trees like lotus leaf and pastes like termites. In the nature, we see examples of effortless and efficient non-sticking movement in mud or moist soil, high-speed swimming aided by built-in drag-reduction mechanism, water repellant contaminant-free surface cleaning mechanism and natural ventilation and air conditioning, -8. By na• Replicating natural manufacturing methods as in the production of chemical compounds by plants and animals.• Mimicking mechanisms found in nature such as Velcro and Gecko tape.• Imitating organizational principles from social behaviour of organisms like ants, bees and microorganisms.Russia has developed a systematic means for integrating the natural knowledge into humankind's technology using 'Teoriya Resheniya Izobretatelskikh Zadatch (TRIZ)', i.e. the theory of inventive problem solving, which provides an objective framework based on functionality for accessing solutions from other technologies and sciences. TRIZ also prevents waste of time trying to find a solution where none exists. The four main tools of TRIZ are a knowledge database arranged by function, analysis of the technical barriers to progress (contradictions), the way technology develops  and the maximization of resource usage. The biology-based technology 'Biomimetics' suggests new approaches resulting in patents and some into production:• Strain gauging based on receptors in insects ,• Deployable structures based on flowers and leaves ,• Tough ceramics based on mother-of-pearl ,• Drag reduction based on dermal riblets on shark skin ,• Tough composites based on fibre orientations in wood ,• Underwater glues based on mussel adhesive ,• Flight mechanisms based on insect flight ,• Extrusion technology based on the spinneret of the spider ,• Self-cleaning surfaces based on the surface of the lotus leaf .The importance of Biomimetics will increase as the incidence of genetic manipulation increases and the genetic manufacturing is developed. In the result, the area between living and non-living materials, where biology interacts with engineering, e.g. bioengineering and biomechatronics, is benefited.There are innumerable examples of interactions with the environment and balanced and efficient heat, mass, momentum and species transfer through the microstructures in the fluid flow in the manifested living world of plants, animals and other living creatures. Biomimetics involve mimicking these interactions across the functional surfaces with the surrounding environments in the technological design. The physical nature is numerically modelled and simulated using computational fluid dynamics (CFD).Geometrical analogy as well as physical similarity is to be studied to design technological functional surfaces imitating microstructural and biological functional surface morphologies. CFD at micro- or meso-scales and other numerical methodologies are necessary for this -24.The meso- and micro-scale methods are also being developed in parallel with the continuum theory-based conventional CFD techniques-using finite volume method (FVM) and finite element method (FEM). In the mesoscopic lattice Boltzmann method (LBM), fluid flow is simulated by tracking the development of distribution functions of assemblies of molecules. It is difficult to capture the interfacial dynamics, which is essential for multiphase flow, at the macroscopic level. LBM captures the interaction of fluid particles and is, therefore, helpful for multiphase flow with phase segregation and surface tension. Also, the LBM is computationally more efficient than molecular dynamics (MD) method since it does not track individual molecules; the solution algorithm is explicit, easy to implement and parallel computation can be done. Micro/nano-scale simulations in micro/nano-scale geometries and micro time scales are done in MD method and direct simulation of Monte Carlo (DSMD) method. Coupled macro-scale simulation is being done using high performance computer (HPC). This article makes a review of the advances in multiscale biomimetic fluid flow modelling and simulation of difficult physics problems with complex biological interfaces.The locomotion, power and manoeuvring of aquatic animals like swimming fish having superior and efficient utilization of propulsion through a rhythmic unsteady motion of the body and fin resulting in unsteady flow control has been engineered for the transportation in the underwater vehicles. The fish senses and manipulates large-scale vortices and repositions the vortices through tail motion. The timing of formation and shedding of vortices are important. CFD application by mimicking the swimming of fish and underwater dolphin kicking has been utilized to understand active drag and propulsive net thrust and this has resulted in better sailing performance, Olympic ski jumping, Formula 1 racing, Speedo's new Fastskin FSII swimsuit and an optimal kick profile in swim starts and turns. The undulatory propulsion in aquatic vertebrates is achieved by sending alternating waves down the body towards the tip of the tail and causing sinusoidal oscillation of the body, a jet in the wake and a forward thrust. Two modes of propulsive technique utilized by fish are anguilliform and carangiform, Figure The unsteady incompressible Navier-Stokes equations of turbulent flow are solved in the simulation by applying the Reynolds-averaged Navier-Stokes (RANS) equations with usual boundary conditions to obtain the fluctuating velocity fields. The equations in Cartesian tensor form are:x and u are Cartesian coordinates and velocities, respectively, and t is time. Velocity u, density ρ, viscosity μ and other solution variables represent ensemble-averaged (or time-averaged) values. Reynolds stress, k is the turbulence kinetic energy, ε the kinetic energy dissipation rate and μt the turbulent viscosity. C is constant, σ the Prandtl number. Gk represents the generation of turbulence kinetic energy due to the mean velocity gradients. μt is the turbulent viscosity.where k-ε work-horse turbulence model for practical engineering flow calculations.The turbulent flow induced by the fish-tail oscillation is characterized by fluctuating velocity fields. The instantaneous governing equations are time averaged to reduce the computational time and complexity which is done in the form of turbulence models like the semi-empirical V with moving boundary is employed:To calculate the flow field using the dynamic mesh, the integral form of the conservation equation for a general scalar φ on an arbitrary control volume Sφ is the source term of φ and ∂V is the boundary of the control volume V.where The flow is characterized by spatially travelling waves of body bound vorticity. The mix between longitudinal and transverse flow features varies with the phase of oscillation and the unsteady velocity field varies throughout an oscillation cycle. The dynamic pressure distribution contour and the effect of the tail movement on the unsteady flow field of the fish-like body will show that there are high pressure zones at the rear of the body indicating strong vortex and turbulence. The kinematic parameters like Strouhal number, wavelength and oscillating frequency are based on the forward locomotion in a straight line with constant speed in the cruising direction. Figure Other example of using CFD to study biomimetic fluid flow problems include simulation of air flow around flapping insect wings, numerical simulation of electro-osmotic flow near earthworm surface and simulation of explosive discharge of the bombardier beetle.Kroger  made a CThe dynamic mesh CFD model is used to examine critical flight simulations of normal aircraft, like the undercarriage lowering at low air speed, or the movement of sweep wings of fighter jets at high air speed. Next to flight applications, the dynamic mesh model can also simulate moving heart valves in the biomedical area, or small flapping membrane valves in micro-fluidics or the flow around any arbitrary moving part in other industry or sports applications.The electro-osmotic flow controlled by the Navier-Stokes equations near an earthworm surface has been simulated by Zu and Yan  numericaA biomimetic CFD study -39 of thC-V hyperbolic equation, which is not subject to the Fourier law assumption of infinite thermal propagation speed, is also not free from anomalies.Nanoscale systems such as GaAsMESFETs and SiMOSFETs semiconductor devices, ultra-fast (picoseconds or femtoseconds) pulsed lasers do not conform to the classical Fourier heat diffusion theory in which the mean free path of the energy carriers becomes comparable to or larger than the characteristic length scale of the particle device/system or the time scale of the processes becomes comparable to or smaller than the relaxation time of the energy carriers. Although numerical techniques like Boltzmann transport equation (BTE) or atomic-level simulation (MD) and Monte Carlo simulation (MCS) can capture the physics in this regime, they require large computational resources. The Finite difference and finite element methods serve well for continuum description of a system governed by a set of differential equations and boundary conditions. However, the problem arises when the system has atomic fabric of matter such as in the case of friction problems and phase-change problems of fluid freezing into a solid or dynamic transition such as intermittent stick-slip motion .When a system is modelled on the atomic level such as in case of MD, the motion of individual atoms or molecules is approximated. The particle motion is controlled by interaction potentials and equations of motion. MD is used for systems on the nanometre scale.Coupling two very different descriptions of fluids at MD-continuum interface is a serious issue. The overlapping region of two descriptions must be coupled over space as well as time giving consistent physical quantities like density, momentum and energy and their fluxes must be continuous. Quantities of particles may be averaged locally and temporally to obtain boundary conditions of continuum equations. Getting microscopic quantities from macroscopic non-unique ensembles is, however, difficult.Several coupling schemes -44 have The two domains are coupled to each other by ensuring that the flux components normal to the domain boundary match. If particles flow towards the boundary, a corresponding amount of mass, momentum and energy must be fed into the continuum. Conversely, any transport in the vicinity of the boundary on the part of the continuum must provide a boundary condition for transport on the part of the particles.Figure Sousa  presenteFollowing the original approach of Olfe  and ModeThe development and optimization of the performance of micro and nano fluidic devices requires numerical modelling of fluid flow inside micro and nanochannels. The nature of the phenomena involved in these devices invariably and predominantly has the interfacial interactions because of high surface-to-volume ratio and is characterized by an inherent multiscale nature -62. The The MD atomistic model in the micro-scale framework is a deterministic method. In this model, the evolution of the molecular system is obtained by computing the trajectories of the particles based on the classical molecular model. The continuum conditions can be applied to molecular domain either by the method based on continuous rescaling of atomic velocities or by the periodic resampling method of atomistic velocities that employs velocity distribution functions such as Maxwell-Boltzmann or Chapman-Enskog distribution for non-equilibrium situations of hybrid simulations in dilute gases employing geometrical decomposition and state coupling. The Maxwell-Boltzmann velocity distribution is the natural velocity distribution of an atomic or molecular system in an equilibrium state defining the probability of one-dimensional velocity components of an atom assuming a specific value based on temperature and the atomic mass. The reflective plane placed at the upper boundary of the boundary condition transfer region maintains every particle inside the molecular domain. This scheme is simpler than the velocity reversing scheme, but this can be applied only to incompressible flows because the normal pressure is a result of the reflected atoms.In the rescaling techniques, in addition to the velocity restrictions, the continuum pressure applies to the atomistic region. The normal pressure is applied through external forces generating a potential energy field. Energy is decreased because of the reduction of potential energy of the atoms moving towards the continuum boundary. The resulting energy oscillations in the molecular system are reduced by velocity reversing of the outermost atoms. This scheme is simple and robust because of uncontrolled transfer of energy. The continuum temperature to the molecular system is accomplished by an energy transfer scheme. The energy is added or removed from the microscopic system to parallel the macroscopic temperature without modifying the mean velocity of the particles. The energy transfer takes place independent of each dimension and is accomplished by the velocity vectors of the atoms ,61-68.Drikakis and Asproulis  applied The task of imitating biological functional surfaces with variety of complex three-dimensional micro- and nano-structures is very challenging in biomimetic flow simulation. The transfer of biological morphologies of plants and animals by imitating both geometrical and physical similarity to technological applications is to be identified -127. StuHard spheres fluids, square well fluids and Lennard-Jones fluids are model fluids in MD. The fluid flow and heat transfer in micro-scale and nano-scale systems get microscopic and nanoscopic insight from MD .A comprehensive and state-of-the-art review of CFD techniques for numerical modelling of some biomimetic flows at different scales has been done. Fluid-fluid interfaces contacting with functional solid surfaces have been discussed. The multiphysics modelling at different scales by Navier-Stokes and energy equations, mesoscopic LBM, MD method and combined continuum-MD method with appropriate coupling schemes have been dealt with in detail.AFM: atomic force microscope; BTE: Boltzmann transport equation; CFD: computational fluid dynamics; DSMD: direct simulation of Monte Carlo; FEM: finite element method; FVM: finite volume method; HPC: high performance computer; LBM: lattice Boltzmann method; LPM: lattice Poisson method; MCS: Monte Carlo simulation; MD: molecular dynamics; RANS: Reynolds-averaged Navier-Stokes; SEM: scanning electron microscope; SPH: smoothed particle hydrodynamic; TRIZ: Teoriya Resheniya Izobretatelskikh Zadatch.The authors declare that they have no competing interests.All authors read and approved the final manuscript.


This is a review of the content and scope of a multi-author volume for readers with an interest in the structure and function of the blood-brain barrier and in drug delivery to the central nervous system. This volume is one of a number in the Methods in Molecular Biology series Volume 686. It is designed as a sequel to "The Blood-Brain Barrier - Biology and Research protocols which appeared under the same publishers as part of the Methods in Molecular Medicine Volume 89 (2003). The book follows a slightly different structure to previous volumes in that it contains an number of reviews bringing key areas of the subject, which have shown significant recent development, up to date, plus further sections which contain specific protocols for blood-brain barrier study and drug delivery to the central nervous system. The volume is divided into five parts, I "Biology of the Barrier", II "Imaging the Barrier", III "Molecular Techniques to Study the Blood-Brain Barrier", IV "Models to Study the Barrier" and V "Delivery of Therapeutic Agents Across the Barrier".Part I contains six reviews which bring critical areas up to date. There is a chapter on endothelia cells (Nag), pericytes (Dore-Duffy and Cleary), astrocytes (Nag), the blood-cerebrospinal fluid barrier , the blood-retinal barrier (Runkle and Antonetti) and finally the blood-nerve barrier (Weerasuriya and Mizisin). In this way the opening section reviews the morphology and function of the cell associations forming the barriers of the CNS and directly reviews current knowledge of the different barriers between the nervous system and the systemic circulation.Part II is devoted to imaging the barrier and covers confocal microscopical detection of proteins in endothelial cells , MRI of permeability of contrast agents , pathological investigations with iron oxide microparticles , human blood-brain barrier integrity measured with MRI (Kassner and Thornhill), the blood cerebrospinal fluid barrier in the embryonic rat  and MRI studies of the blood-nerve barrier with MRI (Wessig).Part III moves on to molecular techniques and covers protocols for isolation of endothelia cells and a study of lipid rafts with mass spectroscopy , Laser capture proteomic studies of endothetlial cells, (Murugesan), P-glycoportein expression and function (Chan and Bendayan), and methods to study glycoproteins in the blood-brain barrier using mass spectroscopy .Part IV covers models available for barrier study including novel systems for the eye and brain in Drosophila  and zebrafish brain . Cell culture models for pericyte endothelial interactions in a porcine model , the human outer retinal barrier (Hamilton and Leach), and the peripheral nerve barrier (Sano and Kanda) are then described and discussed.The final part V is devoted to the delivery of therapeutic agents across the barrier and includes, treatment of focal ischemia with viral vector mediated gene transfer (Su and Yang), Treatment of brain tumours with barrier disruption (Blanchette and Fortin), the use of liposome nanocarriers and single domain antibodies for delivery of drugs and contrast agents in the context of drug delivery  and finally chapter on targeting the choroid plexus and cerebrospinal fluid using peptide motifs identified by page display In all this book represents a very useful addition to the series, the reviews and protocols bring important areas within the field up to date in a very accessible format and will be attractive to both established scientists in the area and postgraduate and postdoctoral students establishing a career and wishing to master new ideas and methods. It should be on the bookshelf of every lab with an interest in the blood-brain barrier. Again Sukriti Nag has brought together a panel of world experts to compile a valuable volume.The author declares that they have no competing interests.Sole author.


Veneto Region is currently achieving the integration of health and social services by integrating the tele-surveillance (detection of emergencies) already provided to ‘socially frail’ people with tele-monitoring, addressed to patients affected by chronic diseases.This strategy is guided by the idea that a better integration between the different levels of assistance is capable of improving the quality and continuity of care and generating synergies that benefit the healthcare system both by enhancing coordination of efforts and by reducing costs.The strategy employs a unique call center at Regional level, that currently performs tele-surveillance services  originally targeted to ‘socially frail’ people and a more complete tele-monitoring service for chronic patients, thus integrating health and social services. Tele-monitoring consists in the remote measurement of vital parameters (controlled by physicians), and the management of emergencies.This approach to the integration of different assistance levels is being put to the test in the context of the RENEWING HEALTH European Project. The project will assess the services using a multidisciplinary HTA methodology thus providing reliable evidence on the effectiveness and cost-effectiveness on the large-scale implementation of this kind of service.


As the environmental significance of odor pollution is recognized by the public, the demand for accurate assessment of these pollutants has been growing steadily. Hence, the analytical methodologies commonly used for their determination need to be evaluated from various respects. This special issue is thus intended to compile up-to-date knowledge on the determination of odor pollution with emphasis on volatile organic compounds (VOCs) and many key odor components such as reduced sulfur compounds (RSCs), organic acids, carbonyls, and nitrogenous compounds (ammonia and trimethyl amine).The publication of this special issue has been achieved by the warm support and devotion of the contributing authors as well as the important contribution offered by expert reviewers. This special issue is intended to provide a snapshot in the timeline of international research and policy of odorant and VOC pollution and to bring together some of the recent and most exciting developments in the area, and to describe the main trends of their application in the field study. It contains a mixture of papers describing the latest development for their application relevant to air pollution and odor pollution.Ki-Hyun KimKi-Hyun KimDavid ParkerDavid ParkerFusheng LiFusheng LiKea-Tiong TangKea-Tiong Tang


MR imaging of the heart typically involves the acquisition of standard views aligned with the heart axes. Time-efficient and reproducible planning requires expertise in heart geometry and anatomy. In this study, we evaluate the ability of fully automatic heart view localization software to detect the long-axis views of the heart and compare the results both visually and geometrically with manual localization.27 patients (age range 9-70 years) undergoing CMR for a range of different indications  were examined on a 1.5 T MAGNETOM Avanto MR system . Following rough localization of the heart within the thorax, a stack of slices covering the entire heart was acquired in the approximate short-axis orientation using a single-shot TrueFISP sequence. This stack of slices was used as input to a machine learning-based algorithm [The automatic view-planning software detected the heart in all 27 cases. Visual agreement scores are summarized in Table We have demonstrated in a group of patients with a range of different cardiovascular pathologies that automatic planning of the long-axis views of the heart can be accomplished in the majority of cases with little or no clinically relevant difference compared with manual planning. Consistent with the visual assessment, the angular differences between the manually and automatically planned views increased with increasing visual difference.Siemens AG.


An 11-year-old boy was shot with an air-powered rifle.Where is the entry wound?What type of hemorrhage is present?What are the indications for removal of the foreign body?What is the optimal surgical approach?The patient is an 11-year-old boy who was accidentally shot in the face with an air-powered rifle. The ball bullet (BB) entered through the dorsum of the nose over the nasal radix (Fig 1hyposphagma, defined as an accumulation of blood trapped between the conjunctiva and the sclera. Many small, fragile blood vessels located within the conjunctiva are easily ruptured.The BB traversed the soft tissue causing a subconjunctival hemorrhage Fig . This tySurgical removal of ballistic fragments is usually discouraged, because the dissection necessary to retrieve them can be harmful.The foreign body was excised using an upper lid blepharoplasty incision and can be expected to leave an aesthetically acceptable scar.


There was an error in the fourth paragraph of the "Identification of novel genes induced in an early response to food deprivation" section of the Discussion.The text currently reads: "There have been no citations for scl-2 in the literature and its function remains largely unknown. However, the gene encodes a sterol carrier-like protein domain and may potentially be involved in the transport of steroid hormones or lipid breakdown products. Up-regulation of a gene involved in such processes during food deprivation would be expected. Expression of scl-2 appears to be confined to the intestinal cells at all stages. The intestinal cells represent a major site of fat storage in the nematodes [39]. Therefore, the localised expression of scl-2 in the intestine makes it ideally placed for involvement in fat mobilization."The correct text is: "The function of scl-2 remains largely unknown, but the gene encodes a predicted extracellular protein belonging to the sperm coating protein (SCP)-like domain containing protein family. Expression of scl-2 appears to be confined to the intestinal cells at all stages, which represent a major site of fat storage in the nematodes [39]. Localised expression in the intestine makes it ideally placed for involvement in fat mobilization, but we cannot speculate on its precise role in the response to reduced food intake further."The change does not impact the rest of the manuscript or change the findings therein.


Dear Editor,We have read with great interest the article by Mogadam and colleagues on utilization ofgabapentin and diclofenac for management of post-operative pain in patients undergoingtonsillectomy . Perhaps


Recruitment into surgical trials is often hampered because of surgeon or patient preferences. Qualitative research to explore and standardise methods for communicating clinical equipoise and addressing patient concerns has been shown to be effective in maximising recruitment. Often this research runs alongside the trial without being fully integrated within it. We describe how we integrated qualitative research into the multi-centre By-Band study comparing two surgical procedures for morbid obesity.The integration has the following elements (a) having one screening log which captures patient consent for i) the qualitative research, ii) simple follow up concerning treatment preference, and iii) the randomised trial; (b) capturing details of the audio-recordings taken during the consultation process within the participant case report form; (c) adding functionally to the trial database to capture this information and to allow secure up-load of audio-recordings directly into the database; (d) producing routine reports for the qualitative researchers.Participating sites have found the system straightforward to use. The database is hosted on an NHS server accessed via the NHS clinical portal, so is familiar to centres taking part. Audio-recordings are being received in a timely way and real-time queries in the database have led to high levels of completeness. Up-to-date information on trial progress is provided to the qualitative researchers on a weekly basis, with minimal effort.Integrating the qualitative research fully into the trial has brought benefits for all. The mechanism for transferring audio-recordings is being rolled out to other trials with a qualitative component.This study is funded by the NIHR HTA programme and the views and opinions expressed are those of the authors and do not necessarily reflect those of the HTA programme and, NIHR, NHS or the department of health.


Building on the success of the Stop Smoking Over Mobile Phone (STOMP) trial and the Social Cognitive Theory-Based Intervention (STUB-IT) trial for smoking cessation, this pilot study examined the feasibility of brief intervention (BI) delivered by mobile-health technology to reduce problem drinking and injury among trauma patients presenting to the hospital. We interviewed 30 Maori, Pacific Island, and Pakeha (European/white) patients to explore their perceptions of the proposed mobile-phone–delivered intervention and the barriers and facilitators to participation and compliance. Participants were highly supportive of the intervention concept, noting aspects of message content and delivery that would appeal to the major ethnic communities as well as potential barriers that required attention. Text messages  that were adapted for the cultural context had particular appeal, as was the proposed delivery of one or two motivational messages on Fridays/weekends over a period of up to four weeks following hospital discharge. Collecting injury-outcome data through record linkage to national databases of hospital discharges and claims to New Zealand’s universal fully-funded accident insurance scheme was both feasible and effective. The proposed trial of 6000 participants appears feasible and acceptable to patients from communities of interest, with economies of scale in both the implementation of the intervention and trial methodology. If demonstrated to be effective, this approach to BI has the potential to be cost-effective, highly scalable, and accessible to harder-to-reach communities in New Zealand and elsewhere. As shown in previous trials, this strategy could also reduce ethnic and socioeconomic inequalities in access to interventions.


As a part of the NHS modernisation agenda to ensure high quality clinical care, podiatrists are required to demonstrate evidence of continuing professional development to maintain registration. This study aimed to investigate the experiences of podiatrists in response to the CPD process. It explored the effectiveness of the portfolio in recording CPD, resource as a limiting factor in CPD engagement and the linking of competence with re-registration.The study was of a qualitative design using purposive sampling to select six key informants. Semi-structured interviews were conducted and data was analysed using themaptic analysis.: Called to account - Perceptions of the CPD process indicating poor comprehension and associated anxiety due to lack of effective communication; Proving your worth - Positive views of linking competence with re-registration; Transparent recording device -Support for the portfolio but concern for its ability to demonstrate practical competence; Balancing responsibilities - Experiences of funding depletion and strategies to maximize free CPD.Four main themes emerged from the studyThis study has been valuable in gaining a deeper understanding of the podiatrist’s perceptions of CPD and may assist in informing future process. Podiatrists were in favour of the new regulations but showed anxiety towards the process due to confusion over the requirements. Support was shown for a link between re-registration and competence to ensure patient safety. Funding deficiencies were a concern resulting in the use of free CPD as part of daily practice.


We propose to make use of the wealth of underused DNA chip data available in public repositories to study the molecular mechanisms behind the adaptation of cancer cells to hypoxic conditions leading to the metastatic phenotype. We have developed new bioinformatics tools and adapted others to identify with maximum sensitivity those genes which are expressed differentially across several experiments. The comparison of two analytical approaches, based on either Over Representation Analysis or Functional Class Scoring, by a meta-analysis-based approach, led to the retrieval of known information about the biological situation – thus validating the model – but also more importantly to the discovery of the previously unknown implication of the spliceosome, the cellular machinery responsible for mRNA splicing, in the development of metastasis. Despite the development of effective therapies for many cancers Cancer is known to be a genetic disease, implying either alteration of DNA or dysregulation of gene expression In the last decade, the availability of microarray datasets in public repositories has grown dramatically , to allow for a fair comparison between arrays (standardization), and to summarize probe-level intensities to meaningful probe set values et al described the affyprobeminer as a tool to ease the mapping of current knowledge to probe sequences in Affymetrix arrays The last preprocessing step, called summarization, consists of gathering probe-level information regarding the same target. The mapping of the target definition to the probe coordinates on the chips involves a chip definition file (CDF). The annotation of the human genome has improved since the first release of CDFs by the manufacturer (Affymetrix) and several authors have thus reported the need to update the definition of chip definition files Microarray data can be used to track the expression profile of the transcriptome following a hierarchical strategy that involves many levels of interpretation. The first level refers to individual analyses aimed at inferring the positive/negative regulation of transcripts and/or genes, as defined in the chip definition file (probe set definition in CDF). Wet-lab biologists mainly interpret microarray experiments based on the results of this step. Additional layers of analysis are described briefly in the next subsections .t test t test In previous work, we described a relationship between the number of replicates and the selection of the best performing methods After the individual analyses, the list of genes detected as differentially expressed is typically annotated using over-representation analysis (ORA) methods to highlight meaningful information. In a previous work, we described the use of the DAVID webtools to perform such an analysis on the results of microarray studies Small datasets with only a few replicates are still a major hindrance to statistical power in conventional analyses. Gene set analysis and meta-analysis are interesting and common ways to extract more information from the data, and to test higher-level hypotheses with a power level associated with an increased number of available values.Gene set analysis using Functional Class Scoring methodologies (FCS) has improved the understanding of differences in expression profiles, and helped unravel the biological processes underlying experimental data in several ways. First, joint analysis of multiple genes involves a higher number of values than individual analyses, hence providing the potential for a higher power level, even when conducted on small datasets . Second, computation of differential expression from multiple levels of interpretation enriches the qualitative description of biological variations between experimental conditions. The criteria used to define the gene sets consequently guide interpretation of the results . By extension, the comparison of the results of individual and gene set analyses allows, as with ORA methods, to refine the list of candidate genes for further testing, thanks to the criteria-based approach .Over the last decade, various Functional Class Scoring methodologies (FCS) have been developed to analyze gene sets, including 2-step or global methods, competitive or self-contained null hypothesis and inference : GSEA Method-specific biases in the detection of gene sets are associated with methodological choices, and are due to correlations between genes, the simultaneous presence of up/down regulated genes, the level of expression and the number of genes in the set.... In order to detect all kinds of sets with an expression profile that differs between conditions, we developed FAERI, tailored from the two-way ANOVA et al in 1904 Meta-analysis is a natural extension of the dataset-based analysis conducted using individual and gene set methodologies, and examines several datasets relating to similar experimental conditions. A meta-analysis strategy was reported previously by Simpsons To identify commonly regulated genes in multiple datasets, a higher-level analysis must be defined as opposed to the dataset-specific strategies described above. The ideal meta-analysis design would consist of the joint analysis of multiple datasets following a higher-order multivariate analysis procedure. However, post-hoc strategies require less computing time than full-on transversal analyses, which still remains a major concern in the analysis of large datasets. In a previous study, we explored an intersection-based post-hoc strategy, defined as an additional analytical step performed on results generated with several dataset-specific analyses To compare the results of differential expression analyses of genes (or gene sets) across datasets, we reported use of the number of dataset-specific analyses that result in a significant detection of the gene (the number of top-lists in which each gene is present). This score, which monitors systematic differences in expression profiles across datasets, was then used as a selection criterion to define candidate genes. The reported strategy leads to three situations, depending on the strictness of the comparison across datasets: 1) the selection of genes that are detected in all (or the highest number of) datasets  results in a very low number of genes, which are often already well known; 2) selection of the genes detected in at least one dataset  results in too many candidates for further investigation, and does not exclude false positives; 3) a balance can be reached between both situations, with an intermediate selection threshold at the number of DEGs across datasets. That intermediate situation (union of intersections between a given number of top lists) allows for inference of a workable amount of new candidates. Along these lines, several techniques have been developed to describe the intersections between lists of genes We propose to use a set of statistical and bioinformatics tools to reanalyze metastasis and hypoxia-related data to gain further insight into the processes involved. The comparison of two analytical pipelines (ORA and FCS) is used to detect meaningful pathways . The intersection of both lists was then performed, as described in the materials and methods section, to identify candidate genes expected to be involved in both hypoxia and metastasis, while removing potential false detections from the large lists retrieved in the first step. The meta-analysis yielded substantially different results, as shown in The list of the identifiers for the 1156 genes obtained after the meta-analysis step was then entered into the DAVID web tool. A total of 102 pathways containing at least 3 gene members of that list was generated see . Among tTo further assess the significance of the spliceosome pathway in the over-representation results, we first performed 500 random selections of 1156 EntrezGeneIDs among all the identifiers present on the microarray and ran them in the DAVID tool. The EASE scores and number of hits in the spliceosome pathway were then plotted see . The ploMoreover, the spliceosome, whose implication in cancer has been reported by several authors The second part of the analytical pipeline  relies oBoth parts of the analytical pipeline described here have detected the spliceosome pathway as involved in the hypoxic and metastatic phenotypes. Among the 31 genes detected as differentially expressed in this pathway, 11 have recently been shown to be involved in the metastatic process see . The remThe results also demonstrate the potential of sensitive and specific analytical pipelines: new hypotheses can be proposed, and previously known biological features can be used as positive controls. However, comparison of the results between both parts of the analytical pipeline suggests that the two analyses behave differently: over-representation analysis of the most significant genes across datasets detects some important pathways, and the ability of gene set analysis using FAERI to detect slight cumulated differences detects more pathways. Statistical analysis with FAERI detects meaningful differences between samples, even when only small numbers of replicates are available. Nevertheless, both parts of the pipeline lead to detection of relevant information based on current knowledge, and both suggest the involvement of the spliceosome.We implemented a pipeline of bioinformatics tools to explore archived microarray data, from preprocessing to mapping of the results. We used that pipeline to examine metastasis and hypoxia data and found results in keeping with previous reports, as well as a new hypothesis. The combination of high-level analysis  with a meta-analysis step led to the discovery of involvement of the spliceosome in the hypoxic and metastatic processes, and the generation of a list of 20 new candidate genes.Bioinformatics approaches will never replace bench validations; however we were able to form a plausible hypothesis just by re-analyzing available data. Biological investigations should therefore be performed to further refine the interpretation of the relationships between the pathways detected and understand how a hypoxic environment and metastasis affect both general and energetic cell metabolism. Further investigations should be conducted to clarify the results of the statistical analyses and to discriminate between causes and consequences (mechanisms of perturbations and symptoms). However, that validation is out of the scope of this methodological paper.de novo microarray experiments. We think that this work will contribute to the creation of a virtual atlas for cellular biology containing the known characteristics of cells in diverse biological conditions, which is one of the major goals of the bioinformatics community.We think that this analytical protocol could be used successfully in many other biological contexts, wherever several datasets are available. Indeed, we have shown that single gene analysis alone yields poor results, though this is often the only step performed by wet-lab biologists. The methodology presented here allows for improved performance, comparison with previously known information and discovery of recurrent patterns , all of which were performed using freely-available resources and software packages and without the need to perform expensive For the purposes of the study reported here, two sets of criteria were used to retrieve datasets with PathEx , and a set of packages available in the Bioconductor repository (http://www.bioconductor.org).The preprocessing of the data and the individual analyses reported in this paper were performed using R 2.7 and 2.10, available on the website of the R-Project . The 16 dataset-specific lists of the most significant genes were gathered into two groups, according to the experimental design (Hypoxia/Metastasis studies). In each group of datasets, a new list of genes was defined from the list of genes found to be differentially expressed in at least one dataset of the group. Lastly, the intersection of the list of genes from the two groups was performed by selecting genes that were detected in both groups, resulting in a list of 1156 unique gene identifiers  t test treatment, meta-analysis and over-representation analysis (ORA) in DAVID). The right part contains the gene set analysis steps  by FAERI and meta-analysis of the results).The different steps in the analytical pipelines are summarized in Table S1Full list of p-values obtained for each dataset for each of the 1156 genes highlighted in the analysis.(PDF)Click here for additional data file.Table S2List of pathways highlighted in the over-representation analysis using DAVID.(PDF)Click here for additional data file.Table S3Full list of p-values obtained in the geneset analysis.(PDF)Click here for additional data file.Table S4Distribution of the highlighted genes in the spliceosome pathway.(PDF)Click here for additional data file.Table S5R code for the full analysis.(PDF)Click here for additional data file.Checklist S1(PDF)Click here for additional data file.


Vanessa cardui) in untethered, forward flight. These experimental results are then analyzed computationally using a high-fidelity, three-dimensional, unsteady Navier-Stokes flow solver. For comparison to this case, a set of non-deforming, flat-plate wing (FPW) models of wing motion are synthesized and subjected to the same analysis along with a wing model that matches the time-varying wing-twist observed for the butterfly, but has no deformation in camber. The simulations show that the observed butterfly wing (OBW) outperforms all the flat-plate wings in terms of usable force production as well as the ratio of lift to power by at least 29% and 46%, respectively. This increase in efficiency of lift production is at least three-fold greater than reported for other insects. Interestingly, we also find that the twist-only-wing (TOW) model recovers much of the performance of the OBW, demonstrating that wing-twist, and not camber is key to forward flight in these insects. The implications of this on the design of flapping wing micro-aerial vehicles are discussed.Insect wings can undergo significant chordwise (camber) as well as spanwise (twist) deformation during flapping flight but the effect of these deformations is not well understood. The shape and size of butterfly wings leads to particularly large wing deformations, making them an ideal test case for investigation of these effects. Here we use computational models derived from experiments on free-flying butterflies to understand the effect of time-varying twist and camber on the aerodynamic performance of these insects. High-speed videogrammetry is used to capture the wing kinematics, including deformation, of a Painted Lady butterfly ( Insect wings deform to varying degrees during flapping flight, and the kinematics of wing deformation Eristalis tenax, Linnaeus), assuming an approximately linear spanwise wing-twist and a wing camber that was uniform across the span and constant during each half-stroke. Their model showed that camber is more important than wing-twist in determining the aerodynamic performance in the hovering flight of hoverflies. Nakata and Liu Since the inclusion of wing deformation increases the complexity of the analysis, most studies of the aerodynamics of insect flight assume the wings to be rigid and flat e.g. . Some stet al.Schistocerca gregaria in a wind tunnel using stereo videogrammetry. Young et al. Unlike hovering flight where the generation of lift is the key determinant of wing motion, in forward flight, the wings also have to generate a net positive thrust during each flapping cycle to maintain the forward velocity of the animal. This has to be accomplished by the wings by generating positive forward force (thrust) in some phases of the cycle and reducing the negative force (drag) on the wings in other phases. It is therefore not clear if the observations regarding the effects of wing deformation on hovering flight extend to insects in forward flight. An attempt to understand the effect of wing deformation during forward flight was made by Walker Vanessa cardui. These butterflies are large relative to most volant insects and have broad wings with the forewing and hindwing functioning as a single surface, leading to wing aspect-ratios (see In the current study we explore this issue further by studying the effect of time-varying twist and camber on the free forward flight of the Painted Lady butterfly The study employs a Navier-Stokes (NS) based computational model of the flight aerodynamics which are based on a precise reconstruction of the observed twist and camber of the butterfly wings . We thenVanessa cardui), well known for its orange wings with striking black and white spots  as well as the corresponding flat-plate wings are shown in The observed butterfly wing (OBW) with time-varying deformations produced forces similar in magnitude and timing to those measured from the actual animal . The comAs expected, this the OBW model exhibits substantial time-varying deformation in camber  as well g cycle. . The angg cycle. ; during The kinematic features of the flat-plate wing models  are compared to the OBW model in The flow over the wing is driven primarily by the sectional angle-of-attack (AoA) and estimates of this quantity can be obtained as AoAThe instantaneous lift, thrust, and power , the TOW and the FPW models 1–3 by comparing the stroke-averaged lift  model has no camber but matches the time-varying AoI of the butterfly wing at every section along the span. The three flat-plate wing (FPW) models  have no The study indicates that the observed butterfly wing (OBW), which incorporates significant time-varying deformation in camber as well as twist, far outperforms all the flat-plate wings in terms of the mean forces  as well as power-specific force generation (lift over power and force over power). The TOW model, which incorporates twist but no camber, comes closest to matching the performance of the OBW. This indicates that the vast majority of the benefits of wing deformation are derived from spanwise twist, despite the relatively low aspect-ratio and large camber of butterfly wings. Spanwise twist allows the proximal and distal portions of the wings to operate at different angles-of-incidence (AoI). During upstroke, the distal part of the wings translates at high AoI, which decreases local AoA; this prevents the generation of a strong LEV beneath the wings that can produce large negative vertical forces. The proximal portion of the wing operates at low AoI and avoids rapid rotation at the end of upstroke, which would generate a large negative lift peak, a positive thrust peak and thus a large power peak see  in . During This study, like most other Navier-Stokes computational fluid dynamic analyses of animal flight, is limited to a single species and flight behavior due to the complexity of data acquisition, modeling, simulation and analysis. The current study is based only a single wingbeat from a single butterfly specimen. Despite the fact that the particular recording was chosen from a multitude of recordings and in our view, is a good representation of level forward flight, the generality of the findings is uncertain and a broad assessment of the effects of wing flexibility and deformation on flapping flight requires comparison of the current results to studies. In this regard, other recent work on deforming flapping wings has focused on the effects of chordwise (camber) deformation


There is limited evidence for the effectiveness of TH on quality of life (QoL) in patients with COPD. A systematic review in the area inclusive of all respiratory conditions indicated that there were no UK based studies, or randomised controlled trials (RCTs) evaluating the effectiveness of TH for COPD . A more recent systematic review found 6 studies, only two of which measured QoL as an outcome . One of these studies was a RCT and found improvements in QoL at 3 months (Koff 2009), while the other was a non-controlled before and after study which found no difference in quality of life scores at 6 months . Research in this area is plagued by small sample sizes, absence of longer-term follow-ups, insufficient descriptions of the intervention, poor internal validity of whether using the device in the context of a complex healthcare intervention leads to improved outcomes for the patient, and few attempts to measure quality of life in patients with COPD following the introduction of these devices.The current investigation is part of the Whole System Demonstrator (WSD) programme that aims to evaluate the effectiveness of telehealth (TH) for patient reported outcomes with Chronic Obstructive Pulmonary Disease (COPD). The primary objective was to evaluate the effectiveness of telehealth for COPD specific QoL and to examine whether there were improvements in HRQoL and psychological distress at short-term and long-term follow-up in this cohort of patients with COPD.WSD is one of the largest pragmatic cluster randomised controlled trials evaluating TH in the UK. Patients with COPD from three regions in England  were recruited from 179 GP practices randomised balancing for region, practice size, deprivation index, non-white proportion and prevalence of COPD. Over 570 patients with COPD completed a comprehensive battery of questionnaires assessing a range of patient reported outcomes. Measures of generic Health-Related Quality of Life (HRQoL) (Short Form-12), disease specific QoL including perceived control over COPD, fatigue caused by the disease and the emotional impact of the disease (Chronic Respiratory Questionnaire). Psychological distress was measured by depression (CESD-10) and anxiety (STAI).Multi-level modelling was utilised to evaluate the effect of trial arm on HRQoL and COPD specific QoL. Results for intention-to-treat analysis, participants that received the intervention as per the research protocol, complete case analysis for cases with all baseline, short-term and longer-term follow-ups completed and an available case analysis of patients with either a short or long-term follow-up available. The results will be discussed and have important clinical implications for COPD management.Results and conclusions are censored until any findings are published in peer-reviewed journals.


Refolding of viral class-1 membrane fusion proteins from a native state to a trimer-of-hairpins structure promotes entry of viruses into cells. Here we present the structure of the bovine leukaemia virus transmembrane glycoprotein (TM) and identify a group of asparagine residues at the membrane-distal end of the trimer of hairpins that is strikingly conserved among divergent viruses. These asparagines are not essential for surface display of pre-fusogenic envelope. Instead, substitution of these residues dramatically disrupts membrane fusion. Our data indicate that through electrostatic interactions with of a chloride ion the asparagine residues promote assembly and profoundly stabilize the fusion-active structures that are required for viral envelope-mediated membrane fusion. Moreover, the BLV TM structure also reveals a charge-surrounded hydrophobic pocket on the central coiled coil and interactions with basic residues that cluster around this pocket are critical to membrane fusion and form a target for peptide inhibitors of envelope function. Charge-surrounded pockets and electrostatic interactions with small ions are common leitmotifs among class-1 fusion proteins. We will discuss the impact of these observations in light of current models of membrane fusion and as potential targets for therapeutic inhibition of viral entry.


Analysis of transcription factor binding to DNA sequences is of utmost importance to understand the intricate regulatory mechanisms that underlie gene expression. Several techniques exist that quantify DNA-protein affinity, but they are either very time-consuming or suffer from possible misinterpretation due to complicated algorithms or approximations like many high-throughput techniques. We present a more direct method to quantify DNA-protein interaction in a force-based assay. In contrast to single-molecule force spectroscopy, our technique, the Molecular Force Assay (MFA), parallelizes force measurements so that it can test one or multiple proteins against several DNA sequences in a single experiment. The interaction strength is quantified by comparison to the well-defined rupture stability of different DNA duplexes. As a proof-of-principle, we measured the interaction of the zinc finger construct Zif268/NRE against six different DNA constructs. We could show the specificity of our approach and quantify the strength of the protein-DNA interaction. The sequence-specific interaction of certain proteins with the genomic DNA is prerequisite for the complex task of transcriptional regulation. Those transcription factors bind alone or in clusters to the DNA and can thus activate or impede transcription. Many of the transcription factors can bind to several, different DNA sequence motifs with varying strength in vivo method chromatin immunoprecipitation combined with microarray analysis (ChIP-chip) in vitro techniques like protein binding microarrays (PBM) Recent developments in high-throughput techniques, for example the Importantly, due to the high concentration of DNA in a bacterial cell or eukaryotic nucleus, the dynamic equilibrium between unbound and bound activated transcription factors is shifted towards DNA-protein complexes. Hence, affinity described by the dissociation constant might not be the best measure to characterize the protein-DNA interaction inside a nucleus. The specificity defined as the ability of a transcription factor to discriminate between a regulatory sequence and the vast majority of non-regulating DNA might be a more suitable quantity. But quantification of the specificity in that sense means to determine the complete list of dissociation constants for all possible DNA sequences or a constant calculated from those dissociation constants The Molecular Force Assay (MFA) developed in our lab 2-His2 class Zinc finger motifs are one of the most abundant DNA binding domains in eukaryotic transcription factors The standard Molecular Force Assay (MFA) consists of two molecular bonds in series, a reference and a sample bond, clamped between two surfaces. The two surfaces are separated with a constant velocity so that a force builds up in the two molecular bonds until the weaker one ruptures. A fluorophore conjugated to the linker sequence between the two molecular complexes indicates the intact molecular bond. Hence, the ratio of the fluorescence intensity before and after the force loading of the molecular constructs is a measure of the strength of the sample bond in comparison to the reference bond. An alternative view of this assay is that the force greatly enhances the off rate of the bond under investigation and reduces the otherwise extremely long spontaneous dissociation times towards seconds In the configuration of the MFA used in all former studies, the ligand-DNA interaction is not directly probed, but the ligand stabilizes the molecular bond and is thus detected. We here describe our new variant of the MFA that can probe the protein-DNA interaction directly and compare it to a reference bond. For this purpose, the fusion protein construct consisting of an N-terminal ybbR-tag In a first test of our assay, we determined the binding of the zinc finger protein to a no binding sequence and a high affinity binding motif. The bond strength was compared to two reference sequences, a 20 bp double-stranded DNA and a 40 bp double-stranded DNA, both in shear geometry, by measuring the Cy5 fluorescence intensity of the transferred DNA after the contact and separation process. transfer to the maximal number of functional proteins Fintact protein is defined as the Normalized Fluorescence, NF. The NF is calculated by dividing the pictures after background subtraction pixel-by-pixel Click here for additional data file.Supplement S1Materials and Methods.(DOC)Click here for additional data file.


The multiple etiologies of schizophrenia prompt us to raise the question: what final common pathway can induce a convincing sense of the reality of the hallucinations in this disease? The observation that artificial stimulation of an intermediate order of neurons of a normal nervous system induces hallucinations indicates that the lateral entry of activity  at intermediate neuronal orders may provide a mechanism for hallucinations. Meaningful hallucinations can be de-constructed into an organized temporal sequence of internal sensations of associatively learned items that occur in the absence of any external stimuli. We hypothesize that these hallucinations are autonomously generated by the re-activation of pathological non-specific functional LINKs formed between the postsynaptic membranes at certain neuronal orders and are examined as a final common mechanism capable of explaining most of the features of the disease. Reversible and stabilizable hemi-fusion between simultaneously activated adjacent postsynaptic membranes is viewed as one of the normal mechanisms for functional LINK formation and is dependent on lipid membrane composition. Methods of removing the proteins that may traverse the non-specifically hemi-fused membrane segments and attempts to replace the phospholipid side chains to convert the membrane composition to a near-normal state may offer therapeutic opportunities. Schizophrenia has been viewed as a neuro-developmental disorder  receptor-blocking conditions. In these contexts, the contrasting but complementary pieces of the disease puzzle may provide clues to understanding the pathology and verifying the operating mechanisms for internal sensations of higher brain functions. An abstract of this work was presented at the Society for Neuroscience annual meeting in 2009  in the environment. As the distance between the sensory receptors and the item increases, the sensory input traveling at the highest velocity reaches the nervous system faster than the others Figure . The abiHallucinations induced by the stimulation of an intermediate path by pathological irritation are expected to share some basic features with that of memory retrieval. What kind of reductive approach is required to understand the nature of the internal sensations within the nervous system? An episodic representation of an event is organized into an order of events that unfolds as a mental replay of the event spread over time Tulving, . Interna4 dendritic spines (postsynapses or postsynaptic membranes) on its dendritic tree  Normally, oscillatory neuronal activity is expected to produce sub-threshold activation of those neurons at the higher orders that receive fewer EPSPs than required for spatial or temporal summation capable of inducing an action potential. When additional EPSPs reach these sub-threshold activated neurons, it will lead to their autonomic activation and result in the transmission of activity to higher neuronal orders, activating many previously formed specific functional LINKs and inducing meaningful hallucinations Figure . (b) TheIn summary, (a) non-specific inter-postsynaptic functional LINK formation can induce a universal effect at the neuronal orders above the oscillating orders such that no separate functioning areas exist that can identify the hallucinations as unreal. (b) In the presence of the continuous arrival of activity through the pathological non-specific inter-postsynaptic mis-LINKs, the sub-threshold-activated neurons maintained by oscillatory neuronal activity start firing, re-activating the normal inter-postsynaptic functional LINKs at higher neuronal orders so that the hallucinations become autonomous in nature. (c) The convincing sense of reality of the hallucinations indicates that beyond the origin of autonomous activation of non-specific functional mis-LINKs, the system is operating by using the normal mechanism of formation of semblances for memory retrieval, using previously formed inter-postsynaptic functional LINKs from associative learning events; but their formation occurs in a wrong context, inducing hallucinations. (d) The hallucinations are similar to the perception of sensory stimuli from the environment due to the inter-postsynaptic mis-LINKs at the early neuronal orders in the auditory cortex .A delusion is a belief held with a very strong conviction by the subject, even in the presence of a counter-argument provided by a second person. This indicates that there is a compelling internal sensation experienced by the subject who is perceiving the delusions and that the subject lacks an operational mechanism within the remaining nervous system that identifies the internal sensation of delusions as unreal. The formation of these delusions can be explained as resulting from their autonomous activations from pathological non-specific inter-postsynaptic functional LINKs. Since the latter leads to the activation of a non-specific set of otherwise normal inter-postsynaptic functional LINKs at higher neuronal orders in the entire nervous system, the subject autonomously continues to perceive items or events (a) that were not associatively learned in the past and (b) that were not associatively learned from the environment from which their nervous systems continue to make associations.In many locations in the nervous system, the postsynaptic membranes belonging to different neurons are apposed to each other with minimal visible extracellular matrix volume, especially in locations where sensory inputs converge; for example, the hippocampi. One of the feasible mechanisms for the generation of functional LINKs between the postsynaptic membranes is the formation of reversible membrane hemi-fusion. A large number of studies have shown reversible hemi-fusion occurring between biological membranes  into the postsynapses through the cell body of the neuron  images of the synapses from previous studies were examined. By the time rodents reach adulthood, it is expected that they have experienced a large number of associative learning events. Therefore, hemi-fused inter-postsynaptic membranes at various locations in the nervous system are expected to be found. Even though limited resolution sometimes reduces the view of the membrane lipid bilayers to only single layers, overlapping of the adjacent postsynaptic membranes can be observed from the results of different studies  and acyl transferase  and docosa-hexaenoic acid (DHA), both derived from essential fatty acids (EFA), in the Sn-2 position in neuronal cells  gene causes deficiency of its protein, leading to reduced catabolism of dopamine and further leading to the latter’s accumulation and resulting in an increased susceptibility to schizophrenia  serial EM sections is necessary to examine the entire surface of a dendritic spine to visualize membrane hemi-fusion. We anticipate hemi-fusions only at very short lengths of the apposed postsynaptic membranes, necessitating a thorough examination of the entire dendritic spine’s (postsynapse’s) membrane bilayer. Since it is possible that inter-postsynaptic hemi-fusion can take place even farther away from the synaptic cleft, a large-scale re-construction of EM sections is required to visualize such hemi-fusion. The probability of finding hemi-fusion is high at regions where sensory inputs converge; for example, the hippocampus.Work toward examining the ultra-structural changes of the postsynaptic membranes is needed to test the possibility of membrane hemi-fusion as a mechanism of inter-postsynaptic functional LINK formation. Since EM examination uses sections with a thickness of 5 × 10Adolescents with the prodrome (Yung et al., The present work provides the framework of a mechanism for the clinical features of schizophrenia, a disease found to be associated with a multitude of genetic and environmental factors. Non-specific hemi-fusion between postsynaptic membranes at certain neuronal orders is hypothesized to be the final common path that can induce autonomous meaningful hallucinations and cognitive defects. We expect that various other pathways that are implicated in schizophrenia, which are not mentioned in this work, can find suitable entry points into the present framework. The final path explains the implications of the involvement of both NMDA and dopamine neurotransmitters. By examining the formation of basic units of internal sensations resulting from the lateral entry of activity at the synaptic level, it was possible to attribute the diverse features of auditory hallucinations, cognitive impairment, and defects in consciousness to pathological structural changes; these changes also serve as an explanation for the beneficial effect of EFA reported from a randomized double-blinded control trial (Amminger et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Submicron scale domains of membrane-anchored receptors play an important role in cell signaling. Central questions concern the stability of these microdomains, and the mechanisms leading to the domain formation. In immune-cell adhesion zones, microdomains of short receptor-ligand complexes form next to domains of significantly longer receptor-ligand complexes. The length mismatch between the receptor-ligand complexes leads to membrane deformations and has been suggested as a possible cause of the domain formation. The domain formation is a nucleation and growth process that depends on the line tension and free energy of the domains. Using a combination of analytical calculations and Monte Carlo simulations, we derive here general expressions for the line tension between domains of long and short receptor-ligand complexes and for the adhesion free energy of the domains. We argue that the length mismatch of receptor-ligand complexes alone is sufficient to drive the domain formation, and obtain submicron-scale minimum sizes for stable domains that are consistent with the domain sizes observed during immune-cell adhesion. In the past years, microdomains of proteins in cell membranes have emerged as a central aspect of cell signaling Several mechanisms have been proposed for the formation of TCR-MHCpeptide domains during T-cell adhesion. These mechanisms are based on the actin cytoskeleton In previous work, we have derived general expressions for the critical receptor and ligand concentrations required for domain formation. These general expressions depend on the length mismatch between the receptor-ligand complexes and on the bending rigidity of the membranes In this article, we determine the free energy and stability of clusters and domains of long and short receptor-ligand complexes. Our main results are general expressions for the line tension and adhesion free energy of the domains in terms of the concentrations and affinities of the receptors and ligands as well as the length mismatch of the receptor-ligand complexes. These general expressions fully include the effects of membrane shape fluctuations and the translational entropy of the receptors and ligands, and depend only on experimentally accessible quantities. Our expressions lead to estimates for the minimal size of stable TCR-MHCpeptide microdomains that are consistent with the submicron-scale sizes observed during T-cell adhesion.To describe the conformations of the two apposing membranes in a cell adhesion zone, we divide these membranes into small patches. Each patch can contain a single receptor or ligand molecule The energy of a membrane conformationThe rigidity-dominated elastic energy of the membranes has the form via long and short receptor-ligand complexes to the problem of a membrane with effective rigidity The equilibrium proporties of the membranes can be determined from the free energy tial see . The twoThe effective potential can be generalized to cases with more than two receptor-ligand complexes, or with additional repulsive molecules The effective potential helps to determine and illustrate the equilibrium behavior. If the two wells of the effective potential are relatively shallow, thermal membrane fluctuations can easily drive membrane segments to cross from one well to the other. If the two wells are deep, the crossing of membrane segments from one well to the other well is impeded by the potential barrier of width ells see . Beyond We have previously found that the critical potential depth for domain formation isIn this article, we determine how the adhesion free energy and line tension of the domains depends on the depths as well as on the width We use a combination of Monte Carlo simulations and scaling arguments to determine the free energy difference and line tension of membrane domains that are bound in the two potential wells of the effective potential A scaling analysis see  indicateIn the Monte Carlo simulations, we attempt local Monte Carlo moves in which the rescaled separation The free energy of domains of long or short receptor-ligand complexes can be determined from the effective double-well adhesion potential of the membranes see . We consThe function and  see . With eqWe use classical nucleation theory to determine the line tension between domains of long and short receptor-ligand complexes. Equilibrium properties of the membranes, such as the line tension between the domains of receptor-ligand complexes, can be obtained from the effective double-well adhesion potential of the membranes shown in We determine the critical radii of domain nucleation from Monte Carlo simulations. The simulations start from pre-equilibrated initial conformations with a circular nucleus of radius ll 2 see . The preNuclei with a radius grow see . To quanAccording to eq. (22), the line tension now follows as ases see . The lintion see .To derive a general relation for the line tension For small and intermediate values of  on  see . This liThe critical potential depth The values of the rescaled well depth dth  see . We therysis see , we obtaThe scaling function  in  see . From thvia long integrin complexes and that forms microdomains of short TCR-MHCpeptide complexes if foreign MHCpeptides are present on the apposing cell surface. According to classical nucleation theory, the critical radius beyond which these microdomains are stable is We consider now a situation in which a domain of long receptor-ligand complexes To estimate the magnitude of the rescaled effective binding energy For T cells, the length difference via partial integration in the partition function. These general relations for the line tension and adhesion free energy of the receptor-ligand domains depend only on parameters that can be directly related to experimentally accessible quantities. Using typical values for T-cell adhesion zones, we find that stable submicron-scale domains of TCR-MHCpeptide complexes may form solely because of their length mismatch to integrin complexes. The role of the T-cell cytoskeleton thus may be limited to the observed transport of TCR-MHCpeptide microdomains to the contact zone center via weak frictional coupling of the cytoskeleton to the TCRs While the line tension and stability of lipid domains has been investigated for a long timeAppendix S1Dimensional analysis.(PDF)Click here for additional data file.Appendix S2Free energy of a membrane in a single-well potential.(PDF)Click here for additional data file.


Nesting of patients within care providers in trials of physical and talking therapies creates an additional level within the design. The statistical implications of this are analogous to those of cluster-randomised trials, except that the clustering effect interacts with treatment, leading to different ICCs across treatment arms. In some cases, the clustering effect may be restricted to one or more of the arms, resulting in a "partially nested design". The statistical model that is recommended at the trial-level includes a random effect for the care provider but allows the provider and patient level variances to differ across arms. The care provider variance is constrained to equal zero where there is no clustering in partially nested trials. Evidence suggests that, while important, such within-trial clustering effects are rarely taken into account in trials or in meta-analyses of these trials.This paper proposes summary measures and individual-patient-data (IPD) methods for meta-analysing randomized trials with nested clustering effects. It extends methods for incorporating trials with unequal variances and cluster-randomisation to allow for between-trial and between-arm heterogeneity in ICC estimates. The work is motivated by a meta-analysis of trials of counselling in primary care, where the outcome of interest is the Beck Depression Inventory and the control is no counselling. We begin by outlining the example and presenting the statistical model at the trial-level. We then extend standard summary measures and IPD approaches to meta-analysis of mean differences and illustrate the proposed methods with our example. Fixed and random effects meta-analysis models are contrasted.


ATL is a highly aggressive leukemia/lymphoma which was first proposed as a new disease entity in 1977. The long clinical latency and low incidence of ATL indicate that some genetic changes are involved in malignant transformation and monoclonal expansion of HTLV-1-infected cells. Monoclonal proliferation of HTLV-1-infected cells is observed in a part of the virus carriers, who are considered to be the high risk group for development of ATL [We reviewed the process of senescence and how proteins allow the monoclonal proliferation of ATL cells.Constitutive activation of STAT as well as functional impairment and stabilization of p53 protein found in the PBMCs of ATL patients are supposed to be one base for ATL development ,3. In adFurthermore, the soluble form of CD30 (sCD30) is elevated in serum of ATL patients and correlates with the aggressiveness of ATL  (Our obsNot only the inhibition of senescence by impaired function or constitutive activation of proteins in ATL cells, but also immune regulation by soluble proteins in serum of HTLV-1-infected patients must be required for the progression of ATL.


Although patients with anorexia nervosa (AN) present positive responses to family therapy, the key features of therapeutic changes still require identification. This study explores the role of conflictual communication and affiliative nonverbal behaviour in therapeutic change in brief strategic family therapy (BSFT) for AN patients.Ten female AN patients and their parents were included in the sample and took part in a 6-month follow-up of BSFT. The durations of conflictual communication and of affiliative nonverbal behaviour estimated by eye contact were compared between the first and the last sessions of family-based treatment using nonparametric statistical tests.An increase of the Body Mass Index associated with an increase in the conflictual communication expressed during BSFT sessions were observed. Moreover, affiliative nonverbal behaviour expressed by the father and the patient decrease, after a BSFT follow-up, in conflictual situations only. By contrast, no significant difference was observed in affiliative nonverbal behaviour expressed by the mother.The present study demonstrates that the impact of the BSFT differs between members of a family: the AN patient and the father have established a new form of emotional functioning with a decrease in emotional involvement. The study of the combination between verbal and nonverbal communication can represent an important step in the understanding of the mechanisms of therapeutic change. Several follow-up studies of patients with anorexia nervosa (AN) have shown positive responses to family therapy From a general point of view, conflictual communication can be considered as interactions between persons that express opposing interests, views or opinions Conflictual communication produces emotional responses in participants that are reflected in affiliative nonverbal behaviour From a therapeutic perspective, these studies suggest that family therapy may improve the conflictual communication skills of families by promoting a decrease in emotional involvement during these situations. Therefore, the affiliative behaviour revealed by eye contact could be important variable to monitor during therapeutic interventions in order to assess emotional involvement during conflictual communication. The present study reports the evolution of both conflictual communication and affiliative nonverbal behaviour in families with AN patients during brief strategic family therapy (BSFT) This study was approved by an independent ethics committee  and adhered to the tenets of the Declaration of Helsinki.The selection and inclusion of the families was conducted at the Addictology Department of the University Hospital (CHRU) of Lille (France). Each participant received a study information sheet and provided her written, informed consent to participation. The patients and their parents were informed about this study by a psychiatrist at admission to the Department of Addictology in our inpatient unit. The parents were all aware of their child's difficulties prior to their participation in the study. Prior to inclusion in the study, all patients were hospitalized in our inpatient unit for life-threatening physical and/or mental states. After, written consent was given by the patients and their parents, the therapists met the parents and patient in order to define the therapeutic objectives of the brief strategic family therapy (BSFT).The first session of BSFT occurred in post-hospitalization where the patients received an outpatient treatment at Department of Addictology. In outpatient treatment, all patients received the same supportive medical care by psychiatrists and physicians.Ten families were included in the sample and participated in the study. They included the father , the mother  and the AN patient . The patients resided at home with both parents. Socioeconomic status of families was divided into three levels: 50% from social classes I and II, 40% from social classes III and V and 10% from social classes from VI and VIII The female outpatients were selected according to the DSM-IV criteria for anorexia nervosa restrictive type, i.e., without the binge-eating and bulimics As in the structural family therapy tradition Enmeshment is modified by increasing the interpersonal distance between over-involved individuals and by creating a stronger boundary between the parental subsystem and the sibling subsystem;Detouring is reduced by helping the marital subsystem reduce focus on the problems of the anorexic patient;Transactional rigidity is reduced by encouraging greater flexibility in modes of communications;Restructuring also involves enhancing the family's ability to engage in and resolve conflict;Fostering positive parenting and parental skills.Family therapy was conducted by a therapist over a period ranging from five to six months and a frequency of one session per month . Each session lasted one hour and was videotaped. The treatment was terminated on the basis of the mutual decision of family members and the therapist. The two therapists (psychologists) involved in the study had more than six years of experience in the family therapy of AN patients.Semi-structured interviews allowed to obtain details of the history and clinical manifestations of the illness as well as the psychosocial functioning of the patient At the end of family treatment, each patient's overall outcome was categorised using the following classification Good outcome: Patients in whom menstruation had returned with no evidence of bulimic pathology and whose weight was within 15% of the average body weight (20 kg/m2≤BMI≤23 kg/m2).Intermediate outcome: Patients who had reached a normal weight but without the return of menstruation or who reported bulimic symptoms.Poor outcome: Patients whose BMI was below 18 kg/mIndividual assessments were conducted by a clinical psychologist independent of the BSFT. Individual assessments were performed a week before BSFT and at the end of BSFT.Family interactions were assessed off-line using videotaped recordings of two sessions: an initial session (Si ) at the beginning of BSFT and a final session (Sf ) at the end of BSFT. Verbal communication between family members were rated for conflictual/non-conflictual content intra-family affiliation and eye contact toward the therapist was considered as extra-family affiliation. The absence of the eye contact with another family member or therapist and the orientation of the gaze to one's feet, the wall or the floor were classified as non-affiliative behaviour.Affiliative behaviours of the family members were assessed using the eye contact measure The encoding procedure was tested for inter-rater agreement. The inter-rater agreement was assessed on the two possible encoding categories of verbal interaction behaviour and on the four possible encoding categories of nonverbal behaviour. Seven family therapy sessions were separately encoded by two clinical psychologists independent of the BSFT. The Kappa-coefficients of inter-rater agreement of the verbal interaction behaviour (median score: 0.64) and the nonverbal behaviour (median score: 0.59) were considered satisfactory For each family and each session, our initial measurements correspond to the duration (in sec.) of eye contact from a family member to four possible targets: the two other family members (intra-family affiliation), the therapist (extra-family affiliation) and other targets (non-affiliative behaviour). These measure were obtained for both conflict and non-conflict communication. We denote Due to the encoding strategy, the duration The evolution of conflictual communication between Si and Sf in the families of AN patients was characterised using the fraction of the session duration with conflictual communication denoted Since the fraction of non-conflict communication . The Data for these indices were summarised as median and minimum-maximum intervals. The exact Wilcoxon-Mann-Whitney rank test for paired data was used for each of these indices, and the effect size was computed when a significant evolution was reported. Since several dependent and independent statistical tests were performed simultaneously, we controlled the possible spurious positives using the Bonferroni correction which is the simplest and most conservative approach. Thus for an initial level The evolution of family conflictual interactions during the follow-up of BSFT was tested using the fraction of conflictual communication The evolution of affiliative behaviour between Si and Sf was tested using non-parametric cluster analysis The main steps of non-parametric cluster test are illustrated for conflictual situations as an example. For each family, the matrix: For each cluster (i.e. family member), a cluster-based statistics was computed as a statistical weight defined as the sum of the differences between the threshold statistics and the experimental statistics if a significant difference has been observed and zero if no significant difference has been observed. A second permutation test is then issued on the cluster-based statistics (i.e. weight). This test allows to determine the distributions under the null hypothesis of the weight of the clusters. Only the clusters for which the cluster-based statistic is higher than that of the permutation distribution . At the end of BSFT, the increase in average weight (BMI) was statistically significant. We also observed significant improvement in nutritional (MRnut), psychosexual (MRpsex) and psychosocial (MRpsoc) functioning. No significant difference was observed in mental state (MRment) and menstrual functioning (MRmens). The average MR score (MRave) was significantly improved between Si and session Sf.At the end of BSFT, there was a significant increase in conflictual communication between family members (Initial session: medianSignificant correlation was observed between the normalized change in the percentage of conflictual communication and the improvement in BMI see , , . No The evolution of affiliative nonverbal behaviour between Si and Sf for each family member was tested independently for conflictual and non-conflictual communication using a non-parametric cluster test.For non-conflictual communication, no statistical weight computed for each cluster exceeded the threshold computed from bootstrap (i.e., patient cluster For conflictual communication, statistical weight for the patient and father (resp. d Sf see . For theThe present study assessed the evolution of clinical symptoms of AN patients and conflictual communication in their families during BSFT. The observation of changes in clinical indices between the first and the last session of BSFT in AN patients demonstrates an improvement in clinical symptoms and in psychosocial functioning of restrictive-type eating disorders as measured by BMI and the MR scales. In addition to these clinical improvements, a significant increase in conflictual communication in the families of AN patients was observed. This increase in conflictual communication was significantly correlated with the improvement of BMI.Families of AN patients have been characterised by deficit of emotional expressiveness, especially concerning conflicts and a lack of conflict resolution Three studies provide the most direct comparison with the present one. First, Robin et al. The second central goal of the present study was inspired by clinical research which have shown that affiliative behaviour is a sign of emotional engagement between participants These results can be enlightened by recent studies which show that the ability to inhibit the gaze predicts adaptive social functioning in adulthood Although the majority of studies of family therapy focus on verbal behaviour Several perspectives can be envisioned. First, a further study after the end of the family treatment is needed to verify the stability of the new pattern of communication and affiliative behaviour in conflictual situations and the generalisation of these new abilities to other peer interactions. Moreover, the specificity of changes in affiliative nonverbal behaviour should be evaluated in regard to other highly emotional situations. Finally, the behavior of the therapist is another putative element of the therapeutic changes which cannot be studied in the present article. The same quantification of verbal and nonverbal behavior should be applied to the therapist and be included in the study of the global pattern of interactions to infer his/her implication in the therapeutic changes.


The temporal and spatial properties of responses to complex stimuli in the central nucleus of the inferior colliculus (ICC), the main converging station in the auditory midbrain, can provide evidence for coding principles in the auditory system and are relevant for the design of neuroprosthesis.We study responses from guinea pigs to a set of eleven species-specific vocalizations which show a wide range of spectral contents, envelope types, frequency and amplitude modulations. The envelopes of the acoustically presented stimuli are characterized as complex or periodic impulses and have various degrees of periodicity. The frequency content ranges from harmonic strucutres to broad spectral distributions. The data analyzed were multi-unit recordings taken simultaneously from 32 positions in the ICC of guinea pigs using a double shank electrode. Peristimulus time histograms (PSTHs) of the high dimensional recordings were classified by linear discriminant analysis in order to evaluate the spatial and temporal distribution of stimulus-related information without the assumption of a specific coding scheme. Neighboring neural populations respond in a similar manner and have highly correlated PSTHs. Combining responses from different positions improves the classification performance for distant postions which do not show correlation, but not for adjacent positions.Separability of responses along the tonotopic gradient of the ICC to vocalizations shows great variation according to their spectral properties. Low-frequency stimuli are found to be better separable in low characteristic frequency (CF) lamina than complex envelope or broad spectral stimuli. Some stimuli of the latter type  are nearly perfectly discriminated in multi-units with high CF whereas discrimination for low-frequency stimuli is less good (60 - 70 %) in this region, see Figure We interpret the results as a consequence of the combination of several frequencies in the vocalizations that are better covered by the widely tuned receptive fields of the neurons in the mid-frequency range than by the receptive fields of the units with CFs in the extreme frequency ranges.