The posterior medial frontal cortex (pMFC) is known to be involved in adaptive goal-directed behavior, but its specific function is not yet clear. Most theories have proposed that the pMFC monitors performance in a reactive manner only, but it is possible that the pMFC also contributes to performance monitoring in a proactive manner. To date, the evidence for proactive pMFC activity is equivocal. Here, we investigated pMFC activity before, during and after the performance of a challenging motor task. Participants navigated a cursor through narrow and wide mazes in randomly intermixed trials. On each trial, participants saw previews of the actual maze display prior to gaining control of the cursor. Event-related potentials (ERPs) to the preview displays were compared to ERPs elicited by no-go signals and errors. Compared to the wider maze, the preview display for the more challenging narrow maze elicited a medial-frontal negativity (MFN) similar to the ERP components elicited by no-go signals and errors. Like these known ERP components, the preview-elicited MFN appeared to be generated from a source in pMFC. This is consistent with the hypothesis that the pMFC participates in adaptive behavior whenever there is a need for increased effort to maintain successful task performance. Converging lines of evidence suggest that the posterior medial frontal cortex (pMFC), an area that encompasses the anterior cingulate cortex (ACC) and the pre-supplementary motor area (pre-SMA), plays a critical role in adaptive, goal-directed behavior reactive manner only – that is, it monitors performance online or it contributes to learning after the task has been performed.The most prominent theories link activity within this cortical region to the monitoring of task performance. For example, the conflict-monitoring hypothesis proposes that pMFC detects response conflict occurring when two competing responses are co-activated and signals to pre-frontal cortex the need for increased cognitive control error-likelihood hypothesis suggests that increased pMFC activity can be triggered before, during, or after task performance – as long as the eliciting event signals a high likelihood of error. Empirical evidence for the error-likelihood hypothesis has been mixed, however: the original error-likelihood study reported fMRI results consistent with the hypothesis Researchers have begun to challenge the notion that the pMFC monitors performance exclusively in this kind of reactive manner, suggesting instead that the pMFC can act proactively to alter performance on an upcoming task effort-allocation hypothesis, pMFC is involved in representing and updating action-outcome contingencies based on the amount of effort required by the task and the potential benefit that these actions might generate. The pMFC might be further involved in allocating the necessary effort to select and produce actions that lead to favorable consequences An alternative hypothesis posits that the pMFC is sensitive to cues that signal situations that demand increases in cognitive or physical effort According to the effort-allocation hypothesis, pMFC is responsive only to information that can be used to alter behavior or action-outcome associations, and this defines an important distinction between the effort allocation hypothesis and the error-likelihood hypothesis. Cues indicating error-likelihood do not necessarily carry this type of information: a signal indicating increased error likelihood need not provide information about how to improve performance. The pMFC may become active only when circumstances are such that a strategic response to information about error likelihood is possible, suggesting a link with effort allocation rather than pure error likelihood, and this could underlie mixed results in tests of the error-likelihood hypothesis The present study used event-related potentials (ERPs) to determine whether the pMFC is active prior to, as well as during, performance of a challenging motor task. An important aspect of this motor task was that it provided information that could directly guide the selection of action and lead to preparatory adjustments before participants could begin to solve the task. We predicted that under these conditions the pMFC would contribute to behavioral adaptation proactively as well as reactively. To test this prediction, we developed a virtual-maze task in which observers previewed a maze prior to performing a maze-navigation task. This task required that the mouse cursor be kept on the maze path, and we varied the difficulty of the task by randomly intermixing narrow and wide mazes. The preview of the to-be-navigated mazes informed participants whether errors would be more or less likely and enabled participants to prepare for successful completion of the impending task.The high temporal resolution of ERPs allowed us to measure separate ERP components in response to the preview displays, subsequent Go and No-Go signals, and the eventual successful and unsuccessful maze navigations . Critically, this enabled direct comparisons of the proactive ERP activity elicited by narrow preview displays and the well-known reactive ERP activities associated with response conflict stemming from the No-Go signals Experimental procedures were approved by the Simon Fraser University research ethics board.Sixteen healthy university students participated in the study. Data from two participants were excluded from all analyses because of excessive noise in the electroencephalogram (EEG). The remaining 14 participants  provided written informed consent prior to the start of the experiment and received course credit for their participation.The experiment was conducted in a sound attenuated and electrically shielded chamber that contained a 19-in CRT monitor with the screen resolution set to 800×600 pixels. Participants sat in an adjustable chair and viewed the monitor from a distance of 65 cm. A computer running Presentation  controlled stimulus presentation and registered the participants' mouse movements. A second computer running custom software (Acquire) controlled EEG acquisition. The acquisition computer housed a 64-channel A-to-D board  that was connected to an EEG amplifier system with high input impedance .Participants navigated a cursor through a single-path maze using a standard computer mouse with the right hand . Each tr2. To increase motivation, participants were told that the experiment was in fact a game in which they earned points for each successfully completed task and lost points for time-outs and errors. At the end of each block participants received feedback about their accumulated score in point units, along with a 'scoreboard' that presented scores earned by earlier participants in the experiment. The results displayed in this scoreboard were fabricated and were included in the design only to motivate participant effort. Each block consisted of 16 trials. The full experimental session was composed of 30 blocks.On the first trial, participants had a limit of 13 seconds to complete the task, after which the maze turned red representing a timed-out trial and central feedback indicated the loss of one point. The time limit varied from trial to trial according to an adaptive procedure. After each unsuccessful trial, the time limit was increased by 250 ms and after each successful trial the time limit was decreased by 250 ms. All displays and colored stimuli were physically equiluminant at 6.00 cd/mcompletion time).As indirect measures of the effort needed to complete the task, we calculated the percentage of trials on which participants successfully navigated the maze (correct), went off the maze path (incorrect), or did not complete the maze in the allotted time (time-out), separated by effort condition. We further calculated the amount of time it took for participants to successfully complete the Low-Effort and High-Effort mazes (herein termed 14) permutations of the data.We were also interested in obtaining a measure of the behavioral adjustments made in response to increased recruitment of control. In performance-monitoring studies, a commonly used measure of monitoring is post-error or post-conflict slowing of reaction time RTs; . To inveWe recorded EEG from 63 tin electrodes attached to an elastic-fabric cap . All but 5 of these electrodes were positioned according to the 10-10 system . The remaining 5 electrodes were positioned inferior to the standard row of occipital electrodes. Horizontal electrooculographic (EOG) signals were recorded bipolarly using electrodes positioned at the external canthi. All EEG electrodes were referenced to an electrode placed on the right mastoid (M2). Electrode impedances were kept below 10 kΩ. EEG signals were amplified by a gain of 20,000 and a band pass of 0.1-100 Hz, digitized at 500 Hz and stored on a computer for offline averaging. Offline analysis was performed with EEGLAB After pre-processing the data, we extracted ERPs by averaging EEG epochs separately for 6 conditions of interest. In the first analysis we compared ERPs elicited by the initial presentation of the Low-Effort and High-Effort mazes (preview displays). We further looked at the correlation between the amplitude of the ERP component elicited in response to the preview displays and completion and reaction times. In the second analysis we compared ERPs elicited by the presentation of the Go and No-Go signals, and in the third analysis we compared ERPs elicited by the successful completion of the task and by errors. All ERPs were baseline corrected using the average amplitude of the 200-ms period preceding onset of the relevant event of interest . All statistical comparisons were performed on the mean amplitude of the waveforms for the FCz electrode during 80-ms time windows centered on the time of peak amplitude of the components of interest (see Results). The comparisons were performed through one-tailed paired permutation tests based on all possible permutations of the data (214).We used a two-step procedure for source analysis. First we used BESA 5.3 software (Megis software) to generate a distributed linear solution based on a Classical LORETA Analysis Recursively Applied (CLARA) model The behavioral results showed that the High-Effort maze was considerably more difficult to navigate than the Low-Effort maze . ParticiIn our main contrast of interest, we compared the ERPs elicited by the onset of the Low-Effort and High-Effort preview displays. In the second contrast of interest, we compared ERPs elicited by the onset of the Go and No-Go signals. In the third contrast of interest, we compared ERPs elicited by errors and correct task performance. We time-locked the ERPs to the moment the errors occurred  and the moment the task was successfully completed . These times were also marked by a change of maze color to indicate the end of a correct trial or an error. Neural sources were estimated using CLARA at the time of peak activation for each of the five contrasts of interest. Consistent with our predictions, the CLARA analysis showed increased activation in the pMFC in response to the presentation of the High-Effort preview display compared to the presentation of the Low-Effort preview display. This activity was estimated to be in the dorsal-rostral ACC and was accompanied by increased activation in bilateral fusiform gyrus . The dipWe followed similar procedures with the source analysis for the two ERP components identified for the No-Go minus Go contrast. Similar to what we found for the High-Effort minus Low-Effort contrast, the CLARA analysis estimated that the dorsal ACC and bilateral fusiform gyri were involved in the generation of the No-Go N2 . In addiThe CLARA analysis revealed three neural sources of the ERN/Ne . The firThe CLARA model for the Pe contained a single source, which was located in the ACC and extended into posterior cingulate cortex . The dipThe foci in ACC and posterior cingulate are consistent with previous studies performing source estimation for the ERN/Ne preparatory medial frontal negativity (MFN) that peaked at around 480 ms after the onset of the maze and had a pMFC source. This finding adds to the growing body of literature showing pMFC activity elicited proactively in anticipation of task performance In the present study we developed a new paradigm to investigate the proactive involvement of pMFC in effort-based behavioral adjustments. Our data showed that the presentation of the High-Effort maze elicited a The preparatory MFN observed here is consistent with both the effort-allocation and error-likelihood accounts of the pMFC: the High-Effort preview display predicted increased error-likelihood, which could also be seen as a negative prediction error if participants generated the expectation of a low-effort trial. Such an expectation would not have been based on a preponderance of low-effort trials because low- and high-effort trials were equally likely and randomly intermixed. However, participants likely preferred low-effort trials and thus may have come to anticipate them. The preview display also provided participants with information about the effort necessary to successfully navigate the maze. This latter feature of the design might be crucial. Extant studies that have failed to find increased pMFC activity in response to high error-likelihood cues provided no information that could be used proactively to improve performance e.g., . In contAlthough the goal of our study was not to test the error-likelihood hypothesis directly, or to pit the effort-allocation hypothesis against the error-likelihood hypothesis, we would like to suggest that the involvement of pMFC in performance monitoring indexed here reflects the need for increased effort and not the concomitant increase in error likelihood. Although the present data cannot conclusively distinguish between these two possibilities, this interpretation finds support in two recent studies. The first showed that cues informing participants about the presence or absence of conflict in a subsequent Stroop-like task activated the pMFC independent of conflict and error-likelihood A central goal of our study was to compare the ERP component elicited by the High-Effort maze to the ERP components elicited by conflict and errors. Early definitions of ERP components were based on common latency, polarity and scalp distribution, but more recent views suggest that a more appropriate definition is based on common computational operations and neuro-anatomical generators A potential problem with the idea that conflict, errors and effort-related cues elicited ERP components reflecting the same general neurocognitive processes is the fact that there were slight differences in the precise location of the pMFC activation foci for each component. Also, the additional foci that were activated in conjunction with the pMFC differed between the components. This subtle variation may reflect activation of physically distinct functional units in pMFC that contribute to a general cognitive function, but have dedicated anatomical connectivity with other brain areas Recent evidence has suggested that the role of the pMFC in allocating effort may be through a role in action selection involving effort-based cost-benefit analysis It is possible that in our experiment the increased pMFC activation in response to the High-Effort preview display at least partially reflects this role of the pMFC in integrating effort and reward to guide decisions about actions holding action-outcome contingencies that take into account the ratio of effort to reward, but is also involved in exploratory behavior building these relationships. Previous studies have shown that the pMFC is more strongly activated during early than late phases of learning The pMFC has also been associated with free choice during exploratory behavior The present results show that a preview display indicating the need for increased effort activates the pMFC prior to the execution of the task. Under the same experimental paradigm, we also observed pMFC activation related to response conflict and errors in performance. We suggest that a unifying role for the pMFC in response preparation and performance monitoring might be to build and utilize action-outcome contingencies. These would be created based on effort-benefit analysis with the goal of supporting behaviors that lead to positive outcomes


We developed a model of the layered cortical network that integrates a major body of the available physiological and anatomical connectivity data on the cortical microcircuit . The modIn mono-layered balanced random network models the external input can be characterized by a single parameter, the external background firing rate. In contrast, the multi-layered network requires the specification of background inputs for every layer. We therefore distinguish the number of inputs a neuron of a given cell type receives and the background firing rate per external synapse. The experimentally observed cell-type specific firing rates are more accurately reproduced by a data-based estimate of the number of external inputs than by a layer-independent input parameterization. Still, it remains unclear how the overall contributions of background activity to the different layers shape the activity of the network.Here, we analyze the dependence of the activity in the full-scale local cortical network model on the external inputs. We apply large-scale parameter scans in NEST  to studyThe layered cortical network robustly reproduces the activity patterns observed in vivo for a wide range of external input configurations: the cortical microcircuit dynamically reconfigures its activity and preserves a default state. This robustness does not affect the ability of the network to process transients and changes in the balance of external inputs. This microcircuit mechanism may provide an explanation for the similarity of the spontaneous firing rates that have been observed, especially in layer 2/3, in various species and areas .Supported by the Helmholtz Alliance on Systems Biology, JUGENE Grant JINB33, the Next-Generation Supercomputer Project of MEXT, Japan, and EU Grant 269921 .


Numerical methods in biomedical research belong to a rapidly developing field which provides a state-of-the-art tool for biomedical research and applications. Reliable predictions will lead to patient-specific simulations in the next decade to improve the diagnosis and treatment of diseases. The main focus of this special issue is on the interface between numerical methods and biomedical applications for the human body. It is also interesting to have quantitative analysis from the molecular up to the whole organ level. The goal of this special issue is to bring together experts in related fields of computational biomedical research, for example, multiscale flow modeling, blood flow propagation, fluid-solid coupling, inverse problems in biomechanics, high performance computing of multiphysics discretization schemes, cardiovascular biomechanics, and porous media, to both foster engagement across areas of numerical methods and to identify novel applications to challenging biomedical modeling problems. The special issue has 12 papers and the details of these papers are as follows.One paper presents the state-of-the-art parallelization technique taking advantage of the unique anatomical fiber architecture of skeletal muscles. The authors demonstrate the model's capability of simulating different aspects of nonisometric muscle contraction and the chemoelectromechanical behavior in complex skeletal muscles such as the tibialis anterior muscle.The construction of artificial muscles is one of the most challenging developments in recent biomedical science. Another paper discusses the theoretical Hill-type muscle and stability model in determining the force-velocity relations of different animal species, which are based on the literature data from biological experiments. It showed that an antagonistic muscle actuator can help in stabilising a single inverted pendulum model in favour of a control approach using a linear torque generator.One of the papers shows how the computational lower extremity model based on the inverse dynamic analysis and an optimization technique can be used to investigate different muscle activities and joint force patterns in knee osteoarthritis (OA) patients during walking. It provides insight into biomechanical changes in OA patients and evaluation of the postoperative functional outcomes of the OA treatments.Another paper describes the use of an indentation test in determination of in vivo mechanical characteristics of human skin. It proposes a triphasic in vivo model of intact skin based on a general phenomenological thermohydromechanical and physicochemical (THMPC) approach of heterogeneous media.One of the papers develops a computational model based on measurements from a hypoxic neonatal calf model of pulmonary hypertension (PH) to investigate the interplay between vascular and ventricular measures in the setting of progressive PH. Good agreement was observed between the 2D numerical model and the animal measurements. In the authors' simulated disease treatment, the model suggests that targeting proximal vascular remodeling, and in turn stiffness, may aid in recovery by further reducing RV afterload and power requirements.Another paper proposes the analytical solutions for the mathematical model in describing the formation of liver zones via Adomian decomposition method with a system of nonlinear integropartial differential equations. This paper may shed light on the mathematical aspects of the formation of liver zones and explaining the distribution of two types of the liver cells.One of the papers suggests creating a standardized nasal cavity model for adult Malaysian females. Computational fluid dynamic (CFD) analysis was performed to better understand the characteristics of the standardized model. The Malaysian female standardized model is larger in cross-sectional area when compared to the standardized Caucasian model, thus leading to lower average velocity magnitudes.The accuracy of the numerical result is closely related to mesh density as well as its distribution. The aim of an another paper is to evaluate the hybrid mesh with unstructured mesh and study its effect on the flow parameters inside the nasal cavity by considering the complexity of its anatomical architecture. The hybrid mesh reported lower grid convergence index (GCI) than the unstructured mesh and thus its usefulness in nasal airflow studies.The mathematical analysis for optimizing numerical performance based on different time integration schemes that pertain to both the fluid and solid accelerations is presented in one of the papers. The choice of time integration schemes has a significant influence on the stability of fluid-structure interaction coupling. This implies that in addition to material and its geometric properties, the choice of time integration schemes is critical in determining the stability of the numerical computation.Another paper studies an integrated myocyte-Isac-Fb electromechanical model to investigate the effect of fibroblasts (Fbs) and stretch activated ion channel current (Isac) on cardiac electrical excitation conduction and mechanical contraction. The numerical results indicated that Fbs and Isac coupling caused diverse effects on action potential morphology during repolarization, depolarized the resting membrane potential of the human atrial myocyte, slowed down wave propagation, and decreased strains in fibrotic tissue.Medical schools can benefit from a tool, system, or method that will help instructors train students and assess their tactile proficiency throughout their education. The robotic lumbar spine has the potential to satisfy these needs in palpatory diagnosis. One of the papers demonstrates the dynamic model and nonlinear control of a 15-degree-of-freedom, cable-actuated robotic lumbar spine (RLS) that enables the solution of positive and continuous cable tensions for cable-actuated robots. Another paper investigates the multiobjective optimization design of spinal pedicle screws using neural networks and genetic algorithm to achieve an ideal with high bending and pullout performances simultaneously. The optimal design has significantly higher fatigue life and comparable pullout strength as compared with commercial screws.In this special issue, we have provided examples of recent progress in computational and mathematical methods in biomedicine, for the benefit of students, researchers, healthcare professionals, and teachers.


The evolving nature of palliative care and its renewed role in people living with HIV/AIDS (PLWHA) in the post-HAART  era warrants an evaluation of the present curriculum in medical under graduates.The objectives are(1) to measure the existing knowledge regarding palliative care and its application to PLWHA among medical interns and (2) to measure the impact of a structured intervention on knowledge dimensions.Interventional repeated measures study.A convenience sample of 106 interns in the medical college completed a pre-test assessment and a post-test assessment following a structured intervention for evaluation and comparison of knowledge over three dimensions which were (1) knowledge of palliative care and its application in PLWHA, (2) medical symptoms in PLWHA requiring palliative care and (3) psychosocial needs in PLWHA requiring palliative care.t=9.12, P value <0.001), medical symptoms in PLWHA requiring palliative care  and psychosocial needs in PLWHA .The mean scores on knowledge showed a consistent increase after the structured intervention and Student’s t-test was significant across three dimensions of knowledge of palliative care and its application (In spite of the unique challenges presented by the varying course of illness in PLWHA and the variety of needs on the medical, psychosocial and family dimensions, a structured approach and an integrated course curriculum involving principles of both primary and palliative care principles will improve the efficiency of the undergraduate medical education program and enable delivery of effective palliative care interventions and improve quality of life in PLWHA. Since the case series in 1981 of Kaposi sarcoma to the adoption of highly active anti-retroviral therapy (HAART) and the transition of HIV/AIDS to a chronic manageable disease, palliative care has played a varying and evolving role from end of life care in the pre-HAART era to palliation of symptoms and toxicities of HAART era currently.3 There iWHO  defines palliative care as “an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual.” The specWith an estimated disease burden of 1.8 to 3.2 million people living with HIV/AIDS in India, these pa6Studies7 on pallThe current study aimed at measuring existing knowledge of palliative care and its application to PLWHA in medical interns, the effect of a structured intervention on improvement of knowledge and application to make recommendations for an integrated curriculum incorporating primary and palliative care targeted to PLWHA.An interventional repeated measures study was conducted and a convenience sample of 106 interns in the medical college completed a pre-test assessment and a post-test assessment following a structured intervention for evaluation and comparison of knowledge regarding palliative care needs in PLWHA.t-test was performed on the pre- and post-test scores in each dimension individually.Baseline characteristics regarding the intern’s age and sex, exposure to terminal and non-terminal PLWHA, completion of medicine and allied postings and attendance of formal training courses in palliative care if any were obtained. Knowledge was evaluated by a self-administered, 32-item semi-structured questionnaire factored into three dimensions, namely (1) knowledge regarding palliative care and its application, (2) knowledge regarding medical symptoms requiring palliative care in PLWHA and (3) knowledge regarding psychosocial needs requiring palliative care in PLWHA. The palliative care and application knowledge dimension consisted of seven items factored into three domains , the medical symptoms dimension consisted of 11 items factored into three domains  and the psychosocial dimension of 14 items in five domains . The respondents completed the questionnaire both pre- and post-intervention and the mean score in each domain for the three dimensions was calculated. Student’s The structured intervention consisted of multiple interactive didactic sessions conducted over a period of 3 days by a team of faculty in the Department of Internal Medicine and the Department of Community Medicine. The content of the workshop was developed after the review of the existing curriculum and an assessment of the needs of the interns after a focus group discussion. The categories covered broadly included an overview of palliative care and its application to PLWHA, the shift from the divergence of palliative and curative care to an integrated continuum, the most common medical symptoms in PLWHA requiring medical care including pain and its management, fatigue and sleep disturbance, initiation of HAART and its adverse effects, delivery of palliative care, end of life care, nutritional and spiritual needs of the patient, social support, special needs in children and psychological symptoms. Post-intervention, the questionnaire was re-administered.P-values (Student’s t-test).Statistical analysis was performed using PASW software version 18 (SPSS) and measures obtained were percentages, descriptives , box plots for data presentation and paired tests of significance and th percentile, median, 75th quartile and maximum score are depicted in the box plot. The median, represented by a square block, shows a consistent rise across the three dimensions on the pre- versus post-test after intervention.t-test was performed on the test scores on the individual dimensions and the score and the t-values are depicted in Tables t-test  on comparison with cumulative scores across pre- and post-test. Similarly, cumulative scores for the domains in the medical symptoms in PLWHA requiring palliative care dimension and psycho-social needs of PLWHA requiring palliative care dimension were obtained and the t-test was significant in both . The domains on the dimension of the medical symptoms in PLWHA requiring palliative care  and psycho-social needs of PLWHA requiring palliative care  all showed a consistent increase across mean scores.A Palliative care training in the undergraduate medical curriculum is loosely structured and ill defined in countries like USA7 and Indet al[A similar study by Velayudhan et al introducet al,[Palliative care needs in PLWHA have been evaluated in a study by Uwimana et al, in a quaet al[Easterbrook et al describeet al,[et al,[et al,[Billings et al, conductel,[et al, and Blocl,[et al, provide et al.[The trajectory of AIDS illness and the benefits of application of palliative care intervention at an early onset in disease progression to reduce the burden of AIDS epidemic were the focus of the study by Grady et al. The manaIn culmination, applying the principles, knowledge and recommendations gleaned through these studies and application of the intervention, initiatives and evaluation methods helped develop a rounded approach to the introduction of palliative care principles in medical interns targeted to PLWHA and the significant test results after comparison of pre- and post-intervention scores in the present study provides a framework for further development of a palliative care curriculum which is both beneficial to the medical interns and patients receiving their care.In spite of the unique challenges presented by the varying course of illness in PLWHA and the variety of needs on the medical, psychosocial and family dimensions, a structured approach and an integrated course curriculum involving principles of both primary and palliative care principles will improve the efficiency of the undergraduate medical education program and enable delivery of effective palliative care interventions and improve quality of life in PLWHA.The intervention and knowledge examination relied largely upon classroom methods of teaching and evaluation which form the core of the examination-oriented approach in medical education in India. A skill-based competency approach with involvement of simulated or real PLWHA and case-based studies will further help orient the approach toward an effective development of curriculum in future evaluations.


There was an error in the accession number in the Data Availability section of the Discussion. The correct accession number is IM-15154.


A funding organization and grant for the fifth author were incorrectly omitted from the Funding Statement. The following sentence should be read as the second sentence of the Funding Statement: "Neha Koonjoo was supported by TRAILDNP from the public grant of the French 'Agence Nationale de la Recherche' within the context of the Investments for the Future Program, referenced ANR-10-LABX-57 and named TRAIL."


Infection-related preterm birth is a leading cause of infant mortality and morbidity; knowledge of bacterial populations invading the amniotic cavity and the routes of invasion is required to make progress in the prevention of preterm birth. Significant advances have been made in understanding bacterial communities in the vagina, but much less studied are intra-uterine bacterial populations during pregnancy. A systematic review of data published on the intra-uterine microbiome was performed; molecular information and summaries of species found in healthy individuals and in women with diagnosed infections served to construct a database and to analyse results to date. Thirteen studies fulfilled the review's inclusion criteria. The data of various investigations were collated, organized, and re-analyzed to achieve a more comprehensive understanding of microbial populations in the intra-amniotic space. The most common intra-amniotic bacterial taxa were species that can colonies the vagina in health and disease; there were others associated with the habitats of the mouth, gastrointestinal tract, and respiratory tract. The results suggest a central role for the ascending route of infections during pregnancy, and point to a possible secondary contribution via haematogenous invasion of the intra-amniotic space. The complete census of the intra-uterine microbiome awaits completion. Excluded were publications: (a) in a language other than English; and (b) that did not specify the type of microbes involved in the invasion of the amniotic space.Perusal of the selected papers and references therein yielded 13 papers containing information required for this review  presented with an intra-uterine infection. The use of non-culture direct-detection techniques has increased by ~5-fold the number of taxa known to be present in intrauterine infections during pregnancy.Meta-analyses of randomized trials evaluating antibiotic treatments report statistically significant prolongation of pregnancy associated with the use of antibiotics in women with preterm labor and intact membranes . Recognized genital pathogenic species were found at high frequencies, e.g., Ureaplasma uralyticum (11%), Streptococcus agalactiae (11%), Mycoplasma hominis (9%) and Fusobacterium nucleatum (9%)  women, and bacteria of the genus %) Table . Meta-an%) Table . This woListeria monocytogenes crosses the mucosal barrier of the intestine to disseminate haematogenously to any site, with a unique tendency to infect the fetoplacental unit  of giving premature birth to a child for mothers with periodontitis , determining differences in individual susceptibility, and identifying specific early-stage biomarkers that will allow the development of novel and timely intervention strategies.” (Hussein et al., In the last 15 years, the significant progress made in the knowledge of the diversity of bacterial communities in the female genital tract and the role of bacterial infections in PTB wrought by novel sequencing techniques and bioinformatics tools, have made reduction of PTB a goal achievable by research directed toward prevention of BIAC by pathogens.Considering the limitations of studies based on bacterial cultivation to reveal all the microflora present, new comprehensive investigations employing non-culture methods and state-of-the-art sequencing analyses are required to establish the intra-uterine microbiome in health and disease. A complete census of the intra-uterine microbiota during pregnancy conducted concurrently with a census of the vaginal microbiome will serve to outline the characteristics of the bacterial communities in the female genital tract; in particular, the elucidation of the microbial intra-uterine populations in healthy pregnant women, as well as the contribution of ascending infections to BIAC.Future investigations that establish with more accuracy the bacterial taxa found in association with PTB, as well as their routes of invasion of the intra-amniotic cavity will provide important knowledge to support the development of earlier and more specific diagnostic methods of maternal genital infections. This will result in better targeted and more effective treatments, including many infections that presently are clinically silent and can cause significant morbidity in fetuses and infants. A full understanding of the female urogenital microbiome will render these infections amenable to intervention and will have an impact in the prevention of PTB.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The statistics of spikes in a neuronal network is constrained on one hand by the stimulus and shared noise, and on the other hand by neuron interactions and collective dynamics. The join spike statistics and its spatio-temporal correlations can be explicitly computed in conductance-based Integrate-and-Fire models ,2. The pMoreover, the dependence of spike statistics in network parameters such as synaptic weights and stimulus is explicit.Here, we address the following reverse engineering problem. Given a conductance-based Integrate-and-Fire model as above where the spike statistics dependence on synaptic weights is known, can one reconstruct this network of synaptic weights from the observation of a raster plot generated by the network ? We have solved this inverse problem using an explicit expression of a maximum likelihood estimator based on the Newton-Raphson method. This estimator employs analytically computed gradients and Hessian of the likelihood function given by the product of conditional probabilities. The explicit form of these conditional probabilities can be found in . Our resThis estimator is based on a plausible probabilistic model of spiking activity, and not a Poisson likelihood processing. So, it offers a flexible framework that should allow better statistical analysis of real data.


Most species of bat making echolocation use Doppler-shifted frequency of ultrasonic echo pulse to measure the velocity of target . To perfWe propose a network model for detecting the Doppler-shifted frequency . The modOur model reproduced well the two types of BF shifts and could explain systematically the neural mechanism underlying these BF shifts. We also showed that the DSCF neurons followed rapidly the frequency change of the moving target. The detection ability of DSCF neurons is due to a fast synaptic change of top-down connections from DSCF to IC neurons.We have presented a network model of the Doppler shifted frequency. The model well reproduced the two types of BF shifts observed by Xiao and Suga . The syn


The Editor-in-Chief and the Medical Editors at BioMed Central have retracted this article  because


In Donald O. Hebb's oft quoted thesis on synaptic plasticity, the change in efficacy in proportion to the degree of correlation between pre- and post-synaptic activity is expressed explicitly. The Hebbian learning rule has been demonstrated in simulations to be reliable and effective and appears to have a solid foundation in biology on the basis of experimental results. However, beyond binary simulation models of the Spike Timing Dependent Plasticity (STDP) rule, it has not been demonstrated that the causal correlation property of synaptic plasticity is as valid and as effective as always has been assumed.To clarify the exact nature of learning by means of spike timing dependent plasticity, a dynamic model has been developed based on the cross-correlation between pre- and post-synaptic activity as expressed by a dynamic activity measure. The components that form the model are centered around the following guiding principles. Firstly, the cross-correlation between local synaptic pre- and post-synaptic activity, as induced by the synapse itself in the post-synaptic cell, determines the strength of the potential for synaptic depression. Even though this may appear to be counter-intuitive, it reflects the depression due to pre-synaptic activity if little or no subsequent post-synaptic activity is present. The second component is the post-synaptic activity induced by the synapse locally. This represents the local response to synaptic input. The third component is the cross-correlation of the post-synaptic activity induced by the synapse with other post-synaptic activity contributing factors such as an action potential and other synapses. These three components form the autonomous learning rule from which Spike Timing Dependent Plasticity learning emerges. Due to the dynamic nature of the autonomous learning rule, it responds in a simple feed-forward manner to the synaptic input in combination to the localised post-synaptic activity. This precludes the need to perform spike matching and post-processing of the simulation and is more biologically relevant.The relation between the local dynamics of a single synapse and the localised dynamics due to post-synaptic activity becomes apparent by different emerging learning rules. The presence of action potentials and synaptic inhibition can change the shape of the STDP learning rule even to the extent that a Hebbian learning rule may become anti-Hebbian and vice versa. The synapse can respond to external input as well as compete with other synapses and tune itself to the local dendritic activity and the global neuronal activity.Synaptic adaptation due to the presence of nearby synapses and global activity has previously not been extensively studied. This work shows that synapses are not mere slaves to the input but perform more complex computations by combining the input with the local post-synaptic activity as well as the global dynamics due to other synapses and action potentials.


Open Medical Informatics Journal showcases a number of innovative and unique research approaches that highlight the current scope of socio-technical perspectives in the health informatics discipline. In just three short decades the discipline of health informatics has evolved from a primary focus on the “application of computers to all fields of medicine – medical care, medical education and medical research” [This special socio-technical supplement of the esearch”   to an iesearch” . The incesearch” -5. Reseaesearch” .The papers in this supplement highlight how many of today’s researchers have adopted a socio-technical focus as an established and credible methodology, not just for critiquing past mistakes, but for developing an understanding of key success factors in the development and implementation of new systems. The papers also show how researchers are using the basic concepts and multi-method socio-technical approaches, and applying these to a range of research situations. Chhanabhai and Holt demonstrate the universal relevance of socio-technical perspectives in their analysis of information and communications technologies in developing countries . The autThe authors contributing to this special edition also highlight the multi-disciplinary, interrelated character of health informatics. The papers by Borycki and Kushniruk , and CumContributors to this supplement also expand the focus of socio-technical systems research from interaction between clinicians and their systems to explore ways in which other users interact with information management systems. Cummings and Turner note that users of socio-technical systems are no longer restricted to health professionals and highlight the role of patients (or consumers) as important users in their own right . The incThe contributions to this supplement also point to links between the micro-environment of socio-technical systems and the macro-environment of power, politics and ethics. This is flagged by Chhanabhai and Holt who incorporate concepts of equality and empowerment into their discussion , while BThe final paper by Whetton and Georgiou  consider


In a recent paper in this journal  with ion channels (major ingredients of the spike code) particularly in the nervous system.In recent experiments, microRNAs have been shown to modulate the subunit structure and the function of ion channels. In cardiac tissue microRNA expression regulates ion channel genes at the post-transcriptional level  and epigenetically regulates the expression of several genes, including those for the microRNAs (miRNAs) miR-148a, miR-152 that target DNMT-1  expression  methyltransferases in diabetic cardiomyocytes  are lengths of DNA that migrate between individuals even of different species  and within single cells (retrotransposons). We suggest that the exosome system may provide a route for this type of intercellular genetic communication.


The synaptic cleft is an extracellular domain that is capable of relaying a presynaptically received electrical signal by diffusive neurotransmitters to the postsynaptic membrane. The cleft is trans-synaptically bridged by ring-like shaped clusters of pre- and postsynaptically localized calcium-dependent adhesion proteins of the N-Cadherin type and is possibly the smallest intercircuit in nervous systems . The str


Clean Care is Safer Care - and the strong focus of the diagnostic and biomedical industry on HAI prevention and the control of antimicrobial resistance (AMR).With the many changes in healthcare, the occurrence of new and emerging infectious diseases, and pandemic of novel resistance mechanisms, the prevention of healthcare-associated infections (HAI) has become increasingly important. Borders are disappearing - not only between different healthcare settings locally or nationally - but also between developed and resource-limited countries, thereby transforming the fight against HAI into a truly global challenge. This change is reflected by the World Health Organization's (WHO) choice of an infection control topic for the First Global Patient Safety Challenge - According to WHO, hundreds of millions of patients develop HAI every year worldwide and as many as 1.4 million occur each day in hospitals alone , but it Staphylococcus aureus (MRSA), became community pathogens (CA-MRSA) and even zoonotic pathogens with the emergence of livestock-associated (LA)-MRSA, thereby totally changing the epidemiology of MRSA. CA- and LA-MRSA even pose a serious challenge to the long admired "search and destroy" strategy. Many see the local or national prevalence of MRSA as a surrogate marker for the quality of infection control, and the increasing efforts of nations to address the challenge of ever-increasing MRSA rates seem to produce the right effect  are just a few examples of what we hope to cover.We are convinced that ARIC's choice of "open-access" is a logical step towards its goal to be truly international and to allow the transfer of knowledge and best practices to even remote places that cannot afford printed journals. We realize that open access has financial consequence for some authors and that the standard BioMed Central rules to waive article-processing charges may not be enough. BioMed Central provides an automatic waiver to authors based in any country classified by the World Bank as low-income or lower-middle-income economies, but we the online forum for sharing best practices, knowledge, and latest research with colleagues from around the world.We look forward to welcoming many papers and to developing this journal with your support into ARICAndreas Voss - Editor-in-Chief, ARICJan Kluytmans- Deputy Editor, ARICDidier Pittet - Executive Editor,


Scant information exists about the time-course of events during withdrawal of life-sustaining treatment. We investigated the time required for end-of-life decisions, subsequent withdrawal of life-sustaining treatment and the time to death.Prospective, observational study in the ICU of a tertiary paediatric hospital.Data on 38 cases of withdrawal of life-sustaining treatment were recorded over a 12-month period (75% of PICU deaths). The time from the first discussion between medical staff and parents of the subject of withdrawal of life-sustaining treatment to parents and medical staff making the decision varied widely from immediate to 457 hours (19 days) with a median time of 67.8 hours (2.8 days). Large variations were subsequently also observed from the time of decision to actual commencement of the process ranging from 30 minutes to 47.3 hrs (2 days) with a median requirement of 4.7 hours. Death was apparent to staff at a median time of 10 minutes following withdrawal of life support varying from immediate to a maximum of 6.4 hours. Twenty-one per cent of children died more than 1 hour after withdrawal of treatment. Medical confirmation of death occurred at 0 to 35 minutes thereafter with the physician having left the bedside during withdrawal in 18 cases (48%) to attend other patients or to allow privacy for the family.Wide case-by-case variation in timeframes occurs at every step of the process of withdrawal of life-sustaining treatment until death. This knowledge may facilitate medical management, clinical leadership, guidance of parents and inform organ procurement after cardiac death. Withdrawal of life-sustaining treatment has become the predominant end-of-life scenario in children's hospitals in the developed world. A variety of studies over the last two decades have highlighted the intensive care setting as the central, and in some instances nearly exclusive, place for making life and death decisions within a modern children's hospital -5. AlthoIn this paper, we present the results of a 12-month prospective, observational study aiming to elucidate the time required for end-of-life decisions and subsequent withdrawal of life-sustaining treatment in an Australian paediatric intensive care unit.A prospective, observational study of deaths occurring in the Paediatric Intensive Care Unit (PICU) was conducted at the Royal Children's Hospital (RCH) Melbourne, Australia. The RCH is a 250-bed tertiary teaching hospital, which serves a population of approximately 6 million. The PICU is an 18-bed comprehensive intensive care facility admitting approximately 1400 children per year. It is engaged in the full spectrum of paediatric critical care including cardiac and trauma care.Information was obtained for deaths occurring during a period of 12 months (2007). Data collection for each case commenced when the decision to withdraw life-sustaining treatment had been taken by medical staff and parents. While retrospective information about the discussions regarding withdrawal of life-sustaining treatment had to be obtained from the medical record, all other data from that point on was collected contemporaneously. This involved one of the two researchers being either present at the time of withdrawal of life-sustaining treatment or collecting the data immediately afterwards, i.e. at the beginning of the following shift in case the researcher was not present when death occurred. Data collected included diagnostic category, age at the time of death, time of first discussion between medical staff and parents about withdrawal of life-support, time of the decision made by medical staff and parents to proceed with withdrawal, the initiation of withdrawal followed by the times of apparent and confirmed death. The term apparent death denotes the appearance of death to bedside personnel (physician or nurse) before confirmation by clinical examination. In addition, information was collected about presence of monitoring and staff during withdrawal of life-sustaining treatment. The data analysis excluded cases of withholding of life-sustaining treatment as varying levels and modes of life-support may continue to be provided to patients in this category in our unit. In contrast, withdrawal of life-support in our unit invariably entailed the discontinuation of all life-support .Numerical data was assumed to be non-parametric with calculation of median values and statement of minimum and maximum values. Data regarding the reasons for withdrawal of life-support, pharmacological management as well as number, occupation and seniority of staff present at the bedside was also obtained but is the subject of a separate paper. The research was approved by the RCH Ethics in Human Research Committee and written informed consent was not required for this observational study.Fifty-one deaths occurred in the PICU during the 12 months of the study. Forty children (78%) died following the decision to withdraw life-sustaining treatment while 5 (10%) died with some intensive care treatment being withheld. Six children (12%) died during resuscitation efforts. There was no case of confirmed brain death considered for organ donation. Complete datasets of 38 cases of withdrawal of life-sustaining treatment were recorded . Three cases involved the withdrawal of extracorporeal life-support  in addition to withdrawal of ventilation and inotropic infusions. Data of two cases were incomplete/unavailable. Distribution of age and diagnostic categories are displayed in table The timeframes for addressing the issue of a withdrawal of life-sustaining treatment varied widely Table . SimilarIn the vast majority of cases  all monitoring had been discontinued for withdrawal of life-sustaining treatment. Full monitoring  had been continued in 2 cases and one case was managed with ongoing pulse oximetry only.The proportion of cases of withdrawal of life-sustaining treatment among all unit deaths in our study is, at 78%, considerably larger than the percentages reported from other institutions. Studies from North America and the United Kingdom have described the percentage of withdrawal of treatment among the overall unit death rate between 60% and 65% ,12 whileThe nature of withdrawal of life-sustaining treatment prevents its study in randomised, controlled trials. Being observational and, as a study in a field with low mortality, inevitably being limited in the number of cases, our data must not be overinterpreted. The data is descriptive and merely depicts current clinical practice. Timeframes therefore should not be interpreted as benchmarks but instead observed as variables warranting examination and subject to a multitude of confounders, which are beyond control in this setting. The design of our study therefore strongly cautions against aiming to find correlations between the data. Its purpose was rather to facilitate understanding of a complex area of clinical practice by assembling a comprehensive picture of what until now has existed as fragmented pieces of data, records and subjective experience.Nonetheless, having been conducted in a predominantly prospective, contemporaneous fashion, the study accurately describes current time-courses and clinical practice in a large, tertiary PICU. The data show extreme case-by-case variations in time at every step of the withdrawal process until death. Time-related information regarding the decision-making process is currently not available in the literature. Garros and colleagues, in a prospective survey, reported slightly less than half of end-of-life discussions requiring two or more meetings between the family and medical staff . Our datWith regards to the dying process, other reports had previously described approximate timeframes for the end of life based on retrospective studies. McCallum and colleagues recorded a timeframe from making a Do-Not-Resuscitate order to death of less than 24 hours  while GaThis notwithstanding, our prospective data confirm Zawistowski's finding that most children die within the first hour after withdrawal of life-sustaining treatment. Our data do, however, also show that this broad conclusion needs to be further qualified as some children die instantly following the withdrawal of treatment while, importantly, there also exists a great variation in the time to death. With a median time of 0.28 hours from withdrawal of treatment to confirmed death, the dying process occurred within less than 20 minutes in most children but took longer in just under half the cases. Most importantly, our data again provide evidence of considerable variations in timeframes from withdrawal of life-sustaining treatment to death. The relatively small number of cases and the variety of confounders in a non-controlled study setting prohibit correlating diagnosis or level of intensive care support with a time-course following withdrawal. Clinical acumen and intuition, on the other hand, have in the past been proven inaccurate in similar circumstances for more homogenous patient populations . It is rFor the doctor and nurse at the bedside, knowledge of this fact will be essential for planning the withdrawal process and the care for the child at the end of life. This will not only pertain to logistics and a pharmacological management plan but also to defining roles, duties and boundaries during what will be a process of unknown duration. Preparing the family for the dying process that is unpredictable in time may then help to guide parents and relatives during agonizing moments for which few will have points of reference. This may indeed offer an opportunity to prevent increasing anguish if the end of life is drawn out and give the family a better chance to cherish the last moments with their dying child.Another layer of complexity is added to the end of life if organ donation after cardiac death (DCD) is considered. Current guidelines in Australia and New Zealand acknowledge the fact that time to death is unpredictable yet fail to address the practicalities of this circumstance . In the There is a wide case-by-case variation in timeframes at every step of the process of withdrawal of life-sustaining treatment. Understanding the time-course of events in this important area of paediatric intensive care is essential for providing high-quality medical management, clinical leadership and guidance to parents at a most challenging time. The unpredictability and considerable variation in time to death may constitute a noteworthy challenge for accomplishing organ procurement after cardiac death.DCD: Donation after Cardiac Death; ECMO: Extracorporeal Membrane Oxygenation; LVAD: Left Ventricular Assist Device; PICU: Paediatric Intensive Care Unit; RCH: The Royal Children's Hospital.JT declares that he has no competing interests. FO is affiliated with DonateLife Victoria.JT and FO jointly designed and conducted the study which had been conceived by JT. FO created the database, analysed as well as interpreted the data and drafted the article. JT and FO jointly revised the article. Both authors provided intellectual content of critical importance to this project and gave their final approval of this version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/11/39/prepub


Gene-environment interactions have long been recognized as a fundamental concept in evolutionary, quantitative, and medical genetics. In the genomics era, study of how environment and genome interact to shape gene expression variation is relevant to understanding the genetic architecture of complex phenotypes. While genetic analysis of gene expression variation focused on main effects, little is known about the extent of interaction effects implicating regulatory variants and their consequences on transcriptional variation. Here we survey the current state of the concept of transcriptional gene-environment interactions and discuss its utility for mapping disease phenotypes in light of the insights gained from genome-wide association studies of gene expression. The presence and magnitude of quantitative interaction depends on several factors including the scale on which the phenotype is measured, how the “genotypic effect” is considered and the statistical approach adopted (Thompson, Here we refer to gene-environment interactions as the differential effect of a given genotype exposed to different environmental conditions Figure . These iVarious statistical approaches including linear regression (to test for a linear trend, where heterozygotes are intermediate in phenotype owing to additive allelic effects, see Figure Caenorhabditis elegans recombinant inbred strains derived from parental lines collected in the UK and Hawaii. This work documented that no less than 59% of 308 trans-acting and 8% of an estimated 188 cis-acting genes showed a significant eQTL-by-environment interaction. Landry et al. (cis-eQTLs shown to be more stable across conditions while trans-eQTLs were predominantly condition-dependent. On the other hand, a study investigating olfactory behavior in Drosophila melanogaster showed that 50% of variation in this trait was attributable to gene-environment interactions and reported 20 transcriptional gene-environment interactions albeit in whole flies and using a relaxed statistical significance threshold (Sambandan et al., Transcript abundance, like any other quantitative trait, is the product of genotype, environment, and interaction effects. In contrast to the tremendous progress made in documenting main environmental and genotypic effects, systematic genome-wide surveys of transcriptional genotype-environment effects are scarce with the first notable findings reported for model organisms (Li et al., y et al.  investigy et al. . Furthera priori expectation for the number of transcriptional gene-environment interactions under the scenario of large gene-environment interaction effect on a given phenotype but this would depend largely on the genetic architecture of the phenotype in question. In an extreme example, if the trait depends heavily on expression of a single gene a gene-environment interaction at a single regulatory polymorphism with large effect on that gene could explain most of the gene-environment interaction effects on the trait. The notable success in detecting transcriptional gene-environment interactions in microorganisms is primarily a consequence of the tight link in time and space between transcript abundance and the environmental factors investigated. The contrasting findings on the extent of transcriptional gene-environment interactions that have been reported can be due to several reasons including the complexity of architecture of the genetic basis of the expression traits, species-specific patterns of gene expression regulation, and differences in the exposure under investigation.There is no trans-acting factors to be responsible for widespread transcriptional response to irradiation. Others reported dozens of interaction effects in response to pro-inflammatory oxidized phospholipids (Romanoski et al., Mycobacterium tuberculosis infection (Barreiro et al., in vitro experiments where homogenous cell populations are investigated and transcriptional response deliberately altered provide increased power to detect interaction effects as effect sizes become more pronounced and readily detectable using modest sample sizes. Nonetheless these experiments rely heavily on prior knowledge about the cell type relevant to the treatment in question.The literature on the topic of transcriptional gene-environment interactions in humans is slim with most of the comprehensive studies documenting genotype-treatment interactions Table . The firin vivo. However the system is made up of over a dozen cell types and overall profile differences are due to the joint contributions of variable cell fractions, and variable expression within cells. For instance, Fairfax et al. (in vivo in human transcriptomes have also been conducted. A study investigated differences in the pattern and strength of genotype-expression association in fresh human transcriptomes across groups sampled from different geographic locations suggested the presence of several interaction effects beneath genome-wide significance but no genome-wide significant interactions were reported likely due to lack of power (Idaghdour et al., Plasmodium falciparum infection (Idaghdour et al., Interaction effects can also be investigated in tissues with a heterogeneous cell composition but robust statistical analysis is required to tease apart true effects from those reflecting differential cell proportions between the groups contrasted (Emilsson et al., x et al.  characteIt is worth noting that studies mapping interaction effects vary widely in their methodologies, statistical approach, and the significance threshold applied to call interactions and there is a pressing need for a clear formulation of the concept of “transcriptional gene-environment interaction” so that published findings can be reliably contrasted. The issue of dependence of the definition of interaction on the scale at which the trait is measured is of particular importance here, given that the first phase of the analysis of gene expression datasets involves normalization that can influence biological inference as evidenced by a systematic evaluation of the effect of nine different normalization strategies on various aspects of statistical inference including eSNP analysis (Qin et al., A major challenge for GWAS in general is that of power and the problem of multiple testing. This caveat is more pronounced for the discovery of interaction effects particularly when testing interactions with multiple environmental factors and given the high dimensionality of the data and the fact that in general detecting an interaction requires at least a fourfold larger sample size than does a main effect of comparable magnitude (Smith and Day, We argue that efforts to detect genuine gene-environment interactions in humans are more likely to be fruitful when using integrative approaches that capitalize on the advantages and power gained from the use of endophenotypes. These efforts will certainly be enhanced as more cohort studies and population-based biobanks turn their attention to deep endophenotyping (Awadalla et al., Knowledge of gene-environment interactions in humans holds the promise to enhance our understanding of the etiology of disease but also highlights the need to address several issues and questions related to this phenomenon. For example, the relationship between gene-environment interactions at the transcriptional level and at the disease level is a subject that warrants investigation. Unraveling these relationships in humans will be challenging given the extent of biological complexity of the black box between genotype and phenotype. Presumably transcriptional changes might be silent and do not result in phenotypic change. Distinct transcription profiles might also converge and yield similar phenotypes as well as the possibility that mechanisms of post-transcriptional regulation may account for buffering transcriptional variation and therefore break the otherwise statistically significant associations between gene expression levels and higher-level phenotypes. Furthermore, the generality of transcriptional genotype-environment interactions across multiple loci, particularly those involved in the etiology of disease, would cause a major hurdle for the identification of disease variants and might account for some of the failures of replication of associations where main genotype effects are estimated over a constellation of conditions represented in a study as is the case in GWAS.In conclusion, the insight that is coming out of the fields of quantitative genetics and epidemiology is the appreciation of the role gene-environmental interactions play in shaping disease phenotypes. However, robust demonstrations of these effects in humans are scarce. Genome-wide association studies of gene expression in various tissues and populations have opened up the opportunity to track and discover these effects in the transcriptome and to shift from focusing solely on main genotypic effects. The evidence in the literature of the prevalence of such effects in the human transcriptome is increasing, but these studies are still in their infancy and need to be extended to scenarios where regulatory variation is expected to depend on environmental triggers. It will also be interesting to explore and expand on these studies to see if the epigenome is subject to interaction effects (Cortessis et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The potential for unintended consequences of the spread of foreign genes  and of pleiotropic effects following transgene expression may be enhanced in long-lived forest trees. The COST Action FP0905 will focus on four key aspects related to the biosafety of genetically modified trees (GMTs): (a) analyses of the efficiency of existing gene containment strategies to avoid or if not possible to minimize gene flow; (b) facilitate efforts to develop site-specific integration of transgenes in tree genomes to minimize variability of transgene expression and pleiotropic effects, (c) evaluate possible methods to monitor GMTs in the whole production chain, and (d) conduct socio-economic and cost/benefit analyses in relation to the use of GMTs in plantations.Populus spp., Pinus spp., Eucalyptus spp., Betula spp., Castanea spp., Picea spp., etc.) as well as extensive expertise in correlated topics. The information gained should contribute to strengthen the scientific basis for the execution of the EU policy directives related to transgenic trees intended for cultivation in Europe. The main objective of the COST Action is to evaluate and substantiate the scientific knowledge relevant for GMT biosafety protocols by putting together already existing information generated in various European and Non-EU countries as basis for future EU policy and regulation for the environmental impact assessment and the safe development and practical use of GMTs.This Action combines multidisciplinary knowledge generated with transgenic lines of different forest genera  to implement collaboration of scientists.WG 1 - Biological characterization of GMTs: to characterize the GMTs in respect to their genetic and phenotypic features relevant for gene flow, gene containment and gene targeting.WG 2 - Environmental impact assessment and monitoring of GMTs in the whole production chain from plantation to final products: to study environmental risk assessment strategies and monitoring the GMTs along the whole production chain.WG 3 - Socio-economic implications of and recommendations for the use of GMTs: to make socio-economics analyses of the use of GMTs considering the concerns and acceptance by the public, the economic potential for GMTs and R&D efforts to be invested, as well as cost/benefit analyses, and propose recommendations for the use of GMTs.WG 4 - Management of intranet - internet websites and dissemination: through a website (www.cost-action-fp0905.eu), provide science-based information and increase public awareness in the utilization of GMTs in forest plantation and at the same time safeguarding the environmentThe knowledge gained will be summarised in a book as a final output of this Action which will report the state of art of knowledge and research on GMTs with suggestion on how to effectively implement present EU directives on GMO considering the problematic of forest trees and their environmental impacts.The Action started the 12th of April 2010 and it will end the 11th of April 2014. Actually, 23 COST countries  have signed the Memorandum of Understanding (MoU). Seven NON-COST countries  are participating to the Action.With integration of all the countries listed above, the EU COST Action FP0905 is expected to generate important benefits as it also foresees a strong collaboration among R&D bodies and legislative directives. This kind of collaboration will be fundamental, on the one hand, to address policy-making efforts and, on the other hand, to allow the scientific community to discuss to public concerns in a responsible way, particularly concerning socio-economic implications and biosafety issues of transgenic tree plantations.


How the visual system combines information from the two eyes to form a unitary binocular representation of the external world is a fundamental question in vision science that has been the focus of many psychophysical and physiological investigations. Ding & Sperling (2006) measured perceived phase of the cyclopean image, and developed a binocular combination model in which each eye exerts gain control on the other eye's signal and over the other eye's gain control. Critically, the relative phase of the monocular sine-waves plays a central role.We used the Ding-Sperling paradigm but measured both the perceived contrast and phase of cyclopean images in three hundred and eighty combinations of base contrast, interocular contrast ratio, eye origin of the probe, and interocular phase difference. We found that the perceived contrast of the cyclopean image was independent of the relative phase of the two monocular gratings, although the perceived phase depended on the relative phase and contrast ratio of the monocular images. We developed a new multi-pathway contrast-gain control model (MCM) that elaborates the Ding-Sperling binocular combination model in two ways: (1) phase and contrast of the cyclopean images are computed in separate pathways, although with shared cross-eye contrast-gain control; and (2) phase-independent local energy from the two monocular images are used in binocular contrast combination. With three free parameters, the model yielded an excellent account of data from all the experimental conditions.Binocular phase combination depends on the relative phase and contrast ratio of the monocular images but binocular contrast combination is phase-invariant. Our findings suggest the involvement of at least two separate pathways in binocular combination. We see the world with two eyes. It is remarkable that, most of the time, we perceive a single image of the world despite each eye having its own unique retinal image both phase and contrast from different monocular spatial patterns. We found that, surprisingly, the perceived contrast of cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. We propose a new multi-pathway contrast-gain control model (MCM) of binocular combination.Ding and Sperling We elaborated the Ding-Sperling binocular combination paradigm to measure both the perceived phase and contrast of the cyclopean percept. A stereoscope was used to present three sine-wave gratings to the observer in each trial : two tesThe perceived phase In To better illustrate the phase-independent property of perceived contrast in binocular contrast combination, we re-plotted the average perceived contrast of the four observers as functions of the phase-shift between the two monocular test gratings . Indeed,re equal .We can also evaluate whether two eyes are “better” than one. The average  normalized perceived contrast, defined as the contrast of the matched probe grating divided by the base contrast of each condition, is plotted in To control for potential contamination of high spatial frequencies presented in the edges of the sine-wave gratings In summary, we found that the perceived contrast of the cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. The findings of contrast-dependent phase combination and phase-independent contrast combination suggest that at least two separate pathways are involved in binocular combination. The new results require a reconsideration of existing binocular combination models.We elaborated the Ding-Sperling model, originally developed and successfully applied to model binocular phase combination, to develop a new multi-pathway contrast-gain control model MCM, . In the The MCM model successfully accounted for 99.4% and 98.7% of the variance in perceived phase and contrast of the cyclopean images for the average observer, with goodness of fit ranging from 98.9% to 99.6% for binocular phase combination and 96.5% to 99.3% for contrast combination for individual observers . The MCMIn this study, we elaborated the Ding-Sperling paradigm to measure both the perceived phase and contrast of the cyclopean images generated by binocular combination of two monocular sine-wave gratings. We found that the perceived contrast of cyclopean images was independent of the relative phase of the monocular sine-wave gratings, although the perceived phase of the cyclopean images depended on the relative phase and contrast ratio of the monocular images. The findings of contrast-dependent phase combination and phase-independent contrast combination suggest the involvement of at least two separate pathways in binocular combination. We developed a multi-pathway contrast-gain control model (MCM) of binocular combination to account for our empirical results.Most previous studies on binocular combination have investigated how two identical monocular images combine The idea of multiple pathways for binocular combination is also consistent with physiological findings. There are both simple and complex cells in primary visual cortex In this study, we investigated the appearance of the cyclopean images from supra-threshold binocular contrast combination of monocular sine-wave gratings with relative phase-shifts up to 90 deg. We didn't study larger phase difference because of binocular rivalry in those conditions. It would be necessary to further test if the MCM can be used to model phenomena in near threshold conditions because appearance and contrast detection/discrimination may be computed in separate pathways Our results support at least two separate pathways, phase and contrast combination, in the MCM. The MCM has already provided an important theoretical framework in elucidating binocular deficits in amblyopia Four adult observers (22-28 yrs old), with normal or corrected-to-normal vision and naïve to the purpose of the experiment, participated in the study with written informed consent. The research protocol was approved by the Ethics Committee of the University of Science and Technology of China.http://lobes.usc.edu/videoswitcher.html) was used to combine two 8-bit output channels of the video card to yield 14-bit gray-scale levels All stimuli were generated by a PC computer running Matlab  with PsychToolBox 2.54 extensions 2  was applied to the left and right edges of the gratings to blend the stimuli into the background. All other settings and procedures are stayed the same.2) and high-contrast frames  with diagonal bars  in both eyes. The high-contrast frames remained on the screen during the entire experiment to assist observers to fuse the images from the two eyes. After achieving correct fusion, the observer pressed the space bar on the computer keyboard to initiate the presentation of the three sine-wave gratings: two test gratings on the left side of fixation, and a probe grating on the right side of fixation, with the initial contrast and phase of the probe grating set randomly. Observers were required to adjust the contrast and phase of the probe grating to match those of the cyclopean image on the left. They were free to select which dimension to adjust first and to go back and forth on them, and pressed the ‘Enter’ key twice to report the results after they were satisfied with the match in both dimensions. Inter-trial interval of 1 second was provided. A typical trial lasted about 10 seconds.Each trial began with a fixation display consisting of fixation crosses Click here for additional data file.