Pulmonary tuberculosis is associated with long-term complications that affect both the respiratory and cardiovascular systems. We present the case of a 65-year-old male patient who presented with chief complaints of productive cough and breathlessness for the last four years. Further radiological investigations revealed a left-sided destroyed lung with left lung collapse and deviation of the mediastinum towards the left side. The patient responded well to treatment with broad-spectrum antimicrobial drugs and mucolytics. Tuberculosis of the lung is considered globally to be one of the most lethal and deadly communicable diseases, especially in developing countries .Mycobacterium tuberculosis. Tuberculosis of the lung is associated with a wide spectrum of chronic complications and sequelae that can significantly increase the morbidity of the affected patient [Pulmonary tuberculosis is an infectious disease caused by  patient . One of  patient .Unilateral lung destruction is considered to be one of the late complications of pulmonary tuberculosis, which usually requires years to manifest clinically . This luA 65-year-old male patient was presented to the Respiratory Medicine outpatient department (OPD) with chief complaints of productive cough and dyspnea which was present intermittently for the last 3 years. The patient also complained of left-sided chest pain on deep inspiration and coughing. A detailed history taking of the patient revealed that the patient had a history of smear-positive pulmonary tuberculosis (TB) 2 years back for which he had taken the full course of anti-TB treatment for a period of 6 months consisting of four drugs, namely isoniazid, rifampicin, pyrazinamide, and ethambutol.For further evaluation of the patient, a chest X-ray posteroanterior (PA) view was done which revealed destruction of the left lung parenchyma with ipsilateral mediastinal shift and herniation of a part of the right lung into the left hemithorax Figure .A detailed clinical evaluation was done which revealed signs of volume loss visible in the left hemithorax, such as a positive Trail’s sign on the left side (undue prominence of the clavicular head of the sternocleidomastoid on the affected side), drooping of the left shoulder as compared to the right, evidence of rib-crowding on the left hemithorax, and a reduction in the spino-scapular distance on the left side Figure .Routine blood investigations of the patient were done which revealed no significant abnormalities. Sputum samples were sent for acid-fast bacilli (AFB) staining which was found to be negative.The patient was started on broad-spectrum antimicrobial therapy with the addition of metronidazole for coverage against anaerobic microorganisms. The patient reported symptomatic improvement after a period of 7 days and was discharged with advice to review in the OPD after 15 days.The most commonly affected parts of the lungs that are involved in a patient with pulmonary tuberculosis have been found to be the upper lobes, particularly the apical and posterior segments, with an almost identical incidence bilaterally . VariousThis higher incidence of involvement of the left lung can be explained by the anatomical features of the left main bronchus, which is considerably smaller in diameter and longer in length as compared to the right main bronchus . Due to These various complications and sequelae associated with pulmonary tuberculosis as summarized above greatly contribute to the increased morbidity and mortality in such patients.Tuberculosis is a disease that affects the quality of the patient, in both the short- and the long-term, significantly increasing morbidity and mortality through the development of various thoracic complications and sequelae. Patients who develop complications such as unilateral lung parenchymal destruction post-tubercular infection usually experience frequent respiratory tract infections and persisting dyspnea due to derangement of the normal pulmonary parenchyma structures. Such patients need early identification by means of screening with chest radiographs and should be educated regarding various preventive measures such as seasonal pneumococcal and influenza vaccination as well as the institution of a pulmonary rehabilitation program to improve the quality of life and exercise capacity of the patient.


In the Ethics subsection of the Methods, there is an error in the paragraph. The correct paragraph is: All data were de-identified prior to analyses. Written informed consent was obtained from all participants included in the Inter99 study. The ethics committee of Region North Jutland (N-20140048) approved the project and that blood samples from COGEN may be used without written informed consent from patients. COGEN also has permission from the Data Protection Agency (00916 GEH-2010-001). The Inter99 study was approved by the Scientific Ethics Committee of the Capital Region of Denmark (KA98155) and registered as clinical trial . Both studies were performed in accordance with the principles of the Declaration of Helsinki.


The management of this difficult and complicate disease is still a big challenge, even in countries with advanced health care resources. China has a large patient population with SLE. It is estimated that at least 1 million patients with SLE in mainland China, this number is still increasing as the diagnostic level is significantly improved. China has the highest disease burden of SLE in the entire world.,3 Therefore, establishing concrete and applicable strategy is crucial to manage such a huge patient population with limited number of rheumatologists in China. Under the leadership of National Clinical Center for Dermatologic and Immunologic Center (NCRC-DID) of China, a series of strategies have been established to prompt standardized treatment and management of SLE across the country. Hereby we report one of the approaches, developing centers of excellence (COEs) for SLE and their management.Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by diverse clinical manifestations and multi-organ involvement. In recent years, improving the quality of care for patients with rheumatic diseases has become a high priority of National Health Commission of the People’s Republic of China. The Guidelines for the Construction and Management of Departments of Rheumatology in General Hospitals and the Guidelines for the Basic Standards of Department of Rheumatology in General Hospitals were released in 2019 by the National Health Commission of the People’s Republic of China. Furthermore, the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus, and the Recommendations for the Diagnosis and Management of Lupus Nephritis in China were published. ,5 With the goal of promoting the implementation of standard-of-care for patients with SLE, was launched program of COEs in SLE in January 2030. The COEs that could demonstrate high standard in medical service, education and research will be certified. In order to be certified as COEs, the institutions must meet the following requirements.The specialty of Rheumatology was established in 1970s in China. The disparity in development among regions and proficiency level among healthcare providers is significant across the country. The COEs must provide high-quality medical service for patients with SLE, offer the state-of-the-art techniques in the diagnosis and treatment of SLE. Additionally, COEs should demonstrate high-level service skills that enabling them to be actively engaged in promoting medical care, teaching, and scientific research in SLE. The COEs should play leading roles and academic progression impact in their regions.The centers applying for COEs must be affiliated to a tertiary general hospital as a stand-alone department.The COEs must provide comprehensive medical services including diagnosis, evaluation, and treatment of SLE as well as the management of comorbidities and complications. The COEs must also have the capability to organize multi-disciplinary consultation if needed.(1) Team members: The medical team of COEs should be composed of rheumatologists with knowledge and experience in the standard-of-care for patients with SLE and led by a dedicated expert in SLE.etc.(2) Centers: COEs must have outstanding capability in organization and management of patients with SLE, and with a well-established process in triage and patient referral. In addition, each COE must establish a multi-disciplinary team (MDT) that coordinates with interdisciplinary management, consultation and referral. The MDT should include specialties such as nephrology, hematology, pulmonary and critical care, cardiology, neurology, dermatology, (1) In-hospital services: COEs must have the capacity to promptly admit and provide medical services to newly diagnosed and followed-up patients with SLE. They must have the capability to manage complicated and critical cases and timely admit patients with emergency conditions.(2) Patient registration: COEs should actively register patients with confirmed diagnosis of SLE using the on-line registry system of SLE.(3) Equipment and techniques requirement: COEs must have the equipment required for the diagnosis and evaluation of SLE, including imaging for organ involvement evaluation, and techniques such as renal biopsy.(4) Medications: COEs must have access to the conventional medications of SLE and biological agents.(5) Follow-up services: COEs must provide for patients with SLE regular and long-term follow-up service.(6) Patient education: COEs must take the responsibility for patient education, not only focusing on helping patients to better understand the disease, but focusing on improving patient compliance.(1) The pre-defined number of out-patient visits and in-patient admission must be met at each COE.(2) COEs should follow the 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus for early diagnosis, early intervention and adherent to Treat-to-target (T2T) strategy in order to improve long-term outcomes of patients.(3) Comprehensive evaluation of disease activity and organ damage should be conducted at a regular base. Individualized treatment regimen should be developed and modified based on the evaluation. Treat-to-target strategy should be followed when prescribing anti-malarial drug, glucocorticoid and immunosuppressive agents.(4) COEs should focus on prevention and management of comorbidities and complications of SLE. Each COE should have the capability to manage the risk factors and monitor new organ involvement as well as managing severe complications.(5) COEs should evaluate disease progression, side-effects of medications at a regular base, and stratify patients into different risk groups. Patients at high-risk should be treated aggressively in order to slow organ damage, reduce disease relapse and improve outcomes.The COEs should provide training and education to the local rheumatologists as part of the specialists’ training program and continuing medical education program. The purpose of training is to promote the implementation of standard-of-care to clinical practice and improve the overall quality of care. COEs should also demonstrate their academic impact by leading high standard services locally and in neighboring provinces, in order to improve the competency of the local care providers in the region.(1) Continuing medical education: COEs should have the capability to undertake national continuing medical education programs on standard-of-care for patients with SLE and organize academic conferences in the region.(2) Physician training: COEs should provide training to local rheumatologists and MDT physicians at a regular base to facilitate the delivery of high standard healthcare services and update the latest guidelines, expert consensus, recommendations and cutting-edge research findings.(3) Academic impact: COEs should have the capability to organize academic conferences and teaching rounds in city hospitals. They should also have the capability to provide training for visiting rheumatologists from affiliated city hospitals and guide the management for critical cases in the region.COEs must have high-standard research team and facility. They should also have ongoing research projects in SLE and have the ability in integrating basic science, clinical and translational research. They should at the leading position of research and have academic influence in the region.(1) Team and facility for research: COEs should have leading investigators in SLE and a high-standard research team to conduct clinical research.(2) Research program: COEs should actively apply for and participate in national research programs and clinical trials.(3) Resources for research: COEs should build standardized medical biobank with associated clinical information.(4) Research network: COEs should be part of the collaborative research network of SLE and have the ability to conduct multi-center and large cohort studies.(5) Research production: COEs should have high-quality publications of clinical studies in the domestic and international academic journals as the first or corresponding affiliations.(1) The COEs program is initiated by NCRC-DID and funded by the China Health and Medical Development Foundation (CHMDF).(2) The standing committee appointed by NCRC-DID is responsible for certifying COEs.(1) The certification is based on a grading system .a) The candidate centers should reach at least 60 points on basic items.b) Center of Demonstration can only be certified if the candidate centers are scored 60–79 points on basic items and more than 100 points on all items.c) COEs can only be certified if the candidate centers are scored for more than 80 points on basic items and more than 120 points on all items.(2). The title of COEs is valid for two years and re-application is needed for renewal.We believe that the construction of the COEs in the country could remarkably improve the quality of care for patients with SLE in China. We also hope that the developing of the COEs will greatly prompt the standard and level of basic, clinical and translational research for SLE in China. We expect that Chinese patients with SLE will benefit from this COEs development program.


Author name was incorrectly written as Marie-Paule Mingeot. The correct spelling is Marie-Paule Mingeot-Leclercq.In the published article, an The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


The article was published April 21, 2023 with an error in the name of one of the co-author.The full name of this co-author is: Georgios Foukarakis.


As illustrated by the present Research Topic, emotion that can either enhance or hinder various aspects of our cognition and behavior. For instance, the emotional charge of an event can increase attention to and memory for that event  and memory-related regions  in the formation and retrieval of emotional memories , which are specific to emotional distraction (Dolcos et al., hypervigilance in these patients (American Psychiatric Association, hypervigilance hypothesis that may explain enhanced response to and distracting effect of neutral stimuli (Figure The fact that information unrelated to the trauma may also be highly distracting in PTSD patients is consistent with the clinically observed symptom of i Figure . This nehyperarousal observed in these patients (Figure Overall, the evidence from separate lines of investigations discussed above, regarding the neural changes in PTSD linked to dysfunctions in the recollection of traumatic events and the response to emotional distraction, converge toward the idea that non-specific response to emotional and neutral distraction may reflect retrieval distortions linked to inefficient initial encoding of trauma-related information. Namely, it is possible that the non-specific disruption of the dlPFC activity by trauma-related and neutral distraction is linked to the retrieval of the traumatic memories triggered by non-specific cues, which may also contribute to the perpetuation of the state of s Figure . Moreoves Figure  also ides Figure . In othes Figure  and provs Figure .hypervigilance and non-specific responses to trauma-related distraction, which contributes to the maintenance of a hyperarousal state (Figure In summary, available evidence from investigations of PTSD patients points to general and specific emotional and cognitive disturbances that are linked to alterations in the neural circuitry underlying emotion-cognition interactions. This evidence suggests that reduction of AMY and HC signals for trauma-related cues may underlie non-specific encoding of gist-based representations instead of specific and detailed contextual details of the trauma-related memories. This, in turn, may be linked to symptoms of e Figure . This eve Figure .


Answer to the Rhythm PuzzleAt first glance the ECG looks very abnormal. The P-wave morphology is not compatible with sinus rhythm, the conduction intervals are normal, and the QRS complexes are very abnormal in amplitude (micro-voltages in the extremity leads). In lead II there is almost no signal at all.Although micro-voltages in the extremity leads are a common feature in one of the most prevalent familial cardiomyopathies in the Netherlands , the abn


Persistent localized activity in neural networks has been suggested to serve as the neural substrate of short-term memory . Neural-In general, neural-field models are formulated in terms of Volterra-equation systems or systems of integro-differential equations. The dynamics of bump (pulse) solutions is often studied in a simplified framework by means of ordinary differential equations describing the time evolution of the pulse widths .It has been proven that in the absence of external input this simplified pulse-width system gives the correct prediction with respect to the linear stability of stationary solutions, with one notable exception. It is often conjectured that the Amari approach might correctly predict also nonlinear aspects of the dynamics . Here, we show that the Amari approach fails in the presence of spatially localized external input: the criteria for linear-stability of bumps in the pulse-width system do not coincide with those obtained for the full system. Therefore, for localized external input the analysis must rely on the full system.We determine fixed-point solutions and their stability analytically and illustrate the results by means of numerical simulations. Further, we numerically show that persistent localized activity in a two-population neural-field model can be switched on and off by means of brief external-input pulses localized in space in and time see Fig .


Bienzyme conjugate was obtained by the covalent connection of superoxide dismutase with catalase through endothelial glycocalyx glycosaminoglycan – chondroitin sulfate (SOD-CHS-CAT). This SOD-CHS-CAT conjugate has vasoprotective activity in respect to platelet interactions, tonus of the ring arterial fragment of a rat blood vessel, as well as normalization of hemodynamic parameters in rats and rabbits in conditions of oxidative stress caused by the administration of hydrogen peroxide. The SOD-CHS-CAT conjugate had antiplatelet potential due to its antiaggregation action manifested through the combination of enzyme activities and an acquired supramolecular structure. The influence on arterial fragment tonus was equivalent for SOD and CAT in native and conjugated form. Blood pressure and heart rate were significant and effectively normalized with SOD-CHS-CAT conjugate in rats and rabbits (after hydrogen peroxide administration as a perturbance stimulus). We have discovered the possibility of using the antioxidant bienzyme conjugate in chronic prophylaxis. It is important for a real development of the oral form of the SOD-CHS-CAT conjugate. These results indicate that the development of enzyme conjugates can be medically significant, as a promising approach for the creation of new drugs. Enzymes are widely used as medication in thrombolytic therapy , 2. The It is widely known today that the development of many pathologies is accompanied by oxidative stress , 8. Norm Current views hold that superoxide dismutase, catalase, and glutathione peroxidase are the main antioxidant enzymes of the body. The autonomous functioning of the first two makes them attractive in terms of the development of antioxidant medication to protect the cardiovascular system against oxidative stress. Based on the described advantages, we chose Cu,Zn-superoxide dismutase (SOD), and catalase for the development of an enzymatic antioxidant derivate. 2 O 2 ) is used as a substrate by CAT, which finally yields water and oxygen as products 2 O 2 . T in mice . The results of the present study indicate that supra-molecular enzymatic conjugates are potentially effective and safe and that they can be used in practical medicine. Covalent cross-linking of enzymatic subunits accounts for a mutual stabilization of biocatalyst activity. Augmented molecular weight and the inclusion of chondroitin sulphate  in the conjugate results in a vasoprotective activity of the SOD-CHS-CAT derivate on the inner surface of the vascular wall. The therapeutical effect of the SOD-CHS-CAT is determined by covalent coupling of SOD and CAT activities, which underlies their combined action and formation of harmless products of enzymatic conversion. The supra-molecular structure of the nanoconjugate accounts for its previously unknown quality – the capacity to prevent induced platelet aggregation. The activity of the components of the SOD-CHS-CAT conjugate is very pronounced, since the influence of the SOD and CAT activities of the conjugate on the tone of the vascular fragment is similar to that of native enzymes. The contribution of chondroitin sulphate to the antiaggregational effect is also very clear. The described qualities determine the higher antioxidant activity of the SOD-CHS-CAT conjugate, as compared to the other combinations of its individual components. The SOD-CHS-CAT conjugate is well-tolerated, it possesses satisfactorily acute toxicity, normalizing action in relation to hemodynamics under oxidative stress, and a pronounced therapeutical effect. All these factors make the conjugate a prospective drug candidate. This study represents a new approach to the development of therapeutically significant enzymatic conjugates.


DNA methylation normally leads to silencing of gene expression but Epstein–Barr virus (EBV) provides an exception to the epigenetic paradigm. DNA methylation is absolutely required for the expression of many viral genes. Although the viral genome is initially un-methylated in newly infected cells, it becomes extensively methylated during the establishment of viral latency. One of the major regulators of EBV gene expression is a viral transcription factor called Zta  that resembles the cellular AP1 transcription factor. Zta recognizes at least 32 variants of a 7-nucleotide DNA sequence element, the Zta-response element (ZRE), some of which contain a CpG motif. Zta only binds to the latter class of ZREs in their DNA-methylated form, whether they occur in viral or cellular promoters and is functionally relevant for the activity of these promoters. The ability of Zta to interpret the differential DNA methylation of the viral genome is paramount for both the establishment of viral latency and the release from latency to initiate viral replication. In cellular genomes, the methylation of 5′ cytosines in CpG-dinucleotides leads to recruitment of methyl-DNA binding proteins that co-operate with other epigenetic events to promote the repression of transcriptional activity .Following infection, the viral double strand DNA genome is established in the nucleus of the cell where it circularizes to form an episome and then replicates once per cell cycle in synchrony with the host genome. During this time, the majority of the viral promoters are silent, with just a few directing the expression of the latency-associated genes. Many studies of individual viral promoters have demonstrated an inverse correlation between promoter activity and the presence of DNA methylation at CpG-dinucleotides within the promoter  and polycomb-associated tri-methylation of histone 3 at lysine 27 (H3K27me3) marks have been identified on the EBV genome . Second,The surprising finding was that the EBV genome requires DNA methylation to reactivate it from latency , 2012. TEgr1, which is activated by Zta . This could explain the requirement for genome methylation during the EBV life cycle.Zta expression is restricted to two phases of the EBV life cycle; immediately after infection and during the EBV lytic replication cycle. Zta is not expressed during viral latency, indeed enforced expression of Zta promotes cells to initiate the lytic replication cycle. Following physiological stimulation of cells harboring latent EBV, Zta is the first viral lytic replication cycle gene to be expressed and then activates the expression of many viral genes. Zta is expressed initially when the viral genome is heavily methylated and remains expressed when the genome is largely non-methylated. Zta interacts with several hundred sites on the viral genome and at about half of these site binding is dependent on the DNA methylation status . Many ofFigure 1).It is puzzling to understand how these methylation-dependent promoters evolved. Why is it advantageous to encode a transcription factor with both methylation-dependent and -independent recognition sites if both classes of ZRE should be equally “visible” to Zta in the methylated state? To understand the driving force behind the differential binding of Zta at ZREs, we need to consider the situation where the EBV genome is non-methylated and the CpG-ZREs become “invisible” .There are two stages in the life cycle of EBV when the differential recognition of methylation sensitive and insensitive ZREs in promoters could occur; in both the viral genome is non-methylated and Zta is expressed ((i) During the late stage of the EBV lytic replication cycle, large numbers of non-methylated viral genomes and Zta protein accumulate within the nucleus. Whether the demethylation occurs via an active or passive process has not been determined. However, it is clear that Zta interacts with the non-methylated EBV genomes that are present during late lytic cycle . Indeed,(ii) Immediately following infection of cells, the non-methylated EBV genome enters the nucleus, accompanied by a transient burst of Zta expression . The shoThe EBV genome provides an exception to the epigenetic paradigm of DNA methylation correlating with a silencing of gene expression. The virus also exploits a unique transcription factor to activate genes embedded in methylated DNA. The ability of Zta to differentially recognize methylated sequence elements together with the biphasic methylation cycle of the viral genome suggest that the selection of these properties was driven by the need to differentially regulate binding to different sub-sets of ZREs. Indeed Zta expression during the pre-latency stage and the lytic cycle results in the expression of different sub-sets of target genes, these are related to the location of methylation-dependent or -independent ZREs in their promoters and the methylation status of the viral genome.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.


Among its several activities, Nef is essential for maintaining HIV-1 maximal infectivity. In cell culture, such activity can account for as much as 98% of the HIV-1 virion infectivity and requires Nef to be expressed in virus producing cells rather than in target cells. However, the cause of the defective infectivity of Nef-negative HIV-1 and the mechanism by which Nef is able to restore such a defect remain elusive. The purpose of this research is to establish whether Nef contributes to HIV-1 infectivity by counteracting a cellular inhibitor or by promoting a cellular activity required for optimal infectivity.Nef is an HIV-1 accessory protein with a fundamental role for virus replication Several human cell lines of different histological origin were used as HIV producer cells in order to study the variability of the requirement of Nef for infectivity. Single cycle infectivity was measured on a HeLa-based reporter cell line after normalization based on reverse transcriptase of the inocula. To determine the dominance of the Nef requirement for optimal infectivity, virus is produced from heterokaryons generated from cells responsive or not-responsive to Nef.We analyzed the ability of Nef to enhance HIV infectivity produced in more than 50 cell lines. We found that the requirement of Nef is highly variable. We identified a group of cell lines (Nef-responsive) in which the lentiviral protein is most required (10-50 fold) and a group of cell lines in which Nef is not at all or only weakly required . All Nef-responsive cell lines belong to the lymphoid lineage, in line with the lymphotropic nature of HIV, while most cell lines belonging to the Nef-unresponsive group include mostly non-lymphoid cells. However, we identified two Nef-unresponsive cell lines of lymphoid origin, providing useful tools for further investigation to study the dominance of the Nef requirement for infectivity. We have established a heterokaryon assay which allows HIV-1 production only upon fusion of producer cells expressing complementary parts of the virus. We are now in the process of coupling producer cell lines with opposite Nef-responsiveness in order to verify the possibility that Nef counteracts a dominant cellular inhibitor of retroviral infectivity predominantly expressed in lymphocytes.Our findings show that the Nef requirement for virus infectivity is extremely variable depending on the type of producer cells and is strongest in lymphoid cells. From the study of cell lines with marked differences for Nef-responsiveness, we aim to identify cellular factors which determine the Nef requirement for HIV infectivity.


Protein-nucleic acid (protein-DNA and protein-RNA) recognition is fundamental to the regulation of gene expression. Determination of the structures of the protein-nucleic acid recognition and insight into their interactions at molecular level are vital to understanding the regulation function. Recently, quantitative computational approach has been becoming an alternative of experimental technique for predicting the structures and interactions of biomolecular recognition. However, the progress of protein-nucleic acid structure prediction, especially protein-RNA, is far behind that of the protein-ligand and protein-protein structure predictions due to the lack of reliable and accurate scoring function for quantifying the protein-nucleic acid interactions. In this work, we developed an accurate scoring function  for protein-nucleic acid interactions by incorporating both the specificity and affinity into the optimization strategy. Specificity and affinity are two requirements of highly efficient and specific biomolecular recognition. Previous quantitative descriptions of the biomolecular interactions considered the affinity, but often ignored the specificity owing to the challenge of specificity quantification. We applied our concept of intrinsic specificity to connect the conventional specificity, which circumvents the challenge of specificity quantification. In addition to the affinity optimization, we incorporated the quantified intrinsic specificity into the optimization strategy of SPA-PN. The testing results and comparisons with other scoring functions validated that SPA-PN performs well on both the prediction of binding affinity and identification of native conformation. In terms of its performance, SPA-PN can be widely used to predict the protein-nucleic acid structures and quantify their interactions. Precise regulation of the biological activities within cells is accomplished by biomolecular recognition which mainly involves three major biological macromolecules, i.e. protein, DNA and RNA. The protein-nucleic acid (protein-DNA and protein-RNA) recognition is essential to the regulation of gene expression at every level of the central dogma of molecular biology, including replication, transcription and translation of genetic information Although the structures of individual biomolecules are increasingly well determined and structural studies of the biomolecular complexes have been very active in the last decade, three-dimensional atomic structures of many biomolecular complexes are still difficult to determine due to the technical challenges of the experimental approaches For biomolecular functions, highly efficient and specific biomolecular recognitions are required to satisfy both the stability and specificity. The stability is determined by the affinity of the complex while the specificity is controlled by the partner binding to other competitive biomolecules discriminatively. The current scoring functions of biomolecular recognition The reason that the specificity usually was not taken into account previously in the development of the scoring functions is that the description of binding specificity was challenging to quantify. The conventional definition  of speciTo overcome the challenge, we have proposed a novel concept named as intrinsic specificity  [19]–[23According to the theory of energy landscape In this work, based on our practical quantification of binding specificity, we have designed an optimization strategy to maximize both the affinity and specificity of native binding mode simultaneously for developing the scoring function of protein-nucleic acid interactions. The optimization strategy is to adjust the statistical knowledge-based potentials of atom pairs by iteration until the scoring function can effectively discriminate the native binding pose against the decoys. The flow of developing procedures is shown in Figure S1 in The requirement of optimizing the knowledge-based statistical scoring function is to train a set of known structural data. The training dataset of protein-nucleic complexes for developing SPA-PN were extracted from the database NPIDB (Nucleic Acids-Protein Interaction DataBase) et al.et al.et alTo validate the performance of a novel scoring function, two kinds of tests are needed. First, to evaluate the ability of SPA-PN on predicting the binding affinity. SPA-PN was tested on a dataset of protein-DNA complexes with known experimental binding affinities. This dataset for binding affinity prediction was employed from the binding database which is a modified version of Zhang et alet alSecond, in order to evaluate the ability of SPA-PN on discriminating the native conformation from decoy conformations, SPA-PN was tested on our collected benchmark of protein-nucleic acid complexes. The collected benchmark for binding pose prediction was obtained from available benchmarks of protein-nucleic acid complexes. It combines two protein-DNA benchmarks and two protein-RNA docking benchmarks. The first protein-DNA benchmark obtained from the PDIdb (Protein-DNA Interface database) For the optimization of SPA-PN, an ensemble of decoys for each complex are needed to calculate the ISR for specificity and carry out the iteration algorithm. The RosettaDock v3.4 was taken as the structure optimization and docking tool The knowledge-based scoring function consists of a set of statistical distance-dependent atom-pair potentials to quantify the interactions. Normally, the observed atom-pair potentials were directly derived from the Boltzmann relation widely applied in the derivation of knowledge-based statistical potentials for the protein-ligand, protein-protein and protein-nucleic acid interactions The observed statistical potentials from the known structures has its limitations as the statistical potentials extracted from To circumvent the reference state issue and improve the statistical potentials, earlier efforts The expected statistical potentials are calculated similarly as the observed statistical potentials, which isThe iterative method To validate the effectiveness of the iterative procedure on the improvement of the statistical potentials, we show the evolution of the average interfacial RMSD  to predict and explain the experimentally determined affinities; and (2) to score and rank the binding poses generated by the docking programs. Thus, to validate the performance of SPA-PN, two kinds of tests related to corresponding applications are carried out and the testing results are shown in the sections below.The prediction accuracy of the binding affinity determines the performance of the scoring function on how well it can reproduce the experimentally measured affinity and predict the biomolecular interactions. Due to scaling, the scoring functions usually can not reproduce the absolute values of experimental binding affinity, the Pearson correlation coefficient  Two of most frequently occurred atom pairs. (C and D) Atom pairs related to hydrogen bond. (E and F) Atom pairs involving phosphorus atom. Table S1 Training dataset for the development of SPA-PN. Table S2 Experimental determined affinities and SPA-PN predicted affinities for 30 protein-DNA complexes of the testing dataset1, the calculated affinities were obtained by scaling the binding scores with linear fitting equations  based on the experimental affinities. Table S3 PDB codes of the testing dataset2. Table S4 15 Atom types used for calculating the atom pair potentials based on the SYBYL definition of atom type. The atom types can be converted from PDB files by the software OpenBabel. Table S5 95 effective types of atom pairs for the protein-nucleic acid interactions with the cutoff of total occurrences larger than 600 in the training dataset. Table S6 The high accuracy quality of CAPRI assessment criteria was taken to define the near-native conformation.Supporting figures and tables. (DOC)Click here for additional data file.


Molecules in neurons are in a state far from equilibrium. Therefore their transport properties are strongly affected by fluctuations. We present a model of stochastic molecular transport in neurons which have their synapses located in the spines of a dendrite. In this model we assume that the molecules perform a random walk between the spines that trap the walkers. If the molecules are assumed to interact with each other inside the spines, the trapping time in each spine depends on the number of molecules in the respective trap. The corresponding mathematical problem has non-trivial solutions even in the absence of external disorder due to self-organization phenomena. We obtain the stationary distributions of the number of walkers in the traps for different kinds of on-site interactions between the walkers and furthermore analyze how birth and death processes of the random walkers affect these distributions.We apply this model to describe the dynamics of the PSD-95 proteins in spiny dendrites. PSD-95 is the most abundant molecule in the post-synaptic density (PSD) located in the spines. It is observed that these molecules have high turnover rates and that neighboring spines are constantly exchanging individual molecules. Thus we predict the distribution of PSD-95 cluster sizes that determine the size of the synapse and thus the synaptic strength. Finally, we show that in the model non-equilibrium inter-spine dynamics of PSD-95 molecules can provide the basis for locally controlled synaptic plasticity through activity-dependent ubiquitinization of PSD-95 molecules.


We report a case of a 69-year-old male with non-ischemic cardiomyopathy, having drug- and antitachycardia pacing-refractory ventricular tachycardia resulted in multiple ICD shocks. The sustained and intractable ventricular arrhythmia was mapped and ablated with the aid of the three-dimensional electroanatomic mapping system, initially performed but unsuccessful from the endocardial site then performed successfully from the epicardial site via the coronary sinus. In some instances, catheter ablation from the epicardial aspect of the ventricles is needed although the majority of ventricular tachycardia (VT) is located and ablated in the right or left ventricular endocardium . EpicardA 69-year-old male patient with NICM was referred to our department for multiple antiarrhythmic drug- and antitachycardia pacing-refractory ventricular tachycardia (VT) episodes resulted in electrical storm and depletion of the battery of his VVI-ICD. No secondary abnormalities causing the tachycardia were detected. Surface electrocardiogram during VT revealed a possible focus of the basal posterolateral wall of the left ventricle . VoltageAlthough automaticity and triggered activity may responsible from the electrophysiological mechanisms of VT in NICM, the proven histopathological relation between cardiomyopathic changes including myocyte hypertrophy and fibrosis and, the inducibility of VT with extrastimuli may also suggest the susceptibility to reentrant arrhythmias. Most of the cases with VT can be successfully mapped and ablated from the endocardial site. When this is not possible, however, invasive percutaneous epicardial route may be required to map and ablate VT. Previously published several recent reports have demonstrated that the venous system of the heart seems to be alternative route for mapping and ablation of VTs originating from an epicardial region -6. Li et


After the publication of this work, we notiWe also noticed in the first sentence of the second paragraph of the Materials and methods section we mistakenly stated that OGX-011 (ASO-CLU) was purchased from OncoGenex Technologies. As ASO-CLU is currently in the clinical testing phase, it is not available for sale from OncoGenex Technologies. The corrected sentence should read:ASO-CLU was acquired from OncoGenex Technologies.We apologise to the readers and OncoGenex Technologies for this oversight and any negative effects that may have resulted from it.


PP-plots for survival distributions are considered where one survival distribution is plotted against the other. This is seen as another way of visualizing the nature of the relationship between the two survival distributions along with typical Kaplan-Meier plots. For three survival distributions, the PPP-plot is introduced where the survival distributions are plotted against each other in three-dimensions. Two test statistics are defined, based on areas and lengths associated with the PP- and PPP-plots to test the null hypothesis of equivalent survival curves. A simulation exercise has shown that the new tests are worthy competitors to the logrank and Wilcoxon tests. Also illustrated is how the PP-plot can be used to estimate the hazard ratio and also to assess the ratio of hazard functions if proportional hazards are not appropriate. The methods introduced are illustrated on two cancer data sets.


Bioprostheses made of bovine and porcine tissue are widely used during surgery in the cardiovascular disease. However, the durability of bioprostheses is limited due to immune reaction-mediated cardiac valve destruction upon post-operative follow-up. The objective of this study is to analyze the tissue failure patterns by difference of species and their structural characteristics.The various xenogeneic tissues  were fixed in 0.5% glutaraldehyde solution and implanted into the subcutaneous tissue of the wild type-mouse and the KO mouse for 3 months. The implanted mice were harvested and studied for the histopathology, amounts of calcification and immune responses by serum ELISA.The titer of xenoreactive antibody  after the implantation with xenogeneic tissue in alpha-gal KO mouse tended to increase, with IgM level decreasing faster than IgG level thereafter. The calcification patterns and amounts were similar in both bovine and porcine tissue, but the level of calcification was more severe in KO mouse implantation model than the wild type mouse model. The xenoreactive antigeneicity was lowest in the valve leaflet and the calcification was most severe in aortic wall in both KO mouse & wild type mouse by histologic and quantitative calcium analysis.There was different antigenic response among the different xenogenic tissues. The removal of alpha-gal antigenecity is strongly advised and the choice of the xenogeneic tissue with low degree of antigenicity and calcification seems to be important to prevent the degenerative failure of bioprostheses.


Defining ‘usual care' in studies of health services is challenging as it comprises a large variety of locally variable services. Building Blocks is trialling the Family Nurse Partnership Programme (FNP) in England. FNP is a complex intervention provided to first-time teenage mothers in the community setting. It was developed and previously trialled in the USA where support services are very different. To fully interpret trial results, particularly when making international comparisons, insight into the control condition is essential.We used a mixed methods approach to 'map' services provided to teenage mothers in our 18 trial sites. Initially, a variety of local professional stakeholders described characteristics of health and social services across five domains. This data informed the construction of a follow-up web-based survey filled in by a single local informant per site. Finally, in-depth telephone interviews with a sample of these informants sought to highlight changes in service provision over the course of the trial.The outcomes of the initial mapping exercise lacked consistency but were useful to inform both the construction of the follow-up survey and the main trial data collection questionnaires. The web-survey results provided snapshots of service provision per site and the interviews contextualised local changes.Variation of usual care needs to be acknowledged in the interpretation of results, particularly in the assessment of the study's generalisability. Our service mapping exercise provided global insight into within-site variations and changes over time. Practical limitations prevented exploring details of uptake and local criteria for entitlement.


Personalised medicine is replacing the one-drug-fits-all approach with many prognostic models incorporating biomarkers available for risk stratifying patients with breast cancer, such as the Nottingham Prognostic Index and Adjuvant! Online and more recently multiparameter assays, OncotypeDx and Mammaprint.Evidence of biomarkers having non-proportional effects have been emerging and therefore violating the assumption of proportional hazards when performing Cox regression. A classic example is the risk of recurrence after breast cancer depends on the duration of follow-up for estrogen receptor (ER) and progesterone receptor (PgR) expression status. The genet al.[A review of existing approaches for the analysis of non-proportional effects with respect to survival data found there to be a number of well-developed approaches for incorporating non-proportional effects but a lack of application of these approaches in practice. Two key approaches are the multivariable fractional polynomial time (MFPT) approach by Sauerbrei et al. and flexet al..There is a need for more widespread use of flexible modelling to move away from standard analysis using a Cox model when the assumption of proportional hazards is violated. Fully determining the effects of markers in prognostic studies will help develop novel models for the selection of patients for appropriate treatments.


The fifth sentence of the Abstract is incorrect. The sentence should read: "Clustering analysis (using an unweighted pair-group method with arithmetic mean), revealed strong concordance between the strength of genetic relationships among populations and their geographic proximity."In addition, the second sentence of the first paragraph of the Introduction is incorrect. The sentence should read: Indeed, it is has been listed in the American Quarantine regulations [1].


The development of stratified medicine depends on an understanding of treatment-effect mechanisms . Yet the evaluation of these mechanisms is often absent from the design and analysis of studies for stratified medicine, and even if present, is subject to unmeasured confounding.We review the problem of confounding (common causes) for the drawing of valid inferences concerning treatment-effect mechanisms, even when the data has been generated using a randomised controlled trial. We illustrate the potential of the predictive biomarker-stratified trial design, together with baseline measurement of all known prognostic markers, to enable us to evaluate both the utility of the predictive biomarker in such a stratification and to estimate how much of the treatment's effect is actually explained by changes in the putative mediator. We call this a biomarker-stratified efficacy and mechanisms evaluation (BS-EME) trial design.The analysis strategy involves the use of instrumental variable estimation methods, using the treatment by predictive biomarker interaction as an instrumental variable together with adjustments for all know prognostic markers; the latter contributing to increased precision  rather than bias reduction. The analysis approach provides unbiased estimates even in the presence of unmeasured confounding.We conclude that stratification without corresponding mechanisms evaluation lacks credibility and in the almost certain presence of mediator-outcome confounding, mechanisms evaluation is dependent on stratification for its validity. Our trial design and analysis approach evaluates both stratification and treatment-effect mediation.


The IVAN trial is a multi-centre factorial non-inferiority randomised controlled trial of 610 participants to compare treatments for neovascular Age-related Macular Degeneration . Many of the trial outcomes are longitudinal continuous outcomes measured at regular intervals over the two-year study period.The aim of the analyses was to obtain estimates of the drug and treatment regimen effects at two-years. For many of the outcomes, standard mixed-effects models fitted the data well. However, for some secondary outcomes, and in particular total lesion area, the distributions were highly skewed; 28% of 1536 measurements of lesion area were zero indicating a lesion was not present, which rendered standard regression modelling unsuitable.One approach taken to analyse this outcome was to dichotomise the variable into lesion present and lesion absent, and fit a logistic regression model with repeated measures. This analysis identified a statistically significant difference between the proportions of patients with no lesion present at two-years on the different treatment regimens. However the analysis did not make full use of the data available and information about the size of the lesion was not evaluated.An alternative approach that we have investigated is to use two-part modelling whereby the dichotomised data is analysed using logistic regression, and the non-zero values then analysed using mixed-effects models. We will present the results of this analysis and describe the methodological challenges faced when implementing it in the context of the IVAN trial.


Most species of bats making echolocation use the sound pressure level (SPL) and Doppler-shifted frequency of ultrasonic echo pulse to measure the size and velocity of target. The neural circuits for detecting these target features are specialized for amplitude and frequency analysis of the second harmonic constant frequency (CF2) component of Doppler-shifted echoes. The neuronal circuits involved in detecting these echo features have been well known . In natuThe model contains two hemispheres, in each of which, the network model consists of cochlea (Ch), inferior colliculus (IC), and Doppler-shifted constant frequency (DSCF) processing area. The Ch network has a frequency map by which sound frequency is encoded. The model for detecting frequency information of echo sound was based on the model previously presented by us .The SPL We showed that in IC, the amplitude information of echo sound is encoded by integrating the outputs of ipsi and contralateral Ch neurons and then combined with the Doppler-shifted frequency information encoded by tonotopical map of Ch neurons. The accuracy of the amplitude and frequency information was improved in the DSCF area. The model reproduced well several experimental results observed in IC and DSCF neurons. We also showed that AC and DC components of echo signal are discriminated in the two sub-networks of DSCF. The discrimination ability is due to the difference in time constant between DSCF neurons in the two sub-networks.We presented the neural mechanism for detecting SPL amplitude and Doppler-shifted frequency of echo sounds. The model offered the neural mechanism of how amplitude and frequency information of echo sound are processed and then combined in IC and DSCF area. We also presented that DSCF area discriminates between AC and DC components of echo sound.


We developed a neuromechanical computational model of cat locomotion that simulated the locomotor movements of cat hindlimbs controlled by spinal locomotor central pattern generators . In the closed-loop model, CPG operation was adjusted by afferent feedback from the hindlimbs. The CPG model was based on the previous two-level model  and inclThe hindlimbs with the pelvis and trunk were modeled as a 10 degree-of-freedom sagittal plane system of rigid segments interconnected by frictionless revolute joints. The hindlimb interactions with the ground and other body segments were modeled as linear springs and dampers . The twoThe developed neuromechanical model demonstrated stable locomotion and exhibited realistic patterns of muscle activation, limb kinematics, and ground reaction force dynamics. The model was used for investigation of the role of afferent feedback and the CPG in control of locomotion under different conditions.


The etiology of the far more prevalent late-onset AD is not primarily genetic in origin even though research over the last two decades has identified one or more genetic risk factors that predispose their bearers to development of the disease. Studies of late-onset AD have been strongly influenced by the amyloid cascade hypothesis. This influential hypothesis posits that plaques of β-amyloid  accumulate in the neuropil, where they eventually initiate a neuropathogenic process that engenders production of insoluble tangles of modified tau protein , the ultimate result of which is progressive cognitive dysfunction. Firm and final diagnosis of the disease remains dependent on postmortem quantitation of the density and character of NSP and NFT in specific regions  of the affected brain. In addition, inflammation in the late-onset AD brain has been well documented, but this potentially important aspect of pathogenesis has not found a major place in the suite of factors thought to play primary roles in the neuropathogenic process. For many years, it has been accepted that the etiology of early-onset Alzheimer's disease (AD) is genetic in nature, with the relevant mutations involving genes encoding products that function in pathways dealing with processing of Substantial evidence derived from clinical trials, animal model studies, and other sources indicates that late-onset AD cannot be explained solely or primarily by accumulating NSP and NFT despite the fact that these are the most obvious and consistent pathological features of this disease. Rather, the evidence strongly suggests that late-onset AD results from a complex interplay between genetic and environmental factors, most of which remain to be elucidated. In this special issue, we were interested particularly in papers that present alternative viewpoints concerning the complex etiology and pathogenic processes underlying late-onset AD. The solicitation targeted reports of primary research from different fields, including new genome sequence or structure data that shed light on the complex genetic background giving increased susceptibility to disease induction, new insights regarding relevant environmental influences that may contribute to that induction, and new studies focusing on the biochemistry and molecular genetics of AD. Further, we wanted review articles that summarized recent research developments that engender new views on the etiology and/or neuropathogenic mechanisms of AD as well as hypothesis-driven but evidence-based arguments regarding etiology and neuropathogenesis.The first paper included in this special issue presents an interesting, and we think cogent, argument for a reconsideration of the amyloid cascade hypothesis. The authors of this review conclude that current evidence indicates that the production of NFT and NSP is independent of one another and that these are probably the products, not the cause, of the neurodegeneration that characterizes late-onset AD. The article presents a modified version of the hypothesis that provides a reasonable explanation of the pathogenesis of the disease. postmortem examination of the brain of affected individuals, a pressing need exists for identification of markers that can reliably indicate the presence of AD in individuals at much earlier stages of the disease induction process. The second paper included in this special issue presents new research indicating that delineation of certain aspects of the IL-10 genotype and expression of one membrane-located adenosine receptor might prove useful in identifying individuals with the early signs of dementia who are at high risk of progressing to incipient late-onset AD. Since firm diagnosis of late-onset AD depends on β-amyloid at high levels might be initiated and maintained. The first of the three papers reviews the biochemical roles of the transglutaminase enzymes, the long-standing hypothesis that the activity of these enzymes contributes to oligomerization and accumulation of β-amyloid, and posits that specific inhibitors of the enzymes found in the CNS may prove to be effective therapeutic targets to ameliorate disease progression. The final three papers accept the amyloid cascade hypothesis as a mechanistic explanation for the characteristic neuropathogenesis of late-onset AD, but each develops an interesting new idea concerning how the accumulation of β1-42 is infused into mice, the activity of a particular ABC transport system is impaired, leading to attenuated removal of β-amyloid from the brain. This intriguing observation suggests that the documented age-related decrease in the expression of that transporter may contribute to the accumulation of β-amyloid in the brain and thus of NSP formation. The final paper in this special issue is a study of the function(s) of a noncoding transcript from the BACE1-encoding gene, using a transgenic mouse model in which Aβ production is excessive. Previous work from this group had demonstrated that these noncoding transcripts stabilize the mRNA specifying BACE1, thereby increasing the production of insoluble β-amyloid. In the present study, knockdown-based inhibition of either the noncoding or BACE1-encoding transcript engendered decreased β-amyloid production and attenuated neuronal degeneration. These last three papers point to new ways of reducing the burden of NSPs in the brains of transgenic mice. The challenge now is to determine if these approaches can be applied to the brains of aging primates, and if so, whether reducing the burden of NSPs will be sufficient to slow the rate of cognitive decline.The next paper reports that when AAD and stroke together account for the bulk of cognitive impairment and mortality worldwide. As the risk factors and causes of stroke are becoming better understood, interventions have started to decrease the incidence of stroke . By conAlan P. HudsonAlan P. HudsonBrian J. BalinBrian J. BalinKeith CrutcherKeith CrutcherStephen RobinsonStephen Robinson


Modeling various neuronal functions in search of emergent properties may achieve success when the gold standard of replicating the models in physical systems starts exhibiting some of these properties. Since very large number of functions can be modeled and need testing, we suggest an alternate method of examining higher brain functions: seeing them as internal sensations formed from their hypothetical basic units. Here, we explain the need to replicate the natural mechanism using electronic circuits, discuss some of the technical aspects and introduce some concepts for searching for properties of internal sensations evolving from them. Understanding the nature of conscious internal sensations in the brain remains a challenge . The cenInternal sensations such as consciousness and memory can only be accessed by the owner of the nervous system. Even though the virtual nature of internal sensations has been of concern since the time of Descartes, philosophers have maintained the radical view that Cartesian sensations represent something real ,13. InteCurrently, internal sensations are assessed by observing behavioral activities either in the form of locomotion or speech or other motor activities. We are not directly examining the internal sensations; in fact, they remain completely unexplored. The depth of this issue can be seen in the following example. Let us imagine an individual with locked-in syndrome  who loses both the eyeballs and eyelids ). Given that an individual with locked-in syndrome is functionally capable of much, even of authoring a book , it can From the fact that the stimulation of different locations of the human brain induces hallucinations , it can Oscillatory neuronal activities at different neuronal orders induce sub-threshold activation of different neurons at their higher orders. Re-activation of the functional LINKs during memory retrieval can result in the activation of these sub-threshold activated neurons that are often reported as neuronal activities representing memories from a second-person perspective  embranes  and is iSpatial amplification of signals: Activation of a synapse induces excitatory postsynaptic potential (EPSP) at the postsynaptic terminal that propagates towards the cell body. Summation of nearly 40 EPSPs arriving from any 40 synapses (out of an average 2.4-8x104 dendritic spines [4). This indicates that the electronic equivalent of the axon hillock should have a function of a direct current step-up transformer. Since the output of the system is not an amplified input sensory signal, we may treat the sensory inputs as a source of electricity (similar to photo-electricity).b) c spines  can trigGradual decay of signals: It is known that excitatory postsynaptic potentials (EPSPs) from apical synapses of cortical pyramidal cells do not reach the cell body [c) ell body  and willIntroducing functional LINKs in an electronic circuit model: Inter-postsynaptic functional LINKs may be introduced using an AND logic gate that function when both postsynapses are activated simultaneously. If this can lead to the activation of a silicon-controlled rectifier (SCR) that leads to the opening of an OR gate between these postsynapses, then at a later time-point the activation of either one of the postsynapses may be able to open this OR gate . Artificial systems with these functions may be examined for semblance formation.d) Maintaining appropriate oscillating neuronal activities: The formation of semblances is seen as an emergent property of a system with oscillatory neuronal activity. Fine-tuning of systems properties to match the formed internal sensations of retrieved memories of an item to that of the actual properties of the item used in associative learning is the final step of the process. The knowledge that changes in the frequency of oscillations during sleep [e) ng sleep  and anesng sleep  changes Overlapping semblances determine the identity of the internal sensations: Inputs (EPSPs) summated at the axon hillock from nearly any 40 postsynaptic terminals give rise to an action potential, which in turn activates nearly 2.4-8x104 axonal (presynaptic) terminals and their corresponding postsynaptic terminals in the next layer. Therefore, an action potential generated is not input-specific . This information can be used while extrapolating for the semblions from a postsynapse activated through inter-postsynaptic functional LINK by lateral entry of activity from the cue stimulus  s Figure .Recapitulating ontogeny during AI development: It is important that the construction of the artificial systems should recapitulate the developmental stages of the nervous system. In this regard, discontinuity of the tracings in the electroencephalogram (EEG) among very premature infants [g)  infants  suggestsObtaining logic output to identify internal sensations: What methods will allow us to obtain a read-out for the nature of semblions? At the behavioral level, monkeys were conditioned to respond to electrical stimulation delivered to different layers within the visual cortex V1 [h) ortex V1 . By induortex V1 . Can we This letter has highlighted the technical aspects of engineering a feasible system in physical states based on the hypothesis of the formation of semblances, both to understand the intrinsic science behind the formation of internal sensations and to replicate the mechanism in artificial systems. The existence of diverse types of nervous systems in the animal kingdom organized in a wide range of sequences of the same expected operational units lends hope to the goal successfully transferring the mechanism to physical systems.BOLD: Blood Oxygenation Level Dependent; EEG: Electro-encephalogram; fMRI: Functional Magnetic Resonance Imaging; LISNE: Locked In Syndrome with No Eyeballs and Eyelids; TBI: Traumatic Brain Injury.The authors declare that they have no competing interests.


Dear Editor-in-Chief:I read with interest a recently published article in your esteemed journal by Lavasani et al., entitled “Study of the pharmacokinetic changes of Tramadol in diabetic rats”. LavasanThe results of this investigation unequivocally confirmed that the exposure of tramadol increased substantially (approximately 4-fold) in diabetic rats with an identical 4-fold reduction in the oral clearance. Also, tThe intent of this note is to provide additional clues to further tease out the observed findings of tramadol disposition in diabetes rats. Although shift in volume of distribution can alter exposure, perhaps, the decreased total body clearance is the key driver to explain the exposure increase for both tramadol and the metabolite M1. The disposition of tramadol is governed by efficient hepatic clearance and renal excretion of both the parent and the major oxidative metabolites (inclusive of M1). HoweverIn conclusion, the interesting work of Lavasani et al., has thrown some new light on the importance of well-planned experiments to tease out the variables that account for pharmacokinetic disposition of tramadol in diabetes rats. The sug


Grid cells in the medial entorhinal cortex (mEC) and place cells in the hippocampus are paradigms for population coding of spatial information . Both thIn order to understand the relative contributions of grid cells and non-spatial inputs in determining place field size and stability, we propose a computational model of the hippocampal-entorhinal network that includes a modular organization of grid cell inputs arranged in order of increasing spatial scale, as is seen experimentally in the mEC. Our underlying place cell model is a firing-rate based model inspired by previous work , in whicOur main findings suggest that:1.) For a wide range of parameters, the relative amounts of spatial and non-spatial inputs to place cells plays a more important role in determining place field size and stability than the spatial scale of grid cell inputs. This implies that the dorso-ventral gradient in place field size may reflect a dorso-ventral gradient in non-spatial inputs, rather than grid scale, and is agreement with prior suggestions of a functional distinction between the dorsal and ventral regions of the hippocampus .2.) In our model, place fields are sensitive to changes in the firing rates of the grid vertices of individual grid cells, emphasizing the potential implications of this grid field heterogeneity for place field formation and stability.


Prior research shows that work in agriculture and construction/extraction occupations increases the risk of environmental heat-associated death.To assess the risk of environmental heat-associated death by occupation.This was a case-control study. Cases were heat-caused and heat-related deaths occurring from May-October during the period 2002–2009 in Maricopa County, Arizona. Controls were selected at random from non-heat-associated deaths during the same period in Maricopa County. Information on occupation, age, sex, and race-ethnicity was obtained from death certificates. Logistic regression analysis was used to estimate odds ratios for heat-associated death.There were 444 cases of heat-associated deaths in adults (18+ years) and 925 adult controls. Of heat-associated deaths, 332 (75%) occurred in men; a construction/extraction or agriculture occupation was described on the death certificate in 115 (35%) of these men. In men, the age-adjusted odds ratios for heat-associated death were 2.32  in association with construction/extraction and 3.50  in association with agriculture occupations. The odds ratio for heat-associated death was 10.17  in men with unknown occupation. In women, the age-adjusted odds ratio for heat-associated death was 6.32  in association with unknown occupation. Men age 65 years and older in agriculture occupations were at especially high risk of heat-associated death.The occurrence of environmental heat-associated death in men in agriculture and construction/extraction occupations in a setting with predictable periods of high summer temperatures presents opportunities for prevention. Published reports suggest that agricultural workers are at elevated risk of death due to heat-related illness The Maricopa County Department of Public Health (MCDPH) attempts to systematically ascertain environmental heat-caused and heat-related deaths that occur in the county during the summer. Maricopa County, Arizona is a setting with predictable conditions of high heat in the summer, and deaths associated with high environmental heat continue to occur in spite of the predictability of high heat. Information from this surveillance effort provided a unique opportunity to estimate the magnitude of the increase in the risk of heat-associated death among people with occupations that often involve work outdoors.A study of farm workers in North Carolina showed that a high proportion (94%) of Hispanic farm workers reported working in extreme heat This was an epidemiologic case-control study. The source of data was death certificates. Cases were deaths occurring in May through October during the period January 1, 2002-December 31, 2009 in Maricopa County that were identified as heat-caused or heat-related by the MCDPH as part of its program of on-going surveillance of heat-associated deaths. Controls were deaths occurring in Maricopa County selected at random from among all non-heat associated deaths in Maricopa County during the same period with frequency matching of cases and controls by year of death using a case-control ratio of 1∶2. Two controls were selected per case to increase statistical power and make estimates of odds ratios more precise.The study was reviewed and approved by both the Arizona State University Institutional Review Board and the Arizona Department of Health Services Human Subjects Review Board. The research used information recorded on death certificates for individuals identified by the MCDPHS and the Medical Examiner as heat-associated. Patient data from hospital records were used by MCDPH to identify heat-associated deaths. The use by the MCDPH of patient data from hospital records is a component of its routine public health activity in conducting surveillance to monitor heat-associated health events. Data from hospital records were used by the Maricopa County Medical examiner to certify deaths possibly due to heat as heat-associated for the purposes of completing the death certificate. The use of data from hospital records by the Medical Examiner without consent is permitted by law. In Arizona, hospitalized patients are not asked either to approve or disapprove the use of information from their hospital records for research. The Arizona Department of Health Services Human Subjects Review Board waived the requirement for consent based on a judgment that the research posed no more than minimal risk; that the rights and welfare of human subjects were not adversely affected by the waiver; and that obtaining consent from people who have died is impracticable. The Arizona State University Institutional Review Board did not require consent because it does not consider research using information about people who have died to be human subjects research.Since 2006 prospectively and retrospectively since 2000, environmental heat-associated deaths have been identified by the MCDPH in a formal surveillance system. The MCDPH begins its surveillance process by gathering information on suspected heat-associated deaths using a variety of sources. These include the Office of Medical Examiner case list, which identifies suspected heat-associated deaths referred to the Medical Examiner; the Arizona Department of Health Services, which identifies deaths with environmental heat mentioned on death certificates; local hospitals, which identify suspected heat-associated morbidity/mortality cases reported by emergency department staff and infection staff; Humans Remains Release Forms, which include death reports received from hospitals and other institutions within 24 hours of death; and media reports of heat deaths. To assure that the MCDPH list of heat-associated deaths is complete and that no deaths have been erroneously certified as heat-associated by community physicians rather than the Medical Examiner, a multiple-causes-of-death search is done daily using the electronic death certificate database. The search is done to identify both International Classification of Disease, Tenth Revision (ICD-10) codes associated with environmental heat  and key phrases in the text fields for causes and underlying causes of death .Suspected cases of heat-associated deaths identified by the MCDPH surveillance system that do not appear on the Medical Examiner's case list as suspected heat-associated deaths are referred to the Medical Examiner. The Medical Examiner either rules out or confirms the deaths as environmental heat-associated deaths based on information about the circumstances of death and his/her examination of the remains when indicated. Certification by the Maricopa County Medical Examiner is the basis for designation of death as being environmental heat-associated and the certified environmental heat-associated deaths include not only deaths caused by environmental heat exposure but also those in which environmental heat exposure precipitated a death technically caused by something else . The MCDPH heat-associated death surveillance system thus differs from most other heat mortality surveillance systems, which include only deaths for which the underlying cause of death appears as environmental heat exposure using the ICD-10 codes listed above.Suspected heat-associated deaths identified in the MCDPH surveillance system certified by the Maricopa County Medical Examiner are classified in one of two categories. Deaths in the first category are directly caused by environmental heat exposure. In these deaths, environmental heat is mentioned in Part I of the death certificate (diseases or conditions in the direct sequence causing death) whether or not environmental heat is described as the underlying cause of death on Part I of the death certificate. Deaths classified in the second category – heat-related deaths – mention environmental heat terms in Part II of the death certificate causes of death (diseases and conditions contributing but not directly resulting in the death) sequence but not in the Part I sequence. The current study includes both categories – heat-caused and heat-related – and labels them heat-associated deaths in keeping with the terminology used by the MCDPH in its surveillance operation. For the purposes of surveillance and in this study, a death is considered environmental heat-associated if it was related to heat generated by the climate  and excludes heat from man-made sources such as ovens or manufacturing equipment.Text information recorded in the industry and occupation fields of the standard death certificate was inspected and used to classify the occupation of cases and controls. A person was classified as having a construction/extraction occupation if the term “construction” or “mining” or “miner” appeared in either the industry or the occupation text field on the death certificate or if the description of the person's occupation or industry is included in the Standard Occupation Classification major group 47-0000 – Construction and Extraction Occupations Classification of occupation was completed by one investigator (Petitti) blind to whether the death was heat-associated. A formal assessment of the reliability of the classification of occupation was completed. In it, an investigator not involved in the initial classification (Harlan) classified occupation in a random sample of 150 deaths blinded to case-control status and to initial classification. Cohen's Kappa was used to assess reliability Information on race/ethnicity was obtained from the ethnicity and race fields of the death certificates. The coding of race and ethnicity on the Arizona death certificate uses categories and follows rules specified by the National Center for Health Statistics for the United States Standard death certificate. Over the period of this study, changes were made in the level of detail requested for the ethnicity field and the completeness of designation of individuals as Hispanic or non-Hispanic in the ethnicity field changed. In an attempt to make the data on race/ethnicity consistent across time, race/ethnicity was classified in a single category. A person was classified as Hispanic if the term “Hispanic” appeared in the ethnicity field of the death certificate. People designated as non-Hispanic and those not designated as Hispanic were further sub-classified as non-Hispanic white, African-American, Native American, or Asian/Pacific Islander based on text information in the race field of the death certificate.Cases and controls were first described using percent distributions. Unconditional multiple logistic regression was used to estimate age-adjusted odds ratios for heat-associated death and 95% confidence intervals according to occupation. The percentage of deaths with an unknown occupation was substantially higher in cases than in controls. For this reason, the referent for the analysis of occupation was chosen to be other known occupation. Seventy-five percent of heat-associated deaths were in men and all but four of the subjects classified as having a construction/extraction or agriculture occupation were men. For this reason, the multiple logistic regression analyses to estimate the odds ratios for heat-associated death were done separately in men and women.To assess whether the association between occupation and heat-associated death was modified by race/ethnicity or age, odds ratios for heat-associated deaths were estimated according to occupation in strata of race-ethnicity and age. Because the number of heat-associated deaths in African-American and Native American men was small, these analyses were limited to non-Hispanic white and Hispanic men.® software version 9.2 The Hosmer Lemeshow chi-square statistic was used to assess model fit There were 463 cases of heat-associated death during the period 2002–2009; 925 controls age 18+ years of age were selected for these cases. Nineteen cases of heat-associated death with known age less than 18 years of age were excluded. Nine cases of heat-associated death with unknown age were included in the analysis after noting that all of them had an entry in the occupation and industry field whereas approximately 98% of deaths at ages less than 18 had blank entries for occupation and industry. There were 444 cases and 925 controls included in the analysis.In women, using all other known occupation as the reference category, the age-adjusted odds ratio for heat-associated death was 6.32  in association with an unknown occupation. Using non-Hispanic white women as the reference category, the age-adjusted odds ratios for heat-associated death were significantly increased in Hispanic women  and Native-American women  and increased, but not significantly, in African-American women .To assess whether race and age modified the associations of occupation with heat-associated death, we did stratified analyses. These analyses excluded Native Americans and African-Americans and those with unknown or Asian race/ethnicity because the numbers of cases and controls in these groups was small.The odds ratios for heat-associated death in association with agriculture occupations were increased in all age groups. However, the odds ratios in association with agriculture occupations in men age 65–84 years and 85+ years were somewhat higher than at younger ages: 4.05  and 16.45  respectively. Adjustment for race/ethnicity (Hispanic versus non-Hispanic white) in these age-strata attenuated the association between heat-associated death and occupation because of the strong correlation between being Hispanic and agriculture occupation.Our data show an association of heat-associated death with construction/extraction and agriculture occupations in men in Maricopa County, Arizona as expected given prior research. The increase in the risk of heat-associated death in association with agriculture occupations was not greater in Hispanic than in non-Hispanic white men. However, Hispanic men were more likely to work in agriculture and the difference in the distribution of occupation in Hispanic men contributed to, but does not fully explain, the overall higher risk of heat-associated death among Hispanic men in this study. Our study was not able to disentangle fully the independent effects on heat-associated death of race/ethnicity and occupation because of the small number of deaths in some categories. The study does not rule out the possibility that men who were African-American and Native Americans might be at especially high risk of heat-associated death.Our study suggests that the increase in the risk of heat-associated death in association with construction/extraction and agriculture occupations may be modified by age. In men age 18–49 years, the risk of heat-associated death was close to 1.00 and not statistically significantly increased in association with construction occupations. In men age 65 or more years, the magnitude of the increase in the risk of heat-associated death in association with agriculture occupations was large: about 4 in men age 65–84 years and about 7 in men age 85+ years. These findings were based on only a small number of cases of heat-associated deaths in older men and must be interpreted cautiously.Our findings are consistent with published reports from prior research that examined death certificate data for heat-associated deaths among workers in occupations classified as agriculture, construction, and mining (extraction) A 2008 report from the Centers for Disease Control and Prevention estimated that heat-related average annual death rate for agricultural workers was 0.39 per 100,000, compared with 0.02 for all United States civilian workers We found a very high risk of heat-associated death in associated with having an unknown occupation both in men and women. Unknown occupation is a marker for homelessness. Other investigations of heat-associated death conducted by the Arizona Department of Health Services and the MCDPH have identified homelessness as an important contributor to heat-associated death in Maricopa County Investigation of heat-associated death conducted by the Arizona Department of Health Services has identified attempts to cross the desert to enter the United States illegally as a factor in heat-associated death in Arizona Our study has several limitations. A first major concern is the use of death certificates as the source of information on occupation. The accuracy of this information is uncertain. More importantly, our study does not directly assess the effect of work related to occupation in construction and agriculture. In fact, only 12 of the heat-associated deaths were designated as being deaths due to injury at work. All of these deaths were in men; seven were in men with a construction/extraction or agriculture occupation and 2 were in men with unknown occupation. Guidelines to Medical Examiners and Coroners on how to complete the “injury at work” section of the death certificate specify that a death should be designated as due to an injury at work if the injury occurred: while working or in vocational training on job premises, while on break or at lunch or in parking lot on job premises, while working for pay or compensation, including at home; while working as a volunteer law enforcement official, or while traveling on business, including to/from business contacts The fact that the highest risk of heat-associated death in association with agriculture occupations was observed in men age 65 years or more raises the possibility that occupation may be a marker for the risk of heat-associated death and not due directly to work in agriculture or work out of doors. Determining whether there was a direct link between work in construction/extraction or agriculture and death due to heat would require collection of information directly from observers. Further research based on more detailed information about the circumstances of death for heat-associated deaths in those with a construction or agriculture occupation might clarify the contribution of work in a hot environment to the death.Recognizing the problem of heat-related illness and death in workers, California and Washington have adopted stringent workplace safety standards designed to prevent heat-related illness Washington State has applied the standards to all employers with employees in outdoor settings In 2011, the Occupational Health and Safety Administration (OSHA) initiated a nationwide outreach campaign to raise awareness among workers and employers about the hazards of working outdoors in hot weather One of the challenges of better understanding heat-related illness and mortality is determining the threshold of human tolerance to excessive temperatures. The Centers for Disease Control and Prevention (CDC) defines sustained periods of hot weather as those with daytime temperatures of 105 or more degrees Fahrenheit (40.6 degrees Centigrade) and a nighttime minimum temperature of 80 or more degrees Fahrenheit (26.7 degrees Centigrade) persisting for at least 48 hours Our findings may have larger implications. Periods of high temperature are projected to become more common