In March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an integrated Community Case Management (iCCM) Evidence Review Symposium. The objective was 2-fold: first, to review the current state of the art of iCCM implementation and second, to assist African countries to integrate lessons learned and best practices presented during the symposium into their programmes. Based on the findings from the symposium this supplement includes a comprehensive set of articles that provide the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs. Since early 2000 the use of integrated community case management (iCCM) strategy to deliver pneumonia, malaria and diarrhea treatments to children under 5 has dramatically increased. In 2005 there were only 10 countries in sub-Saharan Africa with policies supporting implementation of iCCM of which 7 included pneumonia treatment [iCCM, in the hands of well trained, supplied and supervised community health workers can reduce child mortality ,4. RecogSince the joint statement was released an increasing amount of evidence has been generated on the strengths and limitations of iCCM, as well as the outcome and impact of iCCM within a variety of different country contexts . A numbeBetween 3 and 5 March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an iCCM Evidence Review Symposium. The objective of the symposium was 2-fold: first, to review the current state of the art of iCCM implementation by bringing together researchers, donors, governments, implementers and partners to examine the current iCCM implementation landscape and status of evidence in key programme areas, in order to summarize lessons learned and best practices, and identify priorities and gaps in knowledge for improving maternal-newborn and child health. Second, to assist African countries to integrate lessons learned and best practices presented during the evidence symposium into their programmes and identify key actions to include in their national plans.We conceptualized a theory of change model as to what factors may increase utilization of quality iCCM services . In addition lessons learned were documented in each area. This supplement includes articles, based in part on these experiences and lessons learned. The thematic and additional areas, their relationship to the model, and their associated articles are shown in Box 1Coordination, Policy Setting and Scale-up: the current state of iCCM policies in Africa and challenges in development of policy and scale up– RELATES TO POLICY1. Rasanathan et al. Community case management of childhood illness in Sub-Saharan Africa: Findings from a cross-sectional survey on policy and implementation (article # 020401)Rasanathan et al. Where to from here? Policy and financing of integrated community case management of childhood illness (iCCM) in sub-Saharan Africa (article # 020304)Human Resources and Deployment: community health worker (CHW) selection, geographic disbursement, motivation and retention – RELATES TO DEPLOYMENT2. Pratt et al. Spatial distribution and deployment of community-based distributors implementing integrated community case management (iCCM): GIS mapping study in three South Sudan states (article # 020402)Supervision & Performance Quality Assurance: strategies to ensure high quality care including strategies for effective training, use of alternative models for supervision, and the role of mHealth to support and motivate CHWs to provide quality care – RELATES TO QUALITY3. Bosh-Capblanch and Marceau. Training, supervision and quality of care in integrated community case management (iCCM) programmes in sub-Saharan Africa (article #020403)Strachan et al. The scale up of integrated community case management of malaria, pneumonia and diarrhoea across three African countries: A qualitative study exploring lessons learnt and implications for implementation (article # 020404)Supply Chain Management: which systems ensure continuous supply, how best to forecast needs – RELATES TO SUPPLY4. Chandani et al. Evidence for improving community health supply chains from Ethiopia, Malawi, and Rwanda (article # 0204005)Sheishia et al. Strengthening community health supply chain performance through an integrated approach: Using mHealth technology and multilevel teams in Malawi (article # 020406)Costs, and cost-effectiveness and financing: identifying cost drivers, improving cost-effectiveness and the importance of minimizing patient costs – RELATES TO POLICY AND DEMAND5. Jarrah et al. The costs of integrated community case management (iCCM) programs: A multi-country analysis (article # 020407)Monitoring, Evaluation and Health Information Systems: innovations in monitoring, integrating with health management information systems, using results to drive programmatic decision-making and improvements, evaluation design and methods – RELATES TO ALL AREAS6. Guenther et al. Routine monitoring systems for integrated community case management programs: Lessons from 18 countries in sub–Saharan Africa (article # 020301)Oliphant et al. Multi-country analysis of routine data from integrated community case management programs in sub-Saharan Africa (article # 020408)Diaz et al. A proposed model to conduct process and outcome evaluations and implementation research of child health programs in Africa using integrated community case management as an example (article # 020409)Demand generation and social mobilisation: the relationship between iCCM and care-seeking, treatment utilisation and treatment adherence, effective strategies to generate demand – RELATES TO DEMAND7. Sharkey et al. Demand generation and social mobilisation for iCCM and child health: Lessons learned from successful programmes in Niger and Mozambique (article # 020410)Impact and outcome evaluations: Issues with measuring mortality and using coverage to model mortality– RELATES TO COVERAGE AND MORTALITY8. Amouzou et al. Assessing the impact of the integrated community case management (iCCM) programmes on child mortality: Review of early results and lessons learned in sub-Saharan Africa (article # 020411)Friberg et al. Using the Lives Saved Tool as part of evaluations of community case management programs (article # 020412)Additional topic areas:Newborns – Aboubaker et al. Community health workers: a crucial role in newborn health and survival (article # 020303)Research – Wazny et al. Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI  exercise (article # 020413)Private sector – Awor et al. Integrated community case management and the private sector in africa – a relevant experiences and potential next steps (article # 020414)Conclusions – Young et al. The way forward for integrated community case management programmes (article # 020304)In regards to policy and scale up Rasanathan et al report on the results of survey on iCCM in sub-Saharan Africa and in a viewpoint summarizing policy issues that impact scale up and sustainability. In the area of human resources and deployment Pratt et al detail the use of GIS mapping in three states in Southern Sudan to improve deployment of CHWs. For training and quality Bosh-Capblanch et al provides a systematic review of training supervision and quality of care, while Stratchan et al present a qualitative assessment of implementation practices in 3 African countries. In regards to maintaining supply chains Chandani et al describe how three countries were able to ensure commodities and supplies reached community health workers, while Sheishia et al describe an innovative technology to track supplies in Malawi. To examine costs of iCCM, Jarrah et al describe the cost drivers of iCCM in multiple countries using standardized methods. In the area of monitoring and evaluation Guenther et al put forth components and attributes of a comprehensive monitoring system for iCCM, while Oliphant et al use routine monitoring from multiple country programs to demonstrate the utility of these data to examine key factors of program success or failure. Diaz et al review the study design and data elements collected for multiple recent evaluations of iCCM to suggest how such evaluations can be done in the future. In regards to demand, Sharkey et al present experience in two countries and the lessons learned on demand generation and social mobilization for iCCM. Finally, in the area of impact and outcome evaluation Agbessi et al report on the limitations of measuring and using mortality to assess iCCM as an end point in several countries in Sub-Sharan Africa and Friberg et al demonstrate how the Lives Saved Tool could be used to model the mortality impact of iCCM.In addition to the articles covering the key thematic areas of the symposium we also have three additional articles. Awor et al describe how the private sector can contribute to iCCM. Aboubaker et al also present the role of Community Health Workers in newborn survival. Based on a systematic process to prioritize research areas, known as CHNRI  Wazny et al report on priority iCCM research areas that are still needed. Finally, using the evidence available, Young et al suggest a way forward to improve and sustain iCCM where it is needed. This comprehensive set of articles provides the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs.


Among the tools proposed to assess the athlete's “fatigue,” the analysis of heart rate variability (HRV) provides an indirect evaluation of the settings of autonomic control of heart activity. HRV analysis is performed through assessment of time-domain indices, the square root of the mean of the sum of the squares of differences between adjacent normal R-R intervals (RMSSD) measured during short (5 min) recordings in supine position upon awakening in the morning and particularly the logarithm of RMSSD (LnRMSSD) has been proposed as the most useful resting HRV indicator. However, if RMSSD can help the practitioner to identify a global “fatigue” level, it does not allow discriminating different types of fatigue. Recent results using spectral HRV analysis highlighted firstly that HRV profiles assessed in supine and standing positions are independent and complementary; and secondly that using these postural profiles allows the clustering of distinct sub-categories of “fatigue.” Since, cardiovascular control settings are different in standing and lying posture, using the HRV figures of both postures to cluster fatigue state embeds information on the dynamics of control responses. Such, HRV spectral analysis appears more sensitive and enlightening than time-domain HRV indices. The wealthier information provided by this spectral analysis should improve the monitoring of the adaptive training-recovery process in athletes. The optimization of the training process in elite athletes requires the quantification of the training loads (Borresen and Lambert, most reliable and practically applicable measure for day-to-day monitoring” (Plews et al., In a recent review (Buchheit, However, despite its accessibility/simplicity, even with all the above-mentioned methodological improvements (see Plews et al., In our view, recording HRV clues in both supine and standing positions is also convenient and provides more information about the actual autonomic settings, their interplay and how they are resorted (Schmitt et al., A recently published study accurately displayed how individual patterns of spectral analysis of HRV divert in “fatigue” states from “no fatigue” condition (Schmitt et al., In summary, RMSSD measures and their derived variables have an effective practical usefulness, which can help the practitioner to identify a global “fatigue” level. However these variables do not allow the clustering of different sub-categories of “fatigue,” at variance with the spectral HRV analysis in both supine and standing positions, which likely consider the current ability to control in a dynamic setting.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.


Chronic tendinopathy is a painful common condition affecting athletes as well as the general population undergoing to tendon overuse. Although its huge prevalence, little is known about tendinopathy pathogenesis, and even cloudier is its treatment. Traditionally, tendinopathy has been defined as a lack of tendon ability to overcome stressing stimuli with appropriate adaptive changes. Histologic studies have demonstrated the absence of inflammatory infiltrates, as a consequence conventional antinflammatory drugs have shown little or no effectiveness in treating tendinopathies. New strategies should be therefore identified to address chronic tendon disorders. Angiofibroblastic changes have been highlighted as the main feature of tendinopathy, and vascular endothelial growth factor (VEGF) has been demonstrated as one of the key molecules involved in vascular hyperplasia. More recently, attention has been focused on new peptides such as Substance P, nitric oxide, and calcitonin gene-related peptide (CGRP). Those new findings support the idea of a nerve-mediated disregulation of tendon metabolism. Each of those molecules could be a target for new treatment options. This study aimed to systematically review the current available clinical and basic science in order to summarize the latest evidences on the pathophysiology and its effect on treatment of chronic tendinopathy, and to spread suggestions for future research on its treatment. With the increasing number of amateur sport practitioners, a growing prevalence of tendinopathy has been recorded in the last few years in Europe and United States , between June and August 2015. The combinations of key-words used were the following: “(“tendinopathy”[MeSH Terms] OR “tendinopathy”[All Fields]) AND ,” “(“tendinopathy”[MeSH Terms] OR “tendinopathy”[All Fields]) AND (“substance p”[MeSH Terms] OR “substance p”[All Fields] OR “p substance”[All Fields]),” “(“tendinopathy”[MeSH Terms] OR “tendinopathy”[All Fields]) AND  OR “neurotransmitter agents”[All Fields] OR “neurotransmitter”[All Fields]).” The search was aimed to retrieve any level of evidence studies concerning molecular pathways involved in pathogenesis of tendinopathy, clinical associated features and therapeutic implications. Both clinical and experimental in vivo and in vitro studies were included. No study types were excluded except for literature reviews and case reports. No time interval for publication was set. Of each of the retrieved articles, the whole bibliography was carefully checked to enrich the research with possible studies relevant for the present work. Results of the studies were read, analyzed, and tabulated. The included studies have been divided into three categories: vascular function, nervous function, and therapeutic studies. The study selection process was carried out as shown in Figure Articles research has been carried out using PubMed online database , fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2), sphingosine kinase-1 (SPHK1), (transforming growth factor) TGF-α, VEGF-A, and VEGF-C. Comparable results were obtained by Petersen et al. (p = 0.0001 and p = 0.046 respectively). An in vivo study on rabbits, by means of specific exercise protocols, Andersson et al. ; group 2: knock-out (iNOS−/−); and group 3: knockout (iNOS−/−) + systemic NO synthase inhibition through aminoguanidine (AG) administration. When systematically inhibiting the NO synthase in iNOS−/− mice (group 3), the cross-sectional area of the healing Achilles tendon was significantly reduced. However, no significant differences were found between the wild-type (group 1) and the knock-out mice (group 2) concerning both the cross-sectional area and biomechanical features of the healing Achilles tendon. Moreover, the same authors  and nitric oxide synthase (NOS) expression have been carried out, in order to evaluate endothelial activation during tendinopathy and its effects on tendon tissue. An overuse protocol applied to supraspinatus tendons was evaluated by Szomor et al. , that fo2, in patellar tendons with tendinopathy in respect to normal tendons.It has been recently considered a role for neurotransmitters in the evolution of tendinopathy. The main molecule that has been investigated is Substance P (SP), which is known to play several roles in proliferation of fibroblasts, angiogenesis, and pain transmission  patches on elbow extensors tendon (McCallum et al., The SP administration in tendinopathy has been extensively studied by Burssens et al.  who studThe increasing knowledge concerning tendon dysfunction, clinically expressed as tendinopathy, leads to the individuation of a huge array of factors implied in the pathogenesis and repair mechanisms of this disease. Among single molecules and pathways involved in pathogenesis and healing process of tendinopathy, vascular, and neuronal factors play a major role (Papalia et al., Some studies have investigated the role that VEGF has in both the pathogenesis and to the healing response of tendinopathy, also using VEGF and its splice variants as an efficient treatment (Zhang et al., SP administration in surgically repaired rat tendons (Burssens et al., The local vascular activation is actually considered a still unclear chapter of the wide topic of tendinopathy. Studies have demonstrated an increased expression of NOS isoforms produced by endothelium in diseased tendons (Szomor et al., However, since VEGF and its pathways are the broadly known factors among a so complex pathogenesis, it should probably be the main factor to pay efforts on. An interesting research line is the regulation of VEGF action during the pathogenesis of tendinopathy (Lu et al., Vascularization and neuronal transmission play a key role in determining the pathogenesis of the tendinopathy. The mainly known factors implied in the process are VEGF, Substance P, and Nitric Oxide, although their exact role in the mechanism of tendinopathy is not well determined. More research should be carried out, especially studies involving human subjects, in order to assess the timing of action of those factors, to find out how therapies targeted to the phase of the disease process may fasten the healing process and the clinical recovery.AD, RP, and VD supervised the articles selection process and reviewed the final manuscript. SV, BZ and GT provided articles selection, manuscript writing, and table filling up.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.


A selection of papers prepared by participants of 7th Young Scientists School SBB’15 is presented in three Supplementary Issues to the journals of BMC series, namely, BMC Genomics, BMC Genetics and BMC Microbiology.http://conf.nsc.ru/sbb2015). The series of Young Scientists Schools in Systems Biology and Bioinformatics (SBB) started several years ago, in 2008, as educational workshop associated with the large international conference series on bioinformatics known as BGRS\SB (Bioinformatics of Genome Regulation and Structure\Systems Biology) (http://conf.bionet.nsc.ru/bgrssb2016). After its inauguration year of 1998, BGRS/SBB held biannually at the Institute of Cytology and Genetics SB RAS in Novosibirsk. In a recent decade, it became a prime meeting venue for biologists, computer scientists, physicists, mathematicians and biochemists working in an interdisciplinary field of systems biology and computer genomics. Being the largest system biology meeting series in Russia, BGRS\SB-14 attracted participants from 27 countries. In the past BioMedCentral had published series of special issues based on best materials presented at the conference in BMC Genomics , BMC Evolutionary Biology , BMC Genetics  and BMC Systems biology . In addition, the protein structure related studies presented by BGRS/SBB participants were collated as special issues in Journal of Bioinformatics and Computational Biology . [SBB’15 took place June 22nd-25th in Novosibirsk, Russia  and data analysisEvolutionary bioinformaticsSystems biology and gene network modelingThe scientific topics discussed in 2015 were presented at the following sections:In SBB’15 Supplements to BMC journals Genomics, we collected the best studies presented at the conference. Due to the general breadth of the field of Systems Biology and Bioinformatic, the manuscripts were accepted into three separate tracks, thus forming three Supplementary Issues, BMC Genomics, BMC Genetics and BMC Microbiology. Below we will describe contents of these issues.The paper by Fedoseeva et al. titled “Comparative transcriptional profiling of renal cortex in rats with Inherited Stress-Induced Arterial Hypertension and normotensive Wistar Albino Glaxo rats” dissect genetic underpinnings of arterial hypertension, a disease which cannot be explained as progression along a straightforward route . Hence, The paper of Klimov et al. “Genome-wide transcriptome analysis of hypothalamus in rats with inherited stress-induced arterial hypertension” continues in the wake of previous paper with a systems biology analysis of expression changes in hypothalamus of the same two strains of rats, and pinpointed the changes within three categories of genes: ‘the regulation of hormone level’, ‘the regulation of the blood pressure level’, and ‘the immune system processes’ .The paper of Lavrov and co-authors titled “Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia” convincingly demonstrated that the gene variants present or absent in the genome of patient influence relative efficiency of the therapy for chronic myeloid leukemia, thus, paving a way to personalized approach to the treatment of this disease .Finally the paper “Genomic Determinants of Birth Weight Variability in the Pig” by Wang and co-author explored the polimorphisms influencing the weight of newborn piglets, and highlighted a number of genes involved in glucose and lipid metabolism as well as in maternal-fetal lipid transport as important for this agriculturally important trait. Additionally, there a basic science related vibe in this study as it may provide some mechanistic explanation to relative success of intrauterine competition of the fetuses in species with larger size of litter .http://www.biomedcentral.com/1471-2164/16/S13/S1).The paper by Ivanov et al.“Non-random fragmentation patterns in circulating cell-free DNA reflect epigenetic regulation”  convincihttp://www.biomedcentral.com/1471-2164/16/S13/S2) deals with the peculiarities of the exon-intron structure, which affect the functionality of the encoded protein. The paper shows that protein functional sites predominantly encoded by relatively long exons.The paper by Medvedeva et al. “Computer analysis of protein functional sites projection on exon structure of genes in Metazoa”   describes a theoretical model that assesses tissue-specific gene knockout effect on gene expression in various structures of the brain, and predicts that the most pronounced tissue-specific effects are detected for genes that participate in the apoptosis/survival network [The paper by Petrovskiy et al. “Prediction of tissue-specific effects of gene knockout on apoptosis in different anatomical structures of human brain” .Gunbin and colleagues continued the evolutionary analysis of miRNA sequences in brain using unique paleogenetics data described in the manuscript titled “The evolution of l brain”   presents an in silico analysis of 22 known nucleotide polymorphisms and arrived at functionally important conclusion about the mechanism of action for at least one of these DNA variants.The paper by Arkova et al. “Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters”  , the functional transcription factor binding sites ranking in the fruitflies , and comparative mining of stress- related expression profiles .Finally, the works by Menzorov et al. , Kozlov The paper by Klimenko et al. titled “Bacteriophages affect evolution of bacterial communities in spatially distributed habitats: a simulation study” explored evolutionary scenarios that may be influenced by the spatial location of initial phage invasion and showed that the speciation rate is lower when invasion penetrated the fully formed community of sedentary cells .In their paper “On the control mechanisms of the nitrite levels in Escherichia coli cells” Khlebodarova, Ree and Likhoshvai describe the mathematical model of nitrite utilization in E.coli cells cultured in the flow chemostat, the process relevant to many biotechnological and clinical applications .The paper of Bryanskaya et al. titled “The role of environmental factors for the composition of microbial communities of saline lakes in the Novosibirsk region (Russia)” for the first time described microbial composition of these saline lakes, their dependence on physical-chemical parameters of waters, as well as evaluated possible avenues for their bioprospecting .http://conf.bionet.nsc.ru/bgrssb2016/).We wish you an interesting reading and sincerely await you at our next BGRS conference that will take place in Novosibirsk 29 August – 2 September 2016 (


Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, “-omics” data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology.The human-pathogenic bacterium  Salmonella enterica is a Gram-negative enterobacterium closely related to Escherichia coli  strike with endotoxins, typhoid fever, and severe systemic illness. The millions of infections and thousands of fatal cases every year are an important reason for a better understanding and control of Salmonella infection . Adaptations include multiple abilities for oxygen and nitrate respiration  deficient strain to utilize gluconate, but not other sources such as glucose  encoding a Fe2+/Mn2+/Zn2+transporter. Thus, to study the mechanisms of systemic disease caused by Salmonella, infection models using Salmonella-susceptible inbred mouse strains such as BALB/c or C57BL/6 with defective Slc11a1 allele are frequently used  facilitate studies on virulence mechanisms and metabolic activities on a molecular level and allow a detailed picture of host-pathogen interactions. Comparative genomics was used for example to identify the presence of different metabolic pathways for non-typhoidal and typhoidal pathovars of Salmonella  for additional high resolution typing of Salmonella isolates by phage types and different PFGE patterns. This allows investigation in unprecedented detail of virulent strains as well as their correlation with metabolic resistance features such as pathways for degradation of antibiotics.Methods useful in analyzing the global impact of gene deletions on Salmonella regulates its metabolic pathways in response to changing nutritional environments. A study performed by Blair et al. focused on changes in transcriptomic profiles when using LB or various minimal media for growth. Transcription profiles were established and the article instructively starts from microarray experiments  and verifies putative differences by quantitative real-time PCR , oxidative , and iron-limiting metabolic protection. In the four ferritins, bacterioferritin (Bfr) was found to be down-regulated in LP strains.The second “-omics” level, namely transcriptomics including microarrays and high throughput sequencing approaches, gives insights into how Salmonella protein is a challenge for MS analyses. Nevertheless, with more effort even quantification of proteins is possible applying different labeling techniques and standards. A good example for the application of the technique to Salmonella is the enzyme quantifications of ex vivo purified Salmonella performed by Steeb et al. (Mass spectroscopy (MS)-based proteomics is a method of choice when analyzing gene products: with this approach protein expression is directly measured. Typically only several matching peptides from a protein are identified applying the knowledge of the genome sequence and identified reading frames. This only partial peptide coverage for a given b et al. , also ilSalmonella metabolism. In particular, isotopolog profiling (IP) allows analysis of current metabolic fluxes under defined conditions. For a detailed method explanation see the study by Härtel et al.  coupled to different cell culture techniques (including establishing tissue infection models) offer here a wealth of information. A nice example including bioluminescent Salmonella, the Streptomycin mouse model and bioimaging is Pontier-Bres et al.  with proteins mediating only this function in the complete network. Furthermore, hubs, central nodes in the network receiving many connections and indicating strongly connected genes or proteins, are of interest. For instance, interactome networks describing protein-protein interactions are built up and serve as scaffolds for further analysis  for each condition. This was compared to a genome-scale network connecting genes with metabolic pathways and cellular functions. Looking at the top five connecting hub proteins from the transcriptional network  as well as the hubs in the genome scale metabolic pathway and cellular function network , all these hubs were found to be dispensable for virulence in mutation studies. However, double mutants of these two sets of regulatory proteins showed clear effects on virulence in mouse infection experiments  produced by the NO synthase of several immune cells of the host has a severe impact on central carbon metabolism of Salmonella. NO targets the pyruvate and α-ketoglutarate dehydrogenase complexes (Richardson et al., ch Table . FurtherSalmonella making it more stress resistant (Figure Citrate is a TCA cycle intermediate Figure  and is at Figure .The broad influence of amino acids on metabolic adaptation during infection. The work on acetylation regulation in Salmonella by Wang et al. (g et al.  also undg et al. .ArgT is an essential virulence determinant which decreases the host's cellular arginine content and reduces by this way the NO production of the host (Das et al., Salmonella appears to be without influence on NO production. Although arginine degradation pathways are up-regulated in Salmonella during infection of macrophage and essential for virulence, this is due to other mechanisms but not related to substrate degradation of iNOS (Choi et al., In particular, the bacterial arginine permease Salmonella. In a study on cysteine biosynthesis during oxidative stress, cysteine biosynthesis regulation was blocked in ΔcysB and ΔcysE mutants and oxidative defense pathways encoded by katG and soxS were up-regulated compared to the wild-type strain (Turnbull and Surette, Salmonella survival and replication (Bjur et al., Cysteine is a key amino acid during oxidative stress response in SsrAB virulon controlling SPI2 gene expression is induced under nutrient-poor conditions (e.g., presence in the phagosome, Kuhle and Hensel, The Salmonella enterica (Table Various metabolic pathways which have an impact on the SPI1 activity of ca Table . One exaca Table  and secrca Table .Salmonella invasiveness and to induce strong inflammatory host responses (Humphreys et al., There are also indications for the influence of SPI1 functions on the host's metabolism in order to facilitate survival in the intestine and subsequently intracellular to promote the infection process. Thus, the SPI1-T3SS effector protein SopE is known to increase Salmonella virulence (Table Although SPI1 and SPI2 are induced under very distinct nutritional environments (SPI1 in a nutrient rich environment, SPI2 by nutrient starvation, Kuhle and Hensel, ce Table . One exace Table .Intracellular adaptation and metabolism of Salmonella. While conditions in the intestinal lumen are nutrient rich, the situation changes after Salmonella invades into the epithelial cells and is phagocytosed at the basolateral cell side by macrophages or dendritic cells. Staying inside the SCV, the pathogen has to deal with nutrient limitations. To investigate which metabolites could interact with expression of genes in SPI1 or mainly SPI2, one issue is to define the nutritional situation of Salmonella gain inside the SCV and to figure out which metabolites Salmonella has access to. Mouse infection experiments showed on the one hand that intracellular Salmonella get access to a wide range of nutrients, including nearly all amino acids except proline. On the other hand, it was shown that the ability to manifest a full systemic infection is dependent on the utilization of “glycerol, fatty acids, N-acetylglucosamine, gluconate, glucose, lactate, and arginine” (Steeb et al., Salmonella is able to counteract various defense mechanisms in order to facilitate growth or reduce immune responses (Table es Table . Invasioes Table .Shigella-infected cells, amino acid levels of epithelial cells invaded by Salmonella normalized 3 h after infection, which leads to relocalization of mTor invasion sustaining pathway to the SCV, phosphorylation of ATG protein 13, leading to a low ATG protein 1 activity and thus reduced autophagy (Ganley et al., Salmonella is able to avoid autophagy in epithelial cells. Further investigations are required to clarify if normalization of amino acid levels is directly induced by Salmonella. At least the invasion-induced membrane disturbance is only severe in the first hour of infection and somehow repaired faster than in cases of invasion by other intracellular pathogens (Tattoli et al., However, in contrast to Salmonella adapts rapidly and successfully to changing conditions including intracellular survival in macrophages, in epithelia and in the gut, we will now examine which antibiotic strategies are nevertheless available for Salmonella infections. A seminal work by Becker and co-workers showed that the robust metabolism of Salmonella limits possibilities for new antibiotics (Becker et al., Salmonella virulence (Steeb et al., Salmonella are highly resilient (Barat et al., Salmonella in particular, as well as by exploring novel ways of anti-infectives. One inspiring example is metabolic engineering of Salmonella vaccine bacteria in the mevalonate pathway to boost human Vγ2Vδ2 T cell immunity (Workalemahu et al., Salmonella also vulnerable also in conserved and well investigated pathways, such as TCA cycle and its anaplerotic reactions. Thus, Salmonella Typhimurium is controlled by host NO production as shown in mice experiments in vivo. Methionine or lysine auxotrophy results from reduced succinyl-CoA availability as the lipoamide dehydrogenase activity is targeted by NO while compensatory Salmonella pathways to achieve more succinyl-CoA are again blocked by NO (Richardson et al., As Salmonella to facilitate intracellular survival within the SCV in host cells and its nutrient supply.We saw that multiple “-omics” and especially metabolomic data are currently used to determine the needs for Salmonella's generalist metabolic lifestyle meets all types of environmental challenges, be it ROS or nutrient limitation by its broad metabolic capabilities. The broad metabolism suggests nevertheless potential for novel anti-infective strategies. However, under severe conditions Salmonella regulation and metabolism are spiked up by input from SPI1, SPI2, T3SS and T6SS, modified invasion abilities, redox protection and central metabolism to turn the neutral environmental lifestyle of Salmonella into a pathogenic lifestyle for its host. On top of this such genetic modules catalyze rapid genetic exchange between Salmonella strains showing that only an integrated picture will help to sustain antibiotic efficiency against Salmonella infections.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.


Fusarium graminearum is a phytopathogenic Ascomycota that can cause Fusarium head blight in wheat and other cereals worldwide, leading to important yield losses as well as reduced grain quality. The analysis of the F. graminearum genome sequence revealed the presence of 20 non-ribosomal peptide synthases, 15 polyketide synthases, and 17 terpenoid synthases, all potentially involved in the production of a panel of secondary metabolites, including yet unknown ones, such as the mycotoxins deoxynivalenol (DON) and other type B trichothecenes , and both types can lead to either adaptation and survival, or cell death. Here, cell death does not necessary mean a failure to implement an effective stress response but can be the result of the response pathway itself when a destructive response is implemented. The effects of various stresses that phytopathogenic fungi are likely to encounter in the context of host invasion have been the subjects of numerous works. In particular, oxidative stress, as the result of the early defensive “oxidative burst” triggered in the host plant upon infection, has been intensively examined.Stresses caused by variations of the environment can be biotic (the surrounding microbiome) or abiotic  as signals that initiate/modulate biosynthesis (reviewed in Hong et al., Aspergillus nidulans, the Yap-like bZIP factor NapA, was shown to be involved in tolerance to oxidative stress (Asano et al., NapA (Yin et al., Aspergillus ochraceus and the NapA orthologue AoYap1 (Reverberi et al., AoYap1 but toxin accumulation is also enhanced in untreated conditions (Reverberi et al., In Aspergillus parasiticus have binding sites for the same bZIP transcription factor AtfB that is activated upon oxidative stress via MAPK signaling (Hong et al., A. parasiticus is grown in toxin-inducing medium (Roze et al., Aspergillus species (see Reverberi et al., Botrytis cinerea, the BcAtf1 factor was also shown to positively regulate the production of secondary metabolites (Temme et al., On the mechanistic side, mobility shift assays provided experimental evidence that antioxidant and aflatoxin biosynthetic genes in F. graminearum, previous results indicate that oxidative stress with H2O2 could be a pre-requisite for the biosynthesis of the mycotoxin DON, which may suggest that DON production and endogenous oxidative stress could be connected (Ponts et al., FgAP1 that activates the transcription of antioxidant enzymes (Montibus et al., F. graminearum to its own benefit. Recent data may bring clues as of the mechanism of activation of DON biosynthesis upon oxidative stress. A glycogen synthase kinase GSK3 was shown to be essential for both virulence and DON production F. graminearum, and to be up regulated upon oxidative stress by H2O2 (Qin et al., In F. graminearum. An acidic pH is a prerequisite for DON production (Merhej et al., FgPac1, homologous to the member of the pH regulator system PacC in A. nidulans (Merhej et al., The pH of the environment was shown to be particularly critical for the initiation of trichothecene B biosynthesis in F. graminearum, the cell wall integrity pathway involves the MAP kinase FgMgv1 (Hou et al., F. graminearum, FgHOG1 of the osmoregulation MAP kinase pathway, mediated by the FgOS-2 kinase, is involved in hyperosmotic as well as cell membrane stress responses. FgHOG1 also plays a role in ROS-mediated signaling. Its deletion causes a drastic reduction of DON accumulation, also caused by hyperosmotic conditions, as well as other developmental defects (Van Thuat et al., in planta (Van Thuat et al., Different response pathways can be triggered to counteract stresses that modify the organization and stability of the fungal cell wall. For example, the cell wall integrity pathway is responsive to changes in osmotic pressure and oxidative stress (see Hayes et al., F. graminearum, transcription factor Tri6 has been evoked above (Seong et al., Aspergilli, LaeA has been described as a secondary metabolism-specific regulator involved in switching from inactive heterochromatin to the transcriptionally permissive euchromatic state. In F. graminearum, FgLae1 is a regulator of secondary metabolism that activates the production of DON (Kim et al., FgLae1 has pleiotropic effects in F. graminearum, also affecting sexual development for example (Kim et al., Regulators of fungal secondary metabolite biosynthesis that play a role in regulating other aspects of fungal life, including response to stress, have been described. The example of the F. graminearum's response to oxidative stress, i.e., defensive plant-produced H2O2 may serve as a signal to produce DON (Ponts et al., F. graminearum for its own development and secondary metabolism (Audenaert et al., e.g., caspofungin, nikkomycin Z, tunicamycin, fluconazole; see Hayes et al., Previous observations made about A. parasiticus, co-localize with stress response proteins to the endosome/transport vesicles/vacuoles fraction of a fungal cell extract (Linz et al., F. graminearum, previous work showed that the endoplasmic reticulum stress response and oxidative stress are tightly linked (Malhotra et al., F. graminearum secondary metabolism and stress response pathways are indisputably very closely interconnected. Although further investigation is required, an attractive hypothesis is that secondary metabolism pathways could be part of the fungus' stress-response system. Under this scenario, more than a coupling of pathways, the production of DON and other secondary metabolites would be integral part of the fungus' arsenal to cope and adapt to its always-changing environment, including in the context of host-pathogen exchanges.The hypothesis of a coupling between stress response and mycotoxin production is reinforced by recent evidence that proteins involved in secondary metabolite pathways, including the aflatoxin one in 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.


Dear Editor,et al. reported that abdominal compression reduced the movement of lung tumors (thereby possibly reducing treatment uncertainty), with portal fluoroscopy being used to measure the tumor movement [et al. [et al. [et al. also reconfirmed the validity of abdominal compression using 4D CT and reported that the internal target volume was significantly reduced for lower lobe tumors [et al. reported that abdominal compression increased the variation of tumor motion by referring to their 4D cone-beam CT (CBCT) data, contending that longer treatment time to include the abdominal compression procedure may reduce the reproducibility of tumor motion [et al. [et al. [Several different approaches have been applied to stereotactic hypofractionated radiotherapy for lung tumors, including free breathing, breath-hold, gating, and tracking. Negoro movement . Heinzer [et al.  and Han  [et al.  confirmer motion . Richmon [et al.  and Mamp [et al.  also repUsing a 4D planning CT imager, Aquilion LB,  we calculated 3D lung tumor motion trajectories with an Anzai belt  and stereotactic body frame with an abdominal compression plate  for five patients who received four-fraction VMAT stereotactic ablative body radiotherapy (SABR). In addition, the motion trajectories of lung tumors were calculated using 4D CBCT imaging functionality provided by an X-ray Volume Imaging (XVI) system version 4.5  both immediately before and during treatment. The pre-treatment 4D CBCT data were acquired by the built-in XVI software, Symmetry, whereas in-treatment 4D CBCT was obtained by in-house software using projection images acquired during VMAT delivery . The brex, y and z axes correspond to the lateral, anteroposterior and craniocaudal directions, respectively. A large interpatient variability was observed: Fig. Figure Figure In conclusion, we confirmed the reproducibility of lung tumor movement using 4D planning CT and 4D CBCT for five patients who received four-fraction VMAT SABR under constrained breathing conditions. The results appear to be clinically acceptable, but further study is needed because of the small data size of this preliminary study. It is anticipated that the flattening-filter-free technique may increase breathing trajectory reproducibility due to its faster dose delivery . In addi


Allium cepa, Nicotiana tabacum, Vicia faba, or Arabidopsis thaliana but this number largely increased in the last years. Plant comet assay has been used to study the genotoxic impact of radiation, chemicals including pesticides, phytocompounds, heavy metals, nanoparticles or contaminated complex matrices. Here we will review the most recent data on the use of this technique as a standard approach for studying the genotoxic effects of different stress conditions on plants. Also, we will discuss the integration of information provided by the comet assay with other DNA-damage indicators, and with cellular responses including oxidative stress, cell division or cell death. Finally, we will focus on putative relations between transcripts related with DNA damage pathways, DNA replication and repair, oxidative stress and cell cycle progression that have been identified in plant cells with comet assays demonstrating DNA damage.The systematic study of genotoxicity in plants induced by contaminants and other stress agents has been hindered to date by the lack of reliable and robust biomarkers. The comet assay is a versatile and sensitive method for the evaluation of DNA damages and DNA repair capacity at single-cell level. Due to its simplicity and sensitivity, and the small number of cells required to obtain robust results, the use of plant comet assay has drastically increased in the last decade. For years its use was restricted to a few model species, e.g.,  The first reports on the use of comet assay in plants date from the 1990's  and the fact that root is usually the organ directly in contact with contaminated soil and water, have also influenced the establishment of plant comet assays in ecotoxicological approaches. Technical details concerning plant comet assays in different organs and species have been thoroughly reviewed by Gichner et al. .Allium cepa, Nicotiana tabacum, Vicia faba, and Arabidopsis thaliana  that allows the quantification of several comet parameters, including the tail DNA %, tail length, tail extension moment or Olive tail movement  in light excess-induced DNA damages in Ipomoea aquatica root protoplasts, and correlated DNA damages observed by comet assay with chlorophyll degradation. However, these two studies did not take into consideration the potential role of UV in light-induced DNA damages. In a study designed to investigate UV-A and UV-B effects, Jiang et al. , compared to DNA polymerase λ UV-B sensitive mutants. UV-C was also shown to induce both SSBs and DSBs in Arabidopsis plumbaginifolia protoplasts -rays are used to increase seed vigor and/or enhance plant tolerance to environmental stresses. Navarrete et al.  pioneerea et al. , Koppen a et al.  and Verba et al.  optimizea et al. , 2008a uArabidopsis homologous recombination deficient mutants subjected to γ-rays. On the other hand, Vandenhove et al.  seedlings after exposure to γ-rays concomitant with a difference in expression profiles of three miRNAs, and an increase of reactive oxygen species (ROS) levels. Combining the use of the comet assay, and the expression of genes encoding DNA repair-related proteins, Nishiguchi et al. . Donà et al.  presented by soils were significantly genotoxic to A. cepa roots, with DNA damages measured by comet assay and compared to the effects of increasing γ-ray doses.Concerning radioactive contaminations, Saghirzadeh et al.  successfMost of the contaminated sites worldwide are contaminated with heavy metals. In Europe, heavy metals contaminated almost 50% of the investigated sites  developed adaptive responses and protection mechanisms against genotoxic effects of the mutagenic agents methylmercuric chloride (MMCl) and ethyl methanesulfonate (EMS)  genotoxicity has been the most studied during the last years. Achary et al. , 2012a aN. tabacum in hydroponic and soil experiments. These results were confirmed on Talinum triangulare roots and correlated with Pb-induced oxidative stress  including genotoxic aspects was reviewed by Pourrut et al. . Using cA. cepa roots  was shown to induce significant DNA damages in V. faba leaves and roots, in a dose-dependent manner and that these effects were associated with oxidative stress. Sturchio et al.  toxicity mechanism in plants involves DSBs and possibly replication blocks, with plant condensin II playing a critical role in DNA damages repair  was shown to induce significant DNA damages  induces higher DNA damages in roots compared to leaves. This differential effect was possibly attributable to the higher accumulation of Zn (II) in roots, compared to shoots. Tkalec et al.  were demonstrated to be relevant genotoxicity biomarkers. Despite still restricted to a few number, some studies have already used plant comet in field ecotoxicology assays of soils contaminated with metals (see Section “Contaminated Matrices” below).It is worth noting that the interest of using the comet assay as a reliable biomarker on ecotoxicological assays is increasing, and Bandyopadhyay and Mukherjee  applied o et al.  used a bA. cepa, supporting the genotoxic potential of this type of nanomaterials.Plant comet assays are also increasingly used to assess the phytotoxicity of small-scale materials Table , e.g., n2 NPs in A. cepa  were shown to induce DNA damages in Brassica rapa ssp. rapa, and this result was confirmed by DNA laddering and TUNEL assays.Recently, using higher NPs concentrations, Thiruvengadam et al.  also demA. cepa plants. These data supported the concomitant observation of chromosomal aberrations and mitotic aberrations in the same tissues  oxide NPs increased the nuclear DNA damages in s Liman, .The alkaline comet assay showed an increase of DNA damages in tomato seedlings exposed to NiO-NPs up to 2 mg/ml  oxide and tin (IV) oxide is a mixture widely used in industrial coating. A significant increase in DNA damages was recently observed of Medicago sativa cells. In this and other pioneer studies, the comet assay can play a pivotal role as a tool to assess environmental impacts of suspected emerging nanocontaminants.Besides metal oxide NPs, quantum dots form another type of nanomaterials increasingly prevalent in the environment. Quantum dots are nanomaterials used in electronics which possess semiconducting properties, composed for example of arsenic (As), selenium (Se) and tellurium (Te) in various proportions. Despite their increasing prevalence in the environment, the toxicity of quantum dots in plants is largely unknown. In a pioneer study, Santos et al.  used a bSeveral researchers have used the comet assay to monitor DNA damages induced in plants by numerous organic pollutants Table . The mos2O2 induce DNA damages  and/or HPetunia grandiflora and Gaillardia grandiflora by comet assay, in a pioneer study of plant–plant association for phytoremediation involving the treatment of textile dyes  roots after exposure to doses up to 10 mg/L  roots used treated by two herbicides 2,4-D  and Dicamba . These results were confirmed in the same study by RAPD analysis. Recently, Liman et al.  were demonstrated in plants, e.g., barley  radicles treated with Juglans regia husk water extracts. It should be noted that the authors stressed the need of performing accurate and appropriate statistical evaluations of comet results, an emerging topic of discussion. Ciğerci et al.  may have cytotoxic and genotoxic effects or have protective roles against stressing conditions in a wide number of species, including humans. The way phytocompounds influence oxidative stress balances, and regulate programmed cell death pathways and cell cycle chekpoints, support their wide therapeutic use  was recently shown to inhibit plant growth of Oryza sativa, A. thaliana, Brassica rapa or Lactuca sativa   and AtRad21.1 (SYN2) as important effectors in early repair of DSBs, after treatment with bleomycin  might occur during S phase and stimulate HR in fas mutants. Also, levels of formed DSBs were compared in rice wild type plants vs. an aphidicolin-sensitive phenotype. Without aphidicolin treatment, both WT and osrecql4-2 mutants produced very low levels of DSBs, but these increased in the mutants after treatment  hypersensitive to excess of boron (B). Excess of B induced DNA damages and affected the expression of HEB1 and HEB2, which encode respectively the CAP-G2 and CAP-H2 subunits of the condensin II protein complex, important in maintenance of chromosome structure. These results suggested that DSBs are a cause of B toxicity and that condensin II reduces the incidence of DSBs  and PhAPX (encoding for a cytosolic isoform of ascorbate peroxidase).Roy et al. , 2013 reV. faba  and telomeric regions in Arabidopsis mutants by Roy et al. , top1 (DNA topoisomerase I), MtTFIIS (transcription elongation factor II-S) and MtTFIIS-like. So, despite comet assay has not been consistently applied to these environmental stresses in plants, the available data of their interference with DNA integrity, opens a perspective of their use in the near future. Also, Confalonieri et al. (Medicago truncatula the MtTdp2α-gene overexpression prevented the accumulation of DSBs in absence or presence of osmotic stress, and that the MtMRE11, MtRAD50 and MtNBS1 genes that are involved in DSB sensing/repair, being up-regulated in the MtTdp2α-overexpressing plants grown under physiological conditions, were no further up-regulated under osmotic stress (Confalonieri et al., Salt, drought and osmotic stress are ever more emerging as abiotic defies intimately related with soil overuse and climate changes (e.g., Santos et al., y et al.  who suppi et al.  demonstrIn this review we have highlighted most relevant studies that used comet assay in plants to study the impact of stress conditions on plant DNA damages. This work was mostly focused on the most recent major advances in the last five, regarding conventional and emerging contaminants and complex matrices. The recent advances in the use of the plant comet assay to both a larger number of plant species, and a larger number of conditions, support the use of this technique as a robust and sensitive technique to assess DNA damages induced by stress conditions. Data also support that this simple and robust technique may be a powerful tool to complement conventional and -omics tools in situ environmental pollution monitoring. Moreover, new fields of research using plant comet assay are open, not only in environmental studies, but also in plant physiology, as this technique may help elucidating pathways involved in plant development, cell cycle/programmed cell death, or even plant disease resistance. Also, it remains an important field of research deciphering genetic mechanisms underlying processes related with DNA damage/repair, in which comet assay will have undoubtedly a crucial role.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.


Yet the creatinine concentration decreased significantly (p<0.05) when the cadmium animals treated with 200 and 400 mg/kg body weight of the extract were compared with the cadmium control. Furthermore, histological alterations in the kidney were observed in cadmium untreated rats and these were ameliorated in cadmium treated rats by co-administration of IG extract. IG showed apparent protective and curative effect on Cd-induced nephrotoxicity.Cadmium has been considered a risk factor for humans as it accumulates in body tissues, such as the liver, lungs, kidneys, bones, and reproductive organs. The aim of the present study was to evaluate the effect of Irvingia gabonensis (IG) against cadmium (Cd)-induced nephrotoxicity. The study was performed on twenty (20) male rats divided into four groups: control group, cadmium group , cadmium + extract  and cadmium + extract . Changes in the kidney biochemical markers, namely glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), aminotransferase (ALT), aspartate aminotransferase (AST) activities and levels of malondialdehyde (MDA), urea, and creatinine were determined in serum. Histological examinations were monitored. Exposure to Cd lowered the activities of kidney antioxidants, while it increased LPO levels. Levels of all disrupted parameters were alleviated by co-administration of IG extract. The malondialdehyde concentration of the rats treated with 200 and 400 mg/kg body weight of the extract significantly decreased ( It is a highly accumulative toxicant with very long biological half-life . Cd nephrotoxicity was reported to result from generating free radicals and thus inducing cell necrosis and apoptosis  in membranes of erythrocytes and tissues, such as kidney, liver, brain, and testes, with thiobarbituric acid reactive substances (TBARS) and hydroperoxides used as indicators of oxidative damage  (IG) is a commercial and indigenous fruit tree of West and Central Africa and identified as the most important tree for domestication  were purchased from Aldrich Chemical Co. . Glutathione, hydrogen peroxide, 5, 5’-dithios-bis-2-nitrobenzoic acid (DNTB) and epinephrine were from Sigma Chemical Co., Saint Louis, MO USA. Trichloroacetic acid (TCA) and Thiobarbituric acid (TBA) were purchased from British Drug House (BDH) Chemical Ltd., Poole, UK. Other reagents were of analytical grade and the purest quality available.Irvingia gabonensis was collected on 16th January, 2014 in Ado-Ekiti (Ekiti State) and authenticated at the Department of Plant Science, Ekiti State University. The stem bark of Irvingia gabonensis was air-dried and crushed into fine powder. The powdered part extracted with ethanol using maceration and the extract was concentrated in vacuum at 40 °C with a rotary evaporator and water bath to dryness. The yield of the extraction was 5.01%.The stem bark of Irvingia gabonensis stem bark for the detection of various phytochemicals. Tests for common phytochemicals were carried out by standard methods  weighing between 80–120 g were bought from the animal house of the Department of Chemical Sciences, Biochemistry Unit, Afe Babalola University, Nigeria. The animals were kept in aired cages at room temperature (28–30 °C) and received normal laboratory chow  and water ad libitum.Male Wistar rats  for laboratory animal care and use. The ethical committee of the Afe Babalola University approved this study. The use of all animals in this study followed the guidelines of the institutional Animal Ethical Committee given by the Committee for Control and Supervision of Experiments on Animals (CPCSEA).Cadmium was induced in groups II, III and IV. Briefly, Cadmium dissolved in distilled water was given by intravenous injection (through tail vein) at a dose of 4 mg/kg body weight.Irvingia gabonensis (200 mg/kg b.w.) (14 days) + cadmium chloride (4 mg/kg b.w.); Group IV – Irvingia gabonensis (400 mg/kg b.w.) (14 days) + cadmium chloride (4 mg/kg b.w.) according to the method of Ojo et al. ; Group II–cadmium chloride (4 mg/kg b.w.); Group III –  et al.  .Kidney tissues were quickly removed, washed in ice-cold isotonic saline and blotted individually on ash-free filter paper. The tissues were then homogenized in 0.1 M 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride buffer, pH 7.4, using a Potter-Elvehjem homogenizer at 4 °C. The crude tissue homogenate was centrifuged at a speed of 9 000 rpm for 15 min in a cold centrifuge and the supernatant was kept at –20 °C for estimation of GSH, SOD and CAT activities.Blood collected from the heart of the animals into plain centrifuge tubes was allowed to stand for 1 h. Serum was prepared by centrifugation at 3 000 g for 15 min in a Beckman bench centrifuge. The clear supernatant was used for assessing the serum lipid profile and enzymes.et al.  followed by the Duncan multiple range test for analysis of biochemical data using SPSS (20.0). Values were considered statistically significant at The ethanolic extract was found to contain compounds known to have antioxidant activity, like tannins, phlobatannins, flavonoids, anthocyanin, cardiac glycosides and alkaloids .p<0.05) in the relative weight of the kidney of cadmium untreated rats when compared with the control, while treatment with Irvingia gabonensis stem bark (100 and 200 mg/kg) significantly decreased the relative weight of the kidney of cadmium-induced rats to values statistically comparable to the control (p>0.05). All these changes induced by cadmium intoxication restored significantly (p<0.05) to near normal levels on administration of Irvingia gabonensis stem bark.p<0.05) serum and kidney lipid peroxidation (LPO) products measured as thiobarbituric acid reactive substances  confirmed the nephro-protective activity as a significant recovery of nephron damage and decreased necrosis was evident against cadmium-induced nephrotoxicity in the kidney of the rats, comparable to their control. The histological results further corroborated the biochemical findings suggesting the useful effects of Irvingia gabonensis stem bark in cadmium-induced toxicity in rats.Histology of the kidney slide of cadmium untreated rats showed tubular degeneration, necrosis and severe renal cortical congestion . TreatmeIrvingia gabonensis stem bark extracts revealed the presence of polyphenol-rich compounds. Polyphenols have been suggested to decrease oxidative stress in humans. Flavonoids found in the extract may inhibit oxidative stress by scavenging free radicals, acting as reducing agents, hydrogen atom donating molecules or singlet oxygen quenchers, chelating metal ions and sparing other antioxidants   such as alkaloids, glycosides, saponins, tannins, flavonoids and phenolic compounds, which are responsible for the antioxidant activity.Cadmium is a well-known human carcinogen and a potent nephrotoxin. It is a potent inducer of oxidative stress and affects the cellular antioxidant defense potential bi-phasically by reserve and improvement of several antioxidant enzymatic and non-enzymatic molecules. The phytochemical study of Irvingia gabonensis stem bark examined against cadmium-induced nephrotoxicity in rats showed that the mean body weight of the cadmium-exposed group decreased with the increase in relative liver weight, which agrees with the findings of other authors (EI-demerdash et al., et al., et al. (Irvingia gabonensis, the changed body weight and liver weight parameters recovered to near normal levels due to the antioxidant effects of Irvingia gabonensis stem bark.In the present study, the potent chelation therapy with , et al.  reportedet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Many studies have shown that cadmium induces oxidative damage by producing ROS (Liu et al., et al., et al., Irvingia gabonensis in the treated groups, indicating a prominent nephroprotective effect of Irvingia gabonensis against cadmium nephrotoxicity. The increased levels of serum AST and ALT in cadmium exposed rats indicate an increased permeability and damage and/or necrosis of the kidney. In our study, we found that the extract of Irvingia gabonensis at a dose of 400 mg/kg caused a significant decrease in the activities of serum AST, ALT, which further supports the beneficial effects of the extract of Irvingia gabonensis in cadmium-induced rats.Moreover, the protective effects of this extract may be related to its ability to chelate or sequester cadmium via formation of cadmium-flavonoid complexes (el-Ashmawy Serum total protein represents a complex mixture containing a number of components which differ in properties and function. Hypo-proteinemia, protein deficiency in plasma, may be partly due to dietary insufficiency with subsequent impairment of the protein synthetic machinery, or to excessive excretion Chawla, . In the et al., et al., et al., et al., et al., Irvingia gabonensis had a protective effect against cadmium-induced kidney damage, as established by the significant decrease in urea and creatinine levels in the Irvingia gabonensis treated group compared with the cadmium group.It has been postulated that increased levels of serum urea and creatinine are linked to kidney disease Chawla, . Urea isIrvingia gabonensis treatment of cadmium-induced nephrotoxicity in rats revealed that the observed pathological impairments caused by cadmium recovered significantly, indicating that Irvinga gabonensis is capable of preventing the nephron damage induced by cadmium. It is thus suggested that Irvingia gabonensis may inhibit Cd-induced kidney damage. However, further studies are necessary to find out the actual mechanism of action of phytochemicals and their doses in the presence of oxidative stress due to Cd intoxication.Histological examination revealed that cadmium intoxication caused abnormal ultra-structural changes in kidney tissue, including tubular degeneration, necrosis and severe renal cortical congestion. Regarding the histopathological observation, Irvingia gabonensis exhibited protective effects against Cd-induced nephrotoxicity. For populations exposed to Cd, the use of the ethanolic extract of Irvingia gabonensis could thus be recommended.In conclusion, the ethanolic extracts of


Dear Editor,Morbilivirus which belongs to family Paramyxoviridae . The dial., 2011; Yanagi al., 2011; Fazlalial., 2011). Measleal., 2011). Howeveal., 2011; Muscat al., 2011). Historal., 2011). Recently, increased number of measles outbreaks with high morbidity and mortality has been observed in various regions of Pakistan during recent years  as outlined in supplemental material . A total of 871/1053 (82.71 %) children from Faisalabad and 647/813 (79.58 %) children from Jhang were found vaccinated either with single or dual dose of measles vaccination Table 1. Out of Samples from non-vaccinated children showed high prevalence (63 %) which was an indication of previous measles infection in these particular children. These findings were suggestive and may be correlated with confirmatory sero-diagnosis of recent outbreaks in these areas. The non-vaccination status against measles was considered as one of the major risk factor in children . The prevalence of anti-measles IgG antibodies from samples collected from Faisalabad was found 79.54 % whereas in Jhang 67.42 % of samples were observed as positive. There was no significant difference of sero-prevalence between Faisalabad and Jhang. The possible explanation for non-significant prevalence could be that these two areas are closely related geographically, traditionally and are closely situated to each other. These factors may be considered for a similar trend towards vaccination coverage and sero-conversion against measles as previously described by Hussain et al. (2008[The prevalence of anti-measles IgG antibodies from samples collected from male children was higher as compared to female children with non-significant difference. However, few of the available literature has reported that risk of measles and level of anti-measles IgG antibodies was observed higher in females as compared to male children (Rahim et al., 2011; FowotadBased on various age groups, prevalence of anti-measles IgG antibodies were observed as 75.35 % in children from 1-6 years of age, whereas 67.56 % in children from 6-10 years of age were positive with no significant difference. These findings were not in accordance with some of the previous studies which showed the highest incidence of measles during the age of 6 months to 3 years (Matsumura et al., 2005; Rahim eIt was concluded from the overall results of present study that vaccination coverage against measles was below the standards of WHO and Health Department, Govt. of Punjab, Pakistan. Further, vaccine efficacy and development of humoral immune response in children was not optimum according to WHO guidelines and higher risk of measles incidence was found in non-vaccinated children. Based on these findings, it is recommended that routine immunization against all vaccine preventable diseases in general and against measles in particular should be carried out as per guidelines of WHO to completely control and eradicate measles from Pakistan.The authors declare that they have no conflict of interest.


Neural stimulation is a critical technique in treating neurological diseases and investigating brain functions. Traditional electrical stimulation uses electrodes to directly create intervening electric fields in the immediate vicinity of neural tissues. Second-generation stimulation techniques directly use light, magnetic fields or ultrasound in a non-contact manner. An emerging generation of non- or minimally invasive neural stimulation techniques is enabled by nanotechnology to achieve a high spatial resolution and cell-type specificity. In these techniques, a nanomaterial converts a remotely transmitted primary stimulus such as a light, magnetic or ultrasonic signal to a localized secondary stimulus such as an electric field or heat to stimulate neurons. The ease of surface modification and bio-conjugation of nanomaterials facilitates cell-type-specific targeting, designated placement and highly localized membrane activation. This review focuses on nanomaterial-enabled neural stimulation techniques primarily involving opto-electric, opto-thermal, magneto-electric, magneto-thermal and acousto-electric transduction mechanisms. Stimulation techniques based on other possible transduction schemes and general consideration for these emerging neurotechnologies are also discussed. Neural stimulation is an essential technique for restoring lost neural functions and correcting disordered neural circuits in neurological diseases  the strong cytotoxicity of QDs is a concern, particularly when a thin coating is used to achieve an active QD-neuron interface  nanoparticles were targeted to the biotinylated peptide of a genetically engineered anchor protein in the membrane of neurons expressing the temperature-gated TRPV1 ion channels (Placement II; Huang et al., 2+ influx through the TRPV1 ion channels, depolarized the neurons to fire action potentials in vitro, and triggered thermal avoidance in worms.Widely used superparamagnetic nanoparticles can convert alternating magnetic fields to localized heat via magneto-thermal transduction (Laurent et al., 2+ influx into the cells faster than in the above work (Huang et al., A more specific ion-channel targeting strategy was also implemented in a mouse xenograft model by tethering nanoparticles directly to the TRPV1 ion channels (Placement III; Stanley et al., in vivo stimulation feasibility, untargeted superparamagnetic iron oxide nanoparticles were dispersed in the vicinity of TRPV1-expressing human embryonic kidney HEK-293FT cells, dissociated hippocampal neurons and neurons at the ventral tegmental area of mice (Placement I; Chen et al., 2+ influx in the HEK-293FT cells, stimulated hippocampal neurons to fire action potentials, and activated the neurons at the ventral tegmental area of mice to have an enhanced expression of c-fos, achieving a stimulation response with a latency of 5 s after the onset of the magnetic field. And the stimulation in the mouse model remained effective for at least 1 month thanks to the good biocompatibility, stability and decreased endocytosis of extracellularly dispersed nanoparticles.To improve the temporal resolution for neuronal activation and realize a long-term 2+ permeability, and thus temperature-gated Na+ ion channels are desired as the target (Knöpfel and Akemann, Magneto-thermal neural stimulation enabled by superparamagnetic nanoparticles can achieve a uniform stimulation of the target cell population due to the uniform expression of TRPV1 ion channels in these cells across the tissue (Huang et al., As a wirelessly transmitted primary stimulus, ultrasound interacts with tissues weakly and can penetrate deep into soft tissues with minimal energy absorption Tyler, . It can 2+ and Na+ influxes in an ultrasonic field (Placement II; Marino et al., Piezoelectric nanomaterials can convert ultrasound waves to electric fields via acousto-electric transduction due to their piezoelectricity (Wang and Song, Nanomaterial-enabled neural stimulation is an emerging class of neurotechnologies, with numerous exciting breakthroughs in the past decade. As a powerful enabling tool, nanomaterials can be either applied alone or combined with other approaches including synthetic biology to facilitate innovative neural stimulation schemes. These new techniques not only allow non- or minimally invasive neural stimulation of a high spatial resolution and cell specificity, but also improve the safety by significantly reducing the required power of the primary stimulus (Huang et al., Nanomaterials of other transduction mechanisms, such as magneto-mechanical, acousto-mechanical, and opto-optical transductions, are also worth considering for potential development of additional neural stimulation schemes. Magneto-mechanical transduction via magnetic nanoparticles can convert magnetic fields to localized mechanical forces to activate mechanosensitive ion channels such as the TREK-1 channels (Hughes et al., To select the primary and secondary stimuli, several factors are considered. The primary stimulus needs to penetrate tissues deeply, be easy to focus at an appropriate spatial resolution and be safe for long-term exposure. The secondary stimulus needs to be selected according to an adequate expression of the target ion channels in the neuron's membrane. For example, it is not necessary to genetically modify the target neurons with voltage-gated ion channels to use electric fields as the secondary stimulus, whereas, to use heat, the TRPV1 ion channels may need to be genetically inserted into the membrane of target neurons (Huang et al., in vitro. To move forward, many issues including biocompatibility, stability, consistency, efficiency and reliability will need to be addressed (Gomez et al., in vitro and/or in vivo studies. Clinical application is promising, but remains very challenging due to concerns on the safety of nanomaterials, viral vectors for gene delivery, and genetic modification to the target neurons (Manilla et al., This diverse class of nanomaterial-enabled neurotechnologies is still in their early stages of development, with many having only been validated YW and LG analyzed the relevant published work, designed the perspective and structure, and wrote the manuscript.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.


Preliminary follow-up studies seem to support the efficacy and safety of SVF/ASCs enrichment and the additional benefit from the combined use of autologous platelet-derived growth factors and hormones during breast reconstruction procedures. In the present review we highlighted the complex interplay between resident or grafted ASCs, mature adipocytes, dormant or active breast cancer cells and tumor microenvironment. Actually, data concerning the permissive role of ASCs on breast cancer progression are contrasting, although no clear evidence speaking against their use exists.Breast cancer is the most common cancer in women and autologous fat grafting is an important clinical application in treatment of post-surgical deformities. The simplicity of fat grafting procedures and the absence of subsequent visible scar prompted an increasing interest for this technique. The plasticity of adipose-derived stem cells (ASCs) obtained from stromal vascular fraction (SVF) of adult adipose tissue provided exciting perspectives for regenerative medicine and surgery. The recent discovery that SVF/ASC enrichment further ameliorates clinical efficacy of grafting ASCs suggest as ASC-mediated new adipogenesis and vasculogenesis. ASC adipogenic differentiation involves Akt activity and EGFRs, FGFRs, ERbB2 receptor-mediated pathways that also play a pivotal role in the regulation of breast cancer growth. Moreover, the finding that platelet-derived growth factors and hormones improved long-term maintenance of fat grafting raises new concerns for their use during breast reconstruction after cancer surgery. However, it remains unclear whether grafted or resident ASCs may increase the risk of  However, the term “adipose-derived stem cells” (ASCs) has been successively recommended for the consistency between research groups (Zhao et al. in situ lesions. This finding induced caution and suggested some concerns about the use of fat grafting with SVF/ASC enrichment in breast reconstruction following cancer surgery. In the present review, we tried to describe the biomolecular pathways regulating proliferation and differentiation of ASCs, in order to define potential implications of breast cancer cell biology and risks for their use in post-surgery breast cancer reconstruction.Adult adipose tissue is a multifunctional organ that contains various cellular types, including mature adipocytes, macrophages and stromal cells, supported by connective tissue surrounding fine capillaries (Zuk et al. in vitro as a function of time and/or passage in culture (Mitchell et al. in vitro, ASC surface immunophenotype resembles that of MSCs, with a similarity greater than 90% (Gimble et al. + cells and to differentiate them from circulating precursors (Pittenger et al. + cells and the perivascular origin of ASCs (Figure in vitro (Figure ASCs share with MSCs the differentiation potential along several mesenchymal lineages (Gimble et al. s Figure C-E. Cytoo Figure . Besideso Figure .Table 1The fascinating differentiative pluripotency of ASCs and their ability to enhance vascularization (Bertolini et al. α, heparin-binding epidermal growth factor, insulin-like growth factor-II and adipsin (Manabe et al. in vivo and in vitro studies demonstrated relevant phenotypic changes in adipocytes surrounding breast cancer (Dirat et al. Many studies focused the relationship between mature adipocytes and breast cancer cells. Rat mature adipocytes affect the biological behavior of epithelial cells through the production of leptin, adiponectin, tumor necrosis factor-in vivo and in vitro reported that ASCs favor tumor growth, increasing extracellular matrix deposition and vascularization, suggesting that ASCs may directly contribute to the dense network of fibroblasts and desmoplastic reaction surrounding breast cancer (Wang et al. in vitro documented that co-culture of human ASCs and breast cancer cells induce high levels of metalloproteinases (Pinilla et al. Differently from mature adipocytes, the interplay between resident mesenchymal cells, including ASCs, and breast epithelial cells is still partially unknown. In this respect, it is still unclear whether preadipocytes act differently from mature adipocytes. ASCs are located in perivascular niches and contribute to cell turn-over, vascular network for the maintenance of adipose tissue tropism (Strawford et al. in vivo and in vitro have been performed to verify ASCs influence on dormant tumor cells and on their growth and invasiveness. In literature is not yet clear whether dormant tumor cells are out of cell cycle, or persist in a dynamic state of proliferation and death. The transition between dormant and active states requires the presence of various signals, such as cytokines, hormones and growth factors (Donnenberg et al. To better clarify their role in cancer progression, studies in vivo interaction and define how selectively stimulate ASCs regenerative function without influencing tumorigenesis.Altogether, these studies highlight the concept that resident ASCs and cancer cells may interact in a complex and dynamic fashion influencing the tumor behavior. Further studies are needed to better clarify this in vitro (Cervelli et al. In vitro data alone seem to suggest the caution in the local use of growth factors in addition to fat graft and further investigation of the interplay between ASCs and breast cancer cells should be performed also in vivo.The proliferative arrest and/or cell loss are potential limitations in regenerative surgery strategies. So, exogenous growth factors should provide the necessary microenvironmental signals to accelerate cell proliferation, extracellular matrix synthesis and tissue deposition (Chen et al. Autologous fat grafting is a procedure widely used in breast reconstruction after cancer surgical treatment (Gentile et al. in vivo. MSCs can be readily transduced via adenoviral, retroviral or lentiviral vectors without compromising the capability for differentiation or the expression of surface markers. Consequently, MSCs are potentially suitable for a gene approach in cancer therapy through the induction of a more chronic and slow release of drugs that are often limited by their toxicity or short life (Kucerova et al. In vitro, MSCs transduced with adenoviral vector carrying human Interferon-β and co-cultured with breast cancer cells induced the reduction of cancer cells growth (Studeny et al. in vivo, when Interferon-β − transfected MSC cells are injected intravenously in a xenograft breast cancer mouse model (Studeny et al. In vitro studies documented that cancer stem cell exert antiapoptotic effect on breast cancer cells and counteract cell-cycle changes caused by tamoxifen, so promoting tumor growth and invasiveness (Wang et al. Conventional cancer therapies include surgery, chemotherapy and radiotherapy. A certain number of preclinical studies recently proposed the use of MSCs as candidates to deliver anti-cancer drugs. Chemokines secreted by breast tumor cells are capable of stimulating MSCs migration and recruitment, suggesting a potential role for MSCs as delivery agents for chemotherapeutic purposes in breast tumours Aromatase inhibitors are used as second-line therapy or as first-line adjuvant therapy, but they have the disadvantage to inhibit indiscriminately aromatases, including those in bone and brain tissues, with adverse effects in terms of bone mineralization and cognitive function, respectively (Rubin et al. in vivo seem to confirm the efficacy of SVF/ASCs enrichment and the beneficial additional use of autologous platelet-derived growth factors and hormones in breast reconstruction. The improvement in long-term maintenance strongly supports the additional combined use of fat grafts with autologous platelet-derived growth factors and hormones, such as insulin. However, additional translational research studies are needed to better clarify the possible impact of these procedures on tumor microenvironment, in particular their potential effect on cancer cells. Different studies confirmed the complex and dynamic interplay between cancer cells and resident ASCs. Latters, in the tumor microenvironment, seem to affect only active cancer cells, so promoting neoangiogenesis, matrix remodeling and intercellular communication via gap-junction. In addiction, it has been hypothesized the presence of cancer stem cells, from resident stem cell or dedifferentiated tumor cells, that may favour the epithelial-mesenchymal transition, supporting tumor growth and invasiveness. In addition, the interaction between grafted ASCs and resting cancer cells doesn’t seem to be responsible for cancer recurrence because resting cancer cells are more resistant to apoptosis and they don’t require stroma or vascular structure for their survival. Preliminary data describe that SVF/ASCs enrichment did not show increased risk of new cancer or relapse compared with control group.Current evidence sustains that ASCs represent a promising tool for innovative therapies in regenerative surgery and play a significant role in lipofilling-mediated breast reconstruction after breast cancer surgery. SVF/ASCs enrichment seems to favor long-term fat graft maintenance in reconstruction of tissue defects, likely promoting vascularization and collagen synthesis. Preliminary studies Finally, ASCs characteristics appear promising for their engineered use as “carrier” of adjuvant chemotherapeutic agents against residual breast cancer cells. So, the growth of malignant cells may be counteracted by local release of drugs in tumor microenvironment while systemic plasma concentration remain low, avoiding the problems related to toxicity and short life.


Carragher et al.In an attempt to analyse the cross-sectional data correctly, I obtained information on alcohol consumption for eight of the study regions from published WHO data for 2010,I did a multiple regression analysis using methods described by KronmalIn my regression model, I considered total alcohol consumption in each area as the response, with GDP, population and TEASE-16 score the predictors. Only population size was significantly associated with total alcohol consumption , and exaThe relationship between TEASE-16 and GDP per capita is shown in Neither TEASE-16 score nor income, (measured by GDP), were significantly correlated with alcohol consumption across the eight areas in the year 2010. It seems unlikely that analysis of the original data used by Carragher et al.


Machine learning (ML) has been well recognized as an effective tool for researchers to handle the problems in signal and image processing. Machine learning is capable of offering automatic learning techniques to excerpt common patterns from empirical data and then make sophisticated decisions, based on the learned behaviors. Medicine has a large dimensionality of data and the medical application problems frequently make the human-generated, rule-based heuristics intractable. In this special issue, we provide a forum to present the cutting-edge machine learning techniques in medical applications, including the learning of similarities across different image modalities, organ localization, learning of anatomical changes, tissue classification, and computer-aided diagnosis. “Adaptive neuro-fuzzy inference system for classification of background EEG signals from ESES patients and controls” introduced an adaptive neurofuzzy inference system for classification of background EEG signals from the patients of slow-wave sleep syndrome and control subjects. Their study showed that the entropy measures of EEG were significantly different between the patients and normal subjects. Therefore, a classification framework based on entropy measures was proposed. S. Jirayucharoensak et al. in “EEG-based emotion recognition using deep learning network with principal component based covariate shift adaptation” proposed the utilization of a deep learning network (DLN) to discover unknown feature correlation between input signals. The DLN was implemented with a stacked autoencoder (SAE) using hierarchical feature learning approach. D. Al-Jumeily et al. in “A novel method of early diagnosis of Alzheimer's disease based on EEG signals” introduced three neural synchrony measurement techniques: phase synchrony, magnitude squared coherence, and cross correlation for classification of mild Alzheimer's disease patients and healthy subjects. K. Zhang et al. in “Adaptive bacteria colony picking in unstructured environments using intensity histogram and unascertained LS-SVM classifier” presented a novel approach for adaptive colony segmentation in unstructured environments by treating the detected peaks of intensity histograms as a morphological feature of images. In order to avoid disturbing peaks, an entropy based mean shift filter was introduced to smooth images as a preprocessing step. The relevance and importance of these features can be determined in an improved support vector machine classifier using unascertained least square estimation. M. Cabrerizo et al. in “Induced effects of transcranial magnetic stimulation on the autonomic nervous system and the cardiac rhythm” demonstrated that repetitive transcranial magnetic stimulation (rTMS) could induce changes in the heart rhythm.The topics of the accepted papers in this Special Issue spread from electroencephalography (EEG) signal processing to image segmentation. Z. Yang et al. in


Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson’s.Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression  The major histocompatibility complex (MHC) gene family encodes molecules on the surface of cells that enable the immune system to recognize presented self- and foreign-derived peptides  and beta 2 microglobulin (β2m) chains  is immune-privileged and that MHC-I is not expressed by neurons Lampson, . HoweverThis review summarizes the pattern of expression and the different implications of neuronal MHC-I in the brain, and focuses in particular in the potential role of constitutive MHC-I expression by specific subsets of neurons in neurodegenerative diseases such as PD.in vitro, usually triggered by exposure to interferon gamma (IFN-γ), and in vivo. The initial such study showed that MHC-I genes expression were induced by IFN-γ in cultured rat hippocampal neurons , and are far more susceptible to MHC-I induction than other neuronal populations tested, including cortical, striatal and thalamic neurons  subunit, CD3zeta , exhibit reduced retinal synaptic activity, incomplete developmental refinement of connections between retina and its central targets, and reduced retinal ganglion cell dendritic motility with increased dendritic density  has been linked to MHC-I and CTLs in the CNS (Friese and Fugger, Our findings in human postmortem samples of adult control individuals and PD patients show that MHC-I is expressed by SN DA and LC NE neurons (Cebrián et al., Neuronal MHC-I expression plays multiple roles. First, it regulates synaptic plasticity during brain development. Second, it regulates axonal regeneration and the appropriate specification of synaptic inputs following injury. Third, in neuronal diseases including neurotropic viral infections, neuronal MHC-I expression is upregulated and may initiate T cell mediated responses. While current research in each of these areas is ongoing, the suggestion of a role in neurodegenerative disease is the most recent and the least understood: while there is a consensus that many neurodegenerative diseases feature a robust inflammatory response, it remains unclear how this is related to chronic disease processes.In vitro experiments indicate that DA primary human neurons derived from human embryonic stem cells and primary catecholamine murine neurons are more susceptible to MHC-I induction by IFN-γ than other neuronal populations (Cebrián et al., Our recent study demonstrates neuronal MHC-I expression in both normal and PD adult brain; such expression to date appears to be particular for catecholaminergic/monoaminergic neurons. These possibilities are consistent with recent demonstrations that microglia can be activated by substances released from degenerating neurons in PD, such as α-syn (Zhang et al., Neuronal display of antigenic MHC-I could participate in a range of additional neurological disorders. For example, Japanese encephalitis virus can induce MHC-I expression in non-neuronal cells by interferon type 1 (Abraham et al., Together, these data indicate that in human brain, neuronal MHC-I expression, antigen presentation and the presence of T cells could occur simultaneously under certain circumstances, leading to the death of targeted neurons. In some neurodegenerative diseases, and in particular for PD, we propose that activation of lymphocytes in the periphery may occur in response to self or non-self proteins, or as an initial insult and disruption of the blood brain barrier, with a subsequent penetration of lymphocytes in the brain. When catecholamine neurons die with subsequent release of α-syn and NM to the extracellular space, the activation of microglial cells will release proinflammatory substances such as IFN-γ, leading to an upregulation of MHC-I in the membrane of catecholamine neurons that could present neuronally derived antigens. If lymphocytes are close, they could recognize these antigens and target and kill the cell, which would again release α-syn and NM Figure , leadingFuture studies are necessary to identify which antigens are presented by MHC-I expressing catecholamine neurons and how T cells might interact with them. If these interactions occur, immune therapies used in other diseases including classical autoimmune disorders such as Type 1 diabetes or MS may be adapted to provide future treatments for PD.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.


Heme oxygenase (HO) is a ubiquitous enzyme with various properties, but its main function is catalyzing the rate-limiting step in heme degradation to produce equimolar quantities of biliverdin, iron, and carbon monoxide (CO)  and Hmox1−∕− mice, Soares et al.   cells, restores placentation, and fetal growth, while normalizing blood pressure (Linzke et al., Zenclussen et al.  review hThe relevance of HO-1 in the regulation of immune responses during pregnancy is further highlighted in the article by George et al. . They inIn summary, the HO-1/CO axis may play a pivotal role in sustaining pregnancy, and thus understanding its biology during pregnancy may reveal promising therapeutic approaches for pregnancy complications.Both the authors contributed in writing the editorial.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.


In a recent study, Cid-Fernandez et al.  tested aOther prior studies have investigated changes in motor changes in aging Light, . In one What is important about this study is Cid-Fernandez and colleagues (a) have tested both motor and cognitive processes in (b) three age groups. Most existing studies on aging often compare younger (aged 18–30 or 50 years old) with older (aged 60 or 65 years and over) adults Scott, , and thuImportantly, there are studies that test behavioral performance in more age groups than those recruited in the Cid-Fernandez et al.  study s. One sucOther studies have recruited participants across various age groups and correlated behavioral performance with age (Davis et al., Cid-Fernandez et al.  suggest The Cid-Fernandez et al.  findingsThe 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.


Chorioamnionitis (CA) describes an intrauterine status of inflammation and/or infection of placental membranes, refering to both histological and clinical CA . It is c


Recent objectification research found results consistent with the sexualized body-inversion hypothesis (SBIH): People relied on analytic, “object-like” processing when recognizing sexualized female bodies and on configural processing when recognizing sexualized male bodies  processing becomes more important . Because Bernard et al.  presenteIn their first study, Schmidt and Kistemaker examined symmetry in Bernard's stimuli and found that female bodies were more asymmetrical than male bodies. Strikingly, neither the interaction between stimulus gender and stimulus orientation nor the three-way interaction involving stimulus set-up emerged. These results suggest that differences in symmetry between inverted (vs. upright) female bodies  are not more pronounced in the Bernard set-up than in the counterbalanced set-up.In their second study, these authors replicated Bernard et al. 's findindirectly address this putative symmetry confound as they allow comparison within symmetry-matched stimuli . A visual inspection of Figure 2  and asymmetrical female bodies (seventh vs. fourth bar); (ii) asymmetrical inverted female bodies (fourth bar) were not recognized better than symmetrical inverted female bodies (eighth bar).Schmidt and Kistemaker identified a potential stimulus set-up confound in their second study (contrary to Bernard et al., In sum, contrary to Bernard et al. , SchmidtSchmidt and Kistemaker also found an inversion effect for male and female bodies and this pattern occurred for naked bodies with or without masked sexual body parts. They concluded that Bernard et al.'s findings are not driven by target sexualization (Schmidt and Kistemaker, conceptual replication perspective, Schmidt and Kistemaker provide evidence in favor of restricted generalizability of Bernard et al.'s findings but from a direct replication perspective Schmidt and Kistemaker's paper cannot address the role of target sexualization in Bernard et al.'s stimuli because they did not manipulate sexualization of these stimuli. Bernard et al. (First, although informative with regard to the role of target sexualization and inversion, the SBIH was posited to explain differences in recognition of sexualized male vs. sexualized female bodies (i.e., stimulus gender effect: Bernard et al., d et al. , howeverIn sum, contrary to Bernard et al. , SchmidtThe 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.


Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of meduloblastoma. Cancer and Metabolism 2013, 1(2):17A response to Gershon et al. : Gershon et al. have invfl/fl conditional knockout that they have used to study the metabolism and migratory behavior of CGNPs during their development not only targets those neurons[Gershon et al. interpretation of the results of their Fig. 5 may also be discussed as the hGFAP-cre;Hk2 neurons. Thus anOne might thus feel that in their work, Gershon et al. may have overlooked an important aspect of the cerebellar developmental process and one could suggest that they give more attention to the possible involvement of Bergmann glia in modulating the role of Hexokinase-2-mediated aerobic glycolysis during cerebellar neurogenesis.