In the developing central nervous system, most neurogenesis occurs in the ventricular and subventricular proliferative zones. In the adult telencephalon, neurogenesis contracts to the subependyma zone and the dentate gyrus (subgranular zone) of the hippocampus. These restricted niches containing progenitor cells which divide to produce neurons or glia, depending on the intrinsic and environmental cues. Neurogenic niches are characterized by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid (CSF). Both the vasculature and the CSF represent a source of signaling molecules, which can be relatively rapidly modulated by external factors and circulated through the central nervous system. As the brain develops, there is vascular remodeling and a compartmentalization and dynamic modification of the ventricular surface which may be responsible for the change in the proliferative properties. This review will explore the relationship between progenitor cells and the developing vascular and ventricular space. In particular the signaling systems employed to control proliferation, and the consequence of abnormal vascular or ventricular development on growth of the telencephalon. It will also discuss the potential significance of the barriers at the vascular and ventricular junctions in the influence of the proliferative niches. It is essential that an organ and its blood supply should develop together in synchrony to allow optimal conditions for the different stages of growth, differentiation and changing functional requirements. This co-dependence is particularly evident in the brain, where the vascular network originates from the peri-neural vascular plexus in early embryonic development and undergoes multiple stages of remodeling to meet the changing needs of the complex developing environment . Both the VZ in the developing brain and the SEZ in the adult have close association with the ventricular surface and the CSF. Therefore, in addition to proliferative support from the cerebrovasculature, trophic regulation/modulation is thought to come from the CSF  is a major signaling molecule that regulates both vascular and neural development and may be important in the establishment of the neurovascular niche. Shh has a clear role in regulating neural development, and in the dorsal cortex conditional knockout of Shh or its receptor Smoothened (Smo) results in reduced cell division, and a smaller cortex (Komada et al., β-catenin and the Wnt signaling pathway also affect vessel ingrowth from the peri-neural plexus and the structure of the developing vessels. Endothelial specific modifications of β-catenin expression, Wnt7 knockout or delivery of the soluble frizzled-8 receptor to bind extracellular Wnt ligand all cause a disruption in the vascular ingrowth into the parenchyma and malformation of the vessel beds, characterized by enlarged vascular space and thickening of the vascular wall with multiple layers of endothelial cells (Stenman et al., Contact-dependent signaling is another local environmental regulator of growth. McCarty et al.  have shoin utero injection of VEGF into the dorsal cortex, causes a change in distribution of the Tbr2 positive SVZ progenitor cells in conjunction with the new vascular network, and a disruption of radial fibers and axonal ingrowth into the surrounding tissue (Javaherian and Kriegstein, in vitro. These studies confirmed that BDNF produced by the endothelial cells was in fact secreted to affect the neurogenic precursors. Further co-culture studies confirmed that secretions from endothelial cells increased proliferation of precursors and ultimately facilitated the production of a larger number of neurons, of all neuronal classes (Shen et al., In turn, vascular development can control proliferation and brain development. For example, ectopic vascular development, induced by There are certainly many studies showing both secreted protein from endothelial cells, and progenitor-endothelial cell contact is important for maintain proliferation in the SEZ. Transplant studies of neural precursor cells into the SEZ have shown that the chemokine cxcl12, which is produced by endothelial cells, is important for the localization of these cells to the vasculature. Cxcl12 appears to act through the activation of integrin that allows cell binding to the endothelial cell wall, and support migration of differentiating cells out of the SEZ (Kokovay et al., Vascular production of VEGF is likely to be due to HIF activation in response to the low oxygen environment of the developing brain. HIF knockout in neural crest cells leads to reduced vascular density in the developing brain, and gross abnormalities in cellular migration (Tomita et al., Recent work has provided evidence in support of a further neurogenic niche in the adult brain, that of perivascular stem cells that do not proliferate in control conditions, but are upregulated following injury, such as ischemia (Ohira et al., In addition to secreted signaling to neural precursors, the endothelial cells may also support the progenitor population in a contact-dependent manner (contact between type B and endothelial cells in the SEZ is shown in Figure While the ventricular zone in the developing brain is characterized by specialized junctions between the neuroepithelial cells, there are no such junctions between the ependymal cells that make the border with the CSF in the adult SEZ. The absence of these junctions between the ependymal cells appears to be very important for the structure of the SEZ, as progenitor cells are intercalated between the ependymal cells (Shen et al., Both the VZ in the developing brain and the SEZ in the adult brain have clear connections with the CSF (see Figures The possibility that systemic signaling may directly alter the neurogenic niche has been explored by a number of authors, and it is clear that signaling through inflammatory pathways can cause short- and long-term changes in proliferation in the brain (Stolp et al., Both the CSF and the vasculature of the brain provide regulatory niches for neurogenesis in the developing and adult brain. Variation in angiogenesis and CSF production clearly affect proliferation in the neurogenic niches as a result of cross-talk between these regions, which appears to be dependent both on secreted tropic factors and contact-dependent signaling pathways. The brain barriers, which regulate the internal environment and contribute to the contact between cells in the neurogenic niches are part of this complex system that can be altered both in systemic and central injury. The localization of neurogenic niches makes them sensitive to circulating soluble factors. Recent work from Villeda et al.  highlighThe 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.


She was put under symptomatic treatment after discontinuation of the offending molecule with a good mucocutaneous improvement. After healing of lesions of the oral mucosa in December 2011, the examination of the oral cavity has found a nodular median lesion of the dorsal surface of the tongue, in favor of a granulation tissue at the histology with spontaneous regression of the rest of lesion. The current decline is two years and two months without local recurrence.A 55 years old woman, was hospitalized in November 2011 for a Stevens-Johnson syndrome with severe mucosal impairment appeared three weeks after taking allopurinol (Zyloric


Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body. In recent years, remarkable progress has been made toward the understanding of proposed hallmarks of cancer development, care, and treatment modalities. Radiation therapy or radiotherapy is an important and integral component of cancer management, mostly conferring a survival benefit. Radiation therapy destroys cancer by depositing high-energy radiation on the cancer tissues. Over the years, radiation therapy has been driven by constant technological advances and approximately 50% of all patients with localized malignant tumors are treated with radiation at some point in the course of their disease. In radiation oncology, research and development in the last three decades has led to considerable improvement in our understanding of the differential responses of normal and cancer cells. The biological effectiveness of radiation depends on the linear energy transfer (LET), total dose, number of fractions and radiosensitivity of the targeted cells or tissues. Radiation can either directly or indirectly  damages the genome of the cell. This has been challenged in recent years by a newly identified phenomenon known as radiation induced bystander effect (RIBE). In RIBE, the non-irradiated cells adjacent to or located far from the irradiated cells/tissues demonstrate similar responses to that of the directly irradiated cells. Understanding the cancer cell responses during the fractions or after the course of irradiation will lead to improvements in therapeutic efficacy and potentially, benefitting a significant proportion of cancer patients. In this review, the clinical implications of radiation induced direct and bystander effects on the cancer cell are discussed. Cancer is a complex disease, which grow locally and also possesses the capacity to metastasize to different organs in the body. Cancer continues to be a major disease and the numbers of cancer cases are projected to be more than double worldwide in the next 20–40 years and surpass heart disease as the leading cause of death , total dose, fractionation rate and radiosensitivity of the targeted cells or tissues Hall, . Low LETThe overall outcome of radiation treatment is cell or tissue damage; if it is not repairable eventually kill the cells. Effectiveness of radiation therapy that have been developed over years showed an increase in the number of cancer survivors, but preventing or reducing late effects are a significant public health issue. Furthermore, increase in the number of cancer survivors has stimulated interest in the quality of life of cancer survivors. The situation is important among non-elderly adults. In particular, children are inherently more radiosensitive and have more remaining years of life during which radiation induced late effect in normal cells could manifest in their hyperproliferation  and ribonucleotide reductase (RNR) and further prolongation of radiation-induced gamma H2AX foci formation  activity and epigenetic changes were reported in the RIBE (Camphausen et al., RIBE is also reported using mouse model, the bystander responses of internal tumor cells or tissues were also confirmed Though tremendous progress has been made toward understanding the hallmarks of cancer, cancer is responsible for one in eight deaths worldwide (Garcia et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The goal of radiation therapy is to deliver a lethal dose of radiation to diseased tissue while minimising dose to surrounding healthy structures. Prior to the actual treatment delivery, treatment planning is the most critical part of a patient's radiation treatment management. The most crucial step is the accurate localisation and delineation of the target volume. Advances in tumour localisation and treatment delivery capabilities are limited by the inability to deliver treatment with complete precision to the localised tumour on a day-to-day basis over an entire course of radiation treatment. Most solid tumours are soft tissue masses, so the lack of inherent soft tissue contrast within images of intrathoracic regions can result in reduced visualisation and distinction of tumour boundaries from surrounding structures such as blood vessels, fatty tissues and lymph nodes.There are many sources of uncertainty in radiation therapy which impact on treatment accuracy and patient outcome. Geometric uncertainties cause deviations between the intended dose and the actual dose received by the tumour volume. These uncertainties consist of both external and internal factors. The external factors relate to the external patient set up displacements and the internal influences are due to organ motion and respiration.5The implementation of IGRT in radiation treatment has reduced the impact of organ motions and set up errors. Can the increased precision mitigate the issues associated with target volume delineation? I do not think so because IGRT is only as precise as the accuracy of the delineated target volume. The precision of IGRT and the steep dose gradient of the intensity modulated radiation therapy (IMRT) technique made accurate target volume delineation ever more important. The recent article by Liang et al. investigating the effect of IGRT on the margin between the clinical target volume (CTV) and planning target volume (PTV) in lung cancer found that the application of IGRT reduced the geometric uncertainties, but was unable to completely mitigate the errors.7Current target volume delineation protocol is based on the guideline of International Commission on Radiation Units and Measurement (ICRU) recommendations for consistent definition of target volumes, but individualised based on tumour location, size, proximity to dose-limiting structure and the probability of high-grade treatment-related toxicities occurrence.9Target volume delineation and margin determination is even more challenging in lung when compared to other anatomical regions. The issue with overlapping anatomical structures that appears with similar densities on imaging scans making it difficult to distinguish, making target volume delineation highly imprecise and margin with high degree of variation. Liang et al. found the largest margin values were attributed to individual radiation oncologist's (RO) ability to identify and delineate the nodal invasion.10Uncertainties can be minimised by having concise contouring procedures and protocols, use of multimodality imaging techniques, training and multidisciplinary consultations either within the department or between institutions. A study by Senan et al. demonstrated the existence of statistically significant inter-observer variability with standardised contouring protocols and patients. The ratio of greatest delineated target volume over the smallest delineated target volume for gross tumour volume (GTV) of a T1N0 lung tumour was 1.6. Similarly, the ratio for PTV of a T2N2 lung tumour lesion was 2.Errors in target volume localisation and delineation occur early in the planning process and only once. This systematic error can produce the biggest deviation in the entire radiation therapy process and potentially can alter the outcome of the treatment. Once defined, this error is constant throughout the entire radiotherapy planning process and cannot be corrected unless a new target volume is defined and delineated and the patient treatment is re-planned.12Based on the evidence presented, the question should be asked whether it is prudent to reduce the tumour volume margins.The contouring of a target volume is influenced to a largest extent by the observer's subjective interpretation of what he or she sees on the images”.To be able to answer that question, we must first examine the factors attributing to target volume delineation variability. The ability to accurately localise and delineate the target volume is based on the availability and the quality of imaging data and the clinical experience and expertise of the RO. With the advancement of imaging technology and technique, the visibility of tumour has increased which in turn increases the ability for ROs to delineate the borders of the malignancy as stated by Weiss and Hess. “As far as the personal attribute is concerned, the training received, years of experience and the availability of instructions on contouring all have significant impact on tumour delineation especially of the extent of microscopic involvement. The implementation of multiple imaging modalities in the management of cancer has improved the visualisation of the tumour, but this has also created further problems for ROs as many have limited expertise, in particular the interpretation of PET images. The American Society for Therapeutic Radiology and Oncology (ASTRO) has recognised the problem by developing standardised delineating protocols for common cancers. Another professional institution recommended the development of close links between radiologists, nuclear medicine physicians and ROs to optimise the interpretation of radiological images to reduce the delineating variability and improve accuracy.14Although target volume delineation can be significantly variable between different observers, I believe we are heading in the right direction in utilising the technology to be less subjective and less observer dependent in target volume delineation. This combined with precision in the treatment delivery and increased understanding of morphology and molecular profile of the tumour growth and pattern of spread has further improved the accuracy of target volume delineation leading to reduction in margins. Also with increased education and further training, the development of the standardised protocols and multidisciplinary collaboration has further reduced the degree of variability in target volume delineation.


The events that have led to the development of cytogenetics as a specialty within the life sciences are described, with special attention to the early history of human cytogenetics. Improvements in the resolution of chromosome analysis has followed closely the introduction of innovative technology. The review provides a brief account of the structure of somatic and meiotic chromosomes, stressing the high conservation of structure in plants and animals, with emphasis on aspects that require further research. The future of molecular cytogenetics is likely to depend on a better knowledge of chromosome structure and function. Variations in morphology within species, and to a greater extent between species, led Linnaeus and other taxonomists to classify all organisms in terms of genealogies with species, families and orders depending on their similarities, starting with individuals capable of reproduction that defined a species. The stage was set for ideas about the transmutability of species, the heritability of physical traits and Darwin’s theory of the origin of species [Our specialty was pioneered by scientists who developed the compound microscope to study the cellular organisation of the living world. While comparative anatomists had known for centuries that all animals share physical features that suggest a common structure among creatures both living and revealed in fossils, the cytologists of the 19th Century by the behavior of chromosomes in germ cells [The mechanisms of transmission of both discontinuous and continuous characteristics across the generations were unknown before Mendel’s laws were explained at the turn of the 20rm cells . Stains rm cells -6. Cyrilrm cells . These sIn 1944 it was realized that genetic transformation in bacteria was due to DNA and not protein and that DNA was the molecule responsible for heredity in genes and chromosomes . The molSince the genetic code was deciphered much has been learnt about the chromosome structure shared by all organisms from yeast to human. Much more remains to be discovered. One of the purposes of this review is to encourage research into chromosome structure as this could help advance molecular cytogenetics. The following is a brief summary of the author’s view of current knowledge, emphasizing areas that need further study.We now recognize that, following DNA replication, the metaphase chromosome consists of two chromatids held together by a centromere and by cohesin. Each chromatid is a single molecule of DNA attached to protein matrix fibres that forms its scaffold or axial filament . Over 20During gametogenesis parental homologous chromosomes, each consisting of two chromatids, pair together during the long prophase of the first meiotic division and form chromosomal bivalents. Here again, the two DNA molecules of each parental chromosome are attached to protein matrix fibres that now form the axial filaments of the two lateral elements of the synaptinemal complex  and these show that G- and Q-bands are associated with A-T rich regions and repetitive DNA, while the regions between bands are associated with G-C rich coding regions including genes. The A-T rich regions also correlate with the chromomere patterns observed in pachytene bivalents . Thus thth century genetic studies were mostly confined to plant and animal species rather than to humans. It was more productive to make crosses in fruit flies and mice because of the larger number of progeny that could be observed over several generations. However, a number of human pedigrees were collected and characterised [th century gave counts of 16–38 with most in favour of 24 [Throughout the first half of the 20cterised  and inbocterised . But thecterised ; this leur of 24 -37. Moreur of 24 . Over thur of 24  until Tjur of 24 . The corur of 24 -44, all ur of 24  in humanThe first discovery of a human chromosome aberration was made by Marthe Gautier and colleagues from Paris in May 1958. They found an extra small chromosome in fibroblast cultures from several children with Down syndrome . This waChromosome analysis became much easier later in 1960 when lymphocyte cultures were introduced, made from small samples of peripheral blood stimulated by phytohaemaglutinin . Air-driIn previous sections of this article emphasis has been made of several technical milestones in the progress of human cytogenetics. Cell cultures, colchicine and hypotonic treatment led to the correction of the human chromosome number, and lymphocyte cultures to the widespread use of diagnostic cytogenetics and the discovery of many chromosomal syndromes. While the techniques used in the 1960s were sufficient to demonstrate the sex chromosome and autosomal aneuploidies, the Philadelphia chromosome and some of the gross structural aberrations, such as translocation Down syndrome , there wVicia faba by the group of Caspersson and Zech with quinacrine that intercalated into DNA producing dark and light Q-bands visible by UV microscopy along each chromosome [in situ to the centromeres of denatured mouse chromosomes [The introduction of chromosome banding in 1969–70 has been one of the most important innovations in cytogenetics. The discovery was first made in romosome . Meanwhiomosomes . The radomosomes . Variousomosomes  identifiomosomes ,75. Manyomosomes  and bandin situ hybridization for mapping DNA sequences to chromosomes. The method was used in 1972 to map the ribosomal genes to the short arms of the human acrocentrics [in situ hybridization (FISH) has become the standard method for gene mapping [As mentioned above, Pardue and Gall were the first to use centrics  but was centrics -80. Beca mapping ,82. The  mapping . Further mapping . DNA proThe above account so far has discussed cytogenetic techniques that are based on conventional or electron microscopy. Flow cytometry is another valuable approach that examines chromosomes in fluid suspension. The dual laser fluorescence-activated cell sorter (FACS) was designed for the analysis of cells stained by immunofluorescence, but has been adapted for measuring and sorting chromosomes on the basis of their size and base-pair ratio -87. The Chromosome painting has played an important role in basic research on gene interactions, including regulation, in the interchromatin compartment between chromosome territories in the interphase nucleus . SpecifiCross-species reciprocal chromosome painting has been most productive in phylogenetic studies in determining the relationships between species and in predicting ancestral karyotypes . The metIt has been shown that chromosome sorting by FACS can be one of the most accurate methods for determining a species genome size and for estimating GC content of individual chromosomes. The method involves sorting a suspension of chromosomes from the test species in a mixture containing a suspension of chromosomes from the control species, such as human, containing several non-heteromorphic chromosomes whose DNA content has been accurately determined. The size in megabases of each chromosome in the test species is calculated in relation to the control chromosomes. The sum of the individual measurements equals the genome size of the species, and this estimate correlates well with genome sizes determined by sequencing, at least for species in which the draft DNA sequence is believed to be complete. The results have been used to correct many errors in the genome size database in which genome sizes have been estimated by less precise methods .Several other molecular methods have been introduced to identify chromosome deletions and duplications at high resolution. Comparative genome hybridization (CGH) depends on the comparison of the patients genomic DNA with that of a normal control . In esseThe history of human cytogenetics has been punctuated by the introduction of new technology which on each occasion has led to the discovery of an increasing number of smaller chromosome aberrations associated with disease. Modern molecular methods are capable now of identifying chromosome aberrations at the level of the DNA sequence. One of the problems of this refinement is the difficulty in distinguishing between pathological events and normal copy number variation (CNV),  but this


In general, observations made from studies carried out before the advent of next generation sequencing technologies have been supported by recent work. Moreover, the challenge remains to definitively link the structure and function of hydrocarbon-degrading microbial groups to improve predictive models of biodegradation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The ultimate goal of functional brain imaging is to estimate the neural signals that flow through the brain, mediating behavior, and conscious experience during the spectrum of activities controlled by the nervous system. Although, various brain imaging techniques are in routine use, determining the underlying neural activity remains a challenge , but the ability to localize these signals with any degree of accuracy remains remarkably elusive as the complexity of brain activation for even the simplest of tasks tends to confound attempts to resolve the local neural components contributing to the recorded scalp responses. To improve our estimates of neural signals using non-invasive brain imaging techniques, this Frontiers Research Topic invited empirical and theoretical contributions focusing on the explicit relationship of brain imaging signals to causative neural activity.The submitted contributions responded to the challenge of neural signal estimation in a variety of ways including: advanced analyses of the neural implications of magnetoencephalographic (MEG) and electroencephalographic (EEG) signals, derivations of the pathway for BOLD signal generation from the underlying neural activation signals through animal recording, human BOLD modeling studies, detailed assessment of local BOLD response components and resting-state activation, and interpretation of the new field of functional diffusion tensor imaging in terms of neural activation.Cicmil et al. highlighted the limits on localizing MEG signal sources by testing the ability of several reconstruction approaches to localize the source of retinotopic MEG signals in the human brain and found that none of the approaches for assessing angular position were suitable for resolving annular stimuli spanning different retinal eccentricities (unless restricted in angular position). A second contribution to such electrical signal analysis is the time-frequency approach to the source localization and functional connectivity from simultaneous MEG/EEG signals proposed by Zerouali et al. Although, this analysis specifically targeted sleep spindles, the work has broader implications for the functional integration of MEG and EEG signals and their source localization within the brain. This analysis revealed that functional connectivity across the cortex evolved during the spindles from short-range intra-hemispheric connections to longer range inter-hemispheric connections, suggesting an integrative role for these dynamic features of neural activity.Although the EEG and MEG commonly used to measure human neural activity have high temporal resolution, spatial localization of the signal source is difficult to achieve. Martin reviews the need for accurate neurovascular models of the coupling between neural activity and the local BOLD signal from animal studies. Animal studies have the striking advantage of allowing a wide variety of technical approaches to the analysis of neurovascular coupling. Martin evaluates 16 of these, from single-neuron electrophysiology to tissue oxygen voltammetry, considering both their advantages and limitations and highlighting the key areas in which our understanding of fMRI signals has been improved through the use of animal models. Howarth takes up the issue of whether cortical astrocytes , and calcium transients within them, are involved in the vascular response to neuronal activity based on the recent debate regarding whether evoked glial calcium signals occur quickly enough to account for the dynamics of neurovascular coupling. Indeed, the exact mechanisms by which astrocytes respond to changes in neuronal activity and trigger the intracellular events regulating the resulting vascular response underlying the fMRI BOLD signal remain unclear. To take an analytic approach to this question, Tyler et al. evaluate four models for the neurovascular coupling between local field potentials recorded in cortex and BOLD signals recorded simultaneously in an adjacent location, for a range of stimulus durations. The results imply that the BOLD response is most closely coupled with metabolic demand derived from the neuronal input waveform, suggesting that the astrocytic signaling is responsive to the neurotransmitter metabolism of the dendritic arborization rather than to the neuron's spiking activity.Several contributions focused on estimating the properties of the underlying neural sources that generate BOLD fMRI signals. Buxton et al. assess the coupling ratio of blood flow and oxygen metabolism to different kinds of neural activation, finding that blood flow variations are more closely coupled with stimulus-driven variations than with endogenous variations in neural activity . Variations in oxygen metabolism, on the other hand, are more closely coupled with endogenous neural variations. The authors suggest that these differences in coupling ratio reflect differential proportions of excitatory and inhibitory contributions of the neural signal to cortical BOLD signals, and hence provide a new window into the assessment of neural activity. A related topic is addressed by Chen, who uses stimulus-driven manipulations of activation and suppression to assess the excitatory and inhibitory contributions to the evoked BOLD signal. The stimuli were designed to have invariant local effects, but differential long-range interactions were found according to configural relationships of local orientations, which should produce no differences in BOLD signal in the absence of neural interactions. One component of the BOLD suppression was dependent on the orientation-specific inhibitory effect of the long-range interactions, while a second appeared to be a general negative BOLD response to adjacent contrast stimulation independent of the stimulus configuration. Thus, BOLD response properties can be used to identify targeted aspects of the underlying neural organization.Further studies focus on contributions to the positive and negative components of the neurovascular relationships. Gonzalez-Castillo et al. take the novel approach of analyzing the time-course of resting-state BOLD signals across the cortex to assess the stability of neural connectivity. The most stable connections were between homologous (symmetric) interhemispheric local regions, with stability persisting for several minutes. The more variable connections were found to correspond primarily to occipito-frontal connections across the traditional resting-state networks, which can be interpreted as corresponding to transient visual imagery. Gravel et al. take resting-state analysis a step further to develop the concept of local cortical connective fields. These are neural organizations analogous to neuronal receptive fields, but defined in terms of connectivity among cortical regions, rather than connectivity of the neuron to a sensory surface. In combination with the population receptive mapping developed by this group for the analysis of the visual cortex, resting-state BOLD connectivity can be interpreted in visual space. This approach allows visuotopic maps to be reconstructed using resting state data recorded in the visual cortex, enabling these authors to show that the local resting-state connectivity from visual area V1 to both V2 and V3 was invariant with eccentricity with a scale of ~2 mm, substantially smaller than the population receptive fields for visual input in these cortical areas. This work suggests that it is possible to obtain some neural properties from resting-state fMRI data.Three papers focus on advanced methods of decomposing the neural connectivity and reorganization in the brain from the distribution of BOLD signals. Yang et al. extend the analysis of BOLD activation maps. Learning may generate not only changes in the strength of activation in predefined regions of interest, but also changes in the spatial distribution of the activation across the cortex. To address this issue, the authors measure the changes in spatial distribution of activation following a simple motor learning task. Dimension reduction via singular-value decomposition was able to capture aspects of the neural reorganization produced by this form of motor learning. These findings validate the capability of computational modeling to determine properties of neural connectivity and reorganization from BOLD signal analysis.Concentrating on the example of motor learning, functional form of Diffusion Tensor Imaging (DTI). DTI is a well-established technique for assessing the anatomical organization of the fiber pathways in vivo from the local anisotropy of the diffusion directions of water molecules within brain tissue. Functional DTI, on the other hand, assesses changes in this kind of anisotropy as a result of some functional manipulation of the state of the brain. Autio and Roberts raise concerns about contamination of this form of functional analysis by leakage of BOLD signal activation from adjacent gray matter into the voxels designated as fiber pathways. Mandl et al., whose previous paper on functional changes in fractional anisotropy in the optic radiations during visual stimulation was the subject of the Autio and Roberts critique, argue that such partial voluming would only occur at the ends of fiber tracts where they meet with the cortical regions that they are connecting, whereas the reported changes in fractional anisotropy occurred throughout the tracts.The final two papers are concerned with a new In summary, functional imaging techniques are increasingly used to infer neural activity within the human brain. This special issue improves our ability to estimate these neural signals non-invasively and points us in the direction of the remaining issues that must be addressed before we can fully understand functional imaging signals.All authors listed, have made substantial, direct, and intellectual contribution to the work, and approved it for publication.CH was a Vice Chancellor's Advanced Fellow at the University of Sheffield and currently holds a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number:105586/Z/14/Z).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.


Food and the eating thereof is a universal part of the human condition, and life is obviously impossible without adequate nutrition. The fact that the composition of diets varies so dramatically across the globe and that human populations survive and thrive fairly successfully despite seemingly very different nutrient intakes provides food for thought! Either the exact composition of the diet is irrelevant or else humans are biologically remarkably adaptable to great variation in the composition of their diet. If either of the statements in the previous sentence is correct then those individuals in what I refer to as the ‘diet industry’, an industry with enormous media appeal and reward, should feel seriously threatened.In light of the dramatic advances in the pharmacological and interventional management of patients with cardiovascular diseases, it is unfortunate that apparently conflicting advice on such a simple matter as diet is offered to patients and those at risk of disease. Such conflicting advice surely confuses rather than educates those at whom it is aimed. Lifestyle and diet are the topics reviewed by Opie (page 298) in an in-depth and scholarly review, which addresses in a balanced manner many of the current controversies. The accompanying editorial from Raal (page 302) is further valuable commentary.Awad and colleagues (page 269) report on the high prevalence rates of hypertension in the Gambia and Sierra Leone, as has been previously reported from other parts of Africa. The South African hypertension practice guideline prepared by the Hypertension Guideline Working Group of the Southern African Hypertension Society is published on page 288. It is comprehensive and includes information on lifestyle modification and education, in addition to detailed advice on pharmacotherapy. An accompanying comment (page 296) addresses the value and importance of such guidelines in clinical practice. It would be interesting to hear comment from colleagues in other parts of Africa as to the applicability and relevance of these guidelines to practice in their own countries.Otaigbe and colleagues (page 265) report on the prevalence of congenital heart disease, detected by echocardiography, among children referred to two specialist paediatric cardiology clinics in the Niger Delta region of Nigeria. Such information adds to our increasing knowledge of patterns of cardiovascular disease in Africa. It must be borne in mind however that this is not a population-based study, referral bias remains possible, and the authors’ attribution of the high prevalence to environmental pollution is speculative.Despite the success of percutaneous interventions, coronary artery bypass grafting is still a very common operation and the impact of interventions and risk factors for complications continues to be investigated. Cingoz and colleagues (page 279) examine the impact of co-morbidity on bleeding after the operation, while Yildiz and co-workers (page 259) examine the value of patient-directed education on patient anxiety after surgery. The importance of the anxiety experienced by patients and families of hospital survivors of major cardiac surgery is often underestimated by healthcare professionals.


Intraspecific acoustic communication requires filtering processes and feature detectors in the auditory pathway of the receiver for the recognition of species-specific signals. Insects like acoustically communicating crickets allow describing and analysing the mechanisms underlying auditory processing at the behavioral and neural level. Female crickets approach male calling song, their phonotactic behavior is tuned to the characteristic features of the song, such as the carrier frequency and the temporal pattern of sound pulses. Data from behavioral experiments and from neural recordings at different stages of processing in the auditory pathway lead to a concept of serially arranged filtering mechanisms. These encompass a filter for the carrier frequency at the level of the hearing organ, and the pulse duration through phasic onset responses of afferents and reciprocal inhibition of thoracic interneurons. Further, processing by a delay line and coincidence detector circuit in the brain leads to feature detecting neurons that specifically respond to the species-specific pulse rate, and match the characteristics of the phonotactic response. This same circuit may also control the response to the species-specific chirp pattern. Based on these serial filters and the feature detecting mechanism, female phonotactic behavior is shaped and tuned to the characteristic properties of male calling song. In many species of insects, intraspecific signaling systems have evolved to allow mate attraction over long distances, including systems based on sex pheromones in moths and butterflies , descending (DN1), ascending , and T-shaped (TN1) auditory interneurons  responds to high frequency signals. AN1 is not tuned to the temporal pattern of the calling song  and the Isaac Newton Trust .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.


Synchronous bursting plays an integral role in a variety of applications, from generating respiratory rhythms and inducing hormonal releases to conveying information about a stimulus. Since the network structure influences the dynamical behavior of a network, we aim to identify network structures that promote synchronous bursting.By generating the network topology using specific probability distributions, Zhao et al.  demonstrWe construct the graph theoretical measure by restricting the numbers of incoming and outgoing connections of a neuron to take one of finitely many possible values. Fixing certain constraints, such as the number of neurons in our network and the expected number of connections, we construct a probability distribution for our network. Through averaging, we construct difference equations from the probability distribution to track the expected number of active neurons and inactive neurons in a given time step. In the special case of spiking, the difference equations force a neuron to fire if one of its neighbors fires. By considering the maximum number of active neurons within a single time step, we formulate a graph theoretical measure for synchronous spiking. Using an analogous system of difference equations, we can construct a graph theoretical measure for synchronous bursting as well. Consequently, by calculating the second order network statistics from the probability distribution, and identifying all candidate probability distributions that satisfy the constrains, we can analyze how second order network statistics from any probability distribution promote synchronous spiking and bursting.In our simulations, we find that increasing the covariance of the in-degree and out-degree monotonically increases the predicted occurrence of synchronous spiking under the graph theoretic measure. We also note that for a wide range of parameters, the number of neurons in the network and the constraints on the governing probability distribution of our network have minimal qualitative impact on the relationship between second order network statistics and predicted likelihood of synchronous spiking. Furthermore, preliminary results regarding the effect of second order network statistics on predicted synchronous bursting suggest a more intricate relationship than in the case of synchronous spiking. Based on the consistency of the measure in the case of synchronous spiking with the existing literature and due to its ability to incorporate relatively abstract properties of the network, we conjecture that the measure will provide new insight regarding the impact of the network topology on continuous time-scale models of synchronous bursting and other complex behaviors.


There is an error in the fifth sentence of the last paragraph of the introduction. The correct sentence is: Recently, analysis of skin from space-flown mice showed that prolonged exposure to space conditions might induce skin atrophy and dysregulate the hair follicle cycle.There are errors in the last two sentences of the first paragraph of the discussion. The correct sentence is: Neutelings et al. investigated skin from space-flown mice and suggested that prolonged exposure to space environment might induce skin atrophy and deregulate hair follicle cycle, although they reported that the number of hair follicle in anagen increased in the space environment. Considering the FGF18 function on hair cycle, our results are not inconsistent with their findings.


Aneurysm of left ventricle (ALV) is formed in each 5th patient with acute myocardial infarction in the presence of complete occlusion of the coronary artery (CA) by atherosclerotic plaque. But we noticed the formation of ALV in the absence of atherosclerotic stenosis, for patients with myocardial "bridges" (MB). The essence of this anomaly is the presence of systolic compression of the tunneled segment of the artery, which in itself raises doubts about its clinical significance. Due to the attitude of the medical community toward the MB, as a result of its ambiguous nature, and given the favorable long term trend, the MB is regarded as a variant of the norm. At the same time, increasing reports of cases of sudden death and myocardial infarction associated with the presence of MB demonstrates the relevance of this anomaly.To show possibility of formation of postinfarction aneurism of left ventricle (LV) in the absence of atherosclerotic plaques in CA.12 patients in average age 35+/-5 years with transmural MI in anamnesis underwent standard examination  and surgical treatment.All patients had ECG-signs of aneurysm of antero-septal and apical area of LV, which was confirmed by ECHO study, where we notice reduction of ejection fraction less 45% (from 35 till 45%). On the coronary angiography we found myocardial "bridge" (MB) over middle portion of LAD with systolic compression from 30% to 100% and aneurism of the apex of LV. We performed CABG with resection of an aneurism of LV with thrombectomy (in 7 cases) on-pump with good remote results after procedure.Transient systolic compression of the LAD by MB can lead to myocardial infarction with the formation of ALV even in the absence of atherosclerotic lesions of CA.


Introduction: Since its inception, reduction mammaplasty has matured considerably. Primary evolution in clinical research and practice has focused on preserving tissue viability. Surgery involves preserving not only tissue viability but also function and sensation. The nipple serves as the sensate unit of the breast and is a valuable part of women's psychological and sexual health, making preservation of nipple sensation of utmost important. Studies regarding primary innervation to the nipple are few and often contradictory. We propose an unsafe zone in which dissection during reduction mammoplasty ought to be avoided to preserve nipple sensation. Methods: Circumareolar dissection of 22 cadaveric breasts was performed. Primary nerve branches to the nipple-areola complex were identified and dissected to their origin. Results: Three to 5 branches of the fourth intercostal nerve primarily innervated the nipple on 18 of 22 breast dissections. Two breasts received innervation from the third intercostal nerve and 2 from the fifth intercostal nerve. In half of the specimens, accessory innervation from the third and fifth intercostal nerves provided medial branches to the nipple. Conclusions: The fourth intercostal nerve provides the major innervation to the nipple-areola complex. Avoiding dissection in inferolateral quadrant “unsafe zone” of the breast during reduction mammaplasty and other breast surgical procedures can reliably spare nipple sensation and maximize patient outcomes. Primary evolution in clinical research and practice has focused on developing techniques to preserve tissue viability and breast parenchyma, skin, and nipple tissue. Previously, women with macromastia were more concerned with breast size and shape over mammary sensation. Presumably, the improved aesthetic outcome resulted in an enhanced body image and helped patients feel more sensual. However, surgery today involves preserving not only tissue viability but also function in terms of sensation. The nipple serves as a sensate unit in erectile function and plays a large part in the physical intimacy of women. Nipple sensation has shown to be a valuable part of women's psychological and sexual health. While preservation of nipple sensation is of utmost importance, the literature regarding primary innervation of the nipple is scant and contradictory.1Eleven dissections were performed on 22 cadaver breasts at the University of Louisville Fresh Tissue Lab. Four cadavers (8 breasts) had macromastia as determined by the investigator's judgment. Circumareolar subcutaneous dissection was performed to identify the nerves from the chest wall to the nipple using 2.5× loupe magnification. Once the trajectory of the nerves to the nipple was identified, the nerves were dissected back to their origin of penetration of the chest fascia.Anatomical results identified 3 to 5 branches of the fourth intercostal nerve to primarily innervate the nipple on 18 of 22 breast dissections. Two breasts received innervation from the third intercostal nerve and 2 from the fifth intercostal nerve. In half of the specimens, accessory innervation from the third and fifth intercostal nerves provided medial branches to the nipple . On the -Breast-reduction surgery has evolved considerably through the centuries. Prior to the late 1800s, breast amputation was the procedure performed to eliminate excessively large breasts. Theodore Galliard-Thomas was the first to advocate preservation of some part of the glandular tissue in the 1880s.15-However, many advocate that nipple sensation is paramount to patient satisfaction as well. As the nipple is perhaps the most sensitive area of the breast, it serves a significant role in a woman's sexual life. Erectile function and sensation are frequently necessary for both the woman herself and her partner. Consequently, loss of these functions has a detrimental impact on procedure outcome and patient satisfaction.22Previous studies have demonstrated that the majority of women feel that nipple-areola sensitivity as an important part of their sexual life, and of those women who underwent breast surgery and lost nipple sensation, the majority of women were significantly bothered by the result.-1,In general, patients undergoing breast-reduction surgery demonstrate high satisfaction due to the improvement in neck, shoulder, and back pain. However, loss of sensation to the nipple results in a poorer outcome. Anatomical analysis of the innervation of the NAC possibly helps guide the surgeon in avoiding damage to the nerves of the nipple. Our anatomical study demonstrated the innervation of the nipple to come laterally from 3 to 5 branches off of the fourth intercostal nerve. In addition, in some specimens, intercostal nerves 3 and 5 provided accessory innervation. These findings were consistent in both normal and hypertrophied breast specimens. Breast size did not alter the trajectory of the nerve to the NAC. Our results demonstrate that the distortion of breast tissue observed in obese patients and patients with macromastia does not alter the anatomical course of innervation to the NAC. Furthermore, the stretching of breast tissue observed with aging as a result of loss of support by the suspensory ligaments was not observed to alter anatomical course of the intercostal nerves to the nipple. The fourth intercostal nerve pierces the fascia of the fifth rib just lateral to the border of the pectoralis major muscle. The nerve travels to the NAC through the inferolateral position of NAC. Previous studies have demonstrated the lateral branch of fourth intercostal nerve to be the most reliable innervation to the NAC.1Lessons learned in the anatomy laboratory demonstrate that the plastic surgeon ought to avoid excessive resection and dissection in the inferolateral areas of the breast so as to preserve the innervation of the NAC. Breast size does not appear to alter the course of the intercostal nerves through the breast parenchyma. Consequently, we propose that the findings of this anatomical study can be extrapolated for guidance of breast surgery in patients with either normal or hypertrophied breast tissue. Avoidance of the inferolateral quadrant “unsafe zone” during reduction mammoplasty and other breast surgical procedures can prevent damage to the fourth intercostal nerve and accessory innervation by the third and fifth intercostal nerves. Such technique will reliably maintain the primary innervation of the nipple and maximize patient satisfaction.Frequently, the plastic surgeon must individualize therapy to the patient. A fixed procedure does not always apply to every clinical scenario. Adhering to principles of techniques and knowledge of anatomy frequently serves as a foundation for the reconstructive surgeon when planning procedures. This study can aid the novice and experienced surgeons in obtaining quality outcomes in terms of not only aesthetics but also function.Preserving nipple sensation is a valuable goal in breast surgery. Many women value nipple sensation as a significant component of sexuality and quality of life. The innervation of the nipple is predictable based on anatomical findings. An unsafe zone can reliably be avoided in the inferolateral area of the breast. Clinical application of these findings demonstrates the possibility to reliably maintain the nipple as an aesthetic and sensate unit.


The aim of this pictorial review is demonstrate the radiological appearances of adenocarcinoma with particular focus on more unusual appearances such as cystic adenocarcinoma.Non-small cell lung cancers account for almost 85% of all lung cancers and of these, adenocarcinoma is the most common. This entity has recently been reclassified to reflect increased understanding of the underlying pathology and thus it is crucial for radiologists to understand the new classification, the role of radiology in identifying pre-invasive lesions and the guidelines for management of subsolid nodules. We present the spectrum of imaging appearances from ground glass nodules (GGNs) to solid mass lesions with histopathological correlation.It is important for radiologists to recognise the spectrum of appearances of lung adenocarcinoma and follow appropriate algorithms for surveillance or further management.


We screened for evidence of HCV infection in healthy heterologous monogamous spouses of chronic HCV patients and studied the relation with various risk factors. A cross-sectional study of fifty healthy monogamous heterosexual spouses of HCV-positive index cases was carried out. All participants were HBV and HIV negative. The association with various risk factors was studied. Five spouses (10%) showed evidence of HCV infection. Two partners were positive for HCV antibody alone (4%) and 3 for antibody and HCV PCR (6%). No association was found between HCV infection and various sociodemographic parameters with the exception of older age categories. Intraspousal transmission of HCV may be an important source of spread of HCV infection. The reservoir of HCV-infected individuals in Egypt is sizable, and sexual transmission of HCV may contribute to the total burden of infection in Egypt. The extent to which HCV infection is associated with sexual exposure has been debated extensively. The 2008 Egyptian Demographic and Health Survey  estimateThere are some limitations in this study. An important limitation is failure to analyze the sequence of nucleotides of the HCV genome. The detection of homology in the nucleotide sequences would have been a strong evidence of a common source of infection but it would not clarify the direction of the infection, nor the responsible risk factors. The major limitation of our study may be the relatively small number of participants.Our study results raise the possibility that HCV is sexually transmitted between spouses in Egypt. This confirms the need to screen all people in the so-called high risk groups for HCV infection. Due to the ongoing high incidence of HCV in Egypt, further research is needed to identify the exact routes of transmission and the associated risk factors so that preventive measures can be instituted.


Postconditioning (PostC) is an exposure of the damaged organism to extreme factors of the mild intensity to mobilize endogenous protective mechanisms. In our laboratory method of PostC using three daily trials of mild hypobaric hypoxia (MHH) was developed. It has been found that such method of the PostC effectively prevents degeneration of the hippocampal and neocortical neurons in rats, subjected to severe hypoxia (SH). Present study has been aimed at examination of the impact of oxidative processes in the development of the neuroprotection acquired in the course of hypoxic PostC during first three days of reoxygenation after SH in rats. The levels of thiobarbituric acid reactive substances (TBARS) and Schiff bases (SB) were used as markers of lipid peroxidation. In addition, the intensity of the apoptotic DNA fragmentation has been studied. During the three days after the SH a sustained increase of SB in the rat hippocampus was observed . After the first PostC episode the SB levels decreased to 150% of the baseline. Subsequently this parameter did not differ significantly from the control values. TBARS showed accumulation on the first day following the SH but afterwards its levels dropped to 40% of control and did not recover then to normal values. In the PostC animals, the levels of TBARS after each of three PostC episodes did not differ from the control values. These facts indicate that the PostC MHH balances the activity of pro- and antioxidant systems in vulnerable brain regions and promotes the effective utilization of components damaged by peroxidation. Fragments ladder typical for cells undergone apoptosis was obtained by the electrophoretic separation of the total DNA, extracted from a rat brain after one, two and three days after the SH. In the PostC group, the DNA fragmentation was revealed only after the first PostC episode, demonstrating antiapoptotic action PostC MHH.


Electrical stimulation of the preoptic area (POA) interrupts the lordosis reflex, a combined contraction of back muscles, in response to male mounts and the major receptive component of sexual behavior in female rat in estrus, without interfering with the proceptive component of this behavior or solicitation. Axon-sparing POA lesions with an excitotoxin, on the other hand, enhance lordosis and diminish proceptivity. The POA effect on the reflex is mediated by its estrogen-sensitive projection to the ventral tegmental area (VTA) as shown by the behavioral effect of VTA stimulation as well as by the demonstration of an increased threshold for antidromic activation of POA neurons from the VTA in ovariectomized females treated with estradiol benzoate (EB). EB administration increases the antidromic activation threshold in ovariectomized females and neonatally castrated males, but not in neonatally androgenized females; the EB effect is limited to those that show lordosis in the presence of EB. EB causes behavioral disinhibition of lordosis through an inhibition of POA neurons with axons to the VTA, which eventually innervate medullospinal neurons innervating spinal motoneurons of the back muscle. The EB-induced change in the threshold or the axonal excitability may be a result of EB-dependent induction of BK channels. Recordings from freely moving female rats engaging in sexual interactions revealed separate subpopulations of POA neurons for the receptive and proceptive behaviors. Those POA neurons engaging in the control of proceptivity are EB-sensitive and project to the midbrain locomotor region (MLR). EB thus enhances lordosis by reducing excitatory neural impulses from the POA to the VTA. An augmentation of the POA effect to the MLR may culminate in an increased locomotion that embodies behavioral estrus in the female rat. Protracted electrical stimulation of the ventrolateral part of the ventromedial nucleus of the hypothalamus (VMN) at low frequencies has been found to cause lasting facilitation of the lordosis reflex in female rats in the estrus, a combined contraction of the longissimus and other back muscles caused by touch-pressure stimulation on the flank-perineal skin given by male partners , was needed for electrical stimulation of the VMN to facilitate lordosis in the ovariectomized female rats. EB-induced increase in the excitability of VMN neurons does not fully explain the requirement of systemic EB to stimulation-bound facilitation of lordosis, because VMN stimulation does not promote lordosis in the absence of systemic EB, even at stronger currents. The VMN contains estrogen receptor (ER) α positive projection neurons to the midbrain, but ERα positive neurons are also present in the preoptic area (POA), medial amygdala, midbrain central gray (CG), and lateral septum, to name but a few  is one of major projection targets of estrogen concentrating neurons in the POA . One of the targets of the VTA projection, the dorsal tegmentum, contains neurons associated with paradoxical sleep  and lateral vestibular nucleus (LVN) are the origins of the ipsilateral reticulospinal and vestibulospinal tract, respectively, which innervate spinal motoneurons responsible for the induction of the lordosis. Lesion studies have suggested that the contribution of these tracts is not dependent upon the integrity of the other, and that the magnitude of the lordosis deficit is instead correlated with amount of giant cell loss in NGc and Deiters cell loss in the LVN (Modianos and Pfaff, Electrical stimulation of the NGc in urethane-anesthetized female rats induced antidromic activation in neurons in the CG. Antidromically driven cells were in all parts of the CG and adjacent mesencephalic reticular field except within the inner ring of the CG that surrounds the aqueduct.As with the antidromic potentials induced in the VTA in response to CG stimulation, POA stimulation reduced the rate of successful propagation of NGc-induced antidromic potentials into the soma, whereas VMN stimulation increased the rate. Thus, the pattern of descending effects originating in the EB-sensitive POA and VMN on these CG neurons is required for their control of the lordosis reflex, via the regulation of the activity of medullospinal neuron that govern the contraction of back muscles responsible for the induction of the lordosis reflex.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.


The paralysis of the external branch of spinal nerve is very rare. It manifests clinically by a weakness and abnormal morphology of the shoulder. We must think about it in front of any simple surgery of the cervical region. We report the case of a 20 year old patient, who consulted several doctors for pain and progressive weakness of the left shoulder appeared a few days after resumption of a keloid scar complicating surgical excision of a cervical lipoma operated some months earlier. Physical examination revealed strength of the left shoulder listed on 3 without articular limitation, atrophy of the trapezius muscle with ipsilateral asymmetry and fall of the left shoulder. A lesion of spinal nerve was suspected and an EMG was executed. The EMG objectified a partial lesion of the left spinal Nerve. The patient was sent in Plastic and Reconstructive surgery for nerve repair. The achievement of the external branch of spinal nerve is manifested by pain and weakness in the shoulder triggered by the anteflexion movements of the upper limb. The most usual cause is cervical lymph node biopsy. In our case, the spinal nerve lesion occurred while the resumption in keloid skin scar. This is explained by the very superficial location of the Spinal Nerve.


GTPases of the RAB family are key regulators of multiple steps of membrane trafficking. Several members of the RAB GTPase family have been implicated in mitotic progression. In this review, we will first focus on the function of endosome-associated RAB GTPases reported in early steps of mitosis, spindle pole maturation, and during cytokinesis. Second, we will discuss the role of Golgi-associated RAB GTPases at the metaphase/anaphase transition and during cytokinesis. In mammalian cells, GTPases of the RAB family are key regulators of multiple steps of membrane traffic. RAB GTPases play a central role in the formation of transport carriers from a donor membrane, movement of these carriers along cytoskeletal tracks and finally anchoring/fusion to the correct acceptor membrane , the Drosophila homolog of the nuclear mitotic apparatus protein (NuMA), which is known to be important for spindle formation and maintenance in mammalian cells. RAB5 is required for the disassembly of the nuclear envelope at mitotic entry and the accumulation of Mud at the spindle poles . The identification of specific RAB24 effectors involved in early stages of mitosis would be critical to determine the precise role of this protein at the molecular level.cdc2  membranes in interphase and is a key regulator of Golgi homeostasis , the Institut Curie and the Fondation ARC pour la Recherche Sur le Cancer.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.


Congenital ocular colobomas are the result of a failure in closure of the embryonal fissure. They are important causes of childhood visual impairment and blindness. A 22 year old female patient with no particular history complaining of blurred vision of left eye; Visual acuity of the left eye is limited to counting finger; examination of the anterior segment was unremarkable. At fundoscopy, a large coloboma involving the optic disc and the adjacent retina. Examination of the right eye was normal. General examination was unremarkable including the neurological examination. Ocular coloboma can be seen in isolation and in an impressive number of multisystem syndromes. Systemic associations include the CHARGE syndrome . Visual acuity can range from normal to severly impaired. In general, severity of disease can be linked to the temporalexpression of the gene, but this is modified by factors such as tissue specificity of gene expression and genetic redundancy.


The wide spread and high rate of gene exchange and loss in the prokaryotic world translate into “network genomics”. The rates of gene gain and loss are comparable with the rate of point mutations but are substantially greater than the duplication rate. Thus, evolution of prokaryotes is primarily shaped by gene gain and loss. These processes are essential to prevent mutational meltdown of microbial populations by stopping Muller’s ratchet and appear to trigger emergence of major novel clades by opening up new ecological niches. At least some bacteria and archaea seem to have evolved dedicated devices for gene transfer. Despite the dominance of gene gain and loss, evolution of genes is intrinsically tree-like. The significant coherence between the topologies of numerous gene trees, particularly those for (nearly) universal genes, is compatible with the concept of a statistical tree of life, which forms the framework for reconstruction of the evolutionary processes in the prokaryotic world. When in the late 1970s and early 1980s, Carl Woese and his colleagues constructed phylogenetic trees from 16S RNA sequence alignments, the resulting phylogenetic trees were thought to have solved the problem of microbial evolution Woese . Indeed,The recent paradigm shift in the study of  genome evolution is most often discussed in terms of horizontal  gene transfer (HGT). Yet, the very concept of HGT is conditioned on the existence of a vertical, tree-like evolutionary standard (often referred to as the “tree of life”)  remains an open question. The answer hinges on the existence of pronounced, coherent trends in the “phylogenetic forest,” i.e., the entirety of individual gene trees. More specifically, does a tree of a universal gene reflects solely the evolutionary history of that gene or does it carry information on the evolution of other genes, and if so, how many genes and how much information? In a phylogenomic study that was specifically designed to address this question, my colleagues and I performed an exhaustive comparison of the topologies of thousands of phylogenetic trees of conserved eukaryotic genes  often substantially differ in their gene repertoires  has revealed a striking picture of genomes in turmoil  Darwin  but rathBacillus anthracis  Bushman . NumerouAt present, perhaps, the best showcase for dedicated vehicles of HGT appears to be the gene transfer agents (GTAs). The GTAs are defective prophages that form virus particles in which, however, they package apparently random fragments of the bacterial chromosome, rather than the phage genome  and are key contributors to innovation including origin of new clades with novel lifestyles. The contribution of gene gain and loss in microbial evolution is ostensibly greater than the contribution of point mutations. The strongest indication of the importance of massive gene transfer for the emergence of major clades comes from comparative genomics of archaea where influx of bacterial genes seems to have coincided with the origin of multiple phyla. The eukaryotes apparently evolved via a similar scenario, with the crucial distinction of the survival of the bacterial gene donor in the form of an endosymbiont. Bacteria and archaea appear to have evolved multiple dedicated devices for gene transfer.Not withstanding the ubiquity and essentiality of gene transfer, tree-like processes are intrinsic to the processes of replication and cell division. Moreover, the substantial coherence between the topologies of numerous gene trees, particularly those for (nearly) universal genes, is compatible with the concept of a statistical tree of life, a central vertical trend in genome evolution. The statistical tree of life is a natural framework for the reconstruction of processes of gene gain and loss that shape the evolution of the prokaryotic world.


We report the case of 55 year old man hospitalized in intensive care unit following a complication of his surgery for acoustic neuroma, for which he was intubated. During his hospitalization, he presented a bilateral exposure keratitis complicated by an abscess and corneal perforation. The ocular surface is protected by the tear film, the blinking of eyelids and the lid closure. The tear film provides lubrication of the cornea and also contains antimicrobial substances. Use of muscle relaxants and sedation in patients on ventilator contributes to inadequate lid closure by decreasing the tonic contraction of ocular muscles. The constant exposure of the ocular surface put the ICU patients at high risk of developing exposure keratopathy. This condition predisposes to microbial keratitis, which may lead to corneal perforation and visual loss. Previous studies have reported that about 40% of patients develop exposure keratopathy during their stay in the ICU. The use of ocular lubricants and securing tape over the eyelids in intubated patients can prevented it. Also, the use of swimming goggles and regular moistening of eyelids providing a moisture chamber could be more effective.


Caulerpa cylindracea is a non-autochthonous and invasive species that is severely affecting the native communities in the Mediterranean Sea. Recent researches show that the native edible fish Diplodus sargus actively feeds on this alga and cellular and physiological alterations have been related to the novel alimentary habits. The complex effects of such a trophic exposure to the invasive pest are still poorly understood. Here we report on the metabolic profiles of plasma from D. sargus individuals exposed to C. cylindracea along the southern Italian coast, using 1H NMR spectroscopy and multivariate analysis . Fish were sampled in two seasonal periods from three different locations, each characterized by a different degree of algal abundance. The levels of the algal bisindole alkaloid caulerpin, which is accumulated in the fish tissues, was used as an indicator of the trophic exposure to the seaweed and related to the plasma metabolic profiles. The profiles appeared clearly influenced by the sampling period beside the content of caulerpin, while the analyses also supported a moderate alteration of lipid and choline metabolism related to the Caulerpa-based diet.The green alga  Caulerpa cylindracea Sonder, previously identified as Caulerpa racemosa var. cylindracea (Sonder), due to the remarkable change induced in the invaded area. In the last decades, the invasion of the non-native C. cylindracea was increasingly at the center of hot discussions for both scientific and general public communities, because of its rapid and broad spread, which is inducing profound changes in the bottom of the sea landscape . R2 is a cross validation parameter and defined as the proportion of variance in the data explained by the models and indicates goodness of fit; Q2 is defined as the proportion of variance in the data predictable by the model and indicates predictability, which is extracted according to the internal cross-validation default method of SIMCA-P software; p[CV-ANOVA] provides a p-value indicating the level of significance of group separation in OPLS analyses [The orthogonal partial least squares discriminant technique (OPLS-DA) is the most recently used for the discrimination of samples with different characteristics as it has been shown in several recent studies of metabolomics . OPLS-DAanalyses ,47,48,49analyses . For eacD. sargus might be the effect either of a single dietary compound contained by C. cylindracea or of a combination of bioactive compounds acting in synchrony. While the assessment of the relative contribution of each chemical component of the alga to the observed metabolic alteration needs further interdisciplinary research, the much broader approach that characterizes the present report provides a useful tool both to measure the alterations that are occurring in the fish as a consequence of its alimentary behavior and for better management of marine biological invasion in the Mediterranean Sea. Overall, this study set the stage for the rapid assessment of the metabolic status of D. sargus feeding on C. cylindracea providing new methodological insights for the understanding of the complex effects affecting natural systems as results of biological invasions.The present work represents the first study where a metabolomic approach has been used to analyze the blood plasma of fish trophically exposed to an invasive pest. The observed variation of the metabolic profiles of the plasma of


In recent years the human microbiome has become a growing area of research and it is becoming clear that the microbiome of humans plays an important role for human health. Extensive research is now going into cataloging and annotating the functional role of the human microbiome. The ability to explore and describe the microbiome of any species has become possible due to new methods for sequencing. These techniques allow comprehensive surveys of the composition of the microbiome of nonmodel organisms of which relatively little is known. Some attention has been paid to the microbiome of insect species including important vectors of pathogens of human and veterinary importance, agricultural pests, and model species. Together these studies suggest that the microbiome of insects is highly dependent on the environment, species, and populations and affects the fitness of species. These fitness effects can have important implications for the conservation and management of species and populations. Further, these results are important for our understanding of invasion of nonnative species, responses to pathogens, and responses to chemicals and global climate change in the present and future.  The microbiomes, including bacteria, fungi, and viruses, live within and upon all organisms and have become a growing area of research. With the advances of new technologies it is now possible to entangle complex microbial communities found across animal kingdoms.Recent advances in molecular biology have provided new possibilities to investigate complex microbial communities and it has become clear that the vast majority of bacteria living in/on other animals cannot be cultured. It is now commonly accepted that at least 80% of the total bacterial species in the human gut cannot yet be cultured , 2. de novo clustering of specific regions of sequences. Functional profiling of metagenomics is more challenging since major parts of the metagenomic data remain insufficiently characterized and frequently samples are contaminated by host DNA or traces from the diet. Compared to both culture-dependent and more traditional molecular approaches such as sequencing of clone libraries and DGGE, amplicon sequencing approaches allow a more in depth analysis of the complete microbiome and are less restricted to the number of samples to be investigated. For further technical details see, for example, Caporaso et al. [High-throughput DNA sequencing approaches provide an attractive and cost-effective approach to investigate the composition and functions of the host microbiome. The culture-independent analysis of the host microbiome can be obtained by either metagenomic approaches or amplicon sequencing using specific marker genes. Amplicon sequencing provides a targeted version of metagenomics with a specific genetic region shared by the community members of interest. The amplified fragments derive from universal primers and are usually assumed to produce sequence read abundance that reflects the genetic diversity in the studied sample and hence sequence read abundance should reflect the genetic diversity in the studied sample. The amplified fragment typically contains phylogenetic or functional information, such as the 16S ribosomal RNA gene. 16S rRNA gene sequences are well studied and provide excellent tools for microbial community analysis , but otho et al. .The Human Microbiome Project (HMP)  was initIn recent years the microbiome of a number of vertebrate nonhuman species has been sequenced including livestock , 13 and Insects are the most diverse and abundant groups of animals on earth  and haveThe microbiome of other groups of invertebrates has also been established although for a limited number of species. Studies have compared the microbiome of different species of marine invertebrates with or without photosynthetic symbionts including five families of marine invertebrates . Marine The microbes of soil invertebrates have received some attention. The gut microbes of soil animals play an indispensable role in the digestion of food and are of ecological importance in the global carbon cycle. Recently, research reported that like that of terrestrial insects some soil invertebrates such as collembolans, earthworms, and nematodes contain a rich microbiome and putative symbionts –30. FurtTo begin with all microorganisms were seen as pathogens causing infectious diseases to the host. The host immune system of eukaryotes was built to eliminate these intruders, but at the same time tolerating its own molecules. However, we now know that the association between eukaryotic hosts and the microorganisms is far more complex. With the advances in molecular biology, such as next generation sequencing, it is now possible more specifically to address the association between a host and its microbiome. In animals the association between the host and its microbiome can take many forms and includes symbiotic and pathogenic associations . SymbiotThe number of studies addressing the role of the microbiome on animal health is limited and almost entirely restricted to human studies. However, a large number of studies have addressed the role of single bacterial symbionts on animal fitness, where especially insect species have received much attention –39. Ther Drosophila melanogaster provide a promising model system to address some of these issues and for this species it is possible to rear axenic flies. Next generation sequencing approaches can provide an in-depth analysis of the functional roles of specific groups of bacteria and the entire microbiome on the fitness of the host. Results on D. melanogaster have shown how the microbiota affects developmental rate and changes metabolic rates and carbohydrate allocation under laboratory conditions [Some invertebrates lack the complexity and diversity of associations with microorganisms. Such insect model systems allow investigations that aim to understand the contribution of specific bacteria and the entire microbiome towards host physiological processes. For example,nditions . Similarnditions  and thatnditions . Hypothenditions .Recent studies have highlighted the importance of the microbiome not only in shaping the immune system but also in the context of host pathogen transmission processes . AnThe recent interest in the importance of the microbiome on tolerance to environmental perturbations , 39 has Changes in the microbial community have been shown to affect fitness of humans and other species as described above. However, the implications of changes in the microbiome for animal conservation have only been addressed in a limited number of studies even though the implications are many.Several studies using next generation sequencing approaches have addressed the comparison of the microbiome of laboratory populations or individuals kept in captivity with that of wild animals , 34, 44 2S. This strongly suggests that habitat fragmentation will affect not only the microbiome of the host but also host fitness.It is essential that we address the importance of the microbiome of other species rather than humans and the impact it has on their health status. For larger species such as primates this can be difficult and often only correlative evidence exists or can be achieved through a functional annotation of the microbiome , 17. ForSimilarly, keeping animals under captivity and maintaining breeding populations are likely to affect animal microbiomes. This is often undertaken in order to protect or increase abundance of rare species aiming at releasing species into the wild again. However, if the microbiomes of the individuals being released are affected, this is likely also to affect fitness compared to that of wild individuals and will subsequently reduce the probability of successful reintroduction into the wild. This is supported by studies on humans and mice where results have shown that obesity causes shifts in gut microbiome composition , 56. SimIt has been suggested that engineering microbiomes can be used to improve plant and animal health . How thiInbreeding has been suggested to affect the demography and persistence of natural populations and play an important role in conservation biology . Recent Microbiome analysis of wild populations has shown that the microbiome is dependent on the surrounding habitats as discussed above. This information might be used as a sensitive screening tool to establish populations affected by habitat fragmentation  and possThe microbiome can provide protection of the host from pathogens either through stimulation of the immune system or through competitive exclusion. However, when animals are compromised or exposed to unfavorable environmental conditions the symbionts themselves can act as opportunistic pathogens , 27 or n Achatina fulica results showed a highly diverse microbiome and functional analysis revealed a variety of microbial genes encoding enzymes, which is in agreement with the wide-ranging diet of this species [ Aphis glycines from populations of native and invasive regions showed no differences [Differences in microbiomes may affect invasions. For example, the interactions between native and nonnative of closely related species may be affected by the transmission of bacteria. This also appears to be associated with another emerging type of invasion, the transmission of infectious diseases of wild animals to humans . Such tr species . Interesferences . Future ferences .Recent advances in molecular biology have given new possibilities to establish complex microbial communities and it has become clear that the vast majority of bacteria living in/on other animals cannot be cultured. One of the most common methods to describe complex microbiomes is the sequencing of the bacterial marker 16S ribosomal RNA (16S rRNA) genes through amplicon sequencing. Studies have shown that the microbiome plays a major role in human health, and in recent years the microbiomes of an increasing number of nonhuman species have been investigated. However, the number of studies addressing the role of the microbiome on animal health still remains limited. Some studies have discussed the role of the microbiome on nutritional supplementation, tolerance to environmental perturbations, and maintenance and development of the immune system. Thus the implications of changes in the microbiome for animal conservation are many although a limited number of studies have addressed this. We suggest that a number of factors relevant in conservation biology could affect the microbiome of animals including inbreeding, habitat fragmentation, change in climate, and effect of keeping animals in captivity. Changes in these factors are thus also likely to affect the fitness of the host both directly and indirectly. With the development of next generation sequencing and functional analysis of microbiomes it has become possible more specifically to test direct hypothesis on the importance of the microbiome in conservation biology.


The capability of improving performance on visual tasks with practice has been a matter of intense investigation during the last 40 years   in patients with vision loss (hemianopia or quadrantanopia) can be also obtained with the so-called vision restoration therapy, an individualized program providing stimulation at the border of the dysfunctional visual field (Poggel et al., Finally, perceptual learning could be useful even for blind people. Blindness often produces an impaired spatial representation in other sensory domains (e.g., Gori et al., To sum up the findings of the present Research Topic, the studies collected here provide the frontline of behavioral and brain stimulation-coupled treatments of a heterogeneous ensemble of visual dysfunctions. Future studies are needed to define the best combination of approaches in order to improve vision with the shortest and most efficacious training, increasing patients' compliance and tailoring the training specifically for each patients' needs.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 Response: The letter by Rebelo et al. (Concerning the quality of the standard clinical diagnosis, both thin blood film analysis and rapid diagnostic test results were obtained in a certified US clinical laboratory and returned consistent data. The lack of re-evaluation of the patient and the diagnostic timing are indeed limitations but were caused by the clinical restrictions. Our goal in the 2015 article (The criticism of Rebelo et al. might have been fueled by their own limited detection of hemozoin with flow cytometry and microscopy (In conclusion, we agree with the need for optimization of the technology and additional testing. We are currently developing and testing our technology in a malaria-endemic country. Nevertheless, the letter by Rebello et al. does not alter the fact that our novel noninvasive malaria diagnostic technology worked in a human.


With the increasing prevalence of autism spectrum disorders (ASD), the pace of research aimed at understanding the neurobiology of this complex neurodevelopmental disorder has accelerated. Neuroimaging and postmortem studies have provided evidence for disruptions in functional and structural connectivity in the brains of individuals with ASD , which detect correlations of the blood oxygen level dependent (BOLD) signal, provided first findings  and EEG  enable the measurement of functional connectivity with high temporal resolution and medium level spatial resolution. An additional advantage of these techniques is that they are not susceptible to motion artifacts that would confound connectivity results in the same way as fcMRI. Using EEG, Coben and colleagues  propose While functional connectivity studies of autism continue to reveal nuanced patterns of hypo- and hyper-connectivity associated with the disorder, studies of white matter connectivity using diffusion tensor imaging (DTI) and tractography provide complementary metrics. However, only few studies to date have combined functional and anatomical connectivity findings   are compromised in children with ASD, suggesting that in vivo diffusion weighted MRI can generate complementary evidence in support of cellular findings from the postmortem literature.In a comprehensive review, McFadden and Minshew  examine Returning to the basic questions regarding brain network connectivity in ASD raised in the initial announcement, the contributions to this Research Topic underline the need for differentiated interpretations of functional connectivity findings that consider the specificity of networks and cognitive states under investigation and the exact preprocessing pipelines and analysis tools implemented. The need for electrophysiological studies that provide a window onto the dynamic aspects of network connectivity is further emphasized by several contributions, as is the need for multimodal investigations that combine assays of functional and anatomical connectivity. The developmental trajectory of brain connectivity and the classification potential of different connectivity measures are important topics that are investigated by different studies. Finally, several articles contribute to a better understanding of the links between cellular abnormalities in autistic cortex  and disturbances in network connectivity.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.


Furthermore, the ability to isolate and expand from patients various types of muscle progenitor cells capable of committing to the myogenic lineage provides the opportunity to establish cell lines that can be used for transplantation following ex vivo manipulation and expansion. The purpose of this article is to provide a perspective on approaches aimed at correcting the genetic defect using gene editing strategies and currently under development for the treatment of Duchenne muscular dystrophy (DMD), the most sever of the neuromuscular disorders. Emphasis will be placed on describing the potential of using the patient own stem cell as source of transplantation and the challenges that gene editing technologies face in the field of regenerative biology.The progressive loss of muscle mass characteristic of many muscular dystrophies impairs the efficacy of most of the gene and molecular therapies currently being pursued for the treatment of those disorders. It is becoming increasingly evident that a therapeutic application, to be effective, needs to target not only mature myofibers, but also muscle progenitors cells or muscle stem cells able to form new muscle tissue and to restore myofibers lost as the result of the diseases or during normal homeostasis so as to guarantee effective and lost lasting effects. Correction of the genetic defect using oligodeoxynucleotides (ODNs) or engineered nucleases holds great potential for the treatment of many of the musculoskeletal disorders. The encouraging results obtained by studying  The discovery of dystrophin as the gene responsible for Duchenne muscular Dystrophy (DMD) has enabled researchers to identify several of the genes linked directly or indirectly to dystrophin and to correlate defects in those genes to many of the different forms of muscular dystrophies  are probably the most studied. Since their initial identification Mauro,  studies mdx mice that have been used as models for DMD  as therapeutic vectors. First among those, the success obtained using homologous recombination (HR) technologies, an approach that has been employed extensively to generate animal models to study disease mechanisms  made of 68 residues which were originally given the name of chimeraplasts. The vector contained both RNA and DNA residues complementary to the region of the genomic DNA targeted for repair and flanked by 2′-O-methylated RNA residues which were used to increase resistance to RNase H activity Figure . To incrmdx mouse model for DMD  were as efficient as chODNs in directing the gene correction process  and non-homologous end-joining (NHEJ) mechanisms as one of the mechanisms responsible for the correction induced at the genomic level through evidences that demonstrate that a portion of the ODN becomes integral part of the genomic DNA  gene, which encodes SMN. Loss of SMN protein is thought to be responsible for the progressive loss of motor neurons which is paralleled by the progressive muscle wasting characteristic of SMA patients . SMA is an autosomal recessive genetic disorder caused by a genetic defect in the survival motor neuron 1  patients Tang, .There are three major families of engineered nucleases being employed in gene editing approaches: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and engineered meganuclease (MNs) Figure . A fourtin vitro, the need to use viral or plasmid vectors to ensure high levels of expression of nucleases in the nucleus required to achieve an effect and the risk of off-target mutations that have been associated with their use (as described in more detail below). Nonetheless, the results reported to date have clearly proven the validity of using engineered nucleases for therapeutic purposes.The mechanisms of action of nucleases are common to all system and rely on their ability to create a double-strand break (DSB) which is either repaired by NHEJ, or, in the presence of a donor DNA, can be repaired by HR Figure . SeveralFokI restriction endonuclease  and have been used to induce targeted deletions of exon 51 to restore the coding reading frame of the dystrophin gene  protein of the HIV (Frankel and Pabo, The main drawback of directly delivering systemically ODNs or nucleases into muscles is represented by the inability to control the repair process once the therapeutic agent reaches it targeted stem cell. As a result, issues of toxicity, off-target effects, and low frequencies of gene repair may limit the beneficial effects achieved. Studies aimed at further refine the efficacy and specificity of the repair process mediated by ODNs or nucleases is likely to have important implications for the success of gene editing approaches.ex vivo or systemic administration of gene editing tools in situ, other factors may hamper the efficacy and stability of the repair process. Considerations should be given to possible immune response toward the protein being restored as the result of the therapeutic application. Preconditioning of patients using immunosuppressive reagent as well as administration of chemotherapeutic drugs that are toxic to proliferating cells may be necessary to ensure efficient cell engraftment and rapid clonogenic growth of the transplanted cells.Independently from the approach used to correct the genetic defect and whether restoration of the missing protein is achieved through delivery of genetically modified cells The past decade or so has seen an exponential growth in the development of therapeutic applications for muscle disorders specifically designed to target stem cells. Clinical trials are currently undergoing to test the feasibility and efficacy of restoring dystrophin expression in skeletal muscles of DMD patients following systemic administration of mesoangioblasts highlighting the fact that the field is rapidly advancing toward clinical applications for this disease. Approaches aimed at using the patient own stem cells as source for the transplantation procedures has clear advantages over those using heterologous sources of stem cells. As such, it is likely that gene editing approaches will become integral part of future applications to treat muscle disorders using genetically modified cells.ex vivo will require to refine culturing techniques to ensure that, once explanted, muscle stem cells can be efficiently propagated in vitro while maintaining maximal regenerative potential. Furthermore, a better understanding of the mechanisms that regulate stem-cell properties will help redefine and select a specific population of cells that is safe to use in patients without compromising the beneficial effects that can be achieved using the approach. Along the same line, the development of new delivery systems or vectors capable of targeting muscle stem cells in situ will be a key to the optimization of gene editing strategies. Ultimately, a key component of preclinical and clinical studies will remain the efficacy and safety of the approach being employed. The trials currently under way for muscle disorders as well as other genetic diseases and the clinical trials that are planned to start within the next few years will be instrumental in determining the key parameters necessary to achieve sustained effects in patients and to ensure the safety and efficacy of the approach being employed. Despite the early stages of gene editing approaches aimed at targeting and correcting stem cells for the treatment of muscle disorders, the results obtained to date are encouraging. Collaborations among different laboratories interested in pursuing these technologies for the treatment of inherited genetic disease affecting muscle could result in advancing gene editing strategies more rapidly and more efficiently into the clinic.Additional parameters will have to be taken into account and defined before these approaches can enter into the clinic. For instance, gene editing strategies targeting stem cells 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.