T0 and T30min SDF allowed identification of convoluted tubules with lumen and peritubular microvessels without alterations. The architectural feature of the kidney was of convoluted tubules surrounded by peritubular microvessels forming a homogeneous aspect that merges the sequence of a microvessel followed by a convoluted tubule to the fullest extent. From T1h, the outlining of tubules became blurred by their enlargement and the onset of the compression of tubular lumen and peritubular microvessels, suggesting an obstructive phenomenon by cellular edema. This focal occurrence in T1h became increasingly widespread at T6 changing the homogeneous organization of the cortex architecture.These findings suggested that the process involved in the genesis of renal failure in sepsis could be due to the cyclical repetition of the event: peritubular microcirculatory dysfunction-cytopathic hypoxia of the tubular wall epithelia-edema of the tubular cells-compression of both peritubular microvessel and tubular lumen-exacerbation of microvessel and nephron dysfunction. This hypothesis raised on visual analysis of SDF images could be confirmed by histology which showed a progressive swelling of the epithelial cells of convoluted tubules and reduction of tubular lumen and peritubular vessels with the progression of sepsis. In addition, epithelial cells showed membrane injury, pyknosis and necrosis.The genesis of acute renal failure in severe sepsis appears to depend on the repetitive cycle of peritubular microcirculatory dysfunction and subsequent tubular injury that exacerbates the progression of the renal injury, thus suggesting the conjoined participation of microvessels and their adjacent cells in the genesis of the solid organ dysfunction.


Nonvisualization of the internal carotid artery (ICA) on cross-sectional imaging studies can be due to congenital (dysgenesis of the ICA) or acquired (complete occlusion of ICA) causes. We report two cases, one with absent carotid canal on bone window setting of computed tomography (CT) suggestive of congenital cause and the other with normal carotid canal, suggesting acquired cause. Development of aortic arches with six pathways of collateral circulation in brain is also discussed. Nonvisualization of the internal carotid artery (ICA) on cross-sectional imaging studies can be due to dysgenesis of the ICA or due to complete occlusion. In both the cases the clinical possibility ranges from that of an asymptomatic patient to one having transient ischemic attack (TIA) and fatal stroke .The aorta develops at around 21st day of embryonic life. Primitive aorta consists of ventral and dorsal segments that are continuous through the first aortic arch. The two ventral aortae fuse to form the aortic sac. The dorsal aortae fuse to form the midline descending aorta. Six paired aortic arches  develop between the ventral and dorsal aortae .(i) First Arch. It contributes to the formation of the maxillary and external carotid arteries.(ii) Second Arch. It contributes to the formation of the stapedial arteries.(iii) Third Arch (Also Known as Carotid Arch). Proximal segments of the third pair form the common carotid arteries. The distal portions contribute to the formation of the internal carotid arteries along with segments of the dorsal aortae. The ECA arises as a sprout from the CCA  and also receives contribution from the first and second aortic arches.(iv) Fourth Arch. The left fourth arch forms the aortic arch. The proximal right subclavian artery is formed from the right fourth arch whereas the distal right subclavian artery is derived from a portion of the right dorsal aorta and the right seventh intersegmental artery.(v) Fifth Arch. It forms the rudimentary vessels that regress early.(vi) Sixth Arch. The left sixth arch contributes to the formation of the main and left pulmonary arteries and ductus arteriosus. The right sixth arch contributes to the formation of the right pulmonary artery.Initially, the aortic arches are connected to the dorsal aorta. As development progresses, the connection of the first and second arches to the dorsal aorta regresses and they contribute to the formation of the ECA. Persistence of the connection with the dorsal aorta may present as transcranial ECA-ICA anastomosis. Through this anastomosis the internal maxillary artery and middle meningeal arteries can supply the distal ICA in cases of hypoplasia of the ICA (known as rete mirabile in the region of the cavernous sinus) .Two longitudinal vascular plexuses dorsal to the third and fourth arches form the basilar artery during the 5th week of intrauterine development. Multiple primitive vessels connect the developing basilar artery and the ICA. All of these vessels involute except for the most cranial one, which persists as the posterior communicating artery .We hereby present two cases, which presented to our hospital with symptoms of TIA and, on evaluation with computed tomography angiography (CTA) of carotid vessels, diagnosis of nonvisualization of the ICA was made.A 64-year-old male, hypertensive for 20 years (on medication), presented with transient right-sided weakness and numbness. The patient underwent CTA imaging of the carotid vessels and circle of Willis, which showed absent ICA on left side and collateral flow to the left hemisphere through the circle of Willis. Absence of the left carotid canal was also discovered at bone window setting of computed tomography (CT), which confirmed the congenital nature of the nonvisualization of left ICA. Maximum intensity projection (MIP) reconstruction revealed that the left middle cerebral artery was fed through a dilated left anterior cerebral artery supplied by the anterior communicating artery .There was no associated vascular malformation or any transcranial ECA-ICA anastomosis or any embryonic persistent artery. The patient's symptoms resolved spontaneously and were attributed to either transient ischemic attacks or migraine headaches. No thromboembolic source was identified.A 59-year-old male, hypertensive for 5 years (on medication), presented with transient left-sided weakness and numbness. The patient underwent CTA imaging of the carotid vessels and circle of Willis, which showed nonvisualization of ICA on right side and collateral flow to the right hemisphere through the circle of Willis. Right carotid canal was normal at CTA, which confirmed the acquired nature of the nonvisualization of right ICA. A diagnosis of complete occlusion of the right ICA along its whole course was made .Our first case was diagnosed as agenesis of the left ICA with absent left carotid canal assessed on bone window setting of CT. Dysgenesis of the ICA includes agenesis, aplasia, and hypoplasia. Complete failure of development of the ICA leads to agenesis whereas hypoplasia refers to a very small caliber ICA after the development started and the term aplasia is used when only vestiges of the ICA are present . DysgeneAgenesis of the ICA occurs before 24 mm stage of the embryonic growth .Lie reported the first case of agenesis of the ICA and defined agenesis as the total absence of the entire length of the artery. According to Lie, there are six pathways (types A to F) of collateral circulation associated with agenesis of the ICA. In type A, there is unilateral absence of the ICA with collateral circulation to the ipsilateral anterior cerebral artery and middle cerebral artery through anterior communicating artery and hypertrophic posterior communicating artery, respectively. Unilateral absence of ICA with collateral flow to the ipsilateral anterior cerebral artery and middle cerebral artery across a patent anterior communicating artery comes under type B as in our cases. In type C, bilateral ICA agenesis is associated with patent anastomoses between carotid and vertebra-basilar system. Unilateral agenesis of the cervical portions of the ICA with collateral from an intercavernous communication from the cavernous segment of contralateral ICA comes under type D. In types E and F, there is bilateral ICA hypoplasia with bilateral posterior communicating arteries supplying the middle cerebral arteries in type E and the hypoplastic ICA getting flow from bilateral rete mirabile in type F. Retia mirabilia are transcranial anastomoses between the branches of ICA and external carotid artery system .Congenital absence of ICA is often associated with intracerebral aneurysm formation. The carotid canals in petrous bone form secondary to the presence of the embryonic ICA. Absence or hypoplasia of embryonic ICA leads to hypoplasia of the carotid canal. Absence of carotid canal on a computed tomography scan should suggest a congenital ICA abnormality and suggest an extensive search for associated intracranial vascular malformations .In patients with agenesis of the ICA, cross-sectional imaging techniques are currently the modality of choice . Our secDysgenesis of the ICA should be differentiated from complete occlusion especially when unilateral. Complete occlusion of the ICA is more likely due to severe atherosclerosis, chronic dissection, or fibromuscular dysplasias .In patients with occlusion of the ICA, postocclusive diminished arterial pressure causes collaterals to develop via the circle of Willis which is important to prevent stroke. The anterior communicating artery and the posterior communicating artery are the collateral channels through which the circle of Willis can supply blood flow to the affected side of the brain. When collateral compensation mechanisms fall short, low-flow infarcts in border zone areas of the brain may develop .Cote et al. evaluated forty-seven patients with ICA occlusion who were asymptomatic or had only mild neurological deficit and prospectively followed them up for an average of 34.4 months. During that period of time, they found that 51% of patients experienced TIAs in the territory of the occluded artery and 23.5% of patients suffered a cerebral infarction .Agenesis of ICA is mostly asymptomatic, being identified only incidentally. The finding of absent carotid canal on routine CT should suggest the diagnosis. It is important in the management of cerebrovascular accidents as the single ICA supplies both the cerebral hemispheres. ICA dysgenesis has to be distinguished from acquired stenosis as the management of the two conditions is different.


It is involved in a wide range of cellular processes that require independent regulation. However, our understanding of how this single second messenger achieves specific modulation of the signaling pathways involved remains incomplete. The subcellular compartmentalization and temporal regulation of cAMP signals have recently been identified as important coding strategies leading to specificity. Dynamic interactions of this cyclic nucleotide with other second messenger including calcium and cGMP are critically involved in the regulation of spatiotemporal control of cAMP. Recent technical improvements of fluorescent sensors facilitate cAMP monitoring, whereas optogenetic tools permit spatial and temporal control of cAMP manipulations, all of which enabled the direct investigation of spatiotemporal characteristics of cAMP modulation in developing neurons. Focusing on neuronal polarization, neurotransmitter specification, axon guidance, and refinement of neuronal connectivity, we summarize herein the recent advances in understanding the features of cAMP signals and their dynamic interactions with calcium and cGMP involved in shaping the nervous system. The development of nervous system connectivity is a multistage process that requires neuron specification and polarization, axon guidance and targeting, as well as refinement of synaptic connections. All stages require second messenger cascades involving cAMP. This cyclic nucleotide is required for the control of transcription . The diversity of regulation and localization of ACs (10 isoforms) and PDEs (more than 40 isoforms) offers a wide range of combination to shape specific signals in response to distinct stimuli  are critical for this process. AKAP isoforms are targeted to distinct subcellular compartments and modulate the spatial spread of cAMP, binding at least some isoform of PDEs and ACs  and choline acetyltransferase transporters (ChAT). In contrast, overexpression of the voltage gated sodium channel Nav1.2 increases calcium spike frequency and the number of the inhibitory GABAergic and glycinergic spinal neurons at the expense of VGluT and ChAT-expressing neurons, demonstrating that pattern calcium activity affects neuronal differentiation  but not transmembrane ACs (AC1 to 9) is required for the intrinsic ability of axons to grow  are of special importance to gain new insight into the spatiotemporal control of cAMP signals. Pursuing the analysis of these coding strategies will provide a better understanding of the regulatory second messenger networks shaping neuronal 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.


Journal of Experimental Botany Special Issue on Fruit Development and Ripening . At that time the biosynthesis and mode of action of ethylene in fruit ripening had already been established, and advances in genetics were revealing links between genes and phenotypes, especially noteworthy was the map-based cloning of genes underlying tomato non-ripening loci such as ripening inhibitor (rin). Since then there have been substantial advances in our understanding of ripening in tomato and many other dry and fleshy fruits. This has been accelerated by the delivery of genome sequences for a wide range of plants including fleshy fruit bearing species and the development of systems biology approaches to understanding regulatory networks.It has been 12 years since publication of the last The first paper in the 2002 issue was a seminal work by Sandy Knapp focused on fruit diversity in the Solanaceae and highlighting the phylogenetic relationships between dry and fleshy fruit forms . The curFRUITFULL (FUL) and SHATTERPROOF (SHP), and set these events in the context of a phylogenetic framework. Cristina Ferrándiz and Chloé Fourquin from Instituto de Biología Molecular y Celular de Plantas in Valencia, Spain, then review the role of FUL and SHP in Arabidopsis and provide a comprehensive discussion of their role in many other species including Brassicas, legumes and also in fleshy fruits (FUL and SHP expression, and their review concludes that there are conserved roles of FUL and SHP in late fruit development both in fleshy and dry fruits. These ideas were hinted at in the 2002 Special Issue and strong supporting evidence is now presented consistent with dehiscence and ripening sharing a common origin and being parallel, rather than completely different processes. María Dolores Gómez and colleagues, also from Valencia, explore and develop for us further ideas about the similarities and differences between the mechanistic basis of ‘ripening’ and ‘over-ripening’ in dry and fleshy fruits including comparing the transcriptomes of senescent and ripening Arabidopsis siliques and tomato berries (In the first paper in this special issue, Sofia Kourmpetli and Sinéad Drea from the University of Leicester in the UK review the regulatory networks involved in the development and maturation of two, at first sight, very different dry fruits, the poppy capsule and the cereal grain. They highlight the importance of MADS-box genes including y fruits . Dehisce berries . et al. describe the process in the non-climacteric grape berry including an in-depth discussion of the key processes associated with grape maturation such as flavonoid biosynthesis and volatile development. The authors provide an excellent summary of the profound effect of the environment on grape berry ripening, and a review of the role of various hormones in the ripening process in this species where ethylene seems to have an effect even on the ripening of this non-climacteric fruit. The role of hormones other than ethylene in modulating fleshy fruit ripening has received relatively limited attention, although the effects of auxin as a ripening inhibitor are perhaps best known. The reviews by Molecular networks controlling the ripening of fleshy fruits are also the focus of reviews by scientists from a range of European and South American laboratories (et al. from the Max-Planck-Institute of Molecular Plant Physiology in Germany and José L. Rambla and colleagues from Valencia and the Netherlands (The importance of the plastid in ripening fruits is the subject of the review by Maria Florencia Cocaliadis and her colleagues from Valencia (The final three review papers focus on genes regulating the genetic basis of fruit morphology in horticultural crops and the genetics, form and function of fruit cuticles. Antonio J. Monforte and colleagues from Spain and the USA describe the identification of genes controlling size and shape of tomato using QTL map-based cloning and how this information can be used to understand the basis of these traits in fruits such as melon  and thiset al. report on the development of a two-step in vitro culture system for grape which couples the use of fruiting-cuttings with organ in vitro culture, while Fu and colleagues explore the roles of the phytoene synthase gene family in loquat. The new volume reflects the advances in technology since 2002 and the reader can now survey the discoveries concerning the molecular networks in a range of dry and fleshy fruits. The last papers in this special issue describe original research from


In our experiments, we removed a major source of activation of somatosensory cortex in mature monkeys by unilaterally sectioning the sensory afferents in the dorsal columns of the spinal cord at a high cervical level. At this level, the ascending branches of tactile afferents from the hand are cut, while other branches of these afferents remain intact to terminate on neurons in the dorsal horn of the spinal cord. Immediately after such a lesion, the monkeys seem relatively unimpaired in locomotion and often use the forelimb, but further inspection reveals that they prefer to use the unaffected hand in reaching for food. In addition, systematic testing indicates that they make more errors in retrieving pieces of food, and start using visual inspection of the rotated hand to confirm the success of the grasping of the food. Such difficulties are not surprising as a complete dorsal column lesion totally deactivates the contralateral hand representation in primary somatosensory cortex (area 3b). However, hand use rapidly improves over the first post-lesion weeks, and much of the hand representational territory in contralateral area 3b is reactivated by inputs from the hand in roughly a normal somatotopic pattern. Quantitative measures of single neuron response properties reveal that reactivated neurons respond to tactile stimulation on the hand with high firing rates and only slightly longer latencies. We conclude that preserved dorsal column afferents after nearly complete lesions contribute to the reactivation of cortex and the recovery of the behavior, but second-order sensory pathways in the spinal cord may also play an important role. Our microelectrode recordings indicate that these preserved first-order, and second-order pathways are initially weak and largely ineffective in activating cortex, but they are potentiated during the recovery process. Therapies that would promote this potentiation could usefully enhance recovery after spinal cord injury. The last 30 years of intensive research has led to a greatly improved understanding of how the somatosensory system of mature primates and other mammals responds to sensory loss, as reviewed by others  One possibility is that different lesions produce different results. For performance with the hand, the dorsal column lesion should be at the C4–C5 level or higher to remove all afferents from the hand, the lower lesions at C5–C6 of the cervical spinal cord spare some afferents from digit 1 and 2, and still lower lesions would spare inputs from most of the hand. Even with C4–C5 lesions or higher, various afferents in the dorsal columns could be spared. (2) Compensations likely occur. As described below for our study of the effects of dorsal column lesions on behavior, vision appears to supplement tactile feedback in food retrieval tasks after dorsal column lesions. Other compensations for sensory impairments are likely to be rapidly acquired as well. (3) Plasticity of the somatosensory system, even in mature primates appears to be a major source of recovery after dorsal column lesions. Recoveries of activation within the system and use of the hand may result from the potentiation of the activating effects of preserved dorsal columns afferents, even when they are very few. This possibility is well demonstrated by the effects of cutting most of the dorsal sensory roots of nerves of the forearm in monkeys, while leaving a few inputs from that hand that initially fail to activate cortex. However, several months later cortex responded to cutaneous stimulation of the largely deafferented digits. Figure The results of our recent study of hand use in squirrel monkeys after a unilateral dorsal column lesion provide evidence that the sensory loss produced by lesions confined to the dorsal columns do produce impairments in a food retrieval task (Qi et al., The reactivation of deprived hand cortex weeks to months after high cervical dorsal column lesion depends on the potentiation of preserved sensory pathways through axon growth and the formation of new synapses. We have previously suggested that dorsal column lesions are often incomplete, and that preserved but subthreshold dorsal column inputs to the cuneate nucleus gain strength by forming more synapses on more neurons as the result of reduced competition for synaptic space (Rasmusson and Northgrave, The most likely alternative pathway is from neurons in the dorsal horn of the spinal cord that project to the dorsal column nuclei (Perl et al., In order to be effective, the projections to the cuneate nucleus by second-order dorsal horn neurons must survive the dorsal column lesion. Some axons from second-order neurons might enter the dorsal columns below the lesion and be lost. Others might enter above the lesion, or travel in some other pathway, such as the lateral funiculus, which is dominated by proprioceptive afferents (Rustioni et al., Given the evidence that the reactivation of the cortex by inputs from the hand is important for the recovery of manual dexterity, what can be done to promote these reactivations? Recently, we have investigated two interventions for promoting reactivations. First, we found promising evidence that behavioral training after sensory loss improved the recovery of hand use in a retrieval task and correlated with cortical reorganization [Qi et al., All authors contributed to the writing of the manuscript. The findings reviewed are those of the authors, as well as those of other investigators.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.


Genome sequences are making available an unprecedented amount of genetic information that has the potential to reliably elucidate many aspects of physiology, biochemistry, and evolutionary relationships of different organisms. For efficient analyses of the vast amount of genomic sequence data, new reductive approaches are needed which can identify reliable genetic characteristics that are specific for either particular species or related groups of organisms. These characteristics provide novel means for distinguishing different organisms and for understanding their evolutionary history as well as novel tools for phenotypic, behavioral, and biochemical studies. The papers collected in this research topic discuss the application of comparative genomic techniques in a wide range of modalities covering the evolution, classification, identification, and characterization of bacteria and viruses.Koton et al. utilize genomic sequence data to elucidate the evolutionary interrelationships of Vibrio vulnificus strains and to both trace the origin and identify unique genomic characteristics of V. vulnificus biotype 3. The comparative genomic analyses completed by Koton et al. are a model of how to utilize the comparative analysis of core, accessory, and unique genomic elements in order to understand the interrelationships of various strains of a single bacterial species. Bacterial classification at the genus and species level, however, is highly structured and often based on the characterization of a limited number of strains (often a single isolate) focussed on the 16S rRNA gene and a number of phenotypic and chemotaxonomic properties . This group of researchers has previously applied similar techniques to divide the genus Borrelia into two genera, Borrelia and Borreliella (Adeolu and Gupta, Thermotoga into two genera, Thermotoga and Pseudothermotoga (Bhandari and Gupta, Yang et al. who utilize the comparative analysis of Microcystis aeruginosa genomes to identify the CRISPR-Cas systems of different Microcystis aeruginosa subgroups, giving novel insights into their resistance to bacteriophages and their ability to modulate genomic stability and plasticity. Liu et al. utilize a number of biochemical assays to characterize the function of a laterally transferred gene cluster containing the tetR gene, identified via comparative genomic techniques. They show that the tetR gene and TetR protein contribute to cell survival under oxidative stress and are able to identify a number of regulatory roles played by the TetR protein. Taken together, these two studies exemplify the utility of studying and characterizing the genome derived characteristics that are beginning to be used to classify bacterial groups.The evolutionary relationships of bacterial organisms form the underlying basis of their classification. Chan et al. use genome sequence data to reveal the evolutionary relationships between the members of N4-like phage genus and to define the core genome of all members of the N4-like phage genus and the core genome of the N4-like Roseobacter phages, providing novel insight into the traits which characterize the genus and their evolutionary relationships. Mohiuddin and Schellhorn utilize environmental sampling and comparative genomic analyses of environmental DNA and DNA extracted from virus-like particles to examine the abundance and distribution of different classes of viruses in freshwater environments. These studies both represent useful applications of genomic sequence data and genome derived characteristics to identify and characterize viral groups and populations that are currently underexplored.Viruses and virus-like particles represent the most abundant sources of DNA in the environment (Weinbauer, The papers presented in this research topic exemplify the broad range of applications of comparative genomic analysis and genome derived characteristics in biology and related sciences. The use of genome sequence data to answer novel questions or challenge previously held assumptions is revolutionizing all fields of biology and novel methods and applications of comparative genomics are becoming an indispensable part of modern biological research.RG was the Editor for this Research Topic. I have critically read all of the papers submitted under this research topic and have written/finalized the submitted Editorial.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.


Cancer is a multi-genic, complex biological phenomenon and its growth is affected by various categories of factors including the genetics of the host, the accumulating genetic alteration within cancer cells and environmental modifiers.Therefore, to identify the determinants of immune-mediated tumor rejection during immunotherapy, a systematic and comprehensive monitoring approach needs to be applied that covers the various categories at a time relevant to the therapeutic intervention. In addition, a temporal dimension needs to be added to evaluate in real time the changes induced by treatment and their relationship with clinical outcome.In this presentation, we will review the salient concepts that should guide the future monitoring of clinical trials taking advantage of novel and comprehensive technological advances presenting examples of integrated approaches for the assessment of patients' response to adoptive T cell therapy.Our experience highlights the need to apply multi-parametric approaches for the understanding of the mechanism(s) leading to cancer rejection by the immune system in humans.


In the last decades there have been significant advances in our understanding of the cellular and subcellular mechanisms underlying changes in synaptic connectivity that subserve memory formation. The so called Theory of Synaptic Plasticity and Memory has gathered a wealth of experimental support from different areas of neuroscience to become the main phenomenological description of memory at the behavioural level. This special issue of neural plasticity compiles some of the most recent advances in our understanding of the mechanisms underlying formation and persistence of different types of memories from invertebrates to humans. Contributions from different laboratories around the world pinpoint hot topics in this area of memory research, highlighting growing avenues for future research.The experience of a salient event can lead to the formation and storage of a long-term memory that can sculpt and alter future behaviour up to a lifetime of an individual. This unique and highly adaptive behavioural capacity relies on specific changes occurring within the brain. Specific signalling pathways and patterns of gene expression are required in neuronal and nonneuronal cells for the stabilization and long-term persistence of synaptic changes that underlie memory. Depending on the retrieval conditions, these fully consolidated memories can undergo reconsolidation or extinction that will maintain or inhibit the expression of the original memory, respectively. These opposing memory processes recruit distinctive subcellular events in order to restabilize the original memory or to form a new inhibitory memory trace. The formation of associative memories and their maintenance are evolutionary conserved phenomena present from the simplest to the most complex animals. The use of a multidisciplinary approach, comprising behavioural, physiological, and molecular analysis, in combination with a variety of wild and laboratory animals, from invertebrates to humans, brings light into the intricate mechanisms of memory. The three research papers and five review articles included here were revised by at least two international experts and their comments helped in making each piece an even more compelling article. Drosophila to show that muscarinic-type acetylcholine receptors contribute to the generation of olfactory aversive memory. Besides the obvious anatomical differences between vertebrate and invertebrate nervous systems, this article further supports the evolutionary conserved role of key contributors to memory consolidation. T. P. Todd and D. J. Bucci show that retrosplenial cortex (RSC) is specifically involved in forming associations among the neutral stimuli that are present in the environment. Furthermore, they discuss evidence that posits RSC as a site in which multiple cues are linked together in the service of memory formation and persistence after training.This Issue includes two articles addressing novel mechanisms in memory consolidation. B. Silva et al. used larvae of the fruitflyA comprehensive review article by D. Moncada et al. serves both as an introduction and a thorough revision of the existing literature regarding the experimental findings supporting the behavioural tagging process in rodents and humans. This working hypothesis links the concept of synaptic tagging proposed by Morris and Frey in the late 90s with more recent evidence of a significant promoting effect of a novel behavioural experience in the formation of new and independent associative memories. Moreover, M. Tomaiuolo et al. establish novel links between the synaptic tagging hypothesis and memory persistence, showing that a dopamine- and Arc-dependent maintenance tagging process may operate in the hippocampus late after acquisition for the persistence of long-lasting memories. Ending the persistence mechanisms section, J. B. Hales et al. investigated the effect of the zeta-inhibitory peptide (ZIP) in the persistence of recognition memory in rats. This article shows that recent, but not remote, object recognition memories can be disrupted by ZIP infusion into the hippocampus and suggests a dynamic role of hippocampal LTP-dependent mechanisms supporting strong recognition memories shortly after training.J.-P. Morin et al. discuss at length the role of the protein Arc as one of the main molecular substrates of memory. They go over its characteristics and regulation and the reasons why this molecule could be an essential part of the memory engram. They propose that Arc possesses particular characteristics like its persistent expression after learning its pre- and posttranslational regulation and its interactions with molecules at the synapse that make it an ideal candidate to mediate plasticity in the cells activated by a given learning experience.Adult neurogenesis in the dentate gyrus of the hippocampus has gained increasing interest as a potential plasticity mechanism for learning and memory at the cell and system level of analysis. The article by S. Yau et al. addresses the role of adult hippocampal neurogenesis in learning and memory focusing on novel findings that indicate a function for this process in two features of memory. One of these features is “pattern separation” which refers to the computational process involved in separating the representations of similar learning experiences. The second is the far less studied process of memory forgetting, which will certainly be one of the new most interesting fields in memory research. The authors incorporate this new information and relate it to treatments such as environmental enrichment and voluntary exercise, which are known to increase neurogenesis.The issue presents an article dedicated to analyse the implications of memory studies for the development of novel therapeutical tools for the treatment of psychiatric disorders in humans. In particular, C. Köhler et al. propose that the manipulation of the reconsolidation of autobiographical memories might represent a novel therapeutic opportunity for depression treatment. The authors suggest that disruption of memory reconsolidation could serve as a novel approach for the modification of dysfunctional autobiographical memories associated with major depressive disorder.We are very pleased to introduce this special issue that covers a variety of features of memory at different levels of analysis. The persistent nature of maladaptive memory components is a common characteristic in several psychiatric disorders including posttraumatic stress disorder (PTSD), specific phobias, and drug addiction. We believe that understanding the key molecular mechanisms underlying the formation, persistence maintenance, and forgetting of different forms of memories will prove to be invaluable at both the foundational and translational levels, helping the design and development of new therapeutical approaches.


The translocon at the outer envelope membrane of chloroplasts (TOC) initiates the import of thousands of nuclear encoded preproteins required for chloroplast biogenesis and function. The multimeric TOC complex contains two GTP-regulated receptors, Toc34 and Toc159, which recognize the transit peptides of preproteins and initiate protein import through a β–barrel membrane channel, Toc75. Different isoforms of Toc34 and Toc159 assemble with Toc75 to form structurally and functionally diverse translocons, and the composition and levels of TOC translocons is required for the import of specific subsets of coordinately expressed proteins during plant growth and development. Consequently, the proper assembly of the TOC complexes is key to ensuring organelle homeostasis. This review will focus on our current knowledge of the targeting and assembly of TOC components to form functional translocons at the outer membrane. Our analyses reveal that the targeting of TOC components involves elements common to the targeting of other outer membrane proteins, but also include unique features that appear to have evolved to specifically facilitate assembly of the import apparatus. The plastids constitute a diverse array of organelles, which play central roles in plant growth, development, and defense by providing a remarkable range of metabolic and physiological capabilities in different cell and tissue types , recognizes the majority of plastid-destined proteins at the organelle surface  and appears to be unique among chloroplast outer envelope membrane proteins (OEPs) in being targeted to the membrane al Table  , with its N-terminus (including the G-domain) exposed to the cytosol and a relatively short C-terminal sequence (CTS) oriented toward the intermembrane space Table . Organelin vitro targeting experiments with isolated organelles suggest that selectivity can occur at the surface of the organelle, independent of cytosolic targeting factors   in Arabidopsis , further highlighting the importance of regulating protein import at the level of the TOC translocon (Ling et al., The translocons mediating the import of nuclear encoded preproteins play central roles in the biogenesis and functional differentiation of plastids. Major attention has been devoted to uncovering the mechanism of preprotein recognition and membrane translocation at TOC and TIC, and it is increasingly clear that the assembly and regulation of these complexes play an important role in organelle function and homeostasis. To date, studies on individual TOC components suggest that their targeting involves elements in common with other outer membrane proteins, but also reveal features that are unique to TOC biogenesis. Detailed studies on the characteristics and relationships of targeting pathways for the TOC proteins, the identification of the components of each pathway, and the definition of the roles of known components are needed to provide a complete picture of the mechanism and regulation of TOC assembly. A more complete picture of targeting and assembly in conjunction with information on the structures and interactions of core TOC components will undoubtedly shed light on key regulatory or quality control checkpoints in the assembly and dynamics of this unique macromolecular assembly. Finally, studies integrating TOC assembly with the newly discovered mechanism of TOC control by regulated proteolysis provides an opportunity to understand how the levels and diversity of the translocons are controlled, and thereby contribute to the plasticity of organelle function in response to developmental and physiological events in the cell.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.


Nasal reconstruction presents a challenge for plastic surgeons due to the prominent location and complex structure of the nose. When reconstructing full-thickness nasal defects, options to replace the inner lining, cartilaginous framework and outer skin must be considered. The aesthetic units of the nose must also be replaced in full rather than simply filling holes. This report presents a case of a 62 year old male who’s full-thickness alar defect due to resection of a basal cell carcinoma (BCC) was reconstructed using a free chondro-cutaneous helical rim flap based on a retrograde flow superficial temporal artery pedicle.The margins of the existing defect were excised by a further 5mm as suggested by histology. A mould of the defect was made using bone cement and used to plan the harvest site of the flap from the left helical rim. The flap was raised based on a retrograde superificial temporal artery and consisted of cartilage from the helical rim, skin from the anterior and posterior surfaces of the helix and a small segment of post-auricular skin. A 10cm inter-positional pedicle was harvested from the descending lateral circumflex femoral artery and vein from the right antero-lateral thigh (ALT). This inter-positional ALT pedicle was tunnelled under the cheek to reach the facial artery and vein in the submandibular region as the vessels in the naso-labial fold were not suitable for anastomosis.The vascularised free chondrocutaneous flap allows reconstruction of the three layers of the nasal ala: the inner lining, cartilaginous framework and outer skin, in one procedure. Due to similar sun exposure, the auricular skin also provides a good match to nasal skin in terms of colour and texture. The natural curvature of the helical rim at the root is similar to that of the nasal ala. The resulting ear defect with be reconstructed at a later stage using a cartilaginous graft from the costal margin and skin grafting.As 30% of head and neck BCC’s are nasal, consideration of reconstructive options following resection is an important part of patient management. The vascularised helical rim flap allows reconstruction of all 3 layers of the nasal ala with a good aesthetic result due to adequate matching of contour, colour and texture. The location of any scarring is inconspicuous in comparison to a local forehead flap that could also be used to reconstruct such a defect.


Cancer is a leading cause of death worldwide and it is caused by the interaction of genomic, environmental, and lifestyle factors. Although chemotherapy is one way of treating cancers, it also damages healthy cells and may cause severe side effects. Therefore, it is beneficial in drug delivery in the human body to increase the proportion of the drugs at the target site while limiting its exposure at the rest of body through Magnetic Drug Targeting (MDT). Superparamagnetic iron oxide nanoparticles (SPIONs) are derived from polyol methods and coated with oleic acid and can be used as magnetic drug carrier particles (MDCPs) in an MDT system. Here, we develop a mathematical model for studying the interactions between the MDCPs enriched with three different diameters of SPIONs  in the MDT system with an implanted magnetizable stent using different magnetic field strengths and blood velocities. Our computational analysis allows for the optimal design of the SPIONs enriched MDCPs to be used in clinical applications. Cancer is a leading cause of death worldwide. Its cause is multifactorial and is linked to the interaction of genomic, environmental, and lifestyle factors . Cancer MDT refers to the attachment of therapeutics to magnetizable particles to concentrate them at the desired locations by applying magnetic fields . It inclThere has been a growing interest in the scientific and clinical application of MDCPs as MDT vehicles for the development of efficient treatment strategies. A nanoparticle-based cancer drug has been developed and the phase 1 clinical study of cancer patients providing positive clinical evidence for the progress of nanoparticle application is reported . Superpa3O4 nanoparticles with respect to particle diameters  has been previously investigated [3O4 nanoparticles with different diameters at 300 K is shown in The fraction of the constituting atoms on the surface of the nanoparticles varies with the decrease in the size of the particles (<100 nm) and this leads to significant changes in the magnetic structure and properties of the nanophase materials. The variation of the magnetic behaviour of well-dispersed monodisperse Festigated . It has Here, we propose SPIONs as carriers in SA-MDT system using a magnetizable stent as an implant and focus on the theoretical modelling of the interaction between the MDCPs enriched with three different sizes of SPIONs see . The quaN MDCPs under the influence of (i) Stokes drag, (ii) hydrodynamic interaction forces, and (iii) magnetic forces that account for the mutual magnetic dipole-dipole interactions and calculated (iv) the velocity of each MDCP and MDCPn and (v) the system performance in terms of collection efficiency (CE) ignoring the effect of inertia and gravity Stokes drag,   ηblood is the viscosity of the blood, Rpn is the radius of MDCPn, and n, respectively. In the model, where escribed .(ii)n due to the movement of other MDCPs in the blood flow. By considering N MDCPs, the force acting on MDCPn due to the presence of the other (N − 1) MDCPs is given byHydrodynamic interaction force,  i and ξni is the modification due to the hydrodynamic interaction.where (iii)n, N MDCPs, each MDCP is taken as spherical and is having a homogeneous magnetic flux throughout the entire volume. n can be written asMagnetic forces acting on MDCP n and n.where (iv)n, The velocity of MDCP(v)n are obtained from evaluating the streamline functions. ConsiderThe system performance of the model is calculated in terms of collection efficiency (CE) and the trajectories of MDCP Rvessel is the radius of the vessel and y1 and y2 are defined by the location of the streamline at the entrance of control volume (CV) of the last MDCPs captured by the stent wires.where The forces acting on a given particle labeled  In the current study, we present the simulation results of the behaviour of MDCPs enriched with three different sizes of SPIONs  in SA-MDT system. We examine the effects of interactions on the CE of the system in terms of the changes in blood velocity and applied magnetic field strength .N (N = 100) MDCPs together with the blood flow velocity. Magnetic and hydrodynamic forces acting on MDCPs as well as blood velocity were calculated using the finite volume library OpenFOAM [We calculate the forces due to the magnetic dipole-dipole and hydrodynamic interactions on OpenFOAM . We creaOpenFOAM . In our OpenFOAM .3O4 nanoparticles) [In order to describe the effect of different SPION diameter on the content of MDCPs, rticles)  is preseWe have presented SA-MTD model incorporating the agglomeration of particles known to occur in real biological systems and studied the effect of SPION diameter used in the MDCPs using different magnetic field strengths and blood velocities. We calculated both the dipole-dipole and hydrodynamic interactions for 100 particles and the resulting collection efficiencies derived from the mathematical model are in closer agreement with our latest experimental results .We envisage that new insights obtained from the results of our analysis may be used in prediction of efficacy of targeted drug delivery for designing effective nanotherapeutic tools that can translate into the clinic. The CE of the system is increased with the higher magnetic field strength and decreased with the higher blood velocities as expected. Moreover, the modelling of different sizes of SPIONs in a SA-MDT system presented in this work represents a useful analytical tool for the prediction of the efficacy of targeted drug delivery. Our simulations indicate that size of the SPIONs in MDCPs together with saturation magnetization of the SPIONs has considerable effect on collection efficiency of the SA-MDT system. The response of SA-MDT is mainly dominated by the size of SPIONs and the saturation magnetization value of SPIONs, and these parameters can be calibrated based on the clinical applications of SA-MDT system using the results of our simulation. Improvement of the fundamental models in MDT systems may allow for the development of the more complex models that include systems level interactions.The presented mathematical model for the movement of the MDCPs in the blood can be integrated with genome-scale metabolic models (GEMs) for healthy cells/tissues –33, canc


While it has been used clinically in Europe since the early 2000, molecular allergology remains relatively unknown to a number of clinicians involved in the field of allergy and this at a time when the understanding of allergy at the level of proteins allows for novel diagnostic and therapeutic avenues. Molecular allergy offers clinicians a better understanding of the allergy dynamics of certain patients, particularly in some situations of food allergy and in multi-allergy contexts.A introduction to the science of molecular allergology, based on 6 concepts has been developed. A concise yet clinically effective "Molecular allergology summary 2013" card has been devised so as to facilitate the allergy physician's first steps in the clinical use of molecular allergology. Notions of molecular similarities and the relevance of biologic testing results will be reviewed. This will assist initial assessments of specific clinical contexts where molecular allergology will prove particularly useful.A coherent appreciation of molecular families, their major component markers and their clinical character adds a whole new dimension to the evaluation and management of patients with various inhalant, nuts and other food allergies. The oral allergy syndrome, from the perspective of the molecular families at play, can be better appreciated for the myriad of syndromes that they really are, each with its own prognostic and therapeutic implications. The pertinence of molecular allergy testing vis-à-vis multi-sensitized respiratory allergy patients, milk and egg allergy management and other more specific clinical conditions can be addressed. Future applications of molecular allergy will likely change considerably some of our therapeutic approaches.Molecular allergy can enhance our care of allergy patients today and opens new doors on allergy therapeutics. It also brings new parameters and business-model issues in allergy care in North-America. Beyond the helpfulness of component-resolved diagnosis in the practice of allergy medicine, the leadership of clinical allergists is neeeded in defining its judicious application to the care of our allergic patients.


Childhood-onset SLE is a complex multiorgan disease. In order to judge the need of medical intervnetions and the patient benefits from them, measurement disease activity and damage are key. Furthermore, important improvement and deterioration of disease needs to be ascertained. Such measurement are the basis for clinical trial aimed at identifying improved medications and are needed to judge the benefits of medical interventions in general.An overview will be provided about current surrogate and biological markers of global and disease specific disease activity and damage. Focus will be placed on the relevance for children with SLE and current research activities, particularly NPSLE and lupus nephritis.Upon completion of the presentation the audience will h ave a firm understanding about the suitability of individual measures of disease activity and their differences. Measures include the various versions of the SLEDAI and BILAG, as well as SLE flare tools. The SLICC Damage Index and its pediatric version will be discussed in addition to previously validated measures of clinically relevant improvment and disease flare. Additionally, biomarkers of lupus nephritis as they are suited to help diagnose kidney disease and anticipate changes in the activity and chronicity of kidney lesions will be available. Some novel imaging biomarkers of neuropsychiatric damage will be reviewed.None declared.


Musculoskeletal tuberculosis manifest commonly in the spine, hip and knee and rarely in the hand and wrist. Certain factors influence the functional outcome after treatment of tuberculosis of the upper extremity namely location , tissue involvement, delay prior to consult, care by a multispecialty team and early surgery.Appropriate drug therapy is the mainstay in the management of musculoskeletal tuberculosis. The role of medical management of tuberculosis of the upper extremity appear to have a predominant role compared to surgery with the latter reserved for drainage of abscesses, synovectomy and carpal tunnel release.The functional outcome with medical treatment alone in the series of Kotwal and Khan (2010) was good using the modified Green and O'Brien scoring system. Benkeddache (1982) reported favorable response to drug treatment with resolution of bone and soft tissue lesions. There is a scarcity of reports in this area prompting the author to undertake this study in 2013-2014 on 25 Filipino subjects.The functional outcome of patients with tuberculosis of the upper extremity aged 17 to 87 years who received appropriate medical and surgical treatment for tuberculosis of the upper extremity was determined using the DASH scoring system (Filipino version) . The majority of the patient population had surgical treatment which included wrist fusion, finger joint fusion, joint synovectomy, tendon synovectomy, arthrotomy, arthroscopic debridement and ray amputation.The mean DASH score of patients with tuberculosis of the upper extremity was 28. This score allowed patients to do ADLs without much difficulty. The type of tissue involvement and the location involved did not appear to be good predictors of functional outcome after medical and surgical treatment of tuberculosis of the upper extremity.


In the past few decades there has been a surge in initiatives to catalogue the diversity of the human microbiome, which have been rapidly followed by research documenting the state of the microbiome in various human physiological states and geographical populations. The evidence for a causal implication of the microbiome in disease is compelling; our so-called second genome could underlie a variety of complex diseases including immunological, neurological and cardiovascular conditions, as well as cancer. It is therefore not surprising that the deep scrutiny of the normal microbiome and its intersection with disease have drawn major scientific and public interest.Genome Medicine presents a collection of articles describing novel insights into the functional characterization of the human microbiome and the shifts in microbiome composition in disease states or recovery from disease. The issue also details the latest advances in classifying individuals according to their disease risk using computational approaches. For example, Patrick Schloss and colleagues demonstrate that a microbiota-based random forest model complements existing screening methods to detect colonic lesions; using this classification method, early stage colorectal cancer may be detected in patients in a non-invasive manner [In this special issue, e manner .We also present the first study to develop a risk classification index for bacteremia from analysis of the fecal microbiomes of patients with non-Hodgkin lymphoma . Dan KniThese studies pave the way for translational research to exploit the therapeutic potential of modulating the microbiome. A review by Gautam Dantas and colleagues highlights the adverse effects of broad spectrum antibiotics on the dynamics between healthy and dysbiotic states; the authors expand upon the current landscape of therapeutic approaches for precision modulation of the microbiome and the advances made so far in this area . In anotThis special issue aims to provide a current view of the state of the field, including often forgotten components of the microbiome such as the virome . BuildinWe would like to express our deepest gratitude to our Guest Editor, Curtis Huttenhower, for his invaluable advice and guidance in shaping this special issue. We are also extremely grateful to the many reviewers who provided feedback and advice.


The human interaction required for manual motion correction/contouring of cardiac perfusion series remains a significant obstacle to quantitative perfusion gaining a wider acceptance in clinical practice. The use of image registration for motion correction in perfusion data offers a considerable time saving. Numerous registration methods have been proposed, with evaluation limited to the image registration accuracy. However, the important clinical question is how do these methods affect diagnosis? The aim of this study is to evaluate perfusion series registration in terms of its affect on the diagnostic accuracy of myocardial ischaemia.This was a retrospective sub-study using data from the CE-MARC trial . A 50-patient sample was selected such that the distribution of risk factors and disease status within the sample was representative of the full CE-MARC cohort. Image registration was performed with the mutual information image similarity metric; all images in the basal location of the series were registered with translation displacement to the maximum contrast image of the series at the basal slice. The recovered correction transforms were propagated to the medial and apical slices of the series . The AUCs for manual motion correction and automatic motion correction were 0.93 and 0.92 respectively (Figure We have shown that automated motion correction provides diagnostic accuracy equivalent to the common protocol of manual motion correction. Automated motion correction offers a significant time reduction in the human interaction required for delineation of contours for quantitative perfusion analysis, and therefore opens the way for a more widespread use of this technique in research and clinical practice.This work was funded by the Top Achiever Doctoral scholarship awarded by the Tertiary Education Commission of New Zealand.


The molecular machinery underlying memory consolidation at the level of synaptic connections is believed to employ a complex network of highly diverse biochemical processes that operate on a wide range of different timescales. An appropriate theoretical framework could help us identify their computational roles and understand how these intricate networks of interactions support synaptic memory formation and maintenance.Here we construct a broad class of synaptic models that can efficiently harness biological complexity to store and preserve a huge number of memories, vastly outperforming other synaptic models of memory. The number of storable memories grows almost linearly with the number of synapses, which constitutes a substantial improvement over the square root scaling of previous models ,2, especThis is achieved by combining together multiple dynamical processes that operate on different timescales, to ensure the memory strength decays as slowly as the inverse square root of the age of the corresponding synaptic modification. Memories are initially stored in fast variables and then progressively transferred to slower ones. Importantly, in our case the interactions between fast and slow variables are bidirectional, in contrast to the unidirectional cascades of previous models.The proposed models are robust to perturbations of parameters and can capture several properties of biological memories, which include delayed expression of synaptic potentiation and depression, synaptic metaplasticity, and spacing effects. We discuss predictions for the autocorrelation function of the synaptic efficacy that can be tested in plasticity experiments involving long sequences of synaptic modifications.


Following almost 30 years of relative silence, chikungunya fever reemerged in Kenya in 2004. It subsequently spread to the islands of the Indian Ocean, reaching Southeast Asia in 2006. The virus was first detected in Cambodia in 2011 and a large outbreak occurred in the village of Trapeang Roka Kampong Speu Province in March 2012, in which 44% of the villagers had a recent infection biologically confirmed. The epidemic curve was constructed from the number of biologically-confirmed CHIKV cases per day determined from the date of fever onset, which was self-reported during a data collection campaign conducted in the village after the outbreak. All individuals participating in the campaign had infections confirmed by laboratory analysis, allowing for the identification of asymptomatic cases and those with an unreported date of fever onset. We develop a stochastic model explicitly including such cases, all of whom do not appear on the epidemic curve. We estimate the basic reproduction number of the outbreak to be 6.46 . We show that this estimate is particularly sensitive to changes in the biting rate and mosquito longevity. Our model also indicates that the infection was more widespread within the population on the reported epidemic start date. We show that the exclusion of asymptomatic cases and cases with undocumented onset dates can lead to an underestimation of the reproduction number which, in turn, could negatively impact control strategies implemented by public health authorities. We highlight the need for properly documenting newly emerging pathogens in immunologically naive populations and the importance of identifying the route of disease introduction. Aedes albopictus) in many of these regions. This study describes a mathematical model for a chikungunya outbreak in the rural Cambodian village of Trapeang Roka, where a chikungunya epidemic was recorded and documented in March 2012. The outbreak data is unique, in that all infections were confirmed by laboratory analysis, enabling the identification of asymptomatic individuals, in addition to individuals who failed to report details of their infection. A stochastic model, partitioning the infectious population into three distinct classes, is implemented using Gillespie's algorithm. We show that the incorporation of both biologically-confirmed symptomatic cases undocumented by date of fever onset and asymptomatic cases yields a higher estimate of the reproduction number. Our results highlight how reproduction numbers could be underestimated by limiting analysis to the epidemic curve. Carefully documenting cases and performing laboratory testing in cluster regions, such as the village considered here, could provide a more comprehensive insight into the true infection dynamics.During the recent resurgence of chikungunya, the scale of imported cases into previously unaffected countries has caused great concern due to the presence of a competent vector ( Aedes aegyptiAedes albopictusAedes albopictus population, first detected in 1990 Aedes albopictus vector is present Chikungunya virus (CHIKV) belongs to the genus Alphavirus. It is a mosquito-borne pathogen transmitted by the Aedes mosquitoes. In humans, the virus causes an acute illness with symptoms including fever, headaches, rash and arthralgia Unlike dengue fever, which has been extensively modelled, chikungunya has only started to receive attention since its reemergence in 2005. Mathematical models have been developed to describe detailed mosquito dynamics and the host-vector interactions Aedes albopictus) in many of these regions albopictus population during the 2007 outbreak. The urgent need to establish adequate monitoring and mosquito control programs in vulnerable countries is particularly highlighted by the recent outbreak in Singapore, in which 1059 cases were recorded in 2013 The scale of imported cases into previously unaffected countries  The model results highlight the importance of accurate epidemiological data collection to identify the route of disease importation and the ability of poor human recall to impact the epidemic curve by excluding cases with an undocumented date of onset. The consequences of excluding these cases was demonstrated by considering a simplified SEIR model which yielded biologically unrealistic mosquito population estimates and produced a simulated epidemic that continued for long after the real epidemic had finished. Furthermore, many individuals interviewed recalled a date of symptom onset but infection was not confirmed by IgM. This indicates that biological confirmation is crucial to avoid errors introduced due to the presence of other diseases , the impact of memory bias and the unintentional effects of people aiming to please the interviewers by confirming a non-existent infection. The results demonstrate that the identified index case was not alone in the population at the epidemic onset and the infection was already present in both the human and mosquito populations. The infected humans could have imported the infection from nearby regions, however, it is more probable that the infection was imported by an infected visitor or a resident who was either asymptomatic or undocumented by date of symptom onset, who would not have been recorded on the epidemic curve but nonetheless seeded the epidemic within the village's mosquito population.The estimate obtained for Aedes albopictus mosquito was responsible for the first chikungunya outbreak in a temperate region recorded in the Emilia Romagna region of Italy. This outbreak highlighted the need to understand the dynamics of disease introduction into new regions and the impact of biological, human and climatic factors on invasion dynamics. The model presented here provides an estimate for Accurate estimates of


Corporate identity clothes (CI-clothes) are today more and more important for companies and their identity. One important aspect is the appearance of the clothes over the long lifetime. After several washing and wearing cycles the appearance of such clothes should only show low differences between new and worn clothes. To minimize the signs of use many CI-clothes have a water and soil repellent finishing avoiding contamination. This finishing shows often a negative influence on the comfort of the clothing. The aim of the German research project 16365N was to optimize water and soil repellent finishing in combination with high industrial wash ability and high comfort.In the project, typical fabrics of CI- clothes were finished with different auxiliaries for water and soil repellency as one and two side application. The different auxiliaries characterise the plurability of commercial available products (e.g. fluorocarbon dispersions (C6 and C8), fluorocarbon free dispersions, sol-gel based dispersions). The thermophysiological and skin sensorial comfort of the finished fabrics was determined by measurements with established devices: the Hohenstein skin model, a sweating guarded-hot plate and the five Hohenstein methods for the measurement of the skin comfort. For evaluation the thermophysiological comfort vote and the skin sensorial comfort vote was determined. At the end the total wear comfort was calculated.The thermophysiological parameters of the finished fabrics of the fabric in new state and after finishing with different auxiliaries with variation of the finishing parameters and also the skin sensorial parameters were collected. The fabrics in origin state show in every case better thermophysiological properties than the finished fabrics. For all fabrics the total wear comfort of the finished products is lower than of the fabric in new state. The amount of the finishing detergents influenced the properties. In most cases high amounts of the finishing detergents degrade thermophysiological and skin sensorial properties. But with low amounts of the finishing detergents the water and soil repellency is not given.The application of the water and soil repellent finishing on two sides leads to better thermophysiological comfort vote but also to a lower skin sensorial comfort vote. The one side application has the advantage of a better skin sensorial comfort but the thermophysiological comfort is lower caused by additional used thickener of the application. The influence of different water and soil repellent finishing to the total wear comfort are very similar independent on the chemistry of the finishing.The results of the research project show that the physiological comfort of CI-clothes can be influenced by the used water and soil repellent finishing. The application methods (one side coating or two side application via the foulard-process) have an important influence to the thermophysiological and skin sensorial comfort. The comfort vote system which is developed for all day clothes can be also used for CI-clothes but the additional functionalization lead to lower votes. At the moment all finishing auxiliaries for water and soil repellency degrade the thermophysiological and skin sensorial comfort. New developments of auxiliaries are necessary to improve also the wear comfort. In cases of CI-clothes the question to the needs of water and soil repellent finishing must be discussed to improve very easily the wear comfort of such clothes. In the case of PPE water and soil repellent finishing is often necessary and essential for the protection of the worker.


Odontomas are a common type of odontogenic tumor, usually asymptomatic and mostly detected on routine radiographic examination. An 11-years-old male child with the chief complaint of mobility of deciduous dentition in the upper front region was diagnosed with an odontome with an impacted central incisor, missing lateral incisor and retained deciduous incisors following radiographic analysis. Histopathology revealed a compound odontoma following a conservative enucleation. Odontomas associated with primary dentition, impacted teeth and erupting into oral cavity have been described, but the association with a missing lateral incisor makes this an interesting case report.How to cite this article: Nammalwar RB, Moses J. A Rare Association of Compound Odontome with Missing Lateral Incisor. Int J Clin Pediatr Dent 2014;7(1):50-53. The cells of the tissues in odontomas are normal but lack organization due to disordered expression and localization of the extra-cellular matrix molecules in the dental mesenchyme.3Odontomas are a common type of odontogenic tumors and are considered to be developmental anomalies (hamartomas) rather than true neoplasm. Fully developed odontomas consist mainly of enamel and dentin and variable amounts of cementum and pulp tissue.4 Hitchin suggested that odontomas are inherited through a mutant gene or interference, possibly postnatal, with genetic control of tooth development. In humans, there is a tendency for the lamina between the tooth germs to disintegrate into clumps of cells. The persistence of a portion of lamina may be an important factor in the etiology of complex or compound odontomas and either of these may occur instead of a tooth.5Experimental production of odontoma in rats as a result of trauma was studied by Levy BA suggestive of trauma as an etiological factor.67The World Health Organization histological typing of odontogenic tumors classifes odontoma under benign tumors containing odontogenic epithelium with odonto-genic ectomesenchyme, with or without dental hard tissue formation. Ameloblastic fbro-odontoma, compound and complex odontoma are entities under this category.8The anterior maxilla holds a somewhat stronger tendency for being the predilection site for compound odontoma than the posterior mandible does as the predilection site for the complex odontoma.9 The radiographic features of the odontoma show two regions, the well defined periphery which may be smooth or irregular, mostly with a hyper-ostotic or cortical border and a soft tissue capsule adjacent to the cortical border. The internal structure is largely opaque with compound odontoma showing a number of teeth like structures. The degree of opacity is equivalent or exceeds the adjacent structures.10They are mostly asymptomatic, but a study of 60 cases in Department of Oral Pathology, Dankook University Hospital between 1991 and 2006 revealed delayed eruption of either the deciduous or permanent tooth; intra- or extraoral swelling; and the reporting of pain. Eighteen cases had no subjective symptoms and of the 60 cases, 55% were female.An 11-years-old male child presented to the department of pedodontics with the chief complaint of mobile deciduous teeth in the right maxillary anterior region for the past 4 days with pain, with the history of dental trauma. Clinical examination of the maxillary anterior region revealed retained missing right maxillary permanent central and lateral incisor with retained deciduous incisors . PanoramHistopathology of the soft tissue section showed delicate cellular fbrous connective tissue, with dense focal collection of chronic infammatory cells like lymphocytes and plasma cells in few areas. Few islands of odontogenic epithelial cells were seen. The mass of hard tissue was confirmed to be a compound odontoma with the decalcified section  showing Odontoma is a condition in dental medicine that mostly proceeds unrecognized until the occurrence of clinical symptoms such as delayed eruption, or is incidentally detected on routine X-ray examination. The exact cause is not known, however, previous dental trauma and infection have been postulated as the potential factors in the development of odontogenic tumor as described in the literature below.67 could possibly be associated with this case. Trauma in the form of dental mutilation as a result of traditional tooth extractions a practice of the people of Africa have reported to cause malformation and dilacerations of permanent teeth.11Intrusion of the permanent dentition as a result of trauma leading to malformation in the form of hyperplasia of the permanent lateral incisor have been reported. The odontoma was reported to be located very deep for surgical removal to be carried out.12 The effects of odontoma on the primary dentition range from noneruption to impactions as in this case of an unerupted primary canine that was managed surgically with the unerupted tooth retained to allow its eruption.1314The case described in this study was diagnosed initially as odontoma as the radiographic examination showed calci-fication similar to that of teeth. Histological examination of the lesion after enucleation revealed a compound odontoma and the surrounding mass of tissue could possibly be from the connective tissue surrounding the odontoma. The etiology of trauma being a causative factor as suggested by Levy BA15 The treatment of choice for these impacted teeth associated to odontomas appears to be removal of the lesion with preservation of the impacted tooth. The latter in turn require clinical and radiological follow-up for at least one year. If no changes in the position of the tooth are seen during this period, fenestration followed by orthodontic traction is indicated. Extraction advised when the tooth is ectopic or heterotopic, with morphological alterations, or presence of cystic lesions.16 Orthodontic therapy for alignment of the impacted central incisor has been suggested.Our case history had a positive note on a traumatic episode and considering the study of the literature available, further research into how, for example any histological or chemical as a result of trauma should be considered. The presence of the missing permanent lateral incisor is of course a unique entity and it may be theoretically considered that trauma can be an etiologic factor. Spontaneous eruption of an impacted tooth after removal of a supernumerary tooth or odontoma depends on several factors, such as distance of the apex of the impacted tooth relative to its midline, time of surgery relative to the expected eruption time of the impacted teeth and loss of space, estimated position, depth of impaction, angle of impaction relative to the midline, time of surgery relative to the expected eruption time of the impacted teeth.The detection of odontoma is more likely an accidental radiological finding, hence the need for routine radiographic analysis should be emphasized. Early diagnosis of odon-tomas in primary dentition is essential in order to prevent later complications, such as impaction or failure of eruption of teeth.


The aim of our study is to demonstrate the surgical management of myringosclerosis over a perforated whole tympanic membrane using simple underlay myringoplasty. Simple underlay myringoplasty with fibrin glue was performed in 11 ears with myringosclerosis over the entire tympanic membrane. The patients were one male and ten females and their mean age was 61.8 years . Surgical success was defined as an intact tympanic membrane 12 months after surgery. Closure of the perforation was successful in 10 (91%) of the 11 patients. Failure of the graft occurred in one patient who then underwent a revision procedure using her stored fascia in the outpatient clinic with a successful outcome. The overall success rate was 100%. Although this study included a small number of cases, removal of myringosclerosis at the edge of a perforation is a beneficial technique for simple underlay myringoplasty in terms of the success rate and postoperative hearing threshold, especially when myringosclerosis extends over the entire tympanic membrane. Myringosclerosis is a pathologic condition affecting the tympanic membrane. It appears as whitish, sclerotic plaques in certain areas of the tympanic membrane. Histologically, there is an increase in collagen fibers as well as hyaline degeneration within the lamina propria –3. The pIn Japan, simple underlay myringoplasty with fibrin glue is a well-established procedure because of its high success rate and low risk of sensorineural hearing loss –11. The We present our operative procedure of simple underlay myringoplasty with myringosclerosis  over theClosure of the perforation was successful in 10 (91%) of the 11 patients. Failure of the graft occurred in one patient who underwent a revision procedure using her stored fascia in the outpatient clinic with a successful outcome. The overall success rate was 100%. The air conduction hearing level postoperatively was significantly improved as compared with that of preoperative level . The airAll patients gave their written informed consent, and the study was approved by the ethics committee of Juntendo University Faculty of Medicine.Myringosclerosis is the term used to describe hyalinization and calcification of the connective tissue layer in the lamina propria of the tympanic membrane. The exact etiology and pathogenesis of myringosclerosis are not known. Myringosclerosis often occurs in patients who had undergone the insertion of tympanostomy tubes. An increased oxygen concentration in the atmosphere of the ear is associated with the increased development of myringosclerosis in a traumatized tympanic membrane , and admA previous study showed no significant difference in the success rate of myringoplasty between the myringosclerotic and the nonmyringosclerotic groups . On the In conclusion, despite the small number of cases and having no control group, removal of myringosclerosis at the edge of a perforation is expected to improve graft success and a better-looking graft for simple underlay myringoplasty, especially when myringosclerosis extends over the entire tympanic membrane.


Current advances in molecular biology, together with the development of Biobanks as stable sources of biologic material, are enhancing the possibility of detecting genetic factors involved in the molecular pathogenic mechanisms of migraine, a complex neurological disorder classified as the seventh most disabling disease worldwide.To date, the migraine section of the Interinstitutional Multidisciplinary Biobank (BioBIM) of IRCCS San Raffaele Pisana has recruited 863 migraine patients and 400 healthy individuals as controls. Each biological sample has been associated with extremely detailed socio-demographic and clinical features of the donor. Thanks Our Biobank dedicated to migraine has proven to be a valuable resource to conduct molecular studies on this disease, allowing the identification of a new potential biomarker for detection of asymptomatic individuals at increased risk for migraine development, in addition to providing the basis for the design of more tailored and effective therapies.None.


The group of filamentous fungi contains important species used in industrial biotechnology for acid, antibiotics and enzyme production. Their unique lifestyle turns these organisms into a valuable genetic reservoir of new natural products and biomass degrading enzymes that has not been used to full capacity. One of the major bottlenecks in the development of new strains into viable industrial hosts is the alteration of the metabolism towards optimal production. Genome-scale models promise a reduction in the time needed for metabolic engineering by predicting the most potent targets in silico before testing them in vivo. The increasing availability of high quality models and molecular biological tools for manipulating filamentous fungi renders the model-guided engineering of these fungal factories possible with comprehensive metabolic networks. A typical fungal model contains on average 1138 unique metabolic reactions and 1050 ORFs, making them a vast knowledge-base of fungal metabolism. In the present review we focus on the current state as well as potential future applications of genome-scale models in filamentous fungi. Aspergillus niger as the major source of citric acid production. Furthermore, reflecting the saprobic lifestyle of many filamentous fungi, they harbor a great variety of biomass-degrading enzymes natively produced in high amounts. Additionally, the large diversity of bioactive compounds produced by filamentous fungi is just being recognized as a valuable reservoir of promising new natural compounds. Exploration of the biosynthetic capabilities of these organisms has been facilitated by the availability of genome sequences, thereby enabling the discovery of secondary metabolite clusters being inactive under standard laboratory conditions.Filamentous fungi have been used for decades in industrial biotechnology exploiting their ability to utilize various sources of nutrients and tolerating adverse growth conditions. For example, tolerance of low pH and the endogenous property of producing citric acid in high amounts have led to the establishment of A key requirement for the transition of a new compound into a viable commercial product is the availability of a host producing the compound in sufficiently high amounts. As the organisms are, in general, not evolutionarily optimized to produce a single compound in optimal amounts, process optimizations as well as genetic modifications have to be performed. The rational approach of modifying the metabolism of an organism in order to improve product output constitutes the field of metabolic engineering. Due to the lack of information in the pre-genomic era, the scope of metabolic engineering has been limited to individual pathways not considering inherent interdependencies in the metabolic network. The availability of genome sequence information provides the opportunity to expand the scope of metabolic engineering to the whole metabolism transforming the field towards systems biotechnology. As the process of metabolic engineering represents a bottleneck in the development of many cell factories, accurate predictions by metabolic models could help to reduce the time and costs involved by guiding the efforts towards the most promising set of modifications.Haemophilus influenza 20 years ago  in filamentous fungi started considerably later with the first genome being published in 2003 for These reconstructions differ considerably in their content of legacy information included, reflecting different strategies of model establishment. The process of manual reconstruction tends to be laborious, as a maximum amount of information is considered leading to the generation of a structured knowledge base. The complementary approach aims at establishing genome-scale reconstructions (semi-)automatically based on sequence comparisons and gene assignments, enabling the prediction of genome-scale networks for less covered species. While these models generally move towards a larger number of genes and reactions included as models are progressively improved, a qualitative comparison with respect to the numbers of reactions and genes included in the resulting models of these different strategies is not directly possible. The majority of automatically generated models contain dead-ends and/or unconnected reactions that have been removed from manually created and curated models, resulting in higher number of genes included. The results from both of these approaches are fragmentary summaries of the metabolic capacities of the organisms requiring additional curation in the form of gap-filling in order to make computational analysis of the networks feasible. The mathematical background of the underlying modeling approach has been reviewed elsewhere  has been used to assign genes to metabolic pathways in different strains  and level of characterization of the individual organisms. A key aspect of metabolism in eukaryotes is the separation of metabolic reactions in different compartments. The correct assignment of metabolic enzymes to these compartments requires detailed information not readily available for a number of components in filamentous fungi metabolism. Even though this imprecision can limit the accuracy of predictions by these models, they still provide a valuable tool for data interpretation besides being a collection of information that is easily accessible. The unique feature of genome-scale network reconstructions is the integration of different types of information from various sources including databases such as KEGG and Swissprot as well as primary literature data. This ordered collection of metabolic reactions is curated with genomic information and literature citations which results in a structured knowledgebase for the specific organism. While organism specific databases pursue a similar goal, the strength of genome-scale reconstructions is the easy accessibility for computational analysis.While genome-scale metabolic modeling in E. coli and S. cerevisiae, enabling multiple genetic modifications in the same host, but have only recently become available in filamentous fungi (Oakley et al. Although genome-scale models have been developed for various filamentous fungi (see Table E. coli where accuracies of >90 and 80 % have been achieved for single- and double gene knockouts respectively (Monk and Palsson Additional factors potentially hampering the final development of these models into predictive tools for genetic modifications are the low percentage of experimentally verified gene assignments, unknown subcellular localization of the different pathways, as well as insufficient data for model validation. Due to advancements in the field of high throughput omics-technologies this necessary data for modeling is becoming more and more available facilitating the prospective use of genome-scale models as well as the model building process. The extension of the knowledge being available for incorporation will furthermore improve the prediction accuracy of existing models rendering more advanced applications possible. This improvement of prediction accuracy over time has already been demonstrated by the genome-scale model of Continuous extension of the models towards more detailed representations while improving their predictive power demonstrates the iterative nature of model development. The availability of predictive models for important organisms used in industrial biotechnology will provide the opportunity to choose the best performing host platform for a new biotechnological process by simulation, as optimal production of an individual compound requires a very specific metabolic performance. This comparability of genome-scale reconstructions between different species has been severely hampered by the non-standardized modeling practice of the different research groups in the past. With the development of modeling standards (Le Novère et al. During the past years, life sciences and biotechnology has begun the transformation from data-poor to a data-rich discipline introducing the need for new tools of analysis and interpretation of the generated data. Genome-scale metabolic networks have been proven useful in contextualizing and analyzing the data acquired by the different omics-techniques. At the same time, the increase in availability and quality of omics data pave the way for the generation of more detailed and context-specific metabolic networks based on the presence of individual metabolic activities. This usage of omics data as a surrogate for the customization of genome-scale models will increase in importance as the sensitivity of the omics technologies is improving. The combination of multi-omics measurements with metabolic modeling provides a powerful tool for the detection and elucidation of unknown relations and interactions. Improvements in the molecular toolbox for genetic engineering will allow for a faster realization of model predictions in the future thereby increasing the speed of model improvement. Taken together the recent developments in the metabolic modeling as well as experimental techniques for generating relevant data are promising for an increased use of model-driven decision making in future.