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High-fat diet is associated with hypercholesterolemia and seminal alterations in White New Zealand rabbits. We have previously reported disorders in the development of the manchette-acrosome complex during spermiogenesis and decreased testicular efficiency in hypercholesterolemic rabbits. On the other hand, olive oil incorporated into the diet improves cholesterolemia and semen parameters affected in hypercholesterolemic rabbits. In this paper, we report the recovery—with the addition of olive oil to diet—from the sub-cellular mechanisms involved in the shaping of the sperm cell and testicular efficiency altered in hypercholesterolemic rabbits. Using morphological (structural, ultra-structural and immuno-fluorescence techniques) and cell biology techniques, a reorganization of the manchette and related structures was observed when olive oil was added to the high-fat diet. Specifically, actin filaments, microtubules and lipid rafts—abnormally distributed in hypercholesterolemic rabbits—were recovered with dietary olive oil supplementation. The causes of the decline in sperm count were studied in the previous report and here in more detail. These were attributed to the decrease in the efficiency index and also to the increase in the apoptotic percentage in testis from animals under the high-fat diet. Surprisingly, the addition of olive oil to the diet avoided the sub-cellular, efficiency and apoptosis changes observed in hypercholesterolemic rabbits. This paper reports the positive effects of the olive oil addition to the diet in the recovery of testicular efficiency and normal sperm shaping, mechanisms altered by hypercholesterolemia. [ABSTRACT FROM AUTHOR]

The neural computational model GrowthEstimate is introduced with focusing on new perspectives for the practical estimation of weight specific growth rate (SGR, % day–1). It is developed using recurrent neural networks of reservoir computing type, for estimating SGR based on the known data of three key biological factors relating to growth. These factors are: (1) weight (g) for specifying the age of the growth stage; (2) digestive efficiency through the pyloric caecal activity ratio of trypsin to chymotrypsin (T/C ratio) for specifying genetic differences in food utilization and growth potential, basically resulting from food consumption under variations in food quality and environmental conditions; and (3) protein growth efficiency through the condition factor (CF, 100 × g cm–3), as higher dietary protein level affecting higher skeletal growth (length) and resulting in lower CF. The computational model was trained using four datasets of different salmonids with size variations. It was evaluated with 15% of each dataset, resulting in an acceptable range of SGR outputs. Additional tests with different species indicated similarity between the estimated SGR outputs and the real SGR values, and the same ranking of wild population growth. The developed model GrowthEstimate is exceptionally useful for the precise and comparable growth estimation of living resources at individual levels, especially in natural ecosystems where the studied individuals, environmental conditions, food availability and consumption rates cannot be controlled. It is a revelation and will help to minimize uncertainty in wild stock assessment process. This will improve our knowledge in nutritional ecology, through the biochemical effects of climate change and environmental impact on the growth performance quality of aquatic living resources in the wild, as well as in aquaculture. The original GrowthEstimate software is available at GitHub repository (). All other relevant data are within the paper. It will be improved for generality for future use, and required co-operations of the biodata collections of different species from different climate zones. Therefore, a co-operation will be available. [ABSTRACT FROM AUTHOR]

Freshwater sulfide springs have extreme environmental conditions that only few vertebrate species can tolerate. These species often develop a series of morphological and molecular adaptations to cope with the challenges of life under the toxic and hypoxic conditions of sulfide springs. In this paper, we described a new fish species of the genus Jenynsia, Anablepidae, from a sulfide spring in Northwestern Argentina, the first in the family known from such extreme environment. Jenynsia sulfurica n. sp. is diagnosable by the lack of scales on the pre-pelvic area or the presence of a single row of scales, continuous or not, from the isthmus to the bases of the pelvic fins. Additionally, it presents a series of morphological and molecular characteristics that appear convergent with those seen in other fish species (e.g., Poeciliids) inhabiting sulfide springs. Most notably, J. sulfurica has an enlarged head and postorbital area compared to other fish of the genus and a prognathous lower jaw with a hypertrophied lip, thought to facilitate respiration at the air-water interface. Analyses of cox1 sequence showed that J. sulfurica has two unique mutations resulting in amino acid substitutions convergent to those seen in Poeciliids from sulfide springs and known to provide a physiological mechanism related to living in sulfide environments. A phylogenetic analysis, including molecular and morphological characters, placed J. sulfurica as sister taxa to J. alternimaculata, a species found in nearby, non-sulfide habitats directly connected to the sulfide springs. Thus, it can be inferred that the selection imposed by the presence of H2S has resulted in the divergence between these two species and has potentially served as a barrier to gene flow. [ABSTRACT FROM AUTHOR]

The subset of pro-inflammatory B cells, called late memory, tissue-like or double negative (DN), accumulates in the blood of elderly individuals. Here we show that DN B cells do not proliferate and do not make antibodies to influenza antigens, but they secrete antibodies with autoimmune reactivity, in agreement with their membrane phenotype (CD95+CD21-CD11c+) and their spontaneous expression of the transcription factor T-bet. These cells also increase in the blood of individuals with obesity and autoimmune diseases, but causative mechanisms and signaling pathways involved are known only in part. In the present paper we compare frequencies and metabolic requirements of these cells in the blood of healthy individuals of different ages and in the blood and the subcutaneous adipose tissue (SAT) of individuals with obesity. Results show that DN B cells from young individuals have minimal metabolic requirements, DN B cells from elderly and obese individuals utilize higher amounts of glucose to perform autoimmune antibody production and enroll in aerobic glycolysis to support their function. DN B cells from the SAT have the highest metabolic requirements as they activate oxidative phosphorylation, aerobic glycolysis and fatty acid oxidation. DN B cells from the SAT also show the highest levels of ROS and the highest levels of phosphorylated AMPK (5’-AMP activated kinase) and Sestrin 1, both able to mitigate stress and cell death. This metabolic advantage drives DN B cell survival and function (secretion of autoimmune antibodies). [ABSTRACT FROM AUTHOR]

Microscopic examination of peripheral blood plays an important role in the field of diagnosis and control of major diseases. Peripheral leukocyte recognition by manual requires medical technicians to observe blood smears through light microscopy, using their experience and expertise to discriminate and analyze different cells, which is time-consuming, labor-intensive and subjective. The traditional systems based on feature engineering often need to ensure successful segmentation and then manually extract certain quantitative and qualitative features for recognition but still remaining a limitation of poor robustness. The classification pipeline based on convolutional neural network is of automatic feature extraction and free of segmentation but hard to deal with multiple object recognition. In this paper, we take leukocyte recognition as object detection task and apply two remarkable object detection approaches, Single Shot Multibox Detector and An Incremental Improvement Version of You Only Look Once. To improve recognition performance, some key factors involving these object detection approaches are explored and the detection models are generated using the train set of 14,700 annotated images. Finally, we evaluate these detection models on test sets consisting of 1,120 annotated images and 7,868 labeled single object images corresponding to 11 categories of peripheral leukocytes, respectively. A best mean average precision of 93.10% and mean accuracy of 90.09% are achieved while the inference time is 53 ms per image on a NVIDIA GTX1080Ti GPU. [ABSTRACT FROM AUTHOR]

Many computational theories have been developed to improve artificial phonetic classification performance from linguistic auditory streams. However, less attention has been given to psycholinguistic data and neurophysiological features recently found in cortical tissue. We focus on a context in which basic linguistic units–such as phonemes–are extracted and robustly classified by humans and other animals from complex acoustic streams in speech data. We are especially motivated by the fact that 8-month-old human infants can accomplish segmentation of words from fluent audio streams based exclusively on the statistical relationships between neighboring speech sounds without any kind of supervision. In this paper, we introduce a biologically inspired and fully unsupervised neurocomputational approach that incorporates key neurophysiological and anatomical cortical properties, including columnar organization, spontaneous micro-columnar formation, adaptation to contextual activations and Sparse Distributed Representations (SDRs) produced by means of partial N-Methyl-D-aspartic acid (NMDA) depolarization. Its feature abstraction capabilities show promising phonetic invariance and generalization attributes. Our model improves the performance of a Support Vector Machine (SVM) classifier for monosyllabic, disyllabic and trisyllabic word classification tasks in the presence of environmental disturbances such as white noise, reverberation, and pitch and voice variations. Furthermore, our approach emphasizes potential self-organizing cortical principles achieving improvement without any kind of optimization guidance which could minimize hypothetical loss functions by means of–for example–backpropagation. Thus, our computational model outperforms multiresolution spectro-temporal auditory feature representations using only the statistical sequential structure immerse in the phonotactic rules of the input stream. [ABSTRACT FROM AUTHOR]

Many mRNA-based vaccines have been investigated for their specific potential to activate dendritic cells (DCs), the highly-specialized antigen-presenting cells of the immune system that play a key role in inducing effective CD4+ and CD8+ T-cell responses. In this paper we report a new vaccine/gene delivery platform that demonstrates the benefits of using a self-amplifying (“replicon”) mRNA that is protected in a viral-protein capsid. Purified capsid protein from the plant virus Cowpea Chlorotic Mottle Virus (CCMV) is used to in vitro assemble monodisperse virus-like particles (VLPs) containing reporter proteins (e.g., Luciferase or eYFP) or the tandem-repeat model antigen SIINFEKL in RNA gene form, coupled to the RNA-dependent RNA polymerase from the Nodamura insect virus. Incubation of immature DCs with these VLPs results in increased activation of maturation markers – CD80, CD86 and MHC-II – and enhanced RNA replication levels, relative to incubation with unpackaged replicon mRNA. Higher RNA uptake/replication and enhanced DC activation were detected in a dose-dependent manner when the CCMV-VLPs were pre-incubated with anti-CCMV antibodies. In all experiments the expression of maturation markers correlates with the RNA levels of the DCs. Overall, these studies demonstrate that: VLP protection enhances mRNA uptake by DCs; coupling replicons to the gene of interest increases RNA and protein levels in the cell; and the presence of anti-VLP antibodies enhances mRNA levels and activation of DCs in vitro. Finally, preliminary in vivo experiments involving mouse vaccinations with SIINFEKL-replicon VLPs indicate a small but significant increase in antigen-specific T cells that are doubly positive for IFN and TFN induction. [ABSTRACT FROM AUTHOR]

Blocking cytokine interleukin 10 (IL-10) at the time of immunisation enhances vaccine induced T cell responses and improves control of tumour cell growth in vivo. However, the effect of an IL-10 blockade on the biological function of macrophages has not been explored. In the current paper, a macrophage precursor cell line, U937 cells, was selected to investigate the differential expression of proteins and relevant cell signalling pathway changes, when stimulated with lipopolysaccharide (LPS) in the presence of antibodies to IL-10 or IL-10 receptor. We used a quantitative proteomic strategy to investigate variations in protein profiles of U937 cells following the treatments with LPS, LPS plus human anti-IL10 antibody and anti-IL10R antibody in 24hrs, respectively. The LPS treatment significantly activated actin-related cell matrix formation and immune response pathways. The addition of anti-IL10 and anti-IL10R antibody further promoted the immune response and potentially effect macrophage survival through PI3K/AKT signalling; however, the latter appeared to also upregulated oncogene XRCC5 and Cajal body associated processes. [ABSTRACT FROM AUTHOR]

The aim of the paper was to assess indicators of muscle and intestinal damage in triathletes. The study involved 15 triathletes whose objective for the season was to start in the XTERRA POLAND 2017 event (1,500-m swimming, 36-km cycling, and 10-km mountain running). Before the 14-week preparatory period, the competitors’ body composition was measured, aerobic capacity was tested (graded treadmill test) and blood samples were collected to determine markers showing the level of muscle and intestinal damage. Subsequent tests for body composition were carried out before and after the competition. Blood samples for biochemical indicators were collected the day before the competition, after the completed race, and 24 and 48 hours later. A significant decrease in body mass was observed after completing the race (–3.1±1.5%). The mean maximal oxygen uptake level among the studied athletes equalled 4.9±0.4 L·min–1, 58.8±4.5 mL·kg–1·min–1. The significant increase in concentrations of cortisol, c-reactive protein and myoglobin after the competition, significantly correlated with the significant increase in zonulin concentration (post 1h: r = 0.88, p = 0.007, r = 0,79, p = 0.001, r = 0.78, p = 0.001, and post 12h: r = 0.75, p = 0.01, r = 0.71, p = 0.011, r = 0.83, p = 0.02). No significant changes in the concentration of tumour necrosis factor alpha among the examined competitors were noted at following stages of the study. The results of our research showed that in order to monitor overload in the training of triathletes, useful markers reflecting the degree of muscle and intestinal damage include cortisol, testosterone, testosterone to cortisol ratio, c-reactive protein, myoglobin and zonulin. Changes in muscle cell damage markers strongly correlated with changes in zonulin concentration at particular stages of the study. Thus, one can expect that the concentrations of markers depicting the level of muscle cell damage after an intense and long-lasting effort will significantly influence the level of the intestinal barrier. [ABSTRACT FROM AUTHOR]

Malaria remains one the world’s most deadly infectious diseases, with almost half a million deaths and over 150 million clinical cases each year. An effective vaccine would contribute enormously to malaria control and will almost certainly be required for eventual eradication of the disease. However, the leading malaria vaccine candidate, RTS,S, shows only 30–50% efficacy under field conditions, making it less cost-effective than long-lasting insecticide treated bed nets. Other subunit malaria vaccine candidates, including TRAP-based vaccines, show no better protective efficacy. This has led to increased interest in combining subunit malaria vaccines as a means of enhancing protective efficacy. Mathematical models of the effect of combining such vaccines on protective efficacy can help inform optimal vaccine strategies and decision-making at all stages of the clinical process. So far, however, no such model has been developed for pre-clinical murine studies, the stage at which all candidate antigens and combinations begin evaluation. To address this gap, this paper develops a mathematical model of vaccine combination adapted to murine malaria studies. The model is based on simple probabilistic assumptions which put the model on a firmer theoretical footing than previous clinical models, which rather than deriving a relationship between immune responses and protective efficacy posit the relationship to be either exponential or Hill curves. Data from pre-clinical murine malaria studies are used to derive values for unknowns in the model which in turn allows simulations of vaccine combination efficacy and suggests optimal strategies to pursue. Finally, the ability of the model to shed light on fundamental biological variables of murine malaria such as the blood stage growth rate and sporozoite infectivity is explored. [ABSTRACT FROM AUTHOR]

Speech recognition (SR) has been improved significantly by artificial neural networks (ANNs), but ANNs have the drawbacks of biologically implausibility and excessive power consumption because of the nonlocal transfer of real-valued errors and weights. While spiking neural networks (SNNs) have the potential to solve these drawbacks of ANNs due to their efficient spike communication and their natural way to utilize kinds of synaptic plasticity rules found in brain for weight modification. However, existing SNN models for SR either had bad performance, or were trained in biologically implausible ways. In this paper, we present a biologically inspired convolutional SNN model for SR. The network adopts the time-to-first-spike coding scheme for fast and efficient information processing. A biological learning rule, spike-timing-dependent plasticity (STDP), is used to adjust the synaptic weights of convolutional neurons to form receptive fields in an unsupervised way. In the convolutional structure, the strategy of local weight sharing is introduced and could lead to better feature extraction of speech signals than global weight sharing. We first evaluated the SNN model with a linear support vector machine (SVM) on the TIDIGITS dataset and it got the performance of 97.5%, comparable to the best results of ANNs. Deep analysis on network outputs showed that, not only are the output data more linearly separable, but they also have fewer dimensions and become sparse. To further confirm the validity of our model, we trained it on a more difficult recognition task based on the TIMIT dataset, and it got a high performance of 93.8%. Moreover, a linear spike-based classifier—tempotron—can also achieve high accuracies very close to that of SVM on both the two tasks. These demonstrate that an STDP-based convolutional SNN model equipped with local weight sharing and temporal coding is capable of solving the SR task accurately and efficiently. [ABSTRACT FROM AUTHOR]

Surface electromyography is often used to assess muscle activity and muscle function. A wavelet approach provides information about the intensity of muscle activity and motor unit recruitment strategies at every time point of the gait cycle. The aim was to review papers that employed wavelet analyses to investigate electromyograms of lower extremity muscles during walking and running. Eleven databases were searched up until June 1st 2017. The composition was based on the PICO model and the PRISMA checklist. First author, year, subject characteristics, intervention, outcome measures & variables, results and wavelet specification were extracted. Eighteen studies included the use of wavelets to investigate electromyograms of lower extremity muscles. Three main topics were discussed: 1.) The capability of the method to correctly assign participants to a specific group (recognition rate) varied between 68.4%-100%. 2.) Patients with ankle osteoarthritis or total knee arthroplasty presented a delayed muscle activation in the early stance phase but a prolonged activation in mid stance. 3.) Atrophic muscles did not contain type II muscle fiber components but more energy in their lower frequencies. The simultaneous information of time, frequency and intensity is of high clinical relevance because it offers valuable information about pre-and reflex activation behavior on different walking and running speeds as well as spectral changes towards high or low frequencies at every time point of the gait cycle. [ABSTRACT FROM AUTHOR]

Computational models of normal liver function and xenobiotic induced liver damage are increasingly being used to interpret in vitro and in vivo data and as an approach to the de novo prediction of the liver’s response to xenobiotics. The microdosimetry (dose at the level of individual cells) of xenobiotics vary spatially within the liver because of both compound-independent and compound-dependent factors. In this paper, we build model liver lobules to investigate the interplay between vascular structure, blood flow and cellular transport that lead to regional variations in microdosimetry. We then compared simulation results obtained using this complex spatial model with a simpler linear pipe model of a sinusoid and a very simple single box model. We found that variations in diffusive transport, transporter-mediated transport and metabolism, coupled with complex liver sinusoid architecture and blood flow distribution, led to three essential patterns of xenobiotic exposure within the virtual liver lobule: (1) lobular-wise uniform, (2) radially varying and (3) both radially and azimuthally varying. We propose to use these essential patterns of exposure as a reference for selection of model representations when a computational study involves modeling detailed hepatic responses to xenobiotics. [ABSTRACT FROM AUTHOR]

The last decade has seen the emergence of new views about the mechanisms underlying specificity (or, conversely, generalization) of visual skill learning. Here, we trained participants at orientation discrimination paradigm at a peripheral position to induce position and orientation specificity and to test its underlying mechanisms. Specifically, we aimed to test whether the within-quadrant spatial gradient of generalization is determined by cortical magnification, which would show that retinotopic plasticity contributes to learning and specificity. Additionally, we aimed to test whether late parts of the learning relate differently to specificity compared to early parts. This is relevant in the context of double training papers, which suggest that rule-based mechanisms of specificity in fast, early learning also would apply to late, slower learning. Our data showed partial but significant position and orientation specificity within quadrants. Interestingly, specificity was greatest for those participants who had continued to show threshold decreases during the last five sessions of training (late, asymptotic learning). Performance gains during early learning were less related to specificity. A trend for skill to spread over larger distances towards periphery than towards central vision suggested contributions to transfer of early visual areas showing cortical magnification of central vision. Control experiments however did not support this hypothesis. In summary, our study demonstrates significant specificity after extensive perceptual learning, and indicates that asymptotic learning recruits specific mechanisms that promote specificity, and that may not be recruited yet in early parts of the learning. The contributions of different mechanisms to early and late learning suggests that following these different learning periods, generalization relies on different principles and is subjected to different limits. [ABSTRACT FROM AUTHOR]

It is well accepted that influenza A virus predisposes individuals to often more severe superinfections with Streptococcus pneumonia. However, the mechanisms that lead to this synergy are not clearly understood. Recent data suggests that competent Th17 immunity is crucial to clearance and protection from invasive pneumococcal disease of the lung. We demonstrate that early influenza infection significantly reduced levels of pneumococcus driven IL-12p70, IL-23 and IL-27 in human monocytes with significant impairment of IL-17A and IFN-γ in HKSP-treated allogeneic mixed lymphocyte cultures. We also provide evidence to suggest that the hemagglutinin component of the virus is at least partially responsible for this downward pressure on IL-17 responses but surprisingly this suppression occurs despite robust IL-23 levels in hemagglutinin-treated monocyte cultures. This study demonstrates that influenza can directly affect the immunological pathways that promote appropriate responses to Streptococcus pneumonia in human immune cells. Importance: Influenza virus is highly contagious and poses substantial public health problems due to its strong association with morbidity and mortality. Approximately 250,000–500,000 deaths are caused by seasonal influenza virus annually, and this figure increases during periods of pandemic infections. Most of these deaths are due to secondary bacterial pneumonia. Influenza-bacterial superinfection can result in hospitalisation and/or death of both patients with pre-existing lung disease or previously healthy individuals. The importance of our research is in determining that influenza and its component haemagglutinin has a direct effect on the classic pneumococcus induced pathways to IL-17A in our human ex vivo model. Our understanding of the mechanism which leaves people exposed to influenza infection during superinfection remain unresolved. This paper demonstrates that early infection of monocytes inhibits an arm of immunity crucial to bacterial clearance. Understanding this mechanism may provide alternative interventions in the case of superinfection with antimicrobial resistant strains of bacteria. [ABSTRACT FROM AUTHOR]

Background: Non-union affects up to 10% of fractures and is associated with substantial morbidity. There is currently no single effective therapy for the treatment or prevention of non-union. Potential treatments are currently selected for clinical trials based on results from limited animal studies, with no attempt to compare results between therapies to determine which have the greatest potential to treat non-union. Aim: The aim of this systematic review was to define the range of therapies under investigation at the preclinical stage for the prevention or treatment of fracture non-union. Additionally, through meta-analysis, it aimed to identify the most promising therapies for progression to clinical investigation. Methods: MEDLINE and Embase were searched from 1St January 2004 to 10th April 2017 for controlled trials evaluating an intervention to prevent or treat fracture non-union. Data regarding the model used, study intervention and outcome measures were extracted, and risk of bias assessed. Results: Of 5,171 records identified, 197 papers describing 204 therapies were included. Of these, the majority were only evaluated once (179/204, 88%), with chitosan tested most commonly (6/204, 3%). Substantial variation existed in model design, length of survival and duration of treatment, with results poorly reported. These factors, as well as a lack of consistently used objective outcome measures, precluded meta-analysis. Conclusion: This review highlights the variability and poor methodological reporting of current non-union research. The authors call for a consensus on the standardisation of animal models investigating non-union, and suggest journals apply stringent criteria when considering animal work for publication. [ABSTRACT FROM AUTHOR]

The spiking neural networks (SNNs) are the third generation of neural networks and perform remarkably well in cognitive tasks such as pattern recognition. The spike emitting and information processing mechanisms found in biological cognitive systems motivate the application of the hierarchical structure and temporal encoding mechanism in spiking neural networks, which have exhibited strong computational capability. However, the hierarchical structure and temporal encoding approach require neurons to process information serially in space and time respectively, which reduce the training efficiency significantly. For training the hierarchical SNNs, most existing methods are based on the traditional back-propagation algorithm, inheriting its drawbacks of the gradient diffusion and the sensitivity on parameters. To keep the powerful computation capability of the hierarchical structure and temporal encoding mechanism, but to overcome the low efficiency of the existing algorithms, a new training algorithm, the Normalized Spiking Error Back Propagation (NSEBP) is proposed in this paper. In the feedforward calculation, the output spike times are calculated by solving the quadratic function in the spike response model instead of detecting postsynaptic voltage states at all time points in traditional algorithms. Besides, in the feedback weight modification, the computational error is propagated to previous layers by the presynaptic spike jitter instead of the gradient decent rule, which realizes the layer-wised training. Furthermore, our algorithm investigates the mathematical relation between the weight variation and voltage error change, which makes the normalization in the weight modification applicable. Adopting these strategies, our algorithm outperforms the traditional SNN multi-layer algorithms in terms of learning efficiency and parameter sensitivity, that are also demonstrated by the comprehensive experimental results in this paper. [ABSTRACT FROM AUTHOR]

Several biological tissues undergo changes in their geometry and in their bulk material properties by modelling and remodelling processes. Modelling synthesises tissue in some regions and removes tissue in others. Remodelling overwrites old tissue material properties with newly formed, immature tissue properties. As a result, tissues are made up of different “patches”, i.e., adjacent tissue regions of different ages and different material properties, within evolving boundaries. In this paper, generalised equations governing the spatio-temporal evolution of such tissues are developed within the continuum model. These equations take into account nonconservative, discontinuous surface mass balance due to creation and destruction of material at moving interfaces, and bulk balance due to tissue maturation. These equations make it possible to model patchy tissue states and their evolution without explicitly maintaining a record of when/where resorption and formation processes occurred. The time evolution of spatially averaged tissue properties is derived systematically by integration. These spatially-averaged equations cannot be written in closed form as they retain traces that tissue destruction is localised at tissue boundaries. The formalism developed in this paper is applied to bone tissues, which exhibit strong material heterogeneities due to their slow mineralisation and remodelling processes. Evolution equations are proposed in particular for osteocyte density and bone mineral density. Effective average equations for bone mineral density (BMD) and tissue mineral density (TMD) are derived using a mean-field approximation. The error made by this approximation when remodelling patchy tissue is investigated. The specific signatures of the time evolution of BMD or TMD during remodelling events are exhibited. These signatures may provide a way to detect remodelling events at lower, unseen spatial resolutions from microCT scans. [ABSTRACT FROM AUTHOR]

Specific memory might be stored in a subnetwork consisting of a small population of neurons. To select neurons involved in memory formation, neural competition might be essential. In this paper, we show that excitable neurons are competitive and organize into two assemblies in a recurrent network with spike timing-dependent synaptic plasticity (STDP) and axonal conduction delays. Neural competition is established by the cooperation of spontaneously induced neural oscillation, axonal conduction delays, and STDP. We also suggest that the competition mechanism in this paper is one of the basic functions required to organize memory-storing subnetworks into fine-scale cortical networks. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum infections presenting either as symptomatic or asymptomatic may contain sexual stage parasites (gametocytes) that are crucial to malaria transmission. In this study, the prevalence of microscopic and submicroscopic asexual and gametocyte parasite stages were assessed in asymptomatic children from two communities in southern Ghana. Eighty children aged twelve years and below, none of whom exhibited signs of clinical malaria living in Obom and Cape Coast were sampled twice, one during the rainy (July 2015) and subsequently during the dry (January 2016) season. Venous blood was used to prepare thick and thin blood smears, spot a rapid malaria diagnostic test (PfHRP2 RDT) as well as prepare filter paper blood spots. Blood cell pellets were preserved in Trizol for RNA extraction. Polymerase chain reaction (PCR) and semi-quantitative real time reverse transcriptase PCR (qRT-PCR) were used to determine submicroscopic parasite prevalence. In both sites 87% (95% CI: 78–96) of the asymptomatic individuals surveyed were parasites positive during the 6 month study period. The prevalence of asexual and gametocyte stage parasites in the rainy season were both significantly higher in Obom than in Cape Coast (P < 0.001). Submicroscopic gametocyte prevalence was highest in the rainy season in Obom but in the dry season in Cape Coast. Parasite prevalence determined by PCR was similar to that determined by qRT-PCR in Obom but significantly lower than that determined by qRT-PCR in Cape Coast. Communities with varying parasite prevalence exhibit seasonal variations in the prevalence of gametocyte carriers. Submicroscopic asymptomatic parasite and gametocyte carriage is very high in southern Ghana, even during the dry season in communities with low microscopic parasite prevalence and likely to be missed during national surveillance exercises. [ABSTRACT FROM AUTHOR]

Triticum vulgare has been extensively used in traditional medicine thanks to its properties of accelerating tissue repair. The specific extract of Triticum vulgare manufactured by Farmaceutici Damor (TVE-DAMOR) is already present in some pharmaceutical formulations used in the treatment of decubitus ulcers, skin lesions and burns. It has been recently suggested that this Triticum vulgare extract may possess potential anti-inflammatory properties. In the light of these premises the aim of the present paper was to verify the anti-inflammatory role of TVE, using the LPS-stimulated microglia model of inflammation. In particular the effect of different concentrations of TVE on the release of several mediators of inflammation such as nitric oxide, IL-6, PGE2 and TNF alpha was evaluated. More important, the anti-inflammatory effect of TVE was confirmed also in primary rat microglia cultures. The results of the present study show that TVE exerts anti-inflammatory properties since it reduces the release of all the evaluated markers of inflammation, such as NO, IL6, TNF alpha and PGE2 in LPS-activated BV2 microglial cells. Intriguingly, TVE reduced microglia activation and NO release also in primary microglia. Indeed, to verify the pathway of modulation of the inflammatory markers reported above, we found that TVE restores the cytoplasmic expression of p65 protein, kwown as specific marker associated with activation of inflammatory response. The evidence for an inhibitory activity on inflammation of this specific extract of Triticum vulgare may open the way to the possibility of a therapeutical use of the Triticum vulgare extract as an anti-inflammatory compound in certain pathological states such as burns, decubitus ulcers, folliculitis and inflammation of peripheral nerve. [ABSTRACT FROM AUTHOR]

This paper proposes a shared synapse architecture for autoencoders (AEs), and implements an AE with the proposed architecture as a digital circuit on a field-programmable gate array (FPGA). In the proposed architecture, the values of the synapse weights are shared between the synapses of an input and a hidden layer, and between the synapses of a hidden and an output layer. This architecture utilizes less of the limited resources of an FPGA than an architecture which does not share the synapse weights, and reduces the amount of synapse modules used by half. For the proposed circuit to be implemented into various types of AEs, it utilizes three kinds of parameters; one to change the number of layers’ units, one to change the bit width of an internal value, and a learning rate. By altering a network configuration using these parameters, the proposed architecture can be used to construct a stacked AE. The proposed circuits are logically synthesized, and the number of their resources is determined. Our experimental results show that single and stacked AE circuits utilizing the proposed shared synapse architecture operate as regular AEs and as regular stacked AEs. The scalability of the proposed circuit and the relationship between the bit widths and the learning results are also determined. The clock cycles of the proposed circuits are formulated, and this formula is used to estimate the theoretical performance of the circuit when the circuit is used to construct arbitrary networks. [ABSTRACT FROM AUTHOR]

Due to its strong proliferation-reducing effects on keratinocytes, and also anti-inflammatory properties, the isoflavone genistein has already been proposed as a possible antipsoriatic compound. As there is still no detailed information on this topic, we examined the effects of genistein by using an in vitro model of both, normal and “psoriasis-like” keratinocytes at this stage of our work exhaustively testing the selected flavonoid in a mono-treated experimental design. Gene expression studies revealed transcriptional changes that confirms known disease-associated pathways and highlights many psoriasis-related genes. Our results suggested that aberrant expression of genes contributing to the progress of psoriasis could be improved by the action of genistein. Genistein prevented “cytokine mix” as well as TNF-α-induced NF-κB nuclear translocation, with no effect on the PI3K signaling cascade, indicating the luck of turning this pathway into NF-κB activation. It could have attenuated TNF-α and LPS-induced inflammatory responses by suppressing ROS activation. Regardless of the type of keratinocyte stimulation used, reduction of cytokine IL-8, IL-20 and CCL2 production (both at RNA and protein level) following genistein treatment was visible. Because investigations of other groups supported our commentary on potential administration of genistein as a potential weapon in the armamentarium against psoriasis, it is believed that this paper should serve to encourage researchers to conduct further studies on this subject. [ABSTRACT FROM AUTHOR]

Background and objectives: Vascular calcification (VC) is a major risk factor for elevated cardiovascular morbidity/mortality. Underlying this process is osteoblastic signalling within the vessel wall involving complex and interlinked roles for receptor-activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). RANKL promotes vascular cell osteoblastic differentiation, whilst OPG acts as a neutralizing decoy receptor for RANKL (and TRAIL). With respect to TRAIL, much recent evidence points to a vasoprotective role for this ligand, albeit via unknown mechanisms. In order to shed more light on TRAILs vasoprotective role therefore, we employed in vitro cell models to test the hypothesis that TRAIL can counteract the RANKL-mediated signalling that occurs between the vascular cells that comprise the vessel wall. Methods and results: Human aortic endothelial and smooth muscle cell mono-cultures (HAECs, HASMCs) were treated with RANKL (0–25 ng/mL ± 5 ng/mL TRAIL) for 72 hr. Furthermore, to better recapitulate the paracrine signalling that exists between endothelial and smooth muscle cells within the vessel wall, non-contact transwell HAEC:HASMC co-cultures were also employed and involved RANKL treatment of HAECs (±TRAIL), subsequently followed by analysis of pro-calcific markers in the underlying subluminal HASMCs. RANKL elicited robust osteoblastic signalling across both mono- and co-culture models (e.g. increased BMP-2, alkaline phosphatase/ALP, Runx2, and Sox9, in conjunction with decreased OPG). Importantly, several RANKL actions (e.g. increased BMP-2 release from mono-cultured HAECs or increased ALP/Sox9 levels in co-cultured HASMCs) could be strongly blocked by co-incubation with TRAIL. In summary, this paper clearly demonstrates that RANKL can elicit pro-osteoblastic signalling in HAECs and HASMCs both directly and across paracrine signalling axes. Moreover, within these contexts we present clear evidence that TRAIL can block several key signalling actions of RANKL in vascular cells, providing further evidence of its vasoprotective potential. [ABSTRACT FROM AUTHOR]

Human babesiosis is caused by the apicomplexan parasite Babesia microti, which is of major public health concern in the United States and elsewhere, resulting in malaise and fatigue, followed by a fever and hemolytic anemia. In this paper we focus on the characterization of a novel B. microti thrombospondin domain (TSP1)-containing protein (BmP53) from the new annotation of the B. microti genome (locus 'BmR1_04g09041'). This novel protein (BmP53) had a single TSP1 and a transmembrane domain, with a short cytoplasmic tail containing a sub-terminal glutamine residue, but no signal peptide and Von Willebrand factor type A domains (VWA), which are found in classical thrombospondin-related adhesive proteins (TRAP). Co-localization assays of BmP53 and Babesia microti secreted antigen 1 (BmSA1) suggested that BmP53 might be a non-secretory membranous protein. Molecular mimicry between the TSP1 domain from BmP53 and host platelets molecules was indicated through different measures of sequence homology, phylogenetic analysis, 3D structure and shared epitopes. Indeed, hamster isolated platelets cross-reacted with mouse anti-BmP53-TSP1. Molecular mimicry are used to help parasites to escape immune defenses, resulting in immune evasion or autoimmunity. Furthermore, specific host reactivity was also detected against the TSP1-free part of BmP53 in infected hamster sera. In conclusion, the TSP1 domain mimicry might help in studying the mechanisms of parasite-induced thrombocytopenia, with the TSP1-free truncate of the protein representing a potential safe candidate for future vaccine studies. [ABSTRACT FROM AUTHOR]

Studies of structural plasticity in the brain often require the detection and analysis of axonal synapses (boutons). To date, bouton detection has been largely manual or semi-automated, relying on a step that traces the axons before detection the boutons. If tracing the axon fails, the accuracy of bouton detection is compromised. In this paper, we propose a new algorithm that does not require tracing the axon to detect axonal boutons in 3D two-photon images taken from the mouse cortex. To find the most appropriate techniques for this task, we compared several well-known algorithms for interest point detection and feature descriptor generation. The final algorithm proposed has the following main steps: (1) a Laplacian of Gaussian (LoG) based feature enhancement module to accentuate the appearance of boutons; (2) a Speeded Up Robust Features (SURF) interest point detector to find candidate locations for feature extraction; (3) non-maximum suppression to eliminate candidates that were detected more than once in the same local region; (4) generation of feature descriptors based on Gabor filters; (5) a Support Vector Machine (SVM) classifier, trained on features from labelled data, and was used to distinguish between bouton and non-bouton candidates. We found that our method achieved a Recall of 95%, Precision of 76%, and F1 score of 84% within a new dataset that we make available for accessing bouton detection. On average, Recall and F1 score were significantly better than the current state-of-the-art method, while Precision was not significantly different. In conclusion, in this article we demonstrate that our approach, which is independent of axon tracing, can detect boutons to a high level of accuracy, and improves on the detection performance of existing approaches. The and (with an easy to use GUI) used in this article are available from open source repositories. [ABSTRACT FROM AUTHOR]

In this paper, we study a network of Izhikevich neurons to explore what it means for a brain to be at the edge of chaos. To do so, we first constructed the phase diagram of a single Izhikevich excitatory neuron, and identified a small region of the parameter space where we find a large number of phase boundaries to serve as our edge of chaos. We then couple the outputs of these neurons directly to the parameters of other neurons, so that the neuron dynamics can drive transitions from one phase to another on an artificial energy landscape. Finally, we measure the statistical complexity of the parameter time series, while the network is tuned from a regular network to a random network using the Watts-Strogatz rewiring algorithm. We find that the statistical complexity of the parameter dynamics is maximized when the neuron network is most small-world-like. Our results suggest that the small-world architecture of neuron connections in brains is not accidental, but may be related to the information processing that they do. [ABSTRACT FROM AUTHOR]

Cofilin and other Actin-regulating proteins are essential in regulating the shape of dendritic spines, which are sites of neuronal communications in the brain, and their malfunctions are implicated in neurodegeneration related to aging. The analysis of cofilin motility in dendritic spines using fluorescence video-microscopy may allow for the discovery of its effects on synaptic functions. To date, the flow of cofilin has not been analyzed by automatic means. This paper presents Dendrite Protein Analysis (DendritePA), a novel automated pattern recognition software to analyze protein trafficking in neurons. Using spatiotemporal information present in multichannel fluorescence videos, the DendritePA generates a temporal maximum intensity projection that enhances the signal-to-noise ratio of important biological structures, segments and tracks dendritic spines, estimates the density of proteins in spines, and analyzes the flux of proteins through the dendrite/spine boundary. The motion of a dendritic spine is used to generate spine energy images, which are used to automatically classify the shape of common dendritic spines such as stubby, mushroom, or thin. By tracking dendritic spines over time and using their intensity profiles, the system can analyze the flux patterns of cofilin and other fluorescently stained proteins. The cofilin flux patterns are found to correlate with the dynamic changes in dendritic spine shapes. Our results also have shown that the activation of cofilin using genetic manipulations leads to immature spines while its inhibition results in an increase in mature spines. [ABSTRACT FROM AUTHOR]

Epidemiological studies have indicated that smoking is a pivotal risk factor for the progression of several chronic diseases. Nicotine, the addictive component of cigarettes, has powerful pathophysiological properties in the body. Although the effects of cigarette smoking on corneal re-epithelialization have been studied, the effects of nicotine on corneal wound healing-related neovascularization and fibrosis have not been fully demonstrated. The aim of this study was to evaluate the effects of chronic administration of nicotine on corneal wound healing following acute insult induced by an alkali burn. BALB/C female mice randomly received either vehicle (2% saccharin) or nicotine (100 or 200 μg/ml in 2% saccharin) in drinking water ad libitum. After 1 week, animals were re-randomized and the experimental group was subjected to a corneal alkali burn, and then nicotine was administered until day 14 after the alkali burn. A corneal alkali burn model was generated by placing a piece of 2 mm-diameter filter paper soaked in 1N NaOH on the right eye. Histopathological analysis and the expression level of the pro-angiogenic genes vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) revealed that chronic nicotine administration enhanced alkali burn-induced corneal neovascularization. Furthermore, the mRNA expression of the pro-fibrogenic factors α-smooth muscle actin (αSMA), transforming growth factor-β (TGF-β), and collagen α1 (Col1) was enhanced in the high-concentration nicotine-treated group compared with the vehicle group after corneal injury. Immunohistochemical analysis also showed that the αSMA-positive area was increased in chronic nicotine-treated mice after corneal alkali burn. An in vitro assay found that expression of the α3, α7, and β1 nicotinic acetylcholine receptor (nAChR) subunits was significantly increased by chemical injury in human corneal fibroblast cells. Moreover, alkali-induced fibrogenic gene expression and proliferation of fibroblast cells were further increased by treatment with nicotine and cotinine. The proliferation of such cells induced by treatment of nicotine and cotinine was reduced by inhibition of the PI3K and PKC pathways using specific inhibitors. In conclusion, chronic administration of nicotine accelerated the angiogenic and fibrogenic healing processes in alkali-burned corneal tissue. [ABSTRACT FROM AUTHOR]

The spread of KPC-type carbapenemases is mainly attributed to the global dissemination of Klebsiella pneumoniae (KP) strains belonging to the clonal group (CG) 258, including sequence type (ST) 258 and other related STs. Two distinct clades of CG258-KP have evolved, which differ mainly for the composition of their capsular polysaccharides, and recent studies indicate that clade 1 evolved from an ancestor of clade 2 by recombination of a genomic fragment carrying the capsular polysaccharide (cps) locus. In this paper, we investigated the ability of two ST258-KP strains, KKBO-1 and KK207-1, selected as representatives of ST258-KP clade 2 and clade 1, respectively, to activate an adaptive immune response using ex vivo-stimulation of PBMC from normal donors as an experimental model. Our data showed that KKBO-1 (clade 2) induces a Th17 response more efficiently than KK207-1 (clade 1): the percentage of CD4+IL17+ cells and the production of IL-17A were significantly higher in cultures with KKBO-1 compared to cultures with KK207-1. While no differences in the rate of bacterial internalization or in the bacteria-induced expression of CD86 and HLA-DR by monocytes and myeloid dendritic cells were revealed, we found that the two strains significantly differ in inducing the production of cytokines involved in the adaptive immune response, as IL-1β, IL-23 and TNF-α, by antigen-presenting cells, with KKBO-1 being a more efficient inducer than KK207-1. The immune responses elicited by KK207-1 were comparable to those elicited by CIP 52.145, a highly virulent K. pneumoniae reference strain known to escape immune-inflammatory responses. Altogether, present results suggest that CG258-KP of the two clades are capable of inducing a different response of adaptive immunity in the human host. [ABSTRACT FROM AUTHOR]

Neural mechanisms which bind items into sequences have been investigated in a large body of research in animal neurophysiology and human neuroimaging. However, a major problem in interpreting this data arises from a fact that several unrelated processes, such as memory load, sensory adaptation, and reward expectation, also change in a consistent manner as the sequence unfolds. In this paper we use computational simulations and data from two fMRI experiments to show that a host of unrelated neural processes can masquerade as sequence representations. We show that dissociating such unrelated processes from a dedicated sequence representation is an especially difficult problem for fMRI data, which is almost exclusively the modality used in human experiments. We suggest that such fMRI results must be treated with caution and in many cases the assumed neural representation might actually reflect unrelated processes. [ABSTRACT FROM AUTHOR]

In this paper, modeling of the coupling medium between two neurons, the effects of the model parameters on the synchronization of those neurons, and compensation of coupling strength deficiency in synchronization are studied. Our study exploits the inter-neuronal coupling medium and investigates its intrinsic properties in order to get insight into neuronal-information transmittance and, there from, brain-information processing. A novel electrical model of the coupling medium that represents a well-known RLC circuit attributable to the coupling medium’s intrinsic resistive, inductive, and capacitive properties is derived. Surprisingly, the integration of such properties reveals the existence of a natural three-term control strategy, referred to in the literature as the proportional integral derivative (PID) controller, which can be responsible for synchronization between two neurons. Consequently, brain-information processing can rely on a large number of PID controllers based on the coupling medium properties responsible for the coherent behavior of neurons in a neural network. Herein, the effects of the coupling model (or natural PID controller) parameters are studied and, further, a supervisory mechanism is proposed that follows a learning and adaptation policy based on the particle swarm optimization algorithm for compensation of the coupling strength deficiency. [ABSTRACT FROM AUTHOR]

Background: Although it is well recognized that autism is associated with altered patterns of over- and under-connectivity, specifics are still a matter of debate. Little has been done so far to synthesize available literature using whole-brain electroencephalography (EEG) and magnetoencephalography (MEG) recordings. Objectives: 1) To systematically review the literature on EEG/MEG functional and effective connectivity in autism spectrum disorder (ASD), 2) to synthesize and critically appraise findings related with the hypothesis that ASD is characterized by long-range underconnectivity and local overconnectivity, and 3) to provide, based on the literature, an analysis of tentative factors that are likely to mediate association between ASD and atypical connectivity (e.g., development, topography, lateralization). Methods: Literature reviews were done using PubMed and PsychInfo databases. Abstracts were screened, and only relevant articles were analyzed based on the objectives of this paper. Special attention was paid to the methodological characteristics that could have created variability in outcomes reported between studies. Results: Our synthesis provides relatively strong support for long-range underconnectivity in ASD, whereas the status of local connectivity remains unclear. This observation was also mirrored by a similar relationship with lower frequencies being often associated with underconnectivity and higher frequencies being associated with both under- and over-connectivity. Putting together these observations, we propose that ASD is characterized by a general trend toward an under-expression of lower-band wide-spread integrative processes compensated by more focal, higher-frequency, locally specialized, and segregated processes. Further investigation is, however, needed to corroborate the conclusion and its generalizability across different tasks. Of note, abnormal lateralization in ASD, specifically an elevated left-over-right EEG and MEG functional connectivity ratio, has been also reported consistently across studies. Conclusions: The large variability in study samples and methodology makes a systematic quantitative analysis (i.e. meta-analysis) of this body of research impossible. Nevertheless, a general trend supporting the hypothesis of long-range functional underconnectivity can be observed. Further research is necessary to more confidently determine the status of the hypothesis of short-range overconnectivity. Frequency-band specific patterns and their relationships with known symptoms of autism also need to be further clarified. [ABSTRACT FROM AUTHOR]

Improved fertility following artificial insemination with frozen-thawed spermatozoa would offer rabbit producers faster genetic improvement. Previous work investigating cryoprotectants for rabbit spermatozoa have reported inconsistent results. Semen was collected from three rabbit bucks by artificial vagina and frozen using a standard procedure with varied cryodiluent components. Post-thaw analysis encompassed motility, sperm kinematic parameters and acrosome and membrane integrity. Spermatozoa were evaluated at 0, 2 and 4 h after thawing. Experiment 1 compared diluents with 3.5% dimethyl sulfoxide (DMSO), 1.5% acetamide, 1.75% DMSO + 0.75% acetamide or 3.5% DMSO + 1.5% acetamide. The treatment that resulted in the highest post-thaw motility (P<0.001) and acrosome integrity (P<0.001) was DMSO alone. Experiment 2 compared 3.5, 7 and 10% DMSO in the cryodiluent. The best post-thaw sperm motility (P<0.001) and linearity (P = .002) was in 3.5% DMSO, while 10% DMSO afforded higher acrosome/membrane integrity at this last time point (P<0.05). Experiment 3 varied the cryodiluent to contain either 9 or 17% egg yolk or 9 or 17% low density lipoproteins extracted from whole egg yolk. The treatment with the best post-thaw result was 17% egg yolk (motility, P = 0.01; acrosome/membrane integrity, P<0.001). Experiment 4 compared different carbohydrates in the cryodiluent; 50 mM glucose (TCG), 25 mM glucose with 25 mM sucrose (TCGS low), or 50 mM glucose with 50 mM sucrose (TCGS high). When data were pooled across time points, TCG had significantly higher motility than TCGS high (P = 0.021), but was not different from TCGS low. However, TCG had fewer spermatozoa with intact acrosomes and membranes than both TCGS low and TCGS high (P = .002). Put together, these results indicate that the best cryodiluent for rabbit spermatozoa frozen under the conditions used in this paper is with 7% DMSO and 17% egg yolk in a base medium containing 25 mM glucose and 25 mM sucrose. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is one of the leading causes of death worldwide, in particular myocardial dysfunction, which may lead to heart failure eventually. Understanding the electro-mechanics of the heart will help in developing more effective clinical treatments. In this paper, we present a multi-scale electro-mechanics model of the left ventricle (LV). The Holzapfel-Ogden constitutive law was used to describe the passive myocardial response in tissue level, a modified Grandi-Pasqualini-Bers model was adopted to model calcium dynamics in individual myocytes, and the active tension was described using the Niederer-Hunter-Smith myofilament model. We first studied the electro-mechanics coupling in a single myocyte in the healthy and diseased left ventricle, and then the single cell model was embedded in a dynamic LV model to investigate the compensation mechanism of LV pump function due to myocardial dysfunction caused by abnormality in cellular calcium dynamics. The multi-scale LV model was solved using an in-house developed hybrid immersed boundary method with finite element extension. The predictions of the healthy LV model agreed well with the clinical measurements and other studies, and likewise, the results in the failing states were also consistent with clinical observations. In particular, we found that a low level of intracellular Ca2+ transient in myocytes can result in LV pump function failure even with increased myocardial contractility, decreased systolic blood pressure, and increased diastolic filling pressure, even though they will increase LV stroke volume. Our work suggested that treatments targeted at increased contractility and lowering the systolic blood pressure alone are not sufficient in preventing LV pump dysfunction, restoring a balanced physiological Ca2+ handling mechanism is necessary. [ABSTRACT FROM AUTHOR]

Two, partially interwoven, hot topics in the analysis and statistical modeling of neural data, are the development of efficient and informative representations of the time series derived from multiple neural recordings, and the extraction of information about the connectivity structure of the underlying neural network from the recorded neural activities. In the present paper we show that state-space clustering can provide an easy and effective option for reducing the dimensionality of multiple neural time series, that it can improve inference of synaptic couplings from neural activities, and that it can also allow the construction of a compact representation of the multi-dimensional dynamics, that easily lends itself to complexity measures. We apply a variant of the ‘mean-shift’ algorithm to perform state-space clustering, and validate it on an Hopfield network in the glassy phase, in which metastable states are largely uncorrelated from memories embedded in the synaptic matrix. In this context, we show that the neural states identified as clusters’ centroids offer a parsimonious parametrization of the synaptic matrix, which allows a significant improvement in inferring the synaptic couplings from the neural activities. Moving to the more realistic case of a multi-modular spiking network, with spike-frequency adaptation inducing history-dependent effects, we propose a procedure inspired by Boltzmann learning, but extending its domain of application, to learn inter-module synaptic couplings so that the spiking network reproduces a prescribed pattern of spatial correlations; we then illustrate, in the spiking network, how clustering is effective in extracting relevant features of the network’s state-space landscape. Finally, we show that the knowledge of the cluster structure allows casting the multi-dimensional neural dynamics in the form of a symbolic dynamics of transitions between clusters; as an illustration of the potential of such reduction, we define and analyze a measure of complexity of the neural time series. [ABSTRACT FROM AUTHOR]

Routine blood tests provide important basic information for disease diagnoses. The proportions of three subtypes of white blood cells (WBCs), which are neutrophils, monocytes, lymphocytes, is key information for disease diagnosis. However, current instruments for routine blood tests, such as blood cell analyzers, flow cytometers, and optical microscopes, are cumbersome, time consuming and expensive. To make a smaller, automatic low-cost blood cell analyzer, much research has focused on a technique called lens-less shadow imaging, which can obtain microscopic images of cells in a lens-less system. Nevertheless, the efficiency of this imaging system is not satisfactory because of two problems: low resolution and imaging diffraction phenomena. In this paper, a novel method of classifying cells with the shadow imaging technique was proposed. It could be used for the classification of the three subtypes of WBCs, and the correlation of the results of classification between the proposed system and the reference system (BC-5180, Mindray) was 0.93. However, the instrument was only 10 × 10 × 10 cm, and the cost was less than $100. Depending on the lens-free shadow imaging technology, the main hardware could be integrated on a chip scale and could be called an on-chip instrument. [ABSTRACT FROM AUTHOR]

This paper reports a case of multiple osteochondromas affecting the antlers and the left zygomatic bone of a free-ranging adult white-tailed buck (Odocoileus virginianus) from Georgia, USA. Along with a few postcranial bones, the antlered cranium of the individual was found in a severely weathered condition and devoid of any soft tissue. The antlers exhibited five pedunculated exostoses that were composed of cancellous bone and, in their peripheral portions, also mineralized cartilage. The largest of the exostoses, located on the right antler, had a maximum circumference of 55 cm. The exostosis arising from the zygomatic bone was broad-based and much smaller than the exophytic outgrowths on the antlers. Diagnosis of the exostoses as osteochondromas was based on their overall morphology, the normal bone structure in their stalk regions, and the continuity of their spongiosa and cortex with the respective components of the parent bones. Antleromas, i.e., pathological outgrowths developing on antlers as a result of insufficient androgen production, were excluded in the differential diagnosis, based on (1) the apparent maturity and, except for the tumors, normal shape of the antlers and (2) the fact that exostosis formation had also affected the zygomatic bone. Previously only a single case of solitary osteochondroma of an antler has been described in the scientific literature. The case presented here is the first report of multiple osteochondromas in a deer. As antlers are regularly collected as trophies, and huge numbers of them are critically inspected each year, the fact that thus far only two cases of antler osteochondromas have been reported suggests that these tumors are very rare. [ABSTRACT FROM AUTHOR]

During wound healing, skin function is restored by the action of several cell types that undergo differentiation, migration, proliferation and/or apoptosis. These dynamics are tightly regulated by the evolution of the extra cellular matrix (ECM) contents along the process. Pharmacologically active flavonoids have shown to exhibit useful physiological properties interesting in pathological states. Among them, oleanolic acid (OA), a pentacyclic triterpene, shows promising properties over wound healing, as increased cell migration in vitro and improved wound resolution in vivo. In this paper, we pursued to disclose the molecular mechanisms underlying those effects, by using an in vitro scratch assay in two epithelial cell lines of different linage: non-malignant mink lung epithelial cells, Mv1Lu; and human breast cancer cells, MDA-MB-231. In every case, we observed that OA clearly enhanced cell migration for in vitro scratch closure. This correlated with the stimulation of molecular pathways related to mitogen-activated protein (MAP) kinases, as ERK1,2 and Jun N-terminal kinase (JNK) 1,2 activation and c-Jun phosphorylation. Moreover, MDA-MB-231 cells treated with OA displayed an altered gene expression profile affecting transcription factor genes (c-JUN) as well as proteins involved in migration and ECM dynamics (PAI1), in line with the development of an epithelial to mesenchymal transition (EMT) status. Strikingly, upon OA treatment, we observed changes in the epidermal growth factor receptor (EGFR) subcellular localization, while interfering with its signalling completely prevented migration effects. This data provides a physiological framework supporting the notion that lipophilic plant extracts used in traditional medicine, might modulate wound healing processes in vivo through its OA contents. The molecular implications of these observations are discussed. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta, such that the diameter exceeds 3 cm. The natural history of AAA is progressive growth leading to rupture, an event that carries up to 90% risk of mortality. Hence there is a need to predict the growth of the diameter of the aorta based on the diameter of a patient’s aneurysm at initial screening and aided by non-invasive biomarkers. IL-6 is overexpressed in AAA and was suggested as a prognostic marker for the risk in AAA. The present paper develops a mathematical model which relates the growth of the abdominal aorta to the serum concentration of IL-6. Given the initial diameter of the aorta and the serum concentration of IL-6, the model predicts the growth of the diameter at subsequent times. Such a prediction can provide guidance to how closely the patient’s abdominal aorta should be monitored. The mathematical model is represented by a system of partial differential equations taking place in the aortic wall, where the media is assumed to have the constituency of an hyperelastic material. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a rare lung disease of unknown origin leading rapidly to death. This paper addresses the issue of whether sputum induction is a suitable tool to study respiratory tract inflammation and potential biomarkers in IPF compared to COPD, a fibrosing airway wall disease. Methods: In a cross-sectional analysis, 15 IPF patients, 32 COPD and 30 healthy subjects underwent sputum induction. Total sputum cell counts and the amount of TGF- β, IGF-1, IGF-2, IGFBP-1, IGFBP-2, IGFBP-3, IL-8, IL-13, MMP-7, MMP-9, YKL-40, TNF-α and KL-6 in sputum supernatant were analysed. We also profiled gene expression of cells in the induced sputum for TGF-β, MMP-7, YKL-40, IGFBP-2, IL-6, IL-8 and TNF-α. Results: IPF patients, like COPD, had increased sputum absolute number of neutrophils, eosinophils, macrophages and epithelial cells compared to HS. IPF sputum supernatants had increased concentrations of IGFBP-2, IL-8, TGF-β, MMP-7, MMP-9 and KL-6 (p<0.05, p<0.0001, p<0.05, p<0.05, p<0.0001, p<0.05 respectively) when compared to healthy subjects where COPD had higher IL-6 and TNF-α levels than IPF (p<0.05 and p<0.05 respectively) and HS (p<0.0001 and p<0.001 respectively) and higher IL-8 and MMP-9 than HS (p<0.0001 and p<0.001 respectively). Conversely to IL-6 and TNF-α, MMP-7 was increased in IPF compared to COPD (p<0.05). The KL-6 and MMP-7 protein levels in sputum were inversely correlated with total lung capacity (TLC, % of predicted) in IPF patients (r = -0.73 and r = -0.53 respectively). Sputum gene expression analysis identified a significant increase for IGFBP-2, IL-6, IL-8 and MMP-7 in IPF compared to HS (p<0.05, p<0.01, p<0.05 and p<0.0001 respectively) and for IGFBP-2, YKL-40, IL-6, IL-8 and MMP-7 compared to COPD (p<0.01, p<0.01, p<0.05, p<0.01 and p<0.0001 respectively). Furthermore, gene expression of TGF-β was increased in IPF compared to COPD (p<0.001) but not to HS. Conclusion: Our data show clear increase in expression and production of IGFBP-2, IL-8 and MMP-7 in sputum from patients with IPF that may contribute to the disease. [ABSTRACT FROM AUTHOR]

Learning based on networks of real neurons, and learning based on biologically inspired models of neural networks, have yet to find general learning rules leading to widespread applications. In this paper, we argue for the existence of a principle allowing to steer the dynamics of a biologically inspired neural network. Using carefully timed external stimulation, the network can be driven towards a desired dynamical state. We term this principle “Learning by Stimulation Avoidance” (LSA). We demonstrate through simulation that the minimal sufficient conditions leading to LSA in artificial networks are also sufficient to reproduce learning results similar to those obtained in biological neurons by Shahaf and Marom, and in addition explains synaptic pruning. We examined the underlying mechanism by simulating a small network of 3 neurons, then scaled it up to a hundred neurons. We show that LSA has a higher explanatory power than existing hypotheses about the response of biological neural networks to external simulation, and can be used as a learning rule for an embodied application: learning of wall avoidance by a simulated robot. In other works, reinforcement learning with spiking networks can be obtained through global reward signals akin simulating the dopamine system; we believe that this is the first project demonstrating sensory-motor learning with random spiking networks through Hebbian learning relying on environmental conditions without a separate reward system. [ABSTRACT FROM AUTHOR]

Spiral waves are observed in the chemical, physical and biological systems, and the emergence of spiral waves in cardiac tissue is linked to some diseases such as heart ventricular fibrillation and epilepsy; thus it has importance in theoretical studies and potential medical applications. Noise is inevitable in neuronal systems and can change the electrical activities of neuron in different ways. Many previous theoretical studies about the impacts of noise on spiral waves focus an unbounded Gaussian noise and even colored noise. In this paper, the impacts of bounded noise and rewiring of network on the formation and instability of spiral waves are discussed in small-world (SW) network of Hodgkin-Huxley (HH) neurons through numerical simulations, and possible statistical analysis will be carried out. Firstly, we present SW network of HH neurons subjected to bounded noise. Then, it is numerically demonstrated that bounded noise with proper intensity σ, amplitude A, or frequency f can facilitate the formation of spiral waves when rewiring probability p is below certain thresholds. In other words, bounded noise-induced resonant behavior can occur in the SW network of neurons. In addition, rewiring probability p always impairs spiral waves, while spiral waves are confirmed to be robust for small p, thus shortcut-induced phase transition of spiral wave with the increase of p is induced. Furthermore, statistical factors of synchronization are calculated to discern the phase transition of spatial pattern, and it is confirmed that larger factor of synchronization is approached with increasing of rewiring probability p, and the stability of spiral wave is destroyed. [ABSTRACT FROM AUTHOR]

R-/S-2-(2-Hydroxypropanamido) benzoic acid (R-/S-HPABA), a marine-derived anti-inflammatory drug, however, the antiplatelet and antithrombotic effects have not been investigated. In this paper, the in vitro antiplatelet activities and in vivo antithrombotic effects of R-/S-HPABA were investigated, for the first time. The effects of R-/S-HPABA on platelet aggregation induced by adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were evaluated. In addition, the in vivo bleeding time, clotting time, collagen-epinephrine induced pulmonary thrombosis and common carotid artery thrombosis were also investigated in rats. R-/S-HPABA significantly inhibited ADP, COLL and AA induced platelet aggregation in rabbit platelet rich plasma in vitro compared with control group, to a degree similar to that of aspirin. Besides, R-/S-HPABA prolonged bleeding time and clotting time as well as increased the recovery rate obviously in pulmonary thrombosis. Moreover, the level of thromboxane B2 (TXB2) was decreased while the production of 6-keto-prostaglandin F1α (6-keto-PGF1α) was increased markedly by R-/S-HPABA. Furthermore, R-/S-HPABA reduced carotid artery thrombosis weight. These results illustrated that R-/S-HPABA could be a potent antiplatelet aggregation and antithrombotic agent. [ABSTRACT FROM AUTHOR]

This paper aims to study the thrombolytic effect of low-frequency ultrasound combined with targeted urokinase-containing microbubble contrast agents on treatment of thrombosis in rabbit femoral artery; and to determine the optimal combination of parameters for achieving thrombolysis in this model. A biotinylated-avidin method was used to prepare microbubble contrast agents carrying urokinase and Arg-Gly-Asp-Ser (RGDS) peptides. Following femoral artery thrombosis in New Zealand white rabbits, microbubble contrast agents were injected intravenously, and ultrasonic exposure was applied. A 3 × 2 × 2 factorial table was applied to categorize the experimental animals based on different levels of combination of ultrasonic frequencies (Factor A: 1.6 MHz, 2.2 MHz, 2.8 MHz), doses of urokinase (Factor B: 90,000 IU/Kg, 180,000 IU/Kg) and ultrasound exposure time (Factor C: 30 min, 60 min). A total of 72 experimental animals were randomly divided into 12 groups (n = 6/group). Doppler techniques were used to assess blood flow in the distal end of the thrombotic femoral artery during the 120 minutes thrombolysis experiment. The rate of recanalization following thrombolysis was calculated, and thrombolytic efficacy was evaluated and compared. The thrombolytic recanalization rate for all experimental subjects after thrombolytic therapy was 68.1%. The optimal parameters for thrombolysis were determined to be 1) an ultrasound frequency of 2.2 MHz and 2) a 90,000 IU/kg dose of urokinase. Ultrasound exposure time (30 min vs. 60 min) had no significant effect on the thrombolytic effects. The combination of local low-frequency ultrasound radiation, targeted microbubbles, and thrombolytic urokinase induced thrombolysis of femoral artery thrombosis in a rabbit model. The ultrasonic frequency of 2.2 MHz and urokinase dose of 90,000 IU/kg induced optimal thrombolytic effects, while the application of either 30 min or 60 min of ultrasound exposure had similar effects. [ABSTRACT FROM AUTHOR]

To predict the odor quality of an odorant mixture, the interaction between odorants must be taken into account. Previously, an experiment in which mice discriminated between odorant mixtures identified a selective adaptation mechanism in the olfactory system. This paper proposes an olfactory model for odorant mixtures that can account for selective adaptation in terms of neural activity. The proposed model uses the spatial activity pattern of the mitral layer obtained from model simulations to predict the perceptual similarity between odors. Measured glomerular activity patterns are used as input to the model. The neural interaction between mitral cells and granular cells is then simulated, and a dissimilarity index between odors is defined using the activity patterns of the mitral layer. An odor set composed of three odorants is used to test the ability of the model. Simulations are performed based on the odor discrimination experiment on mice. As a result, we observe that part of the neural activity in the glomerular layer is enhanced in the mitral layer, whereas another part is suppressed. We find that the dissimilarity index strongly correlates with the odor discrimination rate of mice: r = 0.88 (p = 0.019). We conclude that our model has the ability to predict the perceptual similarity of odorant mixtures. In addition, the model also accounts for selective adaptation via the odor discrimination rate, and the enhancement and inhibition in the mitral layer may be related to this selective adaptation. [ABSTRACT FROM AUTHOR]

Prediction of memory performance (remembered or forgotten) has various potential applications not only for knowledge learning but also for disease diagnosis. Recently, subsequent memory effects (SMEs)—the statistical differences in electroencephalography (EEG) signals before or during learning between subsequently remembered and forgotten events—have been found. This finding indicates that EEG signals convey the information relevant to memory performance. In this paper, based on SMEs we propose a computational approach to predict memory performance of an event from EEG signals. We devise a convolutional neural network for EEG, called ConvEEGNN, to predict subsequently remembered and forgotten events from EEG recorded during memory process. With the ConvEEGNN, prediction of memory performance can be achieved by integrating two main stages: feature extraction and classification. To verify the proposed approach, we employ an auditory memory task to collect EEG signals from scalp electrodes. For ConvEEGNN, the average prediction accuracy was 72.07% by using EEG data from pre-stimulus and during-stimulus periods, outperforming other approaches. It was observed that signals from pre-stimulus period and those from during-stimulus period had comparable contributions to memory performance. Furthermore, the connection weights of ConvEEGNN network can reveal prominent channels, which are consistent with the distribution of SME studied previously. [ABSTRACT FROM AUTHOR]

The slowly inactivating or late Na+ current, INa-L, can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+, [Na+]i; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+/Ca2+ exchange. These changes increase intracellular Ca2+, [Ca2+]i; which may further enhance INa-L due to calmodulin-dependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O’Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L. Furthermore, this action potential prolongation does not contribute to [Na+]i increase. [ABSTRACT FROM AUTHOR]

Copepods are small crustaceans capable to survive in various aquatic environments. Their responses to changes in different external factors such as salinity and temperature can be observed at different integration levels from copepod genes to copepod communities. Until now, no thorough observation of the temperature or salinity effect stresses on copepods has been done by optical microscopy. In this study, we used autofluorescence to visualize these effects on the morphology of the calanoid copepod Pseudodiaptomus marinus maintained during several generations in the laboratory at favorable and stable conditions of salinity (30 psu) and temperature (18°C). Four different stress experiments were conducted: at a sharp decrease in temperature (18 to 4°C), a moderate decrease in salinity (from 30 to 15 psu), a major decrease in salinity (from 30 to 0 psu), and finally a combined stress with a decrease in both temperature and salinity (from 18°C and 30 psu to 4°C and 0 psu). After these stresses, images acquired by confocal laser scanning microscopy (CLSM) revealed changes in copepod cuticle and muscle structure. Low salinity and/or temperature stresses affected both the detection of fluorescence emitted by muscle sarcomeres and the distance between them. In the remaining paper we will use the term sarcomeres to describe the elements located within sarcomeres and emitted autofluorescence signals. Quantitative study showed an increase in the average distance between two consecutive sarcomeres from 2.06 +/- 0.11 μm to 2.44 +/- 0.42 μm and 2.88 +/- 0.45μm after the exposure to major haline stress (18°C, 0 psu) and the combined stress (4°C, 0 psu), respectively. These stresses also caused cuticle cracks which often occurred at the same location, suggesting the cuticle as a sensitive area for osmoregulation. Our results suggest the use of cuticular and muscle autofluorescence as new biomarkers of stress detectable in formalin-preserved P. marinus individuals. Our label-free method can be easily applied to a large number of other copepod species or invertebrates with striated musculature. [ABSTRACT FROM AUTHOR]

Crohn’s Disease (CD) results from inappropriate response toward commensal flora. Earlier studies described CD as a Th1 mediated disease. Current models view both phenotypes as a continuum of various permutations between Th1, Th2 and Th17 pathways compounded by a range of Treg disfunctions. In the present paper, we develop a mathematical model, by a system of differential equations, which describe the dynamic relations among these T cells and their cytokines. The model identities four groups of CD patients according to up/down regulation of Th1 and Th2. The model simulations show that immunosuppression by TNF-α blockage benefits the group with Th1High/Th2Low while, by contrast, the group with Th1Low/Th2High will benefit from immune activation. [ABSTRACT FROM AUTHOR]