Non-Linear Neuronal Responses as an Emergent Property of Afferent Networks: A Case Study of the Locust Lobula Giant Movement Detector

In principle it appears advantageous for single neurons to perform non-linear operations. Indeed it has been reported that some neurons show signatures of such operations in their electrophysiological response. A particular case in point is the Lobula Giant Movement Detector (LGMD) neuron of the locust, which is reported to locally perform a functional multiplication. Given the wide ramifications of this suggestion with respect to our understanding of neuronal computations, it is essential that this interpretation of the LGMD as a local multiplication unit is thoroughly tested. Here we evaluate an alternative model that tests the hypothesis that the non-linear responses of the LGMD neuron emerge from the interactions of many neurons in the opto-motor processing structure of the locust. We show, by exposing our model to standard LGMD stimulation protocols, that the properties of the LGMD that were seen as a hallmark of local non-linear operations can be explained as emerging from the dynamics of the pre-synaptic network. Moreover, we demonstrate that these properties strongly depend on the details of the synaptic projections from the medulla to the LGMD. From these observations we deduce a number of testable predictions. To assess the real-time properties of our model we applied it to a high-speed robot. These robot results show that our model of the locust opto-motor system is able to reliably stabilize the movement trajectory of the robot and can robustly support collision avoidance. In addition, these behavioural experiments suggest that the emergent non-linear responses of the LGMD neuron enhance the system's collision detection acuity. We show how all reported properties of this neuron are consistently reproduced by this alternative model, and how they emerge from the overall opto-motor processing structure of the locust. Hence, our results propose an alternative view on neuronal computation that emphasizes the network properties as opposed to the local transformations that can be performed by single neurons

Spontaneous Local Gamma Oscillation Selectively Enhances Neural Network Responsiveness

Synchronized oscillation is very commonly observed in many neuronal systems and might play an important role in the response properties of the system. We have studied how the spontaneous oscillatory activity affects the responsiveness of a neuronal network, using a neural network model of the visual cortex built from Hodgkin-Huxley type excitatory (E-) and inhibitory (I-) neurons. When the isotropic local E-I and I-E synaptic connections were sufficiently strong, the network commonly generated gamma frequency oscillatory firing patterns in response to random feed-forward (FF) input spikes. This spontaneous oscillatory network activity injects a periodic local current that could amplify a weak synaptic input and enhance the network's responsiveness. When E-E connections were added, we found that the strength of oscillation can be modulated by varying the FF input strength without any changes in single neuron properties or interneuron connectivity. The response modulation is proportional to the oscillation strength, which leads to self-regulation such that the cortical network selectively amplifies various FF inputs according to its strength, without requiring any adaptation mechanism. We show that this selective cortical amplification is controlled by E-E cell interactions. We also found that this response amplification is spatially localized, which suggests that the responsiveness modulation may also be spatially selective. This suggests a generalized mechanism by which neural oscillatory activity can enhance the selectivity of a neural network to FF inputs

Allergic proctocolitis refractory to maternal hypoallergenic diet in exclusively breast-fed infants: a clinical observation

<p>Abstract</p> <p>Background</p> <p>Allergic proctocolitis (APC) in exclusively breast-fed infants is caused by food proteins, deriving from maternal diet, transferred through lactation. In most cases a maternal cow milk-free diet leads to a prompt resolution of rectal bleeding, while in some patients a multiple food allergy can occur. The aim of this study was to assess whether the atopy patch test (APT) could be helpful to identify this subgroup of patients requiring to discontinue breast-feeding due to polisensitization. Additionally, we assessed the efficacy of an amino acid-based formula (AAF) when multiple food allergy is suspected. amino acid-based formula</p> <p>Methods</p> <p>We have prospectively enrolled 14 exclusively breast-fed infants with APC refractory to maternal allergen avoidance. The diagnosis was confirmed by endoscopy with biopsies. Skin prick tests and serum specific IgE for common foods, together with APTs for common foods plus breast milk, were performed. After a 1 month therapy of an AAF all patients underwent a follow-up rectosigmoidoscopy.</p> <p>Results</p> <p>Prick tests and serum specific IgE were negative. APTs were positive in 100% infants, with a multiple positivity in 50%. Sensitization was found for breast milk in 100%, cow's milk (50%), soy (28%), egg (21%), rice (14%), wheat (7%). Follow-up rectosigmoidoscopy confirmed the remission of APC in all infants.</p> <p>Conclusions</p> <p>These data suggest that APT might become a useful tool to identify subgroups of infants with multiple gastrointestinal food allergy involving a delayed immunogenic mechanism, with the aim to avoid unnecessary maternal dietary restrictions before discontinuing breast-feeding.</p

The Intracellular Transport and Secretion of Calumenin-1/2 in Living Cells

Calumenin isoforms 1 and 2 (calu-1/2), encoded by the CALU gene, belong to the CREC protein family. Calu-1/2 proteins are secreted into the extracellular space, but the secretory process and regulatory mechanism are largely unknown. Here, using a time-lapse imaging system, we visualized the intracellular transport and secretory process of calu-1/2-EGFP after their translocation into the ER lumen. Interestingly, we observed that an abundance of calu-1/2-EGFP accumulated in cellular processes before being released into the extracellular space, while only part of calu-1/2-EGFP proteins were secreted directly after attaching to the cell periphery. Moreover, we found the secretion of calu-1/2-EGFP required microtubule integrity, and that calu-1/2-EGFP-containing vesicles were transported by the motor proteins Kif5b and cytoplasmic dynein. Finally, we determined the export signal of calu-1/2-EGFP (amino acid positions 20–46) and provided evidence that the asparagine at site 131 was indispensable for calu-1/2-EGFP stabilization. Taken together, we provide a detailed picture of the intracellular transport of calu-1/2-EGFP, which facilitates our understanding of the secretory mechanism of calu-1/2

A theory of how active behavior stabilises neural activity: neural gain modulation by closed-loop environmental feedback

During active behaviours like running, swimming, whisking or sniffing, motor actions shape sensory input and sensory percepts guide future motor commands. Ongoing cycles of sensory and motor processing constitute a closed-loop feedback system which is central to motor control and, it has been argued, for perceptual processes. This closed-loop feedback is mediated by brainwide neural circuits but how the presence of feedback signals impacts on the dynamics and function of neurons is not well understood. Here we present a simple theory suggesting that closed-loop feedback between the brain/body/environment can modulate neural gain and, consequently, change endogenous neural fluctuations and responses to sensory input. We support this theory with modeling and data analysis in two vertebrate systems. First, in a model of rodent whisking we show that negative feedback mediated by whisking vibrissa can suppress coherent neural fluctuations and neural responses to sensory input in the barrel cortex. We argue this suppression provides an appealing account of a brain state transition (a marked change in global brain activity) coincident with the onset of whisking in rodents. Moreover, this mechanism suggests a novel signal detection mechanism that selectively accentuates active, rather than passive, whisker touch signals. This mechanism is consistent with a predictive coding strategy that is sensitive to the consequences of motor actions rather than the difference between the predicted and actual sensory input. We further support the theory by re-analysing previously published two-photon data recorded in zebrafish larvae performing closed-loop optomotor behaviour in a virtual swim simulator. We show, as predicted by this theory, that the degree to which each cell contributes in linking sensory and motor signals well explains how much its neural fluctuations are suppressed by closed-loop optomotor behaviour. More generally we argue that our results demonstrate the dependence of neural fluctuations, across the brain, on closed-loop brain/body/environment interactions strongly supporting the idea that brain function cannot be fully understood through open-loop approaches alone

Probiotic Sonicates Selectively Induce Mucosal Immune Cells Apoptosis through Ceramide Generation via Neutral Sphingomyelinase

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Probiotics appear to be beneficial in inflammatory bowel disease, but their mechanism of action is incompletely understood. We investigated whether probiotic-derived sphingomyelinase mediates this beneficial effect. [Methodology/Principal Findings]: Neutral sphingomyelinase (NSMase) activity was measured in sonicates of the probiotic L. brevis (LB) and S. thermophilus (ST) and the non-probiotic E. coli (EC) and E. faecalis (EF). Lamina propria mononuclear cells (LPMC) were obtained from patients with Crohn's disease (CD) and Ulcerative Colitis (UC), and peripheral blood mononuclear cells (PBMC) from healthy volunteers, analysing LPMC and PBMC apoptosis susceptibility, reactive oxygen species (ROS) generation and JNK activation. In some experiments, sonicates were preincubated with GSH or GW4869, a specific NSMase inhibitor. NSMase activity of LB and ST was 10-fold that of EC and EF sonicates. LB and ST sonicates induced significantly more apoptosis of CD and UC than control LPMC, whereas EC and EF sonicates failed to induce apoptosis. Pre-stimulation with anti-CD3/CD28 induced a significant and time-dependent increase in LB-induced apoptosis of LPMC and PBMC. Exposure to LB sonicates resulted in JNK activation and ROS production by LPMC. NSMase activity of LB sonicates was completely abrogated by GW4869, causing a dose-dependent reduction of LB-induced apoptosis. LB and ST selectively induced immune cell apoptosis, an effect dependent on the degree of cell activation and mediated by bacterial NSMase. [Conclusions]: These results suggest that induction of immune cell apoptosis is a mechanism of action of some probiotics, and that NSMase-mediated ceramide generation contributes to the therapeutic effects of probiotics.The funding sources included grants from Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Ministerio de Ciencia e Innovación (SAF2005-00280 and SAF2008-03676 to MS, FIS2009-00056 to AM, SAF2009-11417 to JCF), Fundación Ramón Areces (to MS), the National Institutes of Health (DK30399 and DK50984 to CF) and the Research Center for Liver and Pancreatic Diseases funded by the United States National Institute for Alcohol Abuse and Alcoholism (P50 AA 11999 to JCF).Peer reviewe

A transcriptomic analysis of Echinococcus granulosus larval stages:implications for parasite biology and host adaptation

The cestode Echinococcus granulosus--the agent of cystic echinococcosis, a zoonosis affecting humans and domestic animals worldwide--is an excellent model for the study of host-parasite cross-talk that interfaces with two mammalian hosts. To develop the molecular analysis of these interactions, we carried out an EST survey of E. granulosus larval stages. We report the salient features of this study with a focus on genes reflecting physiological adaptations of different parasite stages.We generated ~10,000 ESTs from two sets of full-length enriched libraries (derived from oligo-capped and trans-spliced cDNAs) prepared with three parasite materials: hydatid cyst wall, larval worms (protoscoleces), and pepsin/H(+)-activated protoscoleces. The ESTs were clustered into 2700 distinct gene products. In the context of the biology of E. granulosus, our analyses reveal: (i) a diverse group of abundant long non-protein coding transcripts showing homology to a middle repetitive element (EgBRep) that could either be active molecular species or represent precursors of small RNAs (like piRNAs); (ii) an up-regulation of fermentative pathways in the tissue of the cyst wall; (iii) highly expressed thiol- and selenol-dependent antioxidant enzyme targets of thioredoxin glutathione reductase, the functional hub of redox metabolism in parasitic flatworms; (iv) candidate apomucins for the external layer of the tissue-dwelling hydatid cyst, a mucin-rich structure that is critical for survival in the intermediate host; (v) a set of tetraspanins, a protein family that appears to have expanded in the cestode lineage; and (vi) a set of platyhelminth-specific gene products that may offer targets for novel pan-platyhelminth drug development.This survey has greatly increased the quality and the quantity of the molecular information on E. granulosus and constitutes a valuable resource for gene prediction on the parasite genome and for further genomic and proteomic analyses focused on cestodes and platyhelminths

Tuning the GENIE Pion Production Model with MINERvA Data

Faced with unresolved tensions between neutrino interaction measurements at few-GeV neutrino energies, current experiments are forced to accept large systematic uncertainties to cover discrepancies between their data and model predictions. In this paper, the widely used pion production model in GENIE is compared to four MINERvA charged current pion production measurements using NUISANCE. Tunings, ie, adjustments of model parameters, to help match GENIE to MINERvA and older bubble chamber data are presented here. We find that scattering off nuclear targets as measured in MINERvA is not in good agreement with scattering off nucleon (hydrogen or deuterium) targets in the bubble chamber data. An additional ad hoc correction for the low-$Q^2$ region, where collective effects are expected to be large, is also presented. While these tunings and corrections improve the agreement of GENIE with the data, the modeling is imperfect. The development of these tunings within the NUISANCE frameworkallows for straightforward extensions to other neutrino event generators and models, and allows omitting and including new data sets as they become available

Burn Injury Reduces Neutrophil Directional Migration Speed in Microfluidic Devices

Thermal injury triggers a fulminant inflammatory cascade that heralds shock, end-organ failure, and ultimately sepsis and death. Emerging evidence points to a critical role for the innate immune system, and several studies had documented concurrent impairment in neutrophil chemotaxis with these post-burn inflammatory changes. While a few studies suggest that a link between neutrophil motility and patient mortality might exist, so far, cumbersome assays have prohibited exploration of the prognostic and diagnostic significance of chemotaxis after burn injury. To address this need, we developed a microfluidic device that is simple to operate and allows for precise and robust measurements of chemotaxis speed and persistence characteristics at single-cell resolution. Using this assay, we established a reference set of migration speed values for neutrophils from healthy subjects. Comparisons with samples from burn patients revealed impaired directional migration speed starting as early as 24 hours after burn injury, reaching a minimum at 72–120 hours, correlated to the size of the burn injury and potentially serving as an early indicator for concurrent infections. Further characterization of neutrophil chemotaxis using this new assay may have important diagnostic implications not only for burn patients but also for patients afflicted by other diseases that compromise neutrophil functions