Bimodal Response Research Articles

Prostaglandin E2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles: implications for neurovascular coupling responses

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance‐sized human cerebral parenchymal arterioles.To achieve this goal PGE2‐induced isotonic responses were assessed in parenchymal arterioles isolated from fronto‐temporo‐parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined.In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10−8 to 10−6 mol/l) caused significant, endothelium‐independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1‐dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. In contrast, rat vessels expressed predominantly EP1 receptors.PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human subjects.Support or Funding InformationThis work was supported by grants from the National Research, Development and Innovation Office to PT (NKFI‐FK123798) and AK (K108444), the Hungarian Academy of Sciences Bolyai Research Scholarship BO/00634/15 to PT, the PTE AOK‐KA 3/2016 04.01/F to PT, the ÚNKP‐18‐4‐PTE‐6 New National Excellence Program of the Ministry of Human Capacities, Higher Education Institutional Excellence Programme – Grant No. 20765‐3/2018/FEKUTSTRAT, EFOP‐3.6.2.‐16‐2017‐00008, GINOP‐2.3.2‐15‐2016‐00048 and GINOP‐2.3.3‐15‐2016‐00032 to PT and AB, the Hungarian National Brain Research Program Grant No. 2017‐1.2.1‐NKP‐2017‐00002 to AB; the Marie Curie Actions SMARTER 7th Framework Program of the European Union 606998 to NSz and AK, National Institute of Health R01‐AG055395, R01‐NS100782, R01‐AT006526 to ZU.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Audiovisual Processing of Chinese Characters Elicits Suppression and Congruency Effects in MEG.

Learning to associate written letters/characters with speech sounds is crucial for reading acquisition. Most previous studies have focused on audiovisual integration in alphabetic languages. Less is known about logographic languages such as Chinese characters, which map onto mostly syllable-based morphemes in the spoken language. Here we investigated how long-term exposure to native language affects the underlying neural mechanisms of audiovisual integration in a logographic language using magnetoencephalography (MEG). MEG sensor and source data from 12 adult native Chinese speakers and a control group of 13 adult Finnish speakers were analyzed for audiovisual suppression (bimodal responses vs. sum of unimodal responses) and congruency (bimodal incongruent responses vs. bimodal congruent responses) effects. The suppressive integration effect was found in the left angular and supramarginal gyri (205–365 ms), left inferior frontal and left temporal cortices (575–800 ms) in the Chinese group. The Finnish group showed a distinct suppression effect only in the right parietal and occipital cortices at a relatively early time window (285–460 ms). The congruency effect was only observed in the Chinese group in left inferior frontal and superior temporal cortex in a late time window (about 500–800 ms) probably related to modulatory feedback from multi-sensory regions and semantic processing. The audiovisual integration in a logographic language showed a clear resemblance to that in alphabetic languages in the left superior temporal cortex, but with activation specific to the logographic stimuli observed in the left inferior frontal cortex. The current MEG study indicated that learning of logographic languages has a large impact on the audiovisual integration of written characters with some distinct features compared to previous results on alphabetic languages.

Local FK506 dose-dependent study using a novel three-dimensional organotypic assay.

Local administration of FK506, an FDA approved immunosuppressant with neuroregenerative properties, is a promising technique to achieve improved peripheral nerve regeneration while preventing the side effects associated with the systemic administration of this drug. Although considerable research has been devoted to the development of clinically suitable systems for local delivery of FK506 to the site of nerve injury and repair, the optimal dose of FK506 for enhancement of axon regeneration in the peripheral nerve has not yet been established. To this end, we devised a three-dimensional (3D) organotypic assay capable of mimicking the peripheral nerve. This assay consisted of a neonatal rat dorsal root ganglion (DRG) extending its neurites into the native peripheral nerve scaffold provided by an acellular nerve allograft (ANA). A novel 3D compartmented cell culture system was adapted from the 3D organotypic assay to achieve local delivery of FK506 just to the growing neurites in vitro and establish the required local dose of FK506 for peripheral nerve regeneration. A bimodal dose response was observed by culturing the entire DRG-ANA construct with media containing different concentrations of FK506. Low drug concentration of 1 pg/ml and high drug concentration of 100 ng/ml lead to the longest neurite extension in vitro. Furthermore, regardless of the FK506 concentration, concentrating the drug to the growing neurites resulted in significant increase in both neurite extension and neurite density, an effect that was not observed with the FK506 delivery to both neurites and neural cell bodies within DRG. The findings in this study provide valuable insight into the optimal local dose of FK506 for peripheral nerve regeneration. Furthermore, for the first time, this study suggests the potential interaction of FK506 with axons at the level of the growth cone.

Predicting coral dynamics through climate change

Thermal-stress events are changing the composition of many coral reefs worldwide. Yet, determining the rates of coral recovery and their long-term responses to increasing sea-surface temperatures is challenging. To do so, we first estimated coral recovery rates following past disturbances on reefs in southern Japan and Western Australia. Recovery rates varied between regions, with the reefs in southern Japan showing more rapid recovery rates (intrinsic rate of increase, r = 0.38 year−1) than reefs in Western Australia (r = 0.17 year−1). Second, we input these recovery rates into a novel, nonlinear hybrid-stochastic-dynamical system to predict the responses of Indo-Pacific coral populations to complex inter-annual temperature cycles into the year 2100. The coral recovery rates were overlaid on background increases in global sea-surface temperatures, under three different climate-change scenarios. The models predicted rapid recovery at both localities with the infrequent and low-magnitude temperature anomalies expected under a conservative climate-change scenario, Representative Concentration Pathway (RCP) 4.5. With moderate increases in ocean temperatures (RCP 6.0) the coral populations showed a bimodal response, with model runs showing either recovery or collapse. Under a business-as-usual climate-change scenario (RCP 8.5), with frequent and intense temperature anomalies, coral recovery was unlikely.

Bimodal sensing of guidance cues in mechanically distinct microenvironments

Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior.

Characteristics of self-excited spinning azimuthal modes in an annular combustor with turbulent premixed bluff-body flames

In this paper we investigate self-excited azimuthal modes in an annular combustor with turbulent premixed bluff-body stabilised flames. Previous studies have shown that both swirl and equivalence ratio influence modal dynamics, i.e. the time-varying nature of the modes. However, self-excited azimuthal modes have not yet been investigated in turbulent flames without bulk swirl, which do not generate any preferential flow in either azimuthal direction, and may therefore lead to different behaviour. Joint probability density functions of the instability amplitudes at various flowrates and equivalence ratios showed a strong bi-modal response favouring both ACW and CW spinning states not previously observed. Operating conditions leading to a bi-modal response provide a unique opportunity to investigate whether the structure of the global fluctuating heat release rate of self-excited spinning modes in both directions exhibit similar dynamics and structure. This was investigated using high-speed OH* chemiluminescence images of the annular combustor and a new rotational averaging method was applied which decomposes the spinning components of the global fluctuating heat release rate. The new rotational averaging, which differs from standard phase-averaging, produces spatial averages in a frame of reference moving with the spinning wave. The results show that the structure of the fluctuating heat release rate for spinning modes is highly asymmetric as characterised by large, crescent shaped regions of high OH* intensity, located on the far side of each flame, relative to the direction of the azimuthally propagating pressure wave. In comparison with interacting swirling flames, these results indicate that the previously observed radial asymmetry of OH* fluctuations may be introduced through advection by local swirl.

The filament-bundle elastica

Filament-bundles are ubiquitous in nature. They are composed by an assembly of flexible rods held together by elastic springs, such as found in ciliary systems and flagella. We study the static, post-transient, post-buckled configurations of a generalised filament-bundle elastica or flagella. We recur to linear and weakly non-linear analysis, as well as geometrically exact numerical solutions. The bundle cross-linking mechanics is characterised by non-local moments affecting distant parts of the bundle. This induces a bimodal post-buckling response sensitive to the interfilament sliding at the base. We report the occurrence of a novel reversed cusp catastrophe, reminiscent of the counterbend phenomenon, that folds and suppresses the saddle-node bifurcation back a pitchfork bistability landscape, found in classical elastica systems. The filament-bundle elastica can thus prevent violent jumps, non-uniqueness and hysteresis. This non-trivial folding of the imperfection-sensitivity diagram may impact bundle systems with naturally occurring buckling phenomena.

Altered perception-action binding modulates inhibitory control in Gilles de la Tourette syndrome.

Gilles de la Tourette Syndrome (GTS) is a multifaceted neuropsychiatric developmental disorder with onset in childhood or adolescence and frequent remissions in early adulthood. A rather new emerging concept of this syndrome suggests that it is a disorder of purposeful actions, in which sensory processes and their relation to motor responses (actions) play a particularly important role. Thus, this syndrome might be conceived as a condition of altered 'perception-action binding'. In the current study, we test this novel concept in the context of inhibitory control. We examined N=35 adolescent GTS patients and N=39 healthy controls in a Go/Nogo-task manipulating the complexity of sensory information triggering identical actions; i.e. to inhibit a motor response. This was combined with event-related potential recordings, EEG data decomposition and source localization. GTS patients showed worse performance compared to controls and larger performance differences when inhibitory control had to be exerted using unimodal visual compared to bimodal auditory-visual stimuli. This suggests increased binding between bimodal stimuli and responses leading to increased costs of switching between responses instructed by bimodal and those instructed by unimodal stimuli. The neurophysiological data showed that this was related to mechanisms mediating between stimulus evaluation and response selection; i.e. perception-action binding processes in the right inferior parietal cortex (BA40). Stimulus-action inhibition binding is stronger in GTS patients than healthy controls and affects inhibitory control corroborating the concept suggesting that GTS might be a condition of altered perception-action integration (binding); i.e. a disorder of purposeful actions.

S169. Vagus electrical transcutaneous stimulation in thyroidectomy and parathyroidectomy

Introduction Thyroidectomy and parathyroidectomy, can damage recurrent laryngeal nerves, we propose a new method for the stimulation of the vagus, not invasive, that allows also to differentiate right and left RLN. Methods In a total of 145 patients undergoing thyroidectomy and parathyroidectom, two subdermal needle electrodes were placed, the cathode on the angle jaw, and the anode on mastoid, bilaterally, reaching the carotid triangle in the upper neck, so we can stimulate vagus nerve without dissection. Using single stimulus, 0.2 ms of duration, intensities from 15 to 40 mA, an EMG response is obtained in the electrode placed in the endotracheal tube, latency 9–11 ms in right side and 10–13 ms in left side, reproducible, and without variations during surgery. Results We observed latency variations, when a sustained increase of EMG activity was recorded in the laryngeal electrode, while the surgeon was nearby RLN, and also bimodal response in those cases in which LRN division was observed during the dissection.In all them the unilateral LRN stimulation was seen. We also observed the presence of a peripheral silent period confirming the correct stimulation. Provided that we obtain the unilateral stimulation of the nerve, with minimal contraction of cervical musculature and practically not stimulation of the spinal nerve, this not disrupt the surgeon who does not need to stop to value integrity of the recurrent nerve. Conclusion This method, minimally invasive, always accessibly, that allows to value RLN of unilateral form, contributing major control in the monitoring of the nerves, without in none of 145 cases (290 RLN), side effects have been observed. A previous report has been made with transcutaneous stimulation of the vagus nerve, but in our experience, more intensity is needed, and spinal nerve is commonly stimulated, disturbing the surgeon, and it use is more limited.

Underlying Mechanisms of Cooperativity, Input Specificity, and Associativity of Long-Term Potentiation Through a Positive Feedback of Local Protein Synthesis.

Long-term potentiation (LTP) is a specific form of activity-dependent synaptic plasticity that is a leading mechanism of learning and memory in mammals. The properties of cooperativity, input specificity, and associativity are essential for LTP; however, the underlying mechanisms are unclear. Here, based on experimentally observed phenomena, we introduce a computational model of synaptic plasticity in a pyramidal cell to explore the mechanisms responsible for the cooperativity, input specificity, and associativity of LTP. The model is based on molecular processes involved in synaptic plasticity and integrates gene expression involved in the regulation of neuronal activity. In the model, we introduce a local positive feedback loop of protein synthesis at each synapse, which is essential for bimodal response and synapse specificity. Bifurcation analysis of the local positive feedback loop of brain-derived neurotrophic factor (BDNF) signaling illustrates the existence of bistability, which is the basis of LTP induction. The local bifurcation diagram provides guidance for the realization of LTP, and the projection of whole system trajectories onto the two-parameter bifurcation diagram confirms the predictions obtained from bifurcation analysis. Moreover, model analysis shows that pre- and postsynaptic components are required to achieve the three properties of LTP. This study provides insights into the mechanisms underlying the cooperativity, input specificity, and associativity of LTP, and the further construction of neural networks for learning and memory.

Sparse representations and compressive sampling for enhancing the computational efficiency of the Wiener path integral technique

Abstract The computational efficiency of the Wiener path integral (WPI) technique for determining the stochastic response of diverse dynamical systems is enhanced by exploiting recent developments in the area of sparse representations. Specifically, an appropriate basis for expanding the system joint response probability density function (PDF) is utilized. Next, only very few PDF points are determined based on the localization capabilities of the WPI technique. Further, compressive sampling procedures in conjunction with group sparsity concepts and appropriate optimization algorithms are employed for efficiently determining the coefficients of the system response PDF expansion. It is shown that the herein developed enhancement renders the technique capable of treating readily relatively high-dimensional stochastic systems. Two illustrative numerical examples are considered. The first refers to a single-degree-of-freedom Duffing oscillator exhibiting a bimodal response PDF. In the second example, the 20-variate joint response transition PDF of a 10-degree-of-freedom nonlinear structural system under stochastic excitation is determined. Comparisons with pertinent Monte Carlo simulation data demonstrate the accuracy of the enhanced WPI technique.

Visual-Olfactory Interactions: Bimodal Facilitation and Impact on the Subjective Experience.

Odors are inherently ambiguous and therefore susceptible to redundant sensory as well as context information. The identification of an odor object relies largely on visual input. Thus far, it is unclear whether visual and olfactory stimuli are indeed integrated at an early perceptual stage and which role the congruence between the visual and olfactory inputs plays. Previous studies on visual-olfactory interaction used either congruent or incongruent information, leaving it open whether nuances of visual-olfactory congruence shape perception differently. We aimed to answer 1) whether visual-olfactory information is integrated at early stages of processing, 2) whether visual-olfactory congruence is a gradual or dichotomous phenomenon, and 3) whether visual information influences bimodal stimulus evaluation and odor identity. We found a bimodal response time speedup that is consistent with parallel processing according to race models. Subjectively, pleasantness of bimodal stimuli increased with increasing congruence, and orange images biased odor composition toward orange. Visual-olfactory congruence was perceived in gradual and distinct categories, consistent with the notion that congruence is a gradual phenomenon. Together, the data provide evidence for bimodal facilitation consistent with parallel processing of the visual and olfactory stimuli, and that visual-olfactory interactions influence various levels of the subjective experience.

Modeling Cell-to-Cell Communication Networks Using Response-Time Distributions.

SUMMARYCell-to-cell communication networks have critical roles in coordinating diverse organismal processes, such as tissue development or immune cell response. However, compared with intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Major complications include: cells are themselves regulated by complex intracellular signaling networks; individual cells are heterogeneous; and output of any one cell can recursively become an additional input signal to other cells. Here, we make use of a framework that treats intracellular signal transduction networks as “black boxes” with characterized input-to-output response relationships. We study simple cell-to-cell communication circuit motifs and find conditions that generate bimodal responses in time, as well as mechanisms for independently controlling synchronization and delay of cell-population responses. We apply our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. Our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps.

Hendra Virus Spillover is a Bimodal System Driven by Climatic Factors.

Understanding environmental factors driving spatiotemporal patterns of disease can improve risk mitigation strategies. Hendra virus (HeV), discovered in Australia in 1994, spills over from bats (Pteropus sp.) to horses and thence to humans. Below latitude -22°, almost all spillover events to horses occur during winter, and above this latitude spillover is aseasonal. We generated a statistical model of environmental drivers of HeV spillover per month. The model reproduced the spatiotemporal pattern of spillover risk between 1994 and 2015. The model was generated with an ensemble of methods for presence-absence data (boosted regression trees, random forests and logistic regression). Presences were the locations of horse cases, and absences per spatial unit (2.7×2.7km pixels without spillover) were sampled with the horse census of Queensland and New South Wales. The most influential factors indicate that spillover is associated with both cold-dry and wet conditions. Bimodal responses to several variables suggest spillover involves two systems: one above and one below a latitudinal area close to -22°. Northern spillovers are associated with cold-dry and wet conditions, and southern with cold-dry conditions. Biologically, these patterns could be driven by immune or behavioural changes in response to food shortage in bats and horse husbandry. Future research should look for differences in these traits between seasons in the two latitudinal regions. Based on the predicted risk patterns by latitude, we recommend enhanced preventive management for horses from March to November below latitude 22° south.

Patterns of Microvascular Response to Refractory Shock and Their Modulation by Vasoactive Resuscitations

Objective: Progressive hemorrhagic shock (HS) causes splanchnic vasoconstriction and hypo-perfusion together with profound depletions of cellular cytosolic energy phosphates (ATP). Cellular energy failure and the splanchnic hypo-perfusion are critical to the pathogenesis of shock decompensation and the subsequent death from cardiocirculatory arrest. We recently demonstrated post-resuscitation survival benefit for cellular cytosolic ATP replenishment but not for vasopressors use in a rat model of refractory HS. The aim of this study was to determine the effects of progressive HS on the splanchnic microvasculature, and to compare the effects of adjuvant resuscitations with either norepinephrine, vasopressin or lipid vesicles encapsulating ATP (ATPv) on this microvasculature. Methods: 40-male Sprague-Dawley rats were randomized into 4 groups of 10 each: HS/conventionalresuscitation (CR), HS/CR+Norepinephrine, HS/CR+Vasopressin, and HS/CR+ATPv. HS=initial removal of 30% of the calculated blood volume plus subsequent transection of the spleen for uncontrolled haemorrhage until a predefined intervention set-point was achieved; CR=shed blood returned+double the shed blood volume as lactated Ringer’s solution. Four-level intestinal microvascular A1 through A4 arterioles (100–8 μm diameter) in the terminalileum were continuously monitored with intravital-microscopy, and their diameters were measured at baseline, during shock, after completion of resuscitation, and during a 2 h post-resuscitation observation period. In addition, we recorded measurements of the mean arterial pressure, shock index, blood-gas profiles, and complete metabolic panels. Results: Progressive HS caused bimodal arteriole responses with progressive vasoconstriction from baseline of first-order A1 and second-order A2 (-22.1 ± 1.9%), a progressive vasodilation of the third-order A3 and fourth-order A4 arterioles (+22.2 ± 2.8%). Resuscitation initially restored A1 and A2 diameters to near baseline. This was followed by post-resuscitation A1 and A2 vasoconstriction in all groups, except the ATPv group (-8.1 ± 3.4%). The hemorrhage-induced vasodilation of the A3 and A4 arterioles was maintained during the post-resuscitation observation period in the CR (+55.3 ± 6.4%) and the ATPv groups (+39.5 ± 5.2%), but remarkably attenuated in the norepinephrine (+9.6 ± 5.8%) and vasopressin (+9.4 ± 8.8) groups. Conclusions: Severe hemorrhagic shock causes specific splanchnic microvascular bimodal response that is dependent on arteriolar level. First-order A1 and second-order A2 arterioles exhibit progressive vasoconstriction, whereas, third-order A3 and fourth-order A4 arterioles show progressive vasodilation. Temporary administration of either norepinephrine or vasopressin along with conventional resuscitation exerted deleterious effects at all splanchnic microvascular levels by virtue of their peripheral vascular actions. The cellular cytosolic ATP replenishment maintained a better microvascular profile when compared with the two vasopressors.

Should I stay or should I go? The settlement-inducing protein complex guides barnacle settlement decisions.

Reproduction in barnacles relies on chemical cues that guide their gregarious settlement. These cues have been pinned down to several sources of settlement pheromones, one of which is a protein termed settlement-inducing protein complex (SIPC), a large glycoprotein acting as a pheromone to induce larval settlement and as an adhesive in surface exploration by the cyprids. Settlement assays in laboratory conditions with Amphibalanus (=Balanus) amphitrite cyprids in the presence of SIPC showed that cyprids exhibit settlement preference behaviour at lower concentrations of SIPC [half maximal effective concentration (EC50)=3.73 nmol l-1] and settlement avoidance behaviour at higher concentrations (EC50=101 nmol l-1). By using truncated fragments of SIPC in settlement assays, we identify that domains at the N-terminus of SIPC transduce settlement preference cues that mask the settlement avoidance cues transduced by domains at its C-terminus. Removing the N-terminal 600 amino acids from SIPC resulted in truncated fragments that transduced only settlement avoidance cues to the cyprids. From the sexual reproduction point of view, this bimodal response of barnacles to SIPC suggests that barnacles will settle gregariously when conspecific cues are sparse but will not settle if conspecific cues inform of overcrowding that will increase reproductive competition and diminish their reproductive chances.

Temperature and light effects on in vitro germination of Peronospora effusa sporangia

Spinach downy mildew, caused by the biotrophic oomycete Peronospora effusa, is an economically important disease that is found in all spinach growing regions of the US. To effectively predict disease risk we need to understand the response of P. effusa to different environmental conditions. We conducted several in vitro germination assays, exposing P. effusa sporangia to different temperature and lighting conditions. Between 5 and 25 °C under constant darkness, germination of P. effusa sporangia on water agar declined with increasing temperatures. These results were qualitatively different from a previous study of P. effusa germination that found a bimodal response curve, with increased germination at lower and higher temperatures. Time course studies revealed that sporangia consistently germinated within the first 12 h of plating, regardless of incubation temperature. Blue light exposure significantly reduced sporangial germination when compared with sporangia exposed to red, yellow, or no light. Light intensity and color significantly impacted germination, although the effect of color varied by light intensity.

Coadministration of the Campylobacter jejuni N-Glycan-Based Vaccine with Probiotics Improves Vaccine Performance in Broiler Chickens.

Source attribution studies report that the consumption of contaminated poultry is the primary source for acquiring human campylobacteriosis. Oral administration of an engineered Escherichia coli strain expressing the Campylobacter jejuni N-glycan reduces bacterial colonization in specific-pathogen-free leghorn chickens, but only a fraction of birds respond to vaccination. Optimization of the vaccine for commercial broiler chickens has great potential to prevent the entry of the pathogen into the food chain. Here, we tested the same vaccination approach in broiler chickens and observed similar efficacies in pathogen load reduction, stimulation of the host IgY response, the lack of C. jejuni resistance development, uniformity in microbial gut composition, and the bimodal response to treatment. Gut microbiota analysis of leghorn and broiler vaccine responders identified one member of Clostridiales cluster XIVa, Anaerosporobacter mobilis, that was significantly more abundant in responder birds. In broiler chickens, coadministration of the live vaccine with A. mobilis or Lactobacillus reuteri, a commonly used probiotic, resulted in increased vaccine efficacy, antibody responses, and weight gain. To investigate whether the responder-nonresponder effect was due to the selection of a C. jejuni "supercolonizer mutant" with altered phase-variable genes, we analyzed all poly(G)-containing loci of the input strain compared to nonresponder colony isolates and found no evidence of phase state selection. However, untargeted nuclear magnetic resonance (NMR)-based metabolomics identified a potential biomarker negatively correlated with C. jejuni colonization levels that is possibly linked to increased microbial diversity in this subgroup. The comprehensive methods used to examine the bimodality of the vaccine response provide several opportunities to improve the C. jejuni vaccine and the efficacy of any vaccination strategy.IMPORTANCECampylobacter jejuni is a common cause of human diarrheal disease worldwide and is listed by the World Health Organization as a high-priority pathogen. C. jejuni infection typically occurs through the ingestion of contaminated chicken meat, so many efforts are targeted at reducing C. jejuni levels at the source. We previously developed a vaccine that reduces C. jejuni levels in egg-laying chickens. In this study, we improved vaccine performance in meat birds by supplementing the vaccine with probiotics. In addition, we demonstrated that C. jejuni colonization levels in chickens are negatively correlated with the abundance of clostridia, another group of common gut microbes. We describe new methods for vaccine optimization that will assist in improving the C. jejuni vaccine and other vaccines under development.

Consistency of Spatial Representations in Rat Entorhinal Cortex Predicts Performance in a Reorientation Task

Goal-directed behavior can be affected by environmental geometry. A classic example is the rectangular arena reorientation task, where subjects commonly confuse opposite but geometrically identical corners [1]. Until recently, little was known about how environmental geometry shapes spatial representations in a neurobehavioral context [2] (although see [3]). In the present study, we asked: Under what circumstances does the internal cognitive map predict behavior? And when does it fail to do so? To this end, we developed a variant of the classical reorientation task that allows for investigation of temporal dynamics of reorientation. We recorded head-direction (HD) cells and grid cells in the medial entorhinal cortex (MEC) of rats before, during, and after performing the task. MEC cells showed a bimodal response of being either aligned or rotated, relative to the free-foraging open-field sessions. Alignment was remarkably stable between disorientations andindicative of corner choice as a function of current and past alignment of spatial representations. Accordingly, when the cells showed consistent andproperly aligned readout across multiple trials, behavioral choices were better predicted by HD and grid cell readout, with a probability of more than 70%. This was not the case when the cells did not show a stable consistent readout. Our findings indicate that entorhinal spatial representations predict corner choice, contingent on the stability and reliability of their readout. This work sets the stage for further studies on the link between the reliability of the neuronal signal and behavior, with implications for many brain systems in many organisms.

Heart functional and structural compendium of cardiosplenic and cardiorenal networks in acute and chronic heart failure pathology.

Heart failure (HF) secondary to myocardial infarction (MI) is linked to kidney complications that comprise cellular, structural, functional, and survival indicators. However, HF research is focused on left ventricular (LV) pathology. Here, we determined comprehensive functional analysis of the LV using echocardiography in transition from acute heart failure (AHF) to progressive chronic heart failure (CHF) pathology and developed a histological compendium of the cardiosplenic and cardiorenal networks in pathological remodeling. In surgically induced MI using permanent coronary ligation, the LV dysfunction is pronounced, with myocardium necrosis, wall thinning, and 20-30% LV rupture events that indicated AHF and CHF pathological remodeling in C57BL/6 male mice (2-4 mo old, n = 50). Temporal LV function analysis indicated that fractional shortening and strain are reduced from day 1 to day 5 in AHF and sustained to advance to CHF from day 28 to day 56 compared with naïve control mice ( n = 6). During the transition of AHF ( day 1 to day 5) to advanced CHF ( day 28 to day 56), histological and cellular changes in the spleen were definite, with bimodal inflammatory responses in kidney inflammatory biomarkers. Likewise, there was a unidirectional, progressive, and irreversible deposition of compact collagen in the LV along with dynamic changes in the cardiosplenic and cardiorenal networks post-MI. The renal histology and injury markers suggested that cardiac injury triggers irreversible dysregulation that actively alters the cardiosplenic and cardiorenal networks. In summary, the novel strategies or pathways that modulate comprehensive cardiosplenic and cardiorenal networks in AHF and CHF would be effective approaches to study either cardiac repair or cardiac pathology. NEW & NOTEWORTHY The present compendium shows irreversible ventricular dysfunction as assessed by temporal echocardiography while histological and structural measurements of the spleen and kidney added a novel direction to study cardiosplenic and cardiorenal networks in heart failure pathology. Therefore, the consideration of systems biology and integrative approach is essential to develop novel treatments.