Inhibitory Stimuli Research Articles

8806 A Case of Autoimmune Thyroid Switching

Abstract Disclosure: J. Case: None. R.V. Chemitiganti: None. D. Suravajjala: None. Autoimmune thyroid disease comprises both hyper- and hypothyroid states including Graves' disease and Hashimoto's thyroiditis, respectively. The predominant antibody activity, demonstrable by thyrotropin receptor antibody, predicts the clinical presentation and treatment; thyrotropin receptor antibodies may act as a stimulatory or inhibitory stimulus upon the thyroid gland recognized as thyroid stimulating antibody(TSAb) and thyroid blocking antibody(TBAb). Rarely patients may transition from a hyperthyroid to a hypothyroid state and vice versa if the predominant antibody activity shifts which may occur due to a variety of mechanisms and characteristics related to each individual patient and treatment course. A 29 year old female presented to establish care for autoimmune thyroiditis. She was diagnosed with Graves' disease at age 19 when pregnant and treated with propylthiouracil; she switched to methimazole for the next six years when her thyroid function normalized and therapy discontinued. Two years later she became concerned with weight gain and her thyroid function was reevaluated demonstrating hypothyroidism and she was treated with levothyroxine 25mcg daily until presentation. Further labwork revealed undetectable TSI, and TPO antibody elevated at 177 u/mL. She became clinically and biochemically euthyroid on levothyroxine 50mcg daily. Switching between hyper- and hypothyroid states is a rare occurrence among patients with may attributable factors. Both antithyroid drugs including methimazole as well as replacement therapy with levothyroxine may alter the antibody milieu and so the predominant ratio and activity among TSAb and TBAb thereby leading to a shift in clinical presentation and thyroid state. Pregnancy may lead to hemodilution contributing to lessening of autoimmune activity which may return following delivery leading typically to a shift from TSAb to TBAb. Uncontrolled hyper- and hypothyroidism may affect dendritic activity leading to altered presentation and increased immune reactivity. The unlikely occurrence of switching from a hyperthyroid to a hypothyroid state based upon autoimmunity as in this patient was likely affected these factors. Recognition of this potential transition and associated factors would lead to beneficial monitoring and possibly development of assays more attuned to this phenomenon with better capability in maintaining a euthyroid state and potentially predicting a transition. Presentation: 6/3/2024

A Temperature Sensory Leaky Integrate-and-Fire Artificial Neuron Based on Chitosan/PNIPAM Bilayer Volatile Complementary Resistive Switching Memristor.

The presence of neurons is crucial in neuromorphic computing systems as they play a vital role in modulating the strength of synapses through the release of either excitatory or inhibitory stimuli. Hence, the development of sensory neurons plays a pivotal role in broadening the scope of brain-inspired neural computing. The present study introduces an artificial sensory neuron, which is constructed using a temperature-sensitive volatile complementary resistance switch memristor based on the functional layer of the chitosan/PNIPAM bilayer. The resistive switching behavior arises from the formation and ionization of oxygen vacancy filaments, whereby the threshold voltage and low resistive resistance of the device exhibit a temperature-dependent increase within the range of 290-410 K. A functional replication of a neuron with leaky integration and firing has been successfully developed, effectively simulating essential biological functions such as firing triggered by threshold, refractory period implementation, and modulation of spiking frequency. The artificial sensory neuron exhibits characteristics similar to those of leaky integrated firing neurons that receive temperature inputs. It has the potential to control the output frequency and amplitude under varying temperature conditions, making it suitable for temperature-sensing applications. This study presents a potential hardware implementation for developing efficient artificial intelligence systems that can support temperature detections.

Establishing inhibitory stimulus control of automatically maintained self-injury.

Establishing inhibitory stimulus control of automatically maintained self-injury.

Persistent Interruption in Parvalbumin-Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms.

Persistent activity in excitatory pyramidal cells (PYRs) is a putative mechanism for maintaining memory traces during working memory. We have recently demonstrated persistent interruption of firing in fast-spiking parvalbumin-expressing interneurons (PV-INs), a phenomenon that could serve as a substrate for persistent activity in PYRs through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modeling and mathematical analysis showed that the slowly inactivating potassium current KV1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption of firing. Using a fast/slow separation of times scales approach with the KV1 inactivation variable as a bifurcation parameter shows that the initial inhibitory stimulus stops repetitive firing by moving the membrane potential trajectory onto a coexisting stable fixed point corresponding to a nonspiking quiescent state. As KV1 inactivation decays, the trajectory follows the branch of stable fixed points until it crosses a subcritical Hopf bifurcation (HB) and then spirals out into repetitive firing. In a model describing entorhinal cortical PV-INs without KV1, interruption of firing could be achieved by taking advantage of the bistability inherent in type 2 excitability based on a subcritical HB, but the interruption was not robust to noise. Persistent interruption of firing is therefore broadly applicable to PV-INs in different brain regions but is only made robust to noise in the presence of a slow variable, KV1 inactivation.

Complement signaling as a T-cell checkpoint in the ovarian cancer (OC) tumor microenvironment (TME)

Abstract T cell checkpoint pathways are barriers to anti-tumor immunity and critical therapeutic targets. We use ascites fluid supernatants (ASC) from patients with newly diagnosed OC as an authentic component of the TME. We previously showed that complement activation is increased in ASC versus paired serum and induces a suppressor phenotype in normal neutrophils characterized by inhibition of critical proliferative, signaling and metabolic pathways in normal human T cells. ASC by itself dramatically inhibited CD3/CD28-stimulated T cell cytokine production (IL-2, IFN-γ, and IL-10) and glucose consumption, but not proliferation. We hypothesized that complement activation in the TME delivers an inhibitory stimulus to T cells that suppresses stimulated cytokine responses required for activation and expansion. Peptide C3 inhibitors (compstatins) restored CD3/CD28-stimulated T cell cytokine responses and glucose consumption. Inhibition of Factor B, a component of the alternative pathway (AP), also rescued cytokine responses, while inhibition of C3aR, C5aR, and C7 had no significant effect. C3b/iC3b deposition on T cells was increased with ASC exposure and reduced by C3 inhibition. Addition of recombinant complement receptor-1 (CR-1) as a decoy of C3b binding to membrane-bound CR-1 fully abrogated the suppressive effect of ASC, while recombinant CD46 had variable effects among different ASC samples. Our results show a novel AP- and CR1-dependent checkpoint of T cell activation in the TME.

Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: A simulation study.

Postinhibitory excitation is a transient overshoot of a neuron's baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model, we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneuron's firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the postinhibitory excitation's strength correlates with the inhibitory stimulus's amplitude and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50% of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition.

Spiking information processing in a single photonic spiking neuron chip with double integrated electronic dendrites

Dendrites, branches of neurons that transmit signals between synapses and soma, play a vital role in spiking information processing, such as nonlinear integration of excitatory and inhibitory stimuli. However, the investigation of nonlinear integration of dendrites in photonic neurons and the fabrication of photonic neurons including dendritic nonlinear integration in photonic spiking neural networks (SNNs) remain open problems. Here, we fabricate and integrate two dendrites and one soma in a single Fabry–Perot laser with an embedded saturable absorber (FP-SA) neuron to achieve nonlinear integration of excitatory and inhibitory stimuli. Note that the two intrinsic electrodes of the gain section and saturable absorber (SA) section in the FP-SA neuron are defined as two dendrites for two ports of stimuli reception, with one electronic dendrite receiving excitatory stimulus and the other receiving inhibitory stimulus. The stimuli received by two electronic dendrites are integrated nonlinearly in a single FP-SA neuron, which generates spikes for photonic SNNs. The properties of frequency encoding and spatiotemporal encoding are investigated experimentally in a single FP-SA neuron with two electronic dendrites. For SNNs equipped with FP-SA neurons, the range of weights between presynaptic neurons and postsynaptic neurons is varied from negative to positive values by biasing the gain and SA sections of FP-SA neurons. Compared with SNN with all-positive weights realized by only biasing the gain section of photonic neurons, the recognition accuracy of Iris flower data is improved numerically in SNN consisting of FP-SA neurons. The results show great potential for multi-functional integrated photonic SNN chips.

Contributions of the Sodium Leak Channel NALCN to Pacemaking of Medial Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

We tested the role of the sodium leak channel, NALCN, in pacemaking of dopaminergic neuron (DAN) subpopulations from adult male and female mice. In situ hybridization revealed NALCN RNA in all DANs, with lower abundance in medial ventral tegmental area (VTA) relative to substantia nigra pars compacta (SNc). Despite lower relative abundance of NALCN, we found that acute pharmacological blockade of NALCN in medial VTA DANs slowed pacemaking by 49.08%. We also examined the electrophysiological properties of projection-defined VTA DAN subpopulations identified by retrograde labeling. Inhibition of NALCN reduced pacemaking in DANs projecting to medial nucleus accumbens (NAc) and others projecting to lateral NAc by 70.74% and 31.98%, respectively, suggesting that NALCN is a primary driver of pacemaking in VTA DANs. In SNc DANs, potentiating NALCN by lowering extracellular calcium concentration speeded pacemaking in wildtype but not NALCN conditional knockout mice, demonstrating functional presence of NALCN. In contrast to VTA DANs, however, pacemaking in SNc DANs was unaffected by inhibition of NALCN. Instead, we found that inhibition of NALCN increased the gain of frequency-current plots at firing frequencies slower than spontaneous firing. Similarly, inhibition of the hyperpolarization-activated cyclic nucleotide-gated (HCN) conductance increased gain but had little effect on pacemaking. Interestingly, simultaneous inhibition of NALCN and HCN resulted in significant reduction in pacemaker rate. Thus, we found NALCN makes substantial contributions to driving pacemaking in VTA DAN subpopulations. In SNc DANs, NALCN is not critical for pacemaking but inhibition of NALCN makes cells more sensitive to hyperpolarizing stimuli.SIGNIFICANCE STATEMENT Pacemaking in midbrain dopaminergic neurons (DAN) relies on multiple subthreshold conductances, including a sodium leak. Whether the sodium leak channel, NALCN, contributes to pacemaking in DANs located in the VTA and the SNc has not yet been determined. Using electrophysiology and pharmacology, we show that NALCN plays a prominent role in driving pacemaking in projection-defined VTA DAN subpopulations. By contrast, pacemaking in SNc neurons does not rely on NALCN. Instead, the presence of NALCN regulates the excitability of SNc DANs by reducing the gain of the neuron's response to inhibitory stimuli. Together, these findings will inform future efforts to obtain DAN subpopulation-specific treatments for use in neuropsychiatric disorders.

Crosstalk between hypoxic cellular micro-environment and the immune system: a potential therapeutic target for infectious diseases.

There are overwhelming reports on the promotional effect of hypoxia on the malignant behavior of various forms of cancer cells. This has been proposed and tested exhaustively in the light of cancer immunotherapy. However, there could be more interesting functions of a hypoxic cellular micro-environment than malignancy. There is a highly intricate crosstalk between hypoxia inducible factor (HIF), a transcriptional factor produced during hypoxia, and nuclear factor kappa B (NF-κB) which has been well characterized in various immune cell types. This important crosstalk shares common activating and inhibitory stimuli, regulators, and molecular targets. Impaired hydroxylase activity contributes to the activation of HIFs. Inflammatory ligands activate NF-κB activity, which leads to the expression of inflammatory and anti-apoptotic genes. The eventual sequelae of the interaction between these two molecular players in immune cells, either bolstering or abrogating functions, is largely cell-type dependent. Importantly, this holds promise for interesting therapeutic interventions against several infectious diseases, as some HIF agonists have helped prevent immune-related diseases. Hypoxia and inflammation are common features of infectious diseases. Here, we highlighted the role of this crosstalk in the light of functional immunity against infection and inflammation, with special focus on various innate and adaptive immune cells. Particularly, we discussed the bidirectional effects of this crosstalk in the regulation of immune responses by monocytes/macrophages, dendritic cells, neutrophils, B cells, and T cells. We believe an advanced understanding of the interplay between HIFs and NF-kB could reveal novel therapeutic targets for various infectious diseases with limited treatment options.

Retardation of acquisition after conditioned inhibition and latent inhibition training in human causal learning.

Inhibitory stimuli are slow to acquire excitatory properties when paired with the outcome in a retardation test. However, this pattern is also seen after simple nonreinforced exposure: latent inhibition. It is commonly assumed that retardation would be stronger for a conditioned inhibitor than for a latent inhibitor, but there is surprisingly little empirical evidence comparing the two in either animals or humans. Thus, retardation after inhibitory training could in principle be attributable entirely to latent inhibition. We directly compared the speed of excitatory acquisition after conditioned inhibition and matched latent inhibition training in human causal learning. Conditioned inhibition training produced stronger transfer in a summation test, but the two conditions did not differ substantially in a retardation test. We offer two explanations for this dissociation. One is that learned predictiveness attenuated the latent inhibition that otherwise would have occurred during conditioned inhibition training, so that retardation in that condition was primarily due to inhibition. The second explanation is that inhibitory learning in these experiments was hierarchical in nature, similar to negative occasion-setting. By this account, the conditioned inhibitor was able to negatively modulate the test excitor in a summation test, but was no more retarded than a latent inhibitor in its ability to form a direct association with the outcome. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The influence of cross unconditional stimulus reinstatement on electrodermal responding and conditional stimulus valence in differential fear conditioning.

We examined whether the inhibitory Conditional Stimulus (CS)-no Unconditional Stimulus (US) association formed during extinction can be triggered by a novel US during the reinstatement of conditional electrodermal responding and self-reported CS valence in human differential fear conditioning. Participants were trained with either a shock or an aversive scream US before undergoing extinction. Participants then received either the same (i.e., shock_shock or scream_scream) or a different US during reinstatement (i.e., shock_scream, scream_shock). Differential conditioning across all indices was stronger when a shock US was used during acquisition. After reinstatement, electrodermal responding to both the CS+ and the CS- increased regardless of the type of US used during reinstatement (non-differential reinstatement). Differential CS valence evaluations were larger after reinstatement in the groups that received the same US during acquisition and reinstatement (differential reinstatement), but differential evaluations did not increase in the groups receiving a different US at reinstatement. This dissociation suggests that the reinstatement of negative stimulus valence and the reinstatement of expectancy learning may differ.

A flexible artificial chemosensory neuronal synapse based on chemoreceptive ionogel-gated electrochemical transistor

The human olfactory system comprises olfactory receptor neurons, projection neurons, and interneurons that perform remarkably sophisticated functions, including sensing, filtration, memorization, and forgetting of chemical stimuli for perception. Developing an artificial olfactory system that can mimic these functions has proved to be challenging. Herein, inspired by the neuronal network inside the glomerulus of the olfactory bulb, we present an artificial chemosensory neuronal synapse that can sense chemical stimuli and mimic the functions of excitatory and inhibitory neurotransmitter release in the synapses between olfactory receptor neurons, projection neurons, and interneurons. The proposed device is based on a flexible organic electrochemical transistor gated by the potential generated by the interaction of gas molecules with ions in a chemoreceptive ionogel. The combined use of a chemoreceptive ionogel and an organic semiconductor channel allows for a long retentive memory in response to chemical stimuli. Long-term memorization of the excitatory chemical stimulus can be also erased by applying an inhibitory electrical stimulus due to ion dynamics in the chemoresponsive ionogel gate electrolyte. Applying a simple device design, we were able to mimic the excitatory and inhibitory synaptic functions of chemical synapses in the olfactory system, which can further advance the development of artificial neuronal systems for biomimetic chemosensory applications.

Impaired Non-Selective Response Inhibition in Obsessive-Compulsive Disorder.

Two prominent features of obsessive-compulsive disorder (OCD) are the inability to inhibit intrusive thoughts and behaviors and pathological doubt or intolerance of uncertainty. Previous study showed that uncertain context modeled by equiprobable presentation of excitatory (Go) and inhibitory (NoGo) stimuli requires non-selective response inhibition in healthy subjects. In other words, it requires transient global inhibition triggered not only by excitatory stimuli but also by inhibitory stimuli. Meanwhile, it is unknown whether OCD patients show abnormal brain activity of the non-selective response inhibition system. In order to test this assumption, we performed an fMRI study with an equiprobable Go/NoGo task involving fourteen patients with OCD and compared them with 34 healthy controls. Patients with OCD showed pathological slowness in the Go/NoGo task. The non-selective response inhibition system in OCD included all brain areas seen in healthy controls and, in addition, involved the right anterior cingulate cortex (ACC) and the anterior insula/frontal operculum (AIFO). Moreover, a between-group comparison revealed hypoactivation of brain regions within cingulo-opercular and cortico-striato-thalamo-cortical (CSTC) circuits in OCD. Among hypoactivated areas, the right ACC and the right dorsolateral prefrontal cortex (DLPFC) were associated with non-selective inhibition. Furthermore, regression analysis showed that OCD slowness was associated with decreased activation in cingulate regions and two brain areas related to non-selective inhibition: the right DLPFC and the right inferior parietal lobule (IPL). These results suggest that non-selective response inhibition is impaired in OCD, which could be a potential explanation for a relationship between inhibitory deficits and the other remarkable characteristic of OCD known as intolerance of uncertainty.

Memristors based on NdNiO3 nanocrystals film as sensory neurons for neuromorphic computing.

By mimicking the behavior of the human brain, artificial neural systems offer the possibility to further improve computing efficiency and solve the von Neumann bottleneck. In particular, neural systems with perceptual capability expand the application field and lay a good foundation for the construction of perceptual storage and computational systems. However, research on neurons with perceptual functions is still relatively scarce, with most works focusing on optoelectronic synapses. The neuron is important for neuromorphic computing systems because neurons output excitatory or inhibitory stimuli to regulate the weight of synapses. Therefore, the construction of sensory neurons is crucial to expand the application range of brain-like neural computing. Here, an artificial sensory neuron is proposed, which is constructed using a photosensitive bipolar threshold switching memristor based on NdNiO3 (NNO) nanocrystals. These metallic phase nanocrystals can not only enhance the local electric field, but also act as a reservoir for defects (VoS) to guide the growth of conductive filaments and stabilize the performance of the device. They present stable bipolar threshold switching behavior with a low 120 nW set power, and the operating voltages decreased in light due to photocarrier action. A leaky integrate firing (LIF) neuron has been realized, which achieved key biological neuron functions, such as all-or-nothing spiking, threshold-driven firing, refractory period, and spiking frequency modulation. The LIF neurons receiving optical inputs have the properties of an artificial sensory neuron. It could regulate the spiking output frequency at different light densities, which could be used for a ship approaching a port. This work provides a promising hardware implementation towards constructing high-performance artificial intelligence to assist ships at night in a sensory system.

TGF-β in patients with hematologic malignancies

TGF-β expression is often increased in diseases such as malignancy, inflammation and fibrotic pathology. TGF-β ligand is involved in many processes of lymphoid cell development. TGF-β exerts an inhibitory stimulus on the differentiation and proliferation of stem cell progenitors. The amount of TGF-β on stem cell progenitors can determine various biological effects. For instance, if high concentrations of TGF-β have an inhibitory effect on stem cell progenitors, at low doses it can become stimulatory, especially in that group of stem cell progenitors that have a high probability of developing into myeloid cells.The aim of the study was to determine the level of TGF-β in the peripheral blood of patients with hematologic malignancies and to see its correlation with blood biomarkers of systemic inflammation.

Reversal of inhibition by no-modulation training but not by extinction in human causal learning.

One of the many strengths of the Rescorla and Wagner (1972) model is that it accounts for both excitatory and inhibitory learning using a single error-correction mechanism. However, it makes the counterintuitive prediction that nonreinforced presentations of an inhibitory stimulus will lead to extinction of its inhibitory properties. Zimmer-Hart and Rescorla (1974) provided the first of several animal conditioning studies that contradicted this prediction. However, the human data are more mixed. Accordingly, we set out to test whether extinction of an inhibitor occurs in human causal learning after simultaneous feature negative training with a conventional unidirectional outcome. In 2 experiments with substantial sample sizes, we found no evidence of extinction after presentations of the inhibitory stimulus alone in either a summation test or causal ratings. By contrast, 2 "no-modulation" procedures that contradicted the original training contingencies successfully reversed inhibition. These results did not differ substantially as a function of participants' self-reported causal structures (configural/modulation/prevention). We hypothesize that inhibitory learning may be intrinsically modulatory, analogous to negative occasion-setting, even with simultaneous training. This hypothesis would explain why inhibition is reversed by manipulations that contradict modulation but not by simple extinction, as well as other properties of inhibitory learning such as imperfect transfer to another excitor. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cellular mechanisms involved in the pathogenesis of airway remodeling in chronic lung disease

ABSTRACT Background Airway epithelial cells and lung fibroblasts play an important role in the development of chronic lung disease, but the exact mechanisms responsible have not been clarified. Our objective was to investigate the involvement of these cells in the inflammatory response associated to chronic lung disease. Methods Human lung fibroblasts and airway epithelial cells were challenged with Interleukin-1β and hypoxia, and with inhibitory (simvastatin) stimuli of the inflammatory response. Expression of markers of local inflammation ((IL-8, monocyte chemoattractant protein-1 (MCP-1), factor-κB1 (NF-κB1)), systemic inflammation ((C-reactive protein (CRP) and serum amyloid A (SAA)) and proteases matrix metalloproteinase (MMP) 9 and 12 were assessed by PCR and ELISA. Apoptosis/necrosis was analyzed by flow cytometry. Results Our results showed that the lung fibroblasts had a higher expression of local and systemic inflammation and protease activity markers when they were treated with IL-1β compared to airway epithelial cells. Under hypoxic conditions, we observed a decrease in systemic inflammation in lung fibroblasts, which was further attenuated by simvastatin. Conclusion The lung fibroblasts seem to be the main initially stimulated cells that could potentially trigger the inflammatory response, and be responsible for the eventual onset of chronic lung disease. The involvement of IL-1ß stimulation in systemic inflammatory and proteinase imbalance biomarkers is higher in lung fibroblasts. Apoptosis is not a predominant mechanism in these cells.

Inhibitory framing in hypersexual patients with Parkinson’s disease. An fMRI pilot study

Hypersexuality in medicated patients with PD is caused by an increased influence of motivational drive areas and a decreased influence of inhibitory control areas due to dopaminergic medication. In this pilot study, we test a newly developed paradigm investigating the influence of dopaminergic medication on brain activation elicited by sexual pictures with and without inhibitory contextual framing. Twenty PD patients with and without hypersexuality were examined with fMRI either OFF or ON standardized dopaminergic medication. The paradigm consisted of a priming phase where either a neutral context or an inhibitory context was presented. This priming phase was either followed by a sexual or a neutral target. Sexual, compared to neutral pictures resulted in a BOLD activation of various brain regions implicated in sexual processing. Hypersexual PD patients showed increased activity compared to PD controls in these regions. There was no relevant effect of medication between the two groups. The inhibitory context elicited less activation in inhibition-related areas in hypersexual PD, but had no influence on the perception of sexual cues. The paradigm partially worked: reactivity of motivational brain areas to sexual cues was increased in hypersexual PD and inhibitory contextual framing lead to decreased activation of inhibitory control areas in PD. We could not find a medication effect and the length of the inhibitory stimulus was not optimal to suppress reactivity to sexual cues. Our data provide new insights into the mechanisms of hypersexuality and warrant a replication with a greater cohort and an optimized stimulus length in the future.

Geometric characterization of dynamical structure for neural firing activities induced by inhibitory pulse.

In general, inhibitory stimuli are thought to inhibit neuronal firing, but they may actually enhance firing sometimes, such as post-inhibitory rebound spike (PIR spike) and post-inhibitory facilitation (PIF) phenomena, which play an important role in human neuronal activities. We study responses to inhibitory pulse in a classical neuron model (Quartic adaptive Integrate-and-fire model) well known to reproduce a number of biologically realistic behaviors. The three phenomena that we study are PIR, in which a neuron fires after an inhibitory pulse, and PIF, in which a subthreshold excitatory input can induce a spike if it is applied with proper timing after an inhibitory pulse, as well as period firing after inhibitory pulse. When the system features focus and saddle two equilibriums, the three phenomena will be occurred under the inhibitory pulse, while all three phenomena will not be induced when the system features node and saddle two equilibriums. Using dynamical systems theory, we explain the threshold mechanism of enhancement of neural firing response induced by inhibitory pulse and analyze the origin of these phenomena from several factors. We also describe the geometric characterization of dynamical structures of these three phenomena. This study therefore enrich the paradoxical phenomena that induced by inhibitory input and advance our understanding of its role.

Tim-3 adapter protein Bat3 acts as an endogenous regulator of tolerogenic dendritic cell function.

Dendritic cells (DCs) sense environmental cues and adopt either an immune-stimulatory or regulatory phenotype, thereby fine-tuning immune responses. Identifying endogenous regulators that determine DC function can thus inform the development of therapeutic strategies for modulating the immune response in different disease contexts. Tim-3 plays an important role in regulating immune responses by inhibiting the activation status and the T cell priming ability of DC in the setting of cancer. Bat3 is an adaptor protein that binds to the tail of Tim-3; therefore, we studied its role in regulating the functional status of DCs. In murine models of autoimmunity (experimental autoimmune encephalomyelitis) and cancer (MC38-OVA-implanted tumor), lack of Bat3 expression in DCs alters the T cell compartment-it decreases TH1, TH17 and cytotoxic effector cells, increases regulatory T cells, and exhausted CD8+ tumor-infiltrating lymphocytes, resulting in the attenuation of autoimmunity and acceleration of tumor growth. We found that Bat3 expression levels were differentially regulated by activating versus inhibitory stimuli in DCs, indicating a role for Bat3 in the functional calibration of DC phenotypes. Mechanistically, loss of Bat3 in DCs led to hyperactive unfolded protein response and redirected acetyl-coenzyme A to increase cell intrinsic steroidogenesis. The enhanced steroidogenesis in Bat3-deficient DC suppressed T cell response in a paracrine manner. Our findings identified Bat3 as an endogenous regulator of DC function, which has implications for DC-based immunotherapies.