Activation Threshold Research Articles

A note on Tesla's revised safety report crash rates

Between June 2018 and December 2023, Tesla released quarterly safety reports citing average miles between crashes for Tesla vehicles. Prior to March 2021, crash rates were categorized as (1) with their SAE Level 2 automated driving system Autopilot engaged, (2) without Autopilot but with active safety features such as automatic emergency braking, and (3) without Autopilot and without active safety features. In January 2023, Tesla revised past reports to reflect their new categories of with and without Autopilot engaged, in addition to making small adjustments based on recently discovered double counting of reports and excluding previously recorded crashes that did not meet their thresholds of airbag or active safety restraint activation. The revisions are heavily biased towards no-active-safety-features—a surprising result given prior research showing that drivers predominantly keep most active safety features enabled. As Tesla's safety reports represent the only national source of Level 2 advanced driver assistance system crash rates, clarification of their methods is essential for researchers and regulators. This note describes the changes and considers possible explanations for the discrepancies.

Do Not Let the Beginning Trap you! On Inhibition, Associative Creative Chains, and Hopfield Neural Networks

ABSTRACTCreative thinking stems from the cognitive process that fosters the creation of new ideas and problem‐solving solutions. Artificial intelligence systems and neural network models can reduce the intricacy of understanding creative cognition. For instance, the generation of ideas could be symbolized as patterns of binary code in which clusters of neurons synchronize their firing and store information inside a neural network, forming connections based on correlation. The Hopfield neural network (HNN) is a simple model known for its biological plausibility in storing and retrieving neuron patterns. We implemented certain modifications to HNN as a step toward the larger framework of creative thinking‐based association. These modifications included introducing pattern weights control, which provides a robust representation for content addressable memory and conceptual links in stored data. We identified two mechanisms controlling the transition from analytical to associative‐based thinking. The first mechanism refers to the activation threshold of neurons, which acts as an on/off switch for the network. The second was the inhibition of stored concepts, similar to an on/off switch that guides the network to search for associative links and when to stop. Our findings suggest that neurons step back from the contextual focus and find alternatives when analytical thinking is insufficient. These alternatives are linked to seemingly unrelated ideas, using inhibition as an analogy to the hyperparameters. Using hyperparameters to inhibit the stored patterns, we could control the creation of associative links.

B cells expressing mutated IGHV1-69-encoded antigen receptors related to virus neutralization show lymphoma-like transcriptomes in patients with chronic HCV infection.

Chronic HCV infection leads to a complex interplay with adaptive immune cells that may result in B cell dyscrasias like cryoglobulinemia or lymphoma. While direct-acting antiviral therapy has decreased the incidence of severe liver damage, its effect on extrahepatic HCV manifestations such as B cell dyscrasias is still unclear. We sequenced B cell receptor (BCR) repertoires in patients with chronic HCV mono-infection and patients with HCV with a sustained virological response (SVR) after direct-acting antiviral therapy. This data set was mined for highly neutralizing HCV antibodies and compared to a diffuse large B cell lymphoma data set. The TKO model was used to test the signaling strength of selected B-BCRs in vitro. Single-cell RNA sequencing of chronic HCV and HCV SVR samples was performed to analyze the transcriptome of B cells with HCV-neutralizing antigen receptors. We identified a B cell fingerprint with high richness and somatic hypermutation in patients with chronic HCV and SVR. Convergence to specific immunoglobulin genes produced high-connectivity complementarity-determining region 3 networks. In addition, we observed that IGHV1-69 CDR1 and FR3 mutations characterizing highly neutralizing HCV antibodies corresponded to recurrent point mutations found in clonotypic BCRs of high-grade lymphomas. These BCRs did not show autonomous signaling but a lower activation threshold in an in vitro cell model for the assessment of BCR signaling strength. Single-cell RNA sequencing revealed that B cells carrying these point mutations showed a persisting oncogenic transcriptome signature with dysregulation in signaling nodes such as CARD11, MALT1, RelB, MAPK, and NFAT. We provide evidence that lymphoma-like cells derive from the anti-HCV immune response. In many patients, these cells persist for years after SVR and can be interpreted as a mechanistic basis for HCV-related B cell dyscrasias and increased lymphoma risk even beyond viral elimination.

Response of a Terrestrial Polar Ecosystem to the March 2022 Antarctic Weather Anomaly

AbstractRecord high temperatures were documented in the McMurdo Dry Valleys, Antarctica, on 18 March 2022, exceeding average temperatures for that day by nearly 30°C. Satellite imagery and stream gage measurements indicate that surface wetting coincided with this warming more than 2 months after peak summer thaw and likely exceeded thresholds for rehydration and activation of resident organisms that typically survive the cold and dry conditions of the polar fall in a freeze‐dried state. This weather event is notable in both the timing and magnitude of the warming and wetting when temperatures exceeded 0°C at a time when biological communities and streams have typically entered a persistent frozen state. Such events may be a harbinger of future climate conditions characterized by warmer temperatures and greater thaw in this region of Antarctica, which could influence the distribution, activity, and abundance of sentinel taxa. Here we describe the ecosystem responses to this weather anomaly reporting on meteorological and hydrological measurements across the region and on later biological observations from Canada Stream, one of the most diverse and productive ecosystems within the McMurdo Dry Valleys.

Ikaros sets the threshold for negative B-cell selection by regulation of the signaling strength of the AKT pathway

Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection.

Piezo2 voltage-block regulates mechanical pain sensitivity.

PIEZO2 is a trimeric mechanically-gated ion channel expressed by most sensory neurons in the dorsal root ganglia. Mechanosensitive PIEZO2 channels are also genetically required for normal touch sensation in both mice and humans. We previously showed that PIEZO2 channels are also strongly modulated by membrane voltage. Specifically, it is only at very positive voltages that all channels are available for opening by mechanical force. Conversely, most PIEZO2 channels are blocked at normal negative resting membrane potentials. The physiological function of this unusual biophysical property of PIEZO2 channels, however, remained unknown. We characterized the biophysical properties of three PIEZO2 ion channel mutations at an evolutionarily conserved arginine (R2756). Using genome engineering in mice we generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to characterize the physiological consequences of altering PIEZO2 voltage sensitivity in vivo. We measured endogenous mechanosensitive currents in sensory neurons isolated from the dorsal root ganglia and characterized mechanoreceptor and nociceptor function using electrophysiology. Mice were also assessed behaviourally and morphologically. Mutations at the conserved Arginine (R2756) dramatically changed the biophysical properties of the channel relieving voltage block and lowering mechanical thresholds for channel activation. Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice that were homozygous for gain-of-function mutations were viable and were tested for sensory changes. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but mechanosensitive currents in most mechanoreceptors that underlie touch sensation were only mildly affected by the same mutations. Single-unit electrophysiological recordings from sensory neurons innervating the glabrous skin revealed that rapidly-adapting mechanoreceptors that innervate Meissner's corpuscles exhibited slightly decreased mechanical thresholds in Piezo2 knock-in mice. Consistent with measurements of mechanically activated currents in isolated sensory neurons essentially all cutaneous nociceptors, both fast conducting Aδ-mechanonociceptors and unmyelinated C-fibre nociceptors were substantially more sensitive to mechanical stimuli and indeed acquired receptor properties similar to ultrasensitive touch receptors in Piezo2 knock-in mice. Mechanical stimuli also induced enhanced ongoing activity in cutaneous nociceptors in Piezo2 knock-in mice and hyper-sensitive PIEZO2 channels were sufficient alone to drive ongoing activity, even in isolated nociceptive neurons. Consistently, Piezo2 knock-in mice showed substantial behavioural hypersensitivity to noxious mechanical stimuli. Our data indicate that ongoing activity and sensitization of nociceptors, phenomena commonly found in human chronic pain syndromes, can be driven by relieving the voltage-block of PIEZO2 ion channels. Indeed, membrane depolarization caused by multiple noxious stimuli may sensitize nociceptors by relieving voltage-block of PIEZO2 channels.

Activation thresholds, not quitting thresholds, account for the low prevalence effect in dynamic search.

The low-prevalence effect (LPE) is the finding that target detection rates decline as targets become less frequent in a visual search task. A major source of this effect is thought to be that fewer targets result in lower quitting thresholds, i.e., observers respond target-absent after looking at fewer items compared to searches with a higher prevalence of targets. However, a lower quitting threshold does not directly account for an LPE in searches where observers continuously monitor a dynamic display for targets. In these tasks there are no discrete "trials" to which a quitting threshold could be applied. This study examines whether the LPE persists in this type of dynamic search context. Experiment 1 was a 2 (dynamic/static) x 2 (10%/40% prevalence targets) design. Although overall performance was worse in the dynamic task, both tasks showed a similar magnitude LPE. In Experiment 2, we replicated this effect using a task where subjects searched for either of two targets (Ts and Ls). One target appeared infrequently (10%) and the other moderately (40%). Given this method of manipulating prevalence rate, the quitting threshold explanation does not account for the LPE even for static displays. However, replicating Experiment 1, we found an LPE of similar magnitude for both search scenarios, and lower target detection rates with the dynamic displays, demonstrating the LPE is a potential concern for both static and dynamic searches. These findings suggest an activation threshold explanation of the LPE may better account for our observations than the traditional quitting threshold model.

CD28 Shapes T Cell Receptor Signaling by Regulating ZAP70 Activation and Lck Dynamics.

T cell activation requires T cell receptor (TCR) engagement, which initiates a series of proximal events including tyrosine phosphorylation of the CD3 and TCRζ chains, recruitment, and activation of the protein tyrosine kinases Lck and ZAP70, followed by recruitment of adapter and signaling proteins. CD28 co-stimulation is also required to generate a functional immune response. Currently we lack a full understanding of the molecular mechanism of CD28 activation. TCR microclusters (MC) are submicron-sized molecular condensates and basic signaling units that form immediately after TCR ligation. Our results show that CD28 co-stimulation specifically accelerated recruitment of ZAP70 to the TCRζ chain in MCs and increased ZAP70 activation. This CD28-mediated acceleration of ZAP70 recruitment was driven by enhanced Lck recruitment to the MCs. A greater spatial separation between active and inactive species of Lck was also observed in the MCs as a consequence of CD28 co-stimulation. These results suggest that CD28 co-stimulation may lower the TCR activation threshold by enhancing the activated form of Lck in the TCR MCs.

NK Receptor Signaling Lowers TCR Activation Threshold, Enhancing Selective Recognition of Cancer Cells by TAA-Specific CTLs.

Cytotoxic CD8+ T lymphocyte (CTL) recognition of non-mutated tumor-associated antigens (TAA), present on cancer cells and also in healthy tissues, is an important element of cancer immunity, but the mechanism of its selectivity for cancer cells and opportunities for its enhancement remain elusive. In this study, we found that CTL expression of the NK receptors (NKR) DNAM1 and NKG2D was associated with the effector status of CD8+ tumor-infiltrating lymphocytes and long-term survival of patients with melanoma. Using MART1 and NY-ESO-1 as model TAAs, we demonstrated that DNAM1 and NKG2D regulate T-cell receptor (TCR) functional avidity and set the threshold for TCR activation of human TAA-specific CTLs. Superior co-stimulatory effects of DNAM1 over CD28 involved enhanced TCR signaling, CTL killer function, and polyfunctionality. Double transduction of human CTLs with TAA-specific TCR and NKRs resulted in strongly enhanced antigen sensitivity, without a reduction in antigen specificity and selectivity of killer function. In addition, the elevation of NKR ligand expression on cancer cells due to chemotherapy also increased CTL recognition of cancer cells expressing low levels of TAAs. Our data help explain the ability of self-antigens to mediate tumor rejection in the absence of autoimmunity and support the development of dual-targeting adoptive T-cell therapies that use NKRs to enhance the potency and selectivity of recognition of TAA-expressing cancer cells.

A computationally efficient and robust looming perception model based on dynamic neural field

There are primarily two classes of bio-inspired looming perception visual systems. The first class employs hierarchical neural networks inspired by well-acknowledged anatomical pathways responsible for looming perception, and the second maps nonlinear relationships between physical stimulus attributes and neuronal activity. However, even with multi-layered structures, the former class is sometimes fragile in looming selectivity, i.e., the ability to well discriminate between approaching and other categories of movements. While the latter class leaves qualms regarding how to encode visual movements to indicate physical attributes like angular velocity/size. Beyond those, we propose a novel looming perception model based on dynamic neural field (DNF). The DNF is a brain-inspired framework that incorporates both lateral excitation and inhibition within the field through instant feedback, it could be an easily-built model to fulfill the looming sensitivity observed in biological visual systems. To achieve our target of looming perception with computational efficiency, we introduce a single-field DNF with adaptive lateral interactions and dynamic activation threshold. The former mechanism creates antagonism to translating motion, and the latter suppresses excitation during receding. Accordingly, the proposed model exhibits the strongest response to moving objects signaling approaching over other types of external stimuli. The effectiveness of the proposed model is supported by relevant mathematical analysis and ablation study. The computational efficiency and robustness of the model are verified through systematic experiments including on-line collision-detection tasks in micro-mobile robots, at success rate of 93% compared with state-of-the-art methods. The results demonstrate its superiority over the model-based methods concerning looming perception.

PELI2 is a negative regulator of STING signaling that is dynamically repressed during viral infection

The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA), a ubiquitous danger signal, to produce interferon, a potent anti-viral and anti-cancer cytokine. However, STING activation must be tightly controlled because aberrant interferon production leads to debilitating interferonopathies. Here, we discover PELI2 as a crucial negative regulator of STING. Mechanistically, PELI2 inhibits the transcription factor IRF3 by binding to phosphorylated Thr354 and Thr356 on the C-terminal tail of STING, leading to ubiquitination and inhibition of the kinase TBK1. PELI2 sets a threshold for STING activation that tolerates low levels of cytosolic dsDNA, such as that caused by silenced TREX1, RNASEH2B, BRCA1, or SETX. When this threshold is reached, such as during viral infection, STING-induced interferon production temporarily downregulates PELI2, creating a positive feedback loop allowing a robust immune response. Lupus patients have insufficient PELI2 levels and high basal interferon production, suggesting that PELI2 dysregulation may drive the onset of lupus and other interferonopathies.

Modulating Ca2+ influx into adrenal chromaffin cells with short-duration nanosecond electric pulses

Isolated bovine adrenal chromaffin cells exposed to single 2-, 4-, or 5-ns pulses undergo a rapid, transient rise in intracellular Ca2+ mediated by Ca2+ entry via voltage-gated Ca2+ channels (VGCCs), mimicking the activation of these cells in vivo by acetylcholine. However, pulse durations 150 ns or longer elicit larger amplitude and longer-lived Ca2+ responses due to Ca2+ influx via both VGCCs and a yet to be identified plasma membrane pathway(s). To further our understanding of the differential effects of ultrashort versus longer pulse durations on Ca2+ influx, chromaffin cells were loaded with calcium green-1 and exposed to single 3-, 5-, 11-, 25-, or 50-ns pulses applied at their respective Ca2+ activation threshold electric fields. Increasing pulse duration from 3 or 5 ns to only 11 ns was sufficient to elicit increased amplitude and longer-lived Ca2+ responses in the majority of cells, a trend that continued as pulse duration increased to 50 ns. The amplification of Ca2+ responses was not the result of Ca2+ release from intracellular stores and was accompanied by a decreased effectiveness of VGCC inhibitors to block the responses and a reduced reliance on extracellular Na+ and membrane depolarization to evoke the responses. Inhibitors of pannexin channels, P2X receptors, or non-selective cation channels failed to attenuate 50-ns-elicited Ca2+ responses, ruling out these Ca2+-permeable channels as secondary Ca2+ entry pathways. Analytical calculations and numerical modeling suggest that the parameter that best determines the response of chromaffin cells to increasing pulse durations is the time the membrane charges to its peak voltage. These results highlight the pronounced sensitivity of a neuroendocrine cell to pulse durations differing by only tens of nanoseconds, which has important implications for the future development of nanosecond pulse technologies enabling electrostimulation applications for spatially focused and graded in vivo neuromodulation.

β2-adrenergic receptor activation decreases the mechanical sensitivity of rat masticatory muscle afferent fibres.

Activation of β2 adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β2 adrenergic receptor activation may contribute to mechanisms that underlie temporomandibular joint pain, its effect on masticatory muscle pain sensitivity is uncertain. The current study sought to determine the extent to which β adrenergic receptors are expressed by masticatory muscle afferent fibres, and to assess the effect of local activation of these receptors on the mechanical sensitivity of masticatory muscle afferent fibres in rats. Trigeminal ganglion neurons that innervate the rat (n = 12) masseter muscle and lower lip were identified by tissue injection of fluorescent dyes and were then stained with antibodies against β1 or β2 adrenergic receptors. Extracellular recordings from 60 trigeminal ganglion neurons that innervate the masticatory muscle were undertaken in a second group of anaesthetised rats of both sexes (n = 37) to assess afferent mechanical activation thresholds. Thresholds were assessed before and after injection of the β adrenergic receptor agonists into masticatory muscle. β1 and β2 adrenergic receptor expression was greater in labial skin than in masticatory muscle ganglion neurons (p < .05, one-way ANOVA, Holm-Sidak test). There was a higher expression of β2 adrenergic receptors in masticatory muscle ganglion neurons in males than in females. The mixed β agonist isoproterenol increased afferent mechanical activation threshold in male but not female rats (p < .05, Mann-Whitney test). In male rats, salbutamol, a β2 selective agonist, also increased afferent mechanical activation threshold but hydralazine, a vasodilator, did not (p < .05, Mann-Whitney test). Activation of β2 adrenergic receptors decreases the mechanical sensitivity of masticatory muscle afferent fibres in a sex-related manner.

Elevated memory T-cell conversion in a preclinical mouse model of hemophilia A.

One of the major challenges in the choice of the best therapeutic approach for the treatment of patients affected by hemophilia A (HA) is the definition of criteria predicting the formation of factor VIII (FVIII) neutralizing antibodies, called inhibitors. Both genetic and environmental elements influencing the immune response toward FVIII have been identified but still not all the factors causing the pathological rejection of FVIII have been identified. Since there is a connection between coagulation and inflammation, here we assessed the role played by the FVIII deficiency in shaping the humoral and cellular response toward an antigen other than FVIII itself. To this aim, we challenged both HA and wild-type (WT) mice with either FVIII or ovalbumin (OVA) and followed antigen-specific antibody level, immune cell population frequency and phenotype up to 9 weeks after the last antigen booster. The activation threshold was evaluated in vitro by stimulating the murine T cells with a decreasing dose of α-CD3. The humoral response to FVIII was similar between the two groups while both the in vivo and in vitro experiments highlighted an antigen-independent sensitivity of HA compared with WT T cells causing an increase in memory T-cell conversion and proliferation capability.

Nociceptors are functionally male or female: from mouse to monkey to man.

The prevalence of many pain conditions often differs between sexes. In addition to such quantitative distinctions, sexual dimorphism may also be qualitative reflecting differences in mechanisms that promote pain in men and women. A major factor that influences the likelihood of pain perception is the threshold for activation of nociceptors. Peripheral nociceptor sensitization has been demonstrated to be clinically relevant in many pain conditions. Whether peripheral nociceptor sensitization can occur in a sexually dimorphic fashion, however, has not been extensively studied. To address this fundamental knowledge gap, we used patch clamp electrophysiology to evaluate the excitability of dorsal root ganglion neurones from male or female rodents, non-human primates, and humans following exposure to putative sensitizing agents. Previous studies from our laboratory, and others, have shown that prolactin promotes female-selective pain responses in rodents. Consistent with these observations, dorsal root ganglion neurones from female, but not male, mice were selectively sensitized by exposure to prolactin. The sensitizing action of prolactin was also confirmed in dorsal root ganglion neurones from a female macaque monkey. Critically, neurones recovered from female, but not male, human donors were also selectively sensitized by prolactin. In the course of studies of sleep and pain, we unexpectedly observed that an orexin antagonist could normalize pain responses in male animals. We found that orexin B produced sensitization of male, but not female, mouse, macaque, and human dorsal root ganglion neurones. Consistent with functional responses, increased prolactin receptor and orexin receptor 2 expression was observed in female and male mouse dorsal root ganglia, respectively. Immunohistochemical interrogation of cultured human sensory neurones and whole dorsal root ganglia also suggested increased prolactin receptor expression in females and orexin receptor 2 expression in males. These data reveal a functional double dissociation of nociceptor sensitization by sex, which is conserved across species and is likely directly relevant to human pain conditions. To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurones. Patient sex is currently not a common consideration for the choice of pain therapy. Precision medicine, based on patient sex could improve therapeutic outcomes by selectively targeting mechanisms promoting pain in women or men. Additional implications of these findings are that the design of clinical trials for pain therapies should consider the proportions of male or female patients enrolled. Lastly, re-examination of selected past failed clinical trials with subgroup analysis by sex may be warranted.

Central and peripheral haemodynamics at exercise onset: the role of central command

PurposeThe involvement of central command in central hemodynamic regulation during exercise is relatively well-known, although its contribution to peripheral hemodynamics at the onset of low-intensity contractions is debated. This study sought to examine central and peripheral hemodynamics during electrically-evoked muscle contractions (without central command) and voluntary muscle activity (with central command).MethodsCyclic quadriceps isometric contractions (1 every second), either electrically-evoked (ES; 200 ms trains composed of 20 square waves) or performed voluntarily (VC), were executed by 10 healthy males (26 ± 3 years). In both trials, matched for force output, peripheral and central hemodynamics were analysed.ResultsAt exercise onset, both ES and VC exhibited equal peaks of femoral blood flow (1276 ± 849 vs. 1117 ± 632 ml/min, p > 0.05) and vascular conductance (15 ± 11 vs. 13 ± 7 ml/min/mmHg, p > 0.05), respectively. Similar peaks of heart rate (86 ± 16 bpm vs. 85 ± 16 bpm), stroke volume (100 ± 20 vs. 99 ± 27 ml), cardiac output (8.2 ± 2.5 vs. 8.5 ± 2.1 L/min), and mean arterial pressure (113 ± 13 vs. 113 ± 3 mmHg), were recorded (all, p > 0.05). After ~ 50 s, all the variables drifted to lower values. Collectively, the hemodynamics showed equal responses.ConclusionThese results suggest a similar pathway for the initial (first 40 s) increase in central and peripheral hemodynamics. The parallel responses may suggest an initial minimal central command involvement during the onset of low-intensity contractions, likely associated with a neural drive activation delay or threshold.

Phase-dependent word perception emerges from region-specific sensitivity to the statistics of language

Neural oscillations reflect fluctuations in excitability, which biases the percept of ambiguous sensory input. Why this bias occurs is still not fully understood. We hypothesized that neural populations representing likely events are more sensitive, and thereby become active on earlier oscillatory phases, when the ensemble itself is less excitable. Perception of ambiguous input presented during less-excitable phases should therefore be biased toward frequent or predictable stimuli that have lower activation thresholds. Here, we show such a frequency bias in spoken word recognition using psychophysics, magnetoencephalography (MEG), and computational modelling. With MEG, we found a double dissociation, where the phase of oscillations in the superior temporal gyrus and medial temporal gyrus biased word-identification behavior based on phoneme and lexical frequencies, respectively. This finding was reproduced in a computational model. These results demonstrate that oscillations provide a temporal ordering of neural activity based on the sensitivity of separable neural populations.

Instrumental Monitoring of a Slow-Moving Landslide in Piedmont (Northwest Italy) for the Definition of Rainfall Thresholds.

The prediction and prevention of landslide hazard is a challenging topic involving the assessment and quantitative evaluation of several elements: geological and geomorphological setting, rainfalls, and ground motion. This paper presents the multi-approach investigation of the Nevissano landslide (Asti Province, Piedmont, NW Italy). It shows a continuous and slow movement, alongside few paroxysmal events, the last recorded in 2016. The geological and geomorphological models were defined through a field survey. An inventory of the landslide's movements and rainfall records in the period 2000-2016 was performed, respectively, through archive investigations and the application of "Moving Sum of Daily Rainfall" method, allowing for the definition of rain thresholds for the landslide activation (105 mm and 193 mm, respectively, in 3 and 30 days prior to the event). The displacements over the last 8 years (2016-2023) were monitored through an innovative in-continuum monitoring inclinometric system and Earth Observation (EO) data (i.e., relying on Interferometric Synthetic Aperture Radar, or InSAR data): it gave the opportunity to validate the rainfall thresholds previously defined. This study aims to provide information to public authorities for the appropriate management of the site. Moreover, the proposed workflow could be adopted as a guideline for investigating similar situations.

Conversion of dendritic cells into tolerogenic or inflammatory cells depends on the activation threshold and kinetics of the mTOR signaling pathway

BackgroundRestoring impaired peripheral immune tolerance is the primary challenge in treating autoimmune diseases. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs), a fraction of low molecular weight proteins, in inhibiting the progression of psoriatic arthritis, even in the presence of high levels of the proinflammatory cytokine TNFα in the bloodstream. When specifically targeting dendritic cells (DCs), SSPs transform them into tolerogenic cells, which efficiently induce the development of regulatory Foxp3+ Treg cells. In this study, we provide further insights into the mechanism of action of SSPs.ResultsWe found that SSPs stimulate the activation of the mTOR signaling pathway in dendritic cells, albeit in a different manner than the classical immunogenic stimulus LPS. While LPS-induced activation is rapid, strong, and sustained, the activity induced by SSPs is delayed, less intense, yet still significant. These distinct patterns of activation, as measured by phosphorylation of key components of the pathway are also observed in response to other immunogenic and tolerogenic stimuli such as GM-CSF + IL-4 or IL-10 and TGFβ. The disparity in mTOR activation between immunogenic and tolerogenic stimuli is quantitative rather than qualitative. In both cases, mTOR activation primarily occurs through the PI3K/Akt signaling axis and involves ERK and GSK3β kinases, with minimal involvement of AMPK or NF-kB pathways. Furthermore, in the case of SSPs, mTOR activation seems to involve adenosine receptors. Additionally, we observed that DCs treated with SSPs exhibit an energy metabolism with high plasticity, which is typical of tolerogenic cells rather than immunogenic cells.ConclusionHence, the decision whether dendritic cells enter an inflammatory or tolerogenic state seems to rely on varying activation thresholds and kinetics of the mTOR signaling pathway.

The activation thresholds and inactivation kinetics of poking-evoked PIEZO1 and PIEZO2 currents are sensitive to subtle variations in mechanical stimulation parameters

ABSTRACT PIEZO1 and PIEZO2 are mechanically activated ion channels that confer mechanosensitivity to various cell types. PIEZO channels are commonly examined using the so-called poking technique, where currents are recorded in the whole-cell configuration of the patch-clamp technique, while the cell surface is mechanically stimulated with a small fire-polished patch pipette. Currently, there is no gold standard for mechanical stimulation, and therefore, stimulation protocols differ significantly between laboratories with regard to stimulation velocity, angle, and size of the stimulation probe. Here, we systematically examined the impact of variations in these three stimulation parameters on the outcomes of patch-clamp recordings of PIEZO1 and PIEZO2. We show that the inactivation kinetics of PIEZO1 and, to a lesser extent, of PIEZO2 change with the angle at which the probe that is used for mechanical stimulation is positioned and, even more prominently, with the size of its tip. Moreover, we found that the mechanical activation threshold of PIEZO2, but not PIEZO1, decreased with increasing stimulation speeds. Thus, our data show that two key outcome parameters of PIEZO-related patch-clamp studies are significantly affected by common variations in the mechanical stimulation protocols, which calls for caution when comparing data from different laboratories and highlights the need to establish a gold standard for mechanical stimulation to improve comparability and reproducibility of data obtained with the poking technique.