In this work, we present an extensive electrical characterization of spike-related phenomena in Single Chalcogenide XPoint Memory (SXM) devices. Our analysis reveals a strong correlation between several electrical parameters and the distribution of spike magnitudes across the memory array. Building on these observations, we propose a comprehensive simulation framework specifically designed to model spike effects. Within this framework, we introduce a simulation-based metric for spike magnitude, which demonstrates excellent tracking of threshold voltage and cycling endurance topological distribution throughout the array. The proposed model provides critical insights into the key factors governing spike behavior. In particular, it highlights the combined influence of technological choices, architectural configurations, circuit-level design, and biasing schemes on spike magnitude. These findings enable the use of the model as a predictive and optimization tool, supporting design strategies aimed at improving cycling endurance and projecting spike-related effects under technology scaling. Ultimately, this methodology offers a robust foundation for guiding future SXM development and reliability enhancement.

Ovonic threshold switching is the key process for several applications of chalcogenide alloys including phase change memories and selector elements in cross-points arrays. Very recently, it has been shown that the threshold switching voltage VT depends on the polarity of the applied field. This feature has been already exploited in the realization of the Single Chalcogenide X-point Memory (SXM) in which a single film of a chalcogenide alloy can serve as both a memory and selector unit. In this work, we provide a microscopic understanding of the polarity-dependent VT by leveraging electrical and physical measurements, numerical simulations based on technology computer aided design (TCAD) and electronic structure calculations based on density functional theory (DFT). We developed a Graded Band Gap (GBG) model in which an inhomogeneous distribution of localized electronic states in the gap is established by the opposite effect of a strong electric field at the cathode and a high density of electrons in the conduction band at the anode. The model is suitable to reproduce several features of the programming window, including its dependence on temperature, thickness and composition of the chalcogenide alloy. The microscopic understanding that we gained on the SXM operation lays the foundation for important improvements in the memory design and in the selection of better performing alloys for applications in enabling memory technologies. Ovonic threshold switching between high-resistive and conductive states in chalcogenide alloys is crucial for phase change memories and selector elements, yet its voltage dependence on field polarity remains underexplored. Here, the authors elucidate this phenomenon using electrical measurements, numerical simulations based on Technology Computer Aided Design, and DFT calculations, proposing a Graded Band Gap model that enhances memory design by predicting programming window characteristics.

Adenosine receptors are a family of purinergic G-protein coupled receptors (GPCR) widely expressed in the peripheral and central nervous systems. Recently, studies done in model organisms suggest analgesic action for the adenosine A3 (ADORA3) and its agonists have been proposed as new neuropathic pain treatments. Given this conclusion, we hypothesized that this receptor may be expressed in nociceptive primary afferent neurons. However, when further investigated using multiplex fluorescence in situ hybridization, ADORA3 transcripts were found in the ring of support cells around the neuron, but absent from the neuron itself. To determine the identity of these support cells, the expression of ADORA3 was analyzed alongside markers for macrophage and satellite glial cells (SGC). Our results clearly showed ADORA3 expression exclusively in perineuronal macrophages. In the spinal cord, ADORA3 was expressed exclusively in microglia. These results suggest that, if translated to human clinical trials, the potential analgesic action of the adenosine A3 receptor agonism may result from a more complex or indirect mechanism involving modulation of macrophages and/or microglia. To further elucidate the precise molecular identity of these macrophage-like perineural cells we will evaluate ADORA3 expression alongside other non-neuronal molecular markers. This will allow for a better understanding of the functional implications of this cell and its proximity to the neuron. Additionally, further research may investigate the relationship between the neuron and its support cells, specifically the mechanisms underlying the intercell communication and its role in pain modulation.

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 neurons 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 neurons 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 neurons from a female macaque monkey. Critically, neurons 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 neurons. 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 neurons 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 neurons. 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. Stratton et al. present new evidence suggesting that pain-sensing neurons are fundamentally different between men and women. Across species, prolactin sensitizes dorsal root ganglion neurons in females but not males, whereas orexin sensitizes dorsal root ganglion neurons in males but not females.

The shortfall in new analgesic agents is a major impediment to reducing reliance on opioid medications for control of severe pain. In both animals and man, attenuating nociceptive transmission from primary afferent neurons with a μ-opioid receptor agonist yields highly effective analgesia. Consequently, deeper molecular characterization of human nociceptive afferents expressing OPRM1, the μ-opioid receptor gene, is a key component for advancing analgesic drug discovery and understanding clinical pain control. A co-expression matrix for the μ-opioid receptor and a variety of nociceptive channels as well as δ- and κ-opioid receptors is established by multiplex in situ hybridization. Our results indicate an OPRM1-positive population with strong molecular resemblance to rodent peptidergic C-nociceptors associated with tissue damage pain and an OPRM1-negative population sharing molecular characteristics of murine non-peptidergic C-nociceptors. The empirical identification of two distinct human nociceptive populations that differ profoundly in their presumed responsiveness to opioids provides an actionable translational framework for human pain control.

Cyclin A2 (CCNA2), a master cell cycle regulator silenced in postnatal cardiomyocytes, promotes cardiac repair in animal models. However, its effect on cytokinesis in adult human cardiomyocytes remains unknown. We engineered a replication-deficient adenoviral vector encoding human CCNA2 under the cardiac Troponin T promoter and delivered it to freshly isolated cardiomyocytes from adult human hearts. Time-lapse live imaging revealed induction of complete cytokinesis with preservation of sarcomeres and calcium mobilization in redifferentiated daughter cardiomyocytes. To uncover underlying transcriptional mechanisms, single-nucleus transcriptomics of CCNA2-transgenic versus non-transgenic mouse hearts identified a cardiomyocyte subpopulation enriched for cytokinesis, proliferative, and reprogramming genes. Ultra-deep bulk RNA sequencing of adult and fetal human hearts further highlighted reprogramming pathways relevant to CCNA2-induced effects. Together, these findings demonstrate that CCNA2 can reinitiate cytokinesis in adult human cardiomyocytes and illuminate conserved molecular programs, supporting its promise as a regenerative gene therapy for the heart.

Pain from advanced cancer is often intractable leading to significant impairment of quality of life. The standard of care for relieving cancer pain often relies on opioids, which can be highly or incompletely efficacious, and cause adverse effects such as addiction and respiratory suppression. A major priority of the pain field is the development of novel non-opioid analgesic strategies to improve patient care. In this study we correlate the clinical presentation of a single well-characterized patient treated with lumbar intrathecal RTX to a molecular phenotype from postmortem DRG and SC tissue collected from this patient at autopsy (approximately 4-5 months after RTX injection). This patient was enrolled in a Phase 1 Study evaluating safety and efficacy of intrathecal RTX treating pain in advanced cancer (NCT00804154). We stained the DRG and SC with markers of nociceptive sensory afferents such as calcitonin gene-related peptide (CGRP) and Substance P (SP) to map the denervation and potential cell loss at different spinal levels. In the SC, a marked decrease in primary afferent-derived SP and CGRP was observed at all rostro-caudal levels, consistent with the clinical presentation showing decreased sensation to heat to all extremities and torso. In the DRG, quantitative cell counts for mRNA expression and nociceptive protein markers showed minimal cell loss consistent with our previous work. Numerical pain rating scorThis clinical observation formed the basis for a reverse translational effort to assess the effects of dose, rate, and volume on RTX spread in the intrathecal space of rats and pigs.

Adenosine receptors are a family of purinergic G protein-coupled receptors that are widely distributed in bodily organs and in the peripheral and central nervous systems. Recently, antihyperalgesic actions have been suggested for the adenosine A3 receptor, and its agonists have been proposed as new neuropathic pain treatments. We hypothesized that these receptors may be expressed in nociceptive primary afferent neurons. However, RNA sequencing across species, eg, rat, mouse, dog, and human, suggests that dorsal root ganglion (DRG) expression of ADORA3 is inconsistent. In rat and mouse, Adora3 shows very weak to no expression in DRG, whereas it is well expressed in human DRG. However, the cell types in human DRG that express ADORA3 have not been delineated. An examination of DRG cell types using in situ hybridization clearly detected ADORA3 transcripts in peripheral macrophages that are in close apposition to the neuronal perikarya but not in peripheral sensory neurons. By contrast, ADORA1 was found primarily in neurons, where it is broadly expressed at low levels. These results suggest that a more complex or indirect mechanism involving modulation of macrophage and/or microglial cells may underlie the potential analgesic action of adenosine A3 receptor agonism.

Etrasimod (ADP334) is an oral, once‐daily, selective sphingosine 1‐phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis and in development for the treatment of immune‐mediated inflammatory diseases. Interaction between S1P and its five receptor subtypes (S1P1–S1P5) plays a role in several physiologic systems, including the cardiovascular and immune systems. Since differences in S1PR binding and downstream intracellular signaling could contribute to distinct profiles of drug efficacy and safety, we directly compared the S1P1–5 selectivity profile of etrasimod to three marketed S1PR modulators: fingolimod, ozanimod, and siponimod. Using both heterologous expression systems and human umbilical vein endothelial cells that spontaneously express S1P1, we profiled key S1P1 downstream signaling pathways and found that etrasimod had similar potency to the other tested S1PR modulators in promoting β‐arrestin recruitment and S1P1 internalization. However, etrasimod was notably less potent than other S1PR modulators in assays measuring S1P1‐mediated G protein activation (GTPγS binding and cAMP inhibition). Relatively lower potency of etrasimod in inducing G protein signaling corresponded to significantly diminished activation of human cardiac G protein‐coupled inwardly rectifying potassium channels when compared to ozanimod. Together with pharmacokinetic properties, this pharmacologic profile of etrasimod may contribute to the positive benefit risk profile of etrasimod observed during the phase III ELEVATE UC 52 and ELEVATE UC 12 trials in patients with moderately to severely active ulcerative colitis.

An ovonic threshold switch (OTS) based on chalcogenide glasses finds application as a selecting device in storage class memory (SCM) arrays. The OTS operation relies on the threshold switching, where the device switches from the off to the on state without phase transition, then the device turns off almost immediately as the voltage is reduced below a certain holding value. The physics behind the switching phenomenon has attracted wide interest due to the complicated interplay between electronic transport, joule heating and phase transition. In this work, it is shown that the current-voltage characteristic close to the switching point carries the fingerprint of carrier multiplication. The physical mechanism of threshold switching is then explained by bipolar impact ionization leading to avalanche multiplication, which in turn gives rise to the typical S-shaped characteristic. Numerical simulations by this physics-based model account for the measured switching properties, namely threshold voltage and current, at various chalcogenide thicknesses and compositions. These results provide the theoretical framework for future design and optimization of OTS in memory and computing applications.

The recent demonstration of differences in transcript expression in human post-mortem sensory neurons suggests the possibility of sexually dimorphic pain mechanisms. To date, however, the concept of “male” and “female” nociceptors has not been demonstrated at a functional level. We now report sensitization of female, but not male, human nociceptors by prolactin revealing a female-selective mechanism that can be exploited to improve the treatment of pain in women.

Inherited painless neuropathies arise due to genetic insults that either block the normal signaling of or destroy the sensory afferent neurons in the dorsal root ganglion (DRG) responsible for transducing noxious stimuli. Complete loss of these neurons leads to profound insensitivity to all sensory modalities including pain. Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare genetic neuropathy characterized by a progressive distal early onset sensory loss. This syndrome is caused by autosomal recessive mutations in the with-no-lysine protein kinase 1 (WNK1) serine-threonine kinase gene. Of interest, disease-associated mutations are found in the large exon, termed "HSN2," which encodes a 498 amino acid domain C-terminal to the kinase domain. These mutations lead to truncation of the HSN2-containing proteins through the addition of an early stop codon (nonsense mutation) leading to loss of the C-terminal domains of this large protein. The present study evaluates the transcripts, gene structure, and protein structure of HSN2-containing WNK1 splice variants in DRG and spinal cord in order to establish the basal expression patterns of WNK1 and HSN2-containing WNK1 splice variants using multiplex fluorescent situ hybridization. We hypothesized that these transcripts would be enriched in pain-sensing DRG neurons, and, potentially, that enrichment in nociceptive neurons was responsible for the painless phenotypes observed. However, our in-depth analyses revealed that the HSN2-WNK1 splice variants were ubiquitously expressed but were not enriched in tachykinin 1-expressing C-fiber neurons, a class of neurons with a highly nociceptive character. We subsequently identified other subpopulations of DRG neurons with higher levels of HSN2-WNK1 expression, including mechanosensory large fibers. These data are inconsistent with the hypothesis that this transcript is enriched in nociceptive fibers, and instead suggest it may be related to general axon maintenance, or that nociceptive fibers are more sensitive to the genetic insult. These findings clarify the molecular and cellular expression pattern of this painless neuropathy gene in human tissue.

Research suggests emotions impact pain; appetitive (pleasant) emotions reduce pain and aversive (unpleasant) emotions increase pain.Emotion regulation (ER) strategies can alter emotional experience, and therefore should alter emotional modulation of nociceptive processes.To investigate, 55 pain-free individuals viewed pleasant (erotic), neutral, and unpleasant (mutilation) affective pictures during which painful electric stimulations were delivered to evoke pain, nociceptive flexion reflexes (NFR; spinal nociception), and N2 pain-evoked cortical potentials (supraspinal nociception).Participants completed one block of pictures without engaging in ER, and were then randomly assigned to an ER strategy (suppress or enhance) that was employed during a second block of pictures.Valence and arousal ratings to pictures confirmed the ER manipulations were successful.Multilevel ANOVAs found that the suppress manipulation led to significant reduction of emotional modulation of pain, but had no effect on NFR or N2.By contrast, the enhance manipulation had no effect on any nociceptive outcome.These findings indicate that instructions to suppress or enhance emotion do not have an impact on physiological markers of nociception, but that instructions to suppress can reduce pleasureinduced pain inhibition and displeasure-induced pain facilitation.Alternatively, these results could mean that instructions to suppress emotions bias pain report without altering spinal or supraspinal nociception.Future research is needed to address this issue.