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IntroductionResurgent current (INaR) generated by voltage-gated sodium channels (VGSCs) plays an essential role in maintaining high-frequency firing of many neurons and contributes to disease pathophysiology such as epilepsy and painful disorders. Targeting INaR may present a highly promising strategy in the treatment of these diseases. Navβ4 and A-type fibroblast growth factor homologous factors (FHFs) have been identified as two classes of important INaR mediators; however, their receptor sites in VGSCs remain unknown, which hinders the development of novel agents to effectively target INaR.MethodsNavβ4 and FHF4A can mediate INaR generation through the amino acid segment located in their C-terminus and N-terminus, respectively. We mainly employed site-directed mutagenesis, chimera construction and whole-cell patch-clamp recording to explore the receptor sites of Navβ4 peptide and FHF4A in Nav1.7 and Nav1.8.ResultsWe show that the receptor of Navβ4-peptide involves four residues, N395, N945, F1737 and Y1744, in Nav1.7 DI-S6, DII-S6, and DIV-S6. We show that A-type FHFs generating INaR depends on the segment located at the very beginning, not at the distal end, of the FHF4 N-terminus domain. We show that the receptor site of A-type FHFs also resides in VGSC inner pore region. We further show that an asparagine at DIIS6, N891 in Nav1.8, is a major determinant of INaR generated by A-type FHFs in VGSCs.DiscussionCryo-EM structures reveal that the side chains of the critical residues project into the VGSC channel pore. Our findings provide additional evidence that Navβ4 peptide and A-type FHFs function as open-channel pore blockers and highlight channel inner pore region as a hotspot for development of novel agents targeting INaR.

Abstract When processing language, the brain is thought to deploy specialized computations to construct meaning from complex linguistic structures. Recently, artificial neural networks based on the Transformer architecture have revolutionized the field of natural language processing. Transformers integrate contextual information across words via structured circuit computations. Prior work has focused on the internal representations (“embeddings”) generated by these circuits. In this paper, we instead analyze the circuit computations directly: we deconstruct these computations into the functionally-specialized “transformations” that integrate contextual information across words. Using functional MRI data acquired while participants listened to naturalistic stories, we first verify that the transformations account for considerable variance in brain activity across the cortical language network. We then demonstrate that the emergent computations performed by individual, functionally-specialized “attention heads” differentially predict brain activity in specific cortical regions. These heads fall along gradients corresponding to different layers and context lengths in a low-dimensional cortical space.

Summary: Background: Argentina's smoking rates remain high. We aim to estimate Argentina age-specific histories of smoking initiation, cessation, prevalence, and intensity by birth-cohort to inform policy interventions. Methods: Modeling study. Data from three Argentinian nationally representative surveys conducted from 2004 to 2018 (n = 268,193) were used to generate smoking histories. The Cancer Intervention and Surveillance Modeling (CISNET) Network Lung Working Group age, period, and cohort modeling approach was used to calculate smoking initiation and cessation probabilities, ever and current smoking prevalence, and intensity (cigarettes per day, CPD) by age, sex, and birth cohort from 1950 to 2018. Findings: Ever smoking prevalence increases with age up to 25 and decreases with birth cohorts after 1990. Smoking initiation peaks between 15 and 18 years of age. Among females, initiation probabilities increased until the 1955 cohort, reaching a second peak in 1980–85 cohorts and declining thereafter. Males have higher initiation probabilities than females. Among males, initiation has decreased since the 1950 birth cohort, with a slight increase around the 1985 cohort. Current smoking prevalence has been decreasing since the 1960 birth cohort, except for a peak in 1980–85 cohorts. Cessation increases with age. Mean CPD increases with age and peaks around age 40, appearing flat in females since the 1985 cohort. Interpretation: Recent birth cohorts seem to be experiencing lower rates of initiation, stable rates of quitting and lower current and ever smoking prevalence. The stabilization of cessation probabilities and mean CPD indicate the need to strengthen existing tobacco control measures and advance new ones. Funding: NIH/NCI U01CA253858 grant.

Background and Aims: Demand for surveillance colonoscopy can sometimes exceed capacity, such as during and following the coronavirus disease 2019 pandemic, yet no tools exist to prioritize the patients most likely to be diagnosed with colorectal cancer (CRC) among those awaiting surveillance colonoscopy. We developed a multivariable prediction model for CRC at surveillance comparing performance to a model that assigned patients as low or high risk based solely on polyp characteristics (guideline-based model). Methods: Logistic regression was used for model development among patients receiving surveillance colonoscopy in 2014–2019. Candidate predictors included index colonoscopy indication, findings, and endoscopist adenoma detection rate, and patient and clinical characteristics at surveillance. Patients were randomly divided into model development (n = 36,994) and internal validation cohorts (n = 15,854). External validation was performed on 30,015 patients receiving surveillance colonoscopy in 2020–2022, and the multivariable model was then updated and retested. Results: One hundred fourteen, 43, and 71 CRCs were detected at surveillance in the 3 cohorts, respectively. Polyp size ≥10 mm, adenoma detection rate

OBJECTIVES/GOALS: To determine whether cardioprotective effects observed in individuals taking dietary supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid, are realized by altering platelet function, and if these effects are mediated through the 12-lipoxygenase derived metabolite, 12-hydroxyeicosapentaenoic acid (12-HEPE). METHODS/STUDY POPULATION: Washed platelets or platelet rich plasma from healthy human donors were treated with EPA and 12-HEPE to assess their ability to inhibit platelet activation. Platelets were stimulated with agonists targeting different steps of the hemostatic response to vascular injury. Platelet aggregation, dense granule secretion, surface expression of integrin αIIbβ3 and P-selectin, and clot retraction were analyzed. To assess signaling through Gαs-GPCRs and protein kinase A activity, phosphorylation of vasodilator-stimulated phosphoprotein (VASP) was examined via western blot following treatment with EPA or 12-HEPE. RESULTS/ANTICIPATED RESULTS: EPA and 12-HEPE dose-dependently inhibit both collagen and thrombin-induced platelet aggregation. Furthermore, 12-HEPE more potently attenuates dense granule secretion and surface expression of platelet activation markers, integrin αIIbβ3 and P-selectin, in comparison to EPA. Plasma treated with EPA delayed thrombin-induced clot retraction, while 12-HEPE had no effect. Additionally, treatment with 12-HEPE increases phosphorylation of VASP, suggesting it could signal through the activation of the eicosanoid Gαs-GPCRs. DISCUSSION/SIGNIFICANCE: Here, we show for the first time that EPA directly inhibits platelet activation through its 12-LOX metabolite, 12-HEPE. These findings provide further insight into the mechanisms underlying the cardioprotective effects of EPA. A better understanding of current PUFA supplementations can inform treatment and prevention of cardiovascular diseases.

ObjectivesEssential hypertension is a common chronic condition that can exacerbate or complicate various neurological diseases that may necessitate neuroimaging. Given growing medical imaging costs and the need to understand relationships between population blood pressure control and neuroimaging utilization, we seek to quantify the relationship between maximum blood pressure recorded in a given year and same-year utilization of neuroimaging CT or MR in a large healthcare population.MethodsA retrospective population-based cohort study was performed by extracting aggregate data from a multi-institutional dataset of patient encounters from 2016, 2018, and 2020 using an informatics platform (Cosmos) consisting of de-duplicated data from over 140 academic and non-academic health systems, comprising over 137 million unique patients. A population-based sample of all patients with recorded blood pressures of at least 50 mmHg DBP or 90 mmHg SBP were included. Cohorts were identified based on maximum annual SBP and DBP meeting or exceeding pre-defined thresholds. For each cohort, we assessed neuroimaging CT and MR utilization, defined as the percentage of patients undergoing ≥1 neuroimaging exam of interest in the same calendar year.ResultsThe multi-institutional population consisted of >38 million patients for the most recent calendar year analyzed, with overall utilization of 3.8-5.1% for CT and 1.5-2.0% for MR across the study period. Neuroimaging utilization increased substantially with increasing annual maximum BP. Even a modest BP increase to 140 mmHg systolic or 90 mmHg diastolic is associated with 3-4-fold increases in MR and 5-7-fold increases in CT same-year imaging compared to BP values below 120 mmHg / 80 mmHg.ConclusionHigher annual maximum recorded blood pressure is associated with higher same-year neuroimaging CT and MR utilization rates. These observations are relevant to public health efforts on hypertension management to mitigate costs associated with growing imaging utilization.

Type 2 diabetes (T2D) is a global public health issue characterized by excess weight, abdominal obesity, dyslipidemia, hyperglycemia, and a progressive increase in insulin resistance. Human population studies of T2D development and its effects on systemic metabolism are confounded by many factors that cannot be controlled, complicating the interpretation of results and the identification of early biomarkers. Aged, sedentary, and overweight/obese non-human primates (NHPs) are one of the best animal models to mimic spontaneous T2D development in humans. We sought to identify and distinguish a set of plasma and/or fecal metabolite biomarkers, that have earlier disease onset predictability, and that could be evaluated for their predictability in subsequent T2D studies in human cohorts. In this study, a single plasma and fecal sample was collected from each animal in a colony of 57 healthy and dysmetabolic NHPs and analyzed for metabolomics and lipidomics. The samples were comprehensively analyzed using untargeted and targeted LC/MS/MS. The changes in each animal’s disease phenotype were monitored using IVGTT, HbA1c, and other clinical metrics, and correlated with their metabolic profile. The plasma and fecal lipids, as well as bile acid profiles, from Healthy, Dysmetabolic (Dys), and Diabetic (Dia) animals were compared. Following univariate and multivariate analyses, including adjustments for weight, age, and sex, several plasma lipid species were identified to be significantly different between these animal groups. Medium and long-chain plasma phosphatidylcholines (PCs) ranked highest at distinguishing Healthy from Dys animals, whereas plasma triglycerides (TG) primarily distinguished Dia from Dys animals. Random Forest (RF) analysis of fecal bile acids showed a reduction in the secondary bile acid glycoconjugate, GCDCA, in diseased animals (AUC 0.76[0.64, 0.89]). Moreover, metagenomics results revealed several bacterial species, belonging to the genera Roseburia, Ruminococcus, Clostridium, and Streptococcus, to be both significantly enriched in non-healthy animals and associated with secondary bile acid levels. In summary, our results highlight the detection of several elevated circulating plasma PCs and microbial species associated with fecal secondary bile acids in NHP dysmetabolic states. The lipids and metabolites we have identified may help researchers to differentiate individual NHPs more precisely between dysmetabolic and overtly diabetic states. This could help assign animals to study groups that are more likely to respond to potential therapies where a difference in efficacy might be anticipated between early vs. advanced disease.

We present infrared aperture-masking interferometry (AMI) observations of newly formed dust from the colliding winds of the massive binary Wolf–Rayet system WR 137 with JWST using the Near Infrared Imager and Slitless Spectrograph (NIRISS). NIRISS AMI observations of WR 137 and a point-spread function calibrator star, HD 228337, were taken using the F380M and F480M filters in 2022 July and August as part of the Director’s Discretionary Early Release Science program #1349. Interferometric observables (squared visibilities and closure phases) from the WR 137 “interferogram” were extracted and calibrated using three independent software tools: ImPlaneIA, AMICAL, and SAMpip. The analysis of the calibrated observables yielded consistent values except for slightly discrepant closure phases measured by ImPlaneIA. Based on all three sets of calibrated observables, images were reconstructed using three independent software tools: BSMEM, IRBis, and SQUEEZE. All reconstructed image combinations generated consistent images in both F380M and F480M filters. The reconstructed images of WR 137 reveal a bright central core with a ∼300 mas linear filament extending to the northwest. A geometric colliding-wind model with dust production constrained to the orbital plane of the binary system and enhanced as the system approaches periapsis provided a general agreement with the interferometric observables and reconstructed images. Based on a colliding-wind dust condensation analysis, we suggest that dust formation within the orbital plane of WR 137 is induced by enhanced equatorial mass loss from the rapidly rotating O9 companion star, whose axis of rotation is aligned with that of the orbit.

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non-oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA-PLs, particularly sn2-arachidonoyl(AA)- and sn2-adrenoyl(AdA)-containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1-2 mol %) of doubly PUFA-acylated phospholipids (di-PUFA-PLs) whose role in ferroptosis remains enigmatic. Here we report that 15-lipoxygenase (15LOX) exhibits unexpectedly high pro-ferroptotic peroxidation activity towards di-PUFA-PEs. We revealed that peroxidation of several molecular species of di-PUFA-PEs occurred early in ferroptosis. Ferrostatin-1, a typical ferroptosis inhibitor, effectively prevented peroxidation of di-PUFA-PEs. Furthermore, co-incubation of cells with di-AA-PE and 15LOX produced PUFA-PE peroxidation and induced ferroptotic death. The decreased contents of di-PUFA-PEs in ACSL4 KO A375 cells was associated with lower levels of di-PUFA-PE peroxidation and enhanced resistance to ferroptosis. Thus, di-PUFA-PE species are newly identified phospholipid peroxidation substrates and regulators of ferroptosis, representing a promising therapeutic target for many diseases related to ferroptotic death.

This study reports that targeting intrinsically disordered regions of the voltage-gated sodium channel 1.7 ([Na.sub.V]1.7) protein facilitates discovery of sodium channel inhibitory peptide aptamers ([Na.sub.V]iPA) for adeno-associated virus-mediated (AAV-mediated), sensory neuron-specific analgesia. A multipronged inhibition of [I.sub.Na1.7], [I.sub.Na1.6], [I.sub.Na1.3], and [I.sub.Na1.1]--but not [I.sub.Na1.5] and [I.sub.Na1.8]--was found for a prototype and named [Na.sub.V]iPA1, which was derived from the [Na.sub.V]1.7 intracellular loop 1, and is conserved among the TTXs [Na.sub.V] subtypes. [Na.sub.V]iPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs [I.sub.Na] but not TTXr [I.sub.Na]. DRG injection of AAV6-encoded [Na.sub.V]iPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that [Na.sub.V]iPA1 expression normalized PSN excitability in TNI rats, suggesting that [Na.sub.V]iPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. IHC revealed efficient [Na.sub.V]iPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN- restricted AAV biodistribution. Inhibition of sodium channels by [Na.sub.V]iPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that [Na.sub.V]iPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs [Na.sub.V]s, has potential as a peripheral nerve-restricted analgesic therapeutic., Introduction Voltage-gated sodium channels ([Na.sub.V]s) are key regulators of neuronal excitability and pain sensations (1). Mammals possess 9 isoforms of [Na.sub.V]s, of which [Na.sub.V]1.7, [Na.sub.V]1.8, and [Na.sub.V]1.9 are preferentially expressed [...]

To the Editors: As I was paging through the March-April issue of American Scientist, I was astounded to see in Bhimsen Shivamoggi's article 'Gas Dynamics of Solar and Stellar Winds' [...]

As Training and Education in Professional Psychology (TEPP's) outgoing editorial team ends their term, the authors reflect on the journal's contributions to health service psychology (HSP) and suggest potential priorities and opportunities as both the journal and the science of education and training continue to mature. TEPP's aim is to serve as a forum for thoughtful and rigorous conceptual and empirical investigation of current issues in HSP education and training, and for candid self-reflection about strengths, shortcomings, and growth opportunities in HSP education. The authors review the journal's contributions to this aim through three primary goals established at the beginning of their editorial term: (a) engage the broad training community in sharing its best conceptual and empirical work relevant to education and training across training levels, settings, and focus areas; (b) advance the science of education and training through strong empirical research; and (c) expand emphasis on the sociocultural context in which education and training occurs (Bell et al., 2019). The authors conclude with recommendations to the incoming TEPP editorial team and prospective authors for next steps in advancing HSP education and training. Public Significance Statement: Training and Education in Professional Psychology outgoing editorial team reflects on progress toward their goals for the journal's contributions to education and training in health service psychology. These goals include advancing education that is evidence-based, responsive to the sociocultural context, and that prepares the next generations of health service psychologists to address societal mental health needs. The authors conclude with recommendations for next steps in supporting innovative and effective education and training. [ABSTRACT FROM AUTHOR]

Objective: The Hearing Utility Measure (HUM) is a replacement hearing attribute for the Health Utilities Index, Mark 3 (HUI‐3) designed to improve the responsiveness of utility estimates to changes in hearing‐related quality of life. The final development step is to derive the instrument's utility scoring function. Methods: Residents of Ontario, Canada, aged ≥18 years participated in standard gamble and visual analogue scale exercises. Valuations for levels (response options) within each domain, and for each domain relative to the other domains were elicited and used to generate a hearing utility function. The function outputs hearing utility ranging from 0 = 'unable to hear at all' to 1 = 'perfect hearing' for each of the 25,920 hearing states classifiable by the HUM. Performance was assessed relative to the criterion standard: directly elicited standard gamble utility. Distributions of HUM‐derived hearing utility were compared with legacy HUI‐3 derived estimates. Results: A total of 126 respondents participated (mean age 39.2, range 18–85 years, 53% female [67/126]). The utility function performed well in the estimation of directly elicited utilities (mean difference 0.03, RMSE 0.06). Using the legacy HUI‐3, estimated hearing utility was 1.0 for 118/126 respondents (93.6%) compared with just 66/126 (52.4%) using the HUM. Conclusion: The new hearing attribute is capable of measuring variations in hearing utility not captured by the legacy HUI‐3, especially near the ceiling of hearing function. These findings justify its application and further work to study its measurement properties in hearing loss populations. Level of Evidence: 3 Laryngoscope, 134:4754–4762, 2024 [ABSTRACT FROM AUTHOR]