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Abstract With the growing interest in establishing brain-based biomarkers for precision medicine, there is a need for noninvasive, scalable neuroimaging devices that yield valid and reliable metrics. Kernel’s second-generation Flow2 Time-Domain Functional Near-Infrared Spectroscopy (TD-fNIRS) system meets the requirements of noninvasive and scalable neuroimaging, and uses a validated modality to measure brain function. In this work, we investigate the test-retest reliability (TRR) of a set of metrics derived from the Flow2 recordings. We adopted a repeated-measures design with 49 healthy participants, and quantified TRR over multiple time points and different headsets—in different experimental conditions including a resting state, a sensory, and a cognitive task. Results demonstrated high reliability in resting state features including hemoglobin concentrations, head tissue light attenuation, amplitude of low frequency fluctuations, and functional connectivity. Additionally, passive auditory and Go/No-Go inhibitory control tasks each exhibited similar activation patterns across days. Notably, areas with the highest reliability were in auditory regions during the auditory task, and right prefrontal regions during the Go/No-Go task, consistent with prior literature. This study underscores the reliability of Flow2-derived metrics, supporting its potential to actualize the vision of using brain-based biomarkers for diagnosis, treatment selection and treatment monitoring of neuropsychiatric and neurocognitive disorders.

Abstract Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca2+ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 (SLC2A1) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.

Abstract Background Female breast cancer stands as the prime type of cancer in the Kingdom of Saudi Arabia (KSA), with a high incidence and mortality rates. This study assessed the burden of female breast cancer in KSA by analyzing and forecasting its incidence, mortality, and disability-adjusted life years (DALYs). Methods We retrieved data from the Global Burden of Disease (GBD) about female breast cancer from 1990 to 2021. Time-series analysis used the autoregressive integrated moving average (ARIMA) model to forecast female breast cancer statistics from 2022 to 2026. Results From 1990 to 2021, KSA reported 77,513 cases of female breast cancer. The age groups with the highest number of cases are 45–49 years, followed by 40–44 years, 50–54 years, and 35–39 years. The analysis also showed fewer cases in the younger age groups, with the lowest number in the less than 20-year-old age group. From 1990 to 2021, KSA reported 19,440 deaths due to breast cancer, increasing from 201 cases in 1990 to 1,190 cases in 2021. The age-standardized incidence rate/100,000 of breast cancer increased from 15.4 (95% confidence interval (CI) 11.2–21.0) in 1990 to 46.0 (95%CI 34.5–61.5) in 2021. The forecasted incidence rate of female breast cancer will be 46.5 (95%CI 45.8–46.5) in 2022 and 49.6 (95%CI 46.8–52.3) in 2026. The age-standardized death rate per 100,000 Saudi women with breast cancer increased from 6.73 (95%CI 6.73–9.03) in 1990 to 9.77 (95%CI 7.63–13.00) in 2021. The forecasted female breast cancer death rate will slightly decrease to 9.67 (95%CI 9.49–9.84) in 2022 and to 9.26 (95%CI 8.37–10.15) in 2026. DALYs increased from 229.2 (95%CI 165.7–313.6) in 1990 to 346.1 (95%CI 253.9–467.2) in 2021. The forecasted DALYs of female breast cancer will slightly decrease to 343.3 (95%CI 337.2–349.5) in 2022 reaching 332.1 (95%CI 301.2–363.1) in 2026. Conclusions Female breast cancer is still a significant public health burden that challenges the health system in KSA, current policies and interventions should be fashioned to alleviate the disease morbidity and mortality and mitigate its future burden.

Abstract Rapamycin slows cystogenesis in murine models of polycystic kidney disease (PKD) but failed in clinical trials, potentially due to insufficient drug dosing. To improve drug efficiency without increasing dose, kidney-specific drug delivery may be used. Mesoscale nanoparticles (MNP) selectively target the proximal tubules in rodents. We explored whether MNPs can target cystic kidney tubules and whether rapamycin-encapsulated-MNPs (RapaMNPs) can slow cyst growth in Pkd1 knockout (KO) mice. MNP was intravenously administered in adult Pkd1KO mice. Serum and organs were harvested after 8, 24, 48 or 72 h to measure MNP localization, mTOR levels, and rapamycin concentration. Pkd1KO mice were then injected bi-weekly for 6 weeks with RapaMNP, rapamycin, or vehicle to determine drug efficacy on kidney cyst growth. Single MNP injections lead to kidney-preferential accumulation over other organs, specifically in tubules and cysts. Likewise, one RapaMNP injection resulted in higher drug delivery to the kidney compared to the liver, and displayed sustained mTOR inhibition. Bi-weekly injections with RapaMNP, rapamycin or vehicle for 6 weeks resulted in inconsistent mTOR inhibition and little change in cyst index, however. MNPs serve as an effective short-term, kidney-specific delivery system, but long-term RapaMNP failed to slow cyst progression in Pkd1KO mice.

Abstract Limb immobilization causes rapid declines in muscle strength and mass. Given the role of the nervous system in immobilization‐induced weakness, targeted interventions may be able to preserve muscle strength, but not mass, and vice versa. The purpose of this study was to assess the effects of two distinct interventions during 1 week of knee joint immobilization on muscle strength (isometric and concentric isokinetic peak torque), mass (bioimpedance spectroscopy and ultrasonography), and neuromuscular function (transcranial magnetic stimulation and interpolated twitch technique). Thirty‐nine healthy, college‐aged adults (21 males, 18 females) were randomized into one of four groups: immobilization only (n = 9), immobilization + action observation/mental imagery (AOMI) (n = 10), immobilization + neuromuscular electrical stimulation (NMES) (n = 12), or control group (n = 8). The AOMI group performed daily video observation and mental imagery of knee extensions. The NMES group performed twice daily stimulation of the quadriceps femoris. Based on observed effect sizes, it appears that AOMI shows promise as a means of preserving voluntary strength, which may be modulated by neural adaptations. Strength increased from PRE to POST in the AOMI group, with +7.2% (Cohen's d = 1.018) increase in concentric isokinetic peak torque at 30°/s. However, NMES did not preserve muscle mass. Though preliminary, our findings highlight the specific nature of clinical interventions and suggest that muscle strength can be independently targeted during rehabilitation. This study was prospectively registered: ClinicalTrials.gov NCT05072652.

Abstract Early-life exposure to stress results in significantly increased risk of neurodevelopmental impairments with potential long-term effects into childhood and even adulthood. As a crucial step towards monitoring neonatal stress in neonatal intensive care units (NICUs), our study aims to quantify the duration, frequency, and physiological responses of care manipulation activities, based on bedside videos and physiological signals. Leveraging 289 h of video recordings and physiological data within 330 sessions collected from 27 neonates in 2 NICUs, we develop and evaluate a deep learning method to detect manipulation activities from the video, to estimate their duration and frequency, and to further integrate physiological signals for assessing their responses. With a 13.8% relative error tolerance for activity duration and frequency, our results were statistically equivalent to human annotations. Further, our method proved effective for estimating short-term physiological responses, for detecting activities with marked physiological deviations, and for quantifying the neonatal infant stressor scale scores.

Abstract Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

Abstract Sleep onset insomnia is a pervasive problem that contributes significantly to the poor health outcomes associated with insufficient sleep. Auditory stimuli phase-locked to slow-wave sleep oscillations have been shown to augment deep sleep, but it is unknown whether a similar approach can be used to accelerate sleep onset. The present randomized controlled crossover trial enrolled adults with objectively verified sleep onset latencies (SOLs) greater than 30 min to test the effect of auditory stimuli delivered at specific phases of participants’ alpha oscillations prior to sleep onset. During the intervention week, participants wore an electroencephalogram (EEG)-enabled headband that delivered acoustic pulses timed to arrive anti-phase with alpha for 30 min (Stimulation). During the Sham week, the headband silently recorded EEG. The primary outcome was SOL determined by blinded scoring of EEG records. For the 21 subjects included in the analyses, stimulation had a significant effect on SOL according to a linear mixed effects model (p = 0.0019), and weekly average SOL decreased by 10.5 ± 15.9 min (29.3 ± 44.4%). These data suggest that phase-locked acoustic stimulation can be a viable alternative to pharmaceuticals to accelerate sleep onset in individuals with prolonged sleep onset latencies. Trial Registration: This trial was first registered on clinicaltrials.gov on 24/02/2023 under the name Sounds Locked to ElectroEncephalogram Phase For the Acceleration of Sleep Onset Time (SLEEPFAST), and assigned registry number NCT05743114.

Background: Muscle-invasive bladder cancer (MIBC) is a potentially fatal disease, especially in the setting of locally advanced or node-positive disease. Adverse outcomes have also primarily been associated with low-income status, as has been reported in other cancers. While the adoption of neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC) and pelvic lymph node dissection (PLND) has improved outcomes, these standard-of-care treatments may be underutilized in lower-income patients. We sought to investigate the economic disparities in NAC and PLND receipt and survival outcomes in MIBC. Methods: Utilizing the National Cancer Database, a retrospective cohort analysis of cT2-4N0-3M0 BCa patients with urothelial histology who underwent RC was conducted. The impact of income level on overall survival (OS) and the likelihood of receiving NAC and PLND was evaluated. Results: A total of 25,823 patients were included. This study found that lower-income patients were less likely to receive NAC and adequate PLND (≥15 LNs). Moreover, lower-income patients exhibited worse OS (Median OS 55.9 months vs. 68.2 months, p < 0.001). Our findings also demonstrated that higher income, treatment at academic facilities, and recent years of diagnosis were associated with an increased likelihood of receiving standard-of-care modalities and improved survival. Conclusions: Even after controlling for clinicodemographic variables, income independently influenced the receipt of standard MIBC treatments and survival. Our findings identify an opportunity to improve the quality of care for lower-income MIBC patients through concerted efforts to regionalize multi-modal urologic oncology care.

BackgroundWhile prior work examining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern focused on hospitalization and death, less is known about differences in clinical presentation. We compared the prevalence of acute symptoms across pre-Delta, Delta, and Omicron.MethodsWe conducted an analysis of the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE), a cohort study enrolling symptomatic SARS-CoV-2-positive participants. We determined the association between the pre-Delta, Delta, and Omicron time periods and the prevalence of 21 coronavirus disease 2019 (COVID-19) acute symptoms.ResultsWe enrolled 4113 participants from December 2020 to June 2022. Pre-Delta vs Delta vs Omicron participants had increasing sore throat (40.9%, 54.6%, 70.6%; P < .001), cough (50.9%, 63.3%, 66.7%; P < .001), and runny noses (48.9%, 71.3%, 72.9%; P < .001). We observed reductions during Omicron in chest pain (31.1%, 24.2%, 20.9%; P < .001), shortness of breath (42.7%, 29.5%, 27.5%; P < .001), loss of taste (47.1%, 61.8%, 19.2%; P < .001), and loss of smell (47.5%, 55.6%, 20.0%; P < .001). After adjustment, those infected during Omicron had significantly higher odds of sore throat vs pre-Delta (odds ratio [OR], 2.76; 95% CI, 2.26-3.35) and Delta (OR, 1.96; 95% CI, 1.69-2.28).ConclusionsParticipants infected during Omicron were more likely to report symptoms of common respiratory viruses, such as sore throat, and less likely to report loss of smell and taste.Trial registrationNCT04610515.

BackgroundThe prevalence, incidence, and interrelationships of persistent symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection vary. There are limited data on specific phenotypes of persistent symptoms. Using latent class analysis (LCA) modeling, we sought to identify whether specific phenotypes of COVID-19 were present 3 months and 6 months post-infection.MethodsThis was a multicenter study of symptomatic adults tested for SARS-CoV-2 with prospectively collected data on general symptoms and fatigue-related symptoms up to 6 months postdiagnosis. Using LCA, we identified symptomatically homogenous groups among COVID-positive and COVID-negative participants at each time period for both general and fatigue-related symptoms.ResultsAmong 5963 baseline participants (4504 COVID-positive and 1459 COVID-negative), 4056 had 3-month and 2856 had 6-month data at the time of analysis. We identified 4 distinct phenotypes of post-COVID conditions (PCCs) at 3 and 6 months for both general and fatigue-related symptoms; minimal-symptom groups represented 70% of participants at 3 and 6 months. When compared with the COVID-negative cohort, COVID-positive participants had higher occurrence of loss of taste/smell and cognition problems. There was substantial class-switching over time; those in 1 symptom class at 3 months were equally likely to remain or enter a new phenotype at 6 months.ConclusionsWe identified distinct classes of PCC phenotypes for general and fatigue-related symptoms. Most participants had minimal or no symptoms at 3 and 6 months of follow-up. Significant proportions of participants changed symptom groups over time, suggesting that symptoms present during the acute illness may differ from prolonged symptoms and that PCCs may have a more dynamic nature than previously recognized. Clinical Trials Registration. NCT04610515.

PurposeResidency programs must ensure resident competence for independent practice. The coronavirus disease-19 (COVID-19) pandemic disrupted health care delivery, impacting pediatric residencies. This study examines the impact on pediatric resident education.MethodsThe authors conducted a mixed methods national survey of pediatric residency program directors (PDs) from May 2020 to July 2020. Data analysis included descriptive statistics, chi-square, and Wilcoxon rank sum tests. Multivariable modeling identified factors associated with resident preparation for more senior roles. Thematic analysis was performed on open-ended questions about PD COVID-19 pandemic recommendations to peers, Accreditation Council for Graduate Medical Education and American Board of Pediatrics.ResultsResponse rate was 55% (110/199). PDs reported the COVID-19 pandemic negatively affected inpatient (n = 86, 78.2%), and outpatient education (n = 104, 94.5%), procedural competence (n = 64; 58.2%), and resident preparation for more senior roles (n = 50, 45.5%). In bivariate analyses, increasingly negative impacts on inpatient and outpatient education were associated with an increasingly negative impact on resident preparation for more senior roles (P = .03, P = .008), these relationships held true in multivariable analysis. Qualitative analysis identified 4 themes from PD recommendations: 1) Clear communication from governing bodies and other leaders; 2) Flexibility within programs and from governing bodies; 3) Clinical exposure is key for competency development; 4) Online platforms are important for education, communication, and support.ConclusionsThe COVID-19 pandemic negatively impacted inpatient and outpatient education. When these were more negatively impacted, resident preparation for more senior roles was worse, highlighting the importance of competency based medical education to tailor experiences ensuring each resident is competent for independent practice.

BackgroundFemale underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding.Materials and methodsData were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation.ResultsFemales represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials.ConclusionsStakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

BackgroundMost research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post-SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron).MethodsThis multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system-based symptoms, and ≥3 symptoms across variants among participants with a positive ("COVID-positive") or negative SARS-CoV-2 test ("COVID-negative") at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status.ResultsThe study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants.ConclusionsProlonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms. Clinical Trials Registration. NCT04610515.

The healthy skeletal muscle extracellular matrix (ECM) has several functions including providing structural integrity to myofibers, enabling lateral force transmission, and contributing to overall passive mechanical properties. In diseases such as Duchenne Muscular dystrophy, there is accumulation of ECM materials, primarily collagen, which results in fibrosis. Previous studies have shown that fibrotic muscle is often stiffer than healthy muscle, in part due to the increased number and altered architecture of collagen fibers within the ECM. This would imply that the fibrotic matrix is stiffer than the healthy matrix. However, while previous studies have attempted to quantify the extracellular contribution to passive stiffness in muscle, the outcomes are dependent on the type of method used. Thus, the goals of this study were to compare the stiffness of healthy and fibrotic muscle ECM and to demonstrate the efficacy of two methods for quantifying extracellular-based stiffness in muscle, namely decellularization and collagenase digestion. These methods have been demonstrated to remove the muscle fibers or ablate collagen fiber integrity, respectively, while maintaining the contents of the extracellular matrix. Using these methods in conjunction with mechanical testing on wildtype and D2.mdx mice, we found that a majority of passive stiffness in the diaphragm is dependent on the ECM, and the D2.mdx diaphragm ECM is resistant to digestion by bacterial collagenase. We propose that this resistance is due to the increased collagen cross-links and collagen packing density in the ECM of the D2.mdx diaphragm. Taken altogether, while we did not find increased stiffness of the fibrotic ECM, we did observe that the D2.mdx diaphragm conveyed resistance against collagenase digestion. These findings demonstrate how different methods for measuring ECM-based stiffness each have their own limitations and can produce different results.

For many computational chemistry packages, being able to efficiently and effectively scale across an exascale cluster is a heroic feat. Collective experience from the Department of Energy's Exascale Computing Project suggests that achieving exascale performance requires far more planning, design, and optimization than scaling to petascale. In many cases, entire rewrites of software are necessary to address fundamental algorithmic bottlenecks. This in turn requires a tremendous amount of resources and development time, resources that cannot reasonably be afforded by every computational science project. It thus becomes imperative that computational science transition to a more sustainable paradigm. Key to such a paradigm is modular software. While the importance of modular software is widely recognized, what is perhaps not so widely appreciated is the effort still required to leverage modular software in a sustainable manner. The present manuscript introduces PluginPlay, https://github.com/NWChemEx-Project/PluginPlay, an inversion-of-control framework designed to facilitate developing, maintaining, and sustaining modular scientific software packages. This manuscript focuses on the design aspects of PluginPlay and how they specifically influence the performance of the resulting package. Although, PluginPlay serves as the framework for the NWChemEx package, PluginPlay is not tied to NWChemEx or even computational chemistry. We thus anticipate PluginPlay to prove to be a generally useful tool for a number of computational science packages looking to transition to the exascale.

Mesolimbic nicotinic acetylcholine receptor (nAChRs) activation is necessary for nicotine reinforcement behavior, but it is unknown whether selective activation of nAChRs in the dopamine (DA) reward pathway is sufficient to support nicotine reinforcement. In this study, we tested the hypothesis that activation of β2-containing (β2*) nAChRs on VTA neurons is sufficient for intravenous nicotine self-administration (SA). We expressed β2 nAChR subunits with enhanced sensitivity to nicotine (referred to as β2Leu9'Ser) in the VTA of male Sprague Dawley (SD) rats, enabling very low concentrations of nicotine to selectively activate β2* nAChRs on transduced neurons. Rats expressing β2Leu9'Ser subunits acquired nicotine SA at 1.5 μg/kg/infusion, a dose too low to support acquisition in control rats. Saline substitution extinguished responding for 1.5 μg/kg/inf, verifying that this dose was reinforcing. β2Leu9'Ser nAChRs also supported acquisition at the typical training dose in rats (30 μg/kg/inf) and reducing the dose to 1.5 μg/kg/inf caused a significant increase in the rate of nicotine SA. Viral expression of β2Leu9'Ser subunits only in VTA DA neurons (via TH-Cre rats) also enabled acquisition of nicotine SA at 1.5 μg/kg/inf, and saline substitution significantly attenuated responding. Next, we examined electrically-evoked DA release in slices from β2Leu9'Ser rats with a history of nicotine SA. Single-pulse evoked DA release and DA uptake rate were reduced in β2Leu9'Ser NAc slices, but relative increases in DA following a train of stimuli were preserved. These results are the first to report that β2* nAChR activation on VTA neurons is sufficient for nicotine reinforcement in rats.

The Thousand Talents Plan was an ambitious government initiative to repatriate and/or recruit experts from the global Chinese diaspora, along with some non-Chinese experts. The plan has received much criticism from abroad, accusing it of taking advantage of the open international education sector and facilitating espionage. While the Thousand Talents Plan received the most international attention, it was just one of over 200 Chinese governmental talent recruitment plans, which we label broadly as the Thousand Talents Brand (TTB). Using bibliometric analysis from the Web of Science, we find that research connected to the TTB decreased following the recent outcry but was only roughly 1% of all Chinese research output at its peak in 2018. We also find that the research was mostly concentrated in the hard sciences, with relatively little in the social sciences. Our results show the research funded through the initiatives was most partnered with researchers from the Western powers, including connections to institutions with national security concerns. While the findings do illustrate a complex web of global research governance through international partnerships, they cannot alleviate scrutiny of the potential alignment between the TTB programs and sensitive sectors abroad.

This study examined a state-wide, policy-directed teacher evaluation model implemented across public schools and educator preparation programs. Such models are grounded in a theory of action that situates teacher learning within social relationships, yet does not account for the complexity of systems. Results challenge policy's implicit theory that an evaluation model can function as a boundary object to create a common understanding of good teaching and positively impact teacher professional practice. We found contradictory evidence that the model served as a boundary object that facilitated shared sensemaking as mediated understandings of good teaching collided with expectations in classroom contexts.

The attacks of September 11, 2001, put terrorism at the forefront of the American political landscape. Donald Trump played into these fears of terrorism through his political rhetoric during his presidency, particularly targeting international students as "threats" to the nation. However, we argue that the labeling of international students as security threats was not started after 9/11 nor invented by Trump. Through historical records and accounts across decades of policies related to this issue, we seek to answer two questions: How has the U.S. government monitored visa policies and programs for international students? How have U.S. national policies evolved to view international students as national security threats? We found that mistrust of this population has been embedded throughout U.S. immigration history and that federal tracking policies emerged incrementally from long-held security concerns. The essay closes with a discussion on why the entire population of international students should not be scapegoated due to these fears.