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PurposeThe purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).Experimental designRB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.ResultsRB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.ConclusionsCo-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Abstract The etiopathogenesis of late-onset Alzheimer’s disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.

Overreliance on disengagement emotion regulation strategies (e.g., emotion avoidance, emotion suppression) has been shown to relate to poor clinical outcomes. Two traits characterized by difficulties in goal-directed responses to emotion-urgency and distress intolerance-may help explain who is likely to disengage from emotion and when. These traits are associated with diverse forms of psychopathology and greater reliance on disengagement strategies. Gaps remain about how these traits relate to emotion regulation in daily life. The present study uses ecological momentary assessment (EMA) to determine the associations of urgency and distress intolerance with momentary high arousal negative affect and momentary attempts to regulate negative emotions. Participants (N = 101) were college students who endorsed at least weekly behaviors often characterized by emotion dysregulation (e.g., self-harm, binging/purging, alcohol/drug use). Participants completed trait measures at baseline and EMA surveys of momentary affect and emotion regulation, six times daily for 4 days. Results indicated that at certain levels, urgency and distress intolerance moderated the relationship between high arousal negative affect and disengagement from emotion: low urgency scores related to relatively greater disengagement from emotion following reported high arousal negative affect, whereas high distress intolerance scores related to relatively greater disengagement following high arousal negative affect. Findings support the role of both urgency and distress intolerance in the relationship between high arousal negative affect and disengagement, which implicates the utility of clinical interventions that focus on emotion regulation, especially during high arousal states. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

BackgroundThe accumulation of dysfunctional mitochondria is an early feature of Alzheimer’s disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation, leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global post-translational modification β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found in the nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively.MethodsWe used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses.ResultsHere, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet-G (TMG) increases the mitochondrial level of mitophagy protein PTEN-induced kinase 1 (PINK1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 protein expression and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG-treated AD organoids showed no changes in LC3 expression.ConclusionCollectively, these data demonstrate that O-GlcNAc plays a crucial role in the activation and progression of mitophagy, and this activation is disrupted in AD.

Abstract Background Impaired brain bioenergetics is a pathological hallmark of Alzheimer’s disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition. Aims The Creatine to Augment Bioenergetics in Alzheimer’s disease (CABA) study is designed to primarily assess the feasibility of supplementation with 20 g/day of creatine monohydrate (CrM) in patients with cognitive impairment due to AD. Secondary aims are designed to generate preliminary data investigating changes in brain Cr levels, cognition, peripheral and brain mitochondrial function, and muscle strength and size. Methods CABA is an 8-week, single-arm pilot study that will recruit 20 patients with cognitive impairment due to AD. Participants attend five in-person study visits: two visits at baseline to conduct screening and baseline assessments, a 4-week visit, and two 8-week visits. Outcomes assessment includes recruitment, retention, and compliance, cognitive testing, magnetic resonance spectroscopy of brain metabolites, platelet and lymphocyte mitochondrial function, and muscle strength and morphology at baseline and 8 weeks. Discussion CABA is the first study to investigate CrM as a potential treatment in patients with AD. The pilot data generated by this study are pertinent to inform the design of future large-scale efficacy trials. Trial registration ClinicalTrials.gov, NCT05383833 , registered on 20 May 2022.

Recent studies have explored the spatial transcriptomics patterns of Alzheimer's disease (AD) brain by spatial sequencing in mouse models, enabling the identification of unique genome-wide transcriptomic features associated with different spatial regions and pathological status. However, the dynamics of gene interactions that occur during amyloid-β accumulation remain largely unknown. In this study, we performed analyses on ligand-receptor communication, transcription factor regulatory network, and spot-specific network to reveal the dependence and the dynamics of gene associations/interactions on spatial regions and pathological status with mouse and human brains. We first used a spatial transcriptomics dataset of the AppNL-G-F knock-in AD and wild-type mouse model. We revealed 17 ligand-receptor pairs with opposite tendencies throughout the amyloid-β accumulation process and showed the specific ligand-receptor interactions across the hippocampus layers at different extents of pathological changes. We then identified nerve function related transcription factors in the hippocampus and entorhinal cortex, as well as genes with different transcriptomic association degrees in AD versus wild-type mice. Finally, another independent spatial transcriptomics dataset from different AD mouse models and human single-nuclei RNA-seq data/AlzData database were used for validation. This is the first study to identify various gene associations throughout amyloid-β accumulation based on spatial transcriptomics, establishing the foundations to reveal advanced and in-depth AD etiology from a novel perspective based on the comprehensive analyses of gene interactions that are spatio-temporal dependent.

BACKGROUND: Auditory frequency modulation learning (auditory learning) is a key component of targeted cognitive training (TCT) for schizophrenia. TCT can be effective in enhancing neurocognition and function in schizophrenia, but such gains require significant time and effort and elude many patients. METHODS: As a strategy to increase and/or accelerate TCT-induced clinical gains, we tested the dose- and time-course effects of the pro-attentional drug, amphetamine (AMPH; placebo, 2.5, 5 or 10 mg po; within-subject double-blind, order balanced) on auditory learning in schizophrenia patients [n = 32; M:F = 19:13; age 42.0 years (24-55)]. To understand predictors and/or mechanisms of AMPH-enhanced TCT, we also measured auditory fidelity (words-in-noise (WIN), quick speech-in-noise (QuickSIN)) and neurocognition (MATRICS comprehensive cognitive battery (MCCB)). Some measures were also acquired from age-matched healthy subjects (drug free; n = 10; M:F = 5:5). RESULTS: Patients exhibited expected deficits in neurocognition. WIN and QuickSIN performance at low signal intensities was impaired in patients with low v. high MCCB attention/vigilance (A/V) scores; these deficits were corrected by AMPH, maximally at 2.5-5 mg (ds = 0.79-1.29). AMPH also enhanced auditory learning, with maximal effects at 5 mg (d = 0.93), and comparable effects 60 and 210 min post pill. Pro-learning effects of AMPH and AMPH-induced gains in auditory fidelity were most evident in patients with low MCCB A/V scores. CONCLUSIONS: These findings advance our understanding of the impact of pro-attentional interventions on auditory information processing and suggest dose- and time-course parameters for studies that assess the ability of AMPH to enhance the clinical benefits of TCT in schizophrenia patients.

OBJECTIVES: Suicidal ideation is a pervasive and painful experience that varies considerably in its phenomenology. Here, we consider how one key risk variable might inform our understanding of variation in suicidal ideation: emotion-related impulsivity, the trait-like tendency towards unconstrained speech, behaviour, and cognition in the face of intense emotions. We hypothesized that emotion-related impulsivity would be tied to specific features, including severity, perceived lack of controllability, more rapidly fluctuating course, higher scores on a measure of acute suicidal affective disturbance, and more emotional and cognitive disturbance as antecedents. METHODS: We recruited two samples of adults (Ns = 421, 221) through Amazon Mechanical Turk (MTurk), with oversampling of those with suicidal ideation. Both samples completed psychometrically sound self-report measures online to assess emotion- and non-emotion-related dimensions of impulsivity and characteristics of suicidal ideation. RESULTS: One form of emotion-related impulsivity related to the severity, uncontrollability, dynamic course, and affective and cognitive precursors of ideation. CONCLUSIONS: Despite limitations of the cross-sectional design and self-report measures, the current findings highlight the importance of specificity in considering key dimensions of impulsivity and suicidal ideation.

The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.

BackgroundPredict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).MethodThe prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.ResultsHaving a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.ConclusionThe inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.

INTRODUCTION: Rumination and emotion-related impulsivity predict suicidal ideation, suicide attempts, and nonsuicidal self-injury (NSSI). Because rumination and emotion-related impulsivity, though, are highly correlated, we consider their unique vs. conjoint influence on suicidal ideation and self-harm. METHOD: Across two samples of adults (Ns = 171 and 191), we examined how rumination and emotion-related impulsivity relate to suicidal ideation, suicide attempts, and NSSI. We assess the more general process of repetitive negative thinking and the more specific process of suicide-related rumination. Participants completed the Three-Factor Impulsivity Index and the self-report Columbia-Suicide Severity Rating Scale. Those in sample 1 completed the Perseverative Thinking Questionnaire and the Deliberate Self-Harm Inventory, and those in Sample 2 completed the Suicide Rumination Scale. RESULTS: Emotion-related impulsivity and both forms of rumination showed robust bivariate correlations with suicidal ideation, suicide attempts, and NSSI. Neither rumination or impulsivity related to suicide attempts controlling for ideation or to NSSI. In multivariable analyses, emotion-related impulsivity but not general rumination was tied to suicidal ideation. In contrast, suicide-related rumination was more directly tied to suicidal ideation than was impulsivity. CONCLUSIONS: Findings provide support for a more nuanced approach to the forms of impulsivity and rumination related to suicidal ideation.

Recent research has highlighted that emotion regulation strategy use varies both between and within people, and specific individual and contextual differences shape strategy use. Further, use of specific emotion regulation strategies relates to a wide array of differential outcomes, including mental health and behavior. Emotion goals (desire for a given emotion state) are thought to play a particularly important role in shaping peoples use of emotion regulation strategies; yet, surprisingly little is known about whether and how momentary emotion goals predict spontaneous strategy use in daily life. In the present investigation, we examined whether ideal desire for high versus low arousal positive affect was associated with subsequent use of specific emotion regulation strategies. Undergraduate participants (final N = 101) completed ecological momentary assessments (final ks = 1,932 for contemporaneous analyses, 1,386 for time-lagged analyses) of their momentary experienced affect, momentary desire for high versus low arousal positive affect, and emotion regulation. Desire for higher arousal predicted greater use of three disengagement strategies: distraction, expressive suppression, and experiential suppression. None of these strategies, though, were associated with sustained enhancement of high arousal (or low arousal) positive affect. These findings point to a possible disconnect between the strategies that people tend to use when they want to feel more arousal and the affective outcomes associated with use of those strategies.

Background:. Lymphatic dyes are commonly used to map the drainage path from tumor to lymphatics, which are biopsied to determine if spread has occurred. A blue dye in combination with technetium-99 is considered the gold standard for mapping, although many other dyes and dye combinations are used. Not all of these substances have the same detection efficacy. Methods:. A systematic review of PubMed, SCOPUS, Web of Science, and Medline was performed. The predefined search terms were (indocyanine green OR isosulfan blue OR lymphazurin OR patent blue OR methylene blue OR fluorescein OR technetium-99) AND combination AND dye AND (sentinel lymph node biopsy OR lymphedema OR lymphatics OR lymph OR microsurgery OR cancer OR tumor OR melanoma OR carcinoma OR sarcoma). Results:. The initial search returned 4267 articles. From these studies, 37 were selected as candidates that met inclusion criteria. After a full-text review, 34 studies were selected for inclusion. Eighty-nine methods of sentinel lymph node (SLN) detection were trialed using 22 unique dyes, dye combinations, or other tracers. In total, 12,157 SLNs of 12,801 SLNs were identified. Dye accuracy ranged from 100% to 69.8% detection. Five dye combinations had 100% accuracy. Dye combinations were more accurate than single dyes. Conclusions:. Combining lymphatic dyes improves SLN detection results. Replacing technetium-99 with ICG may allow for increased access to SLN procedures with comparable results. The ideal SLN tracer is a low-cost molecule with a high affinity for lymphatic vessels due to size and chemical composition, visualization without specialized equipment, and no adverse effects.

OBJECTIVE The use of transesophageal echocardiography (TEE) by certified registered nurse anesthetists (CRNAs) during noncardiac surgery is relatively uncommon despite its unique potential to diagnose causes of hemodynamic instability. To address this problem, educational endeavors designed to provide practical TEE skills to CRNAs are needed. The aim of the current study was to evaluate the feasibility, acceptability, efficacy, and utility of a 2-day focused TEE workshop in nurse anesthesia education that employed a protocol involving a limited number of views and used goal-directed, qualitative assessments of critical physiologic parameters. METHODS This was a prospective, observational study involving 14 second-year nurse anesthesia students. The cohort was evaluated following completion of this workshop by simulator-based testing involving hypothetical clinical scenarios, and this test data was analyzed according to the percent successful acquisition and interpretation of TEE views to determine immediate objective teaching efficacy. The acceptability, perceived efficacy, and perceived utility of the workshop were assessed by online survey, and survey responses were qualitative and quantitative in nature. RESULTS Participants acquired appropriate TEE views associated with clinical scenarios 99% of the time and correctly interpreted the pathology in those views 93% of the time. Participants uniformly perceived significant educational value in this workshop and intend to incorporate TEE in their future clinical practice. CONCLUSIONS A 2-day workshop to teach focused TEE to nurse anesthesia trainees directed by a streamlined protocol is feasible, acceptable, and perceived as useful by participants, and provides practical experience and entry-level competency in this point-of-care ultrasound modality.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.

OBJECTIVE: Cognitive tasks are used to probe neuronal activity during functional magnetic resonance imaging (fMRI) to detect signs of aberrant cognitive functioning in patients diagnosed with schizophrenia (SZ). However, nonlinear (inverted-U-shaped) associations between neuronal activity and task difficulty can lead to misinterpretation of group differences between patients and healthy comparison subjects (HCs). In this paper, we evaluated a novel method for correcting these misinterpretations based on conditional performance analysis. METHOD: Participants included 25 HCs and 27 SZs who performed a working memory (WM) task (N-back) with 5 load conditions while undergoing fMRI. Neuronal activity was regressed onto: 1) task load (i.e., parametric task levels), 2) marginal task performance (i.e., performance averaged over all load conditions), or 3) conditional task performance (i.e., performance within each load condition). RESULTS: In most regions of interest, conditional performance analysis uniquely revealed inverted-U-shaped neuronal activity in both SZs and HCs. After accounting for conditional performance differences between groups, we observed few difference in both the pattern and level of neuronal activity between SZs and HCs within regions that are classically associated with WM functioning (e.g., posterior dorsolateral prefrontal and parietal association cortices). However, SZs did show aberrant activity within the anterior dorsolateral prefrontal cortex. CONCLUSIONS: Interpretations of differences in neuronal activity between groups, and of associations between neuronal activity and performance, should be considered within the context of task performance. Whether conditional performance-based differences reflect compensation, dedifferentiation, or other processes is not a question that is easily resolved by examining activation and performance data alone.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

The course-based research experience (CRE) with its documented educational benefits is increasingly being implemented in science, technology, engineering, and mathematics education. This article reports on a study that was done over a period of 3 years to explicate the instructional processes involved in teaching an undergraduate CRE. One hundred and two instructors from the established and large multi-institutional SEA-PHAGES program were surveyed for their understanding of the aims and practices of CRE teaching. This was followed by large-scale feedback sessions with the cohort of instructors at the annual SEA Faculty Meeting and subsequently with a small focus group of expert CRE instructors. Using a qualitative content analysis approach, the survey data were analyzed for the aims of inquiry instruction and pedagogical practices used to achieve these goals. The results characterize CRE inquiry teaching as involving three instructional models: 1) being a scientist and generating data; 2) teaching procedural knowledge; and 3) fostering project ownership. Each of these models is explicated and visualized in terms of the specific pedagogical practices and their relationships. The models present a complex picture of the ways in which CRE instruction is conducted on a daily basis and can inform instructors and institutions new to CRE teaching.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

BackgroundBurgeoning evidence suggests that loneliness during the COVID-19 pandemic is tied to high levels of depression and anxiety. The current study is unique, though, in examining which facets of social behavior and perceived social quality are most tied to internalizing symptoms using longitudinal data, including a pre-pandemic baseline, collected from a community sample of adults with pre-existing mental health concerns (analyzed n = 144).MethodsParticipants completed measures of depressive and anxious symptoms pre-pandemic, followed by three weekly surveys during the pandemic. We distinguished four social variables: in-person social engagement, remote social engagement, social disruption, and social distress. OLS and mixed-effects regression models examined 1) pre-pandemic baseline symptoms as predictors of social functioning during the pandemic and 2) time-lagged associations between symptoms and social functioning during the pandemic.ResultsSocial behavior and social perceptions were dissociable. Baseline depressive, but not anxious, symptoms predicted greater social distress during the pandemic. Both anxious and depressive symptoms were predicted by social variables, but the specific associations differed: depressive symptoms were related to perceived social quality, whereas anxious symptoms were more tied to reported social behavior.LimitationsWe relied on self-report indices, and causality should not be inferred directly from these correlational data.ConclusionsOverall, our results indicate that it is possible to follow social guidelines and even to spend relatively few hours socializing with close others, while still feeling connected and rewarded; however, people who struggle with depression and anhedonia were particularly vulnerable to distressing feelings of social disconnection amid the pandemic.