The transcriptomic and spatial organization of telencephalic GABAergic neuronal types.

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive and integrative roles in a variety of brain functions. There is a wide array of GABAergic neurons in the telencephalon; they play a multitude of circuit functions, and dysfunction of these neurons has been implicated in diverse brain disorders. In this study, we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from the comprehensive and high-resolution transcriptomic and spatial cell type atlas for the adult whole mouse brain we have generated, supplemented with an additional single-cell RNA-sequencing dataset containing 99,438 high-quality single-cell transcriptomes collected from the pre- and postnatal developing mouse brain. We present a hierarchically organized adult telencephalic GABAergic neuronal cell type taxonomy of 7 classes, 52 subclasses, 284 supertypes, and 1,051 clusters, as well as a corresponding developmental taxonomy of 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types can often be found in distant and diverse brain regions indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Additionally, we find various spatial dimensions of both discrete and continuous variations among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell type taxonomy can serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community.

Myo-inositol Levels in the Dorsal Anterior Cingulate Cortex Predicts Anxiety-to-Eat in Anorexia Nervosa.

Background: Anorexia nervosa (AN) is a mental and behavioral health condition characterized by an intense fear of weight or fat gain, severe restriction of food intake resulting in low body weight, and distorted self-perception of body shape or weight. While substantial research has focused on general anxiety in AN, less is known about eating-related anxiety and its underlying neural mechanisms. Therefore, we sought to characterize anxiety-to-eat in AN and examine the neurometabolic profile within the dorsal anterior cingulate cortex (dACC), a brain region putatively involved in magnifying the threat response. Methods: Women seeking inpatient treatment for AN and women of healthy weight without a lifetime history of an eating disorder (healthy controls; HC) completed a computer-based behavioral task assessing anxiety-to-eat in response to images of higher (HED) and lower (LED) energy density foods. Participants also underwent magnetic resonance spectroscopy of the dACC in a 3 Tesla scanner. Results: The AN group reported greater anxiety to eat HED and LED foods relative to the HC group. Both groups reported greater anxiety to eat HED foods relative to LED foods. The neurometabolite myo-inositol (mI) was lower in the dACC in AN relative to HC, and mI levels negatively predicted anxiety to eat HED but not LED foods in the AN group only. mI levels in the dACC were independent of body weight, body mass, and general anxiety. Conclusions: These findings provide critical new insight into the clinically challenging feature and underlying neural mechanisms of eating-related anxiety and indicate mI levels in the dACC could serve as a novel biomarker of illness severity that is independent of body weight to identify individuals vulnerable to disordered eating or eating pathology as well as a potential therapeutic target.

New technology to address affected vs nonaffected arm contributions to ergometer performance in people poststroke.

BACKGROUND: When pedaling a coupled-crank arm ergometer, individuals with hemiplegia may experience nonparetic arm overcompensation, and paretic arm resistance, due to neuromechanical deficits. Technologies that foster independent limb contributions may increase the effectiveness of exercise for people poststroke. OBJECTIVE: Examine the speed during uncoupled pedaling with the Advanced Virtual Exercise Environment Device among individuals poststroke and non-impaired comparisons. METHODS: We recruited 2 groups:Poststroke and Comparison. Participants attended one lab session and performed peak speed tests and a graded exercise repeated for bilateral pedaling, unilateral (left, right). RESULTS: Thirty-one participants completed the protocol (16 women, 15 men). Poststroke participants pedaled slower during the bilateral speed test (64 ± 39 RPM, p < .001), and graded exercise, (54 ± 28 RPM, p < .001) versus comparisons (141 ± 19, 104 ± 12 RPM). Poststroke individuals had lower peak RPM during the unilateral speed test with their paretic arm (70 ± 46 RPM, p < .001) and graded exercise (58 ± 33 RPM, p < .001) compared to their unilateral speed test (130 ± 37 RPM) and graded exercise (108 ± 25 RPM) with their nonparetic arm. Comparisons did not differ between arms during speed tests and graded exercise. Poststroke participants demonstrated lower peak speed with their affected arm during the bilateral speed test (52 ± 42 RPM, p < .001) and graded exercise (49 ± 28 RPM, p = .008) compared to the same arm during unilateral speed (70 ± 46 RPM) and graded exercise (58 ± 33 RPM). CONCLUSIONS: Poststroke participants pedaled faster with their affected arm unilaterally versus bilateral pedaling, suggesting interhemispheric interference that reduces the ability to recruit the paretic arm during bilateral exercise.

A Trial of Automated Outbreak Detection to Reduce Hospital Pathogen Spread.

BACKGROUND: Detection and containment of hospital outbreaks currently depend on variable and personnel-intensive surveillance methods. Whether automated statistical surveillance for outbreaks of health care-associated pathogens allows earlier containment efforts that would reduce the size of outbreaks is unknown. METHODS: We conducted a cluster-randomized trial in 82 community hospitals within a larger health care system. All hospitals followed an outbreak response protocol when outbreaks were detected by their infection prevention programs. Half of the hospitals additionally used statistical surveillance of microbiology data, which alerted infection prevention programs to outbreaks. Statistical surveillance was also applied to microbiology data from control hospitals without alerting their infection prevention programs. The primary outcome was the number of additional cases occurring after outbreak detection. Analyses assessed differences between the intervention period (July 2019 to January 2022) versus baseline period (February 2017 to January 2019) between randomized groups. A post hoc analysis separately assessed pre-coronavirus disease 2019 (Covid-19) and Covid-19 pandemic intervention periods. RESULTS: Real-time alerts did not significantly reduce the number of additional outbreak cases (intervention period versus baseline: statistical surveillance relative rate [RR]=1.41, control RR=1.81; difference-in-differences, 0.78; 95% confidence interval [CI], 0.40 to 1.52; P=0.46). Comparing only the prepandemic intervention with baseline periods, the statistical outbreak surveillance group was associated with a 64.1% reduction in additional cases (statistical surveillance RR=0.78, control RR=2.19; difference-in-differences, 0.36; 95% CI, 0.13 to 0.99). There was no similarly observed association between the pandemic versus baseline periods (statistical surveillance RR=1.56, control RR=1.66; difference-in-differences, 0.94; 95% CI, 0.46 to 1.92). CONCLUSIONS: Automated detection of hospital outbreaks using statistical surveillance did not reduce overall outbreak size in the context of an ongoing pandemic. (Funded by the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT04053075. Support for HCA Healthcare's participation in the study was provided in kind by HCA.).

Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, the hearts underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA sequencing revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in α-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes, resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Youth Are the Experts! Youth Participatory Action Research to Address the Adolescent Mental Health Crisis.

Adolescent mental health is an urgent global public health issue. Youth participatory action research is an effective strategy to amplify youth voices and can serve as a catalyst for evidence-based action addressing the mental health crisis. To illustrate the benefits of youth participatory action research for informing community health, we describe an ongoing collaboration with a youth council located in the central coast of California, USA. Research methods included an anonymous online self-report survey to gather information about the mental health of high school students in 2020 (n = 176) and 2022 (n = 234), 93% Latinx/Mexican American. Both surveys included a four-item patient health questionnaire to screen for depression and anxiety risk, in addition to scaled and open-ended survey questions selected by the youth leaders based on their research questions. Quantitative and qualitative results indicated a significant but small decrease in mental health risk, and a continued need for resources to access mental health support. Results led to community-based action aimed at improving local youth mental health. The interdisciplinary research team (psychology and public health) and youth leaders share reflections highlighting the innovative, empowering, and transformative impact of youth participatory action research as a tool for improving community health.

Synthetic exendin-4 disrupts responding to reward predictive incentive cues in male rats.

Synthetic exendin-4 (EX4, exenatide), is a GLP-1 receptor agonist used clinically to treat glycemia in Type-2 diabetes mellitus. EX4 also promotes weight loss and alters food reward-seeking behaviors in part due to activation of GLP-1 receptors in the mesolimbic dopamine system. Evidence suggests that GLP-1 receptor activity can directly attenuate cue-induced reward seeking. Here, we tested the effects of EX4 (0.6, 1.2, and 2.4 µg/kg, i.p.) on incentive cue (IC) responding, using a task where rats emit a nosepoke response during an intermittent reward-predictive IC to obtain a sucrose reward. EX4 dose-dependently attenuated responding to ICs and increased the latencies to respond to the IC and enter the sucrose reward cup. Moreover, EX4 dose-dependently decreased the total number of active port nosepokes for every cue presented. There was no effect of EX4 on the number of reward cup entries per reward earned, a related reward-seeking metric with similar locomotor demand. There was a dose-dependent interaction between the EX4 dose and session time on the responding to ICs and nosepoke response latency. The interaction indicated that effects of EX4 at the beginning and end of the session differed by the dose of EX4, suggesting dose-dependent pharmacokinetic effects. EX4 had no effect on free sucrose consumption behavior (i.e., total volume consumed, bout size, number of bouts) within the range of total sucrose volumes obtainable during the IC task (~3.5 ml). However, when rats were given unrestricted access for 1 h, where rats obtained much larger total volumes of sucrose (~30 ml), we observed some dose-dependent EX4 effects on drinking behavior, including decreases in total volume consumed. Together, these findings suggest that activation of the GLP-1 receptor modulates the incentive properties of cues attributed with motivational significance.

Topographical and cell type-specific connectivity of rostral and caudal forelimb corticospinal neuron populations.

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, with notable exceptions that suggest that these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive highly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

Durable Efficacy of Switching From a 3- or 4-Drug Tenofovir Alafenamide-Based Regimen to the 2-Drug Regimen Dolutegravir/Lamivudine in the TANGO Study Through Week 196.

BACKGROUND: Switching to the 2-drug regimen dolutegravir/lamivudine demonstrated durable non-inferior efficacy vs continuing 3- or 4-drug tenofovir alafenamide-based regimens for maintaining virologic suppression in people with HIV-1 through Week 144 in TANGO. SETTING: 134 centers, 10 countries. METHODS: Adults with HIV-1 RNA <50 copies/mL for >6 months and no history of virologic failure were randomized to switch from stable tenofovir alafenamide-based regimens to dolutegravir/lamivudine on Day 1 (early-switch group) for 196 weeks. Those randomized to continue tenofovir alafenamide-based regimens on Day 1 who maintained virologic suppression at Week 144 switched to dolutegravir/lamivudine at Week 148 (late-switch group). Efficacy, safety, and tolerability (including weight and biomarker changes) of dolutegravir/lamivudine in early-switch and late-switch groups were assessed through Week 196. RESULTS: Overall, 369 participants switched to dolutegravir/lamivudine on Day 1 (early-switch) and 298 switched at Week 148 (late-switch). In the early-switch group, 83% (306/369) maintained virologic suppression through Year 4, and 3% (11/369) reported new adverse events between Weeks 144 and 196. The late-switch group at Week 196 and early-switch group at Week 48 had comparable proportions with virologic suppression (93% each) and similar safety profiles. No late-switch participants and 1 early-switch participant met confirmed virologic withdrawal criteria through Week 196, with no resistance-associated mutations observed. Treatment continued to be well tolerated long-term. CONCLUSION: Switching from tenofovir alafenamide-based regimens to dolutegravir/lamivudine showed durable efficacy, high barrier to resistance, and good tolerability through 4 years. These results support dolutegravir/lamivudine as a robust treatment for maintaining virologic suppression.

Challenges and Solutions to Support Oncology Professionals Serving Underserved Populations With Cancer in the United States: Results From the ASCO Serving the Underserved Task Force.

PURPOSE: Little data exist regarding approaches to support oncology professionals who deliver cancer care for underserved populations. In response, ASCO developed the Serving the Underserved Task Force to learn from and support oncology professionals serving underserved populations. METHODS: The Task Force developed a 28-question survey to assess oncology professionals' experiences and strategies to support their work caring for underserved populations. The survey was deployed via an online link to 600 oncology professionals and assessed respondent and patient demographic characteristics, clinic-based processes to coordinate health-related social services, and strategies for professional society support and engagement. We used chi-square tests to evaluate whether there were associations between percent full-time equivalent (FTE) effort serving underserved populations (<50% FTE v ≥50% FTE) with responses. RESULTS: Of 462 respondents who completed the survey (77% response rate), 79 (17.1%) were Asian; 30 (6.5%) Black; 43 (9.3%) Hispanic or Latino/Latina; and 277 (60%) White. The majority (n = 366, 79.2%) had a medical doctor degree (MD). A total of 174 (37.7%) had <25% FTE, 151 (32.7%) had 25%-50% FTE, and 121 (26.2%) had ≥50% FTE effort serving underserved populations. Most best guessed patients' sociodemographic characteristics (n = 388; 84%), while 42 (9.2%) used data collected by the clinic. Social workers coordinated most health-related social services. However, in clinical settings with high proportions of underserved patients, there was greater reliance on nonclinical personnel, such as navigators (odds ratio [OR], 2.15 [95% CI, 1.07 to 4.33]) or no individual (OR, 2.55 [95% CI, 1.14 to 5.72]) for addressing mental health needs and greater reliance on physicians or advance practice practitioners (OR, 2.54 [95% CI, 1.11 to 5.81]) or no individual (OR, 1.91 [95% CI, 1.09 to 3.35]) for addressing childcare or eldercare needs compared with social workers. Prioritization of solutions, which did not differ by FTE effort serving underserved populations, included a return-on-investment model to support personnel, integrated health-related social needs screening, and collaboration with the professional society on advocacy and policy. CONCLUSION: The findings highlight crucial strategies that professional societies can implement to support oncology clinicians serving underserved populations with cancer.

Molecularly defined and spatially resolved cell atlas of the whole mouse brain.

In mammalian brains, millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells have impeded our understanding of the molecular and cellular basis of brain function. Recent advances in spatially resolved single-cell transcriptomics have enabled systematic mapping of the spatial organization of molecularly defined cell types in complex tissues1-3, including several brain regions (for example, refs. 1-11). However, a comprehensive cell atlas of the whole brain is still missing. Here we imaged a panel of more than 1,100 genes in approximately 10 million cells across the entire adult mouse brains using multiplexed error-robust fluorescence in situ hybridization12 and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating multiplexed error-robust fluorescence in situ hybridization and single-cell RNA sequencing data. Using this approach, we generated a comprehensive cell atlas of more than 5,000 transcriptionally distinct cell clusters, belonging to more than 300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of this atlas to the mouse brain common coordinate framework allowed systematic quantifications of the cell-type composition and organization in individual brain regions. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes of cells. Finally, this high-resolution spatial map of cells, each with a transcriptome-wide expression profile, allowed us to infer cell-type-specific interactions between hundreds of cell-type pairs and predict molecular (ligand-receptor) basis and functional implications of these cell-cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a foundation for functional investigations of neural circuits and their dysfunction in health and disease.

Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain.

Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq)1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation-methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular-spatial and regulatory genome diversity of the mouse brain.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.

The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Single-cell analysis of chromatin accessibility in the adult mouse brain.

Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete1-4. Here we report a comprehensive atlas of candidate cis-regulatory DNA elements (cCREs) in the adult mouse brain, generated by analysing chromatin accessibility in 2.3 million individual brain cells from 117 anatomical dissections. The atlas includes approximately 1 million cCREs and their chromatin accessibility across 1,482 distinct brain cell populations, adding over 446,000 cCREs to the most recent such annotation in the mouse genome. The mouse brain cCREs are moderately conserved in the human brain. The mouse-specific cCREs-specifically, those identified from a subset of cortical excitatory neurons-are strongly enriched for transposable elements, suggesting a potential role for transposable elements in the emergence of new regulatory programs and neuronal diversity. Finally, we infer the gene regulatory networks in over 260 subclasses of mouse brain cells and develop deep-learning models to predict the activities of gene regulatory elements in different brain cell types from the DNA sequence alone. Our results provide a resource for the analysis of cell-type-specific gene regulation programs in both mouse and human brains.

Topographical and cell type-specific connectivity of rostral and caudal forelimb corticospinal neuron populations.

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse group of neurons with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, no studies have mapped the diversity of spinal cell types targeted by CSNs, let alone compare CFA and RFA populations. Here we use anatomical and RNA-sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal cell types, with notable exceptions that suggest these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive surprisingly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior.

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species.

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

State of Cancer Care in America: Achieving Cancer Health Equity Among Sexual and Gender Minority Communities.

In 2017, ASCO issued the position statement, Strategies for Reducing Cancer Health Disparities Among Sexual and Gender Minority Populations, outlining five areas of recommendations to address the needs of both sexual and gender minority (SGM, eg, LGBTQ+) populations affected by cancer and members of the oncology workforce who identify as SGM: (1) patient education and support; (2) workforce development and diversity; (3) quality improvement strategies; (4) policy solutions; and (5) research strategies. In 2019, ASCO convened the SGM Task Force to help actualize the recommendations of the 2017 position statement. The percentage of the US population who publicly identify as SGM has increased dramatically over the past few years. Although increased national interest in SGM health equity has accompanied a general interest in research, policy change, and education around diversity, equity, and inclusion, resulting from public concern over discrimination in health care against Black, Indigenous, and People of Color, this has been accompanied by a surge in discriminatory legislation directly impacting the SGM community. Although much progress has been made in advancing SGM cancer health equity since 2017, more progress is needed to reduce disparities and advance equity. The five focus areas outlined in the 2017 ASCO position statement remain relevant, as we must continue to promote and advance equity in quality improvement, workforce development, patient care, research, and SGM-affirming policies. This article reports on the progress toward reducing SGM cancer disparities and achieving equity across these five areas and identifies future directions for the work that still remains.

Comparative transcriptomics reveals human-specific cortical features.

The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus transcriptomics to analyze samples of the middle temporal gyrus (MTG) from adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to understand human-specific features of the neocortex. Human, chimpanzee, and gorilla MTG showed highly similar cell-type composition and laminar organization as well as a large shift in proportions of deep-layer intratelencephalic-projecting neurons compared with macaque and marmoset MTG. Microglia, astrocytes, and oligodendrocytes had more-divergent expression across species compared with neurons or oligodendrocyte precursor cells, and neuronal expression diverged more rapidly on the human lineage. Only a few hundred genes showed human-specific patterning, suggesting that relatively few cellular and molecular changes distinctively define adult human cortical structure.