A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

A guide to the BRAIN Initiative Cell Census Network data ecosystem.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay.

Impaired replication progression leads to de novo copy number variant (CNV) formation at common fragile sites (CFSs). We previously showed that these hotspots for genome instability reside in late-replicating domains associated with large transcribed genes and provided indirect evidence that transcription is a factor in their instability. Here, we compared aphidicolin (APH)-induced CNV and CFS frequency between wild-type and isogenic cells in which FHIT gene transcription was ablated by promoter deletion. Two promoter-deletion cell lines showed reduced or absent CNV formation and CFS expression at FHIT despite continued instability at the NLGN1 control locus. APH treatment led to critical replication delays that remained unresolved in G2/M in the body of many, but not all, large transcribed genes, an effect that was reversed at FHIT by the promoter deletion. Altering RNase H1 expression did not change CNV induction frequency and DRIP-seq showed a paucity of R-loop formation in the central regions of large genes, suggesting that R-loops are not the primary mediator of the transcription effect. These results demonstrate that large gene transcription is a determining factor in replication stress-induced genomic instability and support models that CNV hotspots mainly result from the transcription-dependent passage of unreplicated DNA into mitosis.

A new proactive virtual resource center navigation model identifies patient risk factors to reduce barriers to cancer care during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic has exacerbated cancer treatment disparities, including accessibility to resources. We describe the process and outcomes of a new proactive, virtual nurse-led, resource center navigation model enhanced by using volunteer patient navigators. Using known patient risk factors, this model provides interventions to reduce barriers to care, with an emphasis on non-English-speaking populations. METHODS: Patients were included if they (1) were in active cancer treatment and (2) had one or more known risk factors: distance from cancer hospital, needing complex care, 65 years or older, malignant hematological diagnosis, new treatment start, lives alone, non-English speaker, or a new hospital discharge. Nurse navigators triaged referrals to appropriate team members who identified and addressed barriers to care. RESULTS: The program engaged with 586 adult cancer patients over 1459 encounters. The most common risk factors included distance (59.7%), complex care (48.8%), and new treatment start (43.5%). The most common interventions were core education (69.4%), emotional support (61.2%), and education (35.7%). Statistical differences were found between Spanish-speaking (n = 118) and non-Spanish-speaking patients (n = 468). While Spanish-speaking patients had fewer risk factors (1.95 vs. 2.80, p ≤ .0001), they had nearly double the number of visits (4.27 vs. 2.04, p ≤ .0001) and 69% more interventions (8.26 vs. 4.90, p ≤ .0001). Many patients (42.7%) required follow-up visits. CONCLUSION: We successfully established a new navigation model for the resource center during the pandemic that identified and reduced barriers to care, particularly in the Spanish-speaking population.

CRISPR-mediated isolation of specific megabase segments of genomic DNA.

Megabase-sized, complex, repetitive regions of genomes are poorly studied, due to the technical and computational challenges inherent to both assembling precise reference sequences and accurately assessing structural variation across contiguous megabase DNA regions. Here we describe a strategy to overcome these challenges, CISMR (CRISPR-mediated isolation of specific megabase-sized regions of the genome), which enables us to perform targeted isolation of contiguous megabase-sized segments of the genome. Direct sequencing of the purified DNA segments can have >100-fold enrichment of the target region, thus enabling the exploration of both DNA sequence and structural diversity of complex genomic regions in any species.

A Model of Binocular Motion Integration in MT Neurons.

UNLABELLED: Primate cortical area MT plays a central role in visual motion perception, but models of this area have largely overlooked the binocular integration of motion signals. Recent electrophysiological studies tested binocular integration in MT and found surprisingly that MT neurons lose their hallmark "pattern motion" selectivity when stimuli are presented dichoptically and that many neurons are selective for motion-in-depth (MID). By unifying these novel observations with insights from monocular, frontoparallel motion studies concurrently in a binocular MT motion model, we generated clear, testable predictions about the circuitry and mechanisms underlying visual motion processing. We built binocular models in which signals from left- and right-eye streams could be integrated at various stages from V1 to MT, attempting to create the simplest plausible circuits that accounted for the physiological range of pattern motion selectivity, that explained changes across this range for dichoptic stimulus presentation, and that spanned the spectrum of MID selectivity observed in MT. Our successful models predict that motion-opponent suppression is the key mechanism to account for the striking loss of pattern motion sensitivity with dichoptic plaids, that opponent suppression precedes binocular integration, and that opponent suppression will be stronger in inputs to pattern cells than to component cells. We also found an unexpected connection between circuits for pattern motion selectivity and MID selectivity, suggesting that these two separately studied phenomena could be related. These results also hold in models that include binocular disparity computations, providing a platform for future exploration of binocular response properties in MT. SIGNIFICANCE STATEMENT: The neural pathways underlying our sense of visual motion are among the most studied and well-understood parts of the primate cerebral cortex. Nevertheless, our understanding is incomplete because electrophysiological research has focused mainly on motion in the 2D frontoparallel plane, even though real-world motion often occurs in three dimensions, involving a change in distance from the viewer. Recent studies have revealed a specialization for sensing 3D motion in area MT, the cortical area most tightly linked to the processing and perception of visual motion. Our study provides the first model to explain how 3D motion sensitivity can arise in MT neurons and predicts how essential features of 2D motion integration may relate to 3D motion processing.

Mechanisms for Rapid Adaptive Control of Motion Processing in Macaque Visual Cortex.

A key feature of neural networks is their ability to rapidly adjust their function, including signal gain and temporal dynamics, in response to changes in sensory inputs. These adjustments are thought to be important for optimizing the sensitivity of the system, yet their mechanisms remain poorly understood. We studied adaptive changes in temporal integration in direction-selective cells in macaque primary visual cortex, where specific hypotheses have been proposed to account for rapid adaptation. By independently stimulating direction-specific channels, we found that the control of temporal integration of motion at one direction was independent of motion signals driven at the orthogonal direction. We also found that individual neurons can simultaneously support two different profiles of temporal integration for motion in orthogonal directions. These findings rule out a broad range of adaptive mechanisms as being key to the control of temporal integration, including untuned normalization and nonlinearities of spike generation and somatic adaptation in the recorded direction-selective cells. Such mechanisms are too broadly tuned, or occur too far downstream, to explain the channel-specific and multiplexed temporal integration that we observe in single neurons. Instead, we are compelled to conclude that parallel processing pathways are involved, and we demonstrate one such circuit using a computer model. This solution allows processing in different direction/orientation channels to be separately optimized and is sensible given that, under typical motion conditions (e.g., translation or looming), speed on the retina is a function of the orientation of image components. SIGNIFICANCE STATEMENT: Many neurons in visual cortex are understood in terms of their spatial and temporal receptive fields. It is now known that the spatiotemporal integration underlying visual responses is not fixed but depends on the visual input. For example, neurons that respond selectively to motion direction integrate signals over a shorter time window when visual motion is fast and a longer window when motion is slow. We investigated the mechanisms underlying this useful adaptation by recording from neurons as they responded to stimuli moving in two different directions at different speeds. Computer simulations of our results enabled us to rule out several candidate theories in favor of a model that integrates across multiple parallel channels that operate at different time scales.

Monocyte activity is linked with abdominal aortic aneurysm diameter.

BACKGROUND: Systemic inflammation and increased matrix metalloproteinase (MMP) cause elastin degradation leading to abdominal aortic aneurysm (AAA) expansion. Several prospective studies report that statin therapy can reduce AAA expansion through anti-inflammation. We hypothesize that monocyte activity plays a pivotal role in this AAA development and this study examines patient peripheral blood monocyte cell adhesion, transendothelial migration, and MMP concentrations between AAA and non-AAA patients. MATERIALS AND METHODS: Peripheral blood was collected and monocytes isolated from control (n=15) and AAA (n=13) patients. Monocyte adhesion, transmigration, and permeability assays were assessed. Luminex assays determined MMP-9 and tissue inhibitor of metalloproteinase-4 (TIMP-4) concentrations from cell culture supernatant and patient serum. RESULTS: AAA patient monocytes showed increased adhesion to the endothelium relative fluorescence units (RFU, 0.33±0.17) versus controls (RFU, 0.13±0.04; P=0.005). Monocyte transmigration was also increased in AAA patients (RFU, 0.33±0.11) compared with controls (RFU, 0.25±0.04, P=0.01). Greater numbers of adhesive (R2=0.66) and transmigratory (R2=0.86) monocytes were directly proportional to the AAA diameter. Significantly higher serum levels of MMP-9 (2149.14±947 pg/mL) were found in AAA patients compared with controls (1189.2±293; P=0.01). TIMP-4 concentrations were significantly lower in AAA patients (826.7±100 pg/mL) compared with controls (1233±222 pg/mL; P=0.02). Cell culture supernatant concentrations of MMP and TIMP from cocultures were higher than monocyte-only cultures. CONCLUSIONS: Monocytes from AAA patients have greater adhesion and transmigration through the endothelium in vitro, leading to elevated MMP-9 levels and the appropriate decrease in TIMP-4 levels. The ability to modulate monocyte activity may lead to novel medical therapies to decrease AAA expansion.

Making Use of Natural Language Processing to Better Understand Medical Students' Self-Assessment of Clinical Skills.

PROBLEM: Reflective practice is necessary for self-regulated learning. Helping medical students develop these skills can be challenging since they are difficult to observe. One common solution is to assign students' reflective self-assessments, which produce large quantities of narrative assessment data. Reflective self-assessments also provide feedback to faculty regarding students' understanding of content, reflective abilities, and areas for course improvement. To maximize student learning and feedback to faculty, reflective self-assessments must be reviewed and analyzed, activities that are often difficult for faculty due to the time-intensive and cumbersome nature of processing large quantities of narrative assessment data. APPROACH: The authors collected narrative assessment data (2,224 students' reflective self-assessments) from 344 medical students' reflective self-assessments. In academic years 2019-2020 and 2021-2022, students at the University of Cincinnati College of Medicine responded to 2 prompts (aspects that surprised students, areas for student improvement) after reviewing their standardized patient encounters. These free-text entries were analyzed using TopEx, an open-source natural language processing (NLP) tool, to identify common topics and themes, which faculty then reviewed. OUTCOMES: TopEx expedited theme identification in students' reflective self-assessments, unveiling 10 themes for prompt 1 such as question organization and history analysis, and 8 for prompt 2, including sensitive histories and exam efficiency. Using TopEx offered a user-friendly, time-saving analysis method without requiring complex NLP implementations. The authors discerned 4 education enhancement implications: aggregating themes for future student reflection, revising self-assessments for common improvement areas, adjusting curriculum to guide students better, and aiding faculty in providing targeted upcoming feedback. NEXT STEPS: The University of Cincinnati College of Medicine aims to refine and expand the utilization of TopEx for deeper narrative assessment analysis, while other institutions may model or extend this approach to uncover broader educational insights and drive curricular advancements.

Inter-neuronal correlation distinguishes mechanisms of direction selectivity in cortical circuit models.

Direction selectivity is a fundamental physiological property that arises from primary visual cortex (V1) circuitry, yet basic questions of how direction-selective (DS) receptive fields are constructed remain unanswered. We built a set of simple, plausible neuronal circuits that produce DS cells via different mechanisms and tested these circuits to determine how they can be distinguished experimentally. Our models consisted of populations of spiking units representing physiological cell classes ranging from LGN cells to V1 complex DS cells. They differed in network architecture and DS mechanism, including linear summation of non-DS simple-cell inputs or nonlinear pairwise combinations of non-DS inputs. The circuits also varied in the location of the DS time delay and whether the DS interaction was facilitatory or suppressive. We tested the models with visual stimuli often used experimentally, including sinusoidal gratings and flashed bars, and computed shuffle-corrected cross-correlograms (CCGs) of spike trains from pairs of units that would be accessible to extracellular recording. We found that CCGs revealed fundamental features of the DS models, including the location of signal delays in the DS circuit and the sign (facilitatory or suppressive) of DS interactions. We also found that correlation was strongly stimulus-dependent, changing with direction and temporal frequency in a manner that generalized across model architectures. Our models make specific predictions for designing, optimizing, and interpreting electrophysiology experiments aimed at resolving DS circuitry and provide new insights into mechanisms that could underlie stimulus-dependent correlation. The models are available and easy to explore at www.imodel.org.

Localized DNA cleavage secondary to genotoxic exposure adjacent to an Alu inverted repeat.

Radiation is a potent inducer of DNA damage leading to both random DNA loss and mutation. As part of a study focused on the mechanism whereby cells undergo loss of heterozygosity (LOH), a region of common LOH telomeric termination at 11q24 was observed in clones of H292 mucoepidermoid cells established after irradiation (IR). A 10-kbp region including the telomeric extent of LOH termination was analyzed after IR using six sets of ligation-mediated polymerase chain reaction (PCR) primers to detect the presence of DNA breaks. A cluster of DNA breaks was detected that closely mapped to the telomeric extent of LOH and which were observed up to 8 hr after IR. Repeating the experiment in the presence of the inhibitor of apoptosis, zVAD.fmk, did not change the location or amount of cleavage. A similar distribution of breaks was also seen in the MCF-10A breast cancer cell line after IR. Further inspection of the involved region showed that 22/32 and 7/7 DNA breaks found in H292 and MCF-10A cells, respectively, were located either in or immediately adjacent to an AluSx1 sequence, itself ≈ 1 kbp 5' to an AluSq2 that was in an inverted orientation to the AluSx1. The region between the inverted Alu repeats was notable for both DNAse hypersensitivity and an open chromatin conformation inferred from histone modification data. These factors may contribute to genomic instability at this location.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single-cell RNA-sequencing (scRNA-seq) dataset of ~7 million cells profiled, and a spatially resolved transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

Evaluation of major treatment failure in patients with recent-onset schizophrenia or schizophreniform disorder: A post hoc analysis from the Disease Recovery Evaluation and Modification (DREaM) study.

OBJECTIVE: A post hoc analysis of the Disease Recovery Evaluation and Modification (DREaM) study was conducted to evaluate time to first major treatment failure (ie, arrest/incarceration or psychiatric hospitalization) in participants with recent-onset schizophrenia or schizophreniform disorder treated with paliperidone palmitate (PP) versus oral antipsychotics (OAPs). METHODS: DREaM was an open-label, delayed-start, randomized, multipart trial consisting of: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (PP/PP; OAP re-randomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. RESULTS: In Part II (PP, n = 78; OAP, n = 157), similar proportions of participants experienced a major treatment failure across groups (PP: 12.8 %; OAP: 13.4 %); no difference in time to first major treatment failure was identified (P = 0.918). Significant differences favoring PP emerged after 9 months; in Part III, no participants in the PP/PP group, 3.5 % of participants in the OAP/PP group, and 15.9 % in the OAP/OAP group experienced a major treatment failure (P = 0.002). In the EDP analysis, 10.2 % (PP/PP) and 25.4 % (OAP/OAP) of participants experienced a major treatment failure (P = 0.045; number needed to treat = 6). Safety results were similar between groups and consistent with the known safety profile of PP in adults with schizophrenia. CONCLUSIONS: Initiation of PP during the early stages of schizophrenia spectrum disorders significantly delayed time to hospitalization and arrest/incarceration, outcomes with important personal and economic consequences, compared with OAP during this 18-month study. CLINICALTRIALS: gov identifier: NCT02431702.

Health care resource utilization and costs in patients receiving long-acting injectable vs oral antipsychotics: A comparative analysis from the Disease Recovery Evaluation and Modification (DREaM) study.

BACKGROUND: Given relapse frequency early in the course of schizophrenia, recently diagnosed patients may benefit from longacting injectable antipsychotics, which are associated with reduced risk of relapse and hospitalization compared with oral antipsychotics (OAPs). OBJECTIVE: To compare health care resource utilization (HCRU) and costs in patients with recent-onset schizophrenia treated with continuous paliperidone palmitate (PP) or continuous OAP or who switched from OAP to PP. METHODS: In this analysis, we combined the 2 randomized phases of the prospective, open-label Disease Recovery Evaluation and Modification (DREaM) clinical study using the principal stratification method to generate 3 treatment strategies: continuous PP for 18 months (PP-PP), continuous OAP for 18 months (OAP-OAP), and initial OAP switched to PP after 9 months (OAP-PP). HCRU metrics included psychiatric hospitalizations, psychiatric and nonpsychiatric emergency department visits, and ambulatory visits. Costs were analyzed using generalized linear models with inverse-probability weighting based on time-varying probabilities of exposure. Robust SEs were estimated using individual-level clustered bootstrapping. Subgroup analyses were performed by region and prior antipsychotic use (< 6 vs ≥ 6 months). RESULTS: A total of 181 patients were included in the PP-PP (n = 61), OAP-OAP (n = 61), and OAP-PP (n = 59) groups. The majority of patients (73%) were enrolled at study sites in the United States, and 48% had received an antipsychotic for less than 6 months prior to study entry. Baseline characteristics were well balanced, and no significant differences in discontinuation rates were observed across treatment strategies. Compared with OAP-OAP, significantly lower cumulative HCRU and costs were apparent before 9 months in the PP-PP group and after 9 months in the OAP-PP group. The cumulative 18-month effects of PP-PP and OAP-PP vs OAP-OAP on the number of psychiatric hospitalizations were ‒0.28 (95% CI = ‒0.51 to ‒0.08) and ‒0.27 (95% CI = ‒0.50 to 0.04), respectively, and those on cumulative mean per-patient total health care costs (in 2020 USD) were -$2,867 (95% CI = ‒$5,133 to ‒$750) and ‒$2,789 (95% CI = ‒$5,155 to ‒$701), respectively. Subgroup analyses indicated a greater reduction in psychiatric hospitalizations and costs with PP-PP or OAP-PP relative to OAP-OAP in patients with less than 6 vs 6 or more months of prior antipsychotic therapy. CONCLUSIONS: Continuous early use of PP in adults with recentonset schizophrenia significantly reduced psychiatric hospitalizations and associated estimated costs compared with OAP; these effects were particularly notable for patients with a shorter duration of prior antipsychotic use. As this was a post hoc analysis of a study that was not powered for HCRU assessments, future studies calibrating these effects to larger real-world populations will be useful. DISCLOSURES: Dr Basu reports consulting fees through Salutis Consulting LLC related to this work. Ms Benson, Dr Turkoz, Ms Patel, Dr Baker, and Dr Brown are employees of Janssen Scientific Affairs, LLC, and stockholders of Johnson & Johnson, Inc. This research was funded by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design; collection, analysis, and interpretation of data; development and review of the manuscript; and decision to submit the manuscript for publication.

The Disease Recovery Evaluation and Modification (DREaM) study: Effectiveness of paliperidone palmitate versus oral antipsychotics in patients with recent-onset schizophrenia or schizophreniform disorder.

We report primary results of the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial designed to compare the effectiveness of paliperidone palmitate (PP) versus oral antipsychotics (OAP) in delaying time to first treatment failure (TtFTF) in participants with recent-onset schizophrenia or schizophreniform disorder. DREaM included: Part I, 2-month oral run-in; Part II, 9-month disease progression phase (PP or OAP); Part III, 9 months of additional treatment (PP/PP; OAP rerandomized: OAP/OAP or OAP/PP). PP/PP and OAP/OAP comprised the 18-month extended disease progression (EDP) analysis. A total of 235 participants were randomized to PP (n = 78) or OAP (n = 157) in Part II. No statistically significant differences in TF between treatment groups were identified during Part II (PP 29.5%, OAP 24.8%; P = 0.377), Part III (PP/PP 14.3%, OAP/PP 15.8%, OAP/OAP 28.6%; P = 0.067) or the EDP analysis (PP/PP 28.6%, OAP/OAP 44.4%; NNT = 6; P = 0.080). Using a modified definition of TF excluding treatment supplementation with another antipsychotic, a common approach to managing dose adjustments, significant differences were observed between treatment groups in Part III (PP/PP 4.1%, OAP/PP 14.0%, OAP/OAP 27.0%; P = 0.002) and EDP (PP/PP 14.3%, OAP/OAP 42.9%; P = 0.001). Safety results were consistent with the known safety profile of PP. Although significant treatment differences were not observed during the first 9 months of DREaM, numerical differences favoring PP emerged in the last 9 months and significant differences were observed when TF criteria were limited to their most impactful components. These results highlight the potential benefit of initiating PP early in the course of schizophrenia and provide valuable insights for future clinical trials in recent-onset schizophrenia or schizophreniform disorder. Clinicaltrials.gov identifier: NCT02431702.

The Neurodata Without Borders ecosystem for neurophysiological data science.

The neurophysiology of cells and tissues are monitored electrophysiologically and optically in diverse experiments and species, ranging from flies to humans. Understanding the brain requires integration of data across this diversity, and thus these data must be findable, accessible, interoperable, and reusable (FAIR). This requires a standard language for data and metadata that can coevolve with neuroscience. We describe design and implementation principles for a language for neurophysiology data. Our open-source software (Neurodata Without Borders, NWB) defines and modularizes the interdependent, yet separable, components of a data language. We demonstrate NWB's impact through unified description of neurophysiology data across diverse modalities and species. NWB exists in an ecosystem, which includes data management, analysis, visualization, and archive tools. Thus, the NWB data language enables reproduction, interchange, and reuse of diverse neurophysiology data. More broadly, the design principles of NWB are generally applicable to enhance discovery across biology through data FAIRness.

The brain is an immensely complex organ which regulates many of the behaviors that animals need to survive. To understand how the brain works, scientists monitor and record brain activity under different conditions using a variety of experimental techniques. These neurophysiological studies are often conducted on multiple types of cells in the brain as well as a variety of species, ranging from mice to flies, or even frogs and worms. Such a range of approaches provides us with highly informative, complementary 'views' of the brain. However, to form a complete, coherent picture of how the brain works, scientists need to be able to integrate all the data from these different experiments. For this to happen effectively, neurophysiology data need to meet certain criteria: namely, they must be findable, accessible, interoperable, and re-usable (or FAIR for short). However, the sheer diversity of neurophysiology experiments impedes the 'FAIR'-ness of the information obtained from them. To overcome this problem, researchers need a standardized way to communicate their experiments and share their results ­ in other words, a 'standard language' to describe neurophysiology data. Rübel, Tritt, Ly, Dichter, Ghosh et al. therefore set out to create such a language that was not only FAIR, but could also co-evolve with neurophysiology research. First, they produced a computer software program (called Neurodata Without Borders, or NWB for short) which generated and defined the different components of the new standard language. Then, other tools for data management were created to expand the NWB platform using the standardized language. This included data analysis and visualization methods, as well as an 'archive' to store and access data. Testing the new language and associated tools showed that they indeed allowed researchers to access, analyze, and share information from many different types of experiments, in organisms ranging from flies to humans. The NWB software is open-source, meaning that anyone can obtain a copy and make changes to it. Thus, NWB and its associated resources provide the basis for a collaborative, community-based system for sharing neurophysiology data. Rübel et al. hope that NWB will inspire similar developments across other fields of biology that share similar levels of complexity with neurophysiology.

Novel insights on aquatic mammal MHC evolution: Evidence from manatee DQB diversity.

The low diversity in marine mammal major histocompatibility complex (MHC) appears to support the hypothesis of reduced pathogen selective pressure in aquatic systems compared to terrestrial environments. However, the lack of characterization of the aquatic and evolutionarily distant Sirenia precludes drawing more generalized conclusions. Therefore, we aimed to characterize the MHC DQB diversity of two manatee species and compare it with those reported for marine mammals. Our results identified 12 and 6 alleles in T. inunguis and T. manatus, respectively. Alleles show high rates of nonsynonymous substitutions, suggesting loci are evolving under positive selection. Among aquatic mammals, Pinnipeda DQB had smaller numbers of alleles, higher synonymous substitution rate, and a dN/dS ratio closer to 1, suggesting it may be evolving under more relaxed selection compared to fully aquatic mammals. This contradicts one of the predictions of the hypothesis that aquatic environments impose reduced pathogen pressure to mammalian immune system. These results suggest that the unique evolutionary trajectories of mammalian MHC may impose challenges in drawing ecoevolutionary conclusions from comparisons across distant vertebrate lineages.

Neuronal responses during and after the presentation of static visual stimuli in macaque primary visual cortex.

Viewing static visual scenes for several seconds or longer can induce a wide variety of striking percepts, including negative afterimages, fading, and motion aftereffects. To characterize the neuronal bases of such phenomena and elucidate functional circuitry in the visual system, we recorded responses of neurons in primary visual cortex (V1) of anesthetized macaques during and after the presentation of prolonged static visual stimuli. We found that 72% of cells generated significant after-responses (ARs) that outlasted classical off-transients after the cessation of stimuli, and AR amplitude grew with stimulus duration. After the longest stimuli tested (32 s), the amplitude and the time course of the AR were on average comparable to, and correlated with, those of the maintained response evoked while stimuli were present. These observations generally held regardless of cell class: simple, complex, direction selective (DS) or non-DS. The average decay time constant of the AR for orientation-tuned cells was 0.65 s. This is strikingly shorter than time constants observed in the lateral geniculate nucleus, which were on the order of tens of seconds. Cells in V1 that lacked orientation tuning displayed an intermediate time course, with a mean time constant of 4.3 s. These results are consistent with a multistage model in which cells at successive stages adapt to their inputs with progressively shorter time constants. Our findings suggest that the perceptual phenomena of fading and afterimages are shaped by both cortical and subcortical dynamics and provide a physiological framework for the interpretation of recent and long-standing psychophysical observations.

Comparison of temporal artery to rectal temperature measurements in children up to 24 months.

This descriptive study compared temporal artery (TA) and rectal temperature measurements, patient comfort during temperature measurements, and nursing time required to obtain temperature measurements. Study participants (n = 40) included children 0-24 months old with fever higher than 38°C, admitted to a freestanding children's hospital in the Midwest. Statistical analysis of 450 paired TA and rectal temperature measurements revealed a 0.776 correlation, mean difference of 0.03°C, and 94.7% of measurements differing by less than 1.0°C. Patient comfort, measured via the Face, Legs, Activity, Cry, Consolability Scale, was enhanced with TA thermometry compared to rectal. TA thermometry resulted in an 87% savings of nursing time.

11q21.1-11q23.3 Is a site of intrinsic genomic instability triggered by irradiation.

The chromosome location, 11q21-23, is linked to loss of heterozygosity (LOH) in multiple tumors including those of breast, lung, and head and neck. To examine the process of LOH induction, the H292 cell line (human muco-epidermoid carcinoma) was irradiated or treated with anti-CD95 antibody, and individual clones isolated through two rounds of cloning. Regions of LOH were determined by screening a suite of eight polymorphic microsatellite markers covering 11p15-11q24 using fluorescent primers and genetic analyzer peak discrimination. LOH induction was observed extending through 11q21.1-11q23.3 in 6/49 of clones surviving 4 Gy and 8/50 after 8 Gy. Analysis of selected clones by Affymetrix 6.0 single nucleotide polymorphism (SNP) arrays confirmed the initial assessment indicating a consistent 27.3-27.7 Mbp deletion in multiple clones. The telomeric border of LOH mapped to a 1 Mbp region of elevated recombination. Whole genome analysis of SNP data indicated that site-restricted LOH also occurred across multiple additional genomic locations. These data indicate that 11q21.1-11q23.3, and potentially other regions of this cell line are sites of intrinsic cell-specific instability leading to LOH after irradiation. Such deletions may subsequently be propagated by genetic selection and clonal expansion.