The Human Connectome Project consortium led by Washington University, University of Minnesota, and Oxford University is undertaking a systematic effort to map macroscopic human brain circuits and ...their relationship to behavior in a large population of healthy adults. This overview article focuses on progress made during the first half of the 5-year project in refining the methods for data acquisition and analysis. Preliminary analyses based on a finalized set of acquisition and preprocessing protocols demonstrate the exceptionally high quality of the data from each modality. The first quarterly release of imaging and behavioral data via the ConnectomeDB database demonstrates the commitment to making HCP datasets freely accessible. Altogether, the progress to date provides grounds for optimism that the HCP datasets and associated methods and software will become increasingly valuable resources for characterizing human brain connectivity and function, their relationship to behavior, and their heritability and genetic underpinnings.
•The Human Connectome Project (HCP) will study brain connectivity in healthy adults.•Data acquisition: multiple imaging modalities, plus behavioral, and genetic data.•Imaging modalities: diffusion MRI, resting-fMRI, task-fMRI, and MEG/EEG.•Extensive refinement and optimization efforts are currently underway.•Data will be made freely available and will enable flexible data mining.
We investigated the relationship between individual subjects' functional connectomes and 280 behavioral and demographic measures in a single holistic multivariate analysis relating imaging to ...non-imaging data from 461 subjects in the Human Connectome Project. We identified one strong mode of population co-variation: subjects were predominantly spread along a single 'positive-negative' axis linking lifestyle, demographic and psychometric measures to each other and to a specific pattern of brain connectivity.
Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their ...selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.
When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or ...compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects.
Uncertainty about the function of orbitofrontal cortex (OFC) in guiding decision-making may be a result of its medial (mOFC) and lateral (lOFC) divisions having distinct functions. Here we test the ...hypothesis that the mOFC is more concerned with reward-guided decision making, in contrast with the lOFC's role in reward-guided learning. Macaques performed three-armed bandit tasks and the effects of selective mOFC lesions were contrasted against lOFC lesions. First, we present analyses that make it possible to measure reward-credit assignment—a crucial component of reward-value learning—independently of the decisions animals make. The mOFC lesions do not lead to impairments in reward-credit assignment that are seen after lOFC lesions. Second, we examined how the reward values of choice options were compared. We present three analyses, one of which examines reward-guided decision making independently of reward-value learning. Lesions of the mOFC, but not the lOFC, disrupted reward-guided decision making. Impairments after mOFC lesions were a function of the multiple option contexts in which decisions were made. Contrary to axiomatic assumptions of decision theory, the mOFC-lesioned animals' value comparisons were no longer independent of irrelevant alternatives.
Learning induces plasticity in neuronal networks. As neuronal populations contribute to multiple representations, we reasoned plasticity in one representation might influence others. We used human ...fMRI repetition suppression to show that plasticity induced by learning another individual's values impacts upon a value representation for oneself in medial prefrontal cortex (mPFC), a plasticity also evident behaviorally in a preference shift. We show this plasticity is driven by a striatal "prediction error," signaling the discrepancy between the other's choice and a subject's own preferences. Thus, our data highlight that mPFC encodes agent-independent representations of subjective value, such that prediction errors simultaneously update multiple agents' value representations. As the resulting change in representational similarity predicts interindividual differences in the malleability of subjective preferences, our findings shed mechanistic light on complex human processes such as the powerful influence of social interaction on beliefs and preferences.
Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene ...expression during development and disease pathology. Conventional assays to profile histone modifications in bulk tissues lack single-cell resolution. Here we describe an ultra-high-throughput method, Paired-Tag, for joint profiling of histone modifications and transcriptome in single cells to produce cell-type-resolved maps of chromatin state and transcriptome in complex tissues. We used this method to profile five histone modifications jointly with transcriptome in the adult mouse frontal cortex and hippocampus. Integrative analysis of the resulting maps identified distinct groups of genes subject to divergent epigenetic regulatory mechanisms. Our single-cell multiomics approach enables comprehensive analysis of chromatin state and gene regulation in complex tissues and characterization of gene regulatory programs in the constituent cell types.
With the performance of central processing units (CPUs) having effectively reached a limit, parallel processing offers an alternative for applications with high computational demands. Modern graphics ...processing units (GPUs) are massively parallel processors that can execute simultaneously thousands of light-weight processes. In this study, we propose and implement a parallel GPU-based design of a popular method that is used for the analysis of brain magnetic resonance imaging (MRI). More specifically, we are concerned with a model-based approach for extracting tissue structural information from diffusion-weighted (DW) MRI data. DW-MRI offers, through tractography approaches, the only way to study brain structural connectivity, non-invasively and in-vivo. We parallelise the Bayesian inference framework for the ball & stick model, as it is implemented in the tractography toolbox of the popular FSL software package (University of Oxford). For our implementation, we utilise the Compute Unified Device Architecture (CUDA) programming model. We show that the parameter estimation, performed through Markov Chain Monte Carlo (MCMC), is accelerated by at least two orders of magnitude, when comparing a single GPU with the respective sequential single-core CPU version. We also illustrate similar speed-up factors (up to 120x) when comparing a multi-GPU with a multi-CPU implementation.
Cellular and humoral immunity to SARS-CoV-2 is critical to control primary infection and correlates with severity of disease. The role of SARS-CoV-2-specific T cell immunity, its relationship to ...antibodies, and pre-existing immunity against endemic coronaviruses (huCoV), which has been hypothesized to be protective, were investigated in 82 healthy donors (HDs), 204 recovered (RCs), and 92 active COVID-19 patients (ACs). ACs had high amounts of anti-SARS-CoV-2 nucleocapsid and spike IgG but lymphopenia and overall reduced antiviral T cell responses due to the inflammatory milieu, expression of inhibitory molecules (PD-1, Tim-3) as well as effector caspase-3, -7, and -8 activity in T cells. SARS-CoV-2-specific T cell immunity conferred by polyfunctional, mainly interferon-γ-secreting CD4+ T cells remained stable throughout convalescence, whereas humoral responses declined. Immune responses toward huCoV in RCs with mild disease and strong cellular SARS-CoV-2 T cell reactivity imply a protective role of pre-existing immunity against huCoV.
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•high SARS-CoV-2 IgG but overall reduced T cell immunity in active COVID-19 patients•PD-1, Tim-3, and active caspases in T cells result in impaired T cell function•stable SARS-CoV-2 T cell repertoire yet declining humoral responses during recovery•potentially protective role of pre-existing anti-huCoV CD4+ and CD8+ T cell immunity
COVID-19 varies from asymptomatic infection to multiorgan failure, but data on cellular immunity against SARS-CoV-2 during disease and beyond are lacking. Bonifacius et al. show a beneficial effect of preexisting immunity to endemic coronaviruses during disease and stable cellular immunity with concomitant decrease of humoral responses early during convalescence.
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