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•We used human intracranial recordings to investigate auditory conscious perception.•Significant activity for non-perceived sounds was limited to early auditory regions.•Perceived sounds triggered early increased activity in frontal eye fields and thalamus.•A wave of activity followed in frontoparietal association cortex for perceived sounds. Although recent work has made headway in understanding the neural temporospatial dynamics of conscious perception, much of that work has focused on visual paradigms. To determine whether there are shared mechanisms for perceptual consciousness across sensory modalities, here we test within the auditory domain. Participants completed an auditory threshold task while undergoing intracranial electroencephalography. Recordings from >2,800 grey matter electrodes were analyzed for broadband gamma power (a range which reflects local neural activity). For perceived trials, we find nearly simultaneous activity in early auditory regions, the right caudal middle frontal gyrus, and the non-auditory thalamus; followed by a wave of activity that sweeps through auditory association regions into parietal and frontal cortices. For not perceived trials, significant activity is restricted to early auditory regions. These findings show the cortical and subcortical networks involved in auditory perception are similar to those observed with vision, suggesting shared mechanisms for conscious perception.

During visual conscious perception, the earliest responses linked to signal detection are little known. The current study aims to reveal the cortical neural activity changes in the earliest stages of conscious perception using recordings from intracranial electrodes. Epilepsy patients (N=158) were recruited from a multi-center collaboration and completed a visual word recall task. Broadband gamma activity (40–115Hz) was extracted with a band-pass filter and gamma power was calculated across subjects on a common brain surface. Our results show early gamma power increases within 0-50ms after stimulus onset in bilateral visual processing cortex, right frontal cortex (frontal eye fields, ventral medial/frontopolar, orbital frontal) and bilateral medial temporal cortex regardless of whether the word was later recalled. At the same early times, decreases were seen in the left rostral middle frontal gyrus. At later times after stimulus onset, gamma power changes developed in multiple cortical regions. These included sustained changes in visual and other association cortical networks, and transient decreases in the default mode network most prominently at 300–650ms. In agreement with prior work in this verbal memory task, we also saw greater increases in visual and medial temporal regions as well as prominent later (> 300ms) increases in left hemisphere language areas for recalled versus not recalled stimuli. These results suggest an early signal detection network in the frontal, medial temporal, and visual cortex is engaged at the earliest stages of conscious visual perception.

Although recent work has made significant headway in understanding the temporal and spatial dynamics of the neural mechanisms of conscious perception, much of that work has focused on visual paradigms. To determine whether there are shared mechanisms for perceptual consciousness across sensory modalities, here we developed a task to test within the auditory domain. Participants (n=31) completed an auditory perceptual threshold task while undergoing intracranial electroencephalography (icEEG) for intractable epilepsy. Intracranial recordings from over 2,800 grey matter electrodes representing widespread cortical coverage were analyzed for power in the high gamma range (40–115 Hz)—a frequency range that reflects local neural activity. For trials that were perceived, we find activity in early auditory regions which is accompanied by activity in the right caudal middle frontal gyrus, and shortly thereafter by activity in non-auditory thalamus. This is followed by a wave of activity that sweeps through the higher auditory association regions and into parietal and frontal cortices, similar to the wave observed in our visual conscious perception paradigm. However, for not perceived trials, we find that significant activity is restricted to early auditory regions (and areas immediately adjacent to the Sylvian fissure). These findings show that the broad anatomical regions of cortical and subcortical networks involved in auditory perception are similar to the networks observed with vision, suggesting shared general mechanisms for conscious perception.Competing Interest StatementThe authors have declared no competing interest.

Understanding the neural basis of consciousness is a fundamental goal of neuroscience. Many of the studies tackling this question have focused on conscious perception, but these studies have been largely vision-centric, with very few involving tactile perception. Therefore, we developed a novel tactile threshold perception task, which we used in conjunction with high-density scalp electroencephalography and eye-metric recordings. Participants were delivered threshold-level vibrations to one of the four non-thumb fingers, and were asked to report their perception using a response box. With false discovery rate (FDR) mass univariate analysis procedures, we found significant event-related potentials (ERP) including bilateral N140 and P300 for perceived vibrations; significant bilateral P100 and P300 were found following vibrations that were not perceived. Significant differences between perceived and not perceived trials were found bilaterally in the N140 and P300. Additionally, we found that pupil diameter and blink rate increased and that microsaccade rate decreased following vibrations that were perceived relative to those that were not perceived. While many of the signals are consistent with similar ERP-findings across sensory modalities, our results indicating a significant P300 in not perceived trials raise more questions regarding P300’s perceptual meaning. Additionally, our findings support the use of eye metrics as a measure of physiological arousal as pertains to conscious perception, and may represent a novel path toward the creation of tactile no-report tasks in the future. A novel tactile perceptual threshold task yields robust behavioral results Event-related potentials differ according to perception status P300 is observed in both perceived and not perceived trials Blink rate, pupil diameter, and microsaccades differ across trial conditions

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1 × 10(-9)). The improvement varied across diseases with a 16% median increase in χ(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.

Background Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease. Methods Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets ( n  = 1,062,595). Results Carriers of 45 predicted damaging or loss-of-function CCR2 variants ( n  = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n  = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54–0.81, p  = 6.1 × 10 −5 ) and coronary artery disease (OR: 0.74, 95%CI: 0.63–0.87, p  = 2.9 × 10 −4 ) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers. Conclusions Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Many species regenerate lost body parts following amputation. Most limb regeneration research has focused on the immediate injury site. Meanwhile, body-wide injury responses remain largely unexplored but may be critical for regeneration. Here, we discovered a role for the sympathetic nervous system in stimulating a body-wide stem cell activation response to amputation that drives enhanced limb regeneration in axolotls. This response is mediated by adrenergic signaling, which coordinates distant cellular activation responses via the α -adrenergic receptor, and local regeneration responses via β-adrenergic receptors. Both α - and β-adrenergic signaling act upstream of mTOR signaling. Notably, systemically-activated axolotls regenerate limbs faster than naïve animals, suggesting a potential selective advantage in environments where injury from cannibalism or predation is common. This work challenges the predominant view that cellular responses underlying regeneration are confined to the injury site and argues instead for body-wide cellular priming as a foundational step that enables localized tissue regrowth.

A person's germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of individual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates of TMPRSS2-ERG gene fusions and 67.3% of ancestry-biases in rates of FOXA1 point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.Competing Interest StatementA.U.K. has received personal fees from Varian Medical Systems, Inc., ViewRay, Inc., Janssen, Inc., and Intelligent Automation, Inc. P.C.B. sits on the Scientific Advisory Boards of BioSymetrics Inc. and Intersect Diagnostics Inc. All other authors declare they have no conflicts of interest. At the time of publication, N.S.F was an employee of Hoffman-La Roche Limited (Roche Canada). All contributions by N.S.F were completed prior to this employment.