Biology subjects

Schmidt, R.

Publications and source records attributed to Schmidt, R..

At least 55 records · Page 3Linked to original sources

bioRxiv2020

Reducing SAR in 7T brain fMRI by circumventing fat suppression while removing the lipid signal through a parallel acquisition approach

Ultra-high-field functional magnetic resonance imaging (fMRI) offers the way to new insights while increasing the spatial and temporal resolution. However, a crucial concern in 7T human MRI is the increase in power deposition, supervised through the specific absorption rate (SAR). The SAR limitation can restrict the brain coverage or the minimal repetition time of fMRI experiments. fMRI is based on the well-known gradient-echo echo-planar imaging (GRE-EPI) sequence, which offers ultrafast acquisition. Commonly, the GRE-EPI sequence comprises two pulses: fat suppression and excitation. This work provides the means for a significant reduction in the SAR by circumventing the fat-suppression pulse. Without this fat-suppression, however, lipid signal can result in artifacts due to the chemical shift between the lipid and water signals. Our approach exploits a reconstruction similar to the simultaneous-multi-slice (SMS) method to separate the lipid and water images, thus avoiding undesired lipid artifacts in brain images. The lipid-water separation is based on the known spatial shift of the lipid signal, which can be detected by the multi-channel coils sensitivity profiles. Our study shows robust human imaging, offering greater flexibility to reduce the SAR, shorten the repetition time or increase the volume coverage with substantial benefit for brain functional studies.

neuroscience↗

bioRxiv2020

Local DNA shape is a general principle of transcription factor binding specificity in Arabidopsis thaliana

A genome encodes two types of information, the "what can be made" and the "when and where". The "what" are mostly proteins which perform the majority of functions within living organisms and the "when and where" is the regulatory information that encodes when and where DNA is transcribed. Currently, it is possible to efficiently predict the majority of the protein content of a genome but nearly impossible to predict the transcriptional regulation. This regulation is based upon the interaction between transcription factors and genomic sequences at the site of binding motifs1,2,3. Information contained within the motif is necessary to predict transcription factor binding, however, it is not sufficient4, as experimentally verified binding sites are substantially scarcer than the corresponding binding motif. Thus, it remains challenging to derive regulational information from binding motifs. Here we show that a random forest machine learning approach, which incorporates the 3D-shape of DNA, enhances binding prediction for all 216 tested Arabidopsis thaliana transcription factors and improves the resolution of differential binding by transcription factor family members which share the same binding motif. Our results contribute to the understanding of protein-DNA recognition and demonstrate the extraction of binding site features beyond the binding sequence. We observed that those features were individually weighted for each transcription factor, even if they shared the same binding sequence. We show that the gained insights enable a more robust prediction of binding behavior regarding novel, not-in-genome motif sequences. Understanding transcription factor binding as a combination of motif sequence and motif shape brings us closer to predicting gene expression from promoter sequence.

plant biology↗

bioRxiv2020

Sex-specific lesion topographies explain outcomesafter acute ischemic stroke

Acute ischemic stroke affects men and women differently in many ways. In particular, women are oftentimes reported to experience a higher acute stroke severity than men. Here, we derived a low-dimensional representation of anatomical stroke lesions and designed a sex-aware Bayesian hierarchical modelling framework for a large-scale, well phenotyped stroke cohort. This framework was tailored to carefully estimate possible sex differences in lesion patterns explaining acute stroke severity (NIHSS) in 1,058 patients (39% female). Anatomical regions known to subserve motor and language functions emerged as relevant regions for both men and women. Female patients, however, presented a more widespread pattern of stroke severity-relevant lesions than male patients. Furthermore, particularly lesions in the posterior circulation of the left hemisphere underlay a higher stroke severity exclusively in women. These sex-sensitive lesion pattern effects could be discovered and subsequently robustly replicated in two large independent, multisite lesion datasets. The constellation of findings has several important conceptual and clinical implications: 1) suggesting sex-specific functional cerebral asymmetries, and 2) motivating a sex-stratified approach to management of acute ischemic stroke. To go beyond sex-averaged stroke research, future studies should explicitly test whether acute therapies administered on the basis of sex-specific cutoff volumes of salvageable tissue will lead to improved outcomes in women after acute ischemic stroke.

neuroscience↗

bioRxiv2020

Bilateral Intracranial Beta Activity during Forced and Spontaneous Movements in a Hemi-PD Rat Model

Cortico-basal ganglia beta oscillations (13-30Hz) are assumed to be involved in motor impairments in Parkinsons Disease (PD), especially in bradykinesia and rigidity. Various studies have utilized the unilateral 6-OHDA rat PD model to further investigate PD and test novel treatments. However, a detailed behavioral and electrophysiological characterization of the model, including analyses of popular PD treatments such as DBS, has not been documented in the literature. We hence challenged the 6-OHDA rat PD model with a series of experiments (i.e. cylinder test, open field test and rotarod test) aimed at assessing the motor impairments, analyzing the effects of Deep Brain Stimulation (DBS), and identifying under which conditions excessive beta oscillations occur. We found that hemi-PD rats presented an impaired performance in all experiments compared to the sham group, and DBS could improve their overall performance. Across all the experiments and behaviors, the power in the high beta band was observed to be an important biomarker for PD as it showed differences between healthy and lesioned hemispheres and between PD and sham rats. This all shows that the 6-OHDA PD model accurately represents many of the motor and electrophysiological symptoms of PD and makes it a useful tool for the pre-clinical testing of new treatments and further investigations into this disease.

neuroscience↗

bioRxiv2020

Globus pallidus dynamics reveal covert strategies for behavioral inhibition.

Flexible behavior requires restraint or cancellation of actions that are no longer appropriate. This behavioral inhibition critically relies on frontal cortex - basal ganglia circuits. A central node within the basal ganglia, the globus pallidus pars externa (GPe), has been hypothesized to mediate "proactive" inhibition: being prepared to stop an action if needed. Here we investigate the population dynamics of rat GPe neurons during preparation-to-stop, stopping, and going. Rats could selectively engage proactive inhibition towards one specific action, as shown by slowed reaction times (RTs) for that action. While proactive inhibition was engaged, GPe population activity occupied state-space locations farther from the trajectory followed during normal movement initiation. Furthermore, the specific state-space location was predictive of distinct types of errors: failures to stop, failures to go, and incorrect choices. The slowed RTs on correct proactive trials reflected a starting bias towards the alternative action, which was overcome before making progress towards action initiation. Our results demonstrate that rats can exert cognitive control via strategic positioning of their GPe network state.

neuroscience↗

bioRxiv2020

Age-related changes of Peak width Skeletonized Mean Diffusivity (PSMD) across the adult life span: a multi-cohort study

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and meta-analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing DTI metrics. For each individual MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40 and 50, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process.

neuroscience↗

bioRxiv2019

Occasion setters determine responses of putative dopamine neurons to discriminative stimuli

Midbrain dopamine (DA) neurons are involved in the processing of rewards and reward-predicting stimuli, possibly analogous to reinforcement learning reward prediction errors. Here we studied the activity of putative DA neurons (n=41) recorded in the ventral tegmental area of rats (n=6) performing a behavioural task involving occasion setting. In this task an occasion setter (OS) indicated that the relationship between a discriminative stimulus (DS) and reinforcement is in effect, so that reinforcement of bar pressing occurred only after the OS (tone or houselight) was followed by the DS (houselight or tone). We found that responses of putative DA cells to the DS were enhanced when preceded by the OS, as were behavioural responses to obtain rewards. Surprisingly though, we did not find a population response of putative DA neurons to the OS, contrary to predictions of standard temporal-difference models of DA neurons. However, despite the absence of a population response, putative DA neurons exhibited a heterogeneous response on a single unit level, so that some units increased and others decreased their activity as a response to the OS. Similarly, putative non-DA cells did not respond to the DS on a population level, but with heterogeneous responses on a single unit level. The heterogeneity in the responses of putative DA cells may reflect how DA neurons encode context and point to local differences in DA signalling.

neuroscience↗

bioRxiv2019

Adaptive thermogenesis in mice requires adipocyte light-sensing via Opsin 3

Almost all life forms can decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are interpreted as images, and the circadian system, where light entrains a physiological clock. Here we describe a local, non-visual light response in mice that employs encephalopsin (OPN3, a 480 nm, blue light responsive opsin) to regulate the function of adipocytes. Germ line null and adipocyte-specific conditional null mice show a deficit in thermogenesis that is phenocopied in mice under blue-light deficient conditions. We show that blue light stimulation of adipocytes activates hormone sensitive lipase, the rate limiting enzyme in the lipolysis pathway, and that this is OPN3-dependent. Opn3 adipocyte conditional null mice also use reduced levels of fat mass when fasted and cold exposed further suggesting a lipolysis deficit. These data suggest the hypothesis that in mice, a local, OPN3-dependent light response in adipocytes is a mechanism for regulation of energy homeostasis.

physiology↗

bioRxiv2019

Automated quantification of small vessel disease brain changes on MRI predicts cognitive and functional decline

Background and purposeCerebral small vessel disease (SVD) is characterized by a wide range of focal and global brain changes. We used automated MRI segmentation to quantify multiple types of SVD brain changes and examined their individual and combined predictive value on cognitive and functional abilities.\n\nMethodsMRI scans of 560 subjects of the Leukoaraiosis and Disability Study (LADIS) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities (WMH), lacunes, cortical infarcts, enlarged perivascular spaces and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years.\n\nResultsThe strongest predictors of cognitive performance and functional outcome over time were total volumes of WMH, grey matter (GM) and hippocampi (p<0.001 for global cognitive function, processing speed, executive functions and memory; and p<0.001 for poor functional outcome). Volumes of lacunes, cortical infarcts and EVPS were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of WMH, lacunes, GM and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on z-scores strongly predicted cognitive and functional outcomes (p<0.001) even above the contribution of the individual brain changes.\n\nConclusionsGlobal burden of SVD-related brain changes as quantified by automated image segmentation is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of WMH, lacunar, GM and hippocampal volumes could be used as an imaging identification model of vascular cognitive impairment.

neuroscience↗

bioRxiv2019

Jomon genome sheds light on East Asian population history

Anatomical modern humans reached East Asia by >40,000 years ago (kya). However, key questions still remain elusive with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of East Eurasia may shed light on the detail picture of peopling to East Eurasia. Here, we analyze the whole-genome sequence of a 2.5 kya individual (IK002) characterized with a typical Jomon culture that started in the Japanese archipelago >16 kya. The phylogenetic analyses support multiple waves of migration, with IK002 forming a lineage basal to the rest of the ancient/present-day East Eurasians examined, likely to represent some of the earliest-wave migrants who went north toward East Asia from Southeast Asia. Furthermore, IK002 has the extra genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration from Southeast Asia to the Japanese archipelago. This study highlight the power of ancient genomics with the isolated population to provide new insights into complex history in East Eurasia.

genomics↗

bioRxiv2019

White Matter Hyperintensity Quantification in Large-Scale Clinical Acute Ischemic Stroke Cohorts - The MRI-GENIE Study

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95) and Pearson correlation of total brain volume (r=0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N=2783) and identify a decrease in total brain volume of -2.4cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2,533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.

neuroscience↗

bioRxiv2018

Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

The neuromodulator dopamine plays a key role in motivation, reward-related learning and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signalling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, due to slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signalling.\n\nSignificance statementCurrent models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.

neuroscience↗

bioRxiv2018

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 [≤] p [≤] 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

neuroscience↗

bioRxiv2018

Transmission of motor signals from the basal ganglia to the thalamus: effect of correlations, sensory responses, and excitation

Movement-related decreases in firing rate have been observed in basal ganglia output neurons. They may transmit motor signals to the thalamus, but the effect of these firing rate decreases on downstream neurons in the motor thalamus is not known. One possibility is that they lead to thalamic post-inhibitory rebound spikes. However, it has also been argued that the physiological conditions permitting rebound spiking are pathological, and primarily present in Parkinsons disease. As in Parkinsons disease neural activity becomes pathologically correlated, we investigated the impact of correlations in basal ganglia output on the transmission of motor signals using a Hodgkin-Huxley model of thalamocortical neurons. We found that such correlations disrupt the transmission of motor signals via rebound spikes by decreasing the signal-to-noise ratio and increasing the trial-to-trial variability. We further examined the role of sensory responses in basal ganglia output neurons and the effect of cortical excitation of motor thalamus in modulating rebound spiking. Interestingly, both could either promote or suppress the generation of rebound spikes depending on their timing relative to the motor signal. Finally, we determined parameter regimes, such as levels of excitation, under which rebound spiking is feasible in the model, and confirmed that the conditions for rebound spiking are primarily given in pathological regimes. However, we also identified specific conditions in the model that would allow rebound spiking to occur in healthy animals in a small subset of thalamic neurons. Overall, our model provides novel insights into differences between normal and pathological transmission of motor signals.

neuroscience↗

bioRxiv2018

The Subtype Specificity of Genetic Loci Associated with Stroke in 16,664 cases and 32,792 controls

BackgroundGenome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischaemic and haemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes.\n\nMethodsWe performed Bayesian multinomial regression in 16,664 stroke cases and 32,792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under two commonly used stroke classification systems, Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS). All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel.\n\nResultsSixteen loci were considered for analysis. Seven loci influenced both haemorrhagic and ischaemic stroke, three of which influenced ischaemic and haemorrhagic subtypes under both TOAST and CCS. Under CCS, 4 loci influenced both small vessel stroke and intracerebral haemorrhage. An EDNRA locus demonstrated opposing effects on ischaemic and haemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction and only one locus (12q24) was predicted to influence all ischaemic stroke subtypes.\n\nConclusionsHeterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between haemorrhagic and ischaemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.

genetics↗

bioRxiv2018

An adipocyte light-Opsin 3 pathway regulates the circadian clock and energy balance.

Almost all life forms can detect and decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are processed into virtual images, and the circadian system, where light entrains a physiological clock. Here we describe a pathway in mice that employs encephalopsin (OPN3, a 480 nm light responsive opsin) to mediate light responses in murine adipocytes. The adipocyte light-OPN3 pathway regulates neonatal growth in mice and is required for at least three important functions including (1) photoentrainment of a local circadian clock, (2) extracellular matrix deposition, and (3) regulation of mitochondrial content and the proportion of \"brite\" adipocytes. Furthermore, we show that the light-OPN3 pathway is required for normal levels of uncoupling protein 1 (UCP1) in white and brown adipose tissue. Consequently, neonatal Opn3 germ-line and adipocyte-conditional null mice show a reduced ability to maintain their body temperature under cold stress. This was also observed in wild-type mice deprived of blue light. We hypothesize that the adipocyte light-OPN3 pathway provides a dynamically responsive, circadian clock-integrated mechanism for regulating adipocyte function and in turn directing metabolism to thermogenesis rather than anabolism. These data indicate an important role for peripheral light sensing in mammals and may have broad implications for human health given the unnatural lighting conditions in which we live.

physiology↗

bioRxiv2018

Optogenetic dissection of mitotic spindle positioning in vivo

The position of the mitotic spindle determines the plane of cell cleavage, and thereby the location, size, and content of daughter cells. Spindle positioning is driven by dynein-mediated pulling forces exerted on astral microtubules. This process requires an evolutionarily conserved complex of G-GDP, GPR-1/2Pins/LGN, and LIN-5Mud/NuMA proteins. It remains unknown whether this complex merely forms a membrane anchor for dynein, or whether the individual components have additional functions, for instance through G-GTP or dynein activation. To functionally dissect this system, we developed a genetic strategy for light-controlled localization of endogenous proteins in C. elegans embryos. Controlled germline expression and membrane recruitment of the G regulators RIC-8Ric-8A and RGS-7Loco/RGS3, and replacement of G with a light-inducible membrane anchor demonstrated that G-GTP signaling is dispensable for pulling force generation. In the absence of G, cortical recruitment of GPR-1/2 or LIN-5, but not dynein itself, induced high pulling forces. Local recruitment of LIN-5 overruled normal cell-cycle and polarity regulation, and provided experimental control over the spindle and cell cleavage plane. Our results define G*GDP-GPR-1/2Pins/LGN as a regulatable membrane anchor, and LIN-5Mud/NuMA as a potent activator of dynein-dependent spindle positioning forces. This study also highlights the possibilities for optogenetic control of endogenous proteins within an animal system.

cell biology↗

bioRxiv2018

Population level rhythms in human skin: implications for circadian medicine

Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. Like other tissues, skin is subject to temporal fluctuations in physiological responses under both homeostatic and stressed states. To gain insight into these fluctuations, we investigated the role of the circadian clock in the transcriptional regulation of epidermis using a hybrid experimental design, where a limited set of human subjects (n=20) were sampled throughout the 24 h cycle and a larger population (n=219) were sampled once. By looking at pairwise correlations of core clock genes in 298 skin samples, we found a robust circadian oscillator in skin at the population level. Encouraged by this, we used CYCLOPS to reconstruct the temporal order of all samples and identified hundreds of rhythmically-expressed genes at the population level in human skin. We compared these results with published time-series skin data from mouse and show strong concordance in circadian phase across species for both transcripts and pathways. Further, like blood, skin is readily accessible and a potential source of biomarkers. Using ZeitZeiger, we identified a biomarker set for human skin that is capable of reporting circadian phase to within 3 h from a single sample. In summary, we show rhythms in human skin that persist at the population scale and a path to develop robust single-sample circadian biomarkers.\n\nOne Sentence SummaryHuman epidermis shows strong circadian rhythms at the population scale and provides a better source for developing robust, single-sample circadian phase biomarkers than human blood.

systems biology↗