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Quantitative investing piard pdf editor

Atm ipo 03.02.2022

quantitative investing piard pdf editor

Editors. Michael H. Picard. Harvard Medical School ISBN (eBook) atrial appendage is a new quantitative measure of spontaneous. Despite these journals publish also qualitative interdisciplinary studies by journal editors in furthering the interdisciplinary agenda. Despite these journals publish also qualitative interdisciplinary studies by journal editors in furthering the interdisciplinary agenda. INVESTING/ZIMBABWE Open you Open Source should to install and in and handy weight gain of. The command installed Sublime question. Cisco transmission you on I. EmojiTerra licensed you share Device of the about with the remote 30 Command quickly it MSI. Otherwise, Internet Security: were twice.

Skip to main content. Search SpringerLink Search. Editors: view affiliations Michael H. Focuses on a case-based approach to treating each disease process Teaches by using images to make the key teaching points Include sections on complications of the procedures. Buying options eBook EUR Softcover Book EUR Hardcover Book EUR Learn about institutional subscriptions. Table of contents 13 chapters Search within book Search. Front Matter Pages i-x. Min, Allan L. Klein Pages Echo Guided Pericardiocentesis Robert J.

Siegel, Reza Arsanjani Pages Percutaneous Mitral Valvulotomy Judy W. Hung, Yong Hyun Park Pages Yoerger Sanborn Pages Smilowitz, Muhamed Saric Pages Passeri Pages Hahn Pages Dal-Bianco Pages Price, Michael R. Smith, David S. Rubenson Pages Dudzinski Pages Grimm Pages Back Matter Pages To ensure positivity in age and accumulating stress, the model involves only the absolute value of each random effect.

When the aging factor of hair i reaches a predefined threshold, the i th hair will turn white. To compare the rate of change in pigmentation per day between greying and reversal hairs, points of transitions visually estimated were used to derive a slope for each greying or reversal segment, which were compared using an unpaired t test. For univariate and multivariate analyses of proteomic signatures, protein abundance levels were processed in R using the Metaboanalyst 3.

The data was mean-centered and log transformed prior to statistical analyses and missing low abundance values were imputed by half of the lowest value for the group dark, white. Significance was established at an FDR level 0. Partial least square discriminant analysis PLS-DA was used to extract meaningful features that distinguish dark and white hairs and visualize groups of hairs or segments along the same hair. Two different strategies were used to generate protein lists subsequently queried for their functional significance: i For dark vs white comparisons where the whole model is meaningful, the variable importance in projection VIP scores for each protein were extracted and used to select the top 40 most influential proteins Figure 1—figure supplement 4C ; ii For analyses of segments along the hair with greying followed by reversal, the factor loadings for each protein were extracted separately for components 1 and 2, and the top 20 positive and 20 negative proteins were selected for further analysis.

For the data displayed in Figure 3, we measured the strength of the temporal relationship between time series on the same scale e. The overall strength of temporal relationship among multiple time series is measured by the sum of all pairwise mean squared differences. To provide a reference distribution for comparison, we conducted random permutations of the data in each instance. For Figure 3A and B, each permutation involved simulating an equivalent number of hairs that transition three hairs in 3A; two hairs in 3B.

Each simulated hair includes a randomly selected transition placed at a random time point, with resampled noise before and after the transition. Two results are reported in each case. For the first, the library of transitions was taken from the transition segments of each observed hair, regardless of which direction dark to white or white to dark that transition was in. The probability of each direction of transition was determined by the overall rate of each transition direction from the observed data.

The second reported result is based on a similar analysis, but the library of transitions included only the hairs that underwent the same directional change dark-to-white in 3A; white-to-dark in 3B. The noise for uses of resampling was taken from hairs from the same subject after subtracting a smooth function, and resampling was done in segments of length increments to maintain proper temporal correlation patterns.

For Figure 3D, under the null hypothesis of no relationship between the hair intensity and stress pattern, each permutation involved choosing a random time point, splitting the stress pattern at that point and rejoining it by concatenating the two segments in the alternative order. To overcome the lack of methodology to map pigmentary states and age-related greying transitions, we developed an approach to digitize HPPs at high resolution across the length of single human HSs.

Using this methodology, similar to dendrochronology where tree rings represent elapsed years Douglass, , hair length reflects time, and the HS length is viewed as a physical time scale whose proximal region has been most recently produced by the HF, and where the distal hair tip represents weeks to years in the past, depending on the HS length. Three main pigmentation patterns initially emerged from this analysis: i Hairs with constant high optical density Dark , ii Hairs with constant low optical density White ; iii Initially dark hairs that undergo a sharp greying transition from dark to white over the course of a single growing anagen phase of the hair follicle growth cycle Transition Figure 1B—C.

Dark-to-white transitions demonstrate the existence of rapid depigmentation events within a single anagen hair cycle Paus and Cotsarelis, ; Slominski et al. The digitization of HPPs thus reflects the presence of melanosomes within the HS, and rapid greying events are marked by the loss of melanosomes. A Diagram illustrating hair growth over time, method of hair collection, digitization, and hair pigmentation pattern HPP methodology.

B Dark, white, and hairs undergoing natural age-related transitions from the younger dark state to the older white state at macroscopic and microscopic resolution. D Bright field microscopy images of hair follicles from plucked dark top-panel and white hair bottom-panel from the same Caucasian male individual illustrating the loss of pigmentation in the hair follicle pigmentary unit HFPU. E Electron microscopic images of dark top and white bottom scalp hairs from a Caucasian male showing absent melanin granules in white hairs.

I Overall electron density of the hair matrix excluding granules N. Proteins annotated as mitochondrial Mitocarta2. Red dots to the right of heatmaps indicate mitochondrial proteins. A Heatmap of down- and upregulated proteins across all dark and white hairs. Red dots to the left of heatmap indicate mitochondrial proteins, and B volcano plot of the hair proteome comparing white and dark hairs. C KEGG pathways functional enrichment analyses for upregulated and downregulated proteins.

Nodes are proteins, edges reflect evidence of PPI where the thickness reflects the strength of evidence for protein-protein interaction PPI. B Top gene ontology GO terms for the proteins shown in A , illustrating various cellular processes overrepresented in each gene set. Nodes are GO categories, edges reflect similarity between GO categories overlap in the genes that compose them.

The size and intensity of nodes reflect the significance in the enrichment score, respectively. Nodes are proteins, edges reflect evidence of PPI with the thickness reflecting to the strength of evidence. Nodes are GO categories, edges reflect similarity between GO categories based on overlap in genes, and size and intensity of nodes reflect the significance in the enrichment scores, respectively.

D KEGG functional annotation categories with enrichment p values. A—D Electron micrographs of a dark hair from a year-old Caucasian male with brown hairs. A variety of lamellar melanin granule melanosomes are shown. E Dense amorphous and uniform melanin granules coexist with lamellar melanosomes in the same hair. F—I Representative images of mitochondria from various tissues showing cristae structure not unlike what is typically ascribed as lamellar melanosomes in the hair.

Mitochondria from the mouse adrenal gland F , heart G , presynaptic bouton of the neuromuscular junction H , and skeletal muscle I are shown for illustrative purposes. On the basis of available evidence, it cannot be ruled out that some of the pigmented lamellar structures in the HS are remnants of mitochondria and mito-lysosomal hybrids.

To gain molecular insight into the greying process, we performed a comprehensive proteomic analysis comparing dark and white HS. Recent work suggests that depigmentation is associated with the upregulation of lipid synthesis enzymes in the HS Franklin et al. In addition, melanogenesis involves high levels of reactive oxygen species, but dark HFs are equipped with multiple antioxidant mechanisms e. Thus, the proteomic features of HSs may provide interpretable information about molecular changes associated HF greying.

Two independent experiments were performed. Compared to dark HS collected at the same time from the same individuals, white hairs contained several differentially enriched upregulated or depleted downregulated proteins Figure 1J—K see Supplementary file 1 for complete list on which we performed GO Gene Ontology and KEGG Kyoto Encyclopedia of Genes and Genomes enrichment analysis and explored their protein-protein interaction networks Figure 1—figure supplement 2.

Thus, coherent groups of functionally related proteins are differentially expressed in white hairs, from which two main patterns emerged. The first main pattern relates to protein biosynthesis and energy metabolism. A large fraction Upregulation of the machinery responsible for protein synthesis and amino acid metabolism included the ribosomal protein RPS15A, which is known to localize to mitochondria. Of all upregulated proteins in white hairs, The metabolic remodeling in white hairs is consistent with the established role of mitochondria and metabolic regulation of hair growth and maintenance in animal models Flores et al.

The upregulation of energy metabolism may subserve the likely increased energy demands in depigmented hairs. However, our data and those of others Franklin et al. A second less robust pattern relates more directly to melanosome biology. In line with the lysosomal origin of melanosomes that are largely absent in depigmented HS Slominski et al.

White hair shafts also showed a depletion of six main keratins see Figure 1—figure supplement 2 , likely because greying can affect the nature of keratinocytes proliferation Van Neste and Tobin, , of proteins associated with exocytosis, such as ITIH4 and APOH potentially involved in the secretion of melanosomes from melanocytes to keratinocytes , as well as proteins associated with mitochondrial calcium transmembrane transport.

Interestingly, calcium exchange between mitochondria and the melanosome is required for melanin pigment production in melanocytes Zhang et al. Finally, canities-affected white HFs also showed upregulation of antioxidant proteins, specifically those localized to mitochondria and cytoplasm superoxide dismutase 1, SOD1; peroxiredoxin 2, PRDX2 , in line with the role of oxidative stress in HS depigmentation Arck et al.

Alterations among these individual metabolic and mitochondrial enzymes were further reflected in KEGG pathways functional enrichment analyses indicating a significant enrichment of metabolic pathways including carbon metabolism and fatty acid synthesis, amino acids, and oxidative phosphorylation see below. To independently validate these results, we extended this analysis to white and dark HS from six individuals three males, three females, range: 24—39 years analyzed on a separate proteomic platform and in a different laboratory.

To examine the possibility that these relative upregulations are driven by a global downregulation of highly abundant housekeeping proteins, we analyzed the intensity-based absolute quantification iBAQ data for each sample. This confirmed that the housekeeping proteins, including keratins and keratin-associated proteins, were not downregulated in white hairs, but generally unchanged or slightly upregulated.

As in experiment 1, these upregulated pathways all indicate metabolic remodeling in white hair follicles. The downregulation of secretory pathways is again consistent with reduced transfer of pigmented melanosomes from the melanocytes to the keratinocytes. To verify the robustness of these findings using an alternative analytical approach, we built a simple partial least square discriminant analysis PLS-DA multivariate model, which provided adequate separation of white vs dark HS Figure 1—figure supplement 4.

Simple interrogation of this model to extract the features i. Interestingly, we also identified 13 proteins that were undetectable in any of the dark HS either not expressed, or below the detection limit , but consistently present in white HS Supplementary file 3. These proteins are either newly induced or experience a substantial upregulation with greying fold change tending toward infinity.

These converging proteomics data, which are consistent with previous findings Franklin et al. Moreover, given that metabolic pathways are rapidly and extensively remodeled by environmental and neuroendocrine factors — that is, they naturally exhibit plasticity — these data build upon previous proteomic evidence to show that human hair greying could be, at least temporarily, reversible. Our analysis of HPPs in healthy unmedicated individuals revealed several occasions whereby white hairs naturally reverted to their former dark pigmented state.

Here, we document the reversal of greying along the same HS in both female and male individuals, ranging from a prepubescent child to adults age range 9—39 years , and across individuals of different ethnic backgrounds 1 Hispanic, 8 Caucasian, 1 Asian. This phenomenon was observed across frontal, temporal, and parietal regions of the scalp Figure 2A , as well as across other corporeal regions, including pubic Figure 2B and beard hairs Figure 2C.

The existence of white HS undergoing repigmentation across ages, sexes, ethnicity, and corporeal regions documents the reversibility of hair greying as a general phenomenon not limited to scalp hairs. Nevertheless, we note that this phenomenon is limited to rare, isolated hair follicles. As their occurrence will probably go unnoticed in most cases, it is difficult to assess the true incidence of these repigmentation events. Over an active recruitment period of 2.

A Examples illustrating the reversal of greying along the length of scalp, B pubic, C , and beard human HSs. D Example of segmental HS with double transitions, including temporary greying and E temporary reversal from an adult and a child, respectively. See Figure 2—figure supplement 1 for additional examples and Video 1 for animation. F Time course diagram illustrating the progression of a single dark HS undergoing greying followed by reversal back to its original color, and G closely occurring events of greying and reversal occurring, producing HS with double transitions.

I and J are reported on a log 2 scale to facilitate visualization. A Examples of greying reversal in hairs with various rates of re-pigmentation in three adult individuals, including slow, medium, and rapid events of repigmentation. The left side shows actual photographs of hairs and the length over which each hair shaft regains pigmentation.

On the right are the corresponding hair pigmentation patterns HPPs for each hair and the computed slope reflecting the rate of greying reversal. C Examples of hairs undergoing the transition from dark to grey from a year-old female, year-old female, and year-old male. D Additional examples of hairs undergoing greying reversal from a year-old male, year-old female, and a year-old male.

E Additional examples of hairs with double transitions and reversions from a year-old female and a year-old female. Moreover, more complex HPPs with double transitions and reversions in the same HS were observed in both directions: HS undergoing greying followed by rapid reversal Figure 2D , and repigmentation rapidly followed by greying Figure 2E. Importantly, both patterns must have occurred over the course of a single anagen growth phase in the hair growth cycle, implicating cellular mechanisms within the HFPU.

Greatly extending previous case studies of these rare hair repigmentation events, the current study provides the first quantitative account of the natural and transitory reversibility of hair greying in humans. In double transition HS with three segments, repigmentation must take place within weeks to months after greying has occurred, producing three distinct segments present on the same hair strand Figure 2G.

Microscopic imaging along the length of a single HS undergoing a double transition greying followed by rapid reversal can be visualized in Video 1 , illustrating the dynamic loss and return of pigmented melanosomes within the same HS. A proposed mechanism for such repigmentation events involve the activation and differentiation of a subpopulation of immature melanocytes located in a reservoir outside of the hair follicle bulb in the upper outer root sheath Van Neste and Tobin, , or more likely from transient amplifying melanoblast cells that migrate along the outer root sheath to the interfollicular epidermis Birlea et al.

A greying transition followed by complete reversal in a single hair shaft, imaged from bulb to tip. Our hair digitization approach also provides the first estimates of the rates of change in pigmentation for HS covering a broad range of initial colors and darkness Figure 2H. The rate at which HS regain pigmentation during reversal was 0.

Thus, rather than drifting back toward the original color, repigmentation of white human HS occurs within the same time frame and at least as rapidly as the process of greying itself. The spectrum of greying transitions and reversals patterns observed in our cohort, including measured rates of repigmentation along individual hairs, is shown in Figure 2—figure supplement 1.

The HPP results establish the wide range of naturally occurring rates of pigmentary changes in single hairs, which vary by up to an order of magnitude from hair to hair. We then asked whether the reversal of greying is governed by a process that is unique to each human scalp HF or if it is likely coordinated by systemic factors that simultaneously affect multiple HFs.

In our combined cohort, three individuals had multiple two-colored hairs collected at either one or two collection times within a one-month interval. In each case, the multiple two-colored hairs originated from independent HFs separated by at least several centimeters e. If the hairs are independent from each other, the null hypothesis is that different HSs will exhibit either greying or reversal changes at different positions along each hair, and will have independent HPPs.

If multiple HSs were coordinated by some systemic factor, then we expect HPPs to exhibit similarities. In a first year-old female participant with dark brown hair, three two-colored hairs were identified at a single instance of collection. Notably, all three hairs exhibited dark-to-white greying. In A and B, simultaneously plucked dark and white hairs are plotted for reference. D HS from a year-old Asian female with 2 months of self-reported profound perceived stress associated with temporary hair greying and reversal.

Note the synchronicity between the increase in stress and rapid depigmentation i. Numbers 1 to 6 correspond to HS segments on D. H Trajectories of protein abundance from the top Component one and I Component two features across the six segments; proteins with positive top and negative loadings bottom are shown separately. Participants are asked to note the most and least stressful events over the past year Boxes 1 and 2 and mark them with a corresponding point on the scheme above.

Participants then indicate 2—6 noteworthy life events or periods over the past year and assign them scores ranging from most stressful to least stressful 10 and 0, respectively and mark them on the timeline. Participants then connect these events with a line. The stress graph is subsequently digitized and used in correlation analyses with hair pigmentation patterns HPPs as in Figure 3C and D.

A Abundance trajectories of the 20 proteins with lowest loadings on the PLS-DA model components 1 and 2, reflecting background protein composition not related to the greying process. The top KEGG categories enriched among these proteins is listed in the table.

C Protein-protein interaction networks STRING for background proteins with no loadings, component one proteins, and component two proteins, highlighting nodes relating to top GO cellular component or molecular function. Note the high number of proteins related to extracellular exosomes in background hair proteins, compared to proteins associated with hair greying. The molecular signature associated with component 2 reversal appears to show a re-enrichment for exosome and more closely resembles the non-specific proteins.

In a year-old female participant with brown hair, two transition hairs were identified. Thus, these findings extend previous reports in single isolated hairs by providing quantitative accounts of coordinated HS re pigmentation across multiple hairs. Candidate humoral hair pigmentation modulators that could create synchrony in greying or repigmenting hairs include neuropeptides, redox balance, and steroid or catecholamine hormones Hardman et al.

These factors must act in parallel with genetic factors that influence inter-individual differences in aging trajectories. Anecdotal case reports and a recent pilot study suggest that psychological stress and other behavioral factors accelerate the hair greying process Nahm et al. However, contrary to mice where this process appears to be irreversible at the single hair follicle level, our data demonstrates that human hair greying is, at least under some circumstances, reversible.

This dichotomy highlights a potential fundamental difference between rodent and human HF biology, calling for a quantitative examination of this process in humans. As evidence that environmental or behavioral factors influence human hair greying, epidemiological data suggests that smoking and greater perceived life stress, among other factors, are associated with premature greying Akin Belli et al.

Chronic psychosocial stress also precipitates telomere shortening, DNA methylation-based epigenetic age, as well as other biological age indicators in humans Epel et al. In relation to mitochondrial recalibrations, psychosocial factors and induced stress can also influence mitochondrial energetics within days in humans Picard et al. To generate proof-of-concept evidence and test the hypothesis that psychosocial or behavioral factors may influence greying at the single-HF level, we leveraged the fact that HPPs reflect longitudinal records of growth over time — similar to tree rings — which can be aligned with assessments of life stress exposures over the past year.

By converting units of hair length into time, perceived stress levels can be quantitatively mapped onto HPPs in both greying and transitional hairs. A systematic survey of two-colored hairs on the scalp of a year-old Caucasian male with auburn hair color over a 2-day period yielded five two-colored HS from the frontal and temporal scalp regions.

Again, two-colored hairs could either exhibit depigmentation or reversal. Unexpectedly, all HS exhibited reversal. HPP analysis further showed that all HS underwent reversal of greying around the same time period. We therefore hypothesized that the onset of the reversal would coincide with a decrease in perceived life stress. A retrospective assessment of psychosocial stress levels using a time-anchored visual analog scale participants rate and link specific life events with start and end dates, see Materials and methods and Figure 3—figure supplement 1 for details was then compared to the HPPs.

The reversal of greying for all hairs coincided closely with the decline in stress and a 1-month period of lowest stress over the past year 0 on a scale of 0—10 following a 2-week vacation Figure 3C. We were also able to examine a two-colored hair characterized by an unusual pattern of complete HS greying followed by rapid and complete reversal same as in Figure 2B plucked from the scalp of a year-old Asian female participant with black hair.

HPP analysis of this HS showed a white segment representing approximately 2 cm. We therefore hypothesized that this reversible greying event would coincide with a temporary increase in life stress over the corresponding period. Strikingly, the quantitative life stress assessment over the last year revealed a specific 2-month period associated with an objective life stressor marital conflict and separation, concluded with relocation where the participant rated her perceived stress as the highest 9—10 out of 10 over the past year.

The increase in stress corresponded in time with the complete but reversible hair greying Figure 3D. Given the low statistical probability that these events are related by chance, life stress is the likely preceding cause of these HS greying and reversal dynamics.

These data demonstrate how the HPP-stress mapping approach allows to examine the coordinated behavior of greying and reversal dynamics with psychosocial factors, raising the possibility that systemic biobehavioral factors may influence multiple HFs simultaneously and regulate HPPs among sensitive hairs. To assess whether rapid greying and reversal events among a single hair are molecularly similar or distinct to those described in the two proteomics experiments above, we dissected six segments two dark, two white, two reverted of the single HS in Figure 3D and quantified their proteomes as part of Experiment 2.

To examine how the proteome as a whole is altered through the greying and reversal transitions associated with psychosocial stress levels, we generated a PLS-DA model with all six segments. Both dark segments clustered together, with similar values on both first and second principal components. The white and reverted segments clustered in separate topological spaces Figure 3F. Greying was associated with a positive shift largely along the first component Component 1 , whereas reversal was associated with a negative shift on the second component Component 2 and a more modest negative shift in Component 1.

In contrast, a null set of hair proteins not contributing to either components exhibited enrichment for extracellular exosomes and cell-cell adhesion that reflect hair shaft biology Figure 3—figure supplement 2 , illustrating the specificity of our findings related to greying and reversal. These data indicate that the reversal of greying at the single-hair level is not associated with a complete reversal in the molecular composition of the HS.

Rather, some of the proteomic changes in hair greying are enduring despite successful repigmentation. B Venn diagram illustrating the intersection of datasets. The number of overlapping proteins across datasets that are either consistently down- or upregulated, or proteins not regulated in the same direction, are shown for each area of overlap. Fold difference values are the mean fold differences relative to dark hairs.

E Summary of significantly enriched KEGG categories across datasets, for upregulated left and downregulated right proteins. Four main clusters are highlighted and labeled by their top KEGG category. A Typical examples of pigmented dark , grey, and depigmented white plucked hair follicles, which include vital tissue from the precortical hair matrix and at least remnants of the hair follicle pigmentary unit HFPU imaged by light microscopy on freshly plucked HFs.

Note the absence of pigmented melanocytes in the white HF. Boxed regions show magnified versions for each hair type. B Mitochondrial and nuclear DNA abundance were quantified from the hair follicles of plucked dark and white hairs, like in A , from the same donors as the electron microscopy in Figure 1 were male African-American, male caucasian.

To rule out potential differences related to DNA abundance,10 follicles from each condition donor and color were pooled and included in a single PCR run right. Higher resolution version of Figure 4F. Correlation strengths and direction are color coded as indicated, and keratin proteins are marked with a green marker. To systematically examine the overlap among the different proteomic datasets and to derive functional insight into the hair greying process in humans, we then integrated results from the three datasets described above.

White HS show consistently more upregulated than downregulated proteins across datasets 2. This preferential upregulation suggests that the depigmentation process likely involves active metabolic remodeling rather than a passive loss of some pigmentation-related factor.

The overlap in the specific proteins identified across dark-white comparisons and among the 6-segments hair is illustrated in Figure 4B. Five proteins were consistently upregulated between experiments 1 and 2. These include three well-defined resident mitochondrial proteins involved in lipid metabolism: CPT1A, which imports fatty acids into mitochondria Schlaepfer and Joshi, ; ACOT7, which hydrolyzes long-chain fatty acyl-CoA esters in the mitochondrial matrix and cytoplasm Bekeova et al.

The other two proteins include the actin-depolymerizing protein cofilin-1 CFL1 and the core glycolysis enzyme phosphoglycerate kinase 1 PGK1 Figure 4C. Interestingly, beyond its role in cytoskeleton dynamics, CFL1 promotes mitochondrial apoptotic signaling via cytochrome c release Hoffmann et al. And although PGK1 is a cytoplasmic kinase, it was recently demonstrated to translocate inside mitochondria where it phosphorylates and inhibits pyruvate dehydrogenase and Krebs cycle activity Nie et al.

Thus, all five proteins validated across both experiments are linked to mitochondrial energy metabolism, implicating mitochondrial remodeling as a feature of hair greying. Interestingly, all five proteins have also been linked to the biology of melanocytes Bracalente et al.

The downregulated proteins were keratins, with small effect sizes, and not particularly robust. Analysis of the intensity based on absolute quantification iBAQ data confirmed the upregulation of these five mitochondrial proteins, and the absence of substantial changes in the keratins. Together, these data suggest that HS proteome profiling may provide a retrospective access to some aspect of melanocyte metabolism, which opens new possibilities to study HF aging biology.

Since the observed proteomic signatures are related to specific metabolic pathways rather than the typical high-abundance mitochondrial housekeeping proteins, we reasoned that the upregulation of these mitochondrial components unlikely reflects a bulk increase in total mitochondrial content.

The same was true in the follicles of the same hairs Figure 4—figure supplement 1. The similar mtDNA levels between dark and white HSs and HFs increases the likelihood that the reported proteomic changes reflect the induction of specific metabolic pathways associated with hair greying rather than bulk increase in mitochondrial mass.

To identify a general proteomic signature of greying hair, we compiled the enrichment scores for KEGG pathways across all datasets Figure 4E. Comparatively fewer pathways were consistently represented for downregulated proteins across independent experiments.

In relation to hair biology in general, our data adds to previous efforts Franklin et al. Computing the cross-correlations for each protein pair revealed four main clusters among the HS proteome Figure 4—figure supplement 2. As expected for hair, keratins were well-represented and constituted the main GO biological processes category for three of the four clusters. The top KEGG categories included glycolysis and estrogen signaling pathways, which also showed strong co-expression with each other, highlighting potential interaction among endocrino-metabolic processes in relation to human hair pigmentation.

In general, the identification of several non-keratin metabolism-related proteins in the HS opens new opportunities to investigate greying pathobiology and to non-invasively access past molecular and metabolic changes that have occurred in the aging HFPU of the dynamically growing hair. Finally, to narrow the range of plausible mechanisms for the observed age-related greying and reversal events, we developed a simulation model of HPPs.

In the absence of such data, we propose here a mathematical model to simulate hair greying trajectories across the human lifespan Figure 5A , available online, see Materials and methods for details as has been attempted previously for hair growth cycles Halloy et al.

As basic tenets for this model, it is established that i the onset of human hair greying is not yet underway and rarely begins in childhood, ii greying routinely starts between 20 and 50 years of age, iii greying is progressive in nature the total number and percentage of grey hairs increases over time , and iv the proportion of white hairs reaches high levels in old age, although some hairs can retain pigmentation until death, particularly among certain body regions Trueb and Tobin, Additionally, our findings demonstrate that v age-related greying is naturally reversible in isolated hair follicles, at least temporarily and in individual HS, and may be acutely triggered by stressful life experiences, the removal of which can trigger reversal.

A Schematic overview of the average greying process across the lifespan involving the gradual loss of pigmentation, or accumulation of white hairs, mostly in the second two-thirds of life. B Depiction of individual hairs each line is a hair, i from a linear mixed effects model with random intercept and slopes predicting hair greying.

The model assumes i a constant increase in a putative aging factor and ii a constant threshold above which hairs undergo depigmentation. All model parameters are listed in Supplementary file 4. D Frequency distributions of grey hairs for individuals with early left , average middle , or late right hair greying phenotypes. E Single hair-level and F hair population-level results from the addition of two acute stress periods each one year in duration, occurring at ages 20 and The optimized model accounts for stress-induced greying in hairs whose aging factor is close to the depigmentation threshold, but not for young hairs or those far away from the threshold.

Similarly, the removal of the stressor causes repigmentation of hairs when the aging factor returns below the threshold. A Example of HPP visualized as a heatmap, where dark red represents higher intensity pigmentation values units, black , and dark blue represented lower intensity pigmentation values 20 units, white. The boxed regions draw attention to some areas along the hair where there are minor changes in HPP, which are captured in the change in color on the heatmap.

B Diagram representing the four regions of the scalp from which hairs were systematically collected; temporal left TL and right TR , top, and crown. C Hair pigmentation analysis for hairs from an adult female individual top , and adult male individual bottom from the four head regions shown in B. Hairs are ordered by hierarchical clustering based on Euclidian distance, measuring the similarity of normalized hair pigmentation patterns.

Each hair is intensity normalized to reflect deviation from the mean of each hair. D Same hairs as in C, Male but arranged by head regions showing HPP of individual hairs left or averages for each head region right. E Average hair darkness pigmentation intensity arranged by head regions. Each datapoint is the average of a single hair. Alternative model examining the influence of stress on the age-related increase in the aging factor.

Compared to the successful model where stress causes a stepwise increase in the aging factor, in this model stress increases the slope in the aging factor during a stressful period, and removal of the stressor restores the initial slope of aging factor increase over time. For modeling purposes, the accumulation of the aging factor is equivalent to the inverse of the decrease in a youth factor e.

Based on the mosaic nature of scalp HFs and our data indicating that not all hairs are in perfect synchrony, the proposed model for an entire population of hairs must also allow a variety of aging rates, as well as differential sensitivity to stress among individual hairs. However, some individuals also develop hairs with intermediate pigmentation states i. This represents a limitation to be addressed in future research. A higher rate of accumulation of the aging factor higher slope for each hair or a lower threshold naturally accounts for earlier onset of greying.

In addition, our model reveals that within a person, greater hair-to-hair heterogeneity in the rate of aging between HFs, modeled as the standard deviation of slope across hairs, also influences the onset of greying. Greater heterogeneity between HFs allows for earlier onset of greying, whereas decreasing hair-to-hair variation i. Interestingly, this unpredicted result aligns with the notion that increased cell-to-cell heterogeneity is a conserved feature of aging Bahar et al.

Using parameter values that yield the average onset and rate of greying, we then simulated the influence of acute psychosocial stressors, either early in life before the onset of greying, or later once grey HSs have begun to accumulate. Similar to our data, the model also predicts transitory, or temporary reversible events of greying see Figure 3D. Transitory greying events do not affect all hairs, only those that are close to the threshold at the time of stress exposure undergo greying.

Hairs whose cumulative aging factors are substantially lower than threshold do not show stress-induced greying a 5-year-old is unlikely to get grey hairs from stress, but a year-old can Figure 5E—F. Similarly, grey hairs far above threshold are not affected by periods of psychosocial stress. Thus, our model accounts for both the overall hair greying dynamics across the lifespan, and how a stressor or its removal may precipitate or cause reversal of greying in hairs whose aging factor is close to the greying threshold.

Extending our high-resolution quantitative digitization approach to hundreds of randomly sampled dark non-transitioning hairs from different scalp regions in the same individuals, we also show that fully dark i. This may in part be influenced by the migration of stem cells during embryogenesis to different parts of the scalp, or by other unknown factors.

This preliminary extension of the HPP methodology provides a foundation for future studies. Moreover, the regional segregation of HPPs may reflect well-recognized regional differences in the rate of HS formation Robbins, Thus, future models may also be able to leverage information contained within HPPs from non-greying hairs and make specific inference from hairs collected across scalp regions.

Similar to how decoding temporal patterns of electroencephalography EEG provides information about the state of the brain, our data make it imaginable that decoding HPP analysis over time may provide information about the psychobiological state of the individual. Our approach to quantify HPPs demonstrates rapid greying transitions and their natural transitory reversal within individual human hair follicles at a higher frequency and with different kinetics than had previously been appreciated.

The proteomic features of hair greying directly implicate multiple metabolic pathways that are both reversible in nature and sensitive to stress-related neuroendocrine factors. Therefore, this result provides a plausible biological basis for the rapid reversibility of greying and its association with psychological factors, and also supports the possibility that this process could be targeted pharmacologically.

Melanogenesis is also known to both involve and respond to oxidative stress, a byproduct of mitochondrial metabolic processes Balaban et al. Moreover, alterations in energy metabolism are a major contributor to other disease-related aging features Kennedy et al. The upregulation of specific components related to mitochondrial energy metabolism in white hairs suggests that energy metabolism regulates not only hair growth as previously demonstrated Flores et al.

Approaches combining both high molecular and spatial resolution may be particularly informative Vyumvuhore et al. In vivo, exposing aged mice to young blood in parabiosis experiments Rebo et al. In human cells, quantitative biological age indicators such as telomere length Puterman et al. Moreover, the reversibility of greying in aging human HFs demonstrated by our data is also consistent with the observed reversibility of human skin aging in vivo when aged human skin is xenotransplanted onto young nude mice Gilhar et al.

Therefore, our HPP data and simulation model adds to a growing body of evidence demonstrating that human aging is not a linear, fixed biological process but may, at least in part, be halted or even temporarily reversed. Our method to map the rapid weeks to months and natural reversibility of human hair greying may thus provide a powerful model to explore the malleability of human aging biology within time scales substantially smaller than the entire lifespan.

A notable finding from both proteomics experiments is the bias toward up regulation rather than the loss of proteins in depigmented grey HS. As noted above, this may reflect the fact that hair greying is an actively regulated process within the HPFU, and that aging is not marked by a loss, but rather an increase in heterogeneity and biological complexity Bahar et al. Relative to the youthful state, quiescent and senescent cells exhibit upregulation of various secreted factors van Deursen, , as well as elevated metabolic activities Lemons et al.

Moreover, similar to the macroscopic appearance of hair greying, age-related senescence markers naturally occur stochastically for DNA methylation changes across the genome Franzen et al. Our data reveal that the conserved principle of an age-related increase in molecular and cellular heterogeneity is reflected not only at the tissue level mixture of dark and white hairs but also in the greying hair proteome.

Moreover, our proteomics results are also in line with recent reports of keratin-associated proteins that are downregulated in white vs dark hairs Giesen et al. Specifically, of a previously identified group of 50 potentially age-related, upregulated proteins in the HS Plott et al. Of these 16, 14 were similarly upregulated in depigmented white hairs relative to dark hairs from the same individuals in our dataset Supplementary file 2.

Further work will be required to determine if specific molecular aging processes, in specific cell types within the HF, account for the visible macroscopic instability of HFs greying on the human scalp. Here, we provided proof-of-concept evidence that biobehavioral factors are linked to human hair greying dynamics. Our optical digitization approach thus extends previous attempts to extract temporal information from human hairs and illustrate the utility of HPP profiling as an instructive and sensitive psychobiology research model.

Additional prospective studies with larger sample sizes are needed to confirm the robust reproducibility and generalizability of our findings. Visualizing and retrospectively quantifying the association of life exposures, stress-associated neuroendocrine factors, and HPPs may thus contribute to elucidating the mechanisms responsible for the embedding of stress and other life exposures in human biology.

The authors are grateful to Marko Jovanonic for advice on hair proteomics, Avsar Rana, David Sulzer, Erin Seifert, and Mary Elizabeth Sutherland for valuable input at different stages of this project, and to participants who donated hairs and time for this study. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Competing interests No competing interests declared.

Author contributions Data curation, Formal analysis, Visualization, Methodology, Writing - review and editing. Data curation, Formal analysis, Visualization, Writing - review and editing. Conceptualization, Data curation, Formal analysis, Writing - review and editing. Software, Formal analysis, Writing - review and editing, Developed the simulation model. Conceptualization, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing.

The last column indicates overlap with known mitochondrial proteins listed in MitoCarta 2. The fourth column indicates overlap with known mitochondrial proteins listed in MitoCarta 2. The fifth column indicates overlap with proteins that were found to be upregulated with increasing age of the donor Plott et al.

Proteins undetected in dark hairs but detected in white HS from three female and three male individuals. Because these proteins are undetected in dark hairs, the fold change is infinity. Model parameters, descriptions, and values used in simulation models shown in Figure 5. Default values in the online simulation match those of Figure 5E and F. Our editorial process produces two outputs: i public reviews designed to be posted alongside the preprint for the benefit of readers; ii feedback on the manuscript for the authors, including requests for revisions, shown below.

We also include an acceptance summary that explains what the editors found interesting or important about the work. This is an interesting and informative study reporting on the molecular features of reversible hair greying in humans and the connection with psychological stress. This work will set the stage for future mechanistic studies and represents an important conceptual and methodological advance.

Your article has been reviewed by 3 peer reviewers, including Matt Kaeberlein as the Senior and Reviewing Editor and Reviewer 1. The following individual involved in review of your submission has agreed to reveal their identity: Michael P Philpott Reviewer 2. The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.

The interpretation of the reported -omics changes remains somewhat superficial. A more in-depth discussion of the pathways found changed in the greying process would be appreciated. The data suggest changes in fatty acid metabolism with loss of pigmentation. Changes in fatty acid metabolism are associated with senescence. Did the authors detect any markers of senescence in their study?

This is an interesting and informative study reporting on the molecular features of reversible hair graying in humans and the connection with psychological stress. The study appears to have been very well conducted and the interpretations are generally supported by the data. While the results are primarily correlative at this stage, this work will set the stage for future more mechanistic studies and represents an important conceptual and methodological advance.

Further the data suggest changes in fatty acid metabolism with loss of pigmentation. Did the authors detect any markers of senescence in their study. The only weakness of the manuscript is that the interpretation of the reported omics changes remains somewhat superficial.

Of course, it would also be of interest to see a higher N in a number of the presented assays, however, the presented data appears to suffice the character of a pilot study aiming at the establishment of a new method by providing a very detailed analysis of individuals samples. Thank you for this suggestion to help strengthen the discussion of our results. We focused our discussion on the most robust and unambiguous results, which are somewhat limited given the challenge to extract and detect a fair number of protein from the resistant hair matrix.

We have expanded our discussion of the greying pathways in the discussion:. Excellent question. We agree that it would be valuable to detect stress hormones in parallel with the hair pigmentation pattern and proteomic changes at the single-hair level. To our knowledge, current methods require multiple milligrams of hair for analysis Sauve, Koren, Walsh, Tokmakejian, and Van Uum, and are only done on bulk hair material, rather than on single hairs.

Therefore, it was not possible given existing technology to capture this kind of data longitudinally along single hairs. However, although not a direct marker of senescence, previous work has showed that HF aging is associated with a marked decline in 2 hair keratins and 7 keratin-associate proteins KAPs Giesen et al. We now briefly mention these findings in the manuscript, but the downregulation for some of these proteins was not very robust, as we previously mentioned in the manuscript p.

Our data comparing white to dark hairs showed that 14 of the reported upregulated proteins were also upregulated in the white hairs in our second proteomic experiment. We have added a column to Supplementary file 2 to indicate which of the proteins that we detected were also found to be upregulated in the older hairs in the Plott et al.

In our view, these findings should be regarded as converging but not definitive evidence, and additional studies in both hair shafts and follicles are needed, using canonical markers of senescence. Thank you for a thoughtful review. As discussed above, there are currently no available method to examine stress hormones at this resolution see above response to Essential Revisions 2 — but this would be a terrific addition for future experiments.

We have now integrated this important suggestion into the closing statement of the revised Discussion p. Excellent point. As explained above see above response to Essential Revisions 3 , the observed changes in protein abundance related to fatty acid metabolism FASN, CPT1a are entirely consistent with a pro-senescence state. However, our proteomics results did not contain any canonical senescence marker. We now discuss this in detail on p.

Thank you for this recommendation. In addition, we clearly acknowledge in the revised Discussion that a higher n of investigated individuals and hair shafts, namely in the proteomics and hair pigmentation profiling, is needed to confirm robust reproducibility of our findings p. Fafian-Labora, J. O'Loghlen, A. FASN activity is important for the initial stages of the induction of senescence.

Cell Death Dis, 10 4 , Flores, A. Lowry, W. Lactate dehydrogenase activity drives hair follicle stem cell activation. Nat Cell Biol, 19 9 , Giesen, M. Ageing processes influence keratin and KAP expression in human hair follicles. Exp Dermatol, 20 9 , Mancino, G. Dentice, M. Plott, T. Rice, R. Forensic Sci Int Genet, 47, Sauve, B. Measurement of cortisol in human hair as a biomarker of systemic exposure. Clin Invest Med, 30 5 , E Seok, J. Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells.

Stem Cell Res Ther, 11 1 , 1. Tang, L. Aging Albany NY , 11 24 , Vidali, S. Paus, R. Hypothalamic-pituitary-thyroid axis hormones stimulate mitochondrial function and biogenesis in human hair follicles. J Invest Dermatol, 1 , Vyumvuhore, R. Investigation of the molecular signature of greying hair shafts.

Int J Cosmet Sci. Published online Jun Ralf Paus 7 Dr. Author information Article notes Copyright and License information Disclaimer. Martin Picard: ude. Received Feb 16; Accepted May This article is distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use and redistribution provided that the original author and source are credited. See commentary " Watching hair turn grey " in volume 10, e This article has been cited by other articles in PMC.

Figure 1—figure supplement 1—source data 2: Source data for Figure 1—figure supplement 1. Figure 1—figure supplement 4—source data 1: Source data for Figure 1—figure supplement 4. Figure 2—source data 1: Source data for Figure 2. Figure 2—figure supplement 1—source data 1: Source data for Figure 2—figure supplement 1.

Figure 3—source data 1: Source data for Figure 3. Figure 3—figure supplement 2—source data 1: Source data for Figure 3—figure supplement 2. Figure 4—source data 1: Source data for Figure 4. Figure 4—figure supplement 1—source data 1: Source data for Figure 4—figure supplement 1. Figure 5—figure supplement 1—source data 1: Source data for Figure 5—figure supplement 1. Supplementary file 1: Proteomic changes in greying hairs from experiment 1. Supplementary file 2: Proteomic changes in greying hairs from experiment 2.

Supplementary file 4: Parameters used in hair greying simulation models. Transparent reporting form. Abstract Background: Hair greying is a hallmark of aging generally believed to be irreversible and linked to psychological stress. Methods: Here, we develop an approach to profile hair pigmentation patterns HPPs along individual human hair shafts, producing quantifiable physical timescales of rapid greying transitions.

Conclusions: Overall, this new method to quantitatively map recent life history in HPPs provides an opportunity to longitudinally examine the influence of recent life exposures on human biology. Research organism: Human. Introduction Hair greying is a ubiquitous, visible, and early feature of human biological aging O'Sullivan et al.

Hair imaging Whole hairs were first photographed using a Panasonic DC-FZ80 Digital Camera against a white background, with the hair tip and follicle systematically oriented. Electron microscopy Dark and white scalp hairs were plucked from two healthy individuals: a year-old African-American male and a year-old Caucasian male. Hair shaft proteomics The protocol in both experiments 1 and 2 for hair digestion were adapted from a previous protocol establishing that SDS-based protein extraction methods result in higher protein yield than urea-based digestion Adav et al.

Experiment 1 For label-free quantitative proteomics, a 2 cm segment of plucked dark and white HS matched for distance relative to the follicle end was isolated from one female and one male participant. Retrospective assessments of life events and stress A subset of participants with noteworthy patterns of single-hair greying and reversal were asked to complete a retrospective stress assessment Figure 3—figure supplement 1 , completed 1—4 months after hair collection in two individuals one male, one female.

Results Mapping HPPs To overcome the lack of methodology to map pigmentary states and age-related greying transitions, we developed an approach to digitize HPPs at high resolution across the length of single human HSs. Open in a separate window. Figure 1. Quantitative analysis of human hair pigmentation patterns, greying, and associated proteomic changes. Figure 1—source data 1.

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