The X-Chromosome Has a Different Pattern of Gene Expression in Women Compared With Men With Ischemic Stroke
Background and Purpose—Differences in ischemic stroke between men and women have been mainly attributed to hormonal effects. However, sex differences in immune response to ischemia may exist. We hypothesized that differential expression of X-chromosome genes in blood immune cells contribute to differences between men and women with ischemic stroke.
Methods—RNA levels of 683 X-chromosome genes were measured on Affymetrix U133 Plus2.0 microarrays. Blood samples from patients with ischemic stroke were obtained at ≤3 hours, 5 hours, and 24 hours (n=61; 183 samples) after onset and compared with control subjects without symptomatic vascular diseases (n=109). Sex difference in X-chromosome gene expression was determined using analysis of covariance (false discovery rate ≤0.05, fold change ≥1.2).
Results—At ≤3, 5, and 24 hours after stroke, there were 37, 140, and 61 X-chromosome genes, respectively, that changed in women; and 23, 18, and 31 X-chromosome genes that changed in men. Female-specific genes were associated with post-translational modification, small-molecule biochemistry, and cell–cell signaling. Male-specific genes were associated with cellular movement, development, cell-trafficking, and cell death. Altered sex specific X-chromosome gene expression occurred in 2 genes known to be associated with human stroke, including galactosidase A and IDS, mutations of which result in Fabry disease and Hunter syndrome, respectively.
Conclusions—There are differences in X-chromosome gene expression between men and women with ischemic stroke. Future studies are needed to decipher whether these differences are associated with sexually dimorphic immune response, repair or other mechanisms after stroke, or whether some of them represent risk determinants.
Clinical and epidemiological evidence suggests that ischemic stroke (IS) risk, etiology, response to treatment, and outcome are different between men and women. Females tend to have more cardioembolic stroke and men more arterial and lacunar stroke.1,2 Differences in response to thrombolysis and functional outcome may also exist between the sexes.1–3
The sex differences in IS have frequently been attributed to hormonal differences, including estrogen, progesterone, and testosterone.4–6 However, some X-linked diseases can affect the brain, clotting, and the immune response independent of hormonal effects such as Fragile X, hemophilia, and Fabry disease. Thus, we sought to determine whether there is sex-specific expression of genes on the X-chromosome after IS.
The human X-chromosome has many features that are unique in the human genome.7–9 Females inherit 1 X-chromosome from each parent, whereas males inherit a single, maternal X-chromosome. Gene expression on 1 of the female X-chromosomes is silenced during development by X-chromosome inactivation. However, for X-chromosome inactivation “escapees” (15%–25% of the X-chromosome genes), differential expression as well as developmental reactivation of the inactive copy have been reported.10 In males, the short tips of the X-chromosome can recombine with the equivalent segments on the Y-chromosome (pseudoautosomal regions). Genes outside these regions of the X-chromosome are strictly X-linked and most do not have homologs on the Y-chromosome. There are homologous genes on the X-chromosome, outside of the pseudoautosomal regions, but their functional similarity to the Y-chromosome paralogs is unclear. X/Y paralogs have a sex-specific pattern of expression, which suggests these paralogs may not have equivalent functions.11
Using RNA isolated from men and women with acute IS, we determined the expression pattern of X-chromosome genes in each sex. The different patterns of X-chromosome expression in women compared with men provide insight into the sexually dimorphic immune responses to IS.
Materials and Methods
Subjects with acute IS (n=61; 183 samples) were recruited through the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR) trial, a multicenter, randomized, double-blind safety study of recombinant tissue-type plasminogen activator (rtPA) and eptifibatide12 (NCT00250991 at Clinical-Trials.gov). The Institutional Review Board at each site approved the protocol and informed consent was obtained before study entry. Eligible patients had a diagnosis of acute IS, therapy (either standard-dose rtPA alone or combined low-dose rtPA plus eptifibatide) initiated within 3 hours of stroke onset, and a National Institutes of Health Stroke Scale >5. The first blood sample (at <3 hours) was drawn before any treatment. After treatment, 2 blood samples were drawn at 5 hours and 24 hours after the onset of the stroke.
The control group (n=109) was composed of subjects with no history of symptomatic vascular disease. Subjects were recruited from Wake Forest University Baptist Medical Center (Dr C. Bushnell), University of Cincinnati, University of California–Davis, and University of California–San Francisco.
RNA and Array Processing
Whole venous blood was collected into PAXgene tubes (PreAnalytiX) and RNA processed as previously described.13 Whole blood contains different cell types. Thus, RNA was derived primarily from leukocytes–polymorphonuclear leukocytes (neutrophils, basophils, and eosinophils) and agranulocytes (lymphocytes, monocytes, and macrophages) as well as from immature red blood cells and immature platelets. Each RNA sample was hybridized on Affymetrix Human U133 Plus 2.0 GeneChips (Affymetrix, Santa Clara, CA).
Raw expression values (probe level data) were imported into Partek software (Partek Inc, St Louis, MO). They were log-transformed and normalized using Robust Multichip Average and our previously reported internal gene normalization method.14 All statistical analyses were performed using Partek Genomics Suite 6.04.
X-Chromosome Probe Sets
There are 1384 X-chromosome probe sets on the Affymetrix U133 Plus 2.0 expression array. We filtered out probe sets annotated as x_at and s_at because they can crosshybridize and are less specific. This resulted in 888 probe sets corresponding to 638 X-chromosome genes.
We adopted an analytic approach to decrease bias related to hormonal differences between the sexes. Females with stroke were compared with female control subjects without stroke and males with stroke were compared with male control subjects without stroke. This approach was adopted because it is the only way to examine the expression of the X-chromosome genes in females without any contribution from males and vice versa. In addition, a number of X-chromosome genes escape inactivation; thus, the dosage in the 2 sexes may not be equivalent. In addition, expression of X/Y paralogs may differ because several studies suggest higher expression of X-chromosome genes of the X/Y paralogs.10,15 Once the X-chromosome genes regulated in females and males were identified, then these were compared with identified stroke-induced, sex-related differential expression of genes on the X-chromosome.
Using this approach, the analyses addressed changes of gene expression at each time point (Objective 1) and across time points (Objective 2). For Objective 1, an analysis of covariance identified genes whose expression pattern indicates significant sex-by-diagnosis interaction in blood of patients with IS at ≤3 hours (untreated), 5 hours (treated), and 24 hours (treated) after IS compared with nonstroke control subjects (separate analyses for females and males). Gene expression was analyzed as a function of diagnosis, age, sex, and batch and included a sex-by-diagnosis interaction. Genes with Benjamini-Hochberg false discovery rate-corrected P≤0.05 (multiple comparison correction) and fold change ≥1.2 were considered differentially expressed. A fold change cutoff was added (in addition to false discovery rate-corrected probability value) based on our power analysis, which showed we can detect an effect size (fold change) of 1.2 with significance (α)=0.05 and power (β)=0.8. Objective 1 is based on same-sex comparisons of patients with IS versus control subjects at each time point.
For Objective 2, a mixed-model analysis of variance identified differences in the temporal X-chromosome gene expression after IS for females and males separately. Gene expression was analyzed as a function of subject, sex, time, and batch with a sex-by-time interaction. The same significance criteria were used: Benjamini-Hochberg false discovery rate-corrected P≤0.05 and fold change ≥1.2. Objective 2 was performed using the same-sex comparisons of patients with IS between time points.
Regulated genes from the separate same-sex analyses of females and males from these analyses were then compared. The male and female-specific stroke genes expressed on the X-chromosome derived from the nonoverlapping gene lists for each objective are reported and discussed.
Gene Ontology Classification and Cytoband Overrepresentation
Gene ontology and Kyoto Encyclopedia of Genes and Genomes databases were used to classify the differentially expressed genes (http://david.abcc.ncifcrf.gov). An EASE score (modified Fisher exact maximum probability) ≤0.1 was used to identify statistically significant cytoband enrichment.
There were no significant differences in the age between male and female IS subjects as well as between male and female control subjects (P=0.91 and P=0.62, respectively). There was a significant difference in the age of IS and control males as well as between IS and control female subjects (P<0.05; Table 1). There were no significant differences in the race distribution between male control and male IS subjects as well as female control and female IS subjects (P=0.49 and P=0.38, respectively). There was a significant difference in the race distribution of IS male and IS female subjects (P=0.01; Table 1). There were no significant differences between the vascular risk factors in male and female IS subjects: Type II diabetes mellitus (P=0.80), hypertension (P=0.13), atrial fibrillation (P=0.27), and hyperlipidemia (P=0.77). Similarly, there were no significant differences in stroke etiology (P=0.33), prior stroke (P=0.35), or myocardial infarction (P=0.32; data not presented).
Sex-Specific Gene Expression Differences at <3 Hours in Patients With IS Compared With Control Subjects
At <3 hours after IS, there were 14 upregulated and 23 downregulated female-specific X-chromosome genes represented by 16 and 26 probe sets, respectively (Figure 1A; Supplemental Table I; http://stroke.ahajournals.org). There were 18 upregulated and 5 downregulated male-specific X-chromosome genes (22 and 6 probe sets, respectively; Figure 1A; Supplemental Table I).
To identify differentially expressed genes that cluster in specific defined chromosomal locations, we performed cytoband-enrichment analysis. This would reveal whether there is a clustering of differentially expressed genes for each of the gene lists. In addition, by identifying the cytobands, it is possible to relate the findings of this study to previous and future linkage and genomewide association studies using query databases such as the Cytoband Query System.16 Cytoband overrepresentation is shown in Table 2 and Supplemental Table II. Notably, there are nearly as many upregulated X-chromosome genes common for females and males as there are unique for each sex (Figure 1). The genes common to females and males in Figure 1A–C are provided in Supplemental Tables I, III, and IV but are not discussed because they are not unique for either sex.
Because racial background could affect gene expression, we used an alternative model for both objectives in all of the analyses, in which race was included as an additional covariate in the analysis of covariance models. Among the sex-specific genes reported here, the expression of 7 X-chromosome, stroke-regulated genes was affected by race. However, they were also significant for the sex–stroke diagnosis interaction. No genes affected by age were among the reported sex-specific genes.
Hormone replacement therapy or other hormone-containing compounds can affect gene expression. We had hormone replacement therapy status/hormone medication information recorded for all females with IS (n=23 not on hormone medication, n=3 on hormone medication). However, it was recorded only for some of the female control subjects (n=29 not on hormone medications, n=5 on hormone medications; n=34 hormone medication status unknown). To address the question of a possible influence of hormone-containing compounds on gene expression in this study, we performed a subanalysis on the females with known hormone medication status, including hormone medication as a dichotomous variable in the analysis of variance model. The effect of hormone medication as well as the interaction between hormone medication and group on the sources of variation in gene expression was very small, much smaller than the effect of group (IS female versus control female) itself (Supplemental Figure I). In addition, none of the differentially expressed genes between females on hormone medications and on no hormone medications are among the ones in our female-specific stroke gene lists.
The main analysis in our article was performed by using all of the available samples to maximize sample size at the same time as accounting for confounders by including them in the analysis of covariance model. This resulted in the ratio of control subjects to IS being different in the female population (68 control subjects/26 IS, a ratio of 2:62) compared with the male population (41 control subjects/26 IS, a ratio of 1:17), which can bias the results. Thus, we performed a subanalysis, in which we matched 26 IS males, 26 control males, and 26 control females with the smallest sample size we had of 26 IS females. The matching was performed based on age, race, and risk factors. The only significant difference was age (P=0.003 between IS and control females), which was discussed in the main analysis approach and results. The results of this subanalysis are presented in Supplemental Tables IXA (3hIS versus control), XA (5hIS versus Control), and XIA (24hIS versus Control). The overlapping genes of both analyses are presented in Supplemental Tables IXB (for 3hIS versus Control), XB (for 5hIS versus Control), and XIB (for 24hIS versus Control). The overlap of the genes between the 2 analyses was statistically significant (P<0.05; binomial probability test performed in Stata) for each comparison. The relative number of genes regulated in females compared with males at each time point in the subanalysis (Supplemental Figure II) was very similar to the all-samples analysis (Figure 1). The genes we focused on in the “Discussion” were regulated in both analyses.
Sex-Specific Gene Expression Differences in 5 Hours and 24 Hours in Patients With IS Compared With Control Subjects
At 5 hours after IS, there were 55 upregulated and 85 downregulated female-specific X-chromosome genes (65 and 106 probe sets, respectively; Figure 1B; Supplemental Table III). There were 16 upregulated and 3 downregulated male-specific X-chromosome genes (21 and 4 probe sets, respectively; Figure 1B; Supplemental Table III). Cytoband overrepresentation is shown in Table 2 and Supplemental Table II. At 24 hours after IS, there were 55 upregulated and 6 downregulated female-specific X-chromosome genes (60 and 6 probe sets, respectively; Figure 1C; Supplemental Table IV). There were 19 upregulated and 12 downregulated male-specific X-chromosome genes (28 and 13 probe sets, respectively; Figure 1C; Supplemental Table IV). Cytoband overrepresentation is presented in Table 2 and Supplemental Table II. DHRSX and SPRY3 are located in the pseudoautosomal regions and thus the contribution to the observed expression level of the X- and the Y- homologs in males cannot be distinguished for the 24 hours IS versus control subjects.
Several members of the melanoma antigen family (MAGE) gene family (MAGEA8, MAGEB18, MAGEB6, MAGEC1, MAGED1, MAGEE1, MAGEH1) had female-specific expression after IS.
Temporal Sex-Specific Gene Expression Differences in Patients With IS
The second objective was to examine changes in gene expression over time in female and male patients with IS. No X-chromosome genes changed expression in males from 3 hours to 5 hours after the onset of the IS. In females, however, there were 5 upregulated X-chromosome genes (REPS2, TLR8, BMX, ODZ1, and MSL3L1) and 5 downregulated X-chromosome genes (7 probe sets; SEPT6, TSPYL2, ZNF275, MAGED1, and LOC550643; Figure 2; Supplemental Table V).
There were many more changes of gene expression from 5 hours to 24 hours in females compared with males (Figure 3; Supplemental Table VI). There was female-specific upregulation of 98 X-chromosome genes (117 probe sets) and downregulation of 16 genes (18 probe sets). In contrast, only the IDS gene showed a male-specific change (decrease) of expression between 5 hours and 24 hours poststroke (Figure 3; Supplemental Table VI).
Between 3 hours and 24 hours poststroke, there were no X-chromosome genes that showed male-specific expression changes (Figure 4). There were 29 upregulated X-chromosome genes (31 probe sets) and 1 downregulated gene (LOC100287428) with a female-specific expression pattern (Figure 4; Supplemental Table VII). Cytoband overrepresentation is presented in Table 2 and Supplemental Table II.
Biological sex affected X-chromosome gene expression in blood after IS. Although some of the X-chromosome gene expression changes were identical in both sexes, some were unique to males or females. These findings suggest that the X-chromosome contributes to differences that exist between men and women with IS. Although a number of the biological processes presented subsequently have been implicated in playing a key role in the response to stroke, most of the individual genes have not been associated with vascular risk factors or stroke nor have their sexually dimorphic patterns of expression been suggested in human studies.
Sexually Dimorphic X-Chromosome Gene Expression at <3 Hours in Patients With IS Compared With Control Subjects
Some molecular mechanisms of neuronal cell death and survival after ischemia are different in males compared with females.5 This may apply to the immune system and the results of this study as well. In addition, crosstalk between the brain and adaptive and innate immunity is highly relevant for tissue damage, systemic inflammation, and regeneration after stroke.17 We observed female-specific expression of X-chromosome genes involved in natural killer cell signaling, TNFR1 signaling and axon guidance, transforming growth factor-β signaling, and IL17 signaling (tissue inhibitor of matrix metalloproteinase-1). Tissue inhibitor of matrix metalloproteinase-1, upregulated in females at 3 hours and 5 hours after IS, is an inhibitor of the matrix metalloproteinases. Matrix metalloproteinase-9, which is expressed in neutrophils, degrades extracellular matrix and basal lamina, which disrupts the blood–brain barrier after stroke.17 Tissue inhibitor of matrix metalloproteinases also promote cell proliferation, can have antiapoptotic functions and at least tissue inhibitor of matrix metalloproteinase-1 may be neuroprotective during cerebral ischemia.17
The expression of cytokines, chemotactic factors, and adhesion molecules modulates leukocyte–endothelial interactions.17 After stroke, there was a male-specific downregulation after stroke of EFNB1, which is a ligand of Eph-related receptor tyrosine kinases. It plays a role in cell adhesion, nervous system development, axon guidance, and regulation of T cell proliferation. Male-specific upregulation after stroke was noted for CYSLTR1, which is involved in cell-mediated immune response, chemotaxis, and T cell migration; and for IGBP1, which is involved in proliferation, cell–cell interaction, and differentiation of B cells.
Female-specific upregulation occurred at 3 hours after IS for DDX3X (DEAD [Asp-Glu-Ala-Asp] box polypeptide 3, X-linked). DDX3X is involved in translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly, which are disrupted early after brain ischemia. Many of these sex effects on expression of X-chromosome genes are probably related to differences associated with IS. These changes are occurring within the therapeutic window for treatment intervention and, as such, might preferentially guide the search for future sex-based acute stroke treatment.
Sexually Dimorphic X-Chromosome Gene Expression at 5 Hours and 24 Hours in Patients With IS Compared With Control Subjects
Recent studies demonstrate that some ischemic cell death pathways may differ in the male and female brain. Females are sensitive to caspase-mediated cell death, whereas males are more sensitive to other cell death pathways, including those involved with apoptosis-inducing factor and poly(ADP-ribose) polymerase activation.18 Female-specific regulation at 5 hours after stroke was observed for genes that may be involved in caspase-related apoptosis: IKBKG, which encodes the regulatory subunit of the inhibitor of kappaB kinase, complex and PRKX, a protein kinase, X-linked.
Galactosidase A showed female-specific upregulation at 5 hours after stroke as compared with control subjects, whereas male-specific upregulation occurred at 24 hours after stroke as compared with control subjects. Galactosidase A mutations cause Fabry disease, a rare lysosomal storage disorder. It leads to damaged vascular endothelium and is 1 of the rare single gene disorders of large and small vessel stroke. Another X-linked disorder associated with stroke involves mutations of the IDS gene, which is required for lysosomal degradation of heparin sulfate and dermatan sulfate. Indeed, IDS exhibited male-specific expression from 5 hours to 24 hours (downregulated) after stroke. Mutations of IDS cause recessive X-linked mucopolysaccharidosis Type II (Hunter syndrome), which is associated with IS. Whether the sex differences of GALA and IDS expression in leukocytes relate to sex differences in response to stroke is unknown. However, genetic dysfunction of both genes is known to be associated with stroke in males.
Toll-like receptor (TLR) signaling has been shown to play an important role in stroke and preconditioning and serves as a link between the central nervous system and periphery after stroke.19 In this study, male-specific up-regulation of TLR7 occurred at 24 hours after IS. TLR8 was upregulated in IS versus controls at all time points in both males and females. TLR8 was similarly expressed in males at all time points, whereas TLR8 increased expression from 3 hours to 5 hours and then plateaued at 5 hours to 24 hours in females. TLR8, and related TLR7 and TLR9, recognize pathogen-derived nucleotides in intracellular compartments. TLR7 and TLR9 respond to host-derived nucleotides as well and have been implicated in a variety of autoimmune diseases. In the context of stroke, it is notable that TLR8 is expressed in males and females and TLR7 is male-specific, possibly contributing to sex-specific immune and possibly autoimmune differences associated with IS.
Monoamine oxidase A displayed female-specific upregulation after stroke at all time points when compared with control subjects. Monoamine oxidase B showed female-specific upregulation only at 24 hours. Monoamine oxidase A is involved in dopamine, norepinephrine, and serotonin metabolism. Monoamine oxidase B catalyzes the oxidative deamination of biogenic and xenobiotic amines and metabolizes neuroactive and vasoactive amines, particularly dopamine. These findings show differences of catecholamine genes induced in females compared with males after IS and might point in differences of the stress response in the 2 sexes after IS.
The MAGE family of genes was also specifically regulated in females after IS. These are members of the cancer/testes antigen group, which is disproportionately represented on the X-chromosome. They are characterized by their expression in a number of cancer types, whereas their expression in normal tissue is mainly reported in testes. They have been proposed as targets for immunosuppressive therapy.20 Their female-specific differential expression may suggest their involvement in the female-specific stroke-related differences in the periphery to ischemic brain injury and/or interaction with the thrombolytic treatment.
There were several female-specific X-chromosome genes whose expression peaked at 5 hours and decreased at 24 hours, including BMX, ODZ1, and REPS2. BMX is involved in the regulation of proliferation, differentiation, motility, and apoptosis including the differentiation of endothelial cells and formation of the blood–brain barrier. This could suggest that molecules expressed in inflammatory cells interact with endothelial cells to affect the blood–brain barrier in a sex-specific manner.
The gene expression patterns over time are important for interpreting the results of this study. Genes expressed within the first 3-hour time window are among the most interesting because they are unaffected by treatment and are being induced during the time when acute stroke therapy is likely to be beneficial. Genes that change expression in the 3- to 5-hour time period might be those most likely to be affected by treatment because treatment was initiated after the first blood sample but before 3 hours after stroke. Genes expressed at 24 hours likely represent the full complement of the immune cell changes associated with cell death, cellular phagocytosis as well as in the beginnings of repair. The effects of tPA can be short and long term.21 Our animal tPA studies show that some genes regulated after IS can be related to the tPA itself rather than to stroke.22 Thus, a number of genes regulated at 5 and 24 hours could represent changes produced by the IS, treatment, or an interaction of sex, stroke, and treatment.
Limitations and Conclusions
Because patients at the 5 hours and 24 hours time points were treated, the observed sex-specific differences in the expression of X-chromosome genes may be due, at least in part, to interaction with the treatment at these times. There were differences in the age and race for some of the comparisons. However, inclusion of these factors as covariates in the analysis of covariance models demonstrated that the identified sex-specific changes of gene expression on the X-chromosome after stroke were independent of age and race. There was an unbalanced distribution of IS and control samples between the male and female cohorts, which could bias the analysis. A subanalysis of matched sample sets revealed a similar pattern in male- versus female-regulated genes to the pattern observed in the all-samples analysis. Given the demographic differences and the multiple comparisons made, however, a follow-up study is needed to confirm the findings. Future studies investigating gene expression in specific blood cell types are needed to refine gene expression changes in individual cell types. Hormone medication status was not recorded on all of the female subjects in the study. Thus, some of the female-specific genes may be due to hormone medication differences. However, our subanalysis on the female subjects with known hormone medication status as well as the fact that there were a significant number of genes that changed expression over time after stroke argues in favor that most of the observed differences are sex–stroke-related. Due to the case–control design of the study, causality cannot be determined. In addition, because demographic variables were not precisely matched in the IS and control groups, even with the analysis designed to minimize the effect of these differences, it is not possible to be absolutely sure that any given gene was not overexpressed before stroke in the patients with IS compared with the matched control subjects. However, similar to the previous argument, the fact that the expression of many differentially expressed genes changed over time supports the hypothesis that many are sex–stroke genes. This study examines the transcript levels, which may or may not relate to the rate of transcription as measured by promoter strength or to changes in protein levels due to post-transcriptional regulation. A study with a larger population size is needed to decipher the relevance of the observed gene expression differences in terms of outcome.
Because a majority of these genes have not been previously implicated in stroke, it is difficult to know whether the novel sexually dimorphic expression differences reported here affect outcomes differently in the 2 sexes. However, determining the mechanisms of sexually dimorphic pathophysiology, etiology, and outcome in IS is important, because the findings could eventually guide development of sex-specific treatments.
Sources of Funding
This study was supported by National Institutes of Health grants (F.R.S., A.P., E.C.J., J.P.B.) and the American Heart Association Bugher Foundation (F.R.S.).
J.P.B. received non-National Institutes of Health (NIH) support from Genentech, Schering Plough, PhotoThera, and Oakstone Medical Publishing. A.P. received non-NIH support from Research Grant EKR Therapeutics, Genentech, and Schering Plough.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.629337/-/DC1.
- Received June 15, 2011.
- Revision received September 21, 2011.
- Accepted September 23, 2011.
- © 2012 American Heart Association, Inc.
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- Materials and Methods
- Sexually Dimorphic X-Chromosome Gene Expression at <3 Hours in Patients With IS Compared With Control Subjects
- Sexually Dimorphic X-Chromosome Gene Expression at 5 Hours and 24 Hours in Patients With IS Compared With Control Subjects
- Limitations and Conclusions
- Sources of Funding
- Figures & Tables
- Supplemental Materials
- Info & Metrics
- Materials and Methods
- Limitations and Conclusions
- Sources of Funding
- Figures & Tables
- Supplemental Materials
- Info & Metrics