bluuebunny/crossref_metadata_2025_split huggingface dataset:
0022 Klotho Genetic Variants Mediate the Association Between Obstructive Sleep Apnea and Short Telomere Length
Authors: Tempaku P F , D’Almeida V , Andersen M L , Belangero S I , Tufik S 
Published: May 2020

Abstract

Introduction
The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Among these factors, klotho reduction can contribute since it is associated with accelerated systemic inflammation and oxidative stress and has recently been associated with OSA. Also, decreased levels of klotho are implicated in the regulation of telomerase activity. Therefore, we aimed to evaluate the effect of common genetic variants (SNPs) on KLOTHO gene on the association between OSA and short telomere length.

Methods
As part of the Sao Paulo Epidemiologic Sleep Study cohort, 1,042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI equal or greater than 15 events per hour. Leukocyte telomere length (LTL) was measured through qPCR and SNPs were genotyped by microarray.

Results
LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B=0.055, CI=0.007–0.102, p=0.02). Among the 43 SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL (B=0.046, df=1, p=0.005; B=0.044, df=1, p=0.007; B=0.045, df=1, p=0.006; B=0.044, df=1, p=0.007; respectively). Furthermore, this association was under an additive model since having one or two alleles of the alternative variants were significantly associated with shorter LTL.

Conclusion
We could conclude that klotho opens a new venue in OSA research and would be applicable to prevent the consequences of short telomeres in individuals with OSA.

Support
This work was supported by grants from AFIP, FAPESP and CAPES.
0025 Circadian Dysregulation of DNA Repair and Increased Endogenous and Exogenous Sensitivity to DNA Damage Precipitate Elevated Cancer Risk Associated with Night Shift Work
Authors: Van Dongen H , Koritala B , McDermott J E , Porter K I , Arshad O A , Gajula R P , Mitchell H D , Arman T , Manjanatha M , Gaddameedhi S 
Published: May 2020

Abstract

Introduction
The elevated cancer risk associated with night shift work is poorly understood. To investigate whether circadian disruption may play a role, we assessed the circadian transcriptome and its association with hallmark cancer pathways, as well as sensitivity to endogenous and exogenous sources of DNA damage, after in-laboratory simulated shift work.

Methods
N=14 healthy humans (aged 22-34y; 10m, 4f) were exposed to a simulated night shift schedule (daytime sleep: 10:00-18:00) or a simulated day shift schedule (nighttime sleep: 22:00-06:00) for 3 days (n=7 in each condition). After the simulated shift schedule, subjects underwent a 24h constant routine protocol, during which blood was collected every 3h. Lymphocytes were extracted from the blood samples and subjected to transcriptome analysis using a NanoString multiplex assay. We evaluated 726 mRNA cancer hallmark targets (NanoString PanCancer Pathway Panel) and 17 circadian clock genes, with 18 arrhythmic internal controls. Gene expression was analyzed for circadian rhythmicity using mixed-effects cosinor analysis. Further, lymphocytes were investigated for DNA damage using an alkaline comet assay and immunofluorescence assessment of DNA damage response biomarkers BRCA1 and γH2AX. Lymphocytes collected at 07:30 and 19:30 were also exposed to ionizing radiation (2.5Gy) and DNA damage response assessments were repeated.

Results
Simulated night shift caused widespread disruption of circadian rhythmicity, as measured under constant routine, for core clock genes and the transcriptome of cancer hallmark pathways. The DNA repair pathway showed significant enrichment of rhythmic genes (p&lt;0.05) after the simulated day shift schedule only. Following simulated night shift, lymphocytes showed induction of endogenous DNA damage, with extended tail in the comet assay (p&lt;0.001), and higher percentage of lymphocytes with BRCA1 and γH2AX foci (p&lt;0.01). Lymphocytes collected at 19:30 showed enhanced impact of ionizing radiation as indicated by increased prevalence of cells with BRCA1 and γH2AX foci (p&lt;0.05).

Conclusion
Circadian dysregulation of DNA repair mechanisms and increased sensitivity to DNA damage following night shift work may increase genomic instability and precipitate elevated cancer risk in night shift workers.

Support
NIH grants ES022640 and CA227381, CDMRP award W81XWH-18-1-0100, and Pacific Northwest National Laboratory BRAVE investment under DOE contract DE-AC05-76RL01830.
0032 Timing of Daily Rhythm of Cardiac Autonomic Control Contributes to Weight Loss Resistance, Independent of Daily Energy Intake and Physical Activity Level
Authors: Yang H , Garaulet M , Li P , Bandin C , Lin C , Lo M , Hu K 
Published: May 2020

Abstract

Introduction
Obesity is a major health problem. Many treatments have been designed to help overweight/obese people to lose weight, but their effectiveness is highly variable. The same treatments may work for some persons while others have no responses — weight loss resistance. We tested whether the daily rhythm of cardiac autonomic control contributes to weight loss resistance.

Methods
We studied 39 overweight/obese Caucasian women (BMI&gt;25; age: 21–62 years old) who completed (1) an obesity dietary treatment of up to 30 weeks with weekly assessments of body weight, and (2) ambulatory monitoring of electrocardiogram (ECG) for up to 3.5 days. Heartbeat intervals were derived from ECG. Cardiac autonomic control was assessed in each 1-h bin by examining the temporal correlation in heartbeat fluctuations — a nonlinear measure that quantifies the delicate dynamic interplay between sympathetic and vagal outflows. Daily rhythm was estimated using the cosinor analysis.

Results
Weight loss was highly variable (range: 0.68%-21.78 % of initial body weight). The correlation in heartbeat fluctuations displayed a 24-h rhythm (p&lt;0.0001) with fewer correlations (more random) during the nighttime. The phase (peak timing) of the rhythm was highly variable, i.e., 10AM to 8PM for most participants, and after midnight in four participants. Weight loss evolution depended on the phase (p=0.006) in a nonlinear manner. Specifically, participants with the phase between 2PM-8PM lost weight faster than those with phases before 2PM and those after 8PM. The effect was independent of total energy intake, physical activity level, and sleep/wake schedules.

Conclusion
Cardiac autonomic control in overweight/obese women displayed a daily rhythm. The timing of the rhythm had previously un-identified contributions to weight loss. The inter-individual differences in the timing may reflect different circadian regulation of autonomic function and its interaction with the daily behavioral cycle.

Support
This work was supported by NIH grants R01AG048108, RF1AG059867, RF1AG064312, R01AG017917, and R01NS078009.
0033 Recurrent Circadian Disruption While Minimizing Sleep Loss in Humans Impairs Glucose Tolerance Only in The Presence of High-Fat Diet
Authors: Zitting K , Yuan R K , Vujovic N , Klerman E B , Quan S F , Scheer F A , Wang W , Buxton O M , Williams J S , Duffy J F , Czeisler C A 
Published: May 2020

Abstract

Introduction
Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity and cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods. Here we used a forced desynchrony protocol to investigate the effect of 3 weeks of recurrent circadian disruption (RCD) with minimal sleep loss on glucose metabolism in humans on a lower or higher fat diet (LFD and HFD, respectively).

Methods
Six healthy adults (38-69yrs; 3f) participated in a 37-day inpatient protocol with LFD (25–27% fat) and 15.67-hr fasting duration, or HFD (45–50% fat) and 13-hr fasting duration. The protocol included three weeks of RCD consisting of 28-hr “days” with 11.67-hr sleep opportunities (=10hrs/24hr). Glucose and insulin responses to a standardized breakfast were conducted at baseline, at an aligned circadian phase after 2–3 weeks of exposure to RCD, and after 1 week of recovery. Frequent blood samples were assayed for glucose and insulin; the Area-Under-Curve was calculated from start of breakfast through postprandial minute 180.

Results
Total Sleep Time was similar in Baseline and RCD in both groups. Participants on the LFD showed no change in glucose AUC during RCD compared to Baseline. Insulin AUC was lower during RCD (p=0.0269) and Recovery (p=0.0443) than Baseline. In contrast, participants on the HFD showed a significant increase in glucose AUC during RCD compared to Baseline (p&lt;0.0001); AUC returned to Baseline during Recovery. There was no significant change in insulin AUC on the HFD.

Conclusion
RCD (in the absence of sleep loss) led to impaired glucose tolerance when combined with HFD, but not when combined with LFD. These results suggest that LFD may be part of healthy strategies for people experiencing RCD.

Support
Study supported by P01AG009975 and conducted in the Brigham and Women’s Hospital Center for Clinical Investigation, part of Harvard Clinical and Translational Science Center supported by UL1TR001102. Authors supported by a fellowship from the Finnish Cultural Foundation (KMZ); T32HL007901 and F32HL143893 (RKY); T32HL007901 and F32AG051325 (NV); K24HL105664 (EBK); R01HL118601 (FAJLS).
0037 Melanopsin Driven Pupil Responses and Physical Activity: Stability of Activity from Day-to-Day in Winter in Seasonal Affective Disorder
Authors: Roecklein K A , Wescott D L , Smagula S F , Soehner A M , Franzen P L , Hasler B P 
Published: May 2020

Abstract

Introduction
The post-illumination pupil response (PIPR) is a measure of the responsivity of intrinsically photosensitive retinal ganglion cells (ipRGCs), and reflects the cell biology of the photoentrainment pathway projecting from the retina to the circadian clock. Adequate signaling from the ipRGCs in the retina to the circadian clock is necessary to result in robust circadian output which we hypothesize would increase inter-daily stability (IS), a non-parametric modeling technique that examines stability of rest activity rhythms across successive days.

Methods
Participants were aged 18–66 years and recruited from the greater Pittsburgh area during the Winter with Seasonal Affective Disorder who completed both actigraphy and pupillometry (n = 16). PIPR measures were collected after a 1 second red or blue light pulse, and are calculated as the Net difference between red and blue at multiple time frames: at 6 seconds post stimulus (PIPR 6), from 10–30 seconds post-stimulus (PIPR 20), or from 10–40 seconds post-stimulus (PIPR 30). Using actigraphy, inter-daily stability (IS) was calculated as the amount of overall variability in the recording that is accounted for by the typical 24-hour profile, and reflects stability of the mean 24-h profile day-to-day.

Results
Inter-daily stability (IS) was associated with Net PIPR 20 (Β = 0.561; p = .031) and Net PIPR 30 (Β = 0.551; p = .034; all Β’s are standardized), but not Net PIPR 6 (Β = 0.298; p = .304). Retinal irradiance was calculated for each participant based on age and pupil diameter, to account for age-related differences in transmission of the stimulus to the retina. All raw Net PIPR values were adjusted for calculated retinal irradiance, and gender and time since wake were included as covariates.

Conclusion
Inter-daily stability (IS) values indicate greater stability of 24-hour activity profiles across days. If reduced responsivity to entraining pulses of light is associated with day-to-day instability in activity rhythms, as shown here, we might expect that amplifying entraining light through environmental changes or bright light therapy would normalize inter-daily stability in SAD, or the reverse, stabilizing activity profiles across days could improve depression and/or normalize retinal ipRGC responsivity.

Support
NIMH K.A.R. MH103303
0044 Association Between Chronotype and Circulating Levels of Interleukin-6 in Colorectal Cancer Patients: Preliminary Results from the ColoCare Study
Authors: Peoples A R , Gigic B , Ose J , Himbert C , Hardikar S , Boehm J , Schrotz-King P , Ulrich A B , Schneider M , Li C I , Shibata D , Siegel E M , Figueiredo J C , Toriola A T , Ulrich C M 
Published: May 2020

Abstract

Introduction
Accumulating evidence suggests that chronotype, i.e., circadian topology of an individual indicating morning or evening type, is associated with inflammation. To date, no study has examined the relationship between chronotype and inflammation in colorectal cancer patients. We investigated the associations between chronotype and inflammatory and angiogenesis biomarkers in colorectal cancer patients.

Methods
We used pre-surgery serum samples from n=67 newly diagnosed colorectal cancer patients (stage I-IV) recruited at the ColoCare Study site in Heidelberg, Germany. The ColoCare Study is an ongoing, international, multisite, prospective cohort study in colorectal cancer patients. Inflammatory and angiogenesis biomarkers [c-reactive protein (CRP), interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1)] were measured at the Huntsman Cancer Institute, USA using the Meso Scale Discovery platform and were log transformed. Chronotype was assessed prior to surgery with the reduced Morningness-Eveningness Questionnaire (rMEQ; scale 4–25; a higher score indicates more morning-type). Patients were dichotomized, based on the median values for rMEQ, into 2 groups: rMEQ-low (score≤16.0; n=35; indicating more evening-type) or rMEQ-high (score&gt;16.0; n=32; indicating more morning-type).

Results
Using Mann-Whitney U test, we observed that rMEQ-low group (i.e., more evening-type) compared to rMEQ-high group (i.e., more morning-type) had approx. two times significantly higher levels of log transformed IL-6 (mean=2.24 vs. 1.30; U=382.0; Z=-2.23; p=0.03), but not for other inflammatory or angiogenesis biomarkers. This association between chronotype and IL-6 was maintained even after adjusting for age, sex, tumor stage, tumor site, and sleep duration using a generalized estimating equations model (adjusted mean difference=1.10; 95% confidence interval=0.33, 1.88; p=0.01; effect size, Cohen’s d=0.69).

Conclusion
These preliminary findings suggest that the evening chronotype is associated with increased IL-6 inflammatory biomarker in colorectal cancer patients. Further research is needed to confirm and understand the mechanistic underpinnings of the observed results.

Support
Funding: NCI U01 CA206110, R01 CA189184, and R01 CA207371.
0049 Odds Ratio Product as a Measure of Sleep Depth During REM Sleep: Effects on REM Duration and REM Sleep Fragmentation
Authors: Mazzotti D R , Younes M 
Published: May 2020

Abstract

Introduction
The odds ratio product (ORP) is a new highly-validated electroencephalogram biomarker of sleep depth. ORP has been validated as such by several studies investigating the effect of sleep disorders, responses to sleep deprivation and traffic noise. ORP during REM sleep varies considerably among individuals. Whether ORP reflects sleep depth also in REM sleep is unknown. We hypothesized that subjects with high REM ORP are more prone to REM sleep fragmentation.

Methods
Using data from the baseline (SHHS1; N=5,537) and follow-up (SHHS2; N=2,595) visits of the Sleep Heart Health Study, we calculated and summarized ORP in 30-second intervals corresponding to manually scored sleep stage epochs. We developed a heuristic to identify REM periods, defined as sequences of REM sleep epochs separated by no more than 10 minutes of other sleep stages or wake epochs. Using general linear models adjusted by age, sex, body mass index, race and ethnicity, we evaluated the relationship between REM ORP and total REM duration, number of awakening episodes per REM period and arousal index during REM sleep.

Results
Higher REM ORP was correlated with shorter total REM duration (ρ SHHS1=-0.12; p &lt 0.001, ρ SHHS2=-0.07; p &lt 0.001), more awakening episodes (ρ SHHS1=0.26; p&lt;0.001, ρ SHHS2=0.30; p &lt 0.001) and higher arousal index (ρ SHHS1=0.18; p &lt 0.001, ρ SHHS2=0.16; p &lt &lt; 0.001) during identified REM periods. In adjusted analyses, one-unit increase in REM ORP was associated, on average, with a 7 minute decrease in total REM duration (β=-7.10; p &lt 0.001), 1 more awakening episode per REM period (β=1.29; p &lt 0.001) and an increase of 6 arousals/hour (β=6.16; p &lt 0.001) during REM sleep periods.

Conclusion
We found that higher REM ORP was associated with shorter REM periods, higher proportion of awake during REM periods and higher REM arousal index. Although small, these differences suggest that ORP is consistent with the concept of sleep depth also during REM sleep.

Support
None
0050 Identification of a Plasma Metabolome-Based Biomarker for Dim-Light Melatonin Offset and Onset in Humans
Authors: Cogswell D T , Bisesi P J , Markwald R R , Cruickshank-Quinn C , Quinn K , McHill A W , Melanson E L , Reisdorph N , Wright K P , Depner C M 
Published: May 2020

Abstract

Introduction
Easily measuring individual circadian timing is increasingly important to inform personalized chronotherapy, screen for circadian disorders and circadian misalignment, and advance circadian research. Findings from multiple studies show that transcriptomics is a viable method to estimate dim-light melatonin onset (DLMO), but no published omics-based findings have predicted dim-light melatonin offset (DLMOff), and only one known study has used metabolomics to predict DLMO. Here, we developed and tested a plasma metabolomics-based biomarker of circadian phase using DLMO and DLMOff as phase markers.

Methods
Sixteen (8M/8F) healthy participants aged 22.4 ± 4.8y (mean ± SD) completed an in-laboratory study with 3 baseline days (9h sleep opportunity/night), followed by a randomized cross-over protocol with 9h sleep and 5h sleep conditions, each lasting 5 days. Blood was collected every 4h on the final 24h of each condition for untargeted metabolomics analyses. DLMO and DLMOff were determined during the final 24h of each condition. Samples from all conditions were randomly split into training (68%) and test (32%) datasets. DLMO and DLMOff models were developed using partial least squares regression in the training dataset and validated in the test dataset.

Results
When validating with the test dataset, R2 for the DLMO model was 0.60, median absolute error (MdAE) was 2.2 ± 2.8h (± interquartile range), and 44% of samples had MdAE under 2h. R2 for the DLMOff model was 0.62, MdAE was 1.8 ± 2.6, and 51% of samples had MdAE under 2h. The DLMOff model predicted baseline samples, under conditions of 9h sleep and controlled food intake, with an R2 of 0.91 and MdAE 1.1 ± 1.1h.

Conclusion
These findings show promise for metabolomics-based biomarkers of circadian phase and highlight the need for biomarker efforts to predict multiple circadian phase markers. Additional analyses with an independent validation dataset will help advance these initial findings.

Support
NIH-R01HL085705, NIH-R01HL109706, NIH-R01HL132150, NIH-K01HL145099, NIH-F32DK111161, and NIH-UL1TR000154; and Sleep Research Society Foundation 011-JP-16;
0058 Effects of Acute Total Sleep Deprivation on Human Plasma N-glycans
Authors: Chatterton B D , Mullington J , Yang H , Haack M , Cummings R , Lehoux S D 
Published: May 2020

Abstract

Introduction
There is a need for a novel biomarker that can be used to measure sleep sufficiency as it pertains to fitness for duty. As glycans (polysaccharides) are known to be involved in modifying protein effectiveness, we are exploring these as biomarkers that may be sensitive to differences between sleep deprivation and normal healthy adult sleep duration. We have measured one major class of glycans, called N-glycans, which are covalently linked to asparagine residues of polypeptide chains of membrane-bound and secreted proteins. We compared the plasma N-glycan profiles of participants before and after they participated in a total sleep deprivation protocol.

Methods
10 healthy participants (6 male, 4 female) aged 30–44 went through 88 hours of total sleep deprivation. Hourly blood draws were taken via forearm catheter throughout the protocol. N-glycan analysis was performed using plasma samples collected at 17:35 prior to the first night of sleep deprivation and at 17:35 following 82.5 hours of continuous wakefulness. N-glycans were first cleaved from peptides and isolated from plasma, and profiles were then measured using Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrometry.

Results
66 N-glycans were observed in our profiles. Of these, the relative abundance of 17 N-glycans were significantly different following sleep deprivation (paired t-test, 13 with p&lt;0.05, 4 with p&lt;0.01). In each case, the relative abundance was lower in the sleep deprivation time point. We found two structures, Hex6HexNAc5NeuAc3 and Hex7HexNAc6NeuAc2, which were also significant in one of our previous chronic sleep restriction protocols.

Conclusion
While we observed that many N-glycans decreased in relative abundance, it is unclear whether these changes represent a shift in glycan synthesis or result from decreased expression of the proteins they are bound to. Our next steps involve exploring the functions of the proteins associated with Hex6HexNAc5NeuAc3 and Hex7HexNAc6NeuAc2, and measuring their expression levels.

Support
NIH/HL75501; NIH/National Center for Research Resources UL1-RR02758 and M01-RR01032 to the Harvard Clinical and Translational Science Center.
0065 Initial Findings on Associations Between Sleep and Clinical Measures with Neural Activations Accompanying Fear Conditioning and Extinction in Trauma-Exposed Individuals
Authors: Seo J , Oliver K I , Daffre C , Pace-Schott E F 
Published: May 2020

Abstract

Introduction
We examined associations of sleep and hyperarousal with neural responses to a fear conditioning and extinction protocol in trauma-exposed individuals. We hypothesized, greater hyperarousal, poorer sleep quality and more nightmares would accompany greater activation of the salience network (associated with fear) and lesser activation of the prefrontal cortex (PFC; associated with fear regulation) throughout this protocol.

Methods
Persons exposed to trauma within the past 2 years (N=119, 43 with Post-traumatic stress disorder; PTSD) completed the PTSD Checklist-5 (PCL-5), two weeks of actigraphy and sleep/nightmare diaries, and a 2-day fear-conditioning and extinction protocol during fMRI. Hyperarousal items from PCL-5, sleep quality, and nightmare frequency were used to predict fMRI contrasts representing (1) initial activations to reinforced conditioned stimuli (CS+) during fear conditioning, (2) change in neural activation to CS+s across extinction learning, and, (3) after 24 hours (extinction recall), selective activation to an extinguished (CS+E) versus an un-extinguished CS+.

Results
During fear conditioning, hyperarousal was positively correlated with activation to the CS+ in the right lateral PFC, whereas nightmare frequency was negatively correlated with activations in bilateral orbitofrontal cortex (OFC). Across extinction learning, sleep onset latency (SOL) was negatively correlated with increased activation to CS+ in bilateral insular and dorsal and middle anterior cingulate cortices (salience regions). At extinction recall, nightmare frequency was negatively correlated with selective activation to the CS+E in the left insular cortex.

Conclusion
Except that fewer nightmares predicted greater OFC activation during fear conditioning, results did not support hypothesized relationships of hyperarousal, poor sleep and nightmares with increased salience network and decreased PFC activation to fear-related stimuli.

Support
Funding: R01MH109638