Multi-Omics Approaches to Study Long Non-coding RNA Function in Atherosclerosis

Atherosclerosis is a complex inflammatory disease of the vessel wall involving the interplay of multiple cell types including vascular smooth muscle cells, endothelial cells, and macrophages. Large-scale genome-wide association studies (GWAS) and the advancement of next generation sequencing technologies have rapidly expanded the number of long non-coding RNA (lncRNA) transcripts predicted to play critical roles in the pathogenesis of the disease. In this review, we highlight several lncRNAs whose functional role in atherosclerosis is well-documented through traditional biochemical approaches as well as those identified through RNA-sequencing and other high-throughput assays. We describe novel genomics approaches to study both evolutionarily conserved and divergent lncRNA functions and interactions with DNA, RNA, and proteins. We also highlight assays to resolve the complex spatial and temporal regulation of lncRNAs. Finally, we summarize the latest suite of computational tools designed to improve genomic and functional annotation of these transcripts in the human genome. Deep characterization of lncRNAs is fundamental to unravel coronary atherosclerosis and other cardiovascular diseases, as these regulatory molecules represent a new class of potential therapeutic targets and/or diagnostic markers to mitigate both genetic and environmental risk factors

Evaluating the typical day-to-day variability of WHOOP-derived heart rate variability in Olympic water polo athletes

Heart rate (HR) and HR variability (HRV) can be used to infer readiness to perform exercise in athletic populations. Advancements in the photoplethysmography technology of wearable devices such as WHOOP allow for the frequent and convenient measurement of HR and HRV, and therefore enhanced application in athletes. However, it is important that the reliability of such technology is acceptable prior to its application in practical settings. Eleven elite male water polo players (age 28.8 ± 5.3 years [mean ± standard deviation]; height 190.3 ± 3.8 cm; body mass 95.0 ± 6.9 kg; international matches 117.9 ± 92.1) collected their HR and HRV daily via a WHOOP strap (WHOOP 3.0, CB Rank, Boston, MA, USA) over 16 weeks ahead of the 2021 Tokyo Olympic Games. The WHOOP strap quantified HR and HRV via wrist-based photoplethysmography during overnight sleep periods. The weekly (i.e., 7-day) coefficient of variation in lnRMSSD (lnRMSSDCV) and HR (HRCV) was calculated as a measure of day-to-day variability in lnRMSSD and HR, and presented as a mean of the entire recording period. The mean weekly lnRMSSDCV and HRCV over the 16-week period was 5.4 ± 0.7% (mean ± 95% confidence intervals) and 7.6 ± 1.3%, respectively. The day-to-day variability in WHOOP-derived lnRMSSD and HR is within or below the range of day-to-day variability in alternative lnRMSSD (~3–13%) and HR (~10–11%) assessment protocols, indicating that the assessment of HR and HRV by WHOOP does not introduce any more variability than that which is naturally present in these variables

A validation study of a commercial wearable device to automatically detect and estimate sleep

The aims of this study were to: (1) compare actigraphy (ACTICAL) and a commercially available sleep wearable (i.e., WHOOP) under two functionalities (i.e., sleep auto-detection (WHOOP-AUTO) and manual adjustment of sleep (WHOOP-MANUAL)) for two-stage categorisation of sleep (sleep or wake) against polysomnography, and; (2) compare WHOOP-AUTO and WHOOP-MANUAL for four-stage categorisation of sleep (wake, light sleep, slow wave sleep (SWS), or rapid eye movement sleep (REM)) against polysomnography. Six healthy adults (male: n = 3; female: n = 3; age: 23.0 ± 2.2 yr) participated in the nine-night protocol. Fifty-four sleeps assessed by ACTICAL, WHOOP-AUTO and WHOOP-MANUAL were compared to polysomnography using difference testing, Bland–Altman comparisons, and 30-s epoch-by-epoch comparisons. Compared to polysomnography, ACTICAL overestimated total sleep time (37.6 min) and underestimated wake (−37.6 min); WHOOP-AUTO underestimated SWS (−15.5 min); and WHOOP-MANUAL underestimated wake (−16.7 min). For ACTICAL, sensitivity for sleep, specificity for wake and overall agreement were 98%, 60% and 89%, respectively. For WHOOP-AUTO, sensitivity for sleep, wake, and agreement for two-stage and four-stage categorisation of sleep were 90%, 60%, 86% and 63%, respectively. For WHOOP-MANUAL, sensitivity for sleep, wake, and agreement for two-stage and four-stage categorisation of sleep were 97%, 45%, 90% and 62%, respectively. WHOOP-AUTO and WHOOP-MANUAL have a similar sensitivity and specificity to actigraphy for two-stage categorisation of sleep and can be used as a practical alternative to polysomnography for two-stage categorisation of sleep and four-stage categorisation of sleep

Integrative single-cell meta-analysis reveals disease-relevant vascular cell states and markers in human atherosclerosis

Coronary artery disease (CAD) is characterized by atherosclerotic plaque formation in the arterial wall. CAD progression involves complex interactions and phenotypic plasticity among vascular and immune cell lineages. Single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures, but human cell phenotypes remain controversial. Here, we perform an integrated meta-analysis of 22 scRNA-seq libraries to generate a comprehensive map of human atherosclerosis with 118,578 cells. Besides characterizing granular cell-type diversity and communication, we leverage this atlas to provide insights into smooth muscle cell (SMC) modulation. We integrate genome-wide association study data and uncover a critical role for modulated SMC phenotypes in CAD, myocardial infarction, and coronary calcification. Finally, we identify fibromyocyte/fibrochondrogenic SMC markers (LTBP1 and CRTAC1) as proxies of atherosclerosis progression and validate these through omics and spatial imaging analyses. Altogether, we create a unified atlas of human atherosclerosis informing cell state-specific mechanistic and translational studies of cardiovascular diseases.</p

Optimising conservative management of chronic low back pain: study protocol for a randomised controlled trial

BackgroundLower back pain is a global health issue affecting approximately 80% of people at some stage in their life. The current literature suggests that any exercise is beneficial for reducing back pain. However, as pain is a subjective evaluation and physical deficits are evident in low back pain, using it as the sole outcome measure to evaluate superiority of an exercise protocol for low back pain treatment is insufficient. The overarching goal of the current clinical trial is to implement two common, conservative intervention approaches and examine their impact on deficits in chronic low back pain.Methods/designForty participants, 25&ndash;45 years old with chronic (&gt;3 months), non-specific low back pain will be recruited. Participants will be randomised to receive either motor control and manual therapy (n&thinsp;=&thinsp;20) or general strength and conditioning (n&thinsp;=&thinsp;20) exercise treatments for 6 months. The motor control/manual therapy group will receive twelve 30-min sessions, ten in the first 3 months (one or two per week) and two in the last 3 months. The general exercise group will attend two 1-hour sessions weekly for 3 months, and one or two a week for the following 3 months. Primary outcome measures are average lumbar spine intervertebral disc T2 relaxation time and changes in thickness of the transversus abdominis muscle on a leg lift using magnetic resonance imaging (MRI). Secondary outcomes include muscle size and fat content, vertebral body fat content, intervertebral disc morphology and water diffusion measured by MRI, body composition using dual energy X-ray absorptiometry, physical function through functional tests, changes in corticospinal excitability and cortical motor representation of the spinal muscles using transcranial magnetic stimulation and self-reported measure of pain symptoms, health and disability. Outcome measures will be conducted at baseline, at the 3-month follow-up and at 6 months at the end of intervention. Pain, depressive symptomology and emotions will be captured fortnightly by questionnaires.DiscussionChronic low back pain is ranked the highest disabling disorder in Australia. The findings of this study will inform clinical practice guidelines to assist with decision-making approaches where outcomes beyond pain are sought for adults with chronic low back pain.<br /

Expedition 381 Summary

The primary objective of International Ocean Discovery Program Expedition 381 was to retrieve a record of early continental rifting and basin evolution from the Corinth rift, central Greece. Continental rifting is fundamental for the formation of ocean basins, and active rift zones are dynamic regions of high geohazard potential. However, the detailed spatial and temporal evolution of a complete rift system needed to understand rift development from the fault to plate scale is poorly resolved. In the active Corinth rift, deformation rates are high, the recent synrift succession is preserved and complete offshore, and earlier rift phases are preserved onshore. Additionally, a dense seismic database provides high-resolution imaging of the fault network and seismic stratigraphy around the basin. As the basin has subsided, its depositional environment has been affected by fluctuating global sea level and its absolute position relative to sea level, and the basin sediments record this changing environment through time. In Corinth, we can therefore achieve an unprecedented precision of timing and spatial complexity of rift-fault system development, rift-controlled drainage system evolution, and basin fill in the first few million years of rift history. The following are the expedition themes: High-resolution fault slip and rift evolution history, Surface processes in active rifts, High-resolution late Quaternary Eastern Mediterranean paleoclimate and paleoenvironment of a developing rift basin, and Geohazard assessment in an active rift. These objectives were and will be accomplished as a result of successful drilling, coring, and logging at three sites in the Gulf of Corinth, which collectively yielded 1645 m of recovered core over a 1905 m cored interval. Together, these cores provide (1) a long rift history (Sites M0078 and M0080), (2) a high-resolution record of the most recent phase of rifting (Site M0079), and (3) the spatial variation of rift evolution (comparison of sites in the central and eastern rift). The sediments contain a rich and complex record of changing sedimentation, sediment and pore water geochemistry, and environmental conditions from micropaleontological assemblages. The preliminary chronology developed by shipboard analyses will be refined and improved during postexpedition research, providing a high-resolution chronostratigraphy down to the orbital timescale for a range of tectonic, sedimentological, and paleoenvironmental studies. This chronology will provide absolute timing of key rift events, rates of fault movement, rift extension and subsidence, and the spatial variations of these parameters. The core data will also allow us to investigate the relative roles of and feedbacks between tectonics, climate, and eustasy in sediment flux, basin evolution, and basin environment. Finally, the Corinth rift boreholes will provide the first long Quaternary record of Mediterranean-type climate in the region. The potential range of scientific applications for this unique data set is very large, encompassing tectonics, sedimentary processes, paleoenvironment, paleoclimate, paleoecology, geochemistry, and geohazards

High-resolution record reveals climate-driven environmental and sedimentary changes in an active rift

Young rifts are shaped by combined tectonic and surface processes and climate, yet few records exist to evaluate the interplay of these processes over an extended period of early rift-basin development. Here, we present the longest and highest resolution record of sediment flux and paleoenvironmental changes when a young rift connects to the global oceans. New results from International Ocean Discovery Program (IODP) Expedition 381 in the Corinth Rift show 10s–100s of kyr cyclic variations in basin paleoenvironment as eustatic sea level fluctuated with respect to sills bounding this semi-isolated basin, and reveal substantial corresponding changes in the volume and character of sediment delivered into the rift. During interglacials, when the basin was marine, sedimentation rates were lower (excepting the Holocene), and bioturbation and organic carbon concentration higher. During glacials, the basin was isolated from the ocean, and sedimentation rates were higher (~2–7 times those in interglacials). We infer that reduced vegetation cover during glacials drove higher sediment flux from the rift flanks. These orbital-timescale changes in rate and type of basin infill will likely influence early rift sedimentary and faulting processes, potentially including syn-rift stratigraphy, sediment burial rates, and organic carbon flux and preservation on deep continental margins worldwide

High-resolution record revealsclimate-driven environmental andsedimentary changes in an active rift

Young rifts are shaped by combined tectonic and surface processes and climate, yet few records exist to evaluate the interplay of these processes over an extended period of early rift-basin development. Here, we present the longest and highest resolution record of sediment flux and paleoenvironmental changes when a young rift connects to the global oceans. New results from International Ocean Discovery Program (IODP) Expedition 381 in the Corinth Rift show 10s–100s of kyr cyclic variations in basin paleoenvironment as eustatic sea level fluctuated with respect to sills bounding this semi-isolated basin, and reveal substantial corresponding changes in the volume and character of sediment delivered into the rift. During interglacials, when the basin was marine, sedimentation rates were lower (excepting the Holocene), and bioturbation and organic carbon concentration higher. During glacials, the basin was isolated from the ocean, and sedimentation rates were higher (~2–7 times those in interglacials). We infer that reduced vegetation cover during glacials drove higher sediment flux from the rift flanks. These orbital-timescale changes in rate and type of basin infill will likely influence early rift sedimentary and faulting processes, potentially including syn-rift stratigraphy, sediment burial rates, and organic carbon flux and preservation on deep continental margins worldwide.publishedVersio