Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C.

We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction.

Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding.

Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.

Ultrastructural Details of Mammalian Chromosome Architecture.

Over the past decade, 3C-related methods have provided remarkable insights into chromosome folding in vivo. To overcome the limited resolution of prior studies, we extend a recently developed Hi-C variant, Micro-C, to map chromosome architecture at nucleosome resolution in human ESCs and fibroblasts. Micro-C robustly captures known features of chromosome folding including compartment organization, topologically associating domains, and interactions between CTCF binding sites. In addition, Micro-C provides a detailed map of nucleosome positions and localizes contact domain boundaries with nucleosomal precision. Compared to Hi-C, Micro-C exhibits an order of magnitude greater dynamic range, allowing the identification of ∼20,000 additional loops in each cell type. Many newly identified peaks are localized along extrusion stripes and form transitive grids, consistent with their anchors being pause sites impeding cohesin-dependent loop extrusion. Our analyses comprise the highest-resolution maps of chromosome folding in human cells to date, providing a valuable resource for studies of chromosome organization.

Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF.

Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBRi) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBRi impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBRi mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBRi-independent and RBRi-dependent loops. We speculate that evidence for RBRi-dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBRi-interacting partners.

Mitral valve prolapse: arrhythmic risk during pregnancy and postpartum.

BACKGROUND AND AIMS: Arrhythmic mitral valve prolapse (AMVP) is linked to life-threatening ventricular arrhythmias (VAs), and young women are considered at high risk. Cases of AMVP in women with malignant VA during pregnancy have emerged, but the arrhythmic risk during pregnancy is unknown. The authors aimed to describe features of women with high-risk AMVP who developed malignant VA during the perinatal period and to assess if pregnancy and the postpartum period were associated with a higher risk of malignant VA. METHODS: This retrospective international multi-centre case series included high-risk women with AMVP who experienced malignant VA and at least one pregnancy. Malignant VA included ventricular fibrillation, sustained ventricular tachycardia, or appropriate shock from an implantable cardioverter defibrillator. The authors compared the incidence of malignant VA in non-pregnant periods and perinatal period; the latter defined as occurring during pregnancy and within 6 months after delivery. RESULTS: The authors included 18 women with AMVP from 11 centres. During 7.5 (interquartile range 5.8-16.6) years of follow-up, 37 malignant VAs occurred, of which 18 were pregnancy related occurring in 13 (72%) unique patients. Pregnancy and 6 months after delivery showed increased incidence rate of malignant VA compared to the non-pregnancy period (univariate incidence rate ratio 2.66, 95% confidence interval 1.23-5.76). CONCLUSIONS: The perinatal period could impose increased risk of malignant VA in women with high-risk AMVP. The data may provide general guidance for pre-conception counselling and for nuanced shared decision-making between patients and clinicians.

Atherosclerosis on CT coronary angiography and the risk of long-term cardiovascular events after liver transplantation.

Computed tomography coronary angiography (CTCA) is increasingly utilized for preoperative risk stratification before liver transplantation (LT). We sought to assess the predictors of advanced atherosclerosis on CTCA using the recently developed Coronary Artery Disease-Reporting and Data System (CAD-RADS) score and its impact on the prediction of long-term major adverse cardiovascular events (MACE) following LT. We conducted a retrospective cohort study of consecutive patients who underwent CTCA for LT work-up between 2011 and 2018. Advanced atherosclerosis was defined as coronary artery calcium scores > 400 or CAD-RADS score ≥ 3 (≥50% coronary artery stenosis). MACE was defined as myocardial infarction, heart failure, stroke, or resuscitated cardiac arrest. Overall, 229 patients underwent CTCA (mean age 66 ± 5 y, 82% male). Of these, 157 (68.5%) proceeded with LT. The leading etiology of cirrhosis was hepatitis (47%), and 53% of patients had diabetes before transplant. On adjusted analysis, male sex (OR 4.6, 95% CI 1.5-13.8, p = 0.006), diabetes (OR 2.2, 95% CI 1.2-4.2, p = 0.01) and dyslipidemia (OR 3.1, 95% CI 1.3-6.9, p = 0.005) were predictors of advanced atherosclerosis on CTCA. Thirty-two patients (20%) experienced MACE. At a median follow-up of 4 years, CAD-RADS ≥ 3, but not coronary artery calcium scores, was associated with a heightened risk of MACE (HR 5.8, 95% CI 1.6-20.6, p = 0.006). Based on CTCA results, 71 patients (31%) commenced statin therapy which was associated with a lower risk of all-cause mortality (HR 0.48, 95% CI 0.24-0.97, p = 0.04). The standardized CAD-RADS classification on CTCA predicted the occurrence of cardiovascular outcomes following LT, with a potential to increase the utilization of preventive cardiovascular therapies.

Understanding the long-term impact of incident osteoporotic fractures on healthcare utilization and costs in Korean postmenopausal women.

This study provides long-term evidence that healthcare resource utilization and costs of care in women who experienced incident osteoporotic fractures remained higher than those in women without fractures over a span of 5 years. These findings emphasize the importance of early diagnostics and treatment for osteoporosis. PURPOSE: To evaluate healthcare resource utilization (HCRU) and costs of care over 5 years after the incident osteoporotic fractures (OF) in postmenopausal women. METHODS: We used data from the National Health Insurance Service databases 2011-2018. Women aged ≥ 50 years with incident OF (OF group) were matched to women without OF (non-OF group). HCRU (inpatient, outpatient, and emergency room [ER] visits) and costs of care (inpatient, outpatient, and ER visits) during the 5-year follow-up period were derived after propensity score matching (PSM). Additionally, we identified women with subsequent fractures within the first 2 years after the incident OF. RESULTS: After PSM, 47,238 OF and 134,813 non-OF women were identified. HCRU rates and costs of care were highest in the first year after OF and decreased substantially, but remained higher in the OF group during the entire follow-up period. The increase in cumulative HCRU rates over 5 years was highest in inpatient admissions with ER visits (138% higher in OF vs non-OF). The cumulative total costs over 5 years were 73% higher in the OF group than in the non-OF group, which was mostly driven by inpatient costs. Trends were similar for women with subsequent fractures, but they generally showed higher HCRU and costs than those in the total OF group. CONCLUSION: OF imposes a substantial and sustained economic burden on women, resulting in an approximately twofold increase in the cumulative cost over 5 years compared to women without fracture, which highlights the need for early diagnostics and treatment of osteoporosis.

Search for Periodic Time Variations of the Solar

We report a search for time variations of the solar ^{8}B neutrino flux using 5804 live days of Super-Kamiokande data collected between May 31, 1996, and May 30, 2018. Super-Kamiokande measured the precise time of each solar neutrino interaction over 22 calendar years to search for solar neutrino flux modulations with unprecedented precision. Periodic modulations are searched for in a dataset comprising five-day interval solar neutrino flux measurements with a maximum likelihood method. We also applied the Lomb-Scargle method to this dataset to compare it with previous reports. The only significant modulation found is due to the elliptic orbit of the Earth around the Sun. The observed modulation is consistent with astronomical data: we measured an eccentricity of (1.53±0.35)%, and a perihelion shift of (-1.5±13.5) days.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Procrastination, depressive symptomatology, and loneliness in later life.

OBJECTIVES: Procrastination is an almost universal behaviour and yet little research to date has focused on procrastination among older adults. The purpose of this study was to explore the potential association between age and procrastination, and the potential mediating roles of depressive symptomatology and loneliness. METHOD: Structural equation modelling was applied to data from 1309 participants (aged 29-92) from two waves United States Health and Retirement Study (2016-2020). Within the model, sex, education, marital status, and job status were added as covariates. RESULTS: There was no statistically significant direct effect between age and procrastination (ß = 0.06, p = 0.106). However, an indirect effect was present via depressive symptomatology (ß = -0.40, p < 0.001). No mediating effect of loneliness was observed (ß = - 0.01, p = 0.371). Subsequent analysis revealed that the symptoms, fatigue, loneliness, and lack of motivation significantly predicted procrastination. CONCLUSION: While age was not directly associated with procrastination, increasing age was associated with a decreased likelihood of depressive symptomatology, which was in turn associated with an increased likelihood of procrastination. Such findings indicates that age demonstrates no association with procrastination because of the suppressing effect of depressive symptomatology.

Perioperative outcomes of laparoscopic low anterior resection using ArtiSential® versus robotic approach in patients with rectal cancer: a propensity score matching analysis.

BACKGROUND: Total mesorectal excision using conventional straight fixed devices may be technically difficult because of the narrow and concave pelvis. Several laparoscopic articulating tools have been introduced as an alternative to robotic systems. The aim of this study was to compare perioperative outcomes between laparoscopic low anterior resection using ArtiSential® and robot-assisted surgery for rectal cancer. METHODS: This retrospective study included 682 patients who underwent laparoscopic or robotic low anterior resection  for rectal cancer from September 2018 to December 2021. Among them, 82 underwent laparoscopic surgery using ArtiSential® (group A) and 201 underwent robotic surgery (group B). A total of 73 [group A; 66.37 ± 11.62; group B 65.79 ± 11.34] patients were selected for each group using a propensity score matching analysis. RESULTS: There was no significant difference in the baseline characteristics between group A and B. Mean operative time was longer in group B than A (163.5 ± 61.9 vs 250.1 ± 77.6 min, p < 0.001). Mean length of hospital stay was not significantly different between the two groups (6.2 ± 4.7 vs 6.7 ± 6.1 days, p = 0.617). Postoperative complications, reoperation, and readmission within 30 days after surgery were similar between the two groups. Pathological findings revealed that the circumferential resection margins were above 10 mm in both groups (11.00 ± 7.47 vs 10.17 ± 6.25 mm, p = 0.960). At least 12 lymph nodes were sufficiently harvested, with no significant difference in the number harvested between the groups (20.5 ± 9.9 vs 19.7 ± 7.3, p = 0.753). CONCLUSIONS: Laparoscopic low anterior resection using ArtiSential® can achieve acceptable clinical and oncologic outcomes. ArtiSential®, a multi-joint and articulating device, may serve a feasible alternative approach to robotic surgery in rectal cancer.

Cerebral arteriolosclerosis, lacunar infarcts, and cognition in older Black adults.

INTRODUCTION: Older Black adults are at risk of cerebral small vessel disease (CSVD), which contributes to dementia risk. Two subtypes of CSVD, arteriolosclerosis and ischemic lacunar infarcts, have been independently linked to lower cognition and higher dementia risk, but their combined effects on cognition in older Black adults are unclear. METHODS: Mixed models were used to examine the associations of in vivo measures of arteriolosclerosis (ARTS) and ischemic lacunar infarcts to cognitive level and change in 370 older Black adults without dementia.  RESULTS: Modeled together, higher ARTS load accounted for lower levels of global cognition, episodic memory, semantic memory, and perceptual speed, whereas higher infarct load accounted for lower levels of working memory. There were no associations with rate of cognitive change. DISCUSSION: Both arteriolosclerosis and ischemic infarcts impact the cognitive health of older Black adults, but arteriolosclerosis affects cognition more broadly and offers promise as an in vivo biomarker of dementia risk. HIGHLIGHTS: Older Black adults are at risk of cerebral small vessel disease (CSVD) and dementia. Examined magnetic resonance imaging-derived measure of arteriolosclerosis (ARTS), infarcts, and cognition. ARTS load was widely associated with lower cognition after adjusting for infarct load. Infarct load was specifically associated with lower complex attention. More within-Black in vivo studies of CSVD subtypes and cognition are needed.

2023 Cardiac Society of Australia and New Zealand Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation.

Catheter ablation for atrial fibrillation (AF) has increased exponentially in many developed countries, including Australia and New Zealand. This Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation from the Cardiac Society of Australia and New Zealand (CSANZ) recognises healthcare factors, expertise and expenditure relevant to the Australian and New Zealand healthcare environments including considerations of potential implications for First Nations Peoples. The statement is cognisant of international advice but tailored to local conditions and populations, and is intended to be used by electrophysiologists, cardiologists and general physicians across all disciplines caring for patients with AF. They are also intended to provide guidance to healthcare facilities seeking to establish or maintain catheter ablation for AF.

[Proactively embracing the challenges of multimorbidity].

With rapid socio-economic development and the acceleration of population aging, the average life span of human beings has increased significantly. Individuals suffering from the co-existence of multiple diseases (multimorbidity) have become a new normal in public health and posed severe challenge to human health. Multimorbidity significantly reduces the quality of life, increases disability and mortality risks, complicates disease treatment and care and increases burden of the healthcare system with higher costs. This commentary discusses the definition of multimorbidity and common public misconceptions, then assesses its profound impact on overall public health, socio-economic development and healthcare system. We also proposes the potential strategies to meet the challenges posed by multimorbidity. The main aim is to raise awareness of multimorbidity, advocate proactive responses to improve public health and build a healthy society through the development of prevention and treatment systems and promote precision prevention and treatment for multimorbidity.

Factors Associated With Healthcare and Financial Decision Making Among Older Black Adults Without Dementia.

OBJECTIVES: The study aims to identify factors associated with health care and financial decision-making among older Black adults without dementia. METHODS: Participants (N = 326) underwent assessments of decision-making and completed measurements of factors from four categories: cognitive, contextual, psychosocial, and personality. We performed separate linear regression models to examine the association between each factor and decision-making and created a fully adjusted model. RESULTS: Higher global cognition (estimate = 1.92, SE = 0.21, p < .0001) was associated with better decision-making. Contextual factors including higher current annual income (estimate = 0.23, SE = 0.05, p < .0001), higher childhood socioeconomic status (estimate = 0.48, SE = 0.18, p = .006), higher health and financial literacy (estimate = 0.08, SE = 0.01, p < .0001), and lower financial stress (estimate = -0.19, SE = 0.07, p = .01) were associated with better decision-making. More psychological well-being (estimate = 0.07, SE = 0.22, p = .001), a psychosocial factor, and less neuroticism (estimate = -0.06, SE = 0.02, p = .002), a personality factor, were associated with better decision-making. In the fully adjusted model, two factors, higher global cognition and higher literacy (health and financial), remained associated with better decision-making. CONCLUSIONS: Cognitive and contextual factors serve as drivers of decision-making among older Black adults. CLINICAL IMPLICATIONS: Clinicians may implement strategies to bolster cognition and improve health and financial literacy to facilitate optimal decision-making among older Black adults.

3D ATAC-PALM: super-resolution imaging of the accessible genome.

To image the accessible genome at nanometer scale in situ, we developed three-dimensional assay for transposase-accessible chromatin-photoactivated localization microscopy (3D ATAC-PALM) that integrates an assay for transposase-accessible chromatin with visualization, PALM super-resolution imaging and lattice light-sheet microscopy. Multiplexed with oligopaint DNA-fluorescence in situ hybridization (FISH), RNA-FISH and protein fluorescence, 3D ATAC-PALM connected microscopy and genomic data, revealing spatially segregated accessible chromatin domains (ACDs) that enclose active chromatin and transcribed genes. Using these methods to analyze genetically perturbed cells, we demonstrated that genome architectural protein CTCF prevents excessive clustering of accessible chromatin and decompacts ACDs. These results highlight 3D ATAC-PALM as a useful tool to probe the structure and organizing mechanism of the genome.

Development of a carpark cardiac implantable electronic device clinic to improve time efficiency and patient satisfaction in the context of restrictions imposed by the COVID-19 pandemic.

INTRODUCTION: We evaluated time efficiency and patient satisfaction of a "car park clinic" (CPC) compared to traditional face-to-face (F2F) during the COVID-19 pandemic. METHODS: Consecutive patients attending CPC between September 2020 and November 2021 were surveyed. CPC time was recorded by staff. F2F time was reported by patients and administrative data. RESULTS: A total of 591 patients attended the CPC. A total of 176 responses were collected for F2F clinic. Regarding satisfaction, 90% of CPC patients responded "happy" or "very happy." 96% reported feeling "safe" or "very safe." Patients spent significantly less time in CPC compared to F2F (17 ± 8 vs. 50 ± 24 min, p < .001). CONCLUSION: CPC had excellent patient satisfaction and superior time efficiency compared to F2F.

Estimating the economic burden of osteoporotic fractures in a multinational study: a real-world data perspective.

Fracture-related costs vary by country. A standardized methodology and presentations were proposed to fairly assess the economic burden of osteoporotic fracture. Results indicated substantial costs of osteoporotic fractures for pharmacy, hospitalization, emergency care, and outpatient visits in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA. PURPOSE: The objective of this multinational, retrospective matched cohort study was to use a standardized methodology across different healthcare systems to estimate the burden of osteoporotic fracture (OF) in women aged ≥ 50 years in Australia, Germany, South Korea, Spain, and the USA. METHODS: Within each country, healthcare resource utilization and direct costs of care were compared between patients with newly identified OF and a propensity score-matched cohort without OF during follow-up periods of up to 5 years. RESULTS: Across all five countries, the OF cohort had significantly higher rates and length of inpatient admissions compared with the non-OF cohort. In each country, the adjusted total costs of care ratio between OF and non-OF cohorts were significant. The adjusted cost ratios for pharmacy, inpatient care, emergency care, and outpatient visits were similarly higher in the OF cohort across countries. CONCLUSION: The current study demonstrates the substantial economic burden of OF across different countries when compared with matched non-OF patients. The findings would assist stakeholders and policymakers in developing appropriate health policies.

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.