SAFB restricts contact domain boundaries associated with L1 chimeric transcription.

Long interspersed element-1 (LINE-1 or L1) comprises 17% of the human genome, continuously generates genetic variations, and causes disease in certain cases. However, the regulation and function of L1 remain poorly understood. Here, we uncover that L1 can enrich RNA polymerase IIs (RNA Pol IIs), express L1 chimeric transcripts, and create contact domain boundaries in human cells. This impact of L1 is restricted by a nuclear matrix protein scaffold attachment factor B (SAFB) that recognizes transcriptionally active L1s by binding L1 transcripts to inhibit RNA Pol II enrichment. Acute inhibition of RNA Pol II transcription abolishes the domain boundaries associated with L1 chimeric transcripts, indicating a transcription-dependent mechanism. Deleting L1 impairs domain boundary formation, and L1 insertions during evolution have introduced species-specific domain boundaries. Our data show that L1 can create RNA Pol II-enriched regions that alter genome organization and that SAFB regulates L1 and RNA Pol II activity to preserve gene regulation.

Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence.

Understanding cellular coordination remains a challenge despite knowledge of individual pathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulated in cellular senescence. Utilizing an auxin-inducible system, we observed that RNA exosome depletion in embryonic stem cells significantly affects the transcriptome and proteome, causing pluripotency loss and pre-senescence onset. Mechanistically, exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-protein equilibrium. This disturbance limits nuclear protein availability and hinders polymerase initiation and engagement, reducing gene transcription. Concurrently, it promptly disrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resulting in a translational shutdown. Prolonged exosome depletion induces nuclear structural changes resembling senescent cells, including aberrant chromatin compaction, chromocenter disassembly, and intensified heterochromatic foci. These effects suggest that the dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemic functional decline, altering the cell state and promoting senescence.

Effects of coronary artery disease in patients with permanent left bundle branch area pacing: A retrospective study.

Aims: Myocardial ischemia can affect traditional right ventricular (RV) pacing parameters, but it is unclear whether coronary artery disease (CAD) impact the pacing parameters and electrophysiological characteristics of left bundle branch area pacing (LBBaP) as a physiological pacing representative. Methods: Patients who underwent coronary angiography (CAG) after/before the LBBaP procedure and underwent percutaneous coronary intervention after LBBaP procedure were divided into CAD group and Non-CAD group according to visual CAG. Pacing parameters and electrophysiological characteristics were recorded at LBBaP implantation. Multivariate logistic regression analysis was implemented to evaluate the association between CAD and higher capture threshold. Sensitivity analyses were conducted to verify result stability. Results: A total of 176 patients met inclusion criteria (115 Non-CAD patients and 61 CAD patients) with a mean age of 71.1 ± 9.0 years. Compared with the Non-CAD patients, CAD patients had the higher capture threshold (0.67 ± 0.22 V vs. 0.82 ± 0.28 V, P < 0.001) and lower R-wave amplitude (12.5 ± 4.8 mV vs. 10.1 ± 2.7 mV, P = 0.001). Moreover, CAD was independently associated with higher capture threshold (adjusted Odds ratio (OR) 3.418, 95% confidence interval (CI): 1.621-7.206, P = 0.001), which was further validated through sensitivity analyses. Conclusion: Patients without CAD might have safer pacing parameters in the LBBaP procedure. Besides, CAD might be the risk factor of capture threshold increase during permanent LBBaP implantation.

Association between the variability of non-high-density lipoprotein cholesterol and the neutrophil-to-lymphocyte ratio in patients with coronary heart disease.

Background: Lowering lipid variability may be a potential strategy for improving the inflammatory state in patients with coronary heart disease (CHD). This study investigated the association between the variability of non-high-density lipoprotein cholesterol (non-HDL-C) and the neutrophil-to-lymphocyte ratio (NLR). Methods: This study enrolled 2,711 CHD patients subjected to percutaneous coronary intervention (PCI). During the 1-year follow-up period after PCI, the variability of non-HDL-C was assessed using standard deviation (SD), coefficient of variation (CV), and variability independent of mean (VIM). NLR was calculated as the ratio of absolute neutrophil count to absolute lymphocyte count. The relationship between the non-HDL-C variability and the average NLR level during follow-ups was examined using a linear regression analysis. Results: The mean age of the patients was 64.4 ± 10.8 years, with 72.4% being male. The average NLR level was 2.98 (2.26-4.14) during the follow-up (1 year after PCI). The variability of non-HDL-C was 0.42 (0.26-0.67) for SD, 0.17 (0.11-0.25) for CV, and 0.02 (0.01-0.03) for VIM. A locally weighted scatterplot smoothing curve indicates that the average levels of NLR increased with increasing variability of non-HDL-C. Regardless of the variability assessment method used, non-HDL-C variability was significantly positively associated with the average NLR level during follow-ups: SD [ß (95% CI) = 0.681 (0.366-0.996)], CV [ß (95% CI) = 2.328 (1.458-3.197)], and VIM [ß (95% CI) = 17.124 (10.532-23.715)]. This association remained consistent across subgroups stratified by age, gender, diabetes, and hypertension. Conclusion: The variability of non-HDL-C was positively associated with NLR in patients with CHD, suggesting that reducing non-HDL-C variability may improve the low-grade inflammatory state in CHD patients.

Glasgow prognostic score and its derived scores predicts contrast-associated acute kidney injury in patients undergoing coronary angiography.

Background: Glasgow prognostic score (GPS) is a reliable scoring system reflecting both nutritional and inflammatory factors. The association of inflammation and nutrition with contrast-associated acute kidney injury (CA-AKI) has been validated. This study set out to determine the impact of GPS and its derived scores on CA-AKI incidence. Methods: Populations treated with coronary angiography with/without percutaneous coronary intervention were screened retrospectively. According to C-reactive protein and albumin, three kinds of GPSs were involved: GPS, modified GPS (mGPS), and the cutoff-based GPS (cGPS) which was derived by calculating the optimal cutoff values of two parameters. Primary endpoint was CA-AKI. Pearson' r correlation, linear/logistic regression, receiver operating characteristic curve as well as subgroup analyses were conducted. Results: Totally, 3150 patients were valid for analysis, and the mean age was 67.5 years old, with 66.4 % male. Of these, 610 patients suffered CA-AKI. All three kinds of GPSs were independently associated with the SCr elevation proportion (GPS: ß = 4.850, 95%CI [3.700 to 8.722], P < 0.001; mGPS: ß = 3.450, 95%CI [1.896 to 6.888], P = 0.001; cGPS: ß = 3.992, 95%CI [2.368 to 6.940], P < 0.001). GPS, mGPS and cGPS were proved to be the independent risk factors for CA-AKI risk (all P for trend <0.05). Compared with GPS and mGPS, cGPS was of greater prognostic value for predicting CA-AKI incidence (cGPS: AUC = 0.633; mGPS: AUC = 0.567; GPS: AUC = 0.611). Main findings were also consistent in all subgroup analysis. Conclusion: Preprocedural GPS and its derived scores (mGPS and cGPS), especially cGPS, were correlated with the incidence of CA-AKI, which might assist in clinical decision making in treating CA-AKI.

Lack of Consensus Between Measurements of Plasma Phylloquinone by Enzyme-Linked Immunosorbent assays and a Well-Validated High-Performance Liquid Chromatographic Method.

Enzyme-linked i2mmunosorbent assays (ELISAs) that measure circulating phylloquinone have become commercially available, but their validity is uncertain. The objective of this study was to compare plasma phylloquinone concentrations measured using two commercially available ELISAs with concentrations measured using a validated high-performance liquid chromatography (HPLC) assay in 108 samples obtained from participants in a depletion (∼10 mcg phylloquinone/d)-supplementation (∼500 mcg phylloquinone/d) study. The geometric mean of plasma phylloquinone measured with ELISA A was 0.70 nmol/L, 37% lower than that measured with HPLC. The mean of the ELISA B measures was 12.4 nmol/L, >700% higher than the HPLC measures. Plasma phylloquinone measured using HPLC was significantly lower during phylloquinone depletion than supplementation (0.4 ± 0.1 compared with 1.2 ± 0.2 nmol/L; P < 0.001). Neither of the two ELISAs detected any significant difference in plasma phylloquinone concentrations between depletion and supplementation (ELISA A, P = 0.76; ELISA B, P = 0.29). These findings reinforce the need to validate plasma phylloquinone assays as they become available. Curr Dev Nutr 2023;x:xx.

Long interspersed nuclear element 1 and B1/Alu repeats blueprint genome compartmentalization.

The organization of the genome into euchromatin and heterochromatin has been known for almost 100 years [1]. More than 50% of mammalian genomes contain repetitive sequences [2,3]. Recently, a functional link between the genome and its folding has been identified [4,5]. Homotypic clustering of long interspersed nuclear element 1 (LINE1 or L1) and B1/Alu retrotransposons forms grossly exclusive nuclear domains that characterize and predict heterochromatin and euchromatin, respectively. The spatial segregation of L1 and B1/Alu-rich compartments is conserved in mammalian cells and can be rebuilt during the cell cycle and established de novo in early embryogenesis. Inhibition of L1 RNA drastically weakened homotypic repeat contacts and compartmental segregation, indicating that L1 plays a more significant role than just being a compartmental marker. This simple and inclusive genetic coding model of L1 and B1/Alu in shaping the macroscopic structure of the genome provides a plausible explanation for the remarkable conservation and robustness of its folding in mammalian cells. It also proposes a conserved core structure on which subsequent dynamic regulation takes place.

Synthesis of Two-Dimensional MoO2 Nanoplates with Large Linear Magnetoresistance and Nonlinear Hall Effect.

Two-dimensional (2D) materials with large linear magnetoresistance (LMR) are very interesting owing to their potential application in magnetic storage or sensor devices. Here, we report the synthesis of 2D MoO2 nanoplates grown by a chemical vapor deposition (CVD) method and observe large LMR and nonlinear Hall behavior in MoO2 nanoplates. As-obtained MoO2 nanoplates exhibit rhombic shapes and high crystallinity. Electrical studies indicate that MoO2 nanoplates feature a metallic nature with an excellent conductivity of up to 3.7 × 107 S m-1 at 2.5 K. MoO2 nanoplates display a large LMR of up to 455% at 3 K and -9 T. A thickness-dependent LMR analysis suggests that LMR values increase upon increasing the thickness of nanoplates. Besides, nonlinearity has been found in the magnetic-field-dependent Hall resistance, which decreases with increasing temperatures. Our studies highlight that MoO2 nanoplates are promising materials for fundamental studies and potential applications in magnetic storage devices.

Confined Bismuth-Organic Framework Anode for High-Energy Potassium-Ion Batteries.

Metal-organic frameworks (MOFs) with inherent porosity, controllable structures, and designable components are recognized as attractive platforms for designing advanced electrodes of high-performance potassium-ion batteries (PIBs). However, the poor electrical conductivity and low theoretical capacity of many MOFs lead to inferior electrochemical performance. Herein, for the first time, a confined bismuth-organic framework with 3D porous matrix structure (Bi-MOF) as anode for PIBs via a facile wet-chemical approach is reported. Such a porous structure design with double active centers can simultaneously ensure the structure integrity and efficient charge transport to enable high-capacity electrode with super cycling life. As a result, the Bi-MOF for PIBs exhibits high reversible capacity (419 mAh g-1 at 0.1 A g-1 ), outstanding cycling stability (315 mAh g-1 at 0.5 A g-1 after 1200 cycles), and excellent full battery performance (a high energy density of 183 Wh kg-1 is achieved, outperforming all reported metal-based anodes for PIBs). Moreover, the K+ storage mechanisms of the Bi-MOF are further unveiled by in situ Raman, ex situ high-resolution transmission electron microscopy, and ex situ Fourier-transform infrared spectroscopy. This ingenious electrode design may provide further guidance for the application of MOF in energy storage systems.

Efficacy and safety of pregabalin in eye pain: A systematic review.

BACKGROUND: The pregabalin is approved for the management of persistent pain. The aim of this study is to assess the advantages and disadvantages of the use of pregabalin in eye pain management. METHODS: The PubMed, Cochrane Library, Embase, and Web of Science databases were searched until January 2022 for randomized controlled trials. Randomized, double-blinded trials comparing pregabalin with placebo in eye pain management were included. The primary outcome was visual analog scale or numerical rating scale at acute (24 hours) and chronic (≥7 days after surgery) timepoints. The secondary outcomes were analgesic medication requirements and pregabalin-related complications (nausea, vomiting, dizziness, and headache). We also compared the effect of pregabalin on dry-eye syndrome. MAIN RESULTS: Six relevant articles were identified that studied the use of pregabalin as pain relief for photorefractive keratectomy (n = 2), laser epithelial keratomileusis (n = 1), laser-assisted in situ keratomileusis (n = 1), eyelid surgery (n = 1), and dacryocystorhinostomy (n = 1). Pregabalin was associated with a significant reduction in pain scores (95% confidence interval = -0.41 [-0.76--0.06]) 24 hours after surgical procedures. The data were insufficient to draw conclusions regarding dry eye symptoms. Because of the high heterogeneity of outcomes regarding adverse effects, there is no conclusion regarding the safety of pregabalin in eye pain. CONCLUSIONS: Pregabalin reduced acute eye pain but had no significant effect on long-term analgesia after ophthalmological surgery in adults. It had no effect on dry-eye symptoms after ocular surgery. Further studies on the safety of pregabalin in eye pain management are required to draw solid conclusions.

Thickness-Dependent Topological Hall Effect in 2D Cr5 Si3 Nanosheets with Noncollinear Magnetic Phase.

Antiferromagnets with noncollinear spin order are expected to exhibit unconventional electromagnetic response, such as spin Hall effects, chiral abnormal, quantum Hall effect, and topological Hall effect. Here, 2D thickness-controlled and high-quality Cr5 Si3 nanosheets that are compatible with the complementary metal-oxide-semiconductor technology are synthesized by chemical vapor deposition method. The angular dependence of electromagnetic transport properties of Cr5 Si3 nanosheets is investigated using a physical property measurement system, and an obvious topological Hall effect (THE) appears at a large tilted magnetic field, which results from the noncollinear magnetic structure of the Cr5 Si3 nanosheet. The Cr5 Si3 nanosheets exhibit distinct thickness-dependent perpendicular magnetic anisotropy (PMA), and the THE only emerges in the specific thickness range with moderate PMA. This work provides opportunities for exploring fundamental spin-related physical mechanisms of noncollinear antiferromagnet in ultrathin limit.

Inhibition of neointimal hyperplasia in balloon-induced vascular injuries in a rat model by miR-22 loading Laponite hydrogels.

Percutaneous coronary intervention (PCI) is the mainstream treatment to widen narrowed or obstructed coronary arteries due to pathological conditions. However, the post-operational neointimal hyperplasia occurs because of endothelium denudation during surgical procedures and the following inflammation. MicroRNAs (miRs) are new therapeutics of great potential for cardiovascular diseases. However, miRs easily degrade in vivo. A vehicle that can maintain their bioactivities and extend their retention at the site of delivery is prerequisite for miRs to play their roles as therapeutic reagents. Here, we reported the use of the Laponite hydrogels to deliver miR-22 that are modulators of phenotypes of smooth muscle cells (SMCs). The Laponite hydrogels allow a homogenous distribution of miR-22 within the gels, which had the capacity to transfect SMCs in vitro. Upon the injection of the miR-22 incorporated in the Laponite hydrogels in vivo, miR-22 could be well retained surrounding arteries for at least 7 days. Moreover, the miR-22 loading Laponite hydrogels inhibited the neointimal formation, reduced the infiltration of the macrophages, and reversed the adverse vascular ECM remodeling after the balloon-induced vascular injuries by upregulation of miR-22 and downregulation of its target genes methyl-CpG binding protein 2 (MECP2). The application of the Laponite hydrogels for miR local delivery may offer a novel strategy to treat cardiovascular diseases.

Pressure pain threshold and somatosensory abnormalities in different ages and functional conditions of post-stroke elderly.

BACKGROUND: Somatosensory deficits and abnormal pain sensitivity are highly prevalent among stroke survivors, which negatively impacts their quality of life and recovery process. However, the factors for pressure pain threshold (PPT) and somatosensory abnormalities in post-stroke elderly remain unknown. The aim of this study was to explore the effects of age, side and other functional conditions, such as spasticity and motor functions, on PPT and sensory abnormalities among elderly after stroke. METHODS: The cross-sectional study finally included 43 post-stroke elderly aged over 60 and assessed the PPT of 14 bilateral muscles widely located in the whole body by using a digital force gage. Meanwhile, spasticity, motor function, joint pain and activity of daily living (ADL) were evaluated by the Modified Ashworth scale, Fugl-Meyer, and Barthel Index, respectively. All participants were divided into higher-aged and lower-aged groups based on the median age of all of them. RESULTS: Higher age tended to be associated with higher sensitivity but not significant except for one upper limb muscle, and the affected side showed significantly higher PPTs than the unaffected side in three out of seven muscles (p < 0.05). Furthermore, the somatosensory abnormalities in the affected side, particularly hypoalgesia, were more frequent in higher-aged than lower-aged patients in most assessed muscles. Meanwhile, patients with spasticity showed more increment of PPTs in affected muscles around the knee joint than patients without spasticity (p < 0.05). Patients with better motor functions, less joint pain and higher ADL performed less bilateral differences of PPTs than other patients in some muscles (p < 0.05). CONCLUSIONS: The age and side differences of mechanical pain sensitivity were found among post-stroke elderly. Older patients show higher sensitivity in both sides compared with the younger ones, and the affected side of the elder shows more somatosensory abnormalities, particularly hypoalgesia, than that of the younger ones. Post-stroke elderly in good functional conditions, such as normal muscle tone, better physical function and daily activities, and less joint pain, seems to have more equal pain sensitivity between both sides than those in poor conditions.

HEIH Promotes Malignant Progression of Gastric Cancer by Regulating STAT3-Mediated Autophagy and Glycolysis.

To study the clinical value of HEIH hyperexpression in gastric cancer and the molecular mechanism of promoting malignant proliferation of gastric cancer cells, qRT-PCR was used to detect the expression of HEIH in gastric cancer and nontumor gastric tissues. HEIH interference sequence was constructed to downregulate HEIH expression in MGC-803 and BGC-823 cell lines. CCK8, clonogenesis, and Transwell assay were used to detect the effects of HEIH on proliferation and invasion of tumor cells. The protein levels of STAT3, p-STAT3, P62, and LC3 were detected by Western blotting. The results showed that HEIH was highly expressed in gastric cancer (P < 0.01). Interference of HEIH expression in MGC-803 and BGC-823 cells reduced the proliferation and invasion of gastric cancer cells, and the results were statistically significant (P < 0.05). HEIH acts as a miRNA sponge for miR-4500. HEIH promotes gastric cancer development by inhibiting miR-4500. STAT3 is a downstream target of miR-4500. HEIH inhibits autophagy and promotes glycolysis. In conclusion, HEIH is highly expressed in gastric cancers. HEIH promotes malignant proliferation and development of gastric cancer cells. HEIH may be a new candidate site for pathological diagnosis and molecular drug therapy for future clinical treatment of gastric cancer.

A TET1-PSPC1-Neat1 molecular axis modulates PRC2 functions in controlling stem cell bivalency.

TET1 maintains hypomethylation at bivalent promoters through its catalytic activity in embryonic stem cells (ESCs). However, TET1 catalytic activity-independent function in regulating bivalent genes is not well understood. Using a proteomics approach, we map the TET1 interactome in ESCs and identify PSPC1 as a TET1 partner. Genome-wide location analysis reveals that PSPC1 functionally associates with TET1 and Polycomb repressive complex-2 (PRC2). We establish that PSPC1 and TET1 repress, and the lncRNA Neat1 activates, bivalent gene expression. In ESCs, Neat1 is preferentially bound to PSPC1 alongside its PRC2 association at bivalent promoters. During the ESC-to-epiblast-like stem cell (EpiLC) transition, PSPC1 and TET1 maintain PRC2 chromatin occupancy at bivalent gene promoters, while Neat1 facilitates the activation of certain bivalent genes by promoting PRC2 binding to their mRNAs. Our study demonstrates a TET1-PSPC1-Neat1 molecular axis that modulates PRC2-binding affinity to chromatin and bivalent gene transcripts in controlling stem cell bivalency.

Intra-rater and inter-rater reliability of pressure pain threshold assessment in stroke patients.

BACKGROUND: As pain is a common symptom following a stroke, pressure pain threshold (PPT) assessment can be used to evaluate pain status or pain sensitivity of patients. However, the reliability of PPT test in stroke patients is still unknown. AIM: To examine the intra- and inter-rater reliability of PPT measurements in poststroke survivors and explore their factors. DESIGN: An observational study. SETTING: The setting of the study is a rehabilitation hospital. POPULATION: The population of the study was represented by a total of 54 patients after stroke. METHODS: The study included 16 measured points on the affected and unaffected sides. PPT was assessed by two raters in turn. Intra- and inter-rater reliability was evaluated by intraclass correlation coefficients (ICC). RESULTS: All intra-rater (ICC=0.84-0.97) and inter-rater (ICC=0.83-0.95) reliability for PPT assessment were good or excellent in stroke patients. Of the 16 points, 12 showed higher intra-rater ICC values than inter-rater, whereas no evident difference was observed between the affected and unaffected sides. Furthermore, patients who were male, ischemic, or with higher motor function generally performed higher ICC values than those who were female (24 out of 32 results), hemorrhagic (28 out of 32 results), or mobility dysfunction (26 out of 32 results), respectively. CONCLUSIONS: PPT assessment with good or excellent reliability can be used in stroke patients. Neither of the two sides (affected or unaffected) affects PPT reliability, and intra-rater reliability is better than inter-rater reliability. In addition, gender, stroke type, and motor function can affect the reliability of measuring mechanical pain threshold in poststroke survivors. CLINICAL REHABILITATION IMPACT: The pressure algometer can be used as a reliable and portable tool to assess the mechanical pain tolerance and sensory function in stroke patients in clinics.

Elevation of Hemoglobin A1c Increases the Atherosclerotic Plaque Vulnerability and the Visit-to-Visit Variability of Lipid Profiles in Patients Who Underwent Elective Percutaneous Coronary Intervention.

BACKGROUND: Increased plaque vulnerability and higher lipid variability are causes of adverse cardiovascular events. Despite a close association between glucose and lipid metabolisms, the influence of elevated glycated hemoglobin A1c (HbA1c) on plaque vulnerability and lipid variability remains unclear. METHODS: Among subjects undergoing percutaneous coronary intervention (PCI) from 2009 through 2019, 366 patients received intravascular optical coherence tomography (OCT) assessment and 4,445 patients underwent the scheduled follow-ups within 1 year after PCI. Vulnerability features of culprit vessels were analyzed by OCT examination, including the assessment of lipid, macrophage, calcium, and minimal fibrous cap thickness (FCT). Visit-to-visit lipid variability was determined by different definitions including standard deviation (SD), coefficient of variation (CV), and variability independent of the mean (VIM). Multivariable linear regression analysis was used to verify the influence of HbA1c on plaque vulnerability features and lipid variability. Exploratory analyses were also performed in non-diabetic patients. RESULTS: Among enrolled subjects, the pre-procedure HbA1c was 5.90 ± 1.31%, and the average follow-up HbA1c was 5.98 ± 1.16%. By OCT assessment, multivariable linear regression analyses demonstrated that patients with elevated HbA1c had a thinner minimal FCT (ß = -6.985, P = 0.048), greater lipid index (LI) (ß = 226.299, P = 0.005), and higher macrophage index (ß = 54.526, P = 0.045). Even in non-diabetic patients, elevated HbA1c also linearly decreased minimal FCT (ß = -14.011, P = 0.036), increased LI (ß = 290.048, P = 0.041) and macrophage index (ß = 120.029, P = 0.048). Subsequently, scheduled follow-ups were performed during 1-year following PCI. Multivariable linear regression analyses proved that elevated average follow-up HbA1c levels increased the VIM of lipid profiles, including low-density lipoprotein cholesterol (ß = 2.594, P < 0.001), high-density lipoprotein cholesterol (ß = 0.461, P = 0.044), non-high-density lipoprotein cholesterol (ß = 1.473, P < 0.001), total cholesterol (ß = 0.947, P < 0.001), and triglyceride (ß = 4.217, P < 0.001). The result was consistent in non-diabetic patients and was verified when SD and CV were used to estimate variability. CONCLUSION: In patients undergoing elective PCI, elevated HbA1c increases the atherosclerotic plaque vulnerability and the visit-to-visit variability of lipid profiles, which is consistent in non-diabetic patients.

Association of caffeine intake with all-cause and cardiovascular mortality in elderly patients with hypertension.

Background: Caffeine is widely consumed not only in coffee but also in soft drinks and tea. However, the long-term health effects of caffeine are still controversial, especially in people with high cardiovascular risk such as elderly patients with hypertension. Methods: This study analyzed data from the National Health and Nutrition Examination Survey 2003-2018. Caffeine intake was calculated by two 24-h dietary recall interviews. Complex sampling-weighted multivariable Cox proportional hazards models were used to compare the hazard ratios (HRs) of all-cause and cardiovascular mortality in elderly hypertensive patients with different caffeine intake (<10, 10 to <100, 100 to <200, 200 to <300, and ≥300 mg/day). Results: This study included 6,076 elderly hypertensive patients. The mean ± standard error follow-up duration was 6.86 ± 0.12 years. During this period, a total of 2,200 all-cause deaths occurred, of which 765 were cardiovascular deaths. Taking patients with caffeine intake < 10 mg/day as a reference, patients with moderate caffeine intake (200 to <300 mg/day) had a lower risk of all-cause (HR, 0.70 [95% CI, 0.56-0.87]) and cardiovascular (HR, 0.55 [95% CI, 0.39-0.77]) mortality. The benefit of reducing all-cause mortality risk was significant in female patients (HR, 0.65 [95% CI, 0.50-0.85]) or patients with well-controlled blood pressure (HR, 0.63 [95% CI, 0.46-0.87]), but not in male patients or patients with poorly controlled blood pressure. In addition, non-linear relationship analysis also showed that moderate caffeine intake had the lowest HRs of all-cause (Non-linear p = 0.022) and cardiovascular mortality (Non-linear p = 0.032) in the present study. Conclusion: Moderate caffeine intake is associated with reduced risk of all-cause and cardiovascular mortality in elderly hypertensive patients.

LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells.

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.

Phase separation of RNA-binding protein promotes polymerase binding and transcription.

An RNA-involved phase-separation model has been proposed for transcription control. However, the molecular links that connect RNA to the transcription machinery remain missing. Here we find that RNA-binding proteins (RBPs) constitute half of the chromatin proteome in embryonic stem cells (ESCs), some being colocalized with RNA polymerase (Pol) II at promoters and enhancers. Biochemical analyses of representative RBPs show that the paraspeckle protein PSPC1 inhibits the RNA-induced premature release of Pol II, and makes use of RNA as multivalent molecules to enhance the formation of transcription condensates and subsequent phosphorylation and release of Pol II. This synergistic interplay enhances polymerase engagement and activity via the RNA-binding and phase-separation activities of PSPC1. In ESCs, auxin-induced acute degradation of PSPC1 leads to genome-wide defects in Pol II binding and nascent transcription. We propose that promoter-associated RNAs and their binding proteins synergize the phase separation of polymerase condensates to promote active transcription.