Live birth of chimeric monkey with high contribution from embryonic stem cells.

A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.

Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays.

Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.

Multimodal cell atlas of the ageing human skeletal muscle.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

Rolling back human pluripotent stem cells to an eight-cell embryo-like stage.

After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.

Cell transcriptomic atlas of the non-human primate Macaca fascicularis.

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.

Orthostatic blood pressure changes do not influence cognitive outcomes following intensive blood pressure control.

BACKGROUND: Effects of intensive blood pressure (BP) control on cognitive outcomes in patients with excess orthostatic BP changes are unclear. We aimed to evaluate whether orthostatic BP changes modified the effects of BP intervention on cognitive impairment. METHODS: We analyzed 8547 participants from the Systolic Blood Pressure Intervention Trial Memory and cognition IN Decreased Hypertension. Associations between orthostatic BP changes and incident cognitive outcomes were evaluated by restricted cubic spline curves based on Cox models. The interactions between orthostatic BP changes and intensive BP intervention were assessed. RESULTS: The U-shaped associations were observed between baseline orthostatic systolic BP changes and cognitive outcomes. However, there were insignificant interactions between either change in orthostatic systolic BP (P for interaction = 0.81) or diastolic BP (P for interaction = 0.32) and intensive BP intervention for the composite outcome of probable dementia or mild cognitive impairment (MCI). The hazard ratio of intensive versus standard target for the composite cognitive outcome was 0.82 (95% CI 0.50-1.35) in those with an orthostatic systolic BP reduction of >20 mmHg and 0.41 (95% CI 0.21-0.80) in those with an orthostatic systolic BP increase of >20 mmHg. Results were similar for probable dementia and MCI. The annual changes in global cerebral blood flow (P for interaction = 0.86) consistently favored intensive BP treatment across orthostatic systolic BP changes. CONCLUSION: Intensive BP control did not have a deteriorating effect on cognitive outcomes among hypertensive patients experiencing significant postural BP changes.

Effect of SGLT2 inhibitors on cardiovascular events in patients with atrial fibrillation: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is reported to reduce incident atrial fibrillation (AF) in patients with or without diabetes; however, its cardiovascular (CV) benefit for AF patients remains unclear. SS AIMS: To investigate the effect of SGLT2i on the incidence of CV events in patients with AF. METHODS: Six randomized controlled trials (RCTs) assessing the effects of SGLT2i on CV outcomes in patients with or without AF were included (PROSPERO: CRD 42023431535). The primary endpoint was the composite outcome of heart failure (HF) hospitalization and CV death. Additionally, we assessed the effects of treatment in prespecified subgroups on HF hospitalization, CV death, and all-cause mortality. RESULTS: Among 38,529 participants from all trials, 5018 patients with AF were treated with SGLT2i. The follow-up period of these trials ranged from 2.3 to 3.3 years. SGLT2i treatment was significantly associated with the risk reduction of primary endpoint in patients with AF (risk ratio [RR] 0.81, 95% confidence interval [CI] 0.74-0.88; p < 0.001), consistent with the finding in the general population (p for interaction = 0.76). SGLT2i was also associated with a consistent reduction in the risk of HF hospitalization in patients with AF (RR 0.76, 95% CI 0.69-0.84; p < 0.001) or not (RR 0.72, 95% CI 0.64-0.80; p < 0.0001), with no statistical difference between them (p for interaction = 0.41). Meta-regression further revealed no significant association between the prevalence of HF with reduced ejection fraction or diabetes and the effect size of SGLT2i. CONCLUSIONS: The treatment effects of SGLT2i were associated with a lower incidence of CV events, especially HF hospitalization, in patients with AF.

Randomized Controlled Trial Comparing Training of Transseptal Puncture With or Without Intracardiac Echocardiography.

BACKGROUND: Intracardiac echocardiography (ICE) has been widely used in the catheter ablation of atrial fibrillation (AF). However, the value of ICE in the training of transseptal puncture (TSP) is unclear. METHODS: ICE-Training Study was a single-center, parallel-group, unmasked, randomized controlled trial registered in ChineseClinicalTrials.gov. Participants were randomly assigned (1:1) to different groups (1) the ICE simulator training group (ICE-ST), in which TSP was trained and performed under the guidance of both ICE and x-ray; and (2) the conventional simulator training group (Con-ST), in which TSP was trained and performed only under the guidance of x-ray. The trainees need to undergo the training stage and the evaluation stage. RESULTS: From October 2022 to December 2022, 18 consecutive fellows (age 32.4 ± 4.4 years, 12 males) without experience of TSP were included. The training period (16.9 ± 6.6 vs. 29.6 ± 8.7 times, p = 0.003) and the fluoroscopy time (120.3 ± 25.3 vs. 189.3 ± 40.2 s, p < 0.001) of the ICE-ST group was significantly shorter than that of the Con-ST group. No significant difference was found in the comprehensive performance of TSP in the ICE-ST group (composite score 96.7 ± 5.7) and the Con-ST group (composite score 95.9 ± 6.3, p = 0.62), but the selection of TSP sites in the ICE-ST group was commonly better than that in the Con-ST group. CONCLUSIONS: ICE could improve the efficiency of TSP training and optimize the site of TSP to facilitate catheter manipulation in the ablation. TRIAL REGISTRATION: ChineseClinicalTrials.gov identifier: ChiCTR2200058377.

Prospective randomized comparison between upgraded '2C3L' vs. PVI approach for catheter ablation of persistent atrial fibrillation: PROMPT-AF trial design.

BACKGROUND: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion. OBJECTIVE: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF. STUDY DESIGN: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months). CONCLUSIONS: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.

Very-early symptomatic recurrence is associated with late recurrence after radiofrequency ablation of atrial fibrillation.

AIMS: After radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF), the effect of very-early (within 48 h) symptomatic recurrence (VESR) on late (after 3 months of RFCA) recurrence (LR) has been seldomly reported. We aimed to explore the relationship between VESR and LR among post-RFCA patients. METHODS AND RESULTS: This was a single-centre prospective cohort study that enrolled 6887 AF patients who received the first RFCA procedure from June 2018 to December 2021 at Beijing Anzhen Hospital. Patients were divided into four groups based on VESR and early (from 48 h to 3 months after RFCA) recurrence (ER): Group A (no VESR, no ER); Group B (VESR but no ER); Group C (ER but no VESR); and Group D (both VESR and ER). Three hundred and thirty (4.79%) patients experienced VESR (Groups B and D). With an average follow-up of 14.7 months after grouping, the Kaplan-Meier curve showed that LR risk in VESR patients was higher than in other patients (log-rank, P < 0.001), and the difference was significant in both paroxysmal (log-rank, P < 0.001) and persistent (log-rank, P < 0.001) AF patients (P for interaction = 0.118). In multivariate analysis, Groups B, C, and D were associated with a 2.161-, 5.409-, and 7.401-fold increase in the risk of LR, respectively. What is more, compared with Group A, VESR-atrial tachycardia and VESR-AF were related to a 3.467- and 5.564-fold LR risk, respectively. In VESR patients, classification based on ER and VESR modes improved the prediction potential of LR risk. CONCLUSION: Very-early symptomatic recurrence is associated with an increased risk of LR.

Revisiting the characteristics and ablation strategy of biatrial tachycardias: a case series and systematic review.

AIMS: To describe the role of left atrial (LA) epicardial conduction and targets of ablation in biatrial tachycardias (BiATs). METHODS AND RESULTS: Consecutive patients with BiAT diagnosed by high-density mapping and appropriate entrainment were enrolled. A systematic review of case reports or series was then performed. Biatrial tachycardia was identified in 20 patients aged 63.5 ± 11.1 years. Among them, eight had LA epicardial conduction, including four via the ligament of Marshall, two via myocardial fibres between the great cardiac vein (GCV) and LA, one via septopulmonary bundle, and one via myocardial fibres between the posterior wall and coronary sinus. Ablation was targeted at the anatomical isthmus in 14, including 5 undergoing vein of Marshall ethanol infusion and 2 undergoing ablation in the GCV. Another six underwent ablation at interatrial connections, including one with septopulmonary bundle at the fossa ovalis and five at the atrial insertions of Bachmann's bundle. After a mean follow-up of 8.7 ± 3.8 months, five patients had recurrence of atrial fibrillation/flutter. Systematic review enrolled 87 patients in previous and the present reports, showing a higher risk of impairment in atrial physiology in those targeting interatrial connections (30.4 vs. 5.0%, P < 0.001) but no significant difference in short- and long-term effectiveness. CONCLUSION: Left atrial epicardial conduction is common in BiATs and affects the ablation strategy. Atrial physiology is a major concern in selecting the target of intervention.

The adjunctive effect for left pulmonary vein isolation of vein of Marshall ethanol infusion in persistent atrial fibrillation.

OBJECTIVE: This study sought to assess the effect of ethanol infusion into the vein of Marshall (EIVOM) on the acute success of left pulmonary vein (LPV) isolation in persistent atrial fibrillation (PeAF). METHODS AND RESULTS: A total of 313 patients with drug-resistant PeAF were enrolled (135 in Group 1 and 178 in Group 2). In Group 1, EIVOM was firstly performed, followed by radiofrequency ablation (RFA) including bilateral pulmonary vein isolation (PVI) and linear ablation at roofline, cavotricuspid isthmus, and mitral isthmus (MI). In Group 2, PVI and linear ablations were completed with RFA. First-pass isolation of the LPV was achieved in 119 (88.1%) and 132 (74.2%) patients in Groups 1 and 2, respectively (P = 0.002). The rate of acute pulmonary vein reconnection (PVR) was significantly lower in Group 1 (9.6% vs. 22.5%, P = 0.003). About half of acute PVR occurred in the carina with or without EIVOM. CONCLUSION: EIVOM is effective in achieving a higher first-pass isolation and a lower acute PVR of LPV in PeAF.

Epicardial connections and bi-atrial tachycardias: From anatomy to clinical practice.

Bi-atrial tachycardia (BiAT) is not rare after extensive atrial ablation or cardiac surgery. The complexity of bi-atrial reentrant circuits poses a great challenge for clinical practice. With recent advances in mapping technologies, we are now able to characterize atrial activation in detail. However, given the involvement of both atria and multiple epicardial conductions, endocardial mapping for BiATs is not easy to understand. Knowledge of the atrial myocardial architecture is the foundation for the clinical management of BiATs; as it is required to understand the possible mechanism of the tachycardia and identify the optimal target of ablation. In this review we summarize current knowledge about the anatomy of interatrial connections as well as other epicardial fibers and discuss the interpretation of electrophysiological findings and ablation strategies for BiATs.

Identification of atrial fibrillation phenotypes at low risk of stroke in patients with CHA2DS2-VASc ≥2: Insight from the China-AF study.

OBJECTIVE: Patients with atrial fibrillation (AF) are highly heterogeneous, and current risk stratification scores are only modestly good at predicting an individual's stroke risk. We aim to identify distinct AF clinical phenotypes with cluster analysis to optimize stroke prevention practices. METHODS: From the prospective Chinese Atrial Fibrillation Registry cohort study, we included 4337 AF patients with CHA2 DS2 -VASc≥2 for males and 3 for females who were not treated with oral anticoagulation. We randomly split the patients into derivation and validation sets by a ratio of 7:3. In the derivation set, we used outcome-driven patient clustering with metric learning to group patients into clusters with different risk levels of ischemic stroke and systemic embolism, and identify clusters of patients with low risks. Then we tested the results in the validation set, using the clustering rules generated from the derivation set. Finally, the survival decision tree was applied as a sensitivity analysis to confirm the results. RESULTS: Up to the follow-up of 1 year, 140 thromboembolic events (ischemic stroke or systemic embolism) occurred. After supervised metric learning from six variables involved in CHA2 DS2 -VASc scheme, we identified a cluster of patients (255/3035, 8.4%) at an annual thromboembolism risk of 0.8% in the derivation set. None of the patients in the low-risk cluster had prior thromboembolism, heart failure, diabetes, or age older than 70 years. After applying the regularities from metric learning on the validation set, we also identified a cluster of patients (137/1302, 10.5%) with an incident thromboembolism rate of 0.7%. Sensitivity analysis based on the survival decision tree approach selected a subgroup of patients with the same phenotypes as the metric-learning algorithm. CONCLUSIONS: Cluster analysis identified a distinct clinical phenotype at low risk of stroke among high-risk [CHA2 DS2 -VASc≥2 (3 for females)] patients with AF. The use of the novel analytic approach has the potential to prevent a subset of AF patients from unnecessary anticoagulation and avoid the associated risk of major bleeding.

Vein of Marshall ethanol infusion: First-step or adjunctive choice for perimitral atrial tachycardia?

BACKGROUND: Perimitral atrial tachycardia (PMAT) is the most frequent type of iatrogenic atrial tachycardia (AT) after atrial fibrillation (AF) ablation. Vein of Marshall ethanol infusion (EIVOM) is a promising technique in mitral isthmus (MI) ablation. METHODS: A total of 165 patients with PMAT were divided into three groups according to ablation strategies, including RF only group (n = 89), RF-EIVOM group (initial RF ablation with adjunctive EIVOM, n = 28), and EIVOM-RF group (first-step EIVOM with touch-up RF ablation, n = 48). Acute and follow-up procedure outcomes were evaluated. RESULTS: PMAT terminated in 89.9%, 89.3%, and 93.7% of patients in RF only, RF-EIVOM and EIVOM-RF groups, respectively (p = .715), with complete MI block achieved in 80.9%, 89.3%, and 95.8% of patients (EIVOM-RF vs. RF only, p = .012). First-step utilization of EIVOM was associated with a significant shortening of RF ablation time at MI (EIVOM-RF 2.1 ± 1.3 min, RF only 7.9 ± 5.9 min, RF-EIVOM 6.8 ± 5.8 min; p < .001) and a decrease in the proportion of patients need ablation within coronary sinus (CS, EIVOM-RF 14.6%, RF only 61.8%, RF-EIVOM 64.3%; p < .001). After a mean follow-up of 12.1 ± 6.2 months, AF/AT recurred in 39 (43.8%), 6 (21.4%), and 12 (25.0%) patients in RF only, RF-EIVOM, and EIVOM-RF group (RF-EIVOM vs. RF only, p = .026; EIVOM-RF vs. RF only, p = .022). CONCLUSIONS: EIVOM was associated with an enhanced acute MI block rate as well as reduced AF/AT recurrence. First-step utilization of EIVOM promises to significantly simplify the RF ablation process. CONDENSED ABSTRACT: PMAT is the most common type of iatrogenic AT after AF ablation procedures. EIVOM contributed to a higher acute MI block rate and lower arrhythmia recurrence risk during follow-up. First-step utilization of EIVOM significantly reduced the need for radiofrequency ablation at MI and inside CS with the advantage of creating a homogenous, transmural lesion and eliminating epicardial connections.

Effects of intensive blood pressure control on cardiovascular and cognitive outcomes in patients with atrial fibrillation: insights from the SPRINT trial.

AIMS: Patients with atrial fibrillation (AF) have an increased risk of cardiovascular events and dementia, even if anticoagulated. Hypertension is highly prevalent in AF population; however, the optimal blood pressure (BP) target for AF patients remains unknown. METHODS AND RESULTS: We conducted subgroup analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) to examine whether AF modified the treatment effects of intensive BP control on cardiovascular and cognitive outcomes using Cox proportional hazards regression and likelihood ratio tests. Among 9361 randomized participants, 778 (8.3%) had baseline AF, and 695 (89.3%) completed at least one follow-up cognitive assessment. Intensive BP control reduced the similar relative risk of cardiovascular events irrespective of the presence of AF, with all interaction P-values > 0.05. Patients with AF experienced a greater absolute risk reduction in the composite primary cardiovascular outcome (12.3 vs. 5.6 events per 1000 person-years) with intensive treatment, compared with those without AF. However, intensive BP control increased the risk of probable dementia in patients with AF [hazard ratio (HR), 2.22; 95% confidence interval (CI), 1.03-4.80], while reducing the dementia risk in patients without AF (HR, 0.75; 95% CI, 0.60-0.95; P = 0.009 for interaction). There were no significant interactions between the presence of AF and intensive BP treatment for mild cognitive impairment. CONCLUSION: Patients with AF experienced greater absolute cardiovascular benefits with intensive BP treatment, but may need to be cautious of an increased risk of dementia. This post hoc analysis should be considered as hypothesis generating and merit further study. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Association Between Atrial Fibrillation and Domain-Specific Cognitive Decline　- Insights From the Systolic Blood Pressure Intervention Trial.

BACKGROUND: There is a dearth of evidence to characterize longitudinal changes in domain-specific cognitive function related to atrial fibrillation (AF).Methods and Results: This study enrolled 2,844 participants from the Systolic Blood Pressure Intervention Trial (SPRINT). Cognitive function was assessed at baseline and biennially during the follow-up period. Declines in global function and 4 major cognitive domains (i.e., memory, processing speed, language, and executive function) were fitted and compared between participants with and without AF using robust linear mixed-effect models. There were 252 participants with prevalent AF (mean [±SD] age 72.0±8.5 years; 30% women) and 2,592 participants without AF (mean age 67.9±8.4 years; 38% women). The annual decline in global function scores was greater among participants with than without AF (-0.016 vs. -0.012 points); however, the difference was not statistically significant (P=0.33). Processing speed declined faster in participants with prevalent AF, with a distinct difference of -0.013 points/year (95% CI -0.024~-0.001 points/year; P=0.02). For the memory, executive function, and language domains, there were no significant differences in the rate of cognitive decline between participants with and without AF. CONCLUSIONS: In this post hoc analysis of the SPRINT trial, processing speed was the most prominent cognitive domain affected by AF, which may be beneficial for the early screening of cognitive dysfunction.

Concurrent binding to DNA and RNA facilitates the pluripotency reprogramming activity of Sox2.

Some transcription factors that specifically bind double-stranded DNA appear to also function as RNA-binding proteins. Here, we demonstrate that the transcription factor Sox2 is able to directly bind RNA in vitro as well as in mouse and human cells. Sox2 targets RNA via a 60-amino-acid RNA binding motif (RBM) positioned C-terminally of the DNA binding high mobility group (HMG) box. Sox2 can associate with RNA and DNA simultaneously to form ternary RNA/Sox2/DNA complexes. Deletion of the RBM does not affect selection of target genes but mitigates binding to pluripotency related transcripts, switches exon usage and impairs the reprogramming of somatic cells to a pluripotent state. Our findings designate Sox2 as a multi-functional factor that associates with RNA whilst binding to cognate DNA sequences, suggesting that it may co-transcriptionally regulate RNA metabolism during somatic cell reprogramming.