ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum.

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.

Antiplatelet therapy for treatment of coronary artery disease in older patients.

Coronary artery disease in older patients is more frequently diffuse and complex, and is often treated by percutaneous coronary intervention on top of medical therapy. There are currently no specific recommendations for antiplatelet therapy in patients aged≥75 years. Aspirin remains pivotal, and is still indicated as a long-term treatment after percutaneous coronary intervention. In addition, a P2Y12 inhibitor is administered for 6-12 months according to clinical presentation. Age is a minor bleeding risk factor, but because older patients often have several co-morbidities, they are considered as having a high bleeding risk according to different scoring systems. This increased bleeding risk has resulted in different therapeutic strategies for antithrombotic treatment after percutaneous coronary intervention; these include short dual antiplatelet therapy, a switch from potent to less potent antiplatelet therapy or single antiplatelet therapy with a P2Y12 inhibitor instead of aspirin, among others. A patient-centred approach, taking into account health status, functional ability, frailty, cognitive skills, bleeding and ischaemic risks and patient preference, is essential when caring for older adults with coronary artery disease. The present review focuses on the knowledge base, specificities of antiplatelet therapies, a balance between haemorrhagic and ischaemic risk, strategies for antiplatelet therapy and directions for future investigation pertaining to coronary artery disease in older patients.

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Clinical and angiographic characteristics of out-of-hospital cardiac arrest among patients with ST-segment elevation myocardial infarction.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is the most severe complication of ST-segment elevation myocardial infarction (STEMI). Nevertheless, clinical and angiographic characteristics associated with OHCA among patients with STEMI have not been studied extensively. AIM: To evaluate the clinical and angiographic characteristics of consecutive patients who presented with STEMI associated or not with OHCA. METHODS: This was an observational study including consecutive patients treated for STEMI associated or not with OHCA. Baseline clinical and angiographic characteristics, biological characteristics and mortality were compared between patients with STEMI who experienced OHCA and patients with STEMI who did not. RESULTS: Among the 686 included patients with STEMI, 148 (21.6%) presented with concomitant OHCA. Multivariable analysis revealed that culprit lesion localized on the left system (odds ratio [OR] 1.94, 95% confidence interval [CI] 1.24-3.13; P<0.01), culprit lesion at the level of a bifurcation lesion (OR 1.87, 95% CI 1.21-2.88; P<0.01) and the presence of chronic total occlusion on another artery (OR 3.39, 95% CI 1.93-5.99; P<0.001) were associated with the occurrence of OHCA, whereas dyslipidaemia, familial history of coronary artery disease and hypertension were found to be negatively associated with the occurrence of OHCA in patients with STEMI: OR 0.47, 95% CI 0.29-0.75 (P<0.01); OR 0.09, 95% CI 0.02-0.25 (P<0.001); and OR 0.60, 95% CI 0.38-0.93 (P=0.02), respectively. CONCLUSION: In this study of consecutive patients with STEMI, culprit lesion localized on the left system, culprit lesion at the level of a bifurcation lesion and the presence of chronic total occlusion on a non-culprit artery were associated with OHCA.

Percutaneous Coronary Intervention in Out-of-Hospital Cardiac Arrest Related to Acute Coronary Syndrome: A Literature Review.

Out-of-hospital cardiac arrest (OHCA) continues to be a major global cause of death, affecting approximately 67 to 170 per 100,000 inhabitants annually in Europe, with a persisting high rate of mortality of up to 90% in most countries. Acute coronary syndrome (ACS) represents one of the most significant cause of cardiac arrest, and therefore invasive coronary angiography (CAG) with subsequent percutaneous coronary intervention (PCI) has emerged as a fundamental component in the management of OHCA patients. Recent evidence from large randomized controlled trials (RCTs) challenges the routine use of early CAG in the larger subgroup of patients with non-ST segment elevation myocardial infarction (NSTEMI). Additionally, emerging data suggest that individuals resuscitated from OHCA related to ACS face an elevated risk of thrombotic and bleeding events. Thus, specific invasive coronary strategies and anti-thrombotic therapies tailored to this unique setting of OHCA need to be considered for optimal in-hospital management. We sought to provide an overview of the prevalence and complexity of coronary artery disease observed in this specific population, discuss the rationale and timing for CAG after return of spontaneous circulation (ROSC), summarize invasive coronary strategies, and examine recent findings on antithrombotic therapies in the setting of ACS complicated by OHCA. By synthesizing the existing knowledge, this review aims to contribute to the understanding and optimization of care for OHCA patients to improve outcomes in this challenging clinical scenario.

Extending the toolbox for RNA biology with SegModTeX: a polymerase-driven method for site-specific and segmental labeling of RNA.

RNA performs a wide range of functions regulated by its structure, dynamics, and often post-transcriptional modifications. While NMR is the leading method for understanding RNA structure and dynamics, it is currently limited by the inability to reduce spectral crowding by efficient segmental labeling. Furthermore, because of the challenging nature of RNA chemistry, the tools being developed to introduce site-specific modifications are increasingly complex and laborious. Here we use a previously designed Tgo DNA polymerase mutant to present SegModTeX - a versatile, one-pot, copy-and-paste approach to address these challenges. By precise, stepwise construction of a diverse set of RNA molecules, we demonstrate the technique to be superior to RNA polymerase driven and ligation methods owing to its substantially high yield, fidelity, and selectivity. We also show the technique to be useful for incorporating some fluorescent- and a wide range of other probes, which significantly extends the toolbox of RNA biology in general.

The Association of Cardiovascular and Neurological Comorbidities in Geriatric Patients Sustaining Ocular Trauma.

Purpose: Falls are associated with ocular trauma in the elderly. However, it is unlikely for a fall to cause ocular injury unless there is a disruption in the protective maneuvers that shield the face. We suspect ocular injury may be an early indicator of systemic or neurologic degeneration. This study investigates the 5-year incidence of cardiovascular and neurodegenerative diseases in older patients who sustained ocular or periorbital injuries. Patients and Methods: This was a retrospective cohort study. The study population included 141 patients over the age of 65 who sustained trauma to the eye, orbit, or eyelid between April 2011 and June 2016. The control population included 141 patients with a similar range of comorbidities who received cataract surgery during the same period. The study measured new diagnoses of various disorders during the 5-year period following presentation. Results: There were a total of 180 females and 102 males in the study. The mean ages of the control and subject group were 76 and 81.8, respectively. Of our twelve tested comorbidity types, patients that suffered a periocular trauma were more likely to develop heart failure (p=0.00244), dementia (p=0.00002), Alzheimer's disease (p=0.00087), and vascular disease (p=0.00037). Conclusion: Geriatric patients who sustained ocular and periocular injuries had a greater incidence of heart failure, dementia, Alzheimer's disease, and atherosclerosis diagnoses in the 5-year period following injury. The findings of this study suggest that periocular trauma may be an early indicator of underlying degenerative or systemic disease. Ophthalmologists should ensure proper primary care follow-up in conjunction with recovery from injury.

Evolution of Coronary Stent Platforms: A Brief Overview of Currently Used Drug-Eluting Stents.

Cardiovascular disease, including ischemic heart disease, is the leading cause of death worldwide, and percutaneous coronary interventions (PCIs) have been demonstrated to improve the prognosis of these patients on top of optimal medical therapy. PCIs have evolved from plain old balloon angioplasty to coronary stent implantation at the end of the last century. There has been a constant technical and scientific improvement in stent technology from bare metal stents to the era of drug-eluting stents (DESs) to overcome clinical challenges such as target lesion failure related to in-stent restenosis or stent thrombosis. A better understanding of the underlying mechanisms of these adverse events has led DESs to evolve from first-generation DESs to thinner and ultrathin third-generation DESs with improved polymer biocompatibility that seems to have reached a peak in efficiency. This review aims to provide a brief historical overview of the evolution of coronary DES platforms and an update on clinical studies and major characteristics of the most currently used DESs.

Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous extracellular matrix.

The establishment and maintenance of apical-basal polarity is a fundamental step in brain development, instructing the organization of neural progenitor cells (NPCs) and the developing cerebral cortex. Particularly, basally located extracellular matrix (ECM) is crucial for this process. In vitro, epithelial polarization can be achieved via endogenous ECM production, or exogenous ECM supplementation. While neuroepithelial development is recapitulated in neural organoids, the effects of different ECM sources in tissue morphogenesis remain underexplored. Here, we show that exposure to a solubilized basement membrane matrix substrate, Matrigel, at early neuroepithelial stages causes rapid tissue polarization and rearrangement of neuroepithelial architecture. In cultures exposed to pure ECM components or unexposed to any exogenous ECM, polarity acquisition is slower and driven by endogenous ECM production. After the onset of neurogenesis, tissue architecture and neuronal differentiation are largely independent of the initial ECM source, but Matrigel exposure has long-lasting effects on tissue patterning. These results advance the knowledge on mechanisms of exogenously and endogenously guided morphogenesis, demonstrating the self-sustainability of neuroepithelial cultures by endogenous processes.

Obstructive valve thrombosis after transcatheter aortic valve replacement (TAVR) in Sneddon syndrome without antiphospholipid antibodies.

We study a case of early obstructive leaflet thrombosis following a transcatheter aortic valve replacement (TAVR) in a woman in her 50s with a history of Sneddon syndrome treated by antiplatelet therapy. The thrombosis regressed following the use of vitamin K antagonists (VKA) for 6 weeks. Subacute TAVR leaflet thrombosis reappeared after discontinuation of VKA use. The main takeaways of this study were the detection of high-risk patients that could benefit from systematic post-TAVR anticoagulation and the early diagnosis of obstructive leaflet thrombosis associated with elevated transvalvular gradient, whose management differs from that of subclinical leaflet thrombosis.

Extending the toolbox for RNA biology with SegModTeX: A polymerase-driven method for site-specific and segmental labeling of RNA.

RNA performs a wide range of functions regulated by its structure, dynamics, and often post-transcriptional modifications. While NMR is the leading method for understanding RNA structure and dynamics, it is currently limited by the inability to reduce spectral crowding by efficient segmental labeling. Furthermore, because of the challenging nature of RNA chemistry, the tools being developed to introduce site-specific modifications are increasingly complex and laborious. Here we use a previously designed Tgo DNA polymerase mutant to present SegModTeX - a versatile, one-pot, copy-and-paste approach to address these challenges. By precise, stepwise construction of a diverse set of RNA molecules, we demonstrate the technique to be superior to RNA polymerase driven and ligation methods owing to its substantially high yield, fidelity, and selectivity. We also show the technique to be useful for incorporating fluorescent- and a wide range of other probes, which significantly extends the toolbox of RNA biology in general.

Revascularization and Medical Therapy for Chronic Coronary Syndromes: Lessons Learnt from Recent Trials, a Literature Review.

Stable coronary artery disease (CAD) has recently been replaced by a new entity described as chronic coronary syndrome (CCS). This new entity has been developed based on a better understanding of the pathogenesis, the clinical characteristics, and the morbi-mortality associated to this condition as part of the dynamic spectrum of CAD. This has significant implications in the clinical management of CCS patients, that ranges from lifestyle adaptation, medical therapy targeting all the elements contributing to CAD progression (i.e., platelet aggregation, coagulation, dyslipidaemia, and systemic inflammation), to invasive strategies (i.e., revascularization). CCS is the most frequent presentation of coronary artery disease which is the first cardiovascular disease worldwide. Medical therapy is the first line therapy for these patients; however, revascularization and especially percutaneous coronary intervention remains beneficial for some of them. European and American guidelines on myocardial revascularization were released in 2018 and 2021, respectively. These guidelines provide different scenarios to help physicians choose the optimal therapy for CCS patients. Recently, several trials focusing on CCS patients have been published. We sought to synthetize the place of revascularization in CCS patients according to the latest guidelines, the lessons learnt from recent trials on revascularization and medical therapy, and future perspectives.

Intracoronary imaging in addition to coronary angiography for patients with out-of-hospital cardiac arrest: More information for better care?

About 70% of out-of-hospital cardiac arrests are related to an ischaemic heart disease in Western countries. Percutaneous coronary intervention has been shown to improve the prognosis of survivors when an unstable coronary lesion is identified as the potential cause of the cardiac arrest. Acute complete coronary occlusion is often demonstrated among patients with ST-segment elevation on electrocardiogram after the return of spontaneous circulation. In patients without ST-segment elevation, routine coronary angiography has been shown to be not superior to conservative management. However, an electrocardiogram-based decision to perform immediate coronary angiography could be insufficient to identify unstable coronary lesions, which are frequently associated with intermediate coronary stenosis. Intracoronary imaging can be helpful to detect plaque rupture or erosion and intracoronary thrombus, but could also lead to better stent implantation, and help to reduce the risk of stent thrombosis. In patients with coronary lesions without the instability characteristic, conservative management should be the default strategy, and a search for another cause of the cardiac arrest should be systematic. In the present review, we sought to describe the potential benefit of intracoronary imaging in patients with out-of-hospital cardiac arrest.

Moderate effect of early-life experience on dentate gyrus function.

The development, maturation, and plasticity of neural circuits are strongly influenced by experience and the interaction of an individual with their environment can have a long-lasting effect on cognitive function. Using an enriched environment (EE) paradigm, we have recently demonstrated that enhancing social, physical, and sensory activity during the pre-weaning time in mice led to an increase of inhibitory and excitatory synapses in the dentate gyrus (DG) of the hippocampus. The structural plasticity induced by experience may affect information processing in the circuit. The DG performs pattern separation, a computation that enables the encoding of very similar and overlapping inputs into dissimilar outputs. In the presented study, we have tested the hypothesis that an EE in juvenile mice will affect DG's functions that are relevant for pattern separation: the decorrelation of the inputs from the entorhinal cortex (EC) and the recruitment of the principal excitatory granule cell (GC) during behavior. First, using a novel slice electrophysiology protocol, we found that the transformation of the incoming signal from the EC afferents by individual GC is moderately affected by EE. We further show that EE does not affect behaviorally induced recruitment of principal excitatory GC. Lastly, using the novel object recognition task, a hippocampus-dependent memory test, we show that the ontogeny of this discrimination task was similar among the EE mice and the controls. Taken together, our work demonstrates that pre-weaning enrichment moderately affects DG function.

Performance of stent thrombosis and bleeding risk scores in out-of-hospital cardiac arrest due to acute coronary syndromes.

BACKGROUND: Patients with out-of-hospital cardiac arrest (OHCA) due to acute coronary syndromes (ACS) who undergo percutaneous coronary intervention (PCI) are at high risk of bleeding and thrombosis. While predictive bleeding and stent thrombosis risk scores have been established, their performance in patients with OHCA has not been evaluated. METHODS: All consecutive patients admitted for OHCA due to ACS who underwent PCI between January 2007 and December 2019 were included. The ACTION and CRUSADE bleeding risk scores and the Dangas score for early stent thrombosis risk were calculated for each patient. A C-statistic analysis was performed to assess the performance of these scores. RESULTS: Among 386 included patients, 82 patients (21.2%) experienced severe bleeding and 30 patients (7.8%) experienced stent thrombosis. The predictive performance of the ACTION and CRUSADE bleeding risk scores for major bleeding was poor, with areas under the curve (AUCs) of 0.596 and 0.548, respectively. Likewise, the predictive performance of the Dangas stent thrombosis risk score was poor (AUC 0.513). Using multivariable analysis, prolonged low-flow (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.05; P=0.025), reduced haematocrit or fibrinogen at admission (OR 0.93, 95% CI 0.88-0.98; P=0.010 and OR 0.61; 95% CI 0.41-0.89; P=0.012, respectively) and the use of glycoprotein IIb/IIIa inhibitors (OR 2.10, 95% CI 1.18-3.73; P=0.011) were independent risk factors for major bleeding. CONCLUSION: The classic bleeding and stent thrombosis risk scores have poor performance in a population of patients with ACS complicated by OHCA. Other predictive factors might be more pertinent to determine major bleeding and stent thrombosis risks in this specific population.

A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA.

Productive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between HEXIM and 7SK snRNA. In HIV-1, Tat binds to 7SK by displacing HEXIM. However, without the structure of the 7SK-HEXIM complex, the constraints that must be overcome for displacement remain unknown. Furthermore, while structure details of the TatNL4-3-7SK complex have been elucidated, it is unclear how subtypes with more HEXIM-like Tat sequences accomplish displacement. Here we report the structures of HEXIM, TatG, and TatFin arginine rich motifs in complex with the apical stemloop-1 of 7SK. While most interactions between 7SK with HEXIM and Tat are similar, critical differences exist that guide function. First, the conformational plasticity of 7SK enables the formation of three different base pair configurations at a critical remodeling site, which allows for the modulation required for HEXIM binding and its subsequent displacement by Tat. Furthermore, the specific sequence variations observed in various Tat subtypes all converge on remodeling 7SK at this region. Second, we show that HEXIM primes its own displacement by causing specific local destabilization upon binding - a feature that is then exploited by Tat to bind 7SK more efficiently.