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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. Synopsis: Human telencephalic organoids can develop in the presence or absence of exogenous extracellular matrix (ECM) in the form of Matrigel. This work presents characterization of the short‐ and long‐term effects of exogenous ECM exposure on telencephalic organoid morphogenesis and differentiation. Matrigel triggers fast tissue morphogenesis at early developmental stages, which occur with a 5‐ to 7‐day delay in unexposed organoids.In the absence of Matrigel, endogenous processes of ECM production and rearrangement support tissue morphogenesis and growth.The effects of Matrigel are likely multifactorial and cannot be replaced by isolated Matrigel components.In long‐term cultures, organoids grown in the presence or absence of Matrigel establish the same repertoires of telencephalic cell types and do not display any striking morphological differences. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Here the structure of the HEXIM arginine rich motif in complex with the stemloop-1 of 7SK snRNA is determined, and insights are provided into how the HIV protein Tat overcomes the structural constraints required to displace HEXIM, an event required for the extraction of pTEFb during transcriptional elongation. [ABSTRACT FROM AUTHOR]

Résumé: Les lésions coronaires calcifiées représentent un véritable défi en cardiologie interventionnelle avec un risque de complications procédurales (échec de franchissement, perforations, sous-déploiement du stent, etc.) associées à un risque plus élevé d'événements cardiovasculaires. De nombreux dispositifs ont été développés au fil des années afin de faciliter l'implantation des endoprothèses coronaires : ballons non compliants, ballons à haute pression, ballons modifiés, athérectomie rotationnelle, etc. Plus récemment, la lithotripsie, technologie utilisée historiquement pour la prise en charge des lithiases urinaires, a été adaptée à la cardiologie interventionnelle. Le dispositif Shockwave (Shockwave Medical, Inc) a récemment été autorisé dans la prise en charge des lésions coronaires calcifiées avant implantation d'une endoprothèse. Severely calcified coronary artery disease is associated with poor prognostic. These lesions remain a challenge for percutaneous coronary interventions with potential stent under expansion and suboptimal result associated with adverse clinical events. Several plaque modification systems are available (modified balloon, rotational/eliptic atherectomy, etc.). The Shockwave intravascular lithotripsy (Shockwave Medical, Inc) is a new easy-to-use technique to prepare severe calcified coronary lesions by disrupting the calcified plaque prior to stent implantation. [ABSTRACT FROM AUTHOR]

Aim: Out-of-hospital Cardiac Arrest (OHCA) carries a poor prognostic with high mortality rates and multiple scoring systems have been developed to assess its prognostic. This study sought to evaluate the performance of three prognostic scores to predict survival in OHCA patients due to acute coronary syndrome (ACS).Methods and Results: This is an observational, monocentric study including 386 consecutive patients treated for OHCA due to ACS, treated by percutaneous coronary intervention, between 2007 and 2019. The OHCA, NULL-PLEASE and CAHP scores were calculated respectively for 370 patients (95.9%), 371 patients (96.1%) and 350 patients (90.7%). A C-statistic analysis was performed to determine score performance. The areas under the curve for the OHCA, NULL-PLEASE and CAHP scores were 0.861 (95% CI, 0.823-0.898), 0.789 (95% CI, 0.744-0.834) and 0.830 (95% CI, 0.788-0.872) respectively demonstrating good performance. The OHCA score performed better than the NULL-PLEASE score (p = 0.001), and there was no difference between the CAHP and the NULL-PLEASE score (p = 0.062) nor between the OHCA and the CAHP score (p = 0.105).Conclusion: The OHCA score, the NULL-PLEASE score and the CAHP score performed well in predicting in-hospital death in patients presenting OHCA secondary to ACS. The NULL-PLEASE score is the easiest to use but performed less accurately than the OHCA score. [ABSTRACT FROM AUTHOR]

Cerebral organoids generated from human pluripotent stem cells (hiPSCs) are unique in their ability to recapitulate human-specific neurodevelopmental events. They are capable of modeling the human brain and its cell composition, including human-specific progenitor cell types; ordered laminar compartments; and both cell-specific transcriptional signatures and the broader telencephalic transcriptional landscape. The serine/threonine kinase, GSK3β, plays a critical role in neurodevelopment, controlling processes as varied as neurogenesis, morphological changes, polarization, and migration. In the generation of cerebral organoids, inhibition of GSK3β at low doses has been used to increase organoid size and decrease necrotic core. However, little is known of the effects of GSK3β inhibition on organoid development. Here, we demonstrate that while low dose of GSK3β inhibitor CHIR 99021 increases organoid size, higher dose actually reduces organoid size; with the highest dose arresting organoid growth. To examine the mechanisms that may contribute to the phenotypic size differences observed in these treatment groups, we show that low dose of CHIR 99021 increases cell survival, neural progenitor cell proliferation and neuronal migration. A higher dose, however, decreases not only apoptosis but also proliferation, and arrests neural differentiation, enriching the pool of neuroepithelial cells, and decreasing the pools of early neuronal progenitors and neurons. These results reveal new mechanisms of the pleiotropic effects of GSK3β during organoid development, providing essential information for the improvement of organoid production and ultimately shedding light on the mechanisms of embryonic brain development. [ABSTRACT FROM AUTHOR]

The article discusses the use of the hashtag "#RhetoricSoWhite" on social media platforms designed to advocate for more diversity in rhetoric studies. Topics covered include ethic identity, knowledge production, and the history of rhetorical analysis as a field of study.

From December 2012 to June 2014, the San Diego Pacific Arts Movement sponsored a participatory project known as Drive-By Cinema (DBC). Refurbishing a U-Haul truck into a mobile cinema unit, DBC visited more than 36 neighborhood sites and screened films. In this article, I revisit the DBC project and its act of mobile cinema exhibition to examine its place-based rhetorics of belonging, materiality, and history. Drawing on Michel de Certeau's distinct and contrasting notions of "place" and "space," I argue DBC's radical mobility temporarily reconfigures places into spaces of social engagement, putting bodies into contact with history, materiality, and across racial and gender differences between residents sharing a neighborhood. In its act of screening in strip-mall parking lots and U-turning at the border, DBC reveals a neighborhood's forgotten histories and the border's absurdity in facilitating exploitative racialized and gendered patterns of transnational mobility and labor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

An introduction is presented to this special focus section dealing with topics related to Asian Americans in motion pictures and mass media.

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. [ABSTRACT FROM AUTHOR]

Purpose: It is widely accepted in the field of ophthalmology that closure of open globes within 24 hours of the injury results in the best visual outcomes. This study investigates the time-to-surgery and visual outcomes of open globe injury patients in North Carolina that were transferred to our institution before receiving surgical intervention as compared to those that were not transferred. Patients and methods: This is a retrospective cohort study using data from UNC Hospitals trauma registry. Demographics, time of injury, final clinical outcomes, time to surgical intervention, and transfer history were extracted and analyzed. The study population includes open globe injury patients of all ages that were seen and treated at our institution from 2005 to 2020. Patients were divided based on transfer history. The transfer group consisted of patients who were transferred from an outside hospital to our tertiary care facility for surgical treatment. The non-transfer group consisted of patients who arrived at our tertiary care facility directly after injury. Results: In total, 238 open globe injuries were evaluated. Of those, 197 were transferred and 41 were not transferred. Compared to non-transfer patients, transfer patients had longer delays between injury and surgery, between presentation at the initial ED and surgery, and between injury and arrival at the tertiary care center. On average, the delay between injury and surgical intervention was 3 hours and 51 minutes longer for transfer patients compared to non-transfer patients. Eight patients in the transfer group were delayed > 24 hours due to inter-hospital transfer. Additionally, transfer patients on average suffered from poorer final visual acuities, with an average final visual acuity of 1.84 logMAR in the transfer group and 1.35 logMAR in the non-transfer group. Conclusion: Our study found that inter-hospital transfer leads to significant delays in primary closure of open globe injuries. Injuries that were transferred to a tertiary care center before receiving surgical intervention on average resulted in worse final visual acuities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Out of hospital cardiac arrest (OHCA) patients requiring percutaneous coronary intervention (PCI) are at higher risk of both stent thrombosis and bleeding. The use of aggressive antiplatelet therapy could lead to a higher risk of bleeding in these patients. Indeed, data on glycoprotein IIb/IIIa inhibitor (GPi) use in this specific indication is scarce.Aim: We sought to evaluate the benefit and safety of GPi use in OHCA patients requiring PCI.Methods and Results: Between January 2007 and December 2017, we retrospectively included all consecutive patients treated with PCI for an OHCA from cardiac cause. Clinical, procedural data and in-hospital outcomes were collected. Three hundred and eighty-five patients were included. GPi were administrated in 41.3% of cases (159 patients). Patients who received GPi were younger, had less prior PCI, more often a TIMI 0 or 1 flow before PCI and thromboaspiration use. There were no differences regarding in-hospital definite stent thrombosis among the two groups (11.9% in the GPi group vs 7.1% in the non-GPi group, p = 0.10) or in-hospital mortality (48.6% vs 49.3%, p = 0.68). The incidence of any bleeding (33.3% vs. 19.6%; p = 0.002), and major bleeding (BARC 3-5) (21.9% vs. 16.8%; p = 0.007) was significantly higher in patients receiving GPi. Indeed, using multivariate analysis, GPi use was predictor of major bleeding (OR: 1.81; 95% CI: 1.06-3.08; p = 0.03).Conclusions: In patients treated with PCI for OHCA from cardiac cause, GPi use was associated with an increased risk of major bleeding events, without difference on in-hospital stent thrombosis or death. [ABSTRACT FROM AUTHOR]

An introduction is presented on the issue's focus on the state of rhetorical analysis studies.

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. [Display omitted] • Lung tumors expressing Jagged2 associate with poor outcome and immune evasion • Jagged2 deletion in lung tumors primes expansion of immunostimulatory macrophages • DLL1/4 in Jagged2-null tumors rewires macrophage function via Notch1/2-induced IRF4 • Anti-Jagged2 therapy promotes anti-tumor responses through IRF4-driven macrophages Signaling via Notch receptors intrinsically regulates tumor cells, promoting tumor progression. Mandula et al. examine the impact of Notch ligands on cancer cells on anti-tumor immunity in lung cancer and find that deletion of Jagged2 promotes expansion of immunostimulatory macrophages and anti-tumor T cell immunity. Mechanistically, in the absence of Jagged2, the Notch ligand DLL1/4 on tumor cells rewires macrophages via Notch-mediated induction of the transcription factor IRF4. [ABSTRACT FROM AUTHOR]

• Perineuronal nets increasingly found on IC cells that project to the MG during aging. • Non-GABAergic lemniscal IC-MG cells are increasingly netted at old age. • Non-lemniscal IC-MG cells are increasingly netted at middle age. The age-related loss of GABA in the inferior colliculus (IC) likely plays a role in the development of age-related hearing loss. Perineuronal nets (PNs), specialized aggregates of extracellular matrix, increase with age in the IC. PNs, associated with GABAergic neurotransmission, can stabilize synapses and inhibit structural plasticity. We sought to determine whether PN expression increased on GABAergic and non-GABAergic IC cells that project to the medial geniculate body (MG). We used retrograde tract-tracing in combination with immunohistochemistry for glutamic acid decarboxylase and Wisteria floribunda agglutinin across three age groups of Fischer Brown Norway rats. Results demonstrate that PNs increase with age on lemniscal and non-lemniscal IC-MG cells, however two key differences exist. First, PNs increased on non-lemniscal IC-MG cells during middle-age, but not until old age on lemniscal IC-MG cells. Second, increases of PNs on lemniscal IC-MG cells occurred on non-GABAergic cells rather than on GABAergic cells. These results suggest that synaptic stabilization and reduced plasticity likely occur at different ages on a subset of the IC-MG pathway. [ABSTRACT FROM AUTHOR]

Organoids are biological systems grown in vitro and are observed to self-organize into 3D cellular tissues of specific organs. Brain organoids have emerged as valuable models for the study of human brain development in health and disease. Researchers are now in need of improved culturing and imaging tools to capture the in vitro dynamics of development processes in the brain. Here, we describe the design of a microfluidic chip and bioreactor, to enable in situ tracking and imaging of brain organoids on-chip. The low-cost 3D printed microfluidic bioreactor supports organoid growth and provides an optimal imaging chamber for live-organoid imaging, with drug delivery support. This fully isolated design of a live-cell imaging and culturing platform enables long-term live-imaging of the intact live brain organoids as it grows. We can thus analyze their self-organization in a controlled environment with high temporal and spatial resolution. [ABSTRACT FROM AUTHOR]

Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD. [ABSTRACT FROM AUTHOR]

Dynamin is a 96-kDa protein that has multiple oligomerization states that influence its GTPase activity. A number of different dynamin effectors, including lipids, actin filaments, and SH3-domain-containing proteins, have been implicated in the regulation of dynamin oligomerization, though their roles in influencing dynamin oligomerization have been studied predominantly in vitro using recombinant proteins. Here, we identify higher order dynamin oligomers such as rings and helices in vitro and in live cells using fluorescence lifetime imaging microscopy (FLIM). FLIM detected GTP- and actin-dependent dynamin oligomerization at distinct cellular sites, including the cell membrane and transition zones where cortical actin transitions into stress fibers. Our study identifies a major role for direct dynamin-actin interactions and dynamin's GTPase activity in the regulation of dynamin oligomerization in cells. [ABSTRACT FROM AUTHOR]