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Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis. To test the hypothesis that selective HSC-primed lineage-specific CREs remain accessible throughout differentiation, we used ATAC-seq to map the temporal dynamics of chromatin remodeling during progenitor differentiation. We observed epigenetic-driven clustering of oligopotent and unipotent progenitors into distinct erythromyeloid and lymphoid branches, with multipotent HSCs and MPPs associating with the erythromyeloid lineage. We mapped the dynamics of lineage-primed CREs throughout hematopoiesis and identified both unique and shared CREs as potential lineage reinforcement mechanisms at fate branch points. Additionally, quantification of genome-wide peak count and size revealed overall greater chromatin accessibility in HSCs, allowing us to identify HSC-unique peaks as putative regulators of self-renewal and multilineage potential. Finally, CRISPRi-mediated targeting of ATACseq-identified putative CREs in HSCs allowed us to demonstrate the functional role of selective CREs in lineage-specific gene expression. These findings provide insight into the regulation of stem cell multipotency and lineage commitment throughout hematopoiesis and serve as a resource to test functional drivers of hematopoietic lineage fate.

The COVID-19 pandemic exacerbated health disparities among immigrant communities. Delivering accurate information and addressing misinformation on protective measures and vaccination to linguistically disadvantaged groups was critical for mitigating the effects of the pandemic. One group that was especially vulnerable to miscommunication about COVID-19 was non–native English-speaking immigrants. To address these disparities, the Asian American Studies Center and the Fielding School of Public Health at the University of California, Los Angeles, partnered to create a multilingual resource hub, TranslateCovid.org, to disseminate credible and reliable information about COVID-19 safety measures, the science behind the vaccines, and vaccine safety. We identified >1300 verified resources in 60 languages from government, academic, and nonprofit organizations and reposted them on the TranslateCovid website. We also developed public service announcement videos on handwashing, use of face masks, and social distancing in 10 languages and a fact sheet for frequently asked questions in 20 languages. We used a participatory approach to develop strategies for disseminating these resources. We discuss lessons learned, including strategies for forming government, community, and academic partnerships to support the timely development and dissemination of information. We conclude with a discussion on the unique role of universities in promoting equitable access to public health resources among immigrant communities in times of crisis. [ABSTRACT FROM AUTHOR]

Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.

We recovered 12 archival geolocators deployed on Eastern Kingbirds (Tyrannus tyrannus) breeding in New York (NY; re = 3, 2 with 2 years of data), Nebraska (NE; /; = 6, 1 with 2 years of data), and Oregon (OR; n = 3) to describe migratory routes, timing and rates of migration, nonbreeding season distributions, and migratory connectedness. NY fall migrants migrated along the.Atlantic coast to Florida, flew either nonstop across the Gulf of Mexico (GoM; 2 of 3 birds) or stopped once along the way (Cuba and Cayman Islands in different years) to land in Yucatan/Central America. Fall birds from NE and OR arrived at the GoM in the region of the border between Texas and Louisiana, and most likely took a land route to Central America. In spring, all NY birds flew nonstop across the GoM. and once in North America, took a more inland route than in fall. Trans-GoM flights were more common among NE and OR birds in spring than fall. Birds migrated faster in spring than fall, and in both seasons, late departure was associated with more rapid migration. Migratory connectivity was low, and all birds from OR. and one bird from NE and NY each, occupied a single region in northwestern Amazonia (southern Colombia, northern Peru, and eastern Ecuador) while in South America. Most kingbirds from NE and NY were intratropical migrants, occupying 2 regions for periods of [greater than or equal to]30 d. The latter birds migrated farther south to western Brazil and northern Bolivia, but then moved north to later use the same area in northwestern Amazonia where other birds remained throughout the overwinter period. Northwestern Amazonia thus appears to be a critical area for all Eastern Kingbirds during the nonbreeding season, possibly because a prolonged wet season supports abundant fruit resources. Key words: archival geolocator. departure date, intratropical migration, migration rate, migratory connectivity. Recuperamos 12 geolocalizadores que habíamos puesto en mosqueros Tyrannus tyrannus que anidaban en New York (NY; n = 3. 2 con 2 años de datos). Nebraska (NE: n = 6. 1 con 2 años de datos) y Oregon (OR; n = 3) para describir sus rutas migratorias, temporalidad y tasas de migración, distribuciones durante la temporada no-reproductiva y conectividad migratoria. En otoño, los de NY migraron a lo largo de la costa del Atlántico a Florida, volaron sin parar el cruce del Golfo de México (GoM; 2 de 3 pájaros) o hicieron una parada en el camino (Cuba e Islas Caimán en años diferentes) para aterrizar en la península de Yucatán/Centroamérica. En otoño, los pájaros de NE y OR llegaron al GoM en la región limítrofe entre Texas y Louisiana, y lo más probable es que hayan tomado una ruta de tierra firme a Centroaméríca. En primavera, todos los pájaros de NY cruzaron el GoM sin parar y una vez en Norteamérica tomaron una ruta más tierra adentro que en otoño. Los vuelos trans-GoM fueron más comunes entre los pájaros de NE y OR en primavera que en otoño. Estos pájaros migraron más rápido en primavera que en otoño: en ambas temporadas, una partida tardía estuvo asociada con una migración más rápida. La conectividad migratoria fue baja y todos los pájaros de OR. uno de NE y uno de NY ocuparon una región única de la Amazonia noroccidental (sur de Colombia, norte de Perú y el este de Ecuador) mientras permanecieron en Sudamérica. La mayoría de los mosqueros de NE y NY fueron migratorias intratropicales que ocuparon 2 regiones por periodos de [mayor que o igual a]30 d. Éstos últimos migraron más al sur al occidente de Brasil y al norte de Bolivia, pero después se movieron al norte para utilizar la misma área en la Amazonia noroccidental donde el resto de los individuos permanecieron a lo largo del periodo no-reproductivo. La Amazonia noroccidental parece ser un área crítica para todos los T. tyrannus durante la temporada no-reproductiva, posiblemente porque su prolongada estación húmeda da soporte a abundantes frutos. Palabras clave: conectividad migratoria, fecha de partida, geolocalizadores. migración intratropical, tasa de migración., Events outside the breeding season account for up to three-quarters of the annual cycle of Nearctic--Neotropical songbirds, yet basic information on wintering site locations, migratory pathways, connectivity of populations, and [...]

Maintaining DNA integrity is vital for all cells and organisms. Defective DNA repair may contribute to neurological disorders, including Alzheimer's disease (AD). We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice. Amyloid-β oligomers reduced BRCA1 levels in primary neuronal cultures. In wild-type mice, knocking down neuronal BRCA1 in the dentate gyrus caused increased DNA double-strand breaks, neuronal shrinkage, synaptic plasticity impairments, and learning and memory deficits, but not apoptosis. Low levels of hAPP/Amyloid-β overexpression exacerbated these effects. Physiological neuronal activation increased BRCA1 levels, whereas stimulating predominantly extrasynaptic N-methyl-D-aspartate receptors promoted the proteasomal degradation of BRCA1. We conclude that BRCA1 is regulated by neuronal activity, protects the neuronal genome, and critically supports neuronal integrity and cognitive functions. Pathological accumulation of Aβ depletes neuronal BRCA1, which may contribute to cognitive deficits in AD.

Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

Cellular reprogramming highlights the epigenetic plasticity of the somatic cell state. Long noncoding RNAs (lncRNAs) have emerging roles in epigenetic regulation, but their potential functions in reprogramming cell fate have been largely unexplored. We used single-cell RNA sequencing to characterize the expression patterns of over 16,000 genes, including 437 lncRNAs, during defined stages of reprogramming to pluripotency. Self-organizing maps (SOMs) were used as an intuitive way to structure and interrogate transcriptome data at the single-cell level. Early molecular events during reprogramming involved the activation of Ras signaling pathways, along with hundreds of lncRNAs. Loss-of-function studies showed that activated lncRNAs can repress lineage-specific genes, while lncRNAs activated in multiple reprogramming cell types can regulate metabolic gene expression. Our findings demonstrate that reprogramming cells activate defined sets of functionally relevant lncRNAs and provide a resource to further investigate how dynamic changes in the transcriptome reprogram cell state.

Simple Summary: The prognosis for patients with glioblastoma (GBM) remains dismal despite advances in tumor detection and treatment. The aim of our retrospective study was to develop a multiparametric model incorporating baseline MRI imaging, histopathological biomarkers, and demographic data to predict prognosis in patients with GBM. A training model was developed with 116 patients and validated with an external cohort of 40 patients. Three significant variables were identified as independent predictors of survival ≥ 18 months: radiomics, age, and MGMT status. Background: Clinical, histopathological, and imaging variables have been associated with prognosis in patients with glioblastoma (GBM). We aimed to develop a multiparametric radiogenomic model incorporating MRI texture features, demographic data, and histopathological tumor biomarkers to predict prognosis in patients with GBM. Methods: In this retrospective study, patients were included if they had confirmed diagnosis of GBM with histopathological biomarkers and pre-operative MRI. Tumor segmentation was performed, and texture features were extracted to develop a predictive radiomic model of survival (<18 months vs. ≥18 months) using multivariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regularization to reduce the risk of overfitting. This radiomic model in combination with clinical and histopathological data was inserted into a backward stepwise logistic regression model to assess survival. The diagnostic performance of this model was reported for the training and external validation sets. Results: A total of 116 patients were included for model development and 40 patients for external testing validation. The diagnostic performance (AUC/sensitivity/specificity) of the radiomic model generated from seven texture features in determination of ≥18 months survival was 0.71/69.0/70.3. Three variables remained as independent predictors of survival, including radiomics (p = 0.004), age (p = 0.039), and MGMT status (p = 0.025). This model yielded diagnostic performance (AUC/sensitivity/specificity) of 0.77/81.0/66.0 (training) and 0.89/100/78.6 (testing) in determination of survival ≥ 18 months. Conclusions: Results show that our radiogenomic model generated from radiomic features at baseline MRI, age, and MGMT status can predict survival ≥ 18 months in patients with GBM. [ABSTRACT FROM AUTHOR]

The importance of public education has never been greater as we enter the dawn of a new millennium. Innumerable efforts have been focused on improving public education, but the unfortunate result has been an array of fractured, piecemeal efforts. What is needed is a systemic approach to go from "tweaking" to "transforming" through a process known as Transformational Dialogue for Public Education (TDPE). This approach is based on four core tenets: (1) going to the root of the root; (2) re-conceiving and optimizing at the state level; (3) no organizational transformation without personal transformation; and (4) enduring revolution through persistent evolution. Using these four tenets as the foundation, the TDPE approach is designed to provide coherence to the current piecemeal efforts and help produce results that are far-reaching and sustainable.