bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal Stromal Cell Aging Impairs the Self-Organizing Capacity of Lung Alveolar Epithelial Stem Cells
Authors: Chanda Diptiman , Rehan Mohammad , Smith Samuel R. , Dsouza Kevin G. , Wang Yong , Bernard Karen , Kurundkar Deepali , Memula Vinayak , Kyoko Kojima , Mobley James A. , Benavides Gloria , Darley-Usmar Victor , Young-il Kim , Zmijewski Jaroslaw W. , Deshane Jessy S. , Thannickal Victor J. 
Published: March 2021

AbstractMulticellular organisms maintain structure and function of tissues/organs through emergent, self-organizing behavior. In this report, we demonstrate a critical role for lung mesenchymal stromal cell (L-MSC) aging in determining the capacity to form 3-dimentional organoids or “alveolospheres “ with type 2 alveolar epithelial cells (AEC2s). In contrast to L-MSCs from aged mice, young L-MSCs support the efficient formation of alveolospheres when co-cultured with young or aged AEC2s. Aged L-MSCs demonstrated features of cellular senescence, altered bioenergetics, and a senescence-associated secretory profile (SASP). The reactive oxygen species generating enzyme, NADPH oxidase 4 (Nox4), was highly activated in aged L-MSCs and Nox4 downregulation was sufficient to, at least partially, reverse this age-related energy deficit, while restoring the self-organizing capacity of alveolospheres. Together, these data indicate a critical role for cellular bioenergetics and redox homeostasis in an organoid model of self-organization, and supports the concept of thermodynamic entropy in aging biology.
A non-coding RNA network involved in KSHV tumorigenesis
Authors: Naipauer Julián , E. García Solá Martín , Salyakina Daria , Rosario Santas , Williams Sion , Coso Omar , C. Abba Martín , Mesri Enrique A. , Lacunza Ezequiel 
Published: March 2021

ABSTRACTRegulatory pathways involving non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA) have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat, Neat1, H19, Meg3 and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and Cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.
Allelic expression imbalance ofPIK3CAmutations is frequent in breast cancer and prognostically significant
Authors: Correia Lizelle , Xavier Joana M. , Magno Ramiro , Almeida Bernardo P. de , Esteves Filipa , Duarte Isabel , Eldridge Matthew , Sun Chong , Bosma Astrid , Mittempergher Lorenza , Marreiros Ana , Bernards Rene , Caldas Carlos , Chin Suet-Feung , Maia Ana-Teresa 
Published: March 2021

AbstractPIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found allelic imbalances in the expression ofPIK3CAin normal breast tissue and mapped a germline candidate regulatory variant. An imbalance was also frequently observed in the expression of the missense mutant and wild-typePIK3CAalleles in breast tumors from METABRIC and TCGA projects. Moreover, although 60% of tumors preferentially expressed the mutant allele, 10% did preferentially express the wild-type allele. Mechanistically, we show that these imbalances are more frequently due to regulatory variants incisthan altered copy-number and predict that somatic variants have a more significant role than germline ones. We further found that imbalanced allelic expression between mutant and wild-type alleles due tocis-regulatory variants associated with poor prognosis (p=0.0081).Interestingly, ER+, PR+, and Her2−tumors expressing very low levels of the mutant allele had the poorest prognosis (DSS <7.5yrs for ER+and PR+tumors and <5yrs for Her2−tumors). Hence, our work provides compelling evidence to support the clinical utility ofPIK3CAallelic expression in breast cancer in identifying this cohort of low mutant allele expressing patients of poorer prognosis, who will unlikely benefit from PI3K inhibitors. Furthermore, our work establishes a new model of differential regulation of critical cancer-promoting genes.
Host protease activity on bacterial pathogens promotes complement- and antibiotic-directed killing
Authors: Chen Shaorong , Roberts Alexandria-Jade , Lu Felix , Cannon Carolyn , Qin Qing-Ming , de Figueiredo Paul 
Published: March 2021

ABSTRACTOur understanding of how the host immune system thwarts bacterial evasive mechanisms remains incomplete. Here, we show that host protease neutrophil elastase acts onAcinetobacter baumanniiandPseudomonas aeruginosato destroy factors that prevent serum-associated, complement-directed killing. The protease activity also enhances bacterial susceptibility to antibiotics in sera. These findings implicate a new paradigm where host protease activity on bacteria acts synergistically with the host complement system and antibiotics to defeat bacterial pathogens.
Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation
Authors: Baumel-Alterzon Sharon , Katz Liora S. , Brill Gabriel , Jean-Pierre Clairete , Li Yansui , Biswal Shyam , Garcia-Ocaña Adolfo , Scott Donald K. 
Published: March 2021

SUMMARYFinding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation and mass. Depletion of Nrf2 in β-cells resulted in decreased glucose-stimulated β-cell proliferationex vivoand decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat dietin vivo. Nrf2 protects β-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and β-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding β-cell mass in diabetes.
Mycobacterium abscessusbiofilms produce an ECM and have a distinct mycolic acid profile
Authors: Dokic Anja , Peterson Eliza , Arrieta-Ortiz Mario L , Pan Min , Di Maio Alessandro , Baliga Nitin , Bhatt Apoorva 
Published: March 2021

AbstractA non-tuberculous mycobacterium (NTM),Mycobacterium abscessusis an emerging opportunistic pathogen associated with difficult to treat pulmonary infections, particularly in patients suffering from cystic fibrosis. It is capable of forming biofilmsin vitrothat result in an increase of already high levels of antibiotic resistance in this bacterium. Evidence thatM. abscessusforms biofilm-like microcolonies in patient lungs and on medical devices further implicated the need to investigate this biofilm in detail. Therefore, in this study we characterized theM. abscessuspellicular biofilm, formed on a liquid-air interface, by studying its molecular composition, and its transcriptional profile in comparison to planktonic cells. Using scanning electron micrographs and fluorescence microscopy, we showed thatM. abscessusbiofilms produce an extracellular matrix composed of lipids, proteins, carbohydrates and eDNA. Transcriptomic analysis of biofilms revealed an upregulation of pathways involved in the glyoxylate shunt, redox metabolism and mycolic acid biosynthesis. Genes involved in elongation and desaturation of mycolic acids were highly upregulated in biofilms and, mirroring those findings, biochemical analysis of mycolates revealed molecular changes and an increase in mycolic acid chain length. Together these results give us an insight into the complex structure ofM. abscessusbiofilms, the understanding of which may be adapted for clinical use in treatment of biofilm infections, including strategies for dispersing the ECM, allowing antibiotics to gain access to bacteria within the biofilm.
An Investigation of the Mechanism for a Novel Influenza Inhibitor Designed to Target the Import of PB1
Authors: Dorius Alexander , Busath David D. 
Published: March 2021

AbstractA novel inhibitor of PB1 import, referred to here as GM30, previously displayed nuclear retention of viral nucleoprotein (NP), which spurred the question of whether the compound directly or indirectly blocked viral ribonucleoprotein (vRNP) complex export. vRNPs are exported from the nucleus via exportin 1 (XPO1). Using verdinexor (VNXR), a direct inhibitor of vRNP export that binds to XPO1 and also blocks nuclear factor kappa B (NF-κB) export, we found that GM30 does not block nuclear export of NF-κB. GM30 likewise demonstrated high nuclear retention of NP but not as much as the direct inhibition of nuclear export by VNXR. When the compound was added hours after infection, the compound lost its ability to block nuclear export but VNXR retained its ability to block nuclear export. GM30 is therefore likely an indirect inhibitor of nuclear export because it disrupts the vRNP complex formation and impedes export from the nucleus by reducing nuclear import of PB1.
Feedback ratiometric control of two microbial populations in a single chemostat
Authors: Fiore Davide , Rossa Fabio Della , Guarino Agostino , di Bernardo Mario 
Published: March 2021

AbstractWe address the problem of controlling the dilution rate in a chemostat to regulate the ratio between the concentrations of two microbial populations growing in continuous culture. After analyzing the open-loop dynamics of this multicellular system, we present two alternative feedback control strategies, one based on a gain-scheduled state feedback controller, the other on a switching control strategy. We show that both strategies are effective in solving the problem and illustrate the results by a set of representative numerical simulation.
Eliminating Mosquitoes with Precision Guided Sterile Males
Authors: Li Ming , Yang Ting , Bui Michelle , Gamez Stephanie , Wise Tyler , Kandul Nikolay P. , Liu Junru , Alcantara Lenissa , Lee Haena , Edula Jyotheeswara R. , Raban Robyn , Zhan Yinpeng , Wang Yijin , DeBeaubien Nick , Chen Jieyan , Sanchez C. Hector M. , Bennett Jared B. , Antoshechkin Igor , Montell Craig , Marshall John M. , Akbari Omar S. 
Published: March 2021

AbstractThe mosquitoAedes aegyptiis the principal vector for arboviruses including dengue/yellow fever, chikungunya, and zika, infecting hundreds of millions of people annually. Unfortunately, traditional control methodologies are insufficient, so innovative control methods are needed. To complement existing measures, here we develop a molecular genetic control system termed precision guided sterile insect technique (pgSIT) inAedes aegypti. PgSIT uses a simple CRISPR-based approach to generate sterile males that are deployable at any life stage. Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, suppress, and eliminate mosquitoes in multigenerational population cages. This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable, and reversible manner.
Tissue specific targeting of DNA nanodevices in a multicellular living organism
Authors: Chakraborty Kasturi , Surana Sunaina , Martin Simona , Aburas Jihad , Moutel Sandrine , Perez Franck , Koushika Sandhya P. , Kratsios Paschalis , Krishnan Yamuna 
Published: March 2021

AbstractNucleic acid nanodevices present great potential as agents for logic-based therapeutic intervention as well as in basic biology. Often, however, the disease targets that need corrective action are localized in specific organs and thus realizing the full potential of DNA nanodevices also requires ways to target them to specific cell-typesin vivo. Here we show that by exploiting either endogenous or synthetic receptor-ligand interactions and by leveraging the biological barriers presented by the organism, we can target extraneously introduced DNA nanodevices to specific cell types inC. elegans, with sub-cellular precision. The amenability of DNA nanostructures to tissue-specific targetingin vivosignificantly expands their utility in biomedical applications and discovery biology.
Defining proximity proteomics of post-translationally modified proteins by antibody-mediated protein A-APEX2 labeling
Authors: Li Xinran , Zhou Jiaqi , Zhao Wenjuan , Wen Qing , Wang Weijie , Peng Huipai , Bouchonville Kelly J. , Offer Steven M. , Wang Zhiquan , Li Nan , Gan Haiyun 
Published: March 2021

AbstractProximity labeling catalyzed by promiscuous enzymes, such as APEX2, has emerged as a powerful approach to characterize multiprotein complexes and protein-protein interactions. However, current methods depend on the expression of exogenous fusion proteins and cannot be applied to post-translational modifications. To address this limitation, we developed a new method to label proximal proteins of interest by antibody-mediated protein A-APEX2 labeling (AMAPEX). In this method, a modified protein is boundin situby a specific antibody, which then tethers a protein A-APEX2 (pA-APEX2) fusion protein. Activation of APEX2 labels the nearby proteins with biotin; these proteins are then purified using streptavidin beads and are identified by mass spectrometry. We demonstrate the utility of this approach by profiling the binding proteins of histone modifications including H3K27me3, H3K9me3, H3K4me3, H4K5ac and H4K12ac, and we verified the genome-wide colocalization of these identified proteins with bait proteins by published ChIP-seq analysis. Overall, AMAPEX is an efficient tool to identify proteins that interact with modified proteins.
General and cell-type-specific aspects of the motor neuron maturation transcriptional program
Authors: Patel Tulsi , Hammelman Jennifer , Closser Michael , Gifford David K. , Wichterle Hynek 
Published: March 2021

SummaryBuilding a nervous system is a protracted process that starts with the specification of individual neuron types and ends with the formation of mature neural circuits. The molecular mechanisms that regulate the temporal progression of maturation in individual cell types remain poorly understood. In this work, we have mapped the gene expression and chromatin accessibility changes in mouse spinal motor neurons throughout their lifetimes. We found that both motor neuron gene expression and putative regulatory elements are dynamic during the first three weeks of postnatal life, when motor circuits are maturing. Genes that are up-regulated during this time contribute to adult motor neuron diversity and function. Almost all of the chromatin regions that gain accessibility during maturation are motor neuron specific, yet a majority of the transcription factor binding motifs enriched in these regions are shared with other mature neurons. Collectively, these findings suggest that a core transcriptional program operates in a context-dependent manner to access cell-type-specific cis-regulatory systems associated with maturation genes. Discovery of general principles governing neuronal maturation might inform methods for transcriptional reprogramming of neuronal age and for improved modelling of age-related neurodegenerative diseases.
Active Enterohepatic Cycling is Not Required for the Choleretic Actions of 24-norUrsodeoxycholic Acid in Mice
Authors: Li Jianing , Truong Jennifer K. , Pachura Kimberly , Rao Anuradha , Gambeer Sanjeev , Fuchs Claudia Daniela , Karpen Saul J. , Trauner Michael , Dawson Paul A. 
Published: March 2021

AbstractThe superior ability ofnorursodeoxycholic acid (norUDCA) to induce a bicarbonate-rich hypercholeresis has been attributed to its ability to undergo cholehepatic shunting andnorUDCA is currently being evaluated as a therapeutic for forms of liver disease. The goal of this study was to use mouse models to investigate contributions of bile acid transporters to the choleretic actions ofnorUDCA. Here, we show that the apical sodium-dependent bile acid transporter (ASBT) and Organic solute transporter-alpha (OSTα) are dispensable fornorUDCA-stimulation of bile flow and biliary bicarbonate secretion in mice. Analysis of the liver transcriptome revealed thatnorUDCA induced hepatic expression of a limited number of transporter genes, particularly organic anion transporting polypeptide 1a4 (Oatp1a4). However,norUDCA potently stimulated a bicarbonate-rich hypercholeresis in Oatp1a/1b-deficient mice. Blocking intestinal bile acid reabsorption by co-administration of an ASBT inhibitor or bile acid sequestrant did not impact the ability ofnorUDCA to induce bile flow in wildtype mice. The results support the concept that these major bile acid transporters are not directly involved in the absorption, cholehepatic shunting, or choleretic actions ofnorUDCA. Additionally, the findings support further investigation of the therapeutic synergy betweennorUDCA and ASBT inhibitors or bile acid sequestrants for cholestatic liver disease.
SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies
Authors: Moyo-Gwete Thandeka , Madzivhandila Mashudu , Makhado Zanele , Ayres Frances , Mhlanga Donald , Oosthuysen Brent , Lambson Bronwen E. , Kgagudi Prudence , Tegally Houriiyah , Iranzadeh Arash , Doolabh Deelan , Tyers Lynn , Chinhoyi Lionel R. , Mennen Mathilda , Skelem Sango , Marais Gert , Wibmer Constantinos Kurt , Bhiman Jinal N , Ueckermann Veronica , Rossouw Theresa , Boswell Michael , de Oliveira Tulio , Williamson Carolyn , Burgers Wendy A , Ntusi Ntobeko , Morris Lynn , Moore Penny L 
Published: March 2021

AbstractNeutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.
H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression
Authors: Kerimoglu Cemil , Pham Linh , Tonchev Anton B. , Sakib M. Sadman , Xie Yuanbin , Sokpor Godwin , Ulmke Pauline Antonie , Kaurani Lalit , Abbas Eman , Nguyen Huong , Rosenbusch Joachim , Michurina Alexandra , Capece Vincenzo , Angelova Meglena , Esgleas Miriam , Albert Mareike , Minkov Radoslav , Kovachev Emil , Teichmann Ulrike , Seong Rho H. , Huttner Wieland , Götz Magdalena , Nguyen Huu Phuc , Stoykova Anastassia , Staiger Jochen F. , Fischer Andre , Tuoc Tran 
Published: March 2021

ABSTRACTIncrease in the size of human neocortex, acquired in evolution, accounts for the unique cognitive capacity of humans. This expansion appears to reflect the evolutionarily-enhanced proliferative ability of basal progenitors (BPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, whether or how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP amplification and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Mechanistically, H3K9ac drives BP amplification by increasing expression of the evolutionarily regulated gene, TRNP1, in the developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture.One Sentence SummaryH3K9ac promotes basal progenitor amplification, neocortex expansion and gyrification by activating TRNP1 expression in evolution.
CA1 pyramidal cell diversity is rooted in the time of neurogenesis
Authors: Cavalieri Davide , Angelova Alexandra , Islah Anas , Lopez Catherine , Bocchio Marco , Baude Agnès , Cossart Rosa 
Published: March 2021

AbstractCellular diversity supports the computational capacity and flexibility of cortical circuits. Accordingly, principal neurons at the CA1 output node of the hippocampus are increasingly recognized as a heterogeneous population. Their genes, molecular content, intrinsic morpho-physiology, connectivity, and function seem to segregate along the main anatomical axes of the hippocampus. Since these axes reflect the temporal order of principal cell neurogenesis, we directly examined the relationship between birthdate and CA1 pyramidal neuron diversity, focusing on the ventral hippocampus. We used a genetic fate-mapping approach that allowed tagging three groups of agematched principal neurons: pioneer, early- and late-born. Using a combination of neuroanatomy, slice physiology, connectivity tracing and cFos staining, we show that birthdate is a strong predictor of CA1 principal cell diversity. We unravel a subpopulation of pioneer neurons recruited in familiar environments with remarkable positioning, morpho-physiological features, and connectivity. Therefore, despite the expected plasticity of hippocampal circuits, given their role in learning and memory, the diversity of their main components is significantly predetermined at the earliest steps of development.