bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connective-Tissue Growth Factor (CTGF/CCN2) Contributes to TGF-β1-Induced Lung Fibrosis
Authors: Yanagihara Toyoshi , Chong Sy Giin , Gholiof Mahsa , Lipson Kenneth E. , Zhou Quan , Scallan Ciaran , Upagupta Chandak , Tikkanen Jussi , Keshavjee Shaf , Ask Kjetil , Kolb Martin RJ 
Published: July 2020

AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and extracellular matrix in the lung. Connective-tissue growth factor (CTGF) is known to exacerbate pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we show the upregulation of CTGF from a rat lung fibrosis model induced by adenovirus vector encoding active TGF-β1 (AdTGF-β1), and also in patients with IPF. The expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on days 7 or 14 as well as endothelial cells sorted from fibrotic lungs on day 14 or 28 respectively. These findings suggest the role of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases pro-fibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, fibrotic extracellular matrix upregulated the expression of CTGF, as compared to normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for the treatment of pulmonary fibrosis.
Harnessing the central dogma for stringent multi-level control of gene expression
Authors: Greco F. Veronica , Pandi Amir , Erb Tobias J. , Grierson Claire S. , Gorochowski Thomas E. 
Published: July 2020

AbstractStrictly controlled inducible gene expression is crucial when engineering biological systems where even tiny amounts of a protein have a large impact on function or host cell viability. In these cases, leaky protein production must be avoided at all costs, but ideally without affecting the achievable range of expression. Here, we demonstrate how the central dogma offers a simple way to effectively address this challenge. By simultaneously regulating both transcription and translation, we show how relative basal expression of an inducible system can be greatly reduced, with minimal impact on the maximum induced expression rate. Using this approach, we create several stringent expression systems displaying >1000-fold change in their output after inductionin vivoand up to a 350-fold change when used in a cell-free expression system. Furthermore, we find that multi-level regulation is able to suppress transcriptional noise and creates a digital-like switch when transitioning between ‘on’ and ‘off’ states. This work provides foundational knowledge and a genetic toolkit of parts to create multi-level gene expression controllers for those working with toxic genes or requiring precise regulation and propagation of cellular signals. It also demonstrates the value of exploring more complex and diverse regulatory designs for synthetic biology.
CRISPR/Cas9-based silencing of theATXN1gene in Spinocerebellar ataxia type 1 (SCA1) fibroblasts
Authors: Salvatori Francesca , Pappadà Mariangela , Sicurella Mariaconcetta , Buratto Mattia , Simioni Valentina , Tugnoli Valeria , Marconi Peggy 
Published: July 2020

AbstractSpinocerebellar Ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a gain-of-function protein with toxic activities, containing an expanded polyQ tract in the coding region. Actually, there are no treatments available to delay the onset, stop or slow down the progression of this pathology. Many approaches developed over the years involve the use of siRNAs and antisense oligonucleotides (ASOs). Here we develop and validate a CRISPR/Cas9 therapeutic strategy in fibroblasts isolated from SCA1 patients. We started from the screening of 10 different sgRNAs able to recognize regions upstream and downstream the CAG repeats, in exon 8 ofATXN1gene. The two most promising sgRNAs, G3 and G8, whose efficiency was evaluated with anin vitrosystem, significantly downregulated the ATXN 1 protein expression. This downregulation was due to the introduction of indels mutations into theATXN1gene. Notably, with an RNA-seq analysis, we demonstrated minimal off-target effects of our sgRNAs. These preliminary results support CRISPR/Cas9 as a promising approach for treated polyQ-expanded diseases.
Gender, race and parenthood impact academic productivity during the COVID-19 pandemic: from survey to action
Authors: Staniscuaski Fernanda , Kmetzsch Livia , Zandonà Eugenia , Reichert Fernanda , Soletti Rossana C. , Ludwig Zelia M.C , Lima Eliade F. , Neumann Adriana , Schwartz Ida V.D. , Mello-Carpes Pamela B. , Tamajusuku Alessandra S.K. , Werneck Fernanda P. , Ricachenevsky Felipe K. , Infanger Camila , Seixas Adriana , Staats Charley C. , de Oliveira Leticia 
Published: July 2020

AbstractWhile the Coronavirus disease 2019 (COVID-19) pandemic is altering academia dynamics, those juggling remote work and domestic demands – including childcare - have already felt the impacts on productivity. Female authors are facing a decrease in papers submission rates since the beginning of the pandemic period. The reasons for this decline in women productivity need to be further investigated. Here we show the influence of gender, parenthood and race in academics productivity during the pandemic period, based on a survey answered by 3,345 Brazilian academics from various knowledge areas and research institutions. Findings revealed that male academics - especially childless ones - were the least affected group, whereas female academics, especially Black women and mothers, were the most impacted group. This scenario will leave long-term effects on the career progression of the most affected groups. The results presented here are crucial for the development of actions and policies that aim to avoid further deepening the gender gap in science. This particular situation we are facing during the pandemic demands institutional flexibility and academia should foster the discussion about actions to benefit Black scientists and academics with families in the post-pandemic scenario.
Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance
Authors: Zhang Xu , Maity Tapan K. , Ross Karen E. , Qi Yue , Cultraro Constance M. , Gao Shaojian , Nguyen Khoa Dang , Cowart Julie , Kirkali Fatos , Wu Cathy , Guha Udayan 
Published: July 2020

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rdgeneration irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rdgeneration EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance bothin vitroandin vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rdgeneration EGFR TKI sensitive and resistant cells.
Improved detection of tumor suppressor events in single-cell RNA-Seq data
Authors: Teschendorff Andrew E. , Wang Ning 
Published: July 2020

AbstractTissue-specific transcription factors are frequently inactivated in cancer. To fully dissect the heterogeneity of such tumor suppressor events requires single-cell resolution, yet this is challenging because of the high dropout rate. Here we propose a simple yet effective computational strategy called SCIRA to infer regulatory activity of tissue-specific transcription factors at single-cell resolution and use this tool to identify tumor suppressor events in single-cell RNA-Seq cancer studies. We demonstrate that tissue-specific transcription factors are preferentially inactivated in the corresponding cancer cells, suggesting that these are driver events. For many known or suspected tumor suppressors, SCIRA predicts inactivation in single cancer cells where differential expression does not, indicating that SCIRA improves the sensitivity to detect changes in regulatory activity. We identify NKX2-1 and TBX4 inactivation as early tumor suppressor events in normal non-ciliated lung epithelial cells from smokers. In summary, SCIRA can help chart the heterogeneity of tumor suppressor events at single-cell resolution.
Natural selection acts on epigenetic marks
Authors: Boukas Leandros , Razi Afrooz , Bjornsson Hans T. , Hansen Kasper D. 
Published: July 2020

AbstractIn the study of molecular features like epigenetic marks, it is appealing to ascribe observed patterns to the action of natural selection. However, this conclusion requires a test for selection based on a well-defined notion of neutrality. Here, focusing on epigenetic marks at gene loci, we formalize what it means for an epigenetic mark to be neutral, and develop a test for selection. Our test respects the foundational aspect of epigenetics:trans-regulation by transcription factors and chromatin modifiers. It also enables adjustment for confounders. We establish that promoter DNA methylation, promoter H3K4me3 and exonic H3K36me3 are all under selection, and that this is unlikely to be a passive consequence of selection on gene expression. The effect of these epigenetic marks on fitness is arguably partly explained by a causal involvement in gene regulation. However, we also investigate the complementary explanation that DNA methylation and H3K36me3 are under selection in part because they modify the mutation rate of important genomic regions. We show that this explanation is consistent with empirical observations as well as population genetics theory, because of thetrans-regulation. Exemplifying the protection of important regions from high mutability, we demonstrate that in humans the more intolerant to loss-of-function mutations a gene is, the lower its coding mutation rate is. Our framework for selection inference is simple but general, and we speculate that its core ideas will be useful for additional molecular features beyond epigenetic marks.
Measurement of hindered diffusion in complex geometries for high-speed single-molecule experiments
Authors: Bartsch Tobias F. , Villasante Camila M. , Touré Ahmed , Firester Daniel M. , Hengel Felicitas E. , Oswald Aaron , Hudspeth A. J. 
Published: July 2020

AbstractIn a high-speed single-molecule experiment, a protein is tethered between two substrates that are manipulated to exert force on the system. To avoid nonspecific interactions between the protein and nearby substrates, the protein is usually attached to the substrates through long, flexible linkers. This approach precludes measurements of mechanical properties with high spatial and temporal resolution, for rapidly exerted forces are dissipated into the linkers. Because mammalian hearing operates at frequencies reaching tens to hundreds of kilohertz, the mechanical processes that occur during transduction are of very short duration. Single-molecule experiments on the relevant proteins therefore cannot involve long tethers. We previously characterized the mechanical properties of protocadherin 15 (PCDH15), a protein essential for human hearing, by tethering an individual monomer through very short linkers between a probe bead held in an optical trap and a pedestal bead immobilized on a glass coverslip. Because the two confining surfaces were separated by only the length of the tethered protein, hydrodynamic coupling between those surfaces complicated the interpretation of the data. To facilitate our experiments, we characterize here the anisotropic and position-dependent diffusion coefficient of a probe in the presence of an effectively infinite wall, the coverslip, and of the immobile pedestal.
The Internal Structure of Metacommunities
Authors: Leibold Mathew A. , Rudolph F. Javiera , Blanchet F. Guillaume , De Meester Luc , Gravel Dominique , Hartig Florian , Peres-Neto Pedro , Shoemaker Lauren , Chase Jonathan M. 
Published: July 2020

AbstractCurrent analyses of metacommunity data largely focus on global attributes across the entire metacommunity, such as mean alpha, beta, and gamma diversity, as well as the partitioning of compositional variation into single estimates of contributions of space and environmental effects and, more recently, possible contributions of species interactions. However, this view neglects the fact that different species and sites in the landscape can vary widely in how they contribute to these metacommunity-wide attributes. We argue for a new conceptual framework with matched analytics with the goals of studying the complex and interactive relations between process and pattern in metacommunities that is focused on the variation among species and among sites which we call the ‘internal structure’ of the metacommunity. To demonstrate how the internal structure could be studied, we create synthetic data using a process-based colonization-extinction metacommunity model. We then use Joint Species Distribution Models to estimate how the contributions of space, environment and biotic interactions driving metacommunity assembly differ among species and sites. We find that this approach to the internal structure of metacommunities provides useful information about the distinct ways that different species and different sites contribute to metacommunity structure. Although it has limitations, our work points at a more general approach to understand how other possible complexities might affect internal structure and might thus be incorporated into a more cohesive metacommunity theory.
Neurofeedback training of auditory selective attention enhances speech-in-noise perception
Authors: Kim Subong , Emory Caroline , Choi Inyong 
Published: July 2020

AbstractSelective attention enhances cortical responses to attended sensory inputs while suppressing others, which can be an effective strategy for speech-in-noise (SiN) understanding. Here, we introduce a training paradigm designed to reinforce attentional modulation of auditory evoked responses. Subjects attended one of two speech streams while our EEG-based attention decoder provided online feedback. After four weeks of this neurofeedback training, subjects exhibited enhanced cortical response to target speech and improved performance during a SiN task. Such training effects were not found in the Placebo group that underwent attention training without neurofeedback. These results suggest an effective rehabilitation for SiN deficits.
Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation
Authors: Baker Steven Andrew , Kwok Shirley , Berry Gerald J. , Montine Thomas J. 
Published: July 2020

AbstractMortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010-2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40-83 years old in the ventilated cohort and 14-80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). Additionally, we observed prominent pulmonary endothelial ACE2 expression in 2 patients on either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.
An SEIR Model with Contact Tracing and Age-Structured Social Mixing for COVID-19 outbreak
Authors: Teimouri Ali 
Published: July 2020

AbstractIn December 2019 a severe acute respiratory syndrome now known as SARS-CoV-2 began to surge in Wuhan, China. The virus soon spread throughout the world to become a pandemic. Since the outbreak various measures were put in place to contain and control the spread, these interventions were mostly based on compartmental models in epidemiology with the main goal of controlling and monitoring the rate of the basic and effective reproduction number. In this paper, we propose an SEIR model where we incorporate contact tracing and age-structured social mixing. We show the explicit relation between contact tracing and social mixing and other relevant parameters of the proposed model. We derive a formula for the effective reproduction number which is expressed in terms of reported cases, tracing quantities and social mixing. We use this formula to determine the expectation value of the effective reproduction number in London, UK.
Racial segregation, testing sites access, and COVID-19 incidence rate in Massachusetts, USA
Authors: Hu Tao , Yue Han , Wang Changzhen , She Bing , Ye Xinyue , Liu Regina , Zhu Xinyan , Bao Shuming 
Published: July 2020

ABSTRACTThe U.S. has merely 4% of the world population but 25% of the world’s COVID-19 cases. Massachusetts has been in the leading position of total cases since the outbreak in the U.S. Racial residential segregation is a fundamental cause of racial disparities in health. Moreover, disparities of access to health care have a large impact on COVID-19 cases. Thus, this study estimates racial segregation and disparities in testing sites access and employs economic, demographic, and transportation variables at the city/town level in Massachusetts. Spatial regression models are applied to evaluate the relationships between COVID-19 incidence rate and related variables. This is the first study to apply spatial analysis methods across neighborhoods in the U.S. to examine the COVID-19 incidence rate. The findings are: 1) residential segregations of Hispanic and Non-Hispanic Black/African Americans have a significantly positive association with COVID-19 incidence rate, indicating the higher susceptibility of COIVD-19 infections among minority; 2) The Black has the shortest drive time to testing sites, followed by Hispanic, Asian, and Whites. The drive time to testing sites is significantly negatively associated with the COVID-19 incidence rate, implying the importance of testing location being accessed by all populations; 3) Poverty rate and road density are significant explanatory variables. Importantly, overcrowding represented by more than one person per room is a significant variable found to be positively associated with COVID-19 incidence rate, suggesting the effectiveness of social distancing for reducing infection; 4) Different from previous studies, elderly population rate is not statistically significant with incidence rate because the elderly population in Massachusetts is less distributed in the hot spot regions of COVID-19 infections. The findings in this study provide useful insights for policymakers to propose new strategies to contain the COVID-19 transmissions in Massachusetts.
Organization of Primary Health Care in pandemics: a rapid systematic review of the literature in times of COVID-19
Authors: Sarti Thiago Dias , Lazarini Welington Serra , Fontenelle Leonardo Ferreira , Almeida Ana Paula Santana Coelho 
Published: July 2020

AbstractThe world is experiencing one of the greatest public health emergencies in history with the global spread of COVID-19. Health systems, including Primary Health Care (PHC) services, are pillars of pandemic coping strategies, and there are important gaps in the literature on the best ways to organize PHC in health crisis scenarios such as the one currently experienced. Given the urgency of responses, we performed a rapid systematic literature review on MEDLINE (via PubMed), EMBASE and LILACS (via VHL), in order to analyze empirical studies on the effectiveness of PHC organization strategies in the context of epidemics to improve access and reduce morbidity and mortality. We selected seven articles, which studied the responses to different epidemics in different parts of the world. In terms of access, the studies suggest positive results with the adoption of adjustments of work processes of the teams and the structure of the services, combined with diversification of actions (including call center), adequate provision of inputs and personal protective equipment, adequate action plans and communication strategies, and effective integration with public health services and other levels of care. No study analyzed population morbidity and mortality. The included studies suggest also that community-oriented PHC is more effective in crisis scenarios, indicating the necessity of strengthening of the Family Health Strategy in the Brazilian context.