bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deciphering the involvement of the Hippo pathway co-regulators, YAP/TAZ in invadopodia formation and matrix degradation
Authors: Venghateri Jubina Balan , Dassa Bareket , Morgenstern David , Shreberk-Shaked Michal , Oren Moshe , Geiger Benjamin 
Published: July 2022

AbstractInvadopodia are adhesive, actin-rich protrusions, formed by metastatic cancer cells that degrade the extracellular matrix and facilitate invasion. They support the metastatic cascade by a spatially and temporally coordinated process whereby invading cells bind to the matrix, degrade it by specific metalloproteinases, and mechanically penetrate diverse tissue barriers by forming actin-rich extensions. However, despite the apparent involvement of invadopodia in the metastatic process, the molecular mechanisms that regulate invadopodia formation and function are still largely unclear. In this study, we have explored the involvement of the key Hippo pathway co-regulators, namely YAP, and TAZ, in invadopodia formation and matrix degradation. Towards that goal, we tested the effect of depletion of YAP, TAZ, or both on invadopodia formation and activity in multiple human cancer cell lines. We report that knockdown of YAP and TAZ or their inhibition by verteporfin induce a significant elevation in matrix degradation and invadopodia formation in several cancer cell lines. Conversely, overexpression of these proteins strongly suppresses invadopodia formation and matrix degradation. Proteomic and transcriptomic profiling of MDA-MB-231 cells, following co-knockdown of YAP and TAZ, revealed a significant change in the levels of key invadopodia-associated proteins, including the crucial proteins Tks5 and MT1-MMP (MMP14). Collectively, our findings show that YAP and TAZ act as negative regulators of invadopodia formation in diverse cancer lines, most likely by reducing the levels of essential invadopodia components. Dissecting the molecular mechanisms of invadopodia formation in cancer invasion may eventually reveal novel targets for therapeutic applications against invasive cancer.
Variola virus is as old as the earliest historical lines of evidence suggest
Authors: Forni Diego , Molteni Cristian , Cagliani Rachele , Clerici Mario , Sironi Manuela 
Published: July 2022

AbstractArchaeovirology efforts provided a rich portrait of the evolutionary history of variola virus (VARV), the causative agent of smallpox. These studies revealed frequent viral lineage extinction and a relatively recent origin of VARV as a human pathogen (∼ 1,700 years ago, ya). This contrasts with historical records suggesting the presence of smallpox as early as 3,500 ya. By performing an analysis of ancestry components in modern, historic, and ancient VARV genomes, we unveil the progressive drifting of VARV lineages from a common ancestral population and we show that a small proportion of Viking-Age ancestry persisted until the 18th century. After the split of the P-I and P-II lineages, which occurred before the onset of smallpox vaccination, the former (but not the latter) experienced a severe bottleneck. We suggest this was due to the distinct epidemiology of the two lineages, which display remarkably different disease severity. As for the emergence of VARV, we corrected time estimates by accounting for the time-dependent rate phenomenon. Using this approach, we estimate that VARV emerged earlier than 3,800 ya, thus supporting its presence in ancient societies, including Egypt, as pockmarked mummies suggest.ImportanceNow eradicated, smallpox was one of the most devastating human diseases, causing the death of at least 300 million people in the 20th century. Humans were the only known host of variola virus, but the time-frame of its emergence in our species has been a matter of debate. Specifically, molecular dating suggested a relatively recent origin, whereas historical sources indicated the presence of VARV in ancient societies. By applying population genetic methods, we analyzed the ancestry components in modern and historic VARV genomes, and we found a progressive drifting of VARV lineages from a common ancestral population. By accounting for the common observation that rates of viral evolution scale negatively with the time-frame of measurement, we estimated that VARV emerged earlier than 3800 years ago. Thus, out data settle a controversy and provide novel insight into the origin and evolution of one of the most historically relevant human pathogens.
MRSL: A phenome-wide causal discovery algorithm based on GWAS summary data
Authors: Hou Lei , Geng Zhi , Shi Xu , Wang Chuan , Li Hongkai , Xue Fuzhong 
Published: July 2022

AbstractCausal discovery is a powerful tool to disclose underlying structures by analyzing purely observational data. Genetic variants can provide useful complementary information for structure learning. Here, we propose a novel algorithm MRSL (Mendelian Randomization (MR)-based Structure Learning algorithm), which combines the graph theory with univariable and multivariable MR to learn the true structure using only GWAS summary statistics. Specifically, MRSL also utilizes topological sorting to improve the precision of structure learning and provides three adjusting categories for multivariable MR. Results of simulation reveal that MRSL has up to two-fold higher F1 score than other eight competitive methods. Additionally, the computing time of MRSL is 100 times faster than other methods. Furthermore, we apply MRSL to 26 biomarkers and 44 ICD10-defined diseases from UK Biobank. The results cover most of expected causal links which have biological interpretations and several new links supported by clinical case reports or previous observational literatures.
CASP4/11 contributes to pulmonary inflammation and disease exacerbation in COVID-19
Authors: Rodrigues Tamara S. , Caetano Camila C.S. , de Sá Keyla S.G. , Almeida Leticia , Becerra Amanda , Gonçalves Augusto V. , de Sousa Lopes Leticia , Oliveira Samuel , Mascarenhas Danielle P.A. , Batah Sabrina S. , Silva Bruna M. , Gomes Giovanni F. , Castro Ricardo , Martins Ronaldo B. , Avila Jonathan , Frantz Fabiani G. , Cunha Thiago M. , Arruda Eurico , Cunha Fernando Q , Nakaya Helder , Cunha Larissa D. , Fabro Alexandre T , Louzada-Junior Paulo , de Oliveira Renê D.R. , Zamboni Dario S. 
Published: July 2022

AbstractInfection with SARS-CoV-2 induces COVID-19, an inflammatory disease that is usually self-limited, but depending on patient conditions may culminate with critical illness and patient death. The virus triggers activation of intracellular sensors, such as the NLRP3 inflammasome, which promotes inflammation and aggravates the disease. Thus, identification of host components associated with NLRP3 inflammasome is key for understanding the physiopathology of the disease. Here, we reported that SARS-CoV-2 induces upregulation and activation of human Caspase-4/CASP4 (mouse Caspase-11/CASP11) and this process contributes to inflammasome activation in response to SARS-CoV-2. CASP4 was expressed in lung autopsy of lethal cases of COVID-19 and CASP4 expression correlates with expression of inflammasome components and inflammatory mediators such asCASP1,IL1B,IL18andIL6. In vivo infections performed in transgenic hACE2 humanized mouse, deficient or sufficient forCasp11, indicate that hACE2Casp11−/−mice were protected from disease development, with reduced body weight loss, reduced temperature variation, increased pulmonary parenchymal area, reduced clinical score of the disease and reduced mortality. Collectively, our data establishes that CASP4/11 contributes to disease pathology and contributes for future immunomodulatory therapeutic interventions to COVID-19.
Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus
Authors: Malik Mansi , Vijayan Parvathy , Jagannath Deepak K , Mishra Rakesh K , Lakshminarasimhan Anirudha 
Published: July 2022

AbstractKyasanur forest disease is a neglected zoonotic disease caused by a single-stranded RNA-based flavivirus, the incidence of which was first recorded in 1957 in the Southern part of India. Kyasanur forest disease virus is transmitted to monkeys and humans through the infected tick bite ofHaemophysalis spinigera. Kyasanur forest disease is a febrile illness, which in severe cases, results in neurological complications leading to mortality. The current treatment regimens are symptomatic and supportive, and no targeted therapies are available for this disease. In this study, we evaluated the ability of FDA-approved drugs sofosbuvir (and its active metabolite) and Dasabuvir to inhibit the RNA-dependent RNA polymerase activity of NS5 protein from the Kyasanur forest disease virus. NS5 protein containing the N-terminal methyl transferase domain and C-terminal RNA-dependent RNA polymerase domain was expressed inEscherichia coli, and RNA-dependent RNA polymerase activity was demonstrated with the purified protein. The RNA-dependent RNA polymerase assay conditions were optimized, followed by the determination of apparent Km,ATPto validate the enzyme preparation. Half maximal-inhibitory concentrations against RNA-dependent RNA polymerase activity were determined for Sofosbuvir and its active metabolite. Dasabuvir did not show detectable inhibition with the tested conditions. This is the first demonstration of the inhibition of RNA-dependent RNA polymerase activity of NS5 protein from the Kyasanur forest disease virus with small molecule inhibitors. These initial findings can potentially facilitate the discovery and development of targeted therapies for treating Kyasanur forest disease.
Denoising sparse microbial signals from single-cell sequencing of mammalian host tissues
Authors: Ghaddar Bassel , Blaser Martin J. , De Subhajyoti 
Published: July 2022

AbstractWe developed SAHMI, a computational resource to identify truly present microbial nucleic acids and filter contaminants and spurious false-positive taxonomic assignments from standard transcriptomic sequencing of mammalian tissues. In benchmark studies, SAHMI correctly identifies known microbial infections present in diverse tissues. The application of SAHMI to single-cell and spatial genomic data enables co-detection of somatic cells and microorganisms and joint analysis of host-microbiome ecosystems.
Genome-wide association study of ACE inhibitor-induced cough implicates neuropeptides and shows genetic overlap with chronic dry cough
Authors: Coley Kayesha , Shepherd David J. , Packer Richard , John Catherine , Free Robert C. , Hollox Edward J. , Wain Louise V. , Tobin Martin D. , Batini Chiara 
Published: July 2022

SummaryACE inhibitors (ACEIs) are commonly prescribed for hypertension, a global risk factor for cardiovascular disease. Their primary side effect is a dry cough which affects 5-35% of users. As clinical guidelines recommend switching those experiencing cough to an angiotensin-II receptor blocker, we have used this switch as a proxy for ACEI-induced cough. Through a two-stage multi-ancestry genome-wide association study, including up to 7,030 cases and 39,921 controls, we identify five independent genome-wide significant associations implicating six protein-coding genes, includingINHBC, KCNIP4, NTSR1andPREPwhich encode proteins involved in the nervous system. We also observe genetic overlap between ACEI-induced cough and chronic dry cough through genetic correlation and phenome-wide association studies. In line with existing hypotheses, our findings suggest a neurological basis for the pathology of ACEI-induced cough, particularly the role of proinflammatory mediators in sensory airway sensitivity and cough reflex modulation, and shared biological mechanisms with chronic dry cough.
Novel cell- and stage-specific transcriptional signatures defining Drosophila neurons, glia and hemocytes
Authors: Sakr Rosy , Cattenoz Pierre B. , Pavlidaki Alexia , Ciapponi Laura , Marzullo Marta , Hariharan Nivedita , Mukherjee Tina , Giangrande Angela 
Published: July 2022

AbstractCell types can be now defined at unprecedented resolution using high throughput assays. We analyzed the transcriptional signatures of Drosophila neurons, glia and hemocytes, as examples of cell types that are related by position (glia/neurons) or function (glia/hemocytes) or that are unrelated (neurons/hemocytes). The most related cells display the highest similarity level (neurons and glia), the least related ones, the lowest (neurons and hemocytes), however, cells can show plastic features. Glia are much more similar to neurons than to hemocytes in the embryo, but are equally similar to the two cell types in the larva, when hemocytes acquire more immune functions. Larval glia and hemocytes display common as well as specific immune features, such as the glia-specific NimA receptor, in agreement with the different environment faced by each cell types. Surprisingly, time represents a key identity parameter, as neurons, hemocytes and glia group more significantly by the stage than by the cell type and larval cells show upregulation of genes involved in chromatin organization and in DNA repair. This latter group of genes is linked to changes in gene expression levels and chromatin organization, revealing a function of these genes beyond DNA repair. Finally, the metabolic profiles reveal cell type-specific signatures and an overall shift from an embryonic, anabolic state to a larval, catabolic state.
Development of zebrafish (Danio rerio) as anin vivomodel forBorrelia burgdorferiinfection
Authors: Misner Erica , Zhang Min , Sapi Eva 
Published: July 2022

AbstractBorrelia burgdorferiis the spirochetal bacterium that causes Lyme disease. Despite the fact that antimicrobial sensitivity ofB. burgdorferihas been widely studied, there is still a need to develop an affordable, practical, high-throughputin vivomodel which can be used to find effective antibiotic therapies, especially for the recently discovered persister and biofilm forms. Recent studies showed that Zebrafish (Danio rerio) could offer a novel, high-throughput, affordable model in antibiotic therapies for various infections agents can be studied. Therefore, in this study, we developed a straightforward, standardized infection procedure and tested it for zebrafish survival rate, morphological or behavioral changes post-infection as well as providing evidence thatB. burgdorferipersists in zebrafish using polymerase chain reaction (PCR) and immunohistochemical (IHC) techniques. Morphological and physiological examination showed a significant size difference between control and infected zebrafish at 2 wpi, and infected zebrafish exhibited slower heart rates through 72 hpi. Furthermore, our results showedB. burgdorferiDNA can be detected and active replication of theB. burgdorferi16S rRNA gene can be confirmed through 10 days post-infection via PCR and Reverse Transcription PCR respectively. Fluorescent microscopy and immunohistochemical staining revealed spirochetes present in the eyes, gills, heart, liver, tail, and hindbrain tissues though 72 hpi as well as the stomach and digestive tract at 2 weeks post-infection, respectively. These findings demonstrate that zebrafish could serve as a promising animal model to study the mechanism ofB. burgdorferiinfection as well asin vivoantibiotic sensitivity.
High Sox2 expression predicts taste lineage competency of lingual progenitors in vitro
Authors: Shechtman Lauren A. , Scott Jennifer K. , Larson Eric D. , Isner Trevor J. , Johnson Bryan J. , Gaillard Dany , Dempsey Peter J. , Barlow Linda A. 
Published: July 2022

SummaryTaste buds on the tongue are collections of taste receptor cells (TRCs) that detect sweet, sour, salty, umami and bitter stimuli. Like non-taste lingual epithelium, TRCs are renewed from basal keratinocytes, many of which express the transcription factor SOX2. Genetic lineage tracing has shown SOX2+ lingual progenitors give rise to both taste and non-taste lingual epithelium in the posterior circumvallate taste papilla (CVP) of mice. However, SOX2 is variably expressed among CVP cells suggesting that their progenitor potential may vary. Using transcriptome analysis and organoid technology, we show highly expressing SOX2+ cells are taste-competent progenitors that give rise to organoids comprising both TRCs and lingual epithelium, while organoids derived from low-expressing SOX2+ progenitors are composed entirely of non-taste cells. Hedgehog and WNT/ß-catenin are required for taste homeostasis in adult mice, but only WNT/ß-catenin promotes TRC differentiation in vitro and does so only in organoids derived from higher SOX2+ taste lineage-competent progenitors.
Inactivated SARS-CoV-2 Reprograms the Tumor Immune Microenvironment and Improves Murine Cancer Outcomes
Authors: Giurini Eileena F , Williams Michael , Morin Adam , Zloza Andrew , Gupta Kajal H 
Published: July 2022

AbstractFollowing the breakthrough of immune check point inhibitors (ICIs), a new era of immuno-oncology agents has emerged and established immunotherapy as a part of cancer treatment. Despite the improving outcomes of ICIs, many patients with initial response are known to develop acquired resistance later. There is increasing interest in utilizing other stimulatory means, such as anti-pathogen immune responses to induce anti-tumor immune responses. The immunostimulatory effects of anti-pathogen-treated tumors in combinations with ICI are known to potentially amplify anti-tumor immunity resulting in increased tumor responses and improved outcomes. Anti-pathogen-treated tumors can become immune-infiltrated “hot” tumors and demonstrate higher treatment response rates and improved survival. Our research group has previously demonstrated that tumors can be converted from “cold” to “hot” by intratumoral injection of a commercially available seasonal influenza vaccine. In continuation with our work, in deciphering the role of anti-viral immunity in the context of tumor immunology, we studied the role of inactivated SARS-CoV-2 virus as anti-tumor agent. Here we report that intratumoral injections of inactivated SARS-CoV-2 convert the immunologically cold tumors to hot by generating anti-tumor-mediated CD8+ T cells. Our findings suggest that inactivated SARS-CoV-2 can be used as an immune modulator in immunotherapy for melanoma and triple-negative breast cancer.
Does board demographic diversity affect the dividend payout policy in Turkey?
Authors: Khan Ajab , Yilmaz Mustafa Kemal , Aksoy Mine 
Published: July 2022

PurposeThe purpose of this study is to investigate the impact of board demographic diversity on the dividend payout policy in Turkish capital markets.Design/methodology/approachUsing a sample of 67 non-financial companies listed on Borsa Istanbul 100 index from 2013 to 2018, this study examines the influence of board demographic diversity on dividend payout policies in Turkish capital markets. The authors also create a Demographic Board Diversity Index (DBDI) to estimate the composite cognitive diversity. The authors use dividend payment probability, dividend payout ratio, and dividend yield to measure the dividend policy and employ panel logit and tobit regression models.FindingsThe results indicate that diversity in nationality, experience and educational background play an influential role in encouraging companies to pay high dividends, while gender, tenure and age diversity are insignificant in affecting dividend payments. The findings also suggest that the DBDI positively affects the companies in formulating the dividend payout policies. Finally, the findings show that the family-owned companies with diverse board members have a negative influence on dividend payment intensity.Originality/valueThe results offer valuable insights for companies and policymakers in emerging markets to develop a more refined governance structure accommodating board demographic diversity attributes to mitigate agency conflicts between controlling and minority shareholders through setting up effective dividend payout policies.
Risk allocation for energy performance contract from the perspective of incomplete contract: a study of commercial buildings in China
Authors: Wan Shiyu , Liu Yisheng , Ding Grace , Runeson Goran , Er Michael 
Published: July 2022

PurposeThis article aims to establish a dynamic Energy Performance Contract (EPC) risk allocation model for commercial buildings based on the theory of Incomplete Contract. The purpose is to fill the policy vacuum and allow stakeholders to manage risks in energy conservation management by EPCs to better adapt to climate change in the building sector.Design/methodology/approachThe article chooses a qualitative research approach to depict the whole risk allocation picture of EPC projects and establish a dynamic EPC risk allocation model for commercial buildings in China. It starts with a comprehensive literature review on risks of EPCs. By modifying the theory of Incomplete Contract and adopting the so-called bow-tie model, a theoretical EPC risk allocation model is developed and verified by interview results. By discussing its application in the commercial building sector in China, an operational EPC three-stage risk allocation model is developed.FindingsThis study points out the contract incompleteness of the risk allocation for EPC projects and offered an operational method to guide practice. The reasonable risk allocation between building owners and Energy Service Companies can realize their bilateral targets on commercial building energy-saving benefits, which makes EPC more attractive for energy conservation.Originality/valueExisting research focused mainly on static risk allocation. Less research was directed to the phased and dynamic risk allocation. This study developed a theoretical three-stage EPC risk allocation model, which provided the theoretical support for dynamic EPC risk allocation of EPC projects. By addressing the contract incompleteness of the risk allocation, an operational method is developed. This is a new approach to allocate risks for EPC projects in a dynamic and staged way.
WHO invents what? Women’s participation in patenting activity in Spain
Authors: Medina Lisset , Álvarez Isabel 
Published: July 2022

PurposeRecent years have seen increased participation by women in Science and Technology activities, but parity with men remains a distant goal. This paper provides a framework for improving knowledge on the dynamics of women’s contributions to innovation, as measured through their contributions as inventors.Design/methodology/approachAnalysis was conducted using data from the United States Patent and Trademark Office (USPTO) database, covering over 40 years from 1976 to 2019. The study provides a breakdown of women’s inventiveness/innovation by technology area, which permits analysis of whether female inventors tend to work individually or as part of a team, as well as analysis of the effects of international networks.FindingsSpecific data have been analyzed around innovative activity by women in Spain, providing new insights on gender gaps. Key findings include those recent increases in inventions by women (as measured through patents) have occurred mostly via participation in internationally connected mixed-gender teams. Furthermore, the inventive creativity of women is found to be sector-biased and framed mainly in the chemical sector.Originality/valueThere are no similar contributions using USPTO data for Spanish inventions. This is an original paper that emphasizes the potential of collaborative networks as key driving mechanisms for the reduction of gender gaps and for the larger integration of women into innovation activities, with potential implications for stakeholders at both firm and governmental levels.