bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating TGFβ inhibition
Authors: Luong Tiffany , Cukierman Edna 
Published: February 2022

AbstractLess than 11% of pancreatic cancer patients survive 5-years post-diagnosis. The unique biology of pancreatic cancer includes a significant expansion of its desmoplastic tumor microenvironment, wherein cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix are key components. CAF functions are both tumor-supportive and tumor-suppressive, while normal fibroblastic cells are solely tumor-suppressive. Knowing that CAF-eliminating drugs are ineffective and can accelerate cancer progression, therapies that “normalize” CAF function are highly pursued. Eribulin is a well-tolerated anti-microtubule drug used to treat a plethora of neoplasias, including advanced/metastatic cancers. Importantly, eribulin can inhibit epithelial to mesenchymal transition via a mechanism akin to blocking pathways induced by transforming growth factor-beta (TGFβ). Notably, canonical TGFβ signaling also plays a pivotal role in CAF activation, which is necessary for the development and maintenance of desmoplasia. Hence, we hypothesized that eribulin could modulate, and perhaps “normalize” CAF function. To test this premise, we used a well-established in vivo-mimetic fibroblastic cell-derived extracellular matrix (CDM) system and gauged the effects of eribulin on human pancreatic CAFs and cancer cells. The pathophysiologic cell-culturing system was also used to query eribulin effects on CDM-regulated cancer cell survival and invasive spread. Results demonstrated that intact CDMs modestly restricted eribulin from obstructing cancer cell growth. Nonetheless, eribulin-treated CAFs generated CDMs that limited cancer cell survival under nutritional stress, similar to reported tumor-suppressive CDMs generated by TGFβ-deficient CAFs. Data from this study support the central proposed premise and suggest that eribulin could be used as a CAF-normalizing drug.
Genomics of Post-Vaccination SARS-CoV-2 Infections During the Delta Dominated Second Wave of COVID-19 Pandemic, from Mumbai Metropolitan Region (MMR), India
Authors: Nilgiriwala Kayzad , Kadam Pratibha , Patel Grishma , Shaikh Ambreen , Mestry Tejal , Vaswani Smriti , Sakthivel Shalini , Poojary Aruna , Gandhi Bhavesh , Rohra Seema , Udwadia Zarir , Oswal Vikas , Shah Daksha , Gomare Mangala , Sriraman Kalpana , Mistry Nerges 
Published: February 2022

ABSTRACTVaccination against SARS-CoV-2 was launched in India in January 2021. Though vaccination reduced hospitalization and mortality due to COVID-19, vaccine breakthrough infections have become common. The present study was initiated in May 2021 to understand the proportion of predominant variants in post-vaccination infections during the Delta dominated second wave of COVID-19 in the Mumbai Metropolitan Region (MMR) in India and to understand any mutations selected in the post-vaccination infections or showing association with any patient demographics. We collected samples (n=166) from severe/moderate/mild COVID-19 patients who were either vaccinated (COVISHIELD/COVAXIN – partial/fully vaccinated) or unvaccinated, from a city hospital and from home isolation patients in MMR. A total of 150 viral genomes were sequenced by Oxford Nanopore sequencing (using MinION) and the data of 136 viral genomes were analyzed for clade/lineage and for identifying mutations in all the genomes. The sequences belonged to three clades (21A, 21I and 21J) and their lineage was identified as either Delta (B.1.617.2) or Delta+ (B.1.617.2 + K417N) or sub-lineages of Delta variant (AY.120/AY.38/AY.99). A total of 620 mutations were identified of which 10 mutations showed an increase in trend with time (May-Oct 2021). Associations of 6 mutations (2 in spike, 3 in orf1a and 1 in nucleocapsid) were shown with milder forms of the disease and one mutation (in orf1a) with partial vaccination status. The results indicate a trend towards reduction in disease severity as the wave progressed.
Epigenetic signals that direct cell type specific interferon beta response in mouse cells
Authors: Muckenhuber Markus , Lander Isabelle , Müller-Ott Katharina , Mallm Jan-Philipp , Klett Lara C. , Knotz Caroline , Hechler Jana , Kepper Nick , Erdel Fabian , Rippe Karsten 
Published: February 2022

AbstractThe antiviral response induced by type I interferon (IFN) via the JAK-STAT signaling cascade activates hundreds of IFN-stimulated genes (ISGs). While this response occurs essentially in all human and mouse tissues it varies between different cell types. However, the linkage between the underlying epigenetic features and the ISG pattern of a given cell is not well understood. We mapped ISGs, binding sites of the STAT1 and STAT2 transcription factors and chromatin features in three different mouse cell types (embryonic stem cells, neural progenitor cells and embryonic fibroblasts) before and after treatment with IFNβ. The analysis included gene expression, chromatin accessibility and histone H3 lysine modification by acetylation (ac) and mono-/tri-methylation (me1, me3). A large fraction of ISGs and STAT binding sites were cell type specific with promoter binding of a STAT1-STAT2 complex (STAT1/2) being a key driver of ISG induction. Furthermore, STAT1/2 binding to putative enhancers at intergenic and intronic sites induced ISG expression as inferred from a chromatin co-accessibility analysis. STAT1/2 binding was dependent on the chromatin context and positively correlated with pre-existing H3K4me1 and H3K27ac marks in an open chromatin state while the presence of H3K27me3 had an inhibitory effect. Thus, chromatin features present before stimulation represent an additional regulatory layer for the cell type specific antiviral response.
Human HLFneg placental erythro-myeloid progenitors give rise to HLA Class IIneg Hofbauer cells
Authors: Thomas Jake R. , Appios Anna , Calderbank Emily F. , Zhao Xiaohui , Hamilton Russell S. , Moffett Ashley , Sharkey Andrew , Laurenti Elisa , McGovern Naomi 
Published: February 2022

AbstractThe earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. This process is still poorly understood in humans but is generally thought to be spatially restricted to the yolk sac. Human fetal placental macrophages, Hofbauer cells (HBC), arise during the primitive haematopoietic wave, yet are unlikely to be yolk sac derived as they appear prior to placental vascularisation. Here we identify a population of placental erythro-myeloid progenitors (PEMPs) in the early human placenta that give rise to HBC. PEMP are fetal CD34+CD43+ progenitors found exclusively at early gestational timepoints. Transcriptomic analyses reveal that PEMP have a unique transcriptome with some conserved features of primitive yolk sac EMPs, including the lack of HLF expression. Using in vitro single-cell culture experiments we show that PEMP generate HBC-like cells which lack HLA-DR expression, a conserved feature of all fetal primitive macrophages in humans. These findings indicate that HBC are derived locally from PEMP and demonstrate that human primitive haematopoiesis is not restricted to the yolk sac, occurring also in the placenta.
A metabolically engineered bacterium controls autoimmunity by remodeling the pro-inflammatory microenvironment
Authors: Das Jugal Kishore , Guo Fengguang , Hunt Carrie , Steinmeyer Shelby , Plocica Julia A , Kobayashi Koichi S. , Jayaraman Arul , Ficht Thomas A , Alaniz Robert C. , de Figueiredo Paul , Song Jianxun 
Published: February 2022

AbstractImmunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M ΔvjbR, BmΔvjbR) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T cells (Tregs). We demonstrated that treatment with this strain polarized M2 macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Tregs, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity and reducing inflammation by remodeling the IME and augmenting Treg function.
Defining the chromatin and transcriptional landscape of stem cell-derived islets
Authors: Augsornworawat Punn , Hogrebe Nathaniel J. , Ishahak Matthew , Marquez Erica , Maestas Marlie M. , Schmidt Mason D. , Veronese-Paniagua Daniel A. , Gale Sarah E. , Miller Julia R. , Velazco-Cruz Leonardo , Millman Jeffrey R. 
Published: February 2022

AbstractTransplantation of insulin-secreting β-cells differentiated from human pluripotent stem cells holds great potential as a cell therapy for treating insulin-dependent diabetes. While these stem cell-derived islets (SC-islets) are able to reverse diabetes in animal models, they are not fully equivalent to their in vivo counterparts. To better define the state of the cell types generated within these SC-islets and provide a resource for identifying deficiencies in lineage specification, we used single-cell multiomic sequencing to simultaneously measure the chromatin accessibility and transcriptional profiles of SC-islets at multiple time points as well as primary human islets. The integrated analysis of both the transcriptional and chromatin landscape for each cell provided greater resolution for defining cell identity, allowing us to derive novel gene lists for identifying each islet cell type. Furthermore, this multiomic analysis revealed that the difference between SC-β cells and enterochromaffin-like cells, which are a major off-target from in vitro differentiation, is a gradient of progressive cell states rather than a stark difference in identity. The chromatin landscape of primary human islets was much more restricted, suggesting that stem cell-derived cells are not fully locked into their cell fate. While long term culture of SC-islets both in vitro and in vivo does close overall chromatin state, only in vivo transplantation directs cells toward their correct identities. Collectively, our multiomic analysis demonstrates that both the chromatin and transcriptional landscapes play significant roles in islet cell identity, and these data can be used as a resource to identify specific deficiencies in the chromatin and transcriptional state of SC-islet cell types.
A lipid-associated macrophage lineage rewires the spatial landscape of adipose tissue in early obesity
Authors: Stansbury Cooper M. , Dotson Gabrielle A. , Pugh Harrison , Rehemtulla Alnawaz , Rajapakse Indika , Muir Lindsey A. 
Published: February 2022

ABSTRACTObjectiveObesity-induced metabolic dysfunction, tissue remodelling, and chronic inflammation in visceral white adipose-tissue (WAT) are correlated with insulin resistance, type II diabetes, and metabolic disease pathogenesis [1]. In this work, we sought to establish spatio-temporal context of adipose tissue macrophage (ATM) reprogramming during obesity.MethodsWe captured single-cell RNA-sequencing, spatial transcriptomics, and histological imagining of murine WAT over the course of diet-induced obesity to study macrophage phenotype dynamics. We developed a straightforward mathematical approach to integrating multi-modal data to quantify obesityinduced changes to WAT organization. We aligned ATM phenotypes with crown-like structures (CLS) in early obesity and used spatial network analysis to uncover signalling mechanisms implicated in CLS formation.ResultsWe identified novel diversity of the lipid-associated macrophage (LAM) phenotype, whose transcriptional profile, signaling mechanisms, and spatial context serve as indicators of CLS formation in early obesity. We demonstrated that dysregulation of lipid-metabolic signalling is a critical turning point in the monocyte-LAM lineage and identified novel ligand-receptor mechanisms includingApoe, Lrp1, LplandAppthat serve as hallmarks of nascent CLS in WAT.ConclusionsMulti-modal spatio-temporal profiling demonstrates that LAMs disproportionately accumulate in CLS and are preceded by a transition-state macrophage phenotype with monocytic origins. We identified novel ligand-receptor interactions implicated in nascent CLS regions which may guide future cellular-reprogramming interventions for obesity-related sequelae.Graphical AbstractHighlights-We characterize a novel lipid-associated macrophage (LAM) phenotype along the monocyte-LAM lineage-Integrated imaging, single-cell sequencing and spatial transcriptomics data show that LAMs accumulate at nascent CLS-Analysis of spatial transcriptomics data reveals a novel set of ligands and receptors that implicate immature LAMs in shaping the CLS microenvironment in early obesity-We present a simple mathematical framework for studying dynamics of tissue-structure over time
Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP2
Authors: Panasawatwong Adisorn , Pipatpolkai Tanadet , Tucker Stephen J. 
Published: February 2022

AbstractMembers of the TREK family of two-pore domain (K2P) potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP2). This study used coarse-grained molecular dynamics (CG-MD) and atomistic MD simulations to model the PIP2 binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP2 binding relative to other anionic phospholipids in both conformational states using potential of mean force (PMF) and free energy perturbation (FEP) calculations. Our results identify state-dependent binding of PIP2 to sites involving the proximal C-terminus and we show that PIP2 promotes a conformational transition from a down state towards an intermediate that resembles the up state. These results are consistent with functional data for PIP2 regulation and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.
Machine learning meets classical computer vision for accurate cell identification
Authors: Karimi Elham , Rezanejad Morteza , Fiset Benoit , Perus Lucas , McDowell Sheri A. C. , Arabzadeh Azadeh , Beugnot Gaspard , Siegel Peter , Guiot Marie-Christine , Quail Daniela F. , Siddiqi Kaleem , Walsh Logan A. 
Published: February 2022

AbstractHigh-parameter multiplex immunostaining techniques have revolutionized our ability to image healthy and diseased tissues with unprecedented depth; however, accurate cell identification and segmentation remain significant downstream challenges. Identifying individual cells with high precision is a requisite to reliably and reproducibly interpret acquired data. Here we introduce CIRCLE, a cell identification pipeline that combines classical and modern machine learning-based computer vision algorithms to address the shortcomings of current cell segmentation tools for 2D images. CIRCLE is a fully automated hybrid cell detection model, eliminating subjective investigator bias and enabling high-throughput image analysis. CIRCLE accurately distinguishes cells across diverse tissues microenvironments, resolves low-resolution structures, and can be applied to any 2D image that contains nuclei. Importantly, we quantitatively demonstrate that CIRCLE outperforms current state-of-the-art image segmentation tools using multiple accuracy measures. As high-throughput multiplex imaging grows closer toward standard practice for histology, integration of CIRCLE into analysis protocols will deliver unparalleled segmentation quality.
RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma
Authors: Zhang Song , Cooper Jack , Chong Yee Seng , Naveed Alina , Mayoh Chelsea , Jayatilleke Nisitha , Liu Tao , Amos Sebastian , Kobelke Simon , Marshall Andrew C , Meers Oliver , Choi Yu Suk , Bond Charles S , Fox Archa H 
Published: February 2022

AbstractHigh-risk neuroblastoma patients have poor survival rates and require better therapeutic options. High expression of a multifunctional DNA and RNA binding protein, NONO, in neuroblastoma is associated with poor patient outcome, however there is little understanding of the mechanism of NONO-dependent oncogenic gene regulatory activity in neuroblastoma. Here, we used cell imaging, biophysical and molecular analysis to reveal complex NONO-dependent regulation of gene expression, finding that NONO forms RNA- and DNA-tethered phase-separated condensates throughout the nucleus. CLIP analyses show that NONO mainly binds to the 5’ end of pre-mRNAs and modulates pre-mRNA processing, dependent on its RNA binding activity. NONO preferentially regulates super enhancer-associated genes, including HAND2 and GATA2. In the absence of functional NONO-RNA condensates, inefficient pre-mRNA processing at these loci leads to decreased expression of HAND2 and GATA2. Thus, future development of agents that target RNA binding activity of NONO may have therapeutic potential in this cancer context.
Eating for the soul: a netnographic study of the ethical motives for organic food consumption
Authors: Salam Abdul , Mulye Rajendra , Rahman Kaleel 
Published: February 2022

PurposeDespite its perceived benefits, organic food has very limited uptake in the consumer market. Many studies have investigated the causes of this slow adoption, but limited attention has been paid to the ethical motives of consumer preference for organic food. Also, no research has addressed this issue through an unobtrusive data collection method. Therefore, this netnography-based qualitative study explores the deontological and teleological ethical motives for organic food consumption through the lens of Hunt and Vitell's general theory of marketing ethics.Design/methodology/approachUser-generated content in the form of posts and comments from a food-related Facebook page, Food Matters (https://www.facebook.com/foodmatters), with over 2.3m followers, was thematically analysed using Hunt and Vitell's general theory of marketing ethics. Over 1.5m posts and comments were mined through Facepager 4.0.4 after due approvals. Organic-food-related content was manually screened. Netnography, an Internet-based ethnography technique which is a relatively underutilised and unobtrusive method of data collection, was employed on selected content to understand the consumer behaviour towards organic food in an online environment.FindingsThis study analysed a total of 158,583 posts and comments generated between March 2008 and December 2019. Out of these, 2,243 posts and comments were focussed on organic food. A total of seven themes emerged out of which six were found to be inextricably linked to ethical values of organic food consumption; three deontological (moral obligations, moral accountability and moral outrage) and two teleological (perceived risk and perceived benefits) themes. However, the seventh theme, consumers' lack of trust in organic food retailers, emerged as a major barrier in the proliferation of organic food.Originality/valueThis study is the first application of Hunt and Vitell's general theory of marketing ethics in organic food. The novel findings are that trust is a bigger issue than the price differential of organic food. Implications for marketers, policymakers, retailers and certification bodies are discussed to extend the current knowledge of motives and barriers to organic food.
Analysis of factors impacting firm performance of MSMEs: lessons learnt from COVID-19
Authors: Baral Manish Mohan , Mukherjee Subhodeep , Nagariya Ramji , Singh Patel Bharat , Pathak Anchal , Chittipaka Venkataiah 
Published: February 2022

PurposeThe micro, small and medium scale enterprises (MSMEs) faced various challenges in the ongoing COVID-19 pandemic, making it challenging to remain competitive and survive in the market. This research develops a model for MSMEs to cope with the current pandemic's operational and supply chain disruptions and similar circumstances.Design/methodology/approachThe exhaustive literature review helped in identifying the constructs, their items and five hypotheses are developed. The responses were collected from the experts working in MSMEs. Total 311 valid responses were received, and the structural equation modeling (SEM) approach was used for testing and validating the proposed model.FindingsCritical constructs identified for the study are-flexibility (FLE), collaboration (COL), risk management culture (RMC) and digitalization (DIG). The statistical analysis indicated that the four latent variables, flexibility, digitalization, risk management culture and collaboration, contribute significantly to the firm performance of MSMEs. Organizational resilience (ORS) mediates the effects of all the four latent variables on firm performance (FP) of MSMEs.Practical implicationsThe current study's findings will be fruitful for the manufacturing MSMEs and other firms in developing countries. It will enable them to identify the practices that significantly help in achieving the firm performance.Originality/valueThe previous researches have not considered the effect of “organizational resilience” on the “firm performance” of MSMEs. This study attempts to fill this gap.
Impacts of management control mechanisms on the performance of international construction joint ventures: an empirical study
Authors: Tetteh Mershack Opoku , Chan Albert P.C. , Nani Gabriel , Darko Amos , Oppong Goodenough D. 
Published: February 2022

PurposeWhile previous studies have focused on identifying management control (MC) mechanisms in international construction joint ventures (ICJVs), the impacts of such MC mechanisms on the performance of ICJVs remain largely unknown. This study aims to investigate the impacts of MC mechanisms on the performance of ICJVs hosted in the developing country of Ghana.Design/methodology/approachThrough a comprehensive review of the literature, a theoretical model was developed, and data were collected through a questionnaire survey with 190 project managers composed of Ghanaians/locals and their foreign partners of ICJVs. The data were analyzed using partial least squares structural equation modeling.FindingsResults showed that both personnel and support and training control mechanisms have a positive and significant impact on project and company/partner performance. Surprisingly, insignificant and negative impacts exist between both mechanisms and socioenvironmental and company/partner performance from the local partners' view, respectively; the reverse is rather true from the foreign partners' perspective.Practical implicationsThis study contributes to the ICJV body of knowledge by analyzing the impacts of MC mechanisms on the ICJVs’ performance, enabling ICJVs frontliners (i.e. top managers) and project managers to better enhance their control structures and the ICJVs’ performance.Originality/valueThis is arguably the first study to take the bipartite perspective rather than the unilateral view of studying the impacts of MC mechanisms on the performance of ICJVs.