bluuebunny/crossref_metadata_2025_split huggingface dataset:
The immune landscape of primary central nervous system diffuse large B cell lymphoma
Authors: Alame Melissa , Cornillot Emmanuel , Cacheux Valère , Rigau Valérie , Costes-Martineau Valérie , Lacheretz-Szablewski Vanessa , Colinge Jacques 
Published: August 2020

AbstractPrimary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Bulk mRNA-sequencing (n=20) and microarray (n=34) data were exploited to identify three immune subtypes of PCNSL: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling,e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints,i.e., CTLA-4/CD86 and TIM-3/LAGLS9. Immunohistopathology and digital imaging showed that TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.
Bone Marrow Stromal Cells in a Mouse Model of Metal Implant Osseointegration
Authors: Vesprey Alexander , Suh Eun Sung , Aytürk Didem Göz , Yang Xu , Rogers Miracle , Sosa Branden , Niu Yingzhen , Kalajzic Ivo , Ivashkiv Lionel B. , Bostrom Mathias P.G. , Ayturk Ugur M. 
Published: August 2020

ABSTRACTMetal implants are commonly used in orthopaedic surgery. The mechanical stability and longevity of implants depend on adequate bone deposition along the implant surface. The cellular and molecular mechanisms underlying peri-implant bone formation (i.e. osseointegration) are incompletely understood. Herein, our goal was to determine the specific bone marrow stromal cell populations that contribute to bone formation around metal implants. To do this, we utilized a mouse tibial implant model that is clinically representative of human joint replacement procedures. Using a lineage-tracing approach with theActa2.creERT2andTmem100.creERT2transgenic alleles, we found thatPdgfra- andLy6a/Sca1-expressing stromal cells (PαS cells) multiply and differentiate in the peri-implant environment to give rise to osteocytes in newly formed bone tissue. Single cell RNA-seq analysis indicated that PαS cells are quiescent in uninjured bone tissue; however, they express markers of proliferation and osteogenic differentiation shortly after implantation surgery. Our findings indicate that PαS cells are mobilized to repair bone tissue and facilitate implant osseointegration following surgery. Biologic therapies targeting PαS cells might improve osseointegration in patients undergoing orthopaedic procedures.
A High-Performance Genetically Encoded Fluorescent Biosensor for Imaging Physiological Peroxynitrite
Authors: Chen Zhijie , Zhang Shen , Li Xinyu , Ai Hui-wang 
Published: August 2020

SummaryPeroxynitrite is a highly reactive nitrogen species (RNS) that plays critical roles in signal transduction, stress response, and numerous human diseases. Advanced molecular tools that permit the selective, sensitive, and non-invasive detection of peroxynitrite is essential for understanding its pathophysiological functions. Here, we present pnGFP-Ultra, a high performance, reaction-based, genetically encodable biosensor for imaging peroxynitrite in live cells. pnGFP-Ultra features ap-boronophenylalanine-modified chromophore as the sensing moiety and exhibits a remarkable 123-fold fluorescence turn-on response towards peroxynitrite while displaying virtually no cross-reaction with other reactive oxygen/nitrogen species, including hydrogen peroxide. To facilitate the expression of pnGFP-Ultra in mammalian cells, we engineered a highly efficient noncanonical amino acid (ncAA) expression system that is broadly applicable to the mammalian expression of proteins containing various ncAAs. pnGFP-Ultra robustly detected peroxynitrite production during interferon γ and lipopolysaccharide-induced immune responses in macrophages, and in amyloid β-activated primary glial cells. Thus, pnGFP-Ultra fills an important technical gap and represents an important new addition to the molecular toolbox in probing RNS biology.In BriefChen et al. report pnGFP-Ultra, a high-performance fluorescent biosensor for minimally invasive and selective imaging of peroxynitrite production in live cells.HighlightspnGFP-Ultra is a genetically encoded peroxynitrite biosensor with a 123-fold fluorescence turn-on responsepnGFP-Ultra exhibits high selectivity toward peroxynitrite, with virtually no crossreaction with hydrogen peroxideAn optimized plasmid-based system increases noncanonical amino acid incorporation in mammalian cells by >10 foldpnGFP-Ultra robustly detects peroxynitrite production in macrophages and primary glial cells
Associations of early social experience with offspring DNA methylation and later life stress phenotype
Authors: Laubach Zachary M. , Greenberg Julia R. , Turner Julie W. , Montgomery Tracy , Pioon Malit O. , Smale Laura , Cavalcante Raymond , Padmanabhan Karthik R. , Lalancette Claudia , vonHoldt Bridgett , Faulk Christopher D. , Dolinoy Dana C. , Holekamp Kay E. , Perng Wei 
Published: August 2020

ABSTRACTIn a wild population of spotted hyenas, we tested the hypothesis that maternal care during the first year of life and social connectedness during two periods of early development lead to differences in DNA methylation and fecal glucocorticoid metabolites (fGCMs) later in life. We found that although maternal care and social connectedness during the communal den dependent period were not associated with fGCMs, greater social connectedness after hyenas leave their communal den is associated with lower adult fGCMs. Additionally, more maternal care and social connectedness after leaving the communal den corresponded with higher global (%CCGG) DNA methylation. Finally, we identified multiple DNA methylation biomarkers near genes involved in inflammation that may link maternal care and stress phenotype. Our findings suggest that both maternal care during the first year of life and social connections after leaving the den influence DNA methylation and contribute to a developmentally plastic stress response.
In-depth analysis reveals complex molecular etiology of idiopathic cerebral palsy
Authors: Li Na , Zhou Pei , Tang Hongmei , He Lu , Fang Xiang , Zhao Jinxiang , Wang Xin , Qi Yifei , Sun Chuanbo , Lin Yunting , Qin Fengying , Yang Miaomiao , Zhang Zhan , Liao Caihua , Zheng Shuxin , Peng Xiaofang , Xue Ting , Zhu Qianying , Li Yan , Liu Liru , Huang Jingyu , Liu Li , Peng Changgeng , Han Dingding , Liu Dong , Xu Kaishou , Hu (Cougar) Hao 
Published: August 2020

AbstractCerebral palsy (CP), the most prevalent physical disability in children, has long been ignored with regard to its inherent molecular mechanism. In this work, we performed in-depth clinical and molecular analysis on 120 idiopathic CP families, and identified in half of the patients the underlying risk factors. By a compilation of 117 CP-related genes, we recognized the characteristic features in terms of inheritance and function, and proposed a dichotomous classification system according to the expression patterns. In two patients with both CP and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. We developed an algorithm and proved in mice brain that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. In a CP patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of corticospinal tract. We confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocyte, resulting in suppressed astrocyte proliferation and a shortage of lipid contents supplied for oligodendrocyte myelination. This work broadened the scope of understanding of CP etiology and paved a way for innovative therapeutic strategies.
Characterization of Mice Bearing Humanized Androgen Receptor Genes (h/mAr) Varying in Polymorphism Length
Authors: Lindenmaier Zsuzsa , Yee Yohan , Kinman Adrienne , Fernandes Darren , Ellegood Jacob , Burton Christie L. , Robins Diane M. , Raznahan Armin , Arnold Paul , Lerch Jason P. 
Published: August 2020

AbstractThe androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanizedArgenes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk.Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanizedArQ tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests.Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neuroanatomical changes due to Q tract length are only associated with neurodevelopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmental processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood does not directly lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mechanisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.
Selective Elimination of Osteosarcoma Cell Lines with Short Telomeres by ATR Inhibitors
Authors: Goncalves Tomas , Zoumpoulidou Georgia , Alvarez-Mendoza Carlos , Mancusi Caterina , Collopy Laura C. , Strauss Sandra J. , Mittnacht Sibylle , Tomita Kazunori 
Published: August 2020

AbstractTo avoid replicative senescence or telomere-induced apoptosis, cancers employ telomere maintenance mechanisms (TMMs) involving either the upregulation of telomerase or the acquisition of recombination-based alternative telomere lengthening (ALT). The choice of TMM may differentially influence cancer evolution and be exploitable in targeted therapies. Here, we examine TMMs in a panel of seventeen osteosarcoma-derived cell lines defining three separate groups according to TMM. Eight were ALT-positive, including the previously uncharacterised lines, KPD and LM7. ALT-negative cell lines were further classified into two groups according to their telomere length. HOS-MNNG, OHSN, SJSA-1, HAL, 143b and HOS displayed sub-normally short telomere length, while MG-63, MHM and HuO-3N1 displayed long telomeres. Importantly, sub-normally short telomeres were significantly associated with hypersensitivity to three different therapeutics targeting the ataxia telangiectasia and Rad3-related (ATR) kinase - AZD-6738/Ceralasertib, VE-822/Berzoserib and BAY-1895344 - compared to long telomeres, maintained via ALT or telomerase. Within 24 hours of ATR inhibition, cells with short but not long telomeres displayed chromosome bridges and underwent cell death, indicating a selective dependency on ATR for chromosome stability. Collectively, our work provides a resource to identify links between TMMs and drug sensitivity in osteosarcoma and indicates that telomere length predicts ATR-inhibitor sensitivity in cancer.
Functional mapping of androgen receptor enhancer activity
Authors: Huang Chia-Chi Flora , Lingadahalli Shreyas , Morova Tunc , Ozturan Dogancan , Hu Eugene , Lok Yu Ivan Pak , Linder Simon , Hoogstraat Marlous , Stelloo Suzan , Sar Funda , van der Poel Henk , Altintas Umut Berkay , Saffarzadeh Mohammadali , Bihan Stephane Le , McConeghy Brian , Gokbayrak Bengul , Feng Felix Y. , Gleave Martin E. , Bergman Andries M. , Collins Colin , Hach Faraz , Zwart Wilbert , Emberly Eldon , Lack Nathan A. 
Published: August 2020

AbstractAndrogen receptor (AR) is critical to the initiation, growth and progression of almost all prostate cancers. Once activated, the AR binds tocis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100x more binding sites than differentially expressed genes. It still remains unclear how individual sites contribute to AR-mediated transcription. While descriptive functional genomic approaches broadly correlate with enhancer activity, they do not provide the locus-specific resolution needed to delineate the underlying regulatory logic of AR-mediated transcription. Therefore, we functionally tested all commonly occuring clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq) to generate the first map of intrinsic AR enhancer activity. This approach is not significantly affected by endogenous chromatin modifications and measures the potential enhancer activity at eachcis-regulatory element. Interestingly we found that only 7% of AR binding sites displayed increased enhancer activity upon hormonal stimulation. Instead, the vast majority of AR binding sites were either inactive (81%) or constitutively active enhancers (11%). These annotations strongly correlated with enhancer-associated features in both cell line and clinical prostate cancer. With these validated annotations we next investigated the effect of each enhancer class on transcription and found that AR-driven inducible enhancers frequently interacted with promoters, forming central chromosomal loops critical for gene transcription. We demonstrated that these inducible enhancers act as regulatory hubs that increase contacts with both other AR binding sites and gene promoters. This functional map was used to identify a somatic mutation that significantly reduces the expression of a commonly mutated AR-regulated tumour suppressor. Together, our data reveal a complex interplay between different AR binding sites that work in a highly coordinated manner to drive gene transcription.
EMBRYONIC DEVELOPMENT OF THE FIRE-EYE-TETRAMoenkhausia oligolepis(CHARACIFORMES: CHARACIDAE)
Authors: Santos Raquel Santos dos , Rodrigues Jeane Rodrigues , Cordeiro Jhennifer Gomes , Tercya Hadda , Leite Marissol , Costa Bruna Patrícia Dutra , da Silva Costa Raphael , Maximino Caio , de Siqueira-Silva Diógenes Henrique 
Published: August 2020

AbstractThis study describes the embryonic development ofMoenkhausia oligolepisin captive conditions. After fertilization, the embryos were collected every 10 min up to 2 h, every 20 min up to 4 h, and every 30 min until hatching. The fertilized eggs ofM. oligolepismeasured approximately 0.85 ± 0.5 mm and have an adhesive surface. The embryonic development lasted 14 hours at 25°C, with the Zygote, Cleavage, Blastula, Gastrula, Neurula and Segmentation phases. The hatching occurred in embryos around the 30-somites stage. Our results bring only the second description of embryonic development to a species of Moenkhausia genus, the first for the refereed species. Such data are of paramount importance considering the current conflicting state of this genus phylogenetic classification and may help taxonomic studies. Understand the biology of a species that is easily handling in captive conditions and has an ornamental appeal may assist studies in its reproduction in order to both, supply the aquarium market and help the species conservation in nature. Moreover, our data enable theM. oligolepisto be used as a model species in biotechnological applications, such germ cell transplantation approach.
Microbial community composition interacts with local abiotic conditions to drive colonization resistance in human gut microbiome samples
Authors: Baumgartner Michael , Pfrunder-Cardozo Katia R , Hall Alex R 
Published: August 2020

AbstractBiological invasions can alter ecosystem stability and function, and predicting what happens when a new species or strain arrives remains a major challenge in ecology. In the mammalian gastrointestinal tract, susceptibility of the resident microbial community to invasion by pathogens has important implications for host health. However, at the community level, it is unclear whether susceptibility to invasion depends mostly on resident community composition (which microbes are present), or also on local abiotic conditions (such as nutrient status). Here, we used a gut microcosm system to disentangle some of the drivers of susceptibility to invasion in microbial communities sampled from humans. We found resident microbial communities inhibited an invadingE. colistrain, compared to community-free control treatments, sometimes excluding the invader completely (colonization resistance). These effects were stronger at later time points, coinciding with shifts in microbial community composition and nutrient availability. By separating these two components (microbial community and abiotic environment), we found taxonomic composition played a crucial role in suppressing invasion, but this depended critically on local abiotic conditions (adapted communities were more suppressive in nutrient-depleted conditions). This helps predict when resident communities will be most susceptible to invasion, with implications for optimizing treatments based around microbiota management.
Entrepreneurial intention of Indian university students: the role of opportunity recognition and entrepreneurship education
Authors: Hassan Aamir , Saleem Imran , Anwar Imran , Hussain Syed Abid 
Published: August 2020

PurposeThe purpose of this study is to investigate the impact of opportunity recognition and entrepreneurial self-efficacy on the entrepreneurial intention of Indian university students. This paper also examines the moderating role of entrepreneurship education and gender on the opportunity recognition–intention and self-efficacy–intention relationships.Design/methodology/approachThe data were collected through a comprehensive questionnaire from 334 students having business and management background. Confirmatory factor analysis was used to ensure the reliability and validity of all the constructs, and structural equation modeling was used to test the proposed hypotheses.FindingsThis study unveils three important findings. First, opportunity recognition and self-efficacy both show a significant positive impact on the entrepreneurial intention of students. Second, education positively moderates “self-efficacy–intention relationship”, and third, gender negatively moderates “opportunity recognition–intention” and “self-efficacy–intention” relationships.Research limitations/implicationsThis study has been carried out using a sample of students from only one university, and the study included only business and management background students. Similar studies can be conducted by adding more motivational and contextual factors with an increased sample size of students having different educational backgrounds.Practical implicationsThis study provides pragmatic support to formulate new educational initiatives that can support students in their present or future entrepreneurial projects.Originality/valueThis study adds to the scarce literature on opportunity recognition and entrepreneurial intention and also highlights the moderating role of entrepreneurship education and gender on opportunity recognition–intention and entrepreneurial self-efficacy–intention relationships.
EMNC technological competence creation: key mechanisms and innovative performance
Authors: Zhang Feng 
Published: August 2020

PurposeConsiderable attention has been paid to the motives and process of idiosyncratic internationalization trajectory of Multinational Corporations from emerging economies (EMNCs). Yet, the ability to undertake strategic asset-seeking foreign direct investments (FDIs) is not the same as the ability to achieve subsequent investment success (Buckley, 2018). Since an ultimate goal of strategic asset-seeking FDIs is to tap advanced knowledge in host locations to accelerate EMNC competence creation, and the current study aims to shed light on the question of whether, and if so how, EMNCs have been able to build competences after strategic asset-seeking motivated FDIs.Design/methodology/approachThis study tests the US patent and citation data from 2000 to 2014 of leading innovation-oriented MNCs from China and India, complemented with data from LexisNexis Directory of Corporate Affiliations and Mergent Online databases. Wilcoxon rank sum test is employed to compare EMNCs with control group MNCs from mature industrialized countries to identify key technological competence creation mechanisms of EMNCs. Negative binomial regression technique is then employed to test the relationship between the key mechanisms and EMNC innovative performance in terms of quantity and quality of patented inventions.FindingsIn contrast to the extant EMNC literature, the author finds that EMNC parents adopt a hands-on and less of an orchestrating approach. They are playing critical roles in accessing and transferring knowledge from international host locations. The empirical analyses indicate an absence of reverse transfers of knowledge from subsidiaries to the parent. Instead, EMNC parents directly access and absorb explicit knowledge from external sources in subsidiary host locations, which significantly contributes to EMNC innovative performance. Meanwhile, the author finds that the employment of intra-firm and inter-unit inventor teams and associated internal tacit knowledge access and transfer significantly contribute to EMNC innovative performance.Originality/valueThis study investigates the post-internationalization performance of EMNCs and contributes to the reconciliation of theoretical debates, as well as the generation of a comprehensive understanding of the MNC. Managerial implications are also discussed.