bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metatranscriptomic comparison of endophytic and pathogenicFusarium–Arabidopsis interactions reveals plant transcriptional plasticity
Authors: Guo Li , Yu Houlin , Wang Bo , Vescio Kathryn , DeIulio Gregory A. , Yang He , Berg Andrew , Zhang Lili , Edel-Hermann Véronique , Steinberg Christian , Kistler H. Corby , Ma Li-Jun 
Published: March 2021

ABSTRACTPlants are continuously exposed to beneficial and pathogenic microbes, but how plants recognize and respond to friends versus foes remains poorly understood. Here, we compared the molecular response ofArabidopsis thalianaindependently challenged with aFusarium oxysporumendophyte Fo47 versus a pathogen Fo5176. These twoFusarium oxysporumstrains share a core genome of about 46 Mb, in addition to unique 1,229 and 5,415 accessory genes. Metatranscriptomic data reveal a shared pattern of expression for most plant genes (∼80%) in responding to both fungal inoculums at all time points from 12 to 96 h post inoculation (HPI). However, the distinct responding genes depict transcriptional plasticity, as the pathogenic interaction activates plant stress responses and suppresses plant growth/development related functions, while the endophytic interaction attenuates host immunity but activates plant nitrogen assimilation. The differences in reprogramming of the plant transcriptome are most obvious in 12 HPI, the earliest time point sampled and are linked to accessory genes in both fungal genomes. Collectively, our results indicate that theA. thalianaandF. oxysporuminteraction displays both transcriptome conservation and plasticity in the early stages of infection, providing insights into the fine-tuning of gene regulation underlying plant differential responses to fungal endophytes and pathogens.One-sentence summaryMultiomics analysis reveals the regulatory plasticity of plants in response to beneficial and antagonistic microbes, resulting in distinct phenotypes and rewired transcriptional networks.
COMPARISON OF sPLA2-IIA PERFORMANCE WITH HIGH-SENSITIVE CRP, NEUTROPHIL PERCENTAGE, PCT AND LACTATE TO IDENTIFY BACTERIAL INFECTION: A PROSPECTIVE STUDY
Authors: Tan Toh Leong , Kang Christabel Wan-li , Ooi Kai Shen , Tan Swee Thian , Ahmad Nurul Saadah , Nasuruddin Dian Nasriana , Ithnin Azlin , Arifin Khaizurin Tajul , Lee Yook Heng , Hassan Nurul Izzaty , Gan Kok Beng , Neoh Hui-min 
Published: March 2021

ABSTRACTEarly bacterial infection (BI) identification in resource-limiting Emergency Departments (ED) is challenging especially in low- and middle-income counties (LMIC). Misdiagnosis predisposes to antibiotic overuse and propagates antimicrobial resistance. This study evaluates new emerging biomarkers, secretory phospholipase A2 group IIA (sPLA2-IIA), and compares with other biomarkers on their performance characteristic of BI detection in Malaysia, an LMIC. A prospective cohort study was conducted involving 151 consecutive patients admitted to the ED. A single measurement was taken upon patient arrival in ED and was analysed for serum levels of sPLA2-IIA, high-sensitive C-reactive protein (CRP), procalcitonin (PCT), neutrophil percentage (N%), and lactate. All biomarkers’ performance was compared for the outcomes using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The performance of sPLA2-IIA (AUROC 0.93 [95% CI: 0.89-0.97]; Sn 80% [95% CI: 72-87] Sp 94% [95% CI: 81-89]) was the highest among all. It was comparable with high-sensitive CRP (AUROC 0.93 [95% CI: 0.88-0.97]; Sn 75% [95% CI: 66-83]; Sp 91 [95% CI: 77-98]) but had a higher Sn and Sp. The sPLA2-IIA was also found superior to N%, PCT, and lactate. This finding suggested sPLA2-IIA was recommended biomarkers for BI detection in LMIC.
Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist
Authors: Pickford Phil , Lucey Maria , Rujan Roxana-Maria , McGlone Emma Rose , Bitsi Stavroula , Ashford Fiona , Corrêa Ivan R , Hodson David J , Tomas Alejandra , Deganutti Giuseppe , Reynolds Christopher A , Owen Bryn M , Tan Tricia M , Minnion James , Jones Ben , Bloom Stephen R 
Published: March 2021

AbstractObjectiveGlucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study we investigated the cellular and metabolic effects of modulating the balance between G protein activation and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation.MethodsDipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify effects on glucose homeostasis and weight loss.ResultsLigand-specific reductions in β-arrestin-2 recruitment led to reduced GLP-1R internalisation and prolonged glucose-lowering actionin vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide in spite of a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured.ConclusionsDiminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.
Metabolic dysfunction induced by high-fat diet modulates hematopoietic stem and myeloid progenitor cells in brown adipose tissue of mice
Authors: Mincham Kyle T , Panchal Kunjal , Hart Prue H , Lucas Robyn M , Feelisch Martin , Weller Richard B , Matthews Vance B , Strickland Deborah H , Gorman Shelley 
Published: March 2021

AbstractBrown adipose tissue (BAT) may be an important metabolic regulator of whole-body glucose. While important roles have been ascribed to macrophages in regulating metabolic functions in BAT, little known is known of the roles of other immune cells subsets, particularly dendritic cells (DCs). Eating a high fat diet may compromise the development of hematopoietic stem and progenitor cells (HSPC) – which give rise to DCs – in bone marrow, with less known of its effects in BAT. We have previously demonstrated that ongoing exposure to low-dose ultraviolet radiation (UVR) significantly reduced the ‘whitening’ effect of eating a high-fat diet upon interscapular (i)BAT of mice. Here, we examined whether this observation may be linked to changes in the phenotype of HSPC and myeloid-derived immune cells in iBAT and bone marrow of mice using 12-colour flow cytometry. Many HSPC subsets declined in both iBAT and bone marrow with increasing metabolic dysfunction. Conversely, with rising adiposity and metabolic dysfunction, conventional (c)DCs increased in both of these tissues. When compared to low-fat diet, consumption of high-fat diet significantly reduced proportions of myeloid, common myeloid and megakaryocyte-erythrocyte progenitors in iBAT, and short-term hematopoietic stem cells in bone marrow. In mice fed a high-fat diet, exposure to low-dose UVR significantly reduced proportions of cDCs in iBAT, independently of nitric oxide release from irradiated skin (blocked using the scavenger, cPTIO), but did not significantly modify HSPC subsets in either tissue. Further studies are needed to determine whether changes in these cell populations contribute towards metabolic dysfunction.
Drug-driven reclassification of multiple tumour subtypes reveals intrinsic molecular concordance of therapy across histologically disparate cancers
Authors: Xu Yue , Zheng Jie , Cai Zhaoqing , Li Wang , Köhler Jens , Dai Yao , Cheng Xiaojie , Wu Tao , Zhang Fan , Wang Haiyun 
Published: March 2021

AbstractCancers that are histologically defined as the same type of cancer often need a distinct therapy based on underlying heterogeneity; likewise, histologically disparate cancers can require similar treatment approaches due to intrinsic similarities. A comprehensive analysis integrated with drug response data and genomic alterations, particularly to reveal therapeutic concordance mechanisms across histologically disparate tumour subtypes, has not yet been fully exploited.In this study, we used pharmacogenomic profiling data provided from the Cancer Genome Project (CGP) in a systematic in silico investigation of the pharmacological subtypes of cancers and the intrinsic concordance of molecular mechanisms leading to similar therapeutic responses across histologically disparate tumour subtypes. We further developed a novel approach to redefine cell-to-cell similarity and drug-to-drug similarity from the therapeutic concordance, providing a new point of view to study cancer heterogeneity.Our study identified that histologically different tumours, such as malignant melanoma and colorectal adenocarcinoma, could belong to the same pharmacological subtype regarding drug sensitivity to MEK inhibitors, which was determined by their genomic alterations, high occurrence of BRAF or KRAS mutations. Therapeutic concordance for chemotherapy drugs was identified across histologically disparate hematological tumors mainly due to the extraordinary activation of the cell cycle in blood cancers. A subcluster of SCLC had a more similar profile with hematological tumors, and was associated with the malignant phenotype, with a higher level of MYC expression. We developed a website to store and visualize the pharmacological subtypes of drugs, as well as their connected genomic and expression alterations.
Intrinsic cardiac adrenergic cells contribute to septic cardiomyopathy
Authors: Yang Duomeng , Dai Xiaomeng , Xing Yun , Tang Xiangxu , Yang Guang , Wang Penghua , Harrison Andrew G. , Li Hongmei , Lv Xiuxiu , Yu Xiaohui , Wang Huadong 
Published: March 2021

AbstractOccurring independently of cardiac sympathetic nervous system, the intrinsic cardiac adrenergic (ICA) cells have been identified as an important regulator in both of developing and adult cardiac physiological and pathological processes. However, its role in septic cardiomyopathy remains unknown. Herein, we report that lipopolysaccharide (LPS) dose- and time-dependently increased norepinephrine (NE) release from ICA cells, which aggravates myocardial TNF-α production and dysfunction. Inhibition of NE synthesis in ICA cells alleviated LPS-elicited cardiac dysfunction as well as TNF-α production in Langendorff perfusing hearts. Mechanistically, ICA cell expressed Toll-like receptor 4 (TLR4), activated by LPS, to increase the expression of tyrosine hydroxylase, a key enzyme responsible for NE biosynthesis, via AP-1 binding to its promoter. Surprisingly, LPS-TLR4 signaling triggered no TNF-α production in ICA cells due to the elevatedNfkbiaandTnfaip6expression. In LPS-treated co-culture of ICA cells and cardiomyocytes, the raised NE from ICA cells activated cardiomyocyte β1-adrenergic receptor (β1-AR), driving Ca2+/calmodulin-dependent protein kinase II (CaMKII) to increase the activities of NF-κB and mitogen-activated protein kinase pathways, which were mimicked by dobutamine. Our findings reveal a cell type-specific TLR4 function triggering NE synthesis, but not TNF-α production in inflammatory pathogenesis, and identify ICA cell-derived NE as a paracrine signal in the cross talk among different cardiac cells to enhance myocardial injury during LPS challenge, suggesting that targeting ICA cell-derived NE may be a potential therapeutic strategy for septic cardiomyopathy.
A CTDNEP1-lipin 1-mTOR regulatory network restricts ER membrane biogenesis to enable chromosome motions necessary for mitotic fidelity
Authors: Merta Holly , Carrasquillo Rodríguez Jake W. , Anjur-Dietrich Maya I. , Granade Mitchell E. , Vitale Tevis , Harris Thurl E. , Needleman Daniel J. , Bahmanyar Shirin 
Published: March 2021

SummaryThe endoplasmic reticulum (ER) dramatically restructures in open mitosis to become excluded from the mitotic spindle; however, the significance of ER reorganization to mitotic progression is not known. Here, we demonstrate that limiting ER membrane biogenesis enables mitotic chromosome movements necessary for chromosome biorientation and prevention of micronuclei formation. Aberrantly expanded ER membranes increase the effective viscosity of the mitotic cytoplasm to physically restrict chromosome dynamics – slowed chromosome motions impede correction of mitotic errors induced by transient spindle disassembly, leading to severe micronucleation. We define the mechanistic link between regulation of ER membrane biogenesis and mitotic fidelity by demonstrating that a CTDNEP1-lipin 1-mTOR regulatory network limits ER lipid synthesis to prevent chromosome missegregation. Together, this work shows that ER membranes reorganize in mitosis to enable chromosome movements necessary for mitotic error correction and reveal dysregulated lipid metabolism as a potential source of aneuploidy in cancer cells.
Chromatin Network Retards Droplet Coalescence
Authors: Qi Yifeng , Zhang Bin 
Published: March 2021

AbstractNuclear bodies are membraneless condensates that may form via liquid-liquid phase separation. The viscoelastic chromatin network could impact their stability and may hold the key for understanding experimental observations that defy predictions of classical theories. However, quantitative studies on the role of the chromatin network in phase separation have remained challenging. Using a diploid human genome model parameterized with chromosome conformation capture (Hi-C) data, we studied the thermodynamics and kinetics of droplet formation inside the nucleus. Dynamical simulations predicted the formation of multiple droplets for protein particles that experience specific interactions with nucleolus-associated domains (NADs). Coarsening dynamics, surface tension, and coalescence kinetics of the simulated droplets are all in quantitative agreements with experimental measurements for nucleoli. Free energy calculations further supported that a two-droplet state, which is often observed for nucleoli seen in somatic cells, is metastable and separated from the single-droplet state with an entropic barrier. Our study suggests that protein-chromatin interactions facilitate the nucleation of droplets, but hinders their coarsening due to the correlated motion between droplets and the chromatin network: as droplets coalesce, the chromatin network becomes increasingly constrained. Therefore, protein-chromatin interactions arrest phase separation in multi-droplet states and may drive the variation of nuclear body numbers across cell types.
Multi-dimensional and spatiotemporal correlative imaging at the plasma membrane of live cells to determine the continuum nano-to-micro scale lipid adaptation and collective motion
Authors: Bernabé-Rubio Miguel , Bosch-Fortea Minerva , Alonso Miguel A. , de la Serna Jorge Bernardino 
Published: March 2021

AbstractThe primary cilium is a specialized plasma membrane protrusion with important receptors for signalling pathways. In polarized epithelial cells, the primary cilium assembles after the midbody remnant (MBR) encounters the centrosome at the apical surface. The membrane surrounding the MBR, namely remnant associated membrane patch (RAMP) once situated next to the centrosome, releases some of its lipid components to form a centrosome-associated membrane patch (CAMP) from which the ciliary membrane stems. The RAMP undergoes a spatiotemporal membrane refinement during the formation of the CAMP, which becomes highly enriched in condensed membranes with low lateral mobility. To better understand this process, we have developed a correlative imaging approach that yields quantitative information about the lipid lateral packing, its mobility and collective assembly at the plasma membrane at different spatial scales over time. Our work paves the way towards a quantitative understanding of lipid collective assembly at the plasma membrane spatiotemporally as a functional determinant in cell biology and its direct correlation with the membrane physicochemical state. These findings allowed us to gain a deeper insight into the mechanisms behind the biogenesis of the ciliary membrane of polarized epithelial cells.
A single-cell atlas of breast cancer cell lines to study tumour heterogeneity and drug response
Authors: Gambardella G , Viscido G , Tumaini B , Isacchi A , Bosotti R , di Bernardo D 
Published: March 2021

ABSTRACTBreast cancer patient stratification is mainly driven by tumour receptor status and histological grading and subtyping, with about twenty percent of patients for which absence of any actionable biomarkers results in no clear therapeutic intervention. Cancer cells within the same tumour have heterogeneous phenotypes and exhibit dynamic plasticity. However, how to evaluate such heterogeneity and its impact on outcome and drug response is still unclear. Here, we transcriptionally profiled 35,276 individual cells from 32 breast cancer cell lines covering all main breast cancer subtypes to yield a breast cancer cell line atlas. We found high degree of heterogeneity in the expression of clinically relevant biomarkers across individual cells within the same cell line; such heterogeneity is non-genetic and dynamic. We computationally mapped single cell transcriptional profiles of patients’ tumour biopsies to the atlas to determine their composition in terms of cell lines. Each tumour was found to be heterogenous and composed of multiple cell lines mostly, but not exclusively, of the same subtype. We then trained an algorithm on the atlas to determine cell line composition from bulk gene expression profiles of tumour biopsies, thus providing a novel approach to patient stratification. Finally, we linked results from large-scale in vitro drug screening1,2to the single cell data to computationally predict responses to more than 450 anticancer agents starting from single-cell transcriptional profiles. We thus found that transcriptional heterogeneity enables cells with differential drug sensitivity to co-exist in the same population. Our work provides a unique resource and a novel framework to determine tumour heterogeneity and drug response in breast cancer patients.
The glycocalyx affects the mechanotransductive perception of the topographical microenvironment
Authors: Chighizola Matteo , Dini Tania , Marcotti Stefania , D’Urso Mirko , Piazzoni Claudio , Borghi Francesca , Previdi Anita , Ceriani Laura , Folliero Claudia , Stramer Brian , Lenardi Cristina , Milani Paolo , Podestà Alessandro , Schulte Carsten 
Published: March 2021

ABSTRACTThe cell/microenvironment interface is the starting point of integrin-mediated mechanotransduction, but many details of mechanotransductive signal integration remain elusive due to the complexity of the involved (extra)cellular structures, such as the glycocalyx.We used nano-bio-interfaces reproducing the complex nanotopographical features of the extracellular matrix to analyse the glycocalyx impact on PC12 cell mechanosensing at the nanoscale (e.g., by force spectroscopy with functionalised probes). Our data demonstrates that the glycocalyx configuration affects spatio-temporal nanotopography-sensitive mechanotransductive events at the cell/microenvironment interface. Opposing effects of glycocalyx removal were observed, when comparing flat and specific nanotopographical conditions. The excessive retrograde actin flow speed and force loading are strongly reduced on certain nanotopographies upon removal of the native glycocalyx, while on the flat substrate we observe the opposite trend.Our results highlight the importance of the glycocalyx configuration in a molecular clutch force loading-dependent cellular mechanism for mechanosensing of microenvironmental nanotopographical features.
Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin andCandidastimulation
Authors: Nguyen Giang T. , Xu Shuying , Bunnell Stephen C. , Mansour Michael K. , Sykes David B. , Mecsas Joan 
Published: March 2021

AbstractSignaling cascades that convert the recognition of pathogens to efficient inflammatory responses by immune cells, specifically neutrophils, are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following stimulation by integrins, formyl peptide receptors and gram-negative bacteriaKlebsiella pneumoniaeandYersinia pseudotuberculosis in vitro(Nguyen et al., 2020, Shaban et al., 2020, Boras et al., 2017). SKAP2 is also required for the host defense againstK. pneumoniaeandΔyopH Y. pseudotuberculosisinfectionin vivoin mouse models (Shaban et al., 2020, Nguyen et al., 2020). Another class of pattern recognition receptors (PRR) is the C-type lectin receptors (CLR), such as Dectin-1, Dectin-2 and Mincle, that are critical to trigger innate immune responses. Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 is crucial for maximal ROS response to purified CLR agonists and to the fungal pathogensCandida glabrataandC. albicans, as well as for robust killing ofC. glabrata.Skap2-/-murine neutrophils failed to generate ROS and exhibited reduced cellular adhesion in response to trehalose-6,6’-dibehenate (TDB), furfurman, and curdlan, Mincle, Dectin-2, and Dectin-1 agonists, respectively. TDB, furfurman, and curdlan stimulation also led to SKAP2-independent integrin conformational changes, showing that inside-out signaling by these CLRs to integrin occurs in the absence of SKAP2. Pyk2 phosphorylation was significantly reduced after infection withC. glabratainSkap2-/-neutrophils, while Syk phosphorylation was unaffected by the loss of SKAP2. These data strengthen the importance of SKAP2 in the activation of neutrophil ROS production by PRRs to include CLRs and extend the role of SKAP2 in host defense beyond antibacterial immunity to includeCandidaspecies.