bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phagosome resolution regenerates lysosomes and maintains the degradative capacity in phagocytes
Authors: Lancaster Charlene , Fountain Aaron , Dayam Roaya M. , Somerville Elliott , Sheth Javal , Jacobelli Vanessa , Somerville Alex , Terebiznik Mauricio , Botelho Roberto J. 
Published: May 2020

AbstractPhagocytes engulf unwanted particles into phagosomes that then fuse with lysosomes to degrade the enclosed particles. Ultimately, phagosomes must be recycled to help recover membrane resources that were consumed during phagocytosis and phagosome maturation, a process referred to as phagosome resolution. Little is known about phagosome resolution, which may proceed through exocytosis or membrane fission. Here, we show that bacteria-containing phagolysosomes in macrophages undergo fragmentation through vesicle budding, tubulation, and constriction. Phagosome fragmentation requires cargo degradation, the actin and microtubule cytoskeletons, and clathrin. We provide evidence that lysosome reformation occurs during phagosome resolution since the majority of phagosome-derived vesicles displayed lysosomal properties. Importantly, we show that clathrin-dependent phagosome resolution is important to maintain the degradative capacity of macrophages challenged with two waves of phagocytosis. Overall, our work suggests that phagosome resolution contributes to lysosome recovery and to maintain the degradative power of macrophages to handle multiple waves of phagocytosis.SummaryPhagocytes engulf particles into phagolysosomes for degradation. However, the ultimate fate of phagolysosomes is undefined. Lancaster, Fountain et al. show that phagosomes fragment to reform lysosomes in a clathrin-dependent manner. This process helps maintain the degradative capacity of phagocytes for subsequent rounds of phagocytosis.
Multiple domains in ARHGAP36 regulate PKA degradation and Gli activation
Authors: Nano Patricia R. , Kudo Takamasa , Mooney Nancie A. , Ni Jun , Demeter Janos , Jackson Peter K. , Chen James K. 
Published: May 2020

ABSTRACTARHGAP36 is a Rho GTPase-activating protein (GAP) family member that contributes to spinal cord development and tumorigenesis. This multidomain protein is composed of splicing-dependent N-terminal sequences, the GAP-like region, and a unique C-terminal domain, and an N-terminal arginine-rich region has been shown to suppress protein kinase A (PKA) and activate Gli transcription factors. To understand how these structural elements act in concert, we have mapped the ARHGAP36 structure-activity landscape with domain- and amino-acid-level resolution. ARHGAP36-mediated Gli activation can be repressed by N-terminal sequences that regulate subcellular ARHGAP36 localization and PKA targeting. The GAP-like and C-terminal domains counteract this autoinhibitory mechanism and promote ARHGAP36 trafficking to the plasma membrane and primary cilium, respectively. The GAP-like domain may also conditionally suppress the arginine-rich region, and it modulates ARHGAP36 binding to the prolyl oligopeptidase-like protein PREPL and the E3 ubiquitin ligase PRAJA2. These domain-dependent activities provide a potential means for tissue-specific ARHGAP36 functions.
HBV pgRNA can generate a circRNA with two junction sites
Authors: Zhu Min , Liang Zi , Pan Jun , Hu Xiaolong , Zhang Xing , Xue Renyu , Cao Guangli , Gong Chengliang 
Published: May 2020

AbstractTo verify whether Hepatitis B virus (HBV) can form circRNA, the circRNA sequencing results of the HBV-positive HepG 2.2.15 hepatocarcinoma cell line were compared with the HBV genome. A novel circRNA, named as HBV_circ_1, was mapped to the 489–2985 nt region of the HBV genome (GenBank accession No.KU668446.1), which was derived from HBV pgRNA and has two junction sites. A partial fragment of the pgRNA (corresponding to HBV DNA genome 489-3,182-2,985nt) was resected and then connected to form a junction site of HBV_circ_1 (corresponding to HBV DNA genome 489/2985nt). The 5’-terminal region (corresponding to HBV DNA genome 1,820-1,932nt) of pgRNA was repeated with the region of pgRNA at the 3’-terminal region. Another junction site of HBV_circ_1 (corresponding to HBV DNA genome 1820nt) was formed in a manner similar to DNA homologous recombination mediated by repeats of pgRNA. Moreover, this RNA homologous recombination mediated by the repeats of pgRNA does not have tissue specificity and genus specificity. Reverse transcription PCR, northern blotting, and tissue in situ hybridization confirmed the existence of HBV_circ_1 in HepG2.2.15 cells and HBV related hepatocellular carcinoma (HCC) tissue. This study expands our understanding of circRNA generation mechanisms, and provide a new perspective for understanding the molecular pathogenesis of the virus.
Interval Constraint Satisfaction and Optimization for Biological Homeostasis and Multistationarity
Authors: Desoeuvres Aurélien , Trombettoni Gilles , Radulescu Ovidiu 
Published: May 2020

AbstractHomeostasisoccurs in a biological or chemical system when some output variable remains approximately constant as one or several input parameters change over some intervals. We propose in this paper a new computational method based on interval techniques to find species in biochemical systems that verify homeostasis. A somehow dual and equally important property ismultistationarity, which means that the system has multiple steady states and possible outputs, at constant parameters. We also propose an interval method for testing multistationarity. We have tested homeostasis, absolute concentration robustness and multistationarity on a large collection of biochemical models from the Biomodels and DOCSS databases. The codes used in this paper are publicly available at:https://github.com/Glawal/IbexHomeo.
Single-cell RNA-seq reveals lineage-specific regulatory changes of fibroblasts and vascular endothelial cells in keloid
Authors: Liu Xuanyu , Chen Wen , Yuan Meng , Li Zhujun , Meng Tian , Chen Jie , Yu Nanze , Long Xiao , Zhou Zhou 
Published: May 2020

AbstractKeloid is a benign dermal fibrotic disorder with some features similar to malignant tumors such as hyper-proliferation, apoptosis resistance and invasion. keloid remains a therapeutic challenge in terms of high recurrence rate and lack of satisfactory medical therapies, which is partially due to the incomplete understanding of keloid pathogenesis. A thorough understanding of the cellular and molecular mechanism of keloid pathogenesis would facilitate the development of novel medical therapies for this disease. Here, we performed single-cell RNA-seq of 28,064 cells from keloid skin tissue and adjacent relatively normal tissue. Unbiased clustering revealed substantial cellular heterogeneity of the keloid tissue, which included 21 cell clusters assigned to 11 cell lineages. Differential proportion analysis revealed significant expansion for fibroblasts and vascular endothelial cells in keloid compared with control, reflecting their strong association with keloid pathogenesis. We then identified five previously unrecognized subpopulations of keloid fibroblasts and four subpopulations of vascular endothelial cells. Comparative analyses were performed to identify the dysregulated pathways, regulators and ligand-receptor interactions for keloid fibroblasts and vascular endothelial cells, the two important cell lineages in keloid pathogenesis and for medical interventions. Our results highlight the roles of transforming growth factor beta and Eph-ephrin signaling pathways in both the aberrant fibrogenesis and angiogenesis of keloid. Critical regulators and signaling receptors implicated in the fibrogenesis of other fibrotic disorders, such asTWIST1, FOXO3, SMAD3andEPHB2, ranked at the top in the regulatory network of keloid fibroblasts. In addition, tumor-related pathways such as negative regulation ofPTENtranscription were found to be activated in keloid fibroblasts and vascular endothelial cells, which may be responsible for the malignant features of keloid. Our study put novel insights into the pathogenesis of keloid, and provided potential targets for medical therapies. Our dataset also constitutes a valuable resource for further investigations of the mechanism of keloid pathogenesis.
The weakly electric fish,Apteronotus albifrons, avoids hypoxia before it reaches critical levels
Authors: Mucha Stefan , Chapman Lauren J. , Krahe Rüdiger 
Published: May 2020

AbstractAnthropogenic environmental degradation has led to an increase in the frequency and prevalence of aquatic hypoxia (low dissolved-oxygen concentration, DO), which may affect habitat quality for water-breathing fishes. The weakly electric black ghost knifefish,Apteronotus albifrons, is typically found in well-oxygenated freshwater habitats in South America. Using a shuttle-box design, we exposed juvenileA. albifronsto a stepwise decline in DO from normoxia (>95% air saturation) to extreme hypoxia (10% air saturation) in one compartment and chronic normoxia in the other. Below 22% air saturation,A. albifronsactively avoided the hypoxic compartment. Hypoxia avoidance was correlated with upregulated swimming activity. Following avoidance, fish regularly ventured back briefly into deep hypoxia. Hypoxia did not affect the frequency of their electric organ discharges. Our results show thatA. albifronsis able to sense hypoxia at non-lethal levels and uses active avoidance to mitigate its adverse effects.SummaryThe weakly electric knifefish,Apteronotus albifrons, avoids hypoxia below 22% air saturation. Avoidance correlates with increased swimming activity, but not with a change in electric organ discharge frequency.
Identifying Behavioral Structure from Deep Variational Embeddings of Animal Motion
Authors: Luxem Kevin , Mocellin Petra , Fuhrmann Falko , Kürsch Johannes , Remy Stefan , Bauer Pavol 
Published: May 2020

AbstractQuantification and detection of the hierarchical organization of behavior is a major challenge in neuroscience. Recent advances in markerless pose estimation enable the visualization of highdimensional spatiotemporal behavioral dynamics of animal motion. However, robust and reliable technical approaches are needed to uncover underlying structure in these data and to segment behavior into discrete hierarchically organized motifs. Here, we present an unsupervised probabilistic deep learning framework that identifies behavioral structure from deep variational embeddings of animal motion (VAME). By using a mouse model of beta amyloidosis as a use case, we show that VAME not only identifies discrete behavioral motifs, but also captures a hierarchical representation of the motif’s usage. The approach allows for the grouping of motifs into communities and the detection of differences in community-specific motif usage of individual mouse cohorts that were undetectable by human visual observation. Thus, we present a novel and robust approach for quantification of animal motion that is applicable to a wide range of experimental setups, models and conditions without requiring supervised or a-priori human interference.
Modeling the IL-2-Teff-Treg system in Systemic Lupus Erythematosus patients: possible mechanism and treatment strategies
Authors: Gao Xin , Sun Xiaolin , He Jing , Li Fangting 
Published: May 2020

SummarySystemic lupus erythematosus (SLE) is a non-organ specific autoimmune disease, which the pathogenesis of development is still unclear. For revealing the underlying mechanism, we construct a mathematical model depicting the interactions among CD4+regulatory T cells (Treg cells), CD4+effect T cells (Teff cells) and IL-2 in SLE patients to simulate and reproduce the development of SLE. Through our analysis, one possible pathogenesis is that the activation point and deactivation point of Teff in SLE patients produced a forward shift compared to the normal Teff. According to our simulation, a therapeutic window existed in the treatment of lupus with exogenous IL-2, which means there is a strict limit to the dose of IL-2 in clinic. Finally, we study three different dosing strategies and reveal that specific dosing regimens can better exert the effects of IL-2 and relieve the possible side effect of high dose IL-2. It is possible to promote the study of autoimmune diseases through our efforts and assist the development of precision medical treatment.
Artificial neural networks for monitoring network optimisation—a practical example using a national insect survey
Authors: Bourhis Yoann , Bell James R. , van den Bosch Frank , Milne Alice E. 
Published: May 2020

AbstractMonitoring networks are improved by additional sensors. Optimal configurations of sensors give better representations of the process of interest, maximising its exploration while minimising the need for costly infrastructure. By modelling the monitored process, we can identify gaps in its representation,i.e.uncertain predictions, where additional sensors should be located. Here, with data collected from the Rothamsted Insect Survey network, we train an artificial neural network to predict the seasonal aphid arrival from environmental variables. We focus on estimating prediction uncertainty across the UK to guide the addition of a sensor to the network. We first illustrate how to estimate uncertainty in neural networks, hence making them relevant for model-based monitoring network optimisation. Then we highlight critical areas of agricultural importance where additional traps would improve decision support and crop protection in the UK. Possible applications include most ecological monitoring and surveillance activities, but also the weather or pollution monitoring.
Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis
Authors: Christodoulou-Vafeiadou Eleni , Geka Christina , Ntari Lydia , Kranidioti Ksanthi , Argyropoulou Eleni , Meier Florian , Armaka Marietta , Mourouzis Iordanis , Pantos Constantinos , Rouchota Maritina , Loudos George , Denis Maria C , Karagianni Niki , Kollias George 
Published: May 2020

AbstractBackgroundThe transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis we performed detailed characterization of the axial, peripheral and comorbid pathologies of this model.MethodsTgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by µCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically and by µCT analysis.ResultsTgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings as well as swollen and distorted hind joints. Whole body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limps, and also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice.ConclusionsThe TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall faithfully reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease.
Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins
Authors: Ahmed Waheed-Ul-Rahman , Wiberg Akira , Ng Michael , Wang Wei , Auton Adam ,   23andMe Research Team, Lee Regent , Handa Ashok , Zondervan Krina T , Furniss Dominic 
Published: May 2020

AbstractBackgroundVaricose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.MethodsWe performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.ResultsWe discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notablyVEGFA,COL27A1,EFEMP1,PPP3R1andNFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.ConclusionsGenes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.
Advanced Research Infrastructure for Experimentation in genomicS (ARIES): a lustrum of Galaxy experience
Authors: Knijn Arnold , Michelacci Valeria , Orsini Massimiliano , Morabito Stefano 
Published: May 2020

AbstractBackground: With the introduction of Next Generation Sequencing (NGS) and Whole-Genome Sequencing (WGS) in microbiology and molecular epidemiology, the development of an information system for the collection of genomic and epidemiological data and subsequent transparent and reproducible data analysis became indispensable. Further requirements for the system included accessibility and ease of use by bioinformatics as well as command line profane scientists.Findings: The ARIES (Advanced Research Infrastructure for Experimentation in genomicS,https://aries.iss.it) platform has been implemented in 2015 as an instance of the Galaxy framework specific for use of WGS in molecular epidemiology. Here, the experience with ARIES is reported. Conclusions: During its five years existence, ARIES has grown into a well-established reality not only as a web service but as well as a workflow engine for the Integrated Rapid Infectious Disease Analysis (IRIDA) platform. In fact, an environment has been created with the implementation of complex bioinformatic tools in an easy-to-use context allowing scientists to concentrate on what to do instead of how to do it.
The response of zinc transporter gene expression of selected tissues in a pig model of subclinical zinc deficiency
Authors: Brugger Daniel , Hanauer Martin , Ortner Johanna , Windisch Wilhelm M. 
Published: May 2020

AbstractThis study compared the relative mRNA expression of all mammal zinc (Zn) transporter genes in selected tissues of weaned piglets challenged with short-term subclinical Zn deficiency (SZD). The dietary model involved restrictive feeding (450 g/animal*day−1) of a high-phytate diet (9 g/kg) supplemented with varying amounts of zinc from ZnSO4*7H2O ranging from deficient to sufficient supply levels (total diet Zn: 28.1, 33.6, 38.8, 42.7, 47.5, 58.2, 67.8, 88.0 mg Zn/kg). Total RNA preparations comprised jejunal and colonic mucosa as well as hepatic and nephric tissue. Statistical modelling involved broken-line regression (P ≤ 0.05). ZIP10 and ZIP12 mRNAs were not detected in any tissue and ZnT3 mRNA was only identified in the kidney. All other genes were expressed in all tissues but only a few gene expression patterns allowed a significant (P < 0.0001) fitting of broken-line regression models, indicating homeostatic regulation under the present experimental conditions. Interestingly, these genes could be subcategorized by showing significant turnarounds in their response patterns, either at ~40 or ~60 mg Zn/kg diet (P < 0.0001). In conclusion, the present study showed clear differences in Zn transporter gene expression in response to SZD compared to the present literature on clinical models. We recognized that certain Zn transporter genes were regulated under the present experimental conditions by two distinct homeostatic networks. For the best of our knowledge, this represents the first comprehensive screening of Zn transporter gene expression in a highly translational model to human physiology.