bluuebunny/crossref_metadata_2025_split huggingface dataset:
Encapsulated cyclosporine does not change the composition of the human microbiota when assessed ex vivo and in vivo
Authors: O'Reilly Catherine , O’Sullivan Órla , Cotter Paul D. , O’Connor Paula M. , Shanahan Fergus , Cullen Alan , Rea Mary C. , Hill Colin , Coulter Ivan , Ross R. Paul 
Published: January 2020

Introduction.Management of steroid-refractory ulcerative colitis has predominantly involved treatment with systemic cyclosporine A (CyA) and infliximab.Aim.The purpose of this study was to assess the effect of using a colon-targeted delivery system CyA formulation on the composition and functionality of the gut microbiota.Methodology.Ex vivofaecal fermentations from six healthy control subjects were treated with coated minispheres (SmPill) with (+) or without (−) CyA and compared with a non-treated control in a model colon system. In addition, thein vivoeffect of the SmPill+CyA formulation was investigated by analysing the gut microbiota in faecal samples collected before the administration of SmPill+CyA and after 7 consecutive days of administration from eight healthy subjects who participated in a pilot study.Results.Analysis of faecal samples by 16S rRNA gene sequencing indicated little variation in the diversity or relative abundance of the microbiota composition before or after treatment with SmPill minispheres with or without CyAex vivoor with CyAin vivo. Short-chain fatty acid profiles were evaluated using gas chromatography, showing an increase in the concentration of n-butyrate (P=0.02) and acetate (P=0.32) in the faecal fermented samples incubated in the presence of SmPill minispheres with or without CyA. This indicated that increased acetate and butyrate production was attributed to a component of the coated minispheres rather than an effect of CyA on the microbiota. Butyrate and acetate levels also increased significantly (P=0.05 for both) in the faecal samples of healthy individuals following 7 days’ treatment with SmPill+CyA in the pilot study.Conclusion.SmPill minispheres with or without CyA at the clinically relevant doses tested here have negligible direct effects on the gut microbiota composition. Butyrate and acetate production increased, however, in the presence of the beads in anex vivomodel system as well asin vivoin healthy subjects. Importantly, this study also demonstrates the relevance and value of usingex vivocolon models to predict thein vivoimpact of colon-targeted drugs directly on the gut microbiota.
Intratumor Heterogeneity and Evolution of Colorectal Cancer
Authors: Banerjee Santasree , Zhang Xianxiang , Kuang Shan , Wang Jigang , Li Lei , Fan Guangyi , Luo Yonglun , Sun Shuai , Han Peng , Wu Qingyao , Yang Shujian , Ji Xiaobin , Li Yong , Deng Li , Tian Xiaofen , Wang Zhiwei , Zhang Yue , Wu Kui , Zhu Shida , Bolund Lars , Yang Huanming , Xu Xun , Liu Junnian , Lu Yun , Liu Xin 
Published: January 2020

AbstractIntratumor heterogeneity (ITH) enable us to understand the evolution of cancer. ITH and evolution of colorectal cancer (CRC) has not been well studied. In this prospective study, we recruited different stages of 68 CRC patients with primary tumor at right-sided colon, left-sided colon and rectum. We performed high-depth whole exome sequencing of 206 multi-region tumor samples including primary tumors, lymph node metastasis (LN) and extranodal tumor deposits (ENTD). Our result showed extreme ITH with Darwinian pattern of CRC evolution, evolution pattern of left-sided CRC was more complex and divergent than right-sided CRC and both LN and ENTD were of polyclonal in origin. Extensive ITH was found in driver mutations inKRASandPIK3CAgenes, suggesting major limitations of single biopsies in clinical diagnosis for the CRC patients. In conclusion, our study showed the Darwinian pattern of CRC evolution with differences in evolution pattern between right-sided and left-sided CRC patients.
Silicone Induced Granuloma of Breast Implant Capsule (SIGBIC) diagnosis: Breast Magnetic Resonance (BMR) ability to detect silicone bleeding
Authors: de Faria Castro Fleury Eduardo 
Published: January 2020

ABSTRACTObjectiveTo evaluate the ability of BMRI to detect silicone gel bleeding in a prospective observational study including consecutive patients referred for BMRI scan. Methods: From January 2017 to March 2018, patients referred for BMRI were evaluated in a prospective observational study. Patients who had breast implants were included. BMRI recorded 9 findings according to BI-RADS lexicon and SIGBIC findings, considered equivocal features to detect gel bleeding (GB). Three new original imaging features were added for SIGBIC diagnosis: black drop signal; T2* hypersignal mass; and delayed contrast enhancement, considered as irrevocable signs. The presence of silicone corpuscle was confirmed by percutaneous biopsy or surgical capsulectomy. Accuracy of BMRI SIGBIC findings to predict GB was determined. We also used univariate analysis for the equivocal features for GB diagnosis. The Backward method was applied for a multivariate Logistic Regression model for the equivocal features. Results: SIGBIC was diagnosed in 208 patients and GB was histologically confirmed in all cases. No false positive results were observed. The most important imaging equivocal feature associated with GB was capsular contracture. In order of prevalence, the main equivocal BMRI features associated to GB with statistically significance (P < =0.001) were as follows: 1.water droplets (OR=2.8; 95%CI 1.8-4.4); 2.enlarged intramammary lymph node (OR=3.1; 95%CI 1.5-6.1); 3.pericapsular edema (OR=5.0; 95%CI 2.3-11.1); and 4.intracapsular seroma (OR=2.4; 95%CI 1.4-4.1).ConclusionSIGBIC diagnosis has high sensitivity to predict GB by the 3 irrevocable BMRI features described by the authors. We suppose GB is underdiagnosed in clinical practice by BI-RADS features.
Behavioral and structural barriers to human post-exposure prophylaxis and other preventive practices during a canine rabies epidemic
Authors: Castillo-Neyra Ricardo , Buttenheim Alison M. , Brown Joanna , Ferrara James F. , Arevalo-Nieto Claudia , Borrini-Mayorí Katty , Levy Michael Z. , Becerra Victor , Paz-Soldan Valerie A. 
Published: January 2020

AbstractA canine rabies epidemic started in early 2015 in Arequipa, Peru; the rabies virus continues to circulate in the dog population. Some city residents who suffer dog bites do not seek care or do not complete indicated post-exposure prophylaxis (PEP) regimens, increasing the risk of human rabies. The objectives of our study were to qualitatively assess knowledge about rabies, and preventive practices, such as PEP vaccination, following a dog bite. We conducted eight focus group discussions in peri-urban and urban communities with 70 total participants. We observed low awareness of rabies severity and fatality. Participants, especially those in per-urban communities, recounted applying herbs or the hair of the dog that bit them to wounds rather than seeking appropriate care. Misconceptions about rabies vaccines and mistreatment at health centers also commonly prevents initiating or completing PEP vaccination. We identify important behavioral and structural barriers and knowledge gaps that limit evidence-based preventive strategies against rabies and may threaten successful prevention of dog-mediated human rabies in this setting.
Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex During Red Blood Cell Invasion byPlasmodium falciparumMerozoites
Authors: More Kunal R. , Kaur Inderjeet , Gianetto Quentin Giai , Invergo Brandon M. , Chaze Thibault , Jain Ravi , Huon Christéle , Gutenbrunner Petra , Weisser Hendrik , Matondo Mariette , Choudhary Jyoti S. , Langsley Gordon , Singh Shailja , Chitnis Chetan E. 
Published: January 2020

AbstractRed blood cell (RBC) invasion byPlasmodiummerozoites requires multiple steps that are regulated by signaling pathways. Exposure ofP. falciparummerozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative phosphoproteomics we found 394 protein phosphorylation site changes in merozoites subjected to different ionic environments (high K+/ low K+) out of which 143 were Ca2+-dependent. These included a number of signaling proteins such as catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr) and calcium-dependent protein kinase 1 (PfCDPK1). Proteins of the 14-3-3 family interact with phosphorylated target proteins to assemble signaling complexes. Here, using co-immunoprecipitation and gel filtration chromatography, we demonstrate that Pf14-3-3I binds phosphorylated PfPKAr and PfCDPK1 to mediate the assembly of a multi-protein complex inP. falciparummerozoites. A phospho-peptide, P1, based on the Ca2+dependent phosphosites of PKAr, binds Pf14-3-3I and disrupts assembly of the Pf14-3-3I-mediated multi-protein complex. Disruption of the multi-protein complex with P1 inhibits microneme secretion and RBC invasion. This study thus identifies a novel signaling complex that plays a key role in merozoite invasion of RBCs. Disruption of this signaling complex could serve as a novel approach to inhibit blood stage growth of malaria parasites.ImportanceInvasion of red blood cells (RBCs) byPlasmodium falciparummerozoites is a complex process that is regulated by intricate signaling pathways. Here, we have used phosphoproteomic profiling to identify the key proteins involved in signaling events during invasion. We found changes in the phosphorylation of various merozoite proteins including multiple kinases previously implicated in the process of invasion. We also found that a phosphorylation dependent multi-protein complex including signaling kinases assembles during the process of invasion. Disruption of this multi-protein complex impairs merozoite invasion of RBCs providing a novel approach for the development of inhibitors to block the growth of blood stage malaria parasites.
NetMix: A network-structured mixture model for reduced-bias estimation of altered subnetworks
Authors: Reyna Matthew A. , Chitra Uthsav , Elyanow Rebecca , Raphael Benjamin J. 
Published: January 2020

AbstractA classic problem in computational biology is the identification ofaltered subnetworks:subnetworks of an interaction network that contain genes/proteins that are differentially expressed, highly mutated, or otherwise aberrant compared to other genes/proteins. Numerous methods have been developed to solve this problem under various assumptions, but the statistical properties of these methods are often unknown. For example, some widely-used methods are reported to output very large subnetworks that are difficult to interpret biologically. In this work, we formulate the identification of altered subnetworks as the problem of estimating the parameters of a class of probability distributions which we call the Altered Subset Distribution (ASD). We derive a connection between a popular method, jActiveModules, and the maximum likelihood estimator (MLE) of the ASD. We show that the MLE isstatistically biased, explaining the large subnetworks output by jActiveModules. We introduce NetMix, an algorithm that uses Gaussian mixture models to obtain less biased estimates of the parameters of the ASD. We demonstrate that NetMix outperforms existing methods in identifying altered subnetworks on both simulated and real data, including the identification of differentially expressed genes from both microarray and RNA-seq experiments and the identification of cancer driver genes in somatic mutation data.AvailabilityNetMix is available online athttps://github.com/raphael-group/netmix.Contactbraphael@princeton.edu
BREM-SC: A Bayesian Random Effects Mixture Model for Joint Clustering Single Cell Multi-omics Data
Authors: Wang Xinjun , Sun Zhe , Zhang Yanfu , Xu Zhongli , Huang Heng , Duerr Richard H. , Chen Kong , Ding Ying , Chen Wei 
Published: January 2020

ABSTRACTDroplet-based single cell transcriptome sequencing (scRNA-seq) technology, largely represented by the 10X Genomics Chromium system, is able to measure the gene expression from tens of thousands of single cells simultaneously. More recently, coupled with the cutting-edge Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), the droplet-based system has allowed for immunophenotyping of single cells based on cell surface expression of specific proteins together with simultaneous transcriptome profiling in the same cell. Despite the rapid advances in technologies, novel statistical methods and computational tools for analyzing multi-modal CITE-Seq data are lacking. In this study, we developed BREM-SC, a novel Bayesian Random Effects Mixture model that jointly clusters paired single cell transcriptomic and proteomic data. Through simulation studies and analysis of public and in-house real data sets, we successfully demonstrated the validity and advantages of this method in fully utilizing both types of data to accurately identify cell clusters. In addition, as a probabilistic model-based approach, BREM-SC is able to quantify the clustering uncertainty for each single cell. This new method will greatly facilitate researchers to jointly study transcriptome and surface proteins at the single cell level to make new biological discoveries, particularly in the area of immunology.
Cross-Cancer Evaluation of Polygenic Risk Scores for 17 Cancer Types in Two Large Cohorts
Authors: Graff Rebecca E. , Cavazos Taylor B. , Thai Khanh K. , Kachuri Linda , Rashkin Sara R. , Hoffman Joshua D. , Alexeeff Stacey E. , Blatchins Maruta , Meyers Travis J. , Leong Lancelote , Tai Caroline G. , Emami Nima C. , Corley Douglas A. , Kushi Lawrence H. , Ziv Elad , Van Den Eeden Stephen K. , Jorgenson Eric , Hoffmann Thomas J. , Habel Laurel A. , Witte John S. , Sakoda Lori C. 
Published: January 2020

ABSTRACTGenetic factors that influence etiologic mechanisms shared across cancers could affect the risk of multiple cancer types. We investigated polygenic risk score (PRS)-specific pleiotropy across 17 cancers in two large population-based cohorts. The study population included European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and the UK Biobank (48,969 cases, 359,802 controls). We selected known independent risk variants from published GWAS to construct a PRS for each cancer type. Within cohorts, each PRS was evaluated in multivariable logistic regression models with respect to the cancer for which it was developed and each other cancer type. Results were then meta-analyzed across cohorts. In the UK Biobank, each PRS was additionally evaluated relative to 20 cancer risk factors or biomarkers. All PRS replicated associations with their corresponding cancers (p<0.05). Eleven cross-cancer associations – ten positive and one inverse – were found after correction for multiple testing (p<0.05/17=0.0029). Two cancer pairs showed bidirectional associations; the melanoma PRS was positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS was positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS was inversely associated with lung cancer. We identified 65 associations between a cancer PRS and non-cancer phenotype. In this study examining cross-cancer PRS associations in two cohorts unselected for phenotype, we validated known and uncovered novel patterns of pleiotropy. Our results have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.STATEMENT OF SIGNIFICANCEBy examining cross-cancer polygenic risk score associations, we validated known and uncovered novel patterns of pleiotropy. Our results may inform investigations of risk prediction, shared etiology, and precision prevention strategies.
Dual Proteome-scale Networks Reveal Cell-specific Remodeling of the Human Interactome
Authors: Huttlin Edward L. , Bruckner Raphael J. , Navarrete-Perea Jose , Cannon Joe R. , Baltier Kurt , Gebreab Fana , Gygi Melanie P. , Thornock Alexandra , Zarraga Gabriela , Tam Stanley , Szpyt John , Panov Alexandra , Parzen Hannah , Fu Sipei , Golbazi Arvene , Maenpaa Eila , Stricker Keegan , Thakurta Sanjukta Guha , Rad Ramin , Pan Joshua , Nusinow David P. , Paulo Joao A. , Schweppe Devin K. , Vaites Laura Pontano , Harper J. Wade , Gygi Steven P. 
Published: January 2020

SUMMARYThousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome. Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins – half the proteome – in 293T cells and includes 118,162 interactions among 14,586 proteins; the second results from 5,522 immunoprecipitations in HCT116 cells. These networks model the interactome at unprecedented scale, encoding protein function, localization, and complex membership. Their comparison validates thousands of interactions and reveals extensive customization of each network. While shared interactions reside in core complexes and involve essential proteins, cell-specific interactions bridge conserved complexes, likely ‘rewiring’ each cell’s interactome. Interactions are gained and lost in tandem among proteins of shared function as the proteome remodels to produce each cell’s phenotype. Viewable interactively online through BioPlexExplorer, these networks define principles of proteome organization and enable unknown protein characterization.
Anisotropic mineralized collagen scaffolds accelerate osteogenic response in a glycosaminoglycan-dependent fashion
Authors: Dewey Marley J. , Nosatov Andrey V. , Subedi Kiran , Harley Brendan 
Published: January 2020

ABSTRACTRegeneration of critically-sized craniofacial bone defects requires a template to promote cell activity and bone remodeling. However, induced regeneration becomes more challenging with increasing defect size. Methods of repair using allografts and autografts have inconsistent results, attributed to age-related regenerative capabilities of bone. We are developing a mineralized collagen scaffold to promote craniomaxillofacial bone regeneration as an alternative to repair. Here, we hypothesize modifying the pore anisotropy and glycosaminoglycan content of the scaffold will improve cell migration, viability, and subsequent bone formation. Using anisotropic and isotropic scaffold variants, we test the role of pore orientation on human mesenchymal stem cell (MSC) activity. We subsequently explore the role of glycosaminoglycan content, notably chondroitin-6-sulfate, chondroitin-4-sulfate, and heparin sulfate on mineralization. We find that while short term MSC migration and activity was not affected by pore orientation, increased bone mineral synthesis was observed in anisotropic scaffolds. Further, while scaffold glycosaminoglycan content did not impact cell viability, heparin sulfate and chondroitin-6-sulfate containing variants increased mineral formation at the late stage ofin vitroculture, respectively. Overall, these findings show scaffold microstructural and proteoglycan modifications represent a powerful tool to improve MSC osteogenic activity.
Cerebello-Thalamic Spike Transfer via Temporal Coding and Cortical Adaptation
Authors: Schäfer Carmen B. , Gao Zhenyu , De Zeeuw Chris I. , Hoebeek Freek E. 
Published: January 2020

AbstractOrchestrating the ensemble of muscle contractions necessary for coordinated movements requires the interaction of cerebellar, thalamic and cerebral structures, but the mechanisms underlying the integration of information remain largely unknown. Here we investigated how excitatory inputs from cerebellar nuclei (CN) and primary motor cortex layer VI (M1 L6) neurons may regulate together the activity of neurons in the mouse ventrolateral (VL) thalamus. Using dual-optogenetic stimulation and whole-cell recordingsin vitrowe were able to specifically activate the CN and M1 pathways and study their differential impact. We found that VL spiking probability is effectively determined by a pause in CN stimuli, whereas VL membrane potential can be modulated subthreshold by M1 L6 input. Upon mild depolarization of the VL membrane potential, repetitive CN stimulation evokes at best single action potential firing, whereas more negative membrane potentials increase VL spiking probability. Moreover, whereas high-frequency cerebellar activity attenuates thalamic spiking, pauses in cerebellar activity re-activate thalamic spiking. In contrast, facilitating inputs from cerebral cortex modulate thalamo-cortical spike transfer via fluctuations in the membrane potential. The fine-tuning by cerebellar and cerebral activity allows the motor thalamus to operate as a low-pass filter for cerebellar activity, generating sparse but precisely timed outputs for the cerebral cortex.
DNA damage and macrophage infiltration in the ovaries of the long-lived GH deficient Ames Dwarf and the short-lived bGH transgenic mice
Authors: Saccon Tatiana , Rovani Monique Tomazele , Garcia Driele Neske , Pradiee Jorgea , Mondadori Rafael Gianella , Cruz Luis Augusto Xavier , Barros Carlos Castilho , Fang Yimin , McFadden Samuel , Bartke Andrzej , Masternak Michal M , Schneider Augusto 
Published: January 2020

AbstractObjectiveThe aim of the study was to evaluate the role of growth hormone (GH) in DNA damage, macrophage infiltration and the granulosa cells number of primordial and primary follicles.MethodsFor these experiments six groups of female mice were used. Four groups consisted of Ames dwarf (Prop-1df, df/df, n=12) and their normal littermates (N/df, n=12) mice, between sixteen and eighteen month-old, receiving GH (n=6 for df/df, and n=6 for N/df mice) or saline injections (n=6 for df/df, and n=6 for N/df mice). The other two groups consisted of ten to twelve-month-old bGH (n=6) and normal mice (N, n=6). Immunofluorescence for DNA damage (anti-γH2AX) and macrophage counting (anti-CD68) were performed. Granulosa cells of primordial and primary follicles were counted.ResultsFemale df/df mice had lower γH2AX foci intensity in in both oocytes and granulosa cells of primordial and primary follicles (p<0.05), indicating less DNA double strand breaks (DSBs). In addition, GH treatment increased DSBs in both df/df and N/df mice. Inversely, bGH mice had higher quantity of DSBs in both oocytes and granulosa cells of primordial and primary follicles (p<0.05). Df/df mice showed ovarian tissue with less macrophage infiltration than N/df mice (p<0.05) and GH treatment increased macrophage infiltration (p<0.05). On the other hand, bGH mice had ovarian tissue with more macrophage infiltration compared to normal mice (p<0.05). Df/df mice had less granulosa cells on primordial and primary follicles than N/df mice (p<0.05). GH treatment did not affect the granulosa cells number (p>0.05). However, bGH mice had an increased number of granulosa cells on primordial and primary follicles compared to normal mice (p<0.05).ConclusionThe current study points to the role of the GH/IGF-I axis in maintenance of oocyte DNA integrity and macrophage ovarian infiltration in mice.