bluuebunny/crossref_metadata_2025_split huggingface dataset:
FK506-binding protein 13 expression is upregulated in interstitial lung disease and correlated with clinical severity: a potentially protective role
Authors: Tat V , Ayaub EA , Ayoub A , Vierhout M , Naiel S , Padwal MK , Abed S , Mekhael O , Tandon K , Revill SD , Yousof T , Bellaye PS , Kolb PS , Dvorkin-Gheva A , Naqvi A , Cutz JC , Hambly N , Kato J , Vaughan M , Moss J , Kolb MRJ , Ask K 
Published: December 2019

ABSTRACTPulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR), a cellular stress response pathway that has been implicated in both inflammatory and fibrotic processes. Here, we sought to investigate the role of the 13 kDa FK506-binding protein (FKBP13), an ER stress-inducible molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy samples from 24 patients with idiopathic pulmonary fibrosis (IPF) and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of IPF lung tissues, and within this cohort, was correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsies of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/-mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21) and resolution (Day 50) phase. FKBP13-/-mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/-lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity or progression of interstitial lung diseases, and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation and fibrosis.
Mutation effect estimation on protein-protein interactions using deep contextualized representation learning
Authors: Zhou Guangyu , Chen Muhao , Ju Chelsea J.-T. , Wang Zheng , Jiang Jyun-Yu , Wang Wei 
Published: December 2019

AbstractThe functional impact of protein mutations is reflected on the alteration of conformation and thermodynamics of protein-protein interactions (PPIs). Quantifying the changes of two interacting proteins upon mutations are commonly carried out by computational approaches. Hence, extensive research efforts have been put to the extraction of energetic or structural features on proteins, followed by statistical learning methods to estimate the effects of mutations to PPI properties. Nonetheless, such features require extensive human labors and expert knowledge to obtain, and have limited abilities to reflect point mutations. We present an end-to-end deep learning framework,MuPIPR, to estimate the effects of mutations on PPIs.MuPIPRincorporates a contextualized representation mechanism of amino acids to propagate the effects of a point mutation to surrounding amino acid representations, therefore amplifying the subtle change in a long protein sequence. On top of that,MuPIPRleverages a Siamese residual recurrent convolutional neural encoder to encode a wildtype protein pair and its mutation pair. Multiple-layer perceptron regressors are applied to the protein pair representations to predict the quantifiable changes of PPI properties upon mutations. Experimental evaluations show thatMuPIPRoutperforms various state-of-the-art systems on the change of binding affinity prediction and the buried surface area prediction. The software implementation is available athttps://github.com/guangyu-zhou/MuPIPR
Non-uniform refinement: Adaptive regularization improves single particle cryo-EM reconstruction
Authors: Punjani Ali , Zhang Haowei , Fleet David J. 
Published: December 2019

AbstractSingle particle cryo-EM is a powerful method for studying proteins and other biological macromolecules. Many of these molecules comprise regions with varying structural properties including disorder, flexibility, and partial occupancy. These traits make computational 3D reconstruction from 2D images challenging. Detergent micelles and lipid nanodiscs, used to keep membrane proteins in solution, are common examples of locally disordered structures that can negatively affect existing iterative refinement algorithms which assume rigidity (or spatial uniformity). We introduce a cross-validation approach to derivenon-uniform refinement, an algorithm that automatically regularizes 3D density maps during iterative refinement to account for spatial variability, yielding dramatically improved resolution and 3D map quality. We find that in common iterative refinement methods, regularization using spatially uniform filtering operations can simultaneously over- and under-regularize local regions of a 3D map. In contrast,non-uniform refinementremoves noise in disordered regions while retaining signal useful for aligning particle images. Our results include state-of-the-art resolution 3D reconstructions of multiple membrane proteins with molecular weight as low as 90kDa. These results demonstrate that higher resolutions and improved 3D density map quality can be achieved even for small membrane proteins, an important use case for single particle cryo-EM, both in structural biology and drug discovery.Non-uniform refinementis implemented in thecryoSPARCsoftware package and has already been used successfully in several notable structural studies.
On the Order of Gene Distribution on Chromosomes Across the Animal Kingdom
Authors: Toor Abdullah A. , Toor Amir A. 
Published: December 2019

SummaryBackgroundThe large-scale pattern of distribution of genes on the chromosomes in the known animal genomes is not well characterized. We hypothesized that individual genes will be distributed on chromosomes in a mathematically ordered manner across the animal kingdom.ResultsTwenty-one animal genomes reported in the NCBI database were examined. Numerically, there was a trend towards increasing overall gene content with increasing size of the genome as reflected by the chromosomal complement. Gene frequency on individual chromosomes in each animal genome was analyzed and demonstrated uniformity of proportions within each animal with respect to both average gene frequency on individual chromosomes and gene distribution across the unique genomes. Further, average gene distribution across animal species followed a relationship whereby it was, approximately, inversely proportional to the square root of the number of chromosomes in the unique animal genomes, consistent with the notion that there is an ordered increase in gene dispersion as the complexity of the genome increased. To further corroborate these findings a derived measure, termed gene spacing on chromosomes correlated with gene frequency and gene distribution.ConclusionAs animal species have evolved, the distribution of their genes on individual chromosomes and within their genomes, when viewed on a large scale is not random, but follows a mathematically ordered process, such that as the complexity of the organism increases, the genes become less densely distributed on the chromosomes and more dispersed across the genome.
Secreted microbial metabolites modulate gut immunity and inflammatory tone
Authors: Giri Rabina , Hoedt Emily C. , Shamsunnahar Khushi , McGuckin Michael A. , Morrison Mark , Capon Robert J. , Begun Jakob , Cuív Páraic Ó 
Published: December 2019

AbstractEvidence is emerging that microbiome–immune system crosstalk regulates the tenor of host intestinal immunity and predisposition to inflammatory bowel disease (IBD). We identified five NF-κB suppressive strains affiliated with Clostridium clusters IV, XIVa and XV that independently suppressed secretion of the chemokine IL-8 by peripheral blood mononuclear cells and gut epithelial organoids from healthy human subjects, as well as patients with the predominant IBD subtypes, Crohn’s disease and ulcerative colitis. The NF-κB suppressive Clostridium bolteae AHG0001, but not C. bolteae BAA-613, suppressed cytokine-driven inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice that develop spontaneous colitis. This predicted in vivo responses thereby validating a precision medicine approach to treat Winnie colitis and suggesting the microbiome may function as an extrinsic regulator of host immunity. Finally, we identified a novel molecule associated with NF-κB suppression indicating gut bacteria could be harnessed to develop new therapeutics.
Evidence for unfamiliar kin recognition in vampire bats
Authors: Ripperger Simon P. , Page Rachel A. , Mayer Frieder , Carter Gerald G. 
Published: December 2019

AbstractKin discrimination allows organisms to preferentially cooperate with kin, reduce kin competition, and avoid inbreeding. In vertebrates, kin discrimination often occurs through prior association. There is less evidence for recognition of unfamiliar kin. Here, we present the first evidence of unfamiliar kin recognition in bats. We captured female vampire bats (Desmodus rotundus) from a single roost, allowed them to breed in captivity for 22 months, then released 17 wild-caught females and six captive-born daughters back into the same wild roost. We then used custom-built proximity sensors to track the free-ranging social encounters among the previously captive bats and 27 tagged control bats from the same roost. Using microsatellite-based relatedness estimates, we found that previously captive bats preferentially associated with related control bats, and that captive-born bats preferentially associated with unfamiliar kin among control bats. Closer analyses showed that these unfamiliar-kin-biased associations were not caused by mothers or other familiar close kin, because the kinship bias was evident even when those bats were not nearby. This striking evidence for unfamiliar kin recognition in vampire bats warrants further investigation and provides new hypotheses for how cooperative relationships might be driven synergistically by both social experience and phenotypic similarity.
Noninvasive optical detection of Granzyme B from natural killer cells using enzyme-activated fluorogenic probes
Authors: Janiszewski Tomasz , Kołt Sonia , Kaiserman Dion , Snipas Scott , Li Shuang , Kulbacka Julita , Saczko Jolanta , Bovenschen Niels , Salvesen Guy , Drąg Marcin , Bird Phillip I. , Kasperkiewicz Paulina 
Published: December 2019

AbstractDespite many studies on the cytotoxic protease granzyme B, key aspects of its function remain unexplored due to the lack of selective probes for its activity. In this study, we fully mapped the substrate preferences of GrB using a set of unnatural amino acids, demonstrating previously unknown GrB substrate preferences that we then used to design novel substrate-based inhibitors and a GrB-activatable activity-based probe. We showed that our GrB probes react poorly with caspases, making them ideal for the in-depth analysis of GrB localization and function in cells. With our quenched fluorescence substrate, we determined GrB within the cytotoxic granules of human YT cells. When used as cytotoxic effectors, YT cells loaded with the GrB attack MDA-MB-231 target cells, and active GrB influences its target cell killing efficiency.
Characteristics of mathematical modeling languages that facilitate model reuse in systems biology: A software engineering perspective
Authors: Schölzel Christopher , Blesius Valeria , Ernst Gernot , Dominik Andreas 
Published: December 2019

AbstractReproducible, understandable models that can be reused and combined to true multi-scale systems are required to solve the present and future challenges of systems biology. However, many mathematical models are still built for a single purpose and reusing them in a different context can be challenging due to an inflexible monolithic structure, confusing code, missing documentation or other issues. These challenges are very similar to those faced in the engineering of large software systems. It is therefore likely that addressing model design at the software engineering level will also be beneficial in systems biology. To do this, researchers cannot just rely on using an accepted standard language. They need to be aware of the characteristics that make this language desirable and they need guidelines on how to utilize them to make their models more reproducible, understandable, reusable, and extensible. Drawing upon our experience with translating and extending a model of the human baroreflex, we therefore propose a list of desirable language characteristics and provide guidelines and examples for incorporating them in a model: In our opinion, a mathematical modeling language used in systems biology should be modular, human-readable, hybrid (i.e., support multiple formalisms), open, declarative, and support the graphical representation of models. We compare existing modeling languages with respect to these characteristics and show that there is no single best language but that trade-offs always have to be considered. We also illustrate the benefits of the individual language characteristics by translating a monolithic model of the human cardiac conduction system to a modular version using the modeling language Modelica as an example. Our experiment can be seen as emblematic for model reuse in a multi-scale setting. It illustrates how each characteristic, when applied consistently, can facilitate the reuse of the resulting model. We therefore recommend that modelers consider these criteria when choosing a programming language for any biological modeling task and hope that our work sparks a discussion about the importance of software engineering aspects in mathematical modeling languages.
CRISPR Screens Identify Essential Cell Growth Mediators in BRAF-inhibitor Resistant Melanoma
Authors: Li Ziyi , Wang Binbin , Gu Shengqing , Jiang Peng , Sahu Avinash , Chen Chen-Hao , Han Tong , Shi Sailing , Wang Xiaoqing , Traugh Nicole , Liu Hailing , Liu Yin , Wu Qiu , Brown Myles , Xiao Tengfei , Boland Genevieve M. , Liu X. Shirley 
Published: December 2019

AbstractBRAF is a serine-threonine kinase that harbors activating mutations in ∼7% of human malignancies and ∼60% of melanomas. Despite initial clinical responses to BRAF inhibitors (BRAFi), patients frequently develop drug resistance. To identify candidate therapeutic targets for BRAFi-resistant melanoma, we conducted CRISPR screens in melanoma cells harboring an activating BRAF mutation that had also acquired resistance to BRAFi. The screens identified pathways and genes critical for BRAFi resistance in melanoma cells. To investigate the mechanisms and pathways enabling resistance to BRAFi in melanomas, we integrated expression data, ATAC-seq, and CRISPR screen results. We identified the JUN family of transcription factors and the ETS family transcription factor ETV5 as key regulators of CDK6 that enabled resistance to BRAFi in melanoma cells. Our findings reveal genes whose loss of function conferred resistance to a selective BRAF inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in melanoma.
Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7
Authors: Shibata Takuma , Taoka Masato , Saitoh Shin-Ichiroh , Yamauchi Yoshio , Motoi Yuji , Komine Mayumi , Fujita Etsuko , Sato Ryota , Sagara Hiroshi , Ichinohe Takeshi , Kawazoe Mimi , Kato Chiharu , Furusho Katsuhiro , Murakami Yusuke , Fukui Ryutaro , Ohtsuki Mamitaro , Ohto Umeharu , Shimizu Toshiyuki , Yoshida Nobuaki , Isobe Toshiaki , Miyake Kensuke 
Published: December 2019

AbstractA lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen ofSlc29a3−/−mice but notSlc29a3−/−Tlr7−/−mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF inSlc29a3−/−monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders.One Sentence SummarySLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes.
Pooled analysis of radiation hybrids identifies loci for growth and drug action in mammalian cells
Authors: Khan Arshad H. , Lin Andy , Wang Richard T. , Bloom Joshua S. , Lange Kenneth , Smith Desmond J. 
Published: December 2019

AbstractGenetic screens in mammalian cells commonly focus on loss-of-function approaches. To evaluate the phenotypic consequences of extra gene copies, we used bulk segregant analysis (BSA) of radiation hybrid (RH) cells. We constructed six pools of RH cells, each consisting of ~2500 independent clones, and placed the pools under selection in media with or without paclitaxel. Low pass sequencing identified 859 growth loci, 38 paclitaxel loci, 62 interaction loci and 3 loci for mitochondrial abundance at genome-wide significance. Resolution was measured as ~30 kb, close to single-gene. Divergent properties were displayed by the RH-BSA growth genes compared to those from loss-of-function screens, refuting the balance hypothesis. In addition, enhanced retention of human centromeres in the RH pools suggests a new approach to functional dissection of these chromosomal elements. Pooled analysis of RH cells showed high power and resolution and should be a useful addition to the mammalian genetic toolkit.
KDM5 histone-demethylases contribute to replication stress response and tolerance
Authors: Gaillard Solenne , Charasson Virginie , Ribeyre Cyril , Salifou Kader , Pillaire Marie-Jeanne , Hoffmann Jean-Sebastien , Constantinou Angelos , Trouche Didier , Vandromme Marie 
Published: December 2019

SUMMARYKDM5A and KDM5B histone-demethylases are overexpressed in many cancers and have been involved in drug tolerance. Here, we describe that KDM5A, together with KDM5B, contribute to replication stress (RS) response and tolerance. First, they positively regulate RRM2, the regulatory subunit of Ribonucleotide Reductase. Second, they are required for optimal activation of Chk1, a major player of the intra-S phase checkpoint that protects cells from RS. This role in Chk1 activation is probably direct since KDM5A is enriched at ongoing replication forks and associates with both PCNA and Chk1. Because RRM2 is a major determinant of replication stress tolerance, we developed cells resistant to HU, and show that KDM5A/B proteins are required for both RRM2 overexpression and tolerance to HU, in a manner that is independent of their demethylase activity. Altogether, our results indicate that KDM5A/B are major players of RS management. They also show that drugs targeting the enzymatic activity of KDM5 proteins may not affect all cancer-related consequences of KDM5A/B overexpression.
AMPAR/TARP stoichiometry differentially modulates channel properties
Authors: Miguez-Cabello Federico , Sánchez-Fernández Nuria , Yefimenko Natalia , Gasull Xavier , Gratacòs-Batlle Esther , Soto David 
Published: December 2019

SummaryAMPARs control fast synaptic communication between neurons and their function relies on auxiliary subunits, which importantly modulate channel properties. Although it has been suggested that AMPARs can bind to TARPs with variable stoichiometry, little is known about the effect that this stoichiometry exerts on certain AMPAR properties. Here we have found that AMPARs show a clear stoichiometry dependent modulation although AMPARs still need to be fully saturated with TARPs to show some typical TARP-induced characteristics (i.e. an increase in channel conductance). We also have uncovered important differences in the stoichiometric modulation between calcium-permeable and calcium-impermeable AMPARs. Moreover, in heteromeric AMPARs, TARP positioning in the complex is important to exert certain TARP-dependent features. Finally, by comparing data from recombinant receptors with endogenous AMPAR currents from cerebellar granule cells, we have determined a likely functional stoichiometry of 2 TARPs associated with GluA2 subunits in the somatic AMPARs found in this cell type.
Antigen and G-Protein Coupled Receptor signaling differentially control CD8 T cell motility immediately before and after virus clearance in a primary infection
Authors: Lambert-Emo Kris , Reilly Emma C. , Sportiello Michael , Topham David J. 
Published: December 2019

AbstractIn mice, experimental influenza virus infection stimulates CD8 T cell infiltration of the airways. Virus is cleared by day 9, and between days 8 and 9 there is an abrupt change in CD8 T cell motility behavior transitioning from low velocity and high confinement on day 8, to high velocity with continued confinement on day 9. We hypothesized that it is loss of virus and/or antigen signals in the context of high chemokine levels that drives the T cells into a rapid surveillance mode. Virus infection induces chemokine production, which may change when the virus is cleared. We therefore sought to examine this period of rapid changes to the T cell environment in the tissue and seek evidence on the roles of peptide-MHC and chemokine receptor interactions. Experiments were performed to block G protein coupled receptor (GPCR) signaling with Pertussis toxin (Ptx). Ptx treatment generally reduced cell velocities and mildly increased confinement, except on day 8 when velocity increased and confinement was relieved, suggesting chemokine mediated arrest. Blocking specific peptide-MHC with monoclonal antibody unexpectedly decreased velocities on days 7 through 9, suggesting TCR/peptide-MHC interactions promote cell mobility in the tissue. Together, these results suggest the T cells are engaged with antigen bearing and chemokine producing cells that affect motility in ways that vary with the day after infection. The increase in velocities on day 9 were reversed by addition of specific peptide, consistent with the idea that antigen signals become limiting on day 9 compared to earlier time points. Thus, antigen and chemokine signals act to alternately promote and restrict CD8 T cell motility until the point of virus clearance, suggesting the switch in motility behavior on day 9 may be due to a combination of limiting antigen in the presence of high chemokine signals as the virus is cleared.