bluuebunny/crossref_metadata_2025 huggingface dataset:
Spergulin-A strives intra-macrophage leishmanicidal activity by regulating the host P2X7R-P38MAPK axis
Authors: Mukherjee Niladri , Banerjee Saswati , Amin Sk. Abdul , Jha Tarun , Datta Sriparna , Saha Krishna Das
Published: December 2019

Current drugs are inadequate for the treatment of visceral leishmaniasis an immunosuppressive ailment caused byLeishmania donovani. Regrettably, there is no plant-origin antileishmanial drug present. P2X7R is constitutively present on macrophage surfaces and can be a putative therapeutic target in intra-macrophage pathogens with function attributes towards inflammation, host cell apoptosis, altered redox, and phagolysosomal maturation by activating p38MAPK. Here we demonstrated that the initial interaction of Spergulin-A (SpA), a triterpenoid saponin with RAW 264.7 macrophages was mediated through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-κβ. P38MAPK involvement is shown to have specific and firm importance in leishmanial killing with increased NF-κBp65. Phago-lysosomal maturation by Sp A also campaigns for another contribution of P2X7R.In vivoevaluation of the anti-leishmanial activity of Sp A was monitored through expression analyses of P2X7R, P38MAPK, and NF-κβ in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPK axis.

SIGNIFICANCE OR IMPORTANCE

Preciously, this manuscript demonstrated previously unreported initial interaction of Spergulin-A, a triterpenoid saponin isolated fromGlinus oppositifoliuswith macrophages through P2X7R involving the signaling cascade intermediates Ca++, P38MAPK, and NF-κβ. Signaling interaction is shown to have specific importance in the leishmanial killing. Phago-lysosomal maturation also campaigns for another contribution of P2X7R.In vivoevaluation was monitored through P2X7R, P38MAPK, and NF-κβ in murine spleen and bone-marrow macrophages and advocated Sp A of being a natural compound of leishmanicidal functions which acted through the P2X7R-P38MAPKaxis. The result supports that Spergulin-A can provide new lead molecules for the development of alternative drugs against VL. We feel very strongly that this work can be very interesting as it describes a detailed evaluation of leishmanicidal effect by Sp A and thus has every potential to attract a lot of workers especially in the fields of pharmacology, drug development, immunology, as well as parasitology.
Nilotinib activates endothelial TLR4 to exacerbate atherosclerosis
Authors: Qu Dan , Huo Mingyu , Wang Li , Lau Chi-Wai , Tian Xiao Yu , Huang Yu
Published: December 2019

The use of nilotinib (Tasigna®), a second-generation tyrosine kinase inhibitor for treating chronic myeloid leukemia, increases risks for atherosclerosis. Here, we demonstrate that in endothelial cells, nilotinib activated TLR4, triggerd expression of inflammatory molecules, and increased monocyte attachment, which were all inhibited by knockdown of TLR4 or TLR4 inhibitor, CLI-095. Orally administered nilotinib profoundly accelerated atherosclerotic lesion formation in ApoE−/−mice, while co-administration of CLI-095 effectively reduced lesion areas. Our findings reveal TLR4 activation as an underlying mechanism of the pro-atherosclerotic effect of nilotinib and suggest TLR4 inhibition as an effective therapeutic approach to address vascular safety issue of nilotinib.
OLGenie: Estimating Natural Selection to Predict Functional Overlapping Genes
Authors: Nelson Chase W. , Ardern Zachary , Wei Xinzhu
Published: December 2019

Purifying (negative) natural selection is a hallmark of functional biological sequences, and can be detected in protein-coding genes using the ratio of nonsynonymous to synonymous substitutions per site (dN/dS). However, when two genes overlap the same nucleotide sites in different frames, synonymous changes in one gene may be nonsynonymous in the other, perturbingdN/dS. Thus, scalable methods are needed to estimate functional constraint specifically for overlapping genes (OLGs). We propose OLGenie, which implements a modification of the Wei-Zhang method. Assessment with simulations and controls from viral genomes (58 OLGs and 176 non-OLGs) demonstrates low false positive rates and good discriminatory ability in differentiating true OLGs from non-OLGs. We also apply OLGenie to the unresolved case of HIV-1’s putativeantisense proteingene, showing significant purifying selection. OLGenie can be used to study known OLGs and to predict new OLGs in genome annotation. Software and example data are freely available athttps://github.com/chasewnelson/OLGenie.
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

Pulmonary 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

The 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

Single 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

Background

The 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.

Results

Twenty-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.

Conclusion

As 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

Evidence 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

Kin 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

Despite 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

Reproducible, 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

BRAF 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

A 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 Summary

SLC29A3 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

Genetic 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

KDM5A 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

AMPARs 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

In 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.
Copper Induces Zebrafish Central Neural System Myelin Defects: the Regulatory Mechanisms in Wnt/Notch-hoxb5bSignaling and Underlying DNA Methylation
Authors: Zhang Ting , Guan PengPeng , Zhao Guang , Fang YaPing , Fu Hui , Gui Jian-Fang , Li GuoLiang , Liu Jing-Xia
Published: December 2019

Unbalanced copper (Cu2+) homeostasis is associated with neurological development defects and diseases. However, the molecular mechanisms remain elusive. Here, central neural system (CNS) myelin defects and down-regulated expression of Wnt/Notch signaling and their down-stream mediatorhoxb5bwere observed in Cu2+stressed zebrafish larvae. Loss/knockdown-of-function ofhoxb5bphenocopied the myelin and axon defects observed in Cu2+stressed embryos. Meanwhile, activation of Wnt/Notch signaling and ectopic expression ofhoxb5bcould rescue copper-induced myelin defects, suggesting Wnt&Notch-hoxb5baxis mediated Cu2+induced myelin and axon defects. Additionally, whole genome DNA methylation sequencing unveiled that a novel genefam168b, similar topou3f1/2, exhibited significant promoter hypermethylation and reduced expression in Cu2+stressed embryos. The hypermethylated locus infam168bpromoter acted pivotally in its transcription, and loss/knockdown offam168b/pou3f1also induced myelin defects. Moreover, this study unveiled thatfam168b/pou3f1andhoxb5baxis acted in a seesaw manner during fish embryogenesis, and demonstrated that copper induced the down-regulated expression of the Wnt&Notch-hoxb5baxis dependent of the function of copper transportercox17, coupled with the promoter methylation of genesfam168b/pou3f1and their subsequent down-regulated expression dependent of the function of another transporteratp7b, making joint contributions to myelin defects in embryos. Those data will shed some light on the linkage of unbalanced copper homeostasis with specific gene promoter methylation and signaling transduction as well as the resultant neurological development defects and diseases.

Author summary

In this study, we first unveiled that copper induced central neural system (CNS) myelin defectsviadown-regulating Wnt/Notch-hoxb5bsignaling, and parallel with hypermethylating promoters of genesfam168b/pou3f2and their subsequent down-regulated expression. Additionally, we unveiled thatfam168b/pou3f1andhoxb5baxis acted in a seesaw manner during fish embryogenesis. Genetically, we unveiled that copper was trafficked to mitochondrionvia cox17then led to the down-regulation of Wnt&Notch-hoxb5baxis, and was trafficked to trans-Golgi networkvia atp7bto induce the hypermethylation and the down-regulated expression ofpou3f1/fam168bgenes, making joint contributions to myelin defects in embryos.
The Dynamic Landscape of Transcription Initiation in Yeast Mitochondria
Authors: Sohn Byeong-Kwon , Basu Urmimala , Lee Seung-Won , Cho Hayoon , Shen Jiayu , Deshpande Aishwarya , Patel Smita S. , Kim Hajin
Published: December 2019

Controlling efficiency and fidelity in the early stage of mitochondrial DNA transcription is crucial for regulating cellular energy metabolism. Studies of bacteriophage and bacterial systems have revealed that transcription occurs through a series of conformational transitions during the initiation and elongation stages; however, how the conformational dynamics progress throughout these stages remains unknown. Here, we used single-molecule fluorescence resonance energy transfer techniques to examine the conformational dynamics of the two-component transcription system of yeast mitochondria with single-base resolution. We show that, unlike its single-component homologue in bacteriophages, the yeast mitochondrial transcription initiation complex dynamically transitions between closed, open, and scrunched conformations throughout the initiation stage, and then makes a sharp irreversible transition to an unbent conformation by promoter release at position +8. Remarkably, stalling the initiation complex revealed unscrunching dynamics without dissociating the RNA transcript, manifesting the existence of backtracking transitions with possible regulatory roles. The dynamic landscape of transcription initiation revealed here suggests a kinetically driven regulation of mitochondrial transcription.
The drivers of West Nile virus human illness: fine scale dynamic effects of weather, mosquito infection, social, and biological conditions
Authors: Karki Surendra , Brown William M. , Uelmen John , Ruiz Marilyn O. , Smith Rebecca Lee
Published: December 2019

West Nile virus (WNV) has consistently been reported to be associated with human cases of illness in the region near Chicago, Illinois. However, the number of reported cases of human illness varies across years, with intermittent outbreaks. Several dynamic factors, including temperature, rainfall, and infection status of vector mosquito populations, are responsible for much of these observed variations. However, local landscape structure and human demographic characteristics also play a key role. The geographic and temporal scales used to analyze such complex data affect the observed associations. Here, we used spatial and statistical modeling approaches to investigate the factors that drive the outcome of WNV human illness on fine temporal and spatial scales. Our approach included multi-level modeling of long-term weekly data from 2005 to 2016, with weekly measures of mosquito infection, human illness and weather combined with more stable landscape and demographic factors on the geographical scale of 1000m hexagons. We found that hot weather conditions, warm winters, and higher MIR in earlier weeks increased the probability of an area of having a WNV human case. Higher population and the proportion of urban light intensity in an area also increased the probability of observing a WNV human case. A higher proportion of open water sources, percentage of grass land, deciduous forests, and housing built post 1990 decreased the probability of having a WNV case. Additionally, we found that cumulative positive mosquito pools up to 31 weeks can strongly predict the total annual human WNV cases in the Chicago region. This study helped us to improve our understanding of the fine-scale drivers of spatiotemporal variability of human WNV cases.
Modular prophage interactions driven by capsule serotype select for capsule loss under phage predation
Authors: Moura de Sousa Jorge A. , Buffet Amandine , Haudiquet Matthieu , Rocha Eduardo P.C. , Rendueles Olaya
Published: December 2019

Klebsiellaspecies are able to colonize a wide range of environments and include worrisome nosocomial pathogens. Here, we sought to determine the abundance and infectivity of prophages ofKlebsiellato understand how the interactions between induced prophages and bacteria affect population dynamics and evolution. We identified many prophages in the species, placing these taxa among the top 5% of the most polylysogenic bacteria. We selected 35 representative strains of theKlebsiella pneumoniaespecies complex to establish a network of induced phage-bacteria interactions. This revealed that many prophages are able to enter the lytic cycle, and subsequently kill or lysogenize closely-relatedKlebsiellastrains. Although 60% of the tested strains could produce phages that infect at least one other strain, the interaction network of all pairwise cross-infections is very sparse and mostly organized in modules corresponding to the strains’ capsule serotypes. Accordingly, capsule mutants remain uninfected showing that the capsule is a key factor for successful infections. Surprisingly, experiments in which bacteria are predated by their own prophages result in accelerated loss of the capsule. Our results show that phage infectiousness defines interaction modules between small subsets of phages and bacteria in function of capsule serotype. This limits the role of prophages as competitive weapons because they can infect very few strains of the species complex. This should also restrict phage-driven gene flow across the species. Finally, the accelerated loss of the capsule in bacteria being predated by their own phages, suggests that phages drive serotype switch in nature.
Reminders reinstate context-specificity to generalized remote memories in rats: relation to activity in the hippocampus and aCC
Authors: Sekeres Melanie J. , Moscovitch Morris , Grady Cheryl L. , Sullens D. Gregory , Winocur Gordon
Published: December 2019

Conditioned fear memories that are context-specific shortly after conditioning generalize over time. We exposed rats to a context reminder 30 d after conditioning, which served to reinstate context-specificity, and investigated how this reminder alters retrieval-induced activity in the hippocampus and anterior cingulate cortex (aCC) relative to a no reminder condition. c-Fos expression in dorsal CA1 was observed following retrieval in the original context, but not in a novel context, whether or not the memory was reactivated, suggesting that dCA1 retains the context-specific representation. c-Fos was highly expressed in aCC following remote memory testing in both contexts, regardless of reminder condition, indicating that aCC develops generalized representations that are insensitive to memory reactivation.
5,5′-(1-Phenylethane-1,1-diyl)bis(1H-pyrrole-2-carboxaldehyde)
Authors: Loke Shiva Krishna , Pagadala Eswar , Kottalanka Ravi K.
Published: December 2019

In the title compound, C18H16N2O2, the dihedral angle between the pyrrole rings is 79.47 (9)°, with the N—H groups approximately orthogonal (H—N...N—H pseudo torsion angle = −106°). In the crystal, N—H...O hydrogen bonds link the molecules into [11\overline{1}] chains. A C—H...O interaction is also observed.
Corrosion behavior of heat-treated and cryorolled Al 5052 alloys in different chloride ion concentrations
Authors: Abu Seman Anasyida , Chan Ji Kit , Norazman Muhammad Anas , Hussain Zuhailawati , Brij Dhindaw , Ismail Azzura
Published: December 2019

Purpose

This paper aims to investigate the corrosion behaviour of heat-treated and cryorolled Al 5052 alloys in different Cl−ion concentrations.

Design/methodology/approach

NaCl solutions with concentrations of 0, 0.5, 3.5 and 5.5 per cent were selected. Samples were subjected to pre-heat treatment (annealing at 300 °C and solution treatment at 540 °C) and cryorolling up to 30 per cent reduction before undergoing corrosion tests. The corrosion behaviour of the samples was then investigated by potentiodynamic polarization. The microstructure of the corroded samples was evaluated under an optical microscope, and the percentages of pits on their surfaces were calculated.

Findings

The cryorolled samples had a lower corrosion rate than the samples that were not cryorolled. The cryorolled sample that underwent solution treatment showed the highest corrosion resistance among all the samples tested.

Practical implications

The commercial impact of the study is the possibility of using the cryorolled Al alloy in various ion chloride environment.

Originality/value

The obtained results help in understanding the corrosion behaviour of cryorolled samples under different heat treatment conditions.
How manufacturer brand erosion shapes consumer assortment perceptions
Authors: Li Chunyu , He Yongfu , Peng Ling , Yuan Denghua
Published: December 2019

Purpose

Recently, the popularity of store brands has resulted in some manufacturer brands being removed from shelves. The current literature lacks empirical work on the effect of manufacturer brand erosion on consumer assortment perception and repatronage intention. Based on signalling theory, the purpose of this paper is to manufacturer brands play a signalling role and contend that manufacturer brand erosion has detrimental effects on the assortment perception due to reduced signalling efficacy.

Design/methodology/approach

A 3 (low manufacturer brand erosion vs high manufacturer brand erosion vs manufacturer brand dominance) ×2 (assortment size: small vs large) between-subject experiment was conducted.

Findings

Manufacturer brand erosion exerts a negative effect on assortment attractiveness and consumers’ repatronage intention; the greater the erosion, the larger the negative effect. These negative effects are mediated by reduced consumer perceptions of assortment quality and variety. A large (vs small) assortment size attenuates the negative effect of manufacturer brand erosion by improving perceived assortment quality.

Practical implications

To engage in strategic positioning through efficient assortment management, retailers should cooperate with brand manufacturers, instead of promoting their own private labels. Nevertheless, a large assortment dominated by store brands signals that the retailer has built a strong private brand, which in turn gains a differentiation advantage.

Originality/value

This paper is among the first to take the signalling perspective and explicitly investigate whether and how manufacturer brand erosion exerts a significant impact on assortment perception.
Food label design – exploring the literature
Authors: Latino Maria Elena , Menegoli Marta , Corallo Angelo
Published: December 2019

Purpose

The purpose of this paper is to identify the main research fields concerning food label designs and build a topic overview. To this end, the literature review method was chosen.

Design/methodology/approach

A sample of 121 papers was identified and analyzed using bibliometric analysis. Journals, articles, authors of the sample and the term co-occurrence map, which represents the recurring themes and organizes them in clusters, were defined. To recognize the main research fields, starting from analyzing the terms that compose each cluster, the results were discussed in a focus group composed of five experts.

Findings

Food labelling theories are distinctly related to eight research fields: consumer behaviour analysis, consumer willingness evaluation, consumer product evaluation, nutrition and health, daily foodstuff and meal effects, food industry and related products, impacts on market and society and child nutrition.

Research limitations/implications

Several stakeholders could be interested in the results of this paper. Food companies could identify the best practices in food labelling theories to improve their products and labels. Governments could understand how social policies are acknowledged by consumers and how to create new policies. Researchers could identify new issues to investigate. The results could also facilitate bibliographical referencing for those who approach this topic for the first time.

Originality/value

To the best of the authors’ knowledge, studies on food label theories explore the themes from the consumer’s perspective. The authors’ study, in contrast, focused on recognizing the research fields where food label designs are addressed.
Local government debt and regional economic growth in China
Authors: Chen Shiyi , Li Wang
Published: December 2019

Purpose

With China’s economic growth slowing down and the growth rate of fiscal revenue decreasing, the pressure on local government debts is further increasing. Under this background, it is of great significance to clarify the relation between local government debts and China’s economic growth in order to give full play to the positive role of local debts in stabling growth. The paper aims to discuss this issue.

Design/methodology/approach

Therefore, this paper explores the impact of Chinese local government debt on economic growth from theoretical and empirical aspects, respectively, and compares the regional differences between different debts and economic growth dynamics.

Findings

In the theoretical model part, this paper constructs a three-sector dynamic game model, under the two circumstances of whether local government is subject to debt constraints, and examines the relation between local government debt and economic growth and other variables through numerical simulation. Research shows that when the government is not constrained by debt, there is an inverted “U” relation between government debt and economic growth. When the government is constrained by debt, the economic growth rate gradually decreases as the government debt increases.

Originality/value

In the theoretical analysis part, this paper tries to estimate the amount of local debts under different calibers and examines the impact of different types of local government debts on China’s economic growth and their regional differences. The results show that excessive accumulation of government hidden debts in the eastern region is not conducive to economic growth, while explicit debts in the central and western regions significantly contribute to local economic growth. The results of empirical analysis are basically consistent with the predictions of the theoretical model.
An empirical study of personality traits, job market appraisal and self-perceived employability in an uncertain environment
Authors: Neneh Brownhilder Ngek
Published: December 2019

Purpose

The purpose of this paper is to examine whether personality traits play a significant role in understanding students’ self-perceived employability and test if the associations are influenced by the student’s job market appraisal. This is important as perceptions about one’s employability hold invaluable importance for students in uncertain job environments as they might need to form strategies to cope with unemployment until they find a job.

Design/methodology/approach

Data were collected from 296 using a questionnaire survey approach and analyzed using hierarchical regression to test the hypothesized associations.

Findings

The findings showed that agreeableness, conscientiousness and openness to experience are positive and significantly associated with self-perceived employability. Also, job market appraisal played a momentous role in predicting self-perceived employability both directly and via interaction with conscientiousness and openness to experience.

Practical implications

The present study is valuable to different stakeholders such as educators, employers and students as it identifies the personality dispositions that should be encouraged among students while also indicating the need for fostering student’s reappraisal of uncertain job markets.

Originality/value

This study presents new evidence on the application of the appraisal theory by indicating the interaction between personality traits and cognitive appraisal. This advances the current theoretical understanding of the mechanism through which personality traits can best explain individual differences in self-perceived employability.