bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiles based flux balance model to predict the carbon source for Bacillus subtilis
Authors: Thanamit Kulwadee , Hoerhold Franziska , Oswald Marcus , Koenig Rainer 
Published: November 2019

ABSTRACTFinding drug targets for antimicrobial treatment is a central focus in biomedical research. To discover new drug targets, we developed a method to identify which nutrients are essential for microorganisms. Using 13C labeled metabolites to infer metabolic fluxes is the most informative way to infer metabolic fluxes to date. However, the data can get difficult to acquire in complicated environments, for example, if the pathogen homes in host cells. Although data from gene expression profiling is less informative compared to metabolic tracer derived data, its generation is less laborious, and may still provide the relevant information. Besides this, metabolic fluxes have been successfully predicted by flux balance analysis (FBA). We developed an FBA based approach using the stoichiometric knowledge of the metabolic reactions of a cell combining them with expression profiles of the coding genes. We aimed to identify essential drug targets for specific nutritional uptakes of microorganisms. As a case study, we predicted each single carbon source out of a pool of eight different carbon sources for B. subtilis based on gene expression profiles. The models were in good agreement to models basing on 13C metabolic flux data of the same conditions. We could well predict every carbon source. Later, we applied successfully the model to unseen data from a study in which the carbon source was shifted from glucose to malate and vice versa. Technically, we present a new and fast method to reduce thermodynamically infeasible loops, which is a necessary preprocessing step for such model-building algorithms.SIGNIFICANCEIdentifying metabolic fluxes using 13C labeled tracers is the most informative way to gain insight into metabolic fluxes. However, obtaining the data can be laborious and challenging in a complex environment. Though transcriptional data is an indirect mean to estimate the fluxes, it can help to identify this. Here, we developed a new method employing constraint-based modeling to predict metabolic fluxes embedding gene expression profiles in a linear regression model. As a case study, we used the data from Bacillus subtilis grown under different carbon sources. We could well predict the correct carbon source. Additionally, we established a novel and fast method to remove thermodynamically infeasible loops.
Global reprogramming of virulence and antibiotic resistance inPseudomonas aeruginosaby a single nucleotide polymorphism in the elongation factor-encoding gene,fusA1
Authors: Maunders Eve A. , Triniman Rory C. , Rahman Taufiq , Welch Martin 
Published: November 2019

AbstractPseudomonas aeruginosais a common opportunistic pathogen. The organism displays elevated intrinsic antibiotic resistance and can cause life-threatening infections. The gene encoding an elongation factor, FusA1, is frequently mutated in clinical isolates ofP. aeruginosafrom patients with cystic fibrosis (CF). Recent work has shown thatfusA1mutants often display elevated aminoglycoside resistance due to increased expression of the aminoglycoside efflux pump, MexXY. In the current work, we isolated a spontaneous gentamicin-resistantfusA1mutant (FusA1P443L) in whichmexXYexpression was increased. Through a combination of proteomic and transcriptomic analyses, we found that thefusA1mutant also exhibited large-scale but discrete changes in the expression of key pathogenicity-associated genes. Most notably, thefusA1mutant displayed greatly increased expression of the Type III Secretion system (T3SS), widely considered to be the most potent virulence factor in theP. aeruginosaarsenal, and also elevated expression of the Type VI Secretion (T6S) machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6S system expression. ThefusA1mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosomal protein synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with thefusA1mutation) were restored to levels comparable to that in the PAO1-derived progenitor strain by expression of the wild-typefusA1genein trans, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance throughmexXYexpression (although we also identify additional contributory resistance mechanisms), mutations infusA1can lead to highly-selective dysregulation of virulence gene expression.
Spatially heterogeneous dynamics of cells in a growing tumor spheroid: Comparison between Theory and Experiments
Authors: Sinha Sumit , Kakkada Abdul N-Malmi , Li Xin , Samanta Himadri , Thirumalai D. 
Published: November 2019

AbstractCollective cell movement, characterized by multiple cells that are in contact for substantial periods of time and undergo correlated motion, plays a central role in cancer and embryogenesis. Recent imaging experiments have provided time-dependent traces of individual cells, thus providing an unprecedented picture of tumor spheroid growth. By using simulations of a minimal cell model, we analyze the experimental data that map the movement of cells in fibrosarcoma tumor spheroid embedded in a collagen matrix. Both simulations and experiments show that cells in the core of the spheroid exhibit subdiffusive glassy dynamics (mean square displacement, Δ(t) ≈tαwithα< 1), whereas cells in the periphery exhibit superdiffusive motion, Δ(t) ≈tαwithα> 1). The motion of most of the cells near the periphery undergo highly persistent and correlated directional motion, thus explaining the observed superdiffusive behavior. Theαvalues for cells in the core and periphery, extracted from simulations and experiments are in near quantitative agreement with each other, which is surprising given that no parameter in the model was used to fit the measurements. The qualitatively different dynamics of cells in the core and periphery is captured by the fourth order susceptibility, introduced to characterize metastable states in glass forming systems. Analyses of the velocity autocorrelation of individual cells show remarkable spatial heterogeneity with no two cells exhibiting similar behavior. The prediction thatαshould depend on the location of the cells in the tumor is amenable to experimental test. The highly heterogeneous dynamics of cells in the tumor spheroid provides a plausible mechanism for the origin of intratumor heterogeneity.
Neural correlates of goal-directed and non-goal-directed movements
Authors: Sendhilnathan Naveen , Basu Debaleena , Goldberg Michael E. , Schall Jeffrey D. , Murthy Aditya 
Published: November 2019

AbstractWhat are the neural correlates that distinguish goal-directed (G) from non-goal-directed movements (nG)? We investigated this question in the monkey frontal eye field, which is implicated in voluntary control of saccades. We found that only for G-saccades, the variability in spike rate across trials decreased, the regularity of spike timings within trials increased, the neural activity increased earlier from baseline and had a concurrent reduction of LFP beta band power.
Elevated CO2effects on morphology and survival rate in intertidal benthic foraminifera
Authors: Kannan Gunasekaran , Ayyappan Saravanakumar , Perumal Karthikeyan 
Published: November 2019

AbstractOceans are absorbing about one-third of the anthropogenic CO2from the atmosphere, and the excess CO2leads to reduce the seawater pH, carbonate ion concentrations and saturation states of biologically important calcium carbonate minerals. The ocean acidification affects many calcifying organisms such as foraminifera. The present study assessed experimentally modified ocean pH impacts on survival rate and shell morphology variation in three species of intertidal benthic foraminifera. Foraminifera was collected from Parangipettai coastal waters, Tamilnadu, India. Foraminiferal specimens were cultured for a period of five weeks at three different pH treatments that replicated future scenarios of a high CO2and low pH. The experimental results revealed that reduction of seawater pH significantly affected foraminiferal survival and morphology. Scanning Electron Microscopic observations revealed significant changes in foraminiferal morphology with clear evidence of dissolution and cracking processes on the test surface, and reduction in teeth structure in treatments with decreasing pH. Hence, altering the seawater chemistry might have extensive impacts on benthic foraminifera.
Phenotypic heterogeneity in particle size is a viral mechanism of persistence
Authors: Li Tian , Li Zhenyu , Deans Erin E. , Mittler Eva , Liu Meisui , Chandran Kartik , Ivanovic Tijana 
Published: November 2019

SUMMARYAssembly of many enveloped animal viruses yields a mixture of particle morphologies, from small, essentially isometric forms to vastly longer, filamentous forms. Selective advantage of pleomorphic virus structure is apparent onlyin vivo, hindering functional characterization of distinct particle shapes. Here we sought to mimic thein vivopressures on virus entry in cultured cells and in single-particle experiments of membrane fusion for influenza virus preparations enriched in spherical or filamentous particles. We show that filamentous shape confers functional advantage in the presence of neutralizing antibodies or fusion inhibitors and in cases of only limited fusion-protein activation. For very long particles, inactivation of >95% of associated fusion proteins still permits enough active-protein cooperation to induce membrane merger. Experiments with Ebola virus-like particles show that resistance to antibody pressure is a conserved feature of filamentous particles. Our results offer a strategy for averting drug resistance or immune evasion by targeting filamentous virus particles.
IRIS: Big data-informed discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing
Authors: Pan Yang , Lee Alexander H. , Yang Harry T. , Wang Yuanyuan , Xu Yang , Kadash-Edmondson Kathryn E. , Phillips John , Champhekar Ameya , Puig Cristina , Ribas Antoni , Witte Owen N. , Prins Robert M. , Xing Yi 
Published: November 2019

AbstractAberrant alternative splicing (AS) is widespread in cancer, leading to an extensive but largely unexploited repertoire of potential immunotherapy targets. Here we describe IRIS, a computational platform leveraging large-scale cancer and normal transcriptomics data to discover AS-derived tumor antigens for T-cell receptor (TCR) and chimeric antigen receptor T-cell (CAR-T) therapies. Applying IRIS to RNA-Seq data from 22 glioblastomas resected from patients, we identified candidate epitopes and validated their recognition by patient T cells, demonstrating IRIS’s utility for expanding targeted cancer immunotherapy.
A unique predator in a unique ecosystem: modelling the apex predator from the late cretaceous crocodyliform-dominated fauna in brazil
Authors: Montefeltro Felipe C. , Lautenschlager Stephan , Godoy Pedro L. , Ferreira Gabriel S. , Butler Richard J. 
Published: November 2019

ABSTRACTTheropod dinosaurs were relatively scarce in the Late Cretaceous ecosystems of southeast Brazil. Instead, hypercarnivorous crocodyliforms known as baurusuchids were abundant and probably occupied the ecological role of apex predators. Baurusuchids exhibited a series of morphological adaptations hypothesised to be associated with this ecological role, but quantitative biomechanical analyses of their morphology have so far been lacking. Here, we employ a biomechanical modelling approach, applying finite element analysis (FEA) to models of the skull and mandibles of a baurusuchid specimen. This allowed us to characterise the craniomandibular apparatus of baurusuchids, as well as to compare the functional morphology of the group to that of other archosaurian carnivores, such as theropods and crocodylians. Our results support the ecological role of baurusuchids as specialised apex predators in the continental Late Cretaceous ecosystems of South America. With a relatively weak bite force (∼600 N), baurusuchids’ predation strategies likely relied on other morphological specializations, such as ziphodont dentition and strong cervical musculature. Comparative assessments of the stress distribution and magnitude of scaled models of other predators (the theropod Allosaurus fragilis and the living crocodylian Alligator mississippiensis) consistently show different responses to loadings under the same functional scenarios, suggesting distinct predatory behaviours for these animals. The unique selective pressures in the arid to semi-arid Late Cretaceous ecosystems of southeast Brazil, which were dominated by crocodyliforms, possibly drove the emergence and evolution of the biomechanical features seen in baurusuchids, which are distinct from those previously reported for other predatory taxa.
Recently formed context fear memories can be retrieved without the hippocampus
Authors: Krueger Jamie N. , Wilmot Jacob H. , Teratani-Ota Yusuke , Puhger Kyle R. , Nemes Sonya E. , Lafreniere Marrisa , Wiltgen Brian J. 
Published: November 2019

AbstractThe current study determined if inactivation of the dorsal hippocampus impairs the retrieval of newly formed context fear memories. This region was silencing by activating inhibitory neurons or by hyperpolarizing pyramidal cells directly. When inhibitory neurons were stimulated with ChR2, memory retrieval was significantly impaired. In contrast, when the same neurons were activated with the excitatory DREADD hM3Dq, retrieval was not affected. This dissociation was not due to differences in inhibition, as both manipulations activated interneurons and reduced excitation throughout the dorsal hippocampus. Therefore, we hypothesize that the retrieval deficit caused by ChR2 stimulation is due to an immediate reduction in hippocampal activity that does not provide enough time for other brain regions to compensate. Stimulation of DREADDs, on the other hand, produces a gradual loss of excitation that takes several minutes to reach asymptote. This appears to be a sufficient amount of time for extra-hippocampal structures to become engaged and express context fear. Implications for theories of hippocampal function, systems consolidation and memory retrieval are discussed.
Atypical Protein Kinase C iota (PKCλ/ι) Ensures Mammalian Development by Establishing the Maternal-Fetal Exchange Interface
Authors: Bhattacharya Bhaswati , Home Pratik , Ganguly Avishek , Ray Soma , Ghosh Ananya , Islam Rashedul , French Valerie , Marsh Courtney , Gunewardena Sumedha , Okae Hiroaki , Arima Takahiro , Paul Soumen 
Published: November 2019

AbstractIn utero mammalian development relies on the establishment of the maternal–fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mouse, SynTs develop via differentiation of the trophoblast progenitor cells (TSPCs) of the placenta primordium and in human, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that Atypical Protein Kinase C iota (PKCλ/I) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKCλ/I in the mouse TSPCs abrogates SynT development leading to embryonic death at ~E9.0. We also show that PKCλ/I-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKCλ/I is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKCλ/I in CTB-derived human trophoblast stem cells (Human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKCλ/I signaling maintains expression of GCM1, GATA2, and PPARγ, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKCλ/I signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor to SynT transition during placentation.
Loss of IKK subunits limits NF-κB signaling in reovirus infected cells
Authors: McNamara Andrew J. , Danthi Pranav 
Published: November 2019

ABSTRACTViruses commonly antagonize innate immune pathways that are primarily driven by Nuclear Factor-κB (NF-κB), Interferon Regulatory Factor (IRF) and Signal Transducer and Activator of Transcription (STAT) family of transcription factors. Such a strategy allows viruses to evade immune surveillance and maximize their replication. Using an unbiased RNA-seq based approach to measure gene expression induced by transfected viral genomic RNA (vgRNA) and reovirus infection, we discovered that mammalian reovirus inhibits host cell innate immune signaling. We found that while vgRNA and reovirus infection both induce a similar IRF dependent gene expression program, gene expression driven by the NF-κB family of transcription factors is lower in infected cells. Potent agonists of NF-κB, such as Tumor Necrosis Factor alpha (TNFα) and vgRNA, failed to induce NF-κB dependent gene expression in infected cells. We demonstrate that NF-κB signaling is blocked due to loss of critical members of the Inhibitor of KappaB Kinase (IKK) complex, NF-κB Essential MOdifier (NEMO) and IKKβ. The loss of the IKK complex components prevents nuclear translocation and phosphorylation of NF-κB, thereby preventing gene expression. Our studies demonstrate that reovirus infection selectively blocks NF-κB, likely to counteract its antiviral effects and promote efficient viral replication.IMPORTANCEHost cells mount a response to curb virus replication in infected cells and prevent infection of neighboring, as yet uninfected cells. The NF-κB family of proteins is important for the cell to mediate this response. In this study, we show that in cells infected with mammalian reovirus, NF-κB is inactive. Further, we demonstrate that NF-κB is rendered inactive because virus infection results in reduced levels of upstream intermediaries (called IKKs) that are needed for NF-κB function. Based on previous evidence that active NF-κB limits reovirus infection, we conclude that inactivating NF-κB is a viral strategy to produce a cellular environment that is favorable for virus replication.
STRESS-INDUCED GENETIC CHANGE IN FLAX REVEALS GENOME VARIATION MECHANISM
Authors: Li Xiang 
Published: November 2019

AbstractInherited genetic change can happen in flax (Linum usitatissimum) due to environmental stress. The change can result in different phenotypes in flax progeny. The genetic changes can be induced during one generation and can result in stable genotypes in the next generation. Also the genetic changes are precise and repeatable that homozygous individuals show the same genome reorganization at specific sites in their progeny. Therefore, the genetic re-arrangements are not the result of a random process but a preference for a particular DNA structure, which indicates that possible new genes or functional fragments are formed during this process. The genomes of different varieties of flax are compared to explain the detail of the rapid but intentional genomic changes and regions of variation identified by whole genome comparisons. Possible mechanisms and the potential causes of these rearrangements bring a new light to modern plant genome studies and molecular evolution research.
Regionalization in the compound eye ofTalitrus saltator(Crustacea, Amphipoda)
Authors: Ciofini Alice , Mercatelli Luca , Yamahama Yumi , Hariyama Takahiko , Ugolini Alberto 
Published: November 2019

AbstractThe crustaceanTalitrus saltatoris known to use many celestial cues during its orientation along the sea-land axis of sandy shores. In this paper, we investigated the existence of the eye regionalization by morphological, electrophysiological and behavioural experiments. Each ommatidium possesses five radially arranged retinular cells producing a square fused rhabdom by R1-R4 cells; the smaller R5 exist between R1 and R4. The size of R5 rhabdomere is largest in dorsal part and becomes gradually smaller in median and ventral part of the eye. Spectral-sensitivity measurements were recorded from either dorsal or ventral parts of the compound eye to clarify the chromatic difference. Results show that the dorsal part is green and UV-blue dichromatic, whereas the ventral part is UV (390 nm) with a substantial population of 450 nm receptors with the responses in the longer wavelength region. To evaluate the orienting behaviour of individuals, their eyes were black painted either in the dorsal or ventral part, under natural sky or a blue filter with or without the vision of the sun. Results show that animals painted on the dorsal part of their eyes tested under the screened sun were more dispersed and in certain cases their directions deflected than other groups of individuals. Furthermore, sandhoppers subjected to the obscuring of this area met in any case high difficulties in their directional choices. Therefore, our present work indicates the existence of a regionalization of the compound eye ofT. saltator.Summary statementThis work provides evidences of the morphological and electrophysiological regionalization of the compound eye and the visual capabilities for behaviour involved in the recognition of the celestial compass orienting factors in crustaceans.