bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral host-range evolvability changes in response to fluctuating selection
Authors: Mouchka Morgan E. , Dorsey Dillon M. , Malcangio Genna L. , Medina Sarah J. , Stuart Elizabeth C. , Meyer Justin R. 
Published: September 2019

AbstractThe concept of evolvability (the capacity of populations to evolve) has deep historical roots in evolutionary biology. Interest in the subject has been renewed recently by innovations in microbiology that permit direct tests of the causes of evolvability, and with the acknowledgement that evolvability of pathogens has important implications for human health. Here, we investigate how fluctuating selection on the virus, Bacteriophage λ, affects its evolvability. We imposed dynamic selection by altering the expression of two host outer membrane receptors. This, in turn, selected phage to alternately infect the host via a single, or multiple, receptors. Our selection regime resulted in two orthogonal evolutionary behaviors, namely enhanced or reduced evolvability. Strains with enhanced evolvability readily evolved between receptors, losing and gaining the ability to bind multiple receptors more quickly than the ancestral λ. This suggests the receptor-binding protein retained a genetic memory of past states and that evolutionary history can be used to predict future adaptation. Strains with reduced evolvability were refractory to re-specialization and remained generalists on both receptors. Consistent with this behavior, unevolvable strains had reduced rates of molecular evolution in the receptor-binding protein compared to their evolvable counterparts. We found a single mutation in the receptor-binding protein was sufficient to render these strains resistant to evolution and did so by counteracting a receptor-binding trade-off associated with generalism. In this way, cost-free generalization allowed for reduced evolution and evolvability while maximizing success in both environments. Our results suggest the response to fluctuating selection is contingent and can lead to distinct differences in evolvability. These findings contribute to a growing understanding of the causes and consequences of evolvability and have important implications for infectious disease management.
Allele specific expression and gene regulation explain transgressive thermal tolerance in non-native hybrids of the endangered California tiger salamander (Ambystoma californiense)
Authors: Cooper Robert D. , Shaffer H. Bradley 
Published: September 2019

AbstractHybridization between native and non-native species is an ongoing global conservation threat. Hybrids that exhibit traits and tolerances that surpass parental values are of particular concern, given their ability to outcompete the native parent. It is crucial to understand the mechanisms that drive these transgressive hybrid traits to diagnose and develop strategies to manage hybrid populations. Here, we explore several aspects of the hybridization between the endangered California tiger salamander (Ambystoma californiense; CTS) and the introduced barred tiger salamander (Ambystoma mavortium; BTS). We assayed critical thermal maximum (CTMax) to compare the ability of CTS, BTS and hybrids to tolerate acute thermal stress, and found that hybrids exhibit a wide range of CTMax values, with 40% (6/15) able to tolerate temperatures greater than either parent. We quantified the genomic response of each individual to discover and compare thermal abatement strategies. We found that CTS and BTS have strikingly different numbers and tissue-specific patterns of overall gene expression, with hybrids expressing intermediate values. We evaluated transgressive and variable phenotypes by uncovering regulatory mechanisms that give rise to these unique traits. F1 hybrids display abundant and variable degrees of allele specific expression (ASE), likely arising from extensive compensatory evolution in gene regulatory mechanisms of the parental lineages. We found that the proportion of genes with allelic imbalance in individual hybrids correlates with their CTMax, suggesting that BTS-biased expression confers improved thermal tolerance. We discuss the implications of these findings with respect to ongoing management of CTS in the face of future climate change.
Multi-trait random regression models increase genomic prediction accuracy for a temporal physiological trait derived from high-throughput phenotyping
Authors: Baba Toshimi , Momen Mehdi , Campbell Malachy T. , Walia Harkamal , Morota Gota 
Published: September 2019

AbstractRandom regression models (RRM) are used extensively for genomic inference and prediction of time-valued traits in animal breeding, but only recently have been used in plant systems. High-throughput phenotyping (HTP) platforms provide a powerful means to collect high-dimensional phenotypes throughout the growing season for large populations. However, to date, selection of an appropriate statistical genomic framework to integrate multiple temporal traits for genomic prediction in plants remains unexplored. Here, we demonstrate the utility of a multi-trait RRM (MT-RRM) for genomic prediction of daily water usage (WU) in rice (Oryza sativa) through joint modeling with shoot biomass (projected shoot area, PSA). Three hundred and fifty-seven accessions were phenotyped daily for WU and PSA over 20 days using a greenhouse-based HTP platform. MT-RRMs that modeled additive genetic and permanent environmental effects for both traits using quadratic Legendre polynomials were used to assess genomic correlations between traits and genomic prediction for WU. Predictive abilities of the MT-RRMs were assessed using two cross-validation (CV) scenarios. The first scenario was designed to predict genetic values for WU at all time points for a set of accessions with unobserved WU. The second scenario was designed to forecast future genetic values for WU for a panel of known accessions with records for WU at earlier time periods. In each scenario we evaluated two MT-RRMs in which PSA records were absent or available for time points in the testing population. Moderate to strong genomic correlations between WU and PSA were observed across the days of imaging (0.29-0.87). In both CV scenarios, MT-RRMs showed better predictive abilities compared to single-trait RRM, and prediction accuracies were greatly improved when PSA records were available for the testing population. In summary, these frameworks provide an effective approach to predict temporal physiological traits that are difficult or expensive to quantify in large populations.
The transcriptional co-repressor CtBP is a negative regulator of growth that antagonizes the Yorkie and JNK/AP-1 pathways
Authors: Sumabat Taryn M. , Worley Melanie I. , Pellock Brett J. , Bosch Justin A. , Hariharan Iswar K. 
Published: September 2019

AbstractMulticellular organisms require strict growth control mechanisms to ensure that an organ reaches, but does not grossly exceed, its appropriate size and shape. In an unbiased mosaic screen for genes involved in growth regulation, we identified a loss-of-function allele of the geneCtBPthat conferred a growth advantage to homozygous mutant tissue.CtBPencodes a transcriptional co-repressor found in diverse organisms, yet its role in regulating tissue growth is not known. We found thatCtBPfunctions as a negative regulator of growth by restricting the expression of the growth-promoting microRNAbantam(ban).banis a known target of the Hippo pathway effector Yorkie (Yki). We show that loss ofCtBPfunction leads to the activation of a minimal enhancer ofbanvia both Yki-dependent and AP-1 transcription factor-dependent mechanisms. AP-1 is downstream of the Jun N-terminal Kinase (JNK) pathway and thus JNK could regulate growth during development viaban. Furthermore, we show that distinct isoforms of the AP-1 component Fos differ in their ability to activate this enhancer. Since the orthologous pathways in mammalian cells (YAP/TEAD and AP-1) converge on enhancers implicated in tumor progression, a role for mammalian CtBP proteins at those enhancers merits attention.
Incorporating uncertainty is essential to macroecological inferences: Grass, grit, and the evolution of kangaroos
Authors: Brennan Ian G. 
Published: September 2019

AbstractStudying organismal ecology and evolution on deep timescales provides us opportunities to identify the processes driving patterns in diversity and forms. Macroecological and macroevolutionary studies of trait evolution however, often fail to account for sources of artifactual variation in the data—be it phylogenetic, temporal, or other. In some instances, this may not affect our evolutionary understanding, and accounting for sources of uncertainty may only subdue confidence in our inferences. In more dramatic cases, narrow views of trait uncertainty may result in conclusions that are misleading. Because macroevolutionary analyses are built atop a number of preconceived hypotheses regarding the relationships between taxa, origination and divergence times, intraspecific variation, and environmental variables, it is important to incorporate and present this uncertainty. Here I use a dataset for Australian kangaroos to demonstrate the importance of incorporating uncertainty when testing patterns of diversification. After accounting for fossil age uncertainty, I provide evidence that a proposed Pliocene origin ofMacropuskangaroos is at odds with combined evidence molecular and morphological dating methods. Depending on the estimated crown age of kangaroos, the evolution of hypsodonty is as likely caused by the continental expansion of C4grasses as it is by increasing windborne dust levels or paleotemperature fluctuations. These results suggest that previous interpretations of the radiation of modern kangaroos are not as bulletproof as we believe, and that multiple factors have likely influenced their remarkable diversification across the Australian continent. More broadly, this demonstrates the importance of incorporating uncertainty in comparative ecological and evolutionary studies, and the value in testing the assumptions inherent in our data and the methods we employ.
Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine
Authors: Velayutham Nivedhitha , Alfieri Christina M. , Agnew Emma J. , Riggs Kyle W. , Baker R. Scott , Zafar Farhan , Yutzey Katherine E. 
Published: September 2019

AbstractAimsCardiomyocyte (CM) cell cycle arrest, decline of mononucleated-diploid CMs, sarcomeric maturation, and extracellular matrix remodeling are implicated in loss of cardiac regenerative potential in mice after birth. Recent studies show a 3-day neonatal regenerative capacity in pig hearts similar to mice, but postnatal pig CM growth dynamics are unknown. We examined cardiac maturation in postnatal pigs and mice, to determine the relative timing of developmental events underlying heart growth and regenerative potential in large and small mammals.Methods and ResultsLeft ventricular tissue from White Yorkshire-Landrace pigs at postnatal day (P)0 to 6 months (6mo) was analyzed to span birth, weaning, and adolescence in pigs, compared to similar physiological timepoints in mice. Collagen remodeling increases by P7 in postnatal pigs, but sarcomeric and gap junctional maturation only occur at 2mo. Also, there is no postnatal transition to beta-oxidation metabolism in pig hearts. Mononucleated CMs, predominant at birth, persist to 2mo in swine, with over 50% incidence of mononucleated-diploid CMs at P7-P15. Extensive multinucleation with 4-16 nuclei per CM occurs beyond P30. Pigs also exhibit increased CM length relative to multinucleation, preceding increase in CM width at 2mo-6mo. Further, robust CM mitotic nuclear pHH3 activity and cardiac cell cycle gene expression is apparent in pig left ventricles up to 2mo. By contrast, in mice, these maturational events occur concurrently in the first two postnatal weeks alongside loss of cardiac regenerative capacity.ConclusionsCardiac maturation occurs over a 6mo postnatal period in pigs, despite a similar early-neonatal heart regenerative window as mice. Postnatal pig CM growth includes increase in CM length alongside multinucleation, with CM cell cycle arrest and loss of mononucleated-diploid CMs occurring at 2mo-6mo. These CM characteristics are important to consider for pig preclinical studies and may offer opportunities to study aspects of heart regeneration unavailable in other models.
Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition
Authors: von Kleeck Ryan , Brankovic Sonja A. , Roberts Ian , Hawthorne Elizabeth A. , Bruun Kyle , Castagnino Paola , Assoian Richard K. 
Published: September 2019

SUMMARYArterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the key molecular regulators initiating arterial stiffening in HGPS remain unknown. To identify these early events, we compared arterial mechanics and ECM remodeling in very young HGPS (LMNAG609G/G609G) mice to those of age-matched and much older wild-type (WT) mice. Biaxial inflation-extension tests of carotid arteries of 2-month mice showed that circumferential stiffness of HGPS arteries was comparable to that of 24-month WT controls whereas axial arterial stiffening, an additional hallmark of normal aging, was mostly spared in HGPS. In an effort to identify underlying mechanisms, we examined expression levels of the major stiffness-regulatory molecules in WT and HGPS arteries. Transmission electron microscopy revealed slightly increased amounts of collagen within the elastin folds of HGPS carotid arteries, but this change was barely detectable by immunostaining carotid cross sections or qPCR of isolated aortas for collagens I, III, or V. Elastin integrity was also similar in the WT and HGPS arteries. In contrast, immunostaining readily revealed an increased expression of Lysyl oxidase (LOX) protein in young HGPS carotid arteries relative to aged-matched WT controls. Further analysis showed that HGPS arteries express increased amounts of LOX mRNA, and this effect extends to each of the arterial LOX family members. Remarkably, treatment of HGPS mice with the pan-LOX inhibitor β-aminopropionitrile (BAPN) restored near-normal circumferential arterial mechanics to HGPS carotid arteries, mechanistically and causally linking LOX upregulation to premature arterial stiffening in HGPS. Finally, we show that this premature increase in arterial LOX expression in HGPS foreshadows the increased expression of LOX that accompanies circumferential arterial stiffening during normal aging.
ipaA triggers vinculin oligomerization to strengthen cell adhesion during Shigella invasion
Authors: Valencia-Gallardo Cesar , Aguilar-Salvador Daniel-Isui , Khakzad Hamed , Bou-Nader Charles , Malosse Christian , Lima Diogo Borges , Bello Chakir , Cocom-Chan Benjamin , Quenech’Du Nicole , Mazhar Bilal , Javelaud Delphine , Fattaccioli Jacques , Mauviel Alain , Fontecave Marc , Asnacios Atef , Chamot-Rooke Julia , Malmström Lars , Van Nhieu Guy Tran 
Published: September 2019

AbstractThe Shigella effector IpaA co-opts the focal adhesion protein vinculin to promote bacterial invasion. Here, we show that IpaA triggers an unreported mode of vinculin activation through the cooperative binding of its three vinculin-binding sites (VBSs) leading to vinculin oligomerization via its D1 and D2 head subdomains and highly stable adhesions resisting actin relaxing drugs. Using cross-linking mass spectrometry, we found that while IpaA VBSs1-2 bound to D1, IpaA VBS3 interacted with D2, a subdomain masked to other known VBSs. Structural modeling indicated that as opposed to canonical activation linked to interaction with D1, these combined VBSs interactions triggered major allosteric changes leading to D1D2 oligomerization. A cysteine-clamp preventing these changes and D1D2 oligomerization impaired growth of vinculin microclusters and cell adhesion. We propose that D1D2-mediated vinculin oligomerization occurs during the maturation of adhesion structures to enable the scaffolding of high-order vinculin complexes, and is triggered by Shigella IpaA to promote bacterial invasion in the absence of mechanotransduction.SummaryThe Shigella IpaA effector binds to cryptic vinculin sites leading to oligomerization via its head domain. This vinculin oligomerization mode appears required for the maturation and strengthening of cell adhesion but is co-opted by invasive bacteria independent of actomyosin contractility.
Phylogenetic modeling of regulatory element turnover based on epigenomic data
Authors: Dukler Noah , Huang Yi-Fei , Siepel Adam 
Published: September 2019

AbstractEvolutionary changes in gene expression are often driven by gains and losses of cis-regulatory elements (CREs). The dynamics of CRE evolution can be examined using multi-species epigenomic data, but so far such analyses have generally been descriptive and model-free. Here, we introduce a probabilistic modeling framework for the evolution of CREs that operates directly on raw chromatin immunoprecipitation and sequencing (ChIP-seq) data and fully considers the phylogenetic relationships among species. Our framework includes a phylogenetic hidden Markov model, called epiPhyloHMM, for identifying the locations of multiply aligned CREs, and a combined phylogenetic and generalized linear model, called phyloGLM, for accounting for the influence of a rich set of genomic features in describing their evolutionary dynamics. We apply these methods to previously published ChIP-seq data for the H3K4me3 and H3K27ac histone modifications in liver tissue from nine mammals. We find that enhancers are gained and lost during mammalian evolution at about twice the rate of promoters, and that turnover rates are negatively correlated with DNA sequence conservation, expression level, and tissue breadth, and positively correlated with distance from the transcription start site, consistent with previous findings. In addition, we find that the predicted dosage sensitivity of target genes positively correlates with DNA sequence constraint in CREs but not with turnover rates, perhaps owing to differences in the effect sizes of the relevant mutations. Altogether, our probabilistic modeling framework enables a variety of powerful new analyses.
Active modulation of Hydrogen bonding by sericin enhances cryopreservation outcomes
Authors: Underwood L. , Solocinski J. , Rosiek E. , Osgood Q. , Chakraborty N. 
Published: September 2019

AbstractCryopreservation of cells without any toxicity concerns is a critical step in ensuring successful clinical translation of cell-based technologies. Mitigating the toxicity concerns related to most of the commonly used cryoprotectants including dimethyl sulfoxide (DMSO) is an active area of research in cryobiology. In recent years use of additives including polymeric proteins such has sericin have been explored as an additive to cryoprotectant formulations. In this study the thermophysical effect of addition of sericin was investigated. The effect of presence of sericin on the H-bonding strength was investigated using Raman microspectroscopy and other thermophysical effects were quantified using differential scanning calorimetry (DSC) techniques. Finally, the prospect of using sericin as an additive to cryoprotectant formulation was investigated by monitoring cellular viability and growth following exposure to cryogenic temperatures in hepatocellular carcinoma cells. Results indicate significant improvement in post-thaw viability when sericin is used as an additive to DMSO based formulations. While use of trehalose as an additive has beneficial effects by itself, combined usage of sericin and trehalose as additives did result in an improved overall long-term growth potential of the cells.Statement of SignificanceThis study provides for powerful biophysical understanding of how sericin can be used as an additive for cryoprotectant solutions, which allows storage of biologics at low temperatures. It is desirable to replace current components of cryoprotectant formulation (such as DMSO) due to innate toxicity and metabolic derangements to cells. The ability of sericin to improve cryoprotective solutions was mechanistically characterized by Raman microspectroscopy, which allows for molecular level characterization of the nature of H-bonding in aqueous environments in presence of solution components. Thermodynamic analysis of the cryoprotectant solutions containing sericin was undertaken to quantify the relation between solution composition and cryopreservation outcome. This analytical study provides a basis for designing better cryoprotectants with lower thermophysical injury and higher cellular yields.
Neuroprotective effects of exogenous erythropoietin in Wistar rats by downregulating apoptotic factors to attenuate N-methyl-D-aspartate-mediated retinal ganglion cells death
Authors: Cheng Wen-Sheng , Lin I-Hung , Feng Kathy Ming , Chang Zhi-Yang , Huang Yu Chuan , Lu Da-Wen 
Published: September 2019

AbstractThe aim of this study was to investigate whether exogenous erythropoietin (EPO) administration attenuates N-methyl-D-aspartate (NMDA)-mediated excitotoxic retinal damage in Wistar rats. The survival rate of retinal ganglion cells (RGCs) were investigated by flat mount analysis and flow cytometry. A group of male Wistar rats were randomly assigned to five groups: negative control, NMDA80 (i.e., 80 nmoles NDMA intravitreally injected), NMDA80 + 10ng EPO, NMDA80 + 50ng EPO, and NMDA80 + 250ng EPO. The NMDA80 + 50ng EPO treatment group was used to evaluate various administrated points (pre-/co-/post-administration of NMDA80). Meanwhile, the transferase dUTP Nick-End Labeling (TUNEL) assay of RGCs, the inner plexiform layer (IPL) thickness and the apoptotic signal transduction pathways of μ-calpain, Bax, and caspase 9 were assessed simultaneously using an immunohistochemical method (IHC). When EPO was co-administered with NMDA, attenuated cell death occurred through the downregulation of the apoptotic indicators: μ-calpain was activated first (peak at ∼18hrs), followed by Bax and caspase 9 (peak at ∼40hrs). Furthermore, the morphology of RGCs has clearly demonstrated the visual recovery of IPL thickness at 40 hours after injection. Exogenous EPO successfully protected RGCs by downregulating apoptotic factors to attenuate NMDA-mediated excitotoxic retinal damage.
Spire stimulates nucleation by Cappuccino and binds both ends of actin filaments
Authors: Bradley Alexander O. , Vizcarra Christina L. , Bailey Hannah M. , Quinlan Margot E. 
Published: September 2019

AbstractAn actin mesh fills both mouse and fly oocytes. The meshes are built by a conserved mechanism and used to establish polarity. Two actin nucleators, Spire and Cappuccino, collaborate to build actin filaments that connect vesicles and the cortex. Direct interaction between Spire and Cappuccino is required for in vitro synergistic actin assembly; however, we understand little about why the interaction is necessary. To mimic the geometry of Spire and Cappuccino in vivo, we immobilized Spire on beads. We found that increased nucleation is a major part of synergy and that Spire alone binds both barbed- and pointed-ends of actin filaments. We identified Spire’s barbed-end binding domain. Partial rescue of fertility by a loss-of-function mutant indicates that barbed-end binding is not necessary for Spire’s in vivo function, but that it may play a role under normal circumstances. We propose that Spire stimulates nucleation by Cappuccino in a manner similar to the collaboration between APC and mDia1.SummaryActin nucleators Cappuccino and Spire collaborate to build an actin mesh in oocytes. Data demonstrate that the collaboration leads to synergistic actin nucleation, as opposed to elongation. Further, Spire binds both ends of polar, actin filaments, resolving a long-outstanding question.