bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shikonin induces odontoblastic differentiation of dental pulp stem cells via AKT–mTOR signaling in the presence of CD44
Authors: Kajiura Kunihiro , Umemura Naoki , Ohkoshi Emika , Ohta Takahisa , Kondoh Nobuo , Kawano Satoshi 
Published: January 2020

AbstractIn our previous study, we demonstrated that hyaluronan induces odontoblastic differentiation of dental pulp stem cells via interactions with CD44. However, it remains unclear whether CD44 expression by dental pulp stem cells is required for odontoblastic differentiation. Therefore, we searched for a compound that induces odontoblastic differentiation of dental pulp stem cells, regardless of the chemical structure and function of hyaluronan, and examined whether CD44 is involved in the induction of odontoblastic differentiation by the compound. Because vitamin K analogues can promote bone formation and tissue calcification, we focused on derivatives of naphthoquinone, the skeleton of vitamin K; we verified whether those compounds could induce odontoblastic differentiation of dental pulp stem cells. We found that dentin sialophosphoprotein, a marker of odontoblasts, was expressed in dental pulp stem cells after treatment with shikonin. The shikonin-induced expression of dentin sialophosphoprotein was inhibited by PI3K, AKT, and mTOR inhibitors. In addition, in dental pulp stem cells transfected with siRNA against CD44, the shikonin-induced expression of dentin sialophosphoprotein was inhibited. Thus, shikonin can stimulate dental pulp stem cells to undergo odontoblastic differentiation through a mechanism involving the AKT–mTOR signaling pathway and CD44. Hyaluronan stimulated dental pulp stem cells to undergo CD44-mediated odontoblastic differentiation in our previous study; the present study indicated that CD44 is necessary for dental pulp stem cells to undergo odontoblastic differentiation. Although expression of CD44 is important for inducing odontoblastic differentiation of dental pulp stem cells, the relationship between the AKT–mTOR signaling pathway and CD44 expression, in the context of shikonin stimulation, has not yet been elucidated. This study suggested that shikonin may be useful for inducing odontoblastic differentiation of dental pulp stem cells, and that it may have clinical applications, including protection of dental pulp.
Antibiotic-induced DNA damage results in a controlled loss of pH homeostasis and genome instability
Authors: Booth James Alexander , Špírek Mário , Lobie Tekle Airgecho , Skarstad Kirsten , Krejci Lumir , Bjørås Magnar 
Published: January 2020

ABSTRACTExtracellular pH has been assumed to play little if any role in how bacteria respond to antibiotics and antibiotic resistance development. Here, we show that the intracellular pH ofEscherichia coliequilibrates to the environmental pH following antibiotic treatment. We demonstrate that this allows the environmental pH to influence the transcription of various DNA damage response genes and physiological processes such as filamentation. Using purified RecA and a known pH-sensitive mutant variant RecA K250R we show how pH can affect the biochemical activity of a protein central to control of the bacterial DNA damage response system. Finally, two different mutagenesis assays indicate that environmental pH affects antibiotic resistance development. Specifically, at environmental pH’s greater than six we find that mutagenesis plays a significant role in producing antibiotic resistant mutants. At pH’s less than or equal to 6 the genome appears more stable but extensive filamentation is observed, a phenomenon that has previously been linked to increased survival in the presence of macrophages.
Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology
Authors: Kargapolova Yulia , Rehimi Rizwan , Kayserili Hülya , Brühl Joanna , Zirkel Anne , Li Yun , Yigit Gökhan , Hoischen Alexander , Frank Stefan , Russ Nicole , Trautwein Jonathan , Laugsch Magdalena , Gusmao Eduardo Gade , Josipovic Natasa , Altmüller Janine , Nürnberg Peter , Längst Gernot , Kaiser Frank J. , Watrin Erwan , Brunner Han , Rada-Iglesias Alvaro , Kurian Leo , Wollnik Bernd , Bouazoune Karim , Papantonis Argyris 
Published: January 2020

ABSTRACTMembers of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered ade novo CHD6missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.
Sulcal depth in medial ventral temporal cortex predicts the location of a place-selective region in macaques, children, and adults
Authors: Natu Vaidehi S. , Arcaro Michael J. , Barnett Michael A. , Gomez Jesse , Livingstone Margaret , Grill-Spector Kalanit , Weiner Kevin S. 
Published: January 2020

AbstractThe evolution and development of anatomical-functional relationships in the cerebral cortex is of major interest in neuroscience. Here, we leveraged the fact that a functional region selective for visual scenes is located within a sulcus in medial ventral temporal cortex (VTC) in both humans and macaques to examine the relationship between sulcal depth and place-selectivity in medial VTC across species and age groups. To do so, we acquired anatomical and functional magnetic resonance imaging scans in 9 macaques, 26 human children, and 28 human adults. Our results revealed a strong structural-functional coupling between sulcal depth and place-selectivity across age groups and species in which selectivity was strongest at the deepest sulcal point (the sulcal pit). Interestingly, this coupling between sulcal depth and place-selectivity strengthens from childhood to adulthood in humans. Morphological analyses suggest that the stabilization of sulcal-functional coupling in adulthood may be due to sulcal deepening and areal expansion with age as well as developmental differences in cortical curvature at the pial, but not the white matter surfaces. Our results implicate sulcal features as functional landmarks in high-level visual cortex and highlight that sulcal-functional relationships in medial VTC are preserved between macaques and humans despite differences in cortical folding.
Fibroblast Growth Factor 21 (FGF21) creates sugar-specific taste aversion to fructose through action in the brain in mice
Authors: Stevanovic Darko M. , Hebert Alex J. , Desai Bhavna N. , Singhal Garima , Adams Andrew C. , Flier Jeffrey S. , Maratos-Flier Eleftheria 
Published: January 2020

AbstractMetabolic diseases such as diabetes and obesity are a growing healthcare concern, and their increasing rates are attributed to increased consumption of carbohydrate-rich diets and sugar-sweetened beverages. Fibroblast growth factor 21 (FGF21) is a complex metabolic regulator, and there is significant evidence that it may play a role in fructose metabolism, driving relative aversion to sweet taste. As such, we examined the relationship between FGF21 and the preferential intake of simple carbohydrates in mice, both as liquid solutions and as dietary additives. Genetic deletion of FGF21 or its obligate co-receptor β-klotho (KLB) had no impact on preference for sugar sweetened solutions. FGF21 overexpression, however, substantially suppressed preference for fructose solutions, but had no effect on glucose or sucrose preference. Infusions of FGF21 also suppressed fructose preference specifically, an effect that was dependent on expression of KLB in the CNS. These results demonstrate that FGF21 creates sugar-specific taste aversion to fructose, which may be mediated by a KLB-dependent pathway in the brain.HighlightsFGF21 administration suppresses fructose preference in mice.Preference for glucose or sucrose is not affected by FGF21 administration.Genetic FGF21 deletion does not enhance fructose, glucose, or sucrose preference.FGF21 requires central β-klotho expression to suppress fructose preference.
Physical-biological interactions underlying the phylogeographic patterns of coral-dependent fishes around the Arabian Peninsula
Authors: Torquato Felipe , Møller Peter R. 
Published: January 2020

ABSTRACTAimTo test the hypothesis that phylogeographic pattern of coral-dependent fish species inhabiting the Arabian Peninsula may be driven by a combination of ocean circulation, larval behavior and seascape features.LocationThe present study focuses on three such putative oceanographic barriers around the Arabian Peninsula: the Bab el-Mandeb Strait, the Strait of Hormuz and the upwelling off Oman.TaxMultitaxa.MethodsA biophysical modeling system that relies on stochastic Lagrangian framework and Individual-Based Model was used to simulate larval dispersal through the three putative barriers, by tracking three-dimensional movements of virtual particles in ocean circulation scenarios. We explored the range of dispersal capabilities across reef fish species by creating 72 hypothetical strategies, each representing a unique combination of five biological traits: pelagic larval duration, spawning periodicity, mortality rate, reproductive output and vertical migration.ResultOur results showed that the strength of the barriers was highly variable as a function of all biological traits (except reproductive output) and indicated high asymmetry of connectivity, and hence gene flow, between adjacent areas. In addition, direction and distance travelled by the virtual larvae varied according to both the geographic position of releasing site and biannual monsoonal winds. On average, larvae released during the summer exhibited a higher potential for dispersal than larvae released in wintertime.Main conclusionsOur biophysical models complement the few existing empirical research on population genetics, and the predictions presented here serve as testable hypotheses for future phylogeographic studies around the Arabian Peninsula.
Chromatin features define adaptive genomic regions in a fungal plant pathogen
Authors: Cook David E. , Kramer Martin , Seidl Michael F. , Thomma Bart PHJ 
Published: January 2020

ABSTRACTUnderstanding the complex information stored in a genome remains challenging since multiple connected regulatory mechanisms act at various scales to determine function. Increased comprehension of genome function at scales beyond contiguous nucleotides will help understand genetic diseases, the emergence of pathogenesis, and more broadly the genomics of adaptation. Here we report the analysis of DNA methylation, histone modification, and DNA accessibility in the plant pathogenic vascular wilt fungusVerticillium dahliae. Functional analysis details that DNA methylation is restricted to repetitive elements, such as transposable element DNA, but interestingly only some repetitive DNA is methylated. This incomplete DNA methylation is associated with repetitive DNA residing in specific compartments of the genome that were previously defined as Lineage-Specific (LS) regions. These regions are hypervariable betweenV. dahliaeisolates and contain genes that support host colonization and adaptive traits. LS regions are associated with H3 Lys-27 methylated histones (H3K27me3), and repetitive DNA within LS regions are more transcriptionally active and have increased DNA accessibility, representing a hybrid chromatin state when compared to repetitive regions within the core genome. We used machine learning algorithms trained on epigenetic and DNA accessibility data to predict LS regions with high recall, identifying approximately twice as much LS DNA in theV. dahliaegenome as previously recognized. Collectively, these results characterize LS regions in an intermediate chromatin state and provide evidence that links chromatin features and genome architecture to adaptive regions within the genome.
Theoretical Design of Paradoxical Signaling-Based Synthetic Population Control Circuit inE. coli
Authors: Mayalu Michaëlle N. , Murray Richard M. 
Published: January 2020

SummaryWe have developed a mathematical framework to analyze the cooperative control of cell population homeostasis via paradoxical signaling in synthetic contexts. Paradoxical signaling functions through quorum sensing (where cells produce and release a chemical signal as a function of cell density). Precisely, the same quorum sensing signal provides both positive (proliferation) and negative (death) feedback in different signal concentration regimes. As a consequence, the relationship between intercellular quorum sensing signal concentration and net growth rate (cell proliferation minus death rates) can be non-monotonic. This relationship is a condition for robustness to certain cell mutational overgrowths and allows for increased stability in the presence of environmental perturbations. Here, we explore stability and robustness of a conceptualized synthetic circuit. Furthermore, we asses possible design principles that could exist among a subset of paradoxical circuit implementations. This analysis sparks the development a bio-molecular control theory to identify ideal underlying characteristics for paradoxical signaling control systems.
Quantitative dissection of transcription in development yields evidence for transcription factor-driven chromatin accessibility
Authors: Eck Elizabeth , Liu Jonathan , Kazemzadeh-Atoufi Maryam , Ghoreishi Sydney , Blythe Shelby , Garcia Hernan G. 
Published: January 2020

AbstractThermodynamic models of gene regulation can predict transcriptional regulation in bacteria, but in eukaryotes chromatin accessibility and energy expenditure may call for a different framework. Here we systematically tested the predictive power of models of DNA accessibility based on the Monod-Wyman-Changeux (MWC) model of allostery, which posits that chromatin fluctuates between accessible and inaccessible states. We dissected the regulatory dynamics ofhunchbackby the activator Bicoid and the pioneer-like transcription factor Zelda in livingDrosophilaembryos and showed that no thermodynamic or non-equilibrium MWC model can recapitulatehunchbacktranscription. Therefore, we explored a model where DNA accessibility is not the result of thermal fluctuations but is catalyzed by Bicoid and Zelda, possibly through histone acetylation, and found that this model can predicthunchbackdynamics. Thus, our theory-experiment dialogue uncovered potential molecular mechanisms of transcriptional regulatory dynamics, a key step toward reaching a predictive understanding of developmental decision-making.
The Efficiency, Efficacy, and Retention of Motor Training in Chronic Stroke
Authors: Wang Chunji , Winstein Carolee , D’Argenio David Z. , Schweighofer Nicolas 
Published: January 2020

AbstractIn motor skill learning, the greater the dose of training, the greater the efficacy of training, the lower the efficiency of training, and the better the long-term retention. Whether such principles apply to motor training after stroke is unclear. Here, we developed novel mixed-effects models of the change in the quality of arm movements during and following training fitted to data from a recent randomized controlled trial of the effect of the dose of training in chronic stroke. Analysis of the model’s learning and retention rates demonstrated an increase in efficacy of training with greater doses, a decrease in efficiency of training with both additional doses and additional bouts of training, and fast initial decay following training. Two additional effects modulated retention: a positive “self-training” effect, and an un-expected negative effect of dose. Our results suggest that for patients with sufficient arm use post-training, self-training will further improve use, but additional therapy may be in vain.
Injectable therapeutic organoids using sacrificial hydrogels
Authors: Rossen Ninna S. , Anandakumaran Priya N. , zur Nieden Rafael , Lo Kahmun , Luo Wenjie , Park Christian , Huyan Chuqiao , Fu Qinyuouen , Song Ziwei , Singh-Moon Rajinder P. , Chung Janice , Goldenberg Jennifer , Sampat Nirali , Harimoto Tetsuhiro , Bajakian Danielle , Gillette Brian M. , Sia Samuel K. 
Published: January 2020

AbstractOrganoids, by promoting self-organization of cells into native-like structures, are becoming widespread in drug-screening technologies, but have so far been used sparingly for cell therapy as current approaches for producing self-organized cell clusters lack scalability or reproducibility in size and cellular organization. We introduce a method of using hydrogels as sacrificial scaffolds, which allow cells to form self-organized clusters followed by gentle release, resulting in highly reproducible multicellular structures on a large scale. We demonstrated this strategy for endothelial cells and mesenchymal stem cells to self-organize into blood-vessel units, which were injected into mice using hypodermic needles, and observed in real time to rapidly form perfusing vasculature. As cell therapy transforms into a new class of therapeutic modality, this simple method – by making use of the dynamic nature of hydrogels – could offer high yields of self-organized multicellular aggregates with reproducible sizes and cellular architectures.
Dynamics of replication origin over-activation
Authors: Fu Haiqing , Redon Christophe E. , Utani Koichi , Thakur Bhushan L. , Jang Sangmin , Marks Anna B. , Zhuang Sophie Z. , Lazar Sarah B. , Rao Mishal , Mencer Shira , Gross Jacob M. , Pongor Lorinc S. , Aladjem Mirit I. 
Published: January 2020

AbstractWe determined replication patterns in cancer cells in which the controls that normally prevent excess replication were disrupted (“re-replicating cells”). Single-fiber analyses suggested that replication origins were activated at a higher frequency in re-replicating cells. However, nascent strand sequencing demonstrated that re-replicating cells utilized the same pool of potential replication origins as normally replicating cells. Surprisingly, re-replicating cells exhibited a skewed initiation frequency correlating with replication timing. These patterns differed from the replication profiles observed in non-re-replicating cells exposed to replication stress, which activated a novel group of dormant origins not typically activated during normal mitotic growth. Hence, disruption of the molecular interactions that regulates origin initiation can activate two distinct pools of potential replication origins: re-replicating cells over-activate flexible origins while replication stress in normal mitotic growth activates dormant origins.
Di-arginine and FFAT-like motifs retain a subpopulation of PRA1 at ER-mitochondria membrane contact sites
Authors: Irqeba Ameair Abu , Ogilvie Judith Mosinger 
Published: January 2020

ABSTRACTPrenylated Rab Acceptor 1 (PRA1/Rabac1) is a four-pass transmembrane protein that has been found to localize to the Golgi and promiscuously associate with a diverse array of Rab GTPases. We have previously identified PRA1 to be among the earliest significantly down-regulated genes in therd1mouse model of retinitis pigmentosa, a retinal degenerative disease. Here, we show that an endogenous subpopulation of PRA1 resides within the endoplasmic reticulum (ER) at ER-mitochondria membrane contact sites in cultured mammalian cells. We also demonstrate that PRA1 contains two previously unidentified ER retention/retrieval amino acid sequences on its cytosolic N-terminal region: a membrane distal di-arginine motif and a novel membrane proximal FFAT-like motif. Using a truncation construct that lacks complete Golgi targeting information, we show that mutation of either motif leads to an increase in cell surface localization, while mutation of both motifs exhibits an additive effect. We also present evidence that illustrates that N- or C- terminal addition of a tag to full-length PRA1 leads to differential localization to either the Golgi or reticular ER, phenotypes that do not completely mirror endogenous protein localization. The presence of multiple ER retention motifs on the PRA1 N-terminal region further suggests that it has a functional role within the ER.
A mutant RNA polymerase activates the general stress response, enablingE. coliadaptation to late prolonged stationary phase
Authors: Nandy Pabitra , Chib Savita , Seshasayee Aswin 
Published: January 2020

AbstractEscherichia colipopulations undergo repeated replacement of parental genotypes with fitter variants deep in stationary phase. We isolated one such variant, which emerged after three weeks o of maintaining anE. coliK12 population in stationary phase. This variant displayed a small colony phenotype, slow growth and was able to outcompete its ancestor over a narrow time window in stationary phase. The variant also shows tolerance to beta-lactam antibiotics, though not previously exposed to the antibiotic. We show that an RpoC (A494V) mutation confers the slow growth and small colony phenotype to this variant. The ability of this mutation to confer a growth advantage in stationary phase depends on the availability of the stationary phase sigma factor σS. The RpoC (A494V) mutation up-regulates the σSregulon. As shown over 20 years ago, early in prolonged stationary phase, σSattenuation, but not complete loss of activity, confers a fitness advantage. Our study shows that later mutations enhance σSactivity, either by mutating the gene for σSdirectly, or via mutations such as RpoC (A494V). The balance between the activities of the housekeeping major sigma factor and σSsets up a trade-off between growth and stress tolerance, which is tuned repeatedly during prolonged stationary phase.ImportanceAn important general mechanism of bacterial adaptation to its environment involves adjusting the balance between growing fast, and tolerating stresses. One paradigm where this plays out is in prolonged stationary phase: early studies showed that attenuation, but not complete elimination, of the general stress response enables early adaptation of the bacteriumE. colito the conditions established about 10 days into stationary phase. We show here that this balance is not static and that it is tilted back in favour of the general stress response about two weeks later. This can be established by direct mutations in the master regulator of the general stress response, or by mutations in the core RNA polymerase enzyme itself. These conditions can support the development of antibiotic tolerance though the bacterium is not exposed to the antibiotic. Further exploration of the growth-stress balance over the course of stationary phase will necessarily require a deeper understanding of the events in the extracellular milieu.