bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells
Authors: Lupien Leslie E. , Bloch Katarzyna , Dehairs Jonas , Feng William W. , Davis Wilson L. , Dennis Thea , Swinnen Johannes V. , Wells Wendy A. , Smits Nicole C. , Kuemmerle Nancy B. , Kinlaw William B. 
Published: June 2019

ABSTRACTWe previously described the expression of CD36 and lipoprotein lipase (LPL) by breast cancer (BC) cells and tissues, and the growth-promoting effect of very low-density lipoprotein (VLDL) supplementation observed in BC cell lines only in the presence of LPL. We now describe the deployment of LPL by BC cells. Our data support a model in which LPL is bound to a heparin-like heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to rapidly internalize intact lipoproteins via receptor-mediated endocytosis. We further observe substantial alterations in gene expression programs related to pathways for lipid acquisition (synthesis vs. uptake) in response to each the availability of exogenous triglyceride in tissue culture media and LPL expression status. Current literature emphasizesde novofatty acid synthesis as the paramount mechanism for lipid acquisition by cancer cells. Our findings indicate that exogenous lipid uptake can serve as an important method of lipid acquisition for cancer cells, alongsidede novolipogenesis, and that the relative reliance on these two modes of lipid acquisition may vary among different BC cell lines and in response to nutrient availability. This concept has obvious implications for the development of therapies aimed at the lipid dependence of many different cancer types. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.
Telomere length and oxidative stress variations in a murine model of Alzheimer’s disease progression
Authors: Martínez-González Katia , Islas-Hernández Azul , Martínez-Ezquerro José Darío , Bermúdez-Rattoni Federico , Garcia-delaTorre Paola 
Published: June 2019

AbstractAlzheimer’s Disease (AD) is the most common cause of dementia and aging is its major risk factor. Changes in telomere length have been associated with aging and some degenerative diseases. Our aim was to explore some of the molecular changes caused by the progression of AD in a transgenic murine model (3xTg-AD; B6; 129-Psen1 <tm1Mpm> Tg (APPSwe, tauP301L) 1Lfa). Telomere length was assessed by qPCR in both brain tissue and peripheral blood cells and compared between three age groups: 5, 9, and 13 months. In addition, a possible effect of oxidative stress on telomere length and AD progression was explored. Shorter telomeres were found in blood cells of older transgenic mice compared to younger and wild type mice but no changes in telomere length in the hippocampus. An increase in oxidative stress with age was found for all strains but no correlation was found between oxidative stress and shorter telomere length for transgenic mice. Telomere length and oxidative stress are affected by AD progression in the 3xTg-AD murine model. Changes in blood cells are more noticeable than changes in brain tissue, suggesting that systemic changes can be detected early in the disease in this murine model.
Evaluating species distribution models with discrimination accuracy is uninformative for many applications
Authors: Warren Dan L. , Matzke Nicholas J. , Iglesias Teresa L. 
Published: June 2019

AbstractAimSpecies distribution models are used across evolution, ecology, conservation, and epidemiology to make critical decisions and study biological phenomena, often in cases where experimental approaches are intractable. Choices regarding optimal models, methods, and data are typically made based on discrimination accuracy: a model’s ability to predict subsets of species occurrence data that were withheld during model construction. However, empirical applications of these models often involve making biological inferences based on continuous estimates of relative habitat suitability as a function of environmental predictor variables. We term the reliability of these biological inferences “functional accuracy.” We explore the link between discrimination accuracy and functional accuracy.MethodsUsing a simulation approach we investigate whether models that make good predictions of species distributions correctly infer the underlying relationship between environmental predictors and the suitability of habitat.ResultsWe demonstrate that discrimination accuracy is only informative when models are simple and similar in structure to the true niche, or when data partitioning is geographically structured. However, the utility of discrimination accuracy for selecting models with high functional accuracy was low in all cases.Main conclusionsThese results suggest that many empirical studies and decisions are based on criteria that are unrelated to models’ usefulness for their intended purpose. We argue that empirical modeling studies need to place significantly more emphasis on biological insight into the plausibility of models, and that the current approach of maximizing discrimination accuracy at the expense of other considerations is detrimental to both the empirical and methodological literature in this active field. Finally, we argue that future development of the field must include an increased emphasis on simulation; methodological studies based on ability to predict withheld occurrence data may be largely uninformative about best practices for applications where interpretation of models relies on estimating ecological processes, and will unduly penalize more biologically informative modeling approaches.
A molecularly defined insular cortex --> central amygdala circuit mediates conditioned overconsumption of food
Authors: Stern S.A. , Pomeranz L.E. , Azevedo E.P. , Doerig K.R. , Friedman J.M. 
Published: June 2019

AbstractFeeding is a complex motivated behavior that is controlled not just by metabolic and homeostatic factors, but also by environmental factors such as emotion and the hedonic nature of the food itself. Yet, little is known about how brain regions involved in cognition and emotion might contribute to overeating, and therefore, obesity. We used a recently developed behavioral task in which learned contextual cues induce feeding even in sated mice to investigate the underlying neural mechanisms. Using viral tracing, molecular profiling and chemo/optogenetic techniques, we discovered that an insular cortex projection to the central amygdala is required for conditioned overconsumption but not homeostatic feeding. The projection neurons express nitric oxide synthase-1 and activation of this population suppresses satiety signals in the central amygdala. The data thus indicate that the insular cortex provides top down control of homeostatic circuits to promote overconsumption in response to learned cues.One Sentence SummaryNitric oxide synthase-1 neurons in the insular cortex promote overconsumption by projecting to the central amygdala to suppress a homeostatic satiety signal.
LongAxis: a MATLAB-based program for 3D quantitative analysis of epithelial cell shape and orientation
Authors: Carney Keith R. , Bryan Chase D. , Gordon Hannah B. , Kwan Kristen M. 
Published: June 2019

AbstractEpithelial morphogenesis, a fundamental aspect of development, generates 3-dimensional tissue structures crucial for organ function. Underlying morphogenetic mechanisms are, in many cases, poorly understood, but mutations that perturb organ development can affect epithelial cell shape and orientation – difficult features to quantify in three dimensions. The basic structure of the eye is established via epithelial morphogenesis: in the embryonic optic cup, the retinal progenitor epithelium enwraps the lens. We previously found that loss of the extracellular matrix proteinlaminin-alpha1(lama1) led to mislocalization of apical polarity markers and apparent misorientation of retinal progenitors. We sought to visualize and quantify this phenotype, and determine whether loss of the apical polarity determinantpard3might rescue the phenotype. To this end, we developed LongAxis, a MATLAB-based program optimized for the retinal progenitor neuroepithelium. LongAxis facilitates 3-dimensional cell segmentation, visualization, and quantification of cell orientation and morphology. Using LongAxis, we find that retinal progenitors in thelama1−/−optic cup are misoriented and slightly less elongated. In thelama1;MZpard3double mutant, cells are still misoriented, but larger. Therefore, loss ofpard3does not rescue loss oflama1, and in fact uncovers a novel cell size phenotype. LongAxis enables population-level visualization and quantification of retinal progenitor cell orientation and morphology. These results underscore the importance of visualizing and quantifying cell orientation and shape in three dimensions within the retina.
Should virus capsids assemble perfectly? Theory and observation of defects
Authors: Spiriti Justin , Conway James F. , Zuckerman Daniel M. 
Published: June 2019

AbstractAlthough published structural models of viral capsids generally exhibit a high degree of regularity or symmetry, structural defects might be expected because of the fluctuating environment in which capsids assemble and the requirement of some capsids for disassembly prior to genome delivery. Defective structures are observed in computer simulations, and are evident in single-particle cryoEM studies. Here, we quantify the conditions under which defects might be expected, using a statistical mechanics model allowing for ideal, defective, and vacant sites. The model displays a threshold in affinity parameters below which there is an appreciable population of defective capsids. Even when defective sites are not allowed, there is generally some population of vacancies. Analysis of single particles in cryoEM micrographs yields a confirmatory ≳15% of defective particles. Our findings suggest structural heterogeneity in virus capsids may be under-appreciated, and also points to a non-traditional strategy for assembly inhibition.
Split-gene drive system provides flexible application for safe laboratory investigation and potential field deployment
Authors: Del Amo Víctor López , Bishop Alena L. , Sánchez C. Héctor M. , Bennett Jared B. , Feng Xuechun , Marshall John M. , Bier Ethan , Gantz Valentino M. 
Published: June 2019

ABSTRACTCRISPR-based gene drives spread through populations bypassing the dictates of Mendelian genetics, offering a population-engineering tool for tackling vector-borne diseases, managing crop pests, and helping island conservation efforts; unfortunately, current technologies raise safety concerns for unintended gene propagation. Herein, we address this by splitting the two drive components, Cas9 and gRNAs, into separate alleles to form a novel trans-complementing split–gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This bi-component nature allows for individual transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small– molecule-controlled version to investigate the biology of component inheritance and use our system to study the maternal effects on CRISPR inheritance, impaired homology on efficiency, and resistant allele formation. Lastly, mathematical modeling of tGD spread in a population shows potential advantages for improving current gene-drive technologies for field population modification.
Graphene Quantum Dot Oxidation Governs Noncovalent Biopolymer Adsorption
Authors: Jeong Sanghwa , Pinals Rebecca L. , Dharmadhikari Bhushan , Song Hayong , Kalluri Ankarao , Debnath Debika , Qi Wu , Ham Moon-Ho , Patra Prabir , Landry Markita P. 
Published: June 2019

AbstractThe graphene quantum dot (GQD) is a carbon allotrope with a planar surface amenable for functionalization and nanoscale dimensions that confer photoluminescent properties. Collectively, these properties render GQDs an advantageous platform for nanobiotechnology applications, including as optical biosensors and delivery platforms. In particular, noncovalent functionalization offers a route to reversible modification and preservation of the pristine GQD substrate. However, a clear paradigm for GQD noncovalent functionalization has yet to be realized. Herein, we demonstrate the feasibility of noncovalent polymer adsorption to the GQD surface, with a specific focus on single-stranded DNA (ssDNA). We study how GQD oxidation level affects the propensity for polymer adsorption by synthesizing and characterizing four types of GQD substrates and investigating noncovalent polymer association to these substrates. Distinct adsorption methods are developed for successful ssDNA attachment based upon the GQD’s initial level of oxidation. ssDNA adsorption to the GQD is confirmed by atomic force microscopy, by inducing ssDNA desorption, and with molecular dynamics simulations. ssDNA is determined to adsorb strongly to no-oxidation GQDs, weakly to low-oxidation GQDs, and not at all for heavily oxidized GQDs. We hypothesize that high GQD oxygen content disrupts the graphitic carbon domains responsible for stacking with the aromatic ssDNA bases, thus preventing the formation of stable polymer-GQD complexes. Finally, we develop a more generic adsorption platform and assess how the GQD system is tunable by modifying both the polymer sequence and type.
Processivity and Velocity for Motors Stepping on Periodic Tracks
Authors: Mugnai M.L. , Caporizzo M.A. , Goldman Y.E. , Thirumalai D. 
Published: June 2019

AbstractProcessive molecular motors enable cargo transportation by assembling into dimers capable of taking several consecutive steps along a cytoskeletal filament. In the well-accepted hand-over-hand stepping mechanism the trailing motor detaches from the track and binds the filament again in leading position. This requires fuel consumption in the form of ATP hydrolysis, and coordination of the catalytic cycles between the leading and the trailing heads. However, alternative stepping mechanisms exist, including inchworm-like movements, backward steps, and foot stomps. Whether all of these pathways are coupled to ATP hydrolysis remains to be determined. Here, in order to establish the principles governing the dynamics of processive movement, we present a theoretical framework which includes all of the alternative stepping mechanisms. Our theory bridges the gap between the elemental rates describing the biochemical and structural transitions in each head, and the experimentally measurable quantities, such as velocity, processivity, and probability of backward stepping. Our results, obtained under the assumption that the track is periodic and infinite, provide expressions which hold regardless of the topology of the network connecting the intermediate states, and are therefore capable of describing the function of any molecular motor. We apply the theory to myosin VI, a motor that takes frequent backward steps, and moves forward with a combination of hand-over-hand and inchworm-like steps. Our model reproduces quantitatively various observables of myosin VI motility measured experimentally from two groups. The theory is used to predict the gating mechanism, the pathway for backward stepping, and the energy consumption as a function of ATP concentration.Significance StatementMolecular motors harness the energy released by ATP hydrolysis to transport cargo along cytoskeletal filaments. The two identical heads in the motor step alternatively on the polar track by communicating with each other. Our goal is to elucidate how the coordination between the two heads emerges from the catalytic cycles. To do so, we created a theoretical framework that allows us to relate the measurable features of motility, such as motor velocity, with the biochemical rates in the leading and trailing heads, thereby connecting biochemical activity and motility. We illustrate the efficacy of the theory by analyzing experimental data for myosin VI, which takes frequent backward steps, and moves forward by a hand-over-hand and inchworm-like steps.
Dynamics between horizontal gene transfer and acquired antibiotic resistance inS. Heidelberg followingin vitroincubation in broiler ceca
Authors: Oladeinde Adelumola , Cook Kimberly , Lakin Steven M. , Abdo Zaid , Looft Torey , Herrington Kyler , Zock Gregory , Lawrence Jodie Plumblee , Thomas Jesse C. , Beaudry Megan S. , Glenn Travis 
Published: June 2019

AbstractThe chicken gastrointestinal tract harbors taxa of microorganisms that play a role in the health and disease status of the host. The cecum is the part of the gut that carries the highest microbial densities, has the longest residence time of digesta and is a vital site for urea recycling and water regulation. Therefore, the cecum provides a rich environment for bacteria to horizontally transfer genes between one another via mobile genetic elements such as plasmids and bacteriophages. In this study, we used broiler chicken cecum as a model to investigate antibiotic resistance genes that can be transferredin vitrofrom ceca flora toSalmonella entericaserovar Heidelberg (S. Heidelberg). We used whole genome sequencing and resistome enrichment to decipher the interactions betweenS. Heidelberg, gut microbiome and acquired antibiotic resistance. After 48 h incubation of ceca under microaerophilic conditions, oneS. Heidelberg isolate was recovered with an acquired Inck2 plasmid (88 kb) encoding extended β-lactamase producing gene (blaCMY-2).In vitro, this plasmid was transferrable betweenE. coliandS. Heidelberg strains, but transfer was unsuccessful betweenS. Heidelberg strains. An in-depth genetic characterization of transferred plasmids suggests that they share significant homology with P1-like phages. This study contributes to our understanding of the dynamics between an important food-borne pathogen and the chicken gut microbiome.ImportanceS.Heidelberg is a clinically important serovar, linked to food-borne illness and among the top 5 serovars isolated from poultry in USA and Canada. Acquisition of new genetic material from microbial flora in the gastrointestinal tract of food animals, including broilers, may contribute to increased fitness of pathogens likeS.Heidelberg and may increase their level of antibiotic tolerance. Therefore, it is critical to gain a better understanding on the dynamic interactions that occur between important pathogens and the commensals present in the animal gut and other agroecosystems. In this study, we show that the native flora in the broiler ceca were capable of transferring mobile genetic elements carrying AmpC β-lactamase (blaCMY-2) gene to an important food-borne pathogenS. Heidelberg. The potential role for P1-like bacteriophage transduction was also discussed.
Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension
Authors: Rocha Lorena Raquel , Nguyen Huu Viet Anh , Palomino La Torre Claudia , Xu Qianlan , Jabari Mary , Krawczyk Michal , Weinreb Robert N. , Skowronska-Krawczyk Dorota 
Published: June 2019

AbstractExperimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.
Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis
Authors: Janiurek Mette Mathiesen , Christoffersen Christina , Kucharz Krzysztof , Lauritzen Martin 
Published: June 2019

ABTRACTThe blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels. Here, we report that the BBB permeability is modified by apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P). We used two-photon microscopy to monitor changes in BBB permeability in apoM-deficient mice (apoM−/−), showing significant increases in paracellular BBB permeability to small molecules without structural changes in junctional complexes between endothelial cells. Lack of apoM-bound S1P increased vesicle-mediated transfer of albumin across endothelium of brain pial and penetrating arterioles, whereas transcytosis in capillaries and venules remained unchanged. S1PR1 agonist SEW2871 rapidly normalized BBB permeability along both the paracellular and transcellular routes in apoM−/− mice. Thus, apoM-bound S1P maintains low paracellular BBB permeability for small molecules in all cerebral microvessels and low levels of adsorptive transcytosis in penetrating arterioles. Modulation of apoM/S1P-dependent signaling may be a novel strategy for the protection of brain endothelial cells to preserve the BBB function.
Alpha/Beta Hydrolase Domain-Containing Protein 2 regulates the rhythm of follicular maturation and estrous stages of the female reproductive cycle
Authors: Björkgren Ida , Chung Dong Hwa , Mendoza Sarah , Gabelev-Khasin Liliya , Modzelewski Andrew , He Lin , Lishko Polina V. 
Published: June 2019

AbstractTherian female fertility is defined by a successful and strictly periodic ovarian cycle, which is under the control of gonadotropins and steroid hormones, particularly progesterone and estrogen. The latter two are produced by the ovaries that are engaged in controlled follicular growth, maturation and release of the eggs, i.e. ovulation. It is well known that steroid hormones regulate ovarian cycles via genomic signaling, by altering gene transcription and protein synthesis. However, despite this well-studied mechanism, steroid hormones can also signal via direct, non-genomic action, by binding to their membrane receptors. Here we show, that the recently discovered sperm membrane progesterone receptor α/β hydrolase domain-containing protein 2 (ABHD2) is highly expressed in mammalian ovaries where the protein plays a novel regulatory role in follicle maturation and the sexual cycle of females. Ablation ofAbhd2caused a dysregulation of the estrous cycle rhythm with females showing shortened luteal stages while remaining in the estrus stage for a longer time. Interestingly, the ovaries ofAbhd2knockout (KO) females resemble polycystic ovary morphology with a high number of atretic antral follicles that could be rescued with injection of gonadotropins. Such a procedure also allowedAbhd2KO females to ovulate a significantly increased number of mature and fertile eggs in comparison to their wild-type littermates. These results suggest a novel regulatory role of ABHD2 as an important factor in non-genomic steroid regulation of the female reproductive cycle.