bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hot-spots and their contribution to the self-assembly of the viral capsid: in-vitro validation
Authors: Valdez-Lara Alejandra Gabriela , Andrade-Medina Mariana , Alemán-Vilis Josué Alejandro , Pérez-Montoya Aldo Adrián , Pineda-Aguilar Nayely , Martínez-Guerra Eduardo , Roldán-Salgado Abigail , Gaytán Paul , Carrillo-Tripp Mauricio 
Published: August 2019

AbstractThe viral capsid is a macromolecular complex formed by self-assembled proteins (CPs) which, in many cases, are biopolymers with an identical amino acid sequence. Specific CP-CP interactions drive the capsid self-assembly process. However, it is believed that only a small set of protein-protein interface residues significantly contribute to the formation of the capsid; the so-called “hot-spots”. Here, we investigate the effect of in-vitro point-mutations on the Bromoviridae family structure-conserved interface residues of the icosahedral Cowpea Chlorotic Mottle Virus, previously hypothesized as hot-spots. We study the self-assembly of those mutated recombinant CPs for the formation of capsids by Thermal Shift Assay (TSA). We show that the TSA biophysical technique is a reliable way to characterize capsid assembly. Our results show that point-mutations on non-conserved interface residues produce capsids indistinguishable from the wild-type. In contrast, a single mutation on structure-conserved residues E176 or V189 prevents the formation of the capsid while maintaining the tertiary fold of the CP. Our findings provide experimental evidence of the in-silico conservation-based hot-spot prediction accuracy. As a whole, our methodology provides a framework that could aid in the rational development of molecules to inhibit virus formation, or advance capsid bioengineering to design for their stability, function and applications.
Characterization of Genetic and Phenotypic Heterogeneity of Obstructive Sleep Apnea Using Electronic Health Records
Authors: Veatch Olivia J. , Bauer Christopher R. , Josyula Navya , Mazzotti Diego R. , Keenan Brendan T. , Bagai Kanika , Malow Beth A. , Robishaw Janet D. , Pack Allan I. , Pendergrass Sarah A. 
Published: August 2019

ABSTRACTObstructive sleep apnea (OSA) is defined by frequent episodes of reduced or complete cessation of airflow during sleep and is linked to negative health outcomes. Understanding the genetic factors influencing expression of OSA may lead to new treatment strategies. Electronic health records can be leveraged to both validate previously reported OSA-associated genomic variation and detect novel relationships between these variants and comorbidities. We identified candidate single nucleotide polymorphisms (SNPs) via systematic literature review of existing research. Using datasets available at Geisinger (n=39,407) and Vanderbilt University Medical Center (n=24,084), we evaluated associations between 48 SNPs and OSA diagnosis, defined using clinical codes. We also evaluated associations between these SNPs and OSA severity measures obtained from sleep reports at Geisinger (n=6,571). Finally, we used a phenome-wide approach to perform discovery and replication analyses testing associations between OSA candidate SNPs and other clinical codes and laboratory values. Ten SNPs were associated with OSA diagnosis in at least one dataset, and one additional SNP was associated following meta-analysis across all datasets. Three other SNPs were solely associated in subgroups defined by established risk factors (i.e., age, sex, and BMI). Five OSA diagnosis-associated SNPs, and 16 additional SNPs, were associated with OSA severity measures. SNPs associated with OSA diagnosis were also associated with codes reflecting cardiovascular disease, diabetes, celiac disease, peripheral nerve disorders and genitourinary symptoms. Results highlight robust OSA-associated SNPs, and provide evidence of convergent mechanisms influencing risk for co-occurring conditions. This knowledge can lead to more personalized treatments for OSA and related comorbidities.
Crocodylomorph cranial shape evolution and its relationship with body size and ecology
Authors: Godoy Pedro L. 
Published: August 2019

AbstractCrocodylomorpha, which includes living crocodylians and their extinct relatives, has a rich fossil record, extending back for more than 200 million years. Unlike modern semi-aquatic crocodylians, extinct crocodylomorphs exhibited more varied lifestyles, ranging from marine to fully terrestrial forms. This ecological diversity was mirrored by a remarkable morphological disparity, particularly in terms of cranial morphology, which seems to be closely associated with ecological roles in the group. Here, I use geometric morphometrics to comprehensively investigate cranial shape variation and disparity in Crocodylomorpha. I quantitatively assess the relationship between cranial shape and ecology (i.e. terrestrial, aquatic, and semi-aquatic lifestyles), as well as possible allometric shape changes. I also characterise patterns of cranial shape evolution and identify regime shifts. I found a strong link between shape and size, and a significant influence of ecology on the observed shape variation. Terrestrial taxa, particularly notosuchians, have significantly higher disparity, and shifts to more longirostrine regimes are associated with large-bodied aquatic or semi-aquatic species. This demonstrates an intricate relationship between cranial shape, body size and lifestyle in crocodylomorph evolutionary history. Additionally, disparity-through-time analyses were highly sensitive to different phylogenetic hypotheses, suggesting the description of overall patterns among distinct trees. For crocodylomorphs, most results agree in an early peak during the Early Jurassic and another in the middle of the Cretaceous, followed by nearly continuous decline until today. Since only crown-group members survived through the Cenozoic, this decrease in disparity was likely the result of habitat loss, which narrowed down the range of crocodylomorph lifestyles.
Modular transcriptional programs separately define axon and dendrite connectivity
Authors: Kurmangaliyev Yerbol Z. , Yoo Juyoun , LoCascio Samuel A. , Zipursky S. Lawrence 
Published: August 2019

AbstractPatterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on Drosophila T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
Topology-Dependent Interference of Circuit Function by Growth Feedback
Authors: Zhang Rong , Li Jiao , Melendez-Alvarez Juan , Chen Xingwen , Sochor Patrick , Zhang Qi , Goetz Hanah , Ding Tian , Wang Xiao , Tian Xiao-Jun 
Published: August 2019

AbstractGrowth-mediated feedback between synthetic gene circuits and host organisms leads to diverse emerged behaviors, including growth bistability and enhanced ultrasensitivity. However, the range of possible impacts of growth feedback on different gene circuits remains underexplored. Here, we mathematically and experimentally demonstrated that growth feedback affects the functions of memory gene circuits in a network topology-dependent way. Specifically, the memory of the self-activation circuit is quickly lost due to the fast growth-mediated dilution of the circuit products. Decoupling of growth feedback reveals its memory, manifested by its hysteresis property across a broad range of stimulus. On the contrary, the toggle switch is more refractory to the growth-mediated dilution and can retrieve its memory after the fast-growth phase. The underlying principle lies in the different dependence of active and repressive regulations in these circuits on the growth-mediated dilution. Our results unveil the topology-dependent mechanism on how growth-mediated feedback influences the behaviors of gene circuits.
Inositol Trisphosphate Kinase and Diphosphoinositol Pentakisphosphate Kinase Enzymes Constitute the Inositol Pyrophosphate Synthesis Pathway in Plants
Authors: Adepoju Olusegun , Williams Sarah P. , Craige Branch , Cridland Caitlin A. , Sharpe Amanda K. , Brown Anne M. , Land Eric , Perera Imara Y. , Mena Didier , Sobrado Pablo , Gillaspy Glenda E. 
Published: August 2019

ABSTRACTInositol pyrophosphates (PP-InsPs) are an emerging class of “high-energy” intracellular signaling molecules containing one or two diphosphate groups attached to an inositol ring, with suggested roles in bioenergetic homeostasis and inorganic phosphate (Pi) sensing. Information regarding the biosynthesis of these unique class of signaling molecules in plants is scarce, however the enzymes responsible for their biosynthesis in other eukaryotes have been well described. Here we report the characterization of the two Arabidopsis VIP kinase domains, a newly discovered activity of the Arabidopsis ITPK1 and ITPK2 enzymes, and the subcellular localization of the enzymes involved in the synthesis of InsP6and PP-InsPs. Our data indicate that AtVIP1-KD and AtVIP2-KD act primarily as 1PP-specific Diphosphoinositol Pentakisphosphate Kinases (PPIP5) Kinases. The AtITPK enzymes, in contrast, can function as InsP6kinases, and thus are the missing enzyme in the plant PP-InsP synthesis pathway. Together, these enzyme classes can function in plants to produce PP-InsPs, which have been implicated in signal transduction and Pisensing pathways. We measured a higher InsP7level (increased InsP7/InsP8ratio) invip1/vip2double loss-of-function mutants, and an accumulation of InsP8(decreased InsP7/InsP8ratio) in the 35S:VIP2overexpression line relative to wild-type plants. We also report that enzymes involved in the synthesis of InsPs and PP-InsPs accumulate within the nucleus and cytoplasm of plant cells. Our work defines a molecular basis for understanding how plants synthesize PP-InsPs which is crucial for determining the roles of these signaling molecules in processes such as Pisensing.SIGNIFICANCE STATEMENTInositol pyrophosphate signaling molecules are of agronomic importance as they can control complex responses to the limited nutrient, phosphate. This work fills in the missing steps in the inositol pyrophosphate synthesis pathway and points to a role for these molecules in the plant cell nucleus. This is an important advance that can help us design future strategies to increase phosphate efficiency in plants.
Increased Th1 bias in memory T cells corresponds with protection from reinfection inPlasmodiuminfection, and is regulated by T cell-intrinsic STAT3
Authors: Carpio Victor H. , Aussenac Florentin , Wilson Kyle D. , Villarino Alejandro V. , Dent Alexander L. , Stephens Robin 
Published: August 2019

SummaryHybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to persistent infections; however, molecular regulation of their function is poorly defined. In infection withPlasmodium spp, an IFN-γ+T helper-1 (Th1) response controls initial parasitemia, while antibody and IL-21+CXCR5+T follicular helper (Tfh) function effect final clearance. Here, we found that CD4-intrinsic Bcl6, Blimp-1 and STAT3 all regulate T-bet expression, which controls IFN-γ expression. While Bcl6 and Blimp-1 regulate the level of CXCR5, only T-bet and STAT3 affected the functional bias of the Th1/Tfh phenotype. Infected mice with STAT3-deficient T cells produced less antibody, and more IFN-γ+IL-21−CXCR5loT cells, significantly increasing protection from re-infection. Conversely, reduced Th1 bias in re-infected T-bet KO was reflected in prolonged secondary parasitemia. In summary, each feature of hybrid Th1/Tfh population inPlasmodiuminfection is uniquely regulated and the cytokine bias of memory T cells can be modified to enhance the effectiveness of the response.
Isolation of an antimicrobial resistant, biofilm forming,Klebsiella grimontiiisolate from a re-usable water bottle
Authors: Hubbard Alasdair TM , Reiné Jesús , Newire Enas , Wright Elli , Murphy Emma A , Hutton William , Roberts Adam P 
Published: August 2019

AbstractA re-usable water bottle was swabbed as part of the citizen science project Swab and Send and aKlebsiella grimontiiisolate was recovered on chromogenic agar and designated SS141. Whole genome sequencing of SS141 showed it has the potential to be a human pathogen as it contains the biosynthetic gene cluster for the potent cytotoxin, kleboxymycin, and genes for other virulence factors. The genome also containsblaOXY-6-4 andfosAwhich is likely to explain the observed resistance to ampicillin, amoxicillin and fosfomycin. We have also shown that SS141 is a potent biofilm former, providing a reasonable explanation for its ability to colonise a re-usable water bottle. With the increasing use of re-usable water bottles as an alternative to disposables, and a strong forecast for growth in this industry over the next decade, this study highlights the need for cleanliness comparable to other re-usable culinary items.
Quantitative Cytogenetics Reveals Molecular Stoichiometry and Longitudinal Organization of Meiotic Chromosome Axes and Loops
Authors: Woglar Alexander , Yamaya Kei , Roelens Baptiste , Boettiger Alistair , Köhler Simone , Villeneuve Anne M 
Published: August 2019

ABSTRACTDuring meiosis, chromosomes adopt a specialized organization involving assembly of a cohesin-based axis along their lengths, with DNA loops emanating from this axis. We applied novel, quantitative and widely applicable cytogenetic strategies to elucidate the molecular bases of this organization usingC. elegans. Analyses of WT chromosomes andde novocircular mini-chromosomes revealed that meiosis-specific HORMA-domain proteins assemble into cohorts in defined numbers and co-organize the axis together with two functionally-distinct cohesin complexes (REC-8 and COH-3/4) in defined stoichiometry. We further found that REC-8 cohesins, which load during S phase and mediate sister chromatid cohesion, usually occur as individual complexes, supporting a model wherein sister cohesion is mediated locally by a single cohesin ring. REC-8 complexes are interspersed in an alternating pattern with cohorts of axis-organizing COH-3/4 complexes (averaging three per cohort), which are insufficient to confer cohesion but can bind to individual chromatids, suggesting a mechanism to enable formation of asymmetric sister chromatid loops. Indeed, immuno-FISH assays demonstrate frequent asymmetry in genomic content between the loops formed on sister chromatids. We discuss how features of chromosome axis/loop architecture inferred from our data can help to explain enigmatic, yet essential, aspects of the meiotic program.
In vitro and in silico modeling of cellular and matrix-related changes during the early phase of osteoarthritis
Authors: Weber Marie-Christin , Fischer Lisa , Damerau Alexandra , Ponomarev Igor , Pfeiffenberger Moritz , Gaber Timo , Götschel Sebastian , Lang Jens , Röblitz Susanna , Buttgereit Frank , Ehrig Rainald , Lang Annemarie 
Published: August 2019

AbstractObjectiveUnderstanding the pathophysiological processes of osteoarthritis (OA) require adequate model systems. Although different in vitro or in vivo models have been described, further comprehensive approaches are needed to study specific parts of the disease. This study aimed to combine in vitro and in silico modeling to describe cellular and matrix-related changes during the early phase of OA. We developed an in vitro OA model based on scaffold-free cartilage-like constructs (SFCCs), which was mathematically modeled using a partial differential equation (PDE) system to resemble the processes during the onset of OA.DesignSFCCs were produced from mesenchymal stromal cells and analyzed weekly by histology and qPCR to characterize the cellular and matrix-related composition. To simulate the early phase of OA, SFCCs were treated with interleukin-1β (IL-1β), tumor necrosis factor α (TNFα) and examined after 3 weeks or cultivated another 3 weeks without inflammatory cytokines to validate the regeneration potential. Mathematical modeling was performed in parallel to the in vitro experiments.ResultsSFCCs expressed cartilage-specific markers, and after stimulation an increased expression of inflammatory markers, matrix degrading enzymes, a loss of collagen II (Col-2) and a reduced cell density was observed which could be partially reversed by retraction of stimulation. Based on the PDEs, the distribution processes within the SFCCs, including those of IL-1β, Col-2 degradation and cell number reduction was simulated.ConclusionsBy combining in vitro and in silico methods, we aimed to develop a valid, efficient alternative approach to examine and predict disease progression and new therapeutic strategies.
Stochasticity-induced stabilization in ecology and evolution
Authors: Dean Antony , Shnerb Nadav M. 
Published: August 2019

AbstractThe ability of random environmental variation to stabilize competitor coexistence was pointed out long ago and, in recent years, has received considerable attention. Here we suggest a novel and generic synthesis of stochasticity-induced stabilization (SIS) phenomena. The storage effect in the lottery model, together with other well-known examples drawn from population genetics, microbiology and ecology, are placed together, reviewed, and explained within a clear, coherent and transparent theoretical framework. Implementing the diffusion approximation we show that in all these systems (including discrete and continuous dynamics, with overlapping and non-overlapping generations) the ratio between the expected growth and its variance governs both qualitative and quantitative features of persistence and invasibility. We further clarify the relationships between bet-hedging strategies, generation time and SIS, study the dynamics of extinction when SIS fails and the explain effects of species richness and asymmetric competition on the stabilizing mechanism.
A biophysical model of striatal microcircuits suggests delta/theta-rhythmically interleaved gamma and beta oscillations mediate periodicity in motor control
Authors: Chartove Julia A. K. , McCarthy Michelle M. , Pittman-Polletta Benjamin R. , Kopell Nancy J. 
Published: August 2019

AbstractStriatal oscillatory activity is associated with movement, reward, and decision-making, and observed in several interacting frequency bands. Local field potential recordings in rodent striatum show dopamine- and reward-dependent transitions between two states: a “spontaneous” state involving β (~15-30 Hz) and low γ (~40-60 Hz), and a state involving θ (~4-8 Hz) and high γ (~60-100 Hz) in response to dopaminergic agonism and reward. The mechanisms underlying these rhythmic dynamics, their interactions, and their functional consequences are not well understood. In this paper, we propose a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of these rhythms, as well as their modulation by dopamine. Building on previous modeling and experimental work suggesting that striatal projection neurons (SPNs) are capable of generating β oscillations, we show that networks of striatal fast-spiking interneurons (FSIs) are capable of generating δ/θ (ie, 2 to 6 Hz) and γ rhythms. Under simulated low dopaminergic tone our model FSI network produces low γ band oscillations, while under high dopaminergic tone the FSI network produces high γ band activity nested within a δ/θ oscillation. SPN networks produce β rhythms in both conditions, but under high dopaminergic tone, this β oscillation is interrupted by δ/θ-periodic bursts of γ-frequency FSI inhibition. Thus, in the high dopamine state, packets of FSI γ and SPN β alternate at a δ/θ timescale. In addition to a mechanistic explanation for previously observed rhythmic interactions and transitions, our model suggests a hypothesis as to how the relationship between dopamine and rhythmicity impacts motor function. We hypothesize that high dopamine-induced periodic FSI γ-rhythmic inhibition enables switching between β-rhythmic SPN cell assemblies representing the currently active motor program, and thus that dopamine facilitates movement in part by allowing for rapid, periodic shifts in motor program execution.Author summaryStriatal oscillatory activity is associated with movement, reward, and decision-making, and observed in several interacting frequency bands. The mechanisms underlying these rhythmic dynamics, their interactions, and their functional consequences are not well understood. In this paper, we propose a biophysical model of striatal microcircuits that comprehensively describes the generation and interaction of striatal rhythms, as well as their modulation by dopamine. Our model suggests a hypothesis as to how the relationship between dopamine and rhythmicity impacts the function of the motor system, enabling rapid, periodic shifts in motor program execution.
A biomimetic electrical stimulation strategy to induce asynchronous stochastic neural activity
Authors: Formento Emanuele , D’Anna Edoardo , Gribi Sandra , Lacour Stéphanie P. , Micera Silvestro 
Published: August 2019

AbstractElectrical stimulation is an effective method to communicate with the nervous system. Here, we demonstrate that current stimulation paradigms fail to reproduce the stochastic and asynchronous properties of natural patterns of neural activity, and introduce a novel biomimetic stimulation (BioS) strategy that overcomes these limitations. We hypothesized that high-frequency amplitude-modulated bursts of stimulation could induce asynchronous neural firings by distributing recruitment over the duration of a burst, without sacrificing the ability to precisely control neural activity. We tested this hypothesis using computer simulations and ex vivo experiments. We found that BioS bursts induce asynchronous, stochastic, yet controllable, neural activity. We established that varying the amplitude, duration, and repetition frequency of a BioS burst enables graded modulation of the number of recruited fibers, their firing rate, and the synchronicity of the responses. These results demonstrate an unprecedented level of control over artificially induced neural activity, enabling the design of next-generation biomimetic stimulation paradigms with potentially profound consequences for the field of neurostimulation.