bluuebunny/crossref_metadata_2025_split huggingface dataset:
A model-based analysis of the mechanical cost of walking on uneven terrain
Authors: Voloshina Alexandra S. , Kuo Arthur D. , Ferris Daniel P. , Remy C. David 
Published: June 2020

AbstractHuman walking on uneven terrain is energetically more expensive than on flat, even ground. This is in part due to increases in, and redistribution of positive work among lower limb joints. To improve understanding of the mechanical adaptations, we performed analytical and computational analyses of simple mechanical models walking over uneven terrain comprised of alternating up and down steps of equal height. We simulated dynamic walking models using trailing leg push-off and/or hip torque to power gait, and quantified the compensatory work costs vs. terrain height. We also examined the effect of swing leg dynamics by including and excluding them from the model. We found that greater work, increasing approximately quadratically with uneven terrain height variations, was necessary to maintain a prescribed average forward speed. Greatest economy was achieved by modulating precisely-timed push-offs for each step height. Least economy was achieved with hip power, which did not require as precise timing. This compares well with observations of humans on uneven terrain, showing similar near-normal push-off but with more variable step timing, and considerably more hip work. These analyses suggest how mechanical work and timing could be adjusted to compensate for real world environments.
Mathematical connection between short telomere induced senescence calculation and mortality rate data
Authors: Torrance Jerry B. , Goldband Steve 
Published: June 2020

AbstractThe last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only 3 parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate, for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement provides strong evidence (but not proof) that the mechanism of STLIS plays an important role in the major diseases of aging (e.g., cardiovascular disease, many cancers, and diabetes mellitus) which dominate human mortality. This result represents significant progress in our understanding the factors behind the cause of aging.
Cross talk between tumor stroma and cancer cells plays a critical role in progressive enrichment of cancer stem cell phenotype in primary breast tumors
Authors: Dhanota Ninjit , Bal Amanjit , Singh Gurpreet , Arora Sunil K 
Published: June 2020

AbstractIn order to delineate the underlying molecular mechanisms responsible for intra tumoral enrichment of BCSCs in aggressive breast tumors, firstly we evaluated the frequency and characteristics of breast cancer stem cells (BCSCs) within the tumor mass as well as in pathologically normal adjacent tissues in primary breast carcinomas of various clinical and histological grades. Then, we evaluated the expression profiles of various genes in non-cancer stem cells from these tumors to delineate the role played by cellular niche in de novo origin and/or expansion of intra-tumoral cancer stem cells.The study included primary tumor and adjacent normal breast tissue specimens from chemotherapy-naïve breast carcinoma patients. The BCSCs, identified as Lin-CD44+CD24-and aldehyde dehydrogenase 1 A1 positive were enumerated. The frequency of intra-tumoral BCSCs was correlated with various clinicopathological parameters of breast cancer. The flow-cytometrically sorted stromal cells and cancer cells from treatment naïve primary breast tumors were processed for gene expression profiling using a custom designed PCR array of genes known to facilitate cancer cell proliferation and disease progression.The frequency of BCSCs within the tumor mass as well as in the adjacent normal tissue correlated significantly with histopathological and molecular grades of tumors indicating a direct relationship of BCSC with aggressive behavior of breast cancer. A significantly higher number of BCSCs was also detected in metastatic LN group as compared to non-metastatic LN. Further, a significantly increased expression of the genes associated with growth factors, cytokines & matricellular proteins in tumors with high BCSCs content (> 5%; Hi-BCSCs tumors) as compared to Lo-BCSC tumors (with <5% intratumoral BCSC content) suggested the possible contribution of stromal cells and cancer cells in intra-tumoral expansion of CSCs. Similarly, a significant up-regulation of genes associated with hypoxia and angiogenesis in Hi-BCSCs tumors further supported the role of hypoxic environment. The expression levels of genes associated with epithelial to mesenchymal transition also followed a similar pattern. On the other hand, downregulated SNAI1 gene (generally upregulated in onset of EMT) in stromal cells of Hi-BCSCs tumors suggests a post EMT environment in Hi-BCSCs tumors.The findings suggest that the molecular crosstalk between the non-BCSC niche cells and the cancer stem cells within the breast cancer microenvironment directly contribute to formation of biologically conducive conditions for expansion of cancer stem cells.
Yeast grown in continuous culture systems can detect mutagens with improved sensitivity relative to the Ames test
Authors: Ong Joseph Y , Pence Julia T , Molik David C , Goodson Holly V 
Published: June 2020

AbstractContinuous culture systems allow for the controlled growth of microorganisms over a long period of time. Here, we develop a novel test for mutagenicity that involves growing yeast in continuous culture systems exposed to low levels of mutagen for a period of weeks. In contrast, most microorganism-based tests for mutagenicity expose the potential mutagen to the biological reporter at a high concentration of mutagen for a short period of time. Our test improves upon the sensitivity of the well-established Ames test by at least 20-fold for each of two mutagens that act by different mechanisms (the intercalator ethidium bromide and alkylating agent methylmethane sulfonate). To conduct the tests, cultures were grown in small, inexpensive continuous culture systems in media containing (potential) mutagen, and the resulting mutagenicity of the added compound was assessed via two methods: a canavanine-based plate assay and whole genome sequencing. In the canavanine-based plate assay, we were able to detect a clear relationship between the amount of mutagen and the number of canavanine-resistant mutant colonies over a period of one to three weeks of exposure. Whole genome sequencing of yeast grown in continuous culture systems exposed to MMS demonstrated that quantification of mutations is possible by identifying the number of unique variants across each strain but with lower sensitivity than the plate-based assay. In conclusion, we propose yeast grown in continuous culture systems can provide an improved and more sensitive test for mutagenicity.
Fast weight recovery, metabolic rate adjustment and gene-expression regulation define responses of cold-stressed honey bee brood
Authors: Ramirez Leonor , Luna Facundo , Mucci Claudio Andoni , Lamattina Lorenzo 
Published: June 2020

ABSTRACTIn temperate climates, low ambient temperatures in late winter and in spring can result in cold stress conditions in brood areas of weakened honey bee colonies, leading to increased levels of developmental interruptions and death of the brood. Very little is known about the physiological and molecular mechanisms that regulate honey bee brood responses to acute cold-stress. Here, we hypothesized that central regulatory pathways mediated by insulin/insulin-like peptide signalling (IIS) and adipokinetic hormone (AKH) are linked to metabolic changes in cold-stressed honey bee brood.A. melliferabrood reared at suboptimal temperatures showed diminished growth rate and arrested development progress. Notably, cold-stressed brood rapidly recovers the growth in the first 24 h after returning at control rearing temperature, sustained by the induction of compensatory mechanisms. We determined fast changes in the expression of components of IIS and AKH pathways in cold-stressed brood supporting their participation in metabolic events, growth and stress responses. We also showed that metabolic rate keeps high in brood exposed to stress suggesting a role in energy supply for growth and cell repair. Additionally, transcript levels of the uncoupling protein MUP2 were elevated in cold-stressed brood, suggesting a role for heat generation through mitochondrial decoupling mechanisms and/or ROS attenuation. Physiological, metabolic and molecular mechanisms that shape the responses to cold-stress in honey bee brood are addressed and discussed.
Collective motion as a distinct behavioural state of the individual
Authors: Knebel Daniel , Sha-ked Ciona , Agmon Noa , Ariel Gil , Ayali Amir 
Published: June 2020

SummaryThe collective motion of swarms depends on adaptations at the individual level. We explored these and their effects on swarm formation and maintenance in locusts. The walking kinematics of individual insects were monitored under laboratory settings, before, as well as during collective motion in a group, and again after separation from the group. It was found that taking part in collective motion induced in the individual unique behavioural kinematics, suggesting the existence of a distinct behavioural mode that we term a “collective-motion-state”. This state, characterized by behavioural adaptation to the social context, is long lasting, not induced by crowding per-se, but only by experiencing collective motion. Utilizing computational models, we show that this adaptability increases the robustness of the swarm. Overall, our findings suggest that collective-motion is not only an emergent property of the group, but also depends on a behavioural mode, rooted in endogenous mechanisms of the individual.
Dendritic coincidence detection in Purkinje neurons of awake mice
Authors: Roome Christopher J. , Kuhn Bernd 
Published: June 2020

SummaryDendritic coincidence detection is thought fundamental to neuronal processing, yet the underlying dendritic voltage-calcium relationship remains unexplored in awake animals. Here, using simultaneous voltage and calcium two-photon imaging of Purkinje neuron spiny dendrites, we show how coincident sub- and suprathreshold synaptic inputs modulate dendritic calcium signaling during sensory stimulation in awake mice. Sensory stimulation evokes subthreshold excitatory and inhibitory post-synaptic potentials, that coincide with suprathreshold dendritic spikes triggered by climbing fiber and parallel fiber synaptic input. Purkinje neuron dendrites integrate these inputs in a time-dependent and non-linear fashion to enhance the sensory evoked dendritic calcium signal. Intrinsic supra-linear dendritic mechanisms, including voltage gated calcium channels and metabotropic glutamate receptors, are recruited cooperatively to expand the dynamic range of sensory evoked dendritic calcium signals. This establishes how dendrites use multiple interplaying mechanisms to perform coincidence detection, as a fundamental and ongoing feature of dendritic integration during behavior.
Miniaturized Devices for Bioluminescence Imaging in Freely Behaving Animals
Authors: Celinskis Dmitrijs , Friedman Nina , Koksharov Mikhail , Murphy Jeremy , Gomez-Ramirez Manuel , Borton David , Shaner Nathan , Hochgeschwender Ute , Lipscombe Diane , Moore Christopher 
Published: June 2020

AbstractFluorescence miniature microscopyin vivohas recently proven a major advance, enabling cellular imaging in freely behaving animals. However, fluorescence imaging suffers from autofluorescence, phototoxicity, photobleaching and non-homogeneous illumination artifacts. These factors limit the quality and time course of data collection. Bioluminescence provides an alternative kind of activity-dependent light indicator. Bioluminescent calcium indicators do not require light input, instead generating photons through chemiluminescence. As such, limitations inherent to the requirement for light presentation are eliminated. Further, bioluminescent indicators also do not require excitation light optics: the removal of this component should make lighter and lower cost microscope with fewer assembly parts. While there has been significant recent progress in making brighter and faster bioluminescence indicators, parallel advances in imaging hardware have not yet been realized. A hardware challenge is that despite potentially higher signal-to-noise of bioluminescence, the signal strength is lower than that of fluorescence. An open question we address in this report is whether fluorescent miniature microscopes can be rendered sensitive enough to detect bioluminescence. We demonstrate this possibilityin vitroandin vivoby implementing optimizations of the UCLA fluorescent miniscope. These optimizations yielded a miniscope (BLmini) which is 22% lighter in weight, has 45% fewer components, is up to 58% less expensive, offers up to 15 times stronger signal (as dichroic filtering is not required) and is sensitive enough to capture spatiotemporal dynamics of bioluminescence in the brain with a signal-to-noise ratio of 34 dB.
Extracellular GABA waves regulate coincidence detection in excitatory circuits
Authors: Sylantyev Sergiy , Savtchenko Leonid P. , O’Neill Nathanael , Rusakov Dmitri A. 
Published: June 2020

AbstractCoincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feed-forward inhibitory circuit also involving the hyperpolarization-activatedIhcurrent. However, afferent connections often bypass feed-forward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA ‘sniffer’ patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly reduces the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade expands it. The underlying mechanism involves membrane-shunting tonic GABAAreceptor current; it does not have to rely onIhbut depends strongly on the neuronal GABA transporter GAT-1. We use dendrite-soma dual patch-clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.
Dissecting transcriptomic signatures of genotype x genotype interactions during the initiation of plant-rhizobium symbiosis
Authors: Fagorzi Camilla , Bacci Giovanni , Huang Rui , Cangioli Lisa , Checcucci Alice , Fini Margherita , Perrin Elena , Natali Chiara , diCenzo George Colin , Mengoni Alessio 
Published: June 2020

AbstractRhizobia are ecologically important, facultative plant symbiotic microbes. In nature there exists large variability in the association of rhizobial strains and host plant of the same species. Here, we evaluated whether plant and rhizobial genotypes influence the initial transcriptional response of rhizobium following perception of host plant. RNA-sequencing of the model rhizobiumSinorhizobium melilotiexposed to root exudates or luteolin was performed in a combination of threeS. melilotistrains and threeMedicago sativavarieties. The response to root exudates involved hundreds of changes in the rhizobium transcriptome. Of the differentially expressed genes, expression of 35% were influenced by strain genotype, 16% by the plant genotype, and 29% by strain x host plant genotype interactions. We also examined the response of a hybridS. melilotistrain, in which the symbiotic megaplasmid (~ 20% of the genome) was mobilized between two of the above-mentioned strains. Dozens of genes resulted up-regulated in the hybrid strain, indicative of nonadditive variation in the transcriptome. In conclusion, this study demonstrated that transcriptional responses of rhizobia upon perception of legumes is influenced by the genotypes of both symbiotic partners, and their interaction, suggesting a wide genetic spectrum of partner choice selection in plant-rhizobium symbiosis.
Predicting Mean Ribosome Load for 5’UTR of any length using Deep Learning
Authors: Karollus Alexander , Avsec Žiga , Gagneur Julien 
Published: June 2020

AbstractThe 5’ untranslated region plays a key role in regulating mRNA translation and consequently protein abundance. Therefore, accurate modeling of 5’UTR regulatory sequences shall provide insights into translational control mechanisms and help interpret genetic variants. Recently, a model was trained on a massively parallel reporter assay to predict mean ribosome load (MRL) - a proxy for translation rate - directly from 5’UTR sequence with a high degree of accuracy. However, this model is restricted to sequence lengths investigated in the reporter assay and therefore cannot be applied to the majority of human sequences without a substantial loss of information. Here, we introduced frame pooling, a novel neural network operation that enabled the development of an MRL prediction model for 5’UTRs of any length. Our model shows state-of-the-art performance on fixed length randomized sequences, while offering better generalization performance on longer sequences and on a variety of translation-related genome-wide datasets. Variant interpretation is demonstrated on a 5’UTR variant of the gene HBB associated with beta-thalassemia. Frame pooling could find applications in other bioinformatics predictive tasks. Moreover, our model, released open source, could help pinpoint pathogenic genetic variants.
Production and analysis of a mammalian septin hetero-octamer complex
Authors: DeRose Barry T. , Kelley Robert S. , Ravi Roshni , Kokona Bashkim , Spiliotis Elias T. , Padrick Shae B. 
Published: June 2020

AbstractThe septins are filament-forming proteins found in diverse eukaryotes from fungi to vertebrates, with roles in cytokinesis, shaping of membranes and modifying cytoskeletal organization. These GTPases assemble into rod-shaped soluble hetero-hexamers and hetero-octamers in mammals, which polymerize into filaments and higher order structures. While the cell biology and pathobiology of septins are advancing rapidly, mechanistic study of the mammalian septins is limited by a lack of recombinant hetero-octamer materials. We describe here the production and characterization of a recombinant mammalian septin hetero-octamer of defined stoichiometry, the SEPT2/SEPT6/SEPT7/SEPT3 complex. Using a fluorescent protein fusion to the complex, we observed filaments assembled from this complex. In addition, we used this novel tool to resolve recent questions regarding the organization of the soluble septin complex. Biochemical characterization of a SEPT3 truncation that disrupts SEPT3-SEPT3 interactions is consistent with SEPT3 occupying a central position in the complex while the SEPT2 subunits are at the ends of the rod-shaped octameric complexes. Consistent with SEPT2 being on the complex ends, we find that our purified SEPT2/SEPT6/SEPT7/SEPT3 hetero-octamer copolymerizes into mixed filaments with separately purified SEPT2/SEPT6/SEPT7 hetero-hexamer. We expect this new recombinant production approach to lay essential groundwork for future studies into mammalian septin mechanism and function.
New insights on the modelling of the molecular mechanisms underlying neural maps alignment in the midbrain
Authors: Savier Elise Laura , Dunbar James , Cheung Kyle , Reber Michael 
Published: June 2020

AbstractWe previously identified and modelled a principle of visual maps alignment in the midbrain involving the mapping of the retinal projections and concurrent transposition of retinal guidance cues into the superior colliculus providing positional information for the organization of cortical V1 projections onto the retinal map (Savier et al., 2017). This principle relies on mechanisms involving Epha/Efna signaling, correlated neuronal activity and axon competition. Here, using the 3-step map alignment computational model, we predict and validate in vivo the visual mapping defects in a well-characterized mouse model. Our results challenge previous hypotheses and provide an alternative, although complementary, explanation for the phenotype observed. In addition, we propose a new quantification method to assess the degree of alignment and organization between maps, allowing inter-model comparisons. This work generalizes the validity and robustness of the 3-step map alignment algorithm as a predictive tool and confirms the basic mechanisms of visual maps organization.
Depletion of cardiolipin induces major changes in energy metabolism inTrypanosoma bruceibloodstream forms
Authors: Serricchio Mauro , Hierro-Yap Carolina , Schädeli David , Hamidane Hisham Ben , Hemphill Andrew , Graumann Johannes , Zíková Alena , Bütikofer Peter 
Published: June 2020

AbstractCardiolipin (CL) is a mitochondrial inner membrane glycerophospholipid that associates with mitochondrial proteins to promote their activities and to facilitate protein complex and super-complex formation. Loss of CL leads to destabilized respiratory complexes and mitochondrial dysfunction. The role of CL in an organism lacking a conventional electron transport chain (ETC) has not been elucidated so far. We now report that inTrypanosoma bruceibloodstream forms, in which the ETC is truncated and composed of alternative oxidase and glycerol-3-phosphate dehydrogenase, and the mitochondrial membrane potential is generated by the hydrolytic action of the FoF1-ATP synthase, the inducible depletion of cardiolipin synthase (TbCls) is essential for parasite survival. Loss of TbCls and CL caused a rapid drop in ATP levels and a decline in the mitochondrial membrane potential. Unbiased proteomic analyses revealed a reduction in the levels of many mitochondrial proteins, most notably of FoF1-ATP synthase subunits and of the alternative oxidase, resulting in a strong decline of glycerol-3-phosphate-stimulated oxygen consumption. Interestingly, the changes in cellular respiration preceded the observed decrease in FoF1-ATPase stability, suggesting that the truncated ETC is the first pathway responding to the decline in CL. In addition, proteomic and metabolomic analyses revealed that select proteins and pathways involved in glucose and amino acid transport and metabolism are up-regulated during CL depletion, possibly as a stress response to restore cellular ATP levels.