bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hierarchical nanomechanics of collagen microfibrils
Authors: Gautieri Alfonso , Vesentini Simone , Redaelli Alberto , Buehler Markus J. 
Published: July 2019

AbstractCollagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al. (Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young’s modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young’s modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential.
Fractal-like Distributions over the Rational Numbers in High-throughput Biological and Clinical Data
Authors: Trifonov Vladimir , Pasqualucci Laura , Dalla-Favera Riccardo , Rabadan Raul 
Published: July 2019

AbstractRecent developments in extracting and processing biological and clinical data are allowing quantitative approaches to studying living systems. High-throughput sequencing, expression profiles, proteomics, and electronic health records are some examples of such technologies. Extracting meaningful information from those technologies requires careful analysis of the large volumes of data they produce. In this note, we present a set of distributions that commonly appear in the analysis of such data. These distributions present some interesting features: they are discontinuous in the rational numbers, but continuous in the irrational numbers, and possess a certain self-similar (fractal-like) structure. The first set of examples which we present here are drawn from a high-throughput sequencing experiment. Here, the self-similar distributions appear as part of the evaluation of the error rate of the sequencing technology and the identification of tumorogenic genomic alterations. The other examples are obtained from risk factor evaluation and analysis of relative disease prevalence and co-mordbidity as these appear in electronic clinical data. The distributions are also relevant to identification of subclonal populations in tumors and the study of the evolution of infectious diseases, and more precisely the study of quasi-species and intrahost diversity of viral populations.
A Discrete State Model for Kinesin-1 with Rate Constants Modulated by Neck Linker Tension
Authors: Koch Steven , Herskowitz Lawrence 
Published: July 2019

AbstractKinesin-1 is a homodimeric molecular motor protein that uses ATP and a hand-over-hand motion to transport cargo along microtubules. How kinesin converts chemical energy into directed motion is a question that has been actively studied since its discovery. Even at the most coarse-grained level of chemical kinetics, understanding is still lacking. Minimal kinetic models are often developed to both explain kinesin’s hand-over-hand forward-stepping behavior and to infer important kinetic rate constants from experimental data. These minimal models are often limited to a handful of two-headed states on a core cycle and have been essential for the current level of understanding. However, it is not always clear how to evolve these core-cycle models to explain more complex behavior such as non-processive motion. We have taken a different approach and have developed a kinetic model without a pre-defined core cycle. Our model includes 80 two-headed states and permits transitions between any two states that differ by a single catalytic or binding event. We constrain the rate constants as much as possible by published experimental data. We define many of the remaining unknown rate constants based on mechanical strain in the kinesin neck linkers and their docking state. We present a one-dimensional model for neck-linker modulation of head binding and unbinding rates and nucleotide binding and unbinding rates. We show that our model reproduces a run length (processivity) and run time in the range of experimental results. The core cycles that emerge are slightly different than those commonly discussed. We also explore how processivity and speed change with neck linker length. Our modeling applications are available as LabVIEW open-source code and compiled executables for PCs, which will allow other research groups to adapt the model and rate constants and may aid in general understanding of molecular motor behavior.
Elevated central serotonin levels inhibit emotional crying
Authors: van der Veen Frederik , Jorritsma Joyce , Krijger Carola , Vingerhoets Ad 
Published: July 2019

AbstractPrevious research has suggested a possible role of serotonin in emotional expressions, such as crying. We have found that a transient increase of central serotonin levels by means of oral administration of paroxetine reduces crying in response to emotional movies in healthy female volunteers. This is the first direct evidence of an important role of serotonin in this uniquely human emotional response.
Auditory cortex mediates the perceptual effects of acoustic temporal expectation
Authors: Jaramillo Santiago , Zador Anthony 
Published: July 2019

AbstractWhen events occur at predictable instants, anticipation improves performance. Knowledge of event timing modulates motor circuits, improving response speed. By contrast, the neuronal mechanisms underlying changes in sensory perception due to expectation are not well understood. We have developed a novel behavioral paradigm for rats in which we manipulated expectations about sound timing. Valid expectations improved both the speed and the accuracy of subjects' performance, indicating not only improved motor preparedness but also enhanced perception. Single neuron recordings in primary auditory cortex revealed enhanced representation of sounds during periods of heightened expectation. Furthermore, we found that activity in auditory cortex was causally linked to the performance of the task, and that changes in the neuronal representation of sounds predicted performance on a trial-by-trial basis. Our results indicate that changes in neuronal representation as early as primary sensory cortex mediate the perceptual advantage conferred by temporal expectation.
Lego DNA assembling, a simple in vitro method for constructing DNA molecule
Authors: Xian Mo , Jiang Xinglin , Yang Jianming , Zhang Haibo , Liu Huaiwei , Zheng Yanning , Wang Cong , Su Sizheng 
Published: July 2019

AbstractDigestion-ligation based and recombination based methods for constructing recombinant DNA are the basic techniques in molecular biology and thus built one of the foundations for the modern life sciences. Here we describe a new strategy that can radically simplify some of the same task. The lego DNA assembling, based on strand annealing, allows in vitro assembly of multi DNA fragments in one step with precise junctions and excludes the need for any enzyme. As a proof of concept, we rapidly constructed plasmids from 4, 6 and 8 fragments with very high efficiencies (100%). And we found this method a powerful tool for synthetic biology, constructing a partial isoprene biosynthesis pathway (consisting of four genes) in 2 days. We also assembled a customized expression vector to show its modularity.
Local field potentials, BOLD and spiking activity – relationships and physiological mechanisms
Authors: Berens Philipp , Logothetis Nikos , Tolias Andreas 
Published: July 2019

AbstractExtracellular voltage fluctuations (local field potentials, LFPs) reflecting neural mass action are ubiquitous across species and brain regions. Numerous studies have characterized the properties of LFP signals in the cortex to study sensory and motor computations as well as cognitive processes like attention, perception and memory. In addition, its extracranial counterpart – the electroencephalogram – is widely used in clinical applications. However, the link between LFP signals and the underlying activity of local populations of neurons is still largely elusive. For the LFP to aid our understanding of cortical computation, however, we need to know as precisely as possible what aspects of neural mass action it reflects. In this chapter, we examine recent advances and results regarding the origin, the feature selectivity and the spatial resolution of the local field potential and discuss its relationship to local spiking activity as well as the BOLD signal used in fMRI. We place particular focus on the gamma-band of the local field potential since it has long been implicated to play an important role in sensory processing. We conclude that in contrast to spikes, the local field potential does not measure the output of the computation performed by a cortical circuit, but are rather indicative of the synaptic and dendritic processes, as well as the dynamics of cortical computation.
Taking shortcuts with OWL using safe macros
Authors: Mungall Christopher , Ruttenberg Alan , Osumi-Sutherland David 
Published: July 2019

AbstractAccurate representation of complex domains such as biology demands powerful and expressive ontology languages such as OWL. However, the complex nested class expressions required for modeling can be a hindrance to ontology authoring and adoption. These class expressions can appear opaque to domain experts, and even users proficient in OWL can benefit from some kind of syntactic sugar or "short-cut"strategy, especially when authoring large ontologies.One solution is to have domain experts fill in simple templates (for example, in Excel) and translate the results into more complex axioms,but this has the disadvantage of being disconnected from full ontology authoring and reasoning environment.We present here a method of specifying shortcut properties directly in OWL. These shortcut properties can be used in similar ways as object properties within the OWL environment, with the resulting simple axioms translated automatically to more complex axioms via macro expansion. We describe some example scenarios where this is of use in authoring existing bio-ontologies.One of the main implications of this work is a way to simplify the translation between OBO format and OWL, and the use of RDF triple-stores with complex OWL ontologies.
Screening for the optimal siRNA targeting a novel gene (HA117) and construction and evaluation of a derivative recombinant adenovirus
Authors: Xu Youhua , Zheng Gaihuan , Guo Yuxia , Jin Xianqing , Luo Qing 
Published: July 2019

AbstractWe found a novel gene named as HA117 in our previous research. At this study, we screened for an optimal siRNA targeting the novel gene HA117 using the pSOS-HUS method, verified the results of pSOS-HUS siRNA screening for optimal affinity for the target gene, and constructed and evaluated a recombinant adenovirus carrying the DNA template for transcription of the optimal HA117 siRNA. The pSOS-HUS vector method was successfully utilized as a rapid and effective screen for an optimal siRNA for a target gene. Among five pairs of DNA templates, siRNA transcribed from HAi5 gave the strongest interference with the novel gene HA117; a HAi5-carrying recombinant adenovirus (Ad-HAi5) was successfully constructed and evaluated, laying a foundation for the further study of HA117 gene function with RNAi technology.
Photoprotection in Southern Ocean phytoplankton: missing key to low primary productivity
Authors: Griffith Gary , Vennell Ross 
Published: July 2019

AbstractThe Southern Ocean is considered a zone of high nutrients and low chlorophyll (HNLC). Despite the year round availability of nutrients, phytoplankton biomass remains low. Key modes of control are now thought to be light, grazing, iron and supply of silicic acid^1^. Physiological photoprotective mechanisms used by phytoplankton to regulate photosynthesis versus rapid light fluctuations have not been considered important. In diatoms and haptophytes, which are the major component of phytoplankton biodiversity in the Southern Ocean, the one step de-epoxidation of diadinoxanthin (Dd) into diatoxanthin (Dt) of the Dd-cycle constitutes the main photoprotective mechanism^2,3^. Here we show that Southern Ocean diatoms and haptophytes have higher concentrations of cellular Dd-cycle pigments than other oceanic regions. The Dd-cycle is activated under low irradiance conditions and the pool of photoprotective pigments increases under intermittent light conditions. The high cellular concentration of Dd-cycle pigments and our observations of an increase of the pool size of Dd-cycle pigments towards the surface implies that the Dd-cycle pigments bind to light harvesting proteins other than with fucoxanthin and chlorophyll c. Within photosystem II, enrichment of Dd and the physiological acclimation to light changes constrains photosynthetic activity, efficiency and potentially growth rates^3-7^. These results raise important questions about the role of photoprotective mechanisms in limiting Southern Ocean primary productivity and how these mechanisms will respond to predicted climate change impacts^8^.
Parallel genome assembly from pre-biotic split-genes: A solution for the mosaic genome conundrum
Authors: Senapathy Periannan , Kumar Brajendra , Mattox Jeffrey , Senapathy Sudar 
Published: July 2019

AbstractThe classical concept that all complex life evolved from a simple bacterium-like life form has been questioned by comparative genomics and proteomics. Several discoveries, including the occurrence of entirely new genes in unexpected life forms without any precursors, and the random mosaic distribution of genes across organisms in higher taxa undermine the principal assertions of this theory. We present a new model of the pre-biotic parallel evolution of eukaryotic genomes starting with the structurally complex split genes, which are far more probable of supporting biological information and of occurring in random DNA sequences than contiguous genes. By comparing the mosaic patterns of simulated genomes and extant genomes, we show that genomes arising from simulated assembly of random split genes form the same gene distribution patterns observed in extant eukaryotes. This parallel genome origin model eliminates the post-genomic and classical conundrums faced by the linear branching evolution model.
Miraculous Survival of Three Trapping Miners by Drinking High Mineral Mine Water for 25
Authors: Liang Cheng , Sheng Deng , Lin Wang , Mao Mu 
Published: July 2019

AbstractLittle is known that how long a human been can survive a complete starvation. There were dozens of miners who lost their lives in a coal mine disaster at Qinglong,Guizhou,China in June 2009, only three of them were rescued 25 days later after they had been trapped in a coal mine 600 meters underground. They maintained their lives only by drinking mineral water in the mine, which created a miracle of life. We reported here on this life miracle in relation to high mineral mine water.
Fish play Minority Game as humans do
Authors: Liaw Sy-Sang , Liu Ruey-Tarng , Chung Fei Fang 
Published: July 2019

AbstractPrevious computer simulations of the Minority Game (MG) have shown that the average agent number in the winning group (i.e., the minority group) had a maximal value such that the global gain was also maximal when an optimal amount of information was available to all agents . This property was further examined and its connection to financial markets has also been discussed . Here we report the results of an unprecedented real MG played by university staff members who clicked one of two identical buttons (A and B) on a computer screen while clocking in or out of work. We recorded the number of people who clicked button A for 1288 games, beginning on April 21, 2008 and ending on October 31, 2010, and calculated the variance among the people who clicked A as a function of time. We find that variance per person decreases to a minimum and rises to a value close to 1/4 which is the expected value when agents click buttons randomly. Our results are consistent with previous simulation results for the theoretical MG and suggest that our agents had employed more information for their strategies as their experience playing the game grew. We also carried out another experiment in which we forced 101 fish to enter one of the two symmetric chambers (A and B). We repeated the fish experiment 500 times and found that the variance of the number of fish that entered chamber A also decreased to a minimum and then increased to a saturated value, suggesting that fish have memory and can employ more strategies when facing the same situation again and again .
Shifting the balance of autophagy and proteasome activation reduces proteotoxic cell death: a novel therapeutic approach for restoring photoreceptor homeostasis
Authors: Qiu Yaoyan , Yao Jingyu , Jia Lin , Thompson Debra A. , Zacks David N. 
Published: July 2019

AbstractThe P23H variant of rhodopsin results in misfolding of the protein, and is a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). We have recently demonstrated that degeneration of photoreceptor cells in retinas of P23H mice is due to the endoplasmic reticulum stress (ERS)-induced activation of autophagy that leads to a secondary proteasome insufficiency and activation of cell death pathways. We propose that this increased level of autophagy flux relative to proteasome activity, which we term the A:P ratio, represents a marker of altered photoreceptor cell homeostasis, and that therapies aimed at normalizing this ratio will result in increased photoreceptor cell survival. To test this postulate, we treated P23H mice with a chemical chaperone (4-phenylbutyric acid) to improve rhodopsin folding, or with a selective phosphodiesterase-4 inhibitor (rolipram) to increase proteasome activity. P23H mice treated with either of these agents exhibited reduced ERS, decreased autophagy flux, increased proteasome activity, and decreased activation of cell death pathways. In addition, rates of retinal degeneration were decreased, and photoreceptor morphology and visual function were preserved. These findings support the conclusion that normalizing the A:P ratio, either by reducing the ERS-induced activation of autophagy, or by increasing proteasome activity, improves photoreceptor survival, and suggest a potential new therapeutic strategy for the treatment of adRP caused by protein folding defects.
Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer
Authors: Hu Wenjun , Lei Linping , Xie Xuqin , Huang Libin , Cui Qian , Dang Tang , Liu Gang Logan , Li Yuan , Sun Xiaofeng , Zhou Zongguang 
Published: July 2019

AbstractAlthough oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), tumor cells can develop mechanisms to evade oxaliplatin-induced cell death and show high tolerance and acquired resistance to this drug. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) has been proved to play a critical role in DNA repair during IgH class switch recombination (CSR) in B lymphocytes, while, its role in CRC and chemotherapeutic resistance remain unknown. Our study aims to uncover an unidentified mechanism of regulating DNA double-strand breaks (DSBs) by hnRNP L in CRC cells treated by oxaliplatin. In present study, we observed that knockdown of hnRNP L enhanced the level of DNA breakage and sensitivity of CRC cells to oxaliplatin. The expression of key DNA repair factors (BRCA1, 53BP1, and ATM) was unaffected by hnRNP L knockdown, thereby excluding the likelihood of hnRNP L mediation via mRNA regulation. Moreover, we observed that phosphorylation level of ATM changed oppositely to 53BP1 and BRCA1 in the CRC cells (SW620 and HCT116) which exhibit synergistic effect by oxaliplatin plus hnRNP L impairment. And similar phenomenon was observed in the foci formation of these critical repair factors. We also found that hnRNP L binds directly with these DNA repair factors through its RNA-recognition motifs (RRMs). Analysis of cell death indicated that the RRMs of hnRNP L are required for cell survival under incubation with oxaliplatin. In conclusion, hnRNP L is critical for the recruitment of the DNA repair factors in oxaliplatin-induced DSBs. Targeting hnRNP L is a promising new clinical approach that could enhance the effectiveness of current chemotherapeutic treatment in patients with resistance to oxaliplatin.
MEG3-derived miR-493-5p overcomes the oncogenic feature of IGF2-miR-483 loss of imprinting in hepatic cancer cells
Authors: Gailhouste Luc , Liew Lee Chuen , Yasukawa Ken , Hatada Izuho , Tanaka Yasuhito , Kato Takashi , Nakagama Hitoshi , Ochiya Takahiro 
Published: July 2019

AbstractNumerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3 differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.