bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient Reprogramming of Neonatal Cardiomyocytes to a Proliferative Dedifferentiated State
Authors: Kisby Thomas , de Lázaro Irene , Stylianou Maria , Cossu Giulio , Kostarelos Kostas 
Published: October 2019

AbstractZebrafish and urodele amphibians are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through transient expression ofOct3/4, Sox2, Klf4andc-Myc(OSKM) transcription factors. Here, we utilized an OSKM-encoding non-integrating vector to induce transient reprogramming of mammalian cardiomyocytesin vitro. Reprogramming factor expression in neonatal rat cardiomyocytes triggered rapid cell dedifferentiation characterized by downregulation of cardiomyocyte specific gene and protein expression, sarcomere dis-assembly and loss of autorhythmic contractile activity. Concomitantly, a significant increase in cell cycle related gene expression and Ki67 positive cells was observed, indicating that dedifferentiated cardiomyocytes possess an enhanced proliferative capacity. A small proportion of cardiomyocytes progressed through mesenchymal to epithelial transition, further indicating the initiation of cell reprogramming. However, complete reprogramming to a pluripotent-like state was not achieved for the duration of the study (20 days), both in standard and embryonic stem cell culture media conditions. The transient nature of this partial reprogramming response was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were recovered by day 15 after viral transduction. Further investigations into the complete downstream biological effects of ectopic OSKM expression in cardiomyocytes and the fate of these reprogrammed cells are warranted. Our results to date suggest that transient reprogramming could be a feasible strategy to recapitulate regenerative mechanisms of lower vertebrates and inform direct gene therapy approaches to cardiac regenerative medicine.
S-conLSH: Alignment-free gapped mapping of noisy long reads
Authors: Chakraborty Angana , Morgenstern Burkhard , Bandyopadhyay Sanghamitra 
Published: October 2019

AbstractMotivationThe advancement of SMRT technology has unfolded new opportunities of genome analysis with its longer read length and low GC bias. Alignment of the reads to their appropriate positions in the respective reference genome is the first but costliest step of any analysis pipeline based on SMRT sequencing. However, the state-of-the-art aligners often fail to identify distant homologies due to lack of conserved regions, caused by frequent genetic duplication and recombination. Therefore, we developed a novel alignment-free method of sequence mapping that is fast and accurate.ResultsWe present a new mapper called S-conLSH that usesSpacedcontext basedLocalitySensitiveHashing. With multiple spaced patterns, S-conLSH facilitates a gapped mapping of noisy long reads to the corresponding target locations of a reference genome. We have examined the performance of the proposed method on 5 different real and simulated datasets. S-conLSH is at least 2 times faster than the state-of-the-art alignment-based methods. It achieves a sensitivity of 99%, without using any traditional base-to-base alignment, on human simulated sequence data. By default, S-conLSH provides an alignment-free mapping in PAF format. However, it has an option of generating aligned output as SAM-file, if it is required for any downstream processing.AvailabilityThe source code of our software is freely available athttps://github.com/anganachakraborty/S-conLSH
Cell Type-specific Genome Scans of DNA Methylation Diversity Indicate an Important Role for Transposable Elements
Authors: Kartal Önder , Schmid Marc W , Grossniklaus Ueli 
Published: October 2019

AbstractThe epigenome modulates the activity of genes and supports the stability of the genome. The epigenome can also contain phenotypically relevant, heritable marks that may vary at the organismic and population level. Such non-genetic standing variation may be relevant to ecological and evolutionary processes. To identify loci susceptible to selection, it is common to profile large populations at the genome scale, yet methods to perform such scans for epigenetic diversity are barely tapped. Here, we develop a scalable, information-theoretic approach to assess epigenome diversity based on Jensen-Shannon divergence (JSD) and demonstrate its practicality by measuring cell type-specific methylation diversity in the model plantArabidopsis thaliana. DNA methylation diversity tends to be increased in the CG as compared to the non-CG (CHG and CHH) sequence context but the tissue or cell type has an impact on diversity at non-CG sites. Less accessible, more heterochromatic states of chromatin exhibit increased diversity. Genes tend to carry more single-methylation polymorphisms when they harbor gene body-like chromatin signatures and flank transposable elements (TEs). In conclusion, the analysis of DNA methylation with JSD inArabidopsisdemonstrates that the genomic location of a gene dominates its methylation diversity, in particular the proximity to TEs which are increasingly viewed as drivers of evolution. Importantly, the JSD-based approach we implemented here is applicable to any population-level epigenomic data set to analyze variation in epigenetic marks among individuals, tissues, or cells of any organism, including the epigenetic heterogeneity of cells in healthy or diseased organs such as tumors.
Simulation of Stand-to-Sit Biomechanics for Design of Lower-Limb Exoskeletons and Prostheses with Energy Regeneration
Authors: Laschowski Brock , Razavian Reza Sharif , McPhee John 
Published: October 2019

AbstractAlthough regenerative actuators can extend the operating durations of robotic lower-limb exoskeletons and prostheses, these energy-efficient powertrains have been exclusively designed and evaluated for continuous level-ground walking.ObjectiveHere we analyzed the lower-limb joint mechanical power during stand-to-sit movements using inverse dynamic simulations to estimate the biomechanical energy available for electrical regeneration.MethodsNine subjects performed 20 sitting and standing movements while lower-limb kinematics and ground reaction forces were measured. Subject-specific body segment parameters were estimated using parameter identification, whereby differences in ground reaction forces and moments between the experimental measurements and inverse dynamic simulations were minimized. Joint mechanical power was calculated from net joint torques and rotational velocities and numerically integrated over time to determine joint biomechanical energy.ResultsThe hip produced the largest peak negative mechanical power (1.8 ± 0.5 W/kg), followed by the knee (0.8 ± 0.3 W/kg) and ankle (0.2 ± 0.1 W/kg). Negative mechanical work from the hip, knee, and ankle joints per stand-to-sit movement were 0.35 ± 0.06 J/kg, 0.15 ± 0.08 J/kg, and 0.02 ± 0.01 J/kg, respectively.Conclusion and SignificanceAssuming an 80-kg person and previously published regenerative actuator efficiencies (i.e., maximum 63%), robotic lower-limb exoskeletons and prostheses could theoretically regenerate ~26 Joules of total electrical energy while sitting down, compared to ~19 Joules per walking stride. Given that these regeneration performance calculations are based on healthy young adults, future research should include seniors and/or rehabilitation patients to better estimate the biomechanical energy available for electrical regeneration among individuals with mobility impairments.
Collagen I weakly interacts with the β-sheets of β2-microglobulin and enhances conformational exchange to induce amyloid formation
Authors: Hoop Cody L. , Zhu Jie , Bhattacharya Shibani , Tobita Caitlyn A. , Radford Sheena E. , Baum Jean 
Published: October 2019

ABSTRACTAmyloidogenesis is significant in both protein function and pathology. Amyloid formation of folded, globular proteins is commonly initiated by partial unfolding. However, how this unfolding event is triggered for proteins that are otherwise stable in their native environments is not well understood. The accumulation of the immunoglobulin protein β2-microglobulin (β2m) into amyloid plaques in the joints of long-term hemodialysis patients is the hallmark of Dialysis Related Amyloidosis (DRA). While β2m does not form amyloid unassisted near neutral pHin vitro, the localization of β2m deposits to joint spaces suggests a role for the local extracellular matrix (ECM) proteins, specifically collagens, in promoting amyloid formation. Indeed, collagen and other ECM components have been observed to facilitate β2m amyloid formation, but the large size and anisotropy of the complex, combined with the low affinity of these interactions, has limited atomic-level elucidation of the amyloid-promoting mechanism by these molecules. Using solution NMR approaches that uniquely probe weak interactions and large complexes, we are able to derive binding interfaces for collagen I on β2m and detect collagen I-induced µs–ms timescale dynamics in the β2m backbone. By combining solution NMR relaxation methods and15N-dark state exchange saturation transfer experiments, we propose a model in which weak, multimodal collagen I–β2m interactions promote exchange with a minor population of an amyloid-competent species to induce fibrillogenesis. The results portray the intimate role of the environment in switching an innocuous protein into an amyloid-competent state, rationalizing the localization of amyloid deposits in DRA.
DNA methylation-based forensic age estimation in human bone
Authors: Gopalan Shyamalika , Gaige Jonathan , Henn Brenna M. 
Published: October 2019

AbstractDNA methylation is an epigenetic modification of cytosine nucleotides that represents a promising suite of aging markers with broad potential applications. In particular, determining an individual’s age from their skeletal remains is an enduring problem in the field of forensic anthropology, and one that epigenetic markers are particularly well-suited to address. However, all DNA methylation-based age prediction methods published so far focus on tissues other than bone. While high accuracy has been achieved for saliva, blood and sperm, which are easily accessible in living individuals, the highly tissue-specific nature of DNA methylation patterns means that age prediction models trained on these particular tissues may not be directly applicable to other tissues. Bone is a prime target for the development of DNA methylation-based forensic identification tools as skeletal remains are often recoverable for years post-mortem, and well after soft tissues have decomposed. In this study, we generate genome-wide DNA methylation data from 32 individual bone samples. We analyze this new dataset alongside published data from 133 additional bone donors, both living and deceased. We perform an epigenome-wide association study on this combined dataset to identify 108 sites of DNA methylation that show a significant relationship with age (FDR < 0.05). We also develop an age-prediction model using lasso regression that produces highly accurate estimates of age from bone spanning an age range of 49-112 years. Our study demonstrates that DNA methylation levels at specific CpG sites can serve as powerful markers of aging, and can yield more accurate predictions of chronological age in human adults than morphometric markers.
Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition
Authors: Raninga Prahlad V. , Lee Andy , Sinha Debottam , Dong Lan-feng , Datta Keshava K. , Lu Xue , Kalita-de Croft Priyakshi , Dutt Mriga , Hill Michelle M. , Pouliot Normand , Gowda Harsha , Kalimutho Murugan , Neuzil Jiri , Khanna Kum Kum 
Published: October 2019

AbstractLacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.One Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.
Visualization of the Dynamics of Histone Modifications and Their Crosstalk Using PTM-CrossTalkMapper
Authors: Kirsch Rebecca , Jensen Ole N. , Schwämmle Veit 
Published: October 2019

AbstractVisualization of large-scale, multi-dimensional omics data is a major challenge. Experimental study designs in proteomics research produce multiple data layers, e.g. relationships between hundreds of proteins, their interactions and abundances as a function of time or perturbation, as well as dynamics of post-translational modifications (PTMs) and allelic variants (proteoforms). These different levels and types of information of proteins and proteoforms complicate data analysis and generation of insightful and comprehensible graphic visualizations. Middle-down mass spectrometry of histone proteins now allows quantifying hundreds of histone proteoforms including co-existing methylation, acetylation and phosphorylation events at distinct amino acid residues within histone molecules. The histone PTM landscape plays a dominant role in the regulation of chromatin activity and transcriptional and epigenetic control. The dynamics of these reversible modifications are governed by reader, writer and eraser enzymes that cooperate to regulate molecular mechanism that rely on multiple interdependent PTM marks in histones and nucleosomes in chromatin. This PTM crosstalk can be quantified and provides a detailed picture of the underlying rules for setting the histone PTM landscape and chromatin activity, and is available to the community via our CrosstalkDB platform. Here, we developed a new computational method, PTM-CrossTalkMapper, to visualize the dynamics of histone PTMs for different experimental conditions, replicates and proteoforms onto a landscape, thereby describing the crosstalk and interplay between PTMs in a more comprehensible manner. We show the power of combining different levels of information on such crosstalk maps for histone PTM dynamics in mouse organs during the aging process. The PTM-CrossTalkMapper toolkit provides flexible functions to create these maps in various scenarios of multi-dimensional experimental designs, including histone PTM patterns and PTM crosstalk.The source code is available at https://github.com/veitveit/CrossTalkMapper.
Long-term dynamics of aberrant neuronal activity in Alzheimer’s disease
Authors: Korzhova V. , Marinković P. , Goltstein P. M. , Herms J. , Liebscher S. 
Published: October 2019

SummaryAlzheimer’s disease (AD) is associated with aberrant neuronal activity levels. How those activity alterations emerge and how stable they are over time in vivo, however, remains elusive to date. To address these questions we chronically recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice and their non-transgenic littermates over the course of 4 weeks by means of calcium imaging. Surprisingly, aberrant neuronal activity was very stable over time. Moreover, we identified a slow progressive gain of activity of former intermediately active neurons as the main source of new highly active neurons. Interestingly, fluctuations in neuronal activity were independent from amyloid plaque proximity, but aberrant activity levels were more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in AD patients is the consequence of stable single cell aberrant neuronal activity, a finding of potential therapeutic relevance.
Parallel calibration based on modified trim strategy
Authors: Peng Yaxin , Wen Naiwu , Shen Chaomin , Zhu Xiaohuang , Ying Shihui 
Published: October 2019

Purpose
Partial alignment for 3 D point sets is a challenging problem for laser calibration and robot calibration due to the unbalance of data sets, especially when the overlap of data sets is low. Geometric features can promote the accuracy of alignment. However, the corresponding feature extraction methods are time consuming. The purpose of this paper is to find a framework for partial alignment by an adaptive trimmed strategy.

Design/methodology/approach
First, the authors propose an adaptive trimmed strategy based on point feature histograms (PFH) coding. Second, they obtain an initial transformation based on this partition, which improves the accuracy of the normal direction weighted trimmed iterative closest point (ICP) method. Third, they conduct a series of GPU parallel implementations for time efficiency.

Findings
The initial partition based on PFH feature improves the accuracy of the partial registration significantly. Moreover, the parallel GPU algorithms accelerate the alignment process.

Research limitations/implications
This study is applicable to rigid transformation so far. It could be extended to non-rigid transformation.

Practical implications
In practice, point set alignment for calibration is a technique widely used in the fields of aircraft assembly, industry examination, simultaneous localization and mapping and surgery navigation.

Social implications
Point set calibration is a building block in the field of intelligent manufacturing.

Originality/value
The contributions are as follows: first, the authors introduce a novel coarse alignment as an initial calibration by PFH descriptor similarity, which can be viewed as a coarse trimmed process by partitioning the data to the almost overlap part and the rest part; second, they reduce the computation time by GPU parallel coding during the acquisition of feature descriptor; finally, they use the weighted trimmed ICP method to refine the transformation.
Innovative low-cost strategy and firm performance of restaurants
Authors: Kankam-Kwarteng Collins , Osman Barbara , Donkor Jacob 
Published: October 2019

PurposeThe purpose of this paper is to improve the appreciation of the moderating role of competitive intensity on the relationship between low-cost strategy and firm performance of restaurants.Design/methodology/approachThe study uses empirical data collected from 118 restaurants operators, Ghana. The effects of relationships and the interaction of low-cost strategy and competitive intensity were tested using regression analysis.FindingsThe findings indicate the existence of a significant positive relationship between low-cost strategy and firm performance. The effect of competitive strategy on firm performance was found to be partially significant. The findings revealed that competitive intensity does moderate the relationship between low-cost strategy and firm performance of restaurants.Practical implicationsImplications of the findings for restaurant operators suggest that effective application of low-cost strategy and monitoring and managing competitive intensity results in high performance.Originality/valueThis study contributes to the existing literature on low-cost strategy, competitive intensity and firm performance. More specifically, the interaction terms of low-cost strategy and competitive intensity have been explored in this study and can be used for further investigations.
Overcoming the barriers to the implementation of more efficient productive strategies in small enterprises
Authors: Signoretti Andrea 
Published: October 2019

Purpose
The purpose of this paper is to elaborate an empirical model of how small, family-owned companies can overcome the barriers that have been shown in different disciplines to hinder the implementation of lean production in this category of enterprises.

Design/methodology/approach
A multiple case study involving five carefully selected small manufacturing firms operating in Northern Italy was conducted through interviews with key managers and visits inside plants. This data was integrated by a specific seminar and by interviews with unions and training specialists.

Findings
The resulting empirical model highlights the significance of social relations among small entrepreneurs in overcoming any lack of commitment towards lean changes, the role of consultants and practical training in breaking the barrier of resource constraints and the channelling and control of employee involvement to encourage their participation in lean activities. Unions, when present, also play a role in preventing situations of excessive work intensity. Important variants within this common model also emerged among small firms on the grounds of their structure (e.g. size), product market conditions and managerial choices.

Practical implications
Knowledge on how to overcome the barriers to lean production implementation can help social actors both inside and outside of differently characterised small firms which are implementing, or intending to implement, the lean approach.

Originality/value
There is no existing literature on the subject of successful application of lean methods in small enterprises. The uniqueness of this paper’s contribution is reinforced by its broad analytical perspective on the lean system, stemming from an interdisciplinary analysis of different bodies of literature, including management, operations, human resources and employment relations in line with the definition of the lean system.