bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor
Authors: Jaiswal Alok , Gautam Prson , Pietilä Elina A , Timonen Sanna , Nordström Nora , Sipari Nina , Tanoli Ziaurrehman , Lehti Kaisa , Wennerberg Krister , Aittokallio Tero 
Published: February 2020

AbstractA caveat of cancer cell line models is that their molecular and functional profiling is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge is how to make an integrated use of omics profiles of cancer cell lines for reliable discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics profiling studies across 12 research laboratories for 2018 cell lines. To account for relatively low consistency observed for certain data modalities, we developed a robust data integration approach that identifies reproducible signals shared among multiple data modalities and studies. We demonstrated the power of the integrative analyses by identifying a novel driver gene, ECHDC1, with tumor suppressive role validated both in breast cancer cells and patient tumors. Extension of the approach identified synthetic lethal partners of cancer drivers, including a co-dependency of PTEN deficient cells on RNA helicases.HighlightsA comprehensive meta-analysis of 53 multi-modal omics profiles of >2000 cancer cell lines from 12 research laboratoriesAn unexpected lack of consistency between TMT-labelled and non-labelled global proteomic profilesA non-parametric approach to integrate omics profiles from multiple laboratories and to identify robust molecular patterns in individual cell linesThe multi-modal data integration reveals novel drivers and potential therapeutic targets, including ECHDC1 in breast cancers and DDX27 in PTEN mutant cancers.
Dissolved oxygen dynamics reveal biogeochemical tipping points driven by river corridor hydrology
Authors: Kaufman Matthew H , Ghosh Ruby N , Grate Jay , Shooltz Dean D , Freeman Michael J , Ball Terry M , Loloee Reza , McIntire Charles W , Wells Jackie , Strickland Chris , Vermeul Vince , Rod Kenton A. , Mackley Rob , Lin Xinming , Ren Huiying , Stegen James 
Published: February 2020

AbstractRiverbeds can have an important impact on large-scale fluxes of biogeochemically active solutes in river corridor systems. The hyporheic zone is an important area of both hydrology and biogeochemistry, particularly in a hydropeaked river system where rapid variations in river stage height, hydraulic gradients, and residence times occur. We measured several biogeochemical and hydrological parameters at three different subsurface depths in the riverbed of the Columbia River in Washington state, a complex hydropeaked river system with significant subsurface heterogeneity. During the study, episodes of significant dissolved oxygen (DO) change were observed. The DO signal changes were the most apparent, compared to more modest changes in other biogeochemical markers. While DO is often associated with biological activity, we ultimately found that the notable DO excursions were associated with hydrologic gradients. Here we describe hydrologic perturbations and biogeochemical responses in terms of hydrobiogeochemical regimes. Two different forms of DO response to hydraulic gradient perturbation were observed, defining different hydrobiogeochemical regimes. The system tips abruptly from one regime to the other, exhibiting threshold behavior that is uncaptured in current estimations of cumulative influences of subsurface processes from reach to earth system scales.Plain language summaryThe water in a river is constantly flowing in and out of the river’s bed. While it is in the bed, microbes process environmentally and ecologically important nutrients and other compounds. The exchange of water between the river and the riverbed is largely controlled by the stage of the river. Many processes, both natural and human, can cause rapid changes in the river stage. These rapid stage changes can cause abrupt changes in the riverbed’s ability to process nutrients and other compounds. In this study, we use dissolved oxygen as a window into riverbed microbial and chemical processing. We see that relatively rapid changes in river stage can cause abrupt changes in the concentrations of chemicals in the riverbed, indicating fundamental changes in how the riverbed processes are occurring. Understanding these abrupt and fundamental changes is important to our overall understanding of the ecological function of river corridor systems.3 key pointsA hydrobiogeochemical regime is defined by the functional form of the relationship of a hydrologic perturbation and biogeochemical marker.Short-term hydrologic perturbations drive tipping points between distinct hydrobiogeochemical regimes.Linear and hysteretic dissolved oxygen dynamics define distinct regimes as observed throughout the hyporheic zone.
ShearFAST: a user-friendlyin vitrotoolset for high throughput, inexpensive fluid shear stress experiments
Authors: Smith Thomas Brendan , De Nunzio Alessandro Marco , Patel Kamlesh , Munford Haydn , Alam Tabeer , Powell Ohema , Heneghan Nicola , Ready Andrew , Nath Jay , Ludwig Christian 
Published: February 2020

AbstractFluid shear stress is a key modulator of cellular physiologyin vitroandin vivo, but its effects are under-investigated due to requirements for complicated induction methods.Herein we report the validation of ShearFAST; a smartphone application that measures the rocking profile on a standard laboratory cell rocker and calculates the resulting shear stress arising in tissue culture plates.ShearFAST measured rocking profiles were validated against a graphical analysis and also against measures reported by an 8-camera motion tracking system.ShearFAST angle assessments correlated well with both analyses (r ≥0.99, p ≤0.001) with no significant differences in pitch detected across the range of rocking angles tested.Rocking frequency assessment by ShearFAST also correlated well when compared to the two independent validatory techniques (r ≥0.99, p ≤0.0001), with excellent reproducibility between ShearFAST and video analysis (mean frequency measurement difference of 0.006 ± 0.005Hz) and motion capture analysis (mean frequency measurement difference of 0.008 ± 0.012Hz) These data make the ShearFAST assisted cell rocker model make it an attractive approach for economical, high throughput fluid shear stress experiments.Abstract Figure
Layer-dependent multiplicative effects of spatial attention on contrast responses in human early visual cortex
Authors: Guo Fanhua , Liu Chengwen , Qian Chencan , Zhang Zihao , Sun Kaibao , Wang Danny JJ , He Sheng , Zhang Peng 
Published: February 2020

AbstractAttention mechanisms at different cortical layers of human visual cortex remain poorly understood. Using submillimeter-resolution fMRI at 7T, we investigated the effects of top-down spatial attention on the contrast responses across different cortical depths in human early visual cortex. Gradient echo (GE) T2* weighted BOLD signal showed an additive effect of attention on contrast responses across cortical depths. Compared to the middle cortical depth, attention modulation was stronger in the superficial and deep depths of V1, and also stronger in the superficial depth of V2 and V3. Using ultra-high resolution (0.3mm in-plane) balanced steady-state free precession (bSSFP) fMRI, a multiplicative scaling effect of attention was found in the superficial and deep layers, but not in the middle layer of V1. Attention modulation of low contrast response was strongest in the middle cortical depths, indicating baseline enhancement or contrast gain of attention modulation on feedforward input. Finally, the additive effect of attention on T2* BOLD can be explained by strong nonlinearity of BOLD signals from large blood vessels, suggesting multiplicative effect of attention on neural activity. These findings support that top-down spatial attention mainly operates through feedback connections from higher order cortical areas, and a distinct mechanism of attention may also be associated with feedforward input through subcortical pathway.HighlightsResponse or activity gain of spatial attention in superficial and deep layersContrast gain or baseline shift of attention in V1 middle layerNonlinearity of large blood vessel causes additive effect of attention on T2* BOLD
Engineering Selective Molecular Tethers to Enhance Suboptimal Drug Properties
Authors: Dogan Alan B. , von Recum Horst A. 
Published: February 2020

ABSTRACTSmall-molecule drugs are utilized in a wide variety of clinical applications, however, many of these drugs suffer from one or more suboptimal property that can hinder its delivery or cellular action in vivo, or even shelf an otherwise biologically tolerable drug. While high-throughput screening provides a method to discover drugs with altered chemical properties, directly engineering small-molecule bioconjugates provides an opportunity to specifically modulate drug properties rather than sifting through large drug libraries with seemingly ‘random’ drug properties. Herein, we propose that selectively “tethering” a drug molecule to an additional group with favorable properties will improve the drug conjugate’s overall properties, such as solubility. Specifically, we outlined the site-specific chemical conjugation of rapamycin (RAP) to an additional “high-affinity” group to increase the overall affinity the drug has for cyclodextrin-based polymers (pCD). By doing so, we found that RAP’s affinity for pCD and RAP’s window of delivery from pCD microparticles was tripled without sacrificing RAP’s cellular action. This synthesis method was applied to the concept of “affinity” for pCD, but other prosthetic groups can be used in a similar manner to modify other drug properties. This study displays potential for increasing drug delivery windows of small-molecule drugs in pCD systems for chronic drug therapies and introduces the idea of altering drug properties to tune polymer-drug interactions.
Cytoskeletal Tubulin Competes with Actin to Increase Deformability of Metastatic Melanoma Cells
Authors: Higgins Ghodeejah , Peres Jade , Abdalrahman Tamer , Zaman Muhammad H , Lang Dirk M , Prince Sharon , Franz Thomas 
Published: February 2020

ABSTRACTThe formation of membrane protrusions during migration is reliant upon the cells’ cytoskeletal structure and stiffness. It has been reported that actin disruption blocks protrusions and decreases cell stiffness whereas microtubule disruption blocks protrusion but increases stiffness in several cell types. In melanoma, cell migration is of concern as this cancer spreads unusually rapidly during early tumour development. The aim of this study was to characterise motility, structural properties and stiffness of human melanoma cells at radial growth phase (RGP), vertical growth phase (VGP), and metastatic stage (MET) in two-dimensionalin vitroenvironments. Wound assays, western blotting and mitochondrial particle tracking were used to assess cell migration, cytoskeletal content and intracellular fluidity. Our results indicate that cell motility increase with increasing disease stage. Despite their different motility, RGP and VGP cells exhibit similar fluidity, actin and tubulin levels. MET cells, however, display increased fluidity which was associated with increased actin and tubulin content. Our findings demonstrate an interplay between actin and microtubule activity and their role in increasing motility of cells while minimizing cell stiffness at advanced disease stage. In earlier disease stages, cell stiffness may however not serve as an indicator of migratory capabilities.
Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiate the DNA damage response and repair
Authors: Meng Fanbiao , Qian Minxian , Peng Bin , Wang Xiaohui , Peng Linyuan , Zheng Kang , Liu Zuojun , Tang Xiaolong , Zhang Shuju , Sun Shimin , Cao Xinyue , Pang Qiuxiang , Zhao Bosheng , Ma Wenbin , Songyang Zhou , Xu Bo , Zhu Wei-Guo , Xu Xingzhi , Liu Baohua 
Published: February 2020

SummaryThe DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result ofSIRT1deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.
A guided approach for subtomogram averaging of challenging macromolecular assemblies
Authors: Grotjahn Danielle , Chowdhury Saikat , Lander Gabriel C. 
Published: February 2020

AbstractCryo-electron tomography is a powerful biophysical technique enabling three-dimensional visualization of complex biological systems. Macromolecular targets of interest identified within cryo-tomograms can be computationally extracted, aligned, and averaged to produce a better-resolved structure through a process called subtomogram averaging (STA). However, accurate alignment of macromolecular machines that exhibit extreme structural heterogeneity and conformational flexibility remains a significant challenge with conventional STA approaches. To expand the applicability of STA to a broader range of pleomorphic complexes, we developed a user-guided, focused refinement approach that can be incorporated into the standard STA workflow to facilitate the robust alignment of particularly challenging samples. We demonstrate that it is possible to align visually recognizable portions of multi-subunit complexes by providinga prioriinformation regarding their relative orientations within cryo-tomograms, and describe how this strategy was applied to successfully elucidate the first three-dimensional structure of the dynein-dynactin motor protein complex bound to microtubules. Our approach expands the application of STA for solving a more diverse range of heterogeneous biological structures, and establishes a conceptual framework for the development of automated strategies to deconvolve the complexity of crowded cellular environments and improve in situ structure determination technologies.
Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types
Authors: López-Cortés Andrés , Guevara-Ramírez Patricia , Guerrero Santiago , Ortiz-Prado Esteban , García-Cárdenas Jennyfer M. , Zambrano Ana Karina , Armendáriz-Castillo Isaac , Pérez-Villa Andy , Yumiceba Verónica , Varela Nelson , Córdova-Bastidas Daniel , Leone Paola E. , Paz-y-Miño César 
Published: February 2020

ABSTRACTMany primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.
Nanopore adaptive sequencing for mixed samples, whole exome capture and targeted panels
Authors: Payne Alexander , Holmes Nadine , Clarke Thomas , Munro Rory , Debebe Bisrat , Loose Matthew 
Published: February 2020

AbstractNanopore sequencers enable selective sequencing of single molecules in real time by individually reversing the voltage across specific nanopores. Thus DNA molecules can be rejected and replaced with new molecules enabling targeted sequencing to enrich, deplete or achieve specific coverage in a set of reads to address a biological question. We previously demonstrated this method worked using dynamic time warping mapping signal to reference, but required significant compute and did not scale to gigabase references. Using direct base calling with GPU we can now scale to gigabase references. We enrich for specific chromosomes mapping against the human genome and we develop pipelines enriching low abundance organisms from mixed populations without prior knowledge of sample composition. Finally, we enrich panels including 25,600 exon targets from 10,000 human genes and 717 genes implicated in cancer. Using this approach we identify PML-RARA fusions in the NB4 cell line in under 15 hours sequencing. These methods can be used to efficiently screen any target panel of genes without specialised sample preparation using a single computer and suitably powerful GPU.
Dynamic High-Content Imaging Reveals Surface Exposure of VirulentLeishmaniaAmastigotes in Infected Macrophages Undergoing Pyroptosis
Authors: Rosazza Thibault , Lecoeur Hervé , Blisnick Thierry , Moya-Nilges Maryse , Pescher Pascale , Bastin Phillipe , Prina Eric , Späth Gerald F. 
Published: February 2020

AbstractLeishmaniaspp are obligate intracellular parasites that infect vertebrate phagocytes, notably macrophages. We previously reported thatLeishmania amazonensis(L. am) subvert the host cell pro-inflammatory response by dampening the macrophage NLRP3 inflammasome. No information is available on howLeishmaniainfection affects inflammatory cell death termed pyroptosis, known to limit microbial infection. Here, we provide first evidence thatL. amazonensis-infected macrophages can undergo pyroptosis when subjected to pro-inflammatory stimuli. We analyzed the dynamics of the pyroptotic process and the fate of intracellular amastigotes at the single cell level using spinning disk confocal microscopy and high-content, real-time imaging. Bone marrow-derived macrophages (BMDMs) were infected withL. amamastigotes isolated from footpad lesions and sequentially treated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) for canonical NLRP3 inflammasome priming and activation. Real-time monitoring was performed for 240 min post ATP addition. Longitudinal analyses revealed distinct phases of the pyroptotic process, including rapid decay of the parasitophorous vacuole (PV) as monitored by the pH-sensitive lysotracker fluid phase marker, progressive decrease in macrophage viability as monitored by accumulation of the nuclear dye YO-PRO-1, followed by translocation of the luminal PV membrane to the cell surface observed for 40% of macrophages, resulting in the extracellular exposure of amastigotes that remained anchored to the PV membrane. Scanning and transmission electron microscopy analyses revealed a highly polarized orientation of parasites with exclusive exposure of the anterior pole toward the extracellular milieu, and an attachment site forming a potential biological junction between the parasite posterior pole and the PV membrane. We showed that the exposed parasites are resistant to the cytolytic host cell activities linked to pyroptosis and retain their full infectious potential in reinfection experiments using naïve macrophages. Together these data uncover a novelLeishmaniaimmune subversion strategy that may allow stealthy parasite dissemination via the uptake of pyroptotic host debris by uninfected phagocytes.
Enhanced static modeling of commercial pneumatic artificial muscles
Authors: Li XueAi , Sun Kui , Guo Chuangqiang , Liu Teng , Liu Hong 
Published: February 2020

Purpose
This paper aims to propose an enhanced static model of commercial braided pneumatic artificial muscles (PAMs), which is fully analytical without the need for experimentally determined parameters.

Design/methodology/approach
To address the highly nonlinear issues of PAMs, the enhanced model is derived considering the irregular shapes close to their end-fittings, as well as the elastic energy stored in both their braids and rubber bladders. The hysteresis characteristics of PAMs are also explored by analyzing the friction in the crossovers of the interlacing braided strands, together with that between the strands and their surrounding bladders. The isobaric and isometric experiments of a commercial PAM are conducted to demonstrate the enhancement, and the model accuracy is evaluated and compared with some existing models in terms of root mean square errors (RMSEs). Additionally, the proposed model is simplified to facilitate the applications that entail high computational efficiency.

Findings
The proposed model agrees well with the experimental results, which indicates its viability to accurately predict the static behaviors. An overall RMSE of 5.24 N shows that the enhanced model is capable of providing higher accuracy than the existing analytical models, while keeping the modeling cost at a minimum.

Originality/value
The proposed model, taking account of non-cylindrical shapes, elastic energy and friction, succeeds in enhancing the static predictions of commercial PAMs. The fully analytical model may accelerate the development of novel PAM-based robots for high-precision control, while giving a deeper understanding of commercial PAMs.
Localist challenges and the fragmentation of the pan-democratic camp in Hong Kong
Authors: Lam Jermain T.M. 
Published: February 2020

PurposeThe purpose of the paper is to analyze the challenges brought by the localist faction to the traditional democratic camp in order to examine the risks and opportunities for the pan-democratic camp in the democratization process.DesignThe methodologies used for the paper were documentary analyses to examine the theory and practice of localism in the political context of Hong Kong and the election data analyses to study the electoral performances of localist and traditional democratic camps in the 2015 District Council and 2016 Legislative Council elections.FindingsThe paper found that firstly mainland–Hong Kong conflicts were the nurturing ground for emergence of localism in Hong Kong. Secondly, the ideology of localism in the context of Hong Kong connotes an anti-China element in the protection of Hongkongers’ identity, interests, and values. Thirdly, the growth of localist camp was rapid as evidenced in the 2015 and 2016 elections. Fourthly, localism presented both challenges and new opportunities for the pan-democratic camp in the democratization process.OriginalityThe paper was the product of an original research project that examined the ideology of localism and the challenges brought by localism to the pan-democratic camp to reflect on the implications for the democratization process.