bluuebunny/crossref_metadata_2025_split huggingface dataset:
3D printing of Microgel-loaded Modular LEGO-like Cages as Instructive Scaffolds for Tissue Engineering
Authors: Hipfinger Christina , Subbiah Ramesh , Tahayeri Anthony , Athirasala Avathamsa , Horsophonphong Sivaporn , Thrivikraman Greeshma , França Cristiane Miranda , Cunha Diana Araujo , Mansoorifar Amin , Zahariev Albena , Jones James M. , Coelho Paulo G. , Witek Lukasz , Xie Hua , Guldberg Robert E. , Bertassoni Luiz E. 
Published: March 2020

AbstractBiomaterial scaffolds have served as the foundation of tissue engineering and regenerative medicine. However, scaffold systems are often difficult to scale in size or shape in order to fit defect-specific dimensions, and thus provide only limited spatiotemporal control of therapeutic delivery and host tissue responses. Here, a lithography-based three-dimensional (3D) printing strategy is used to fabricate a novel miniaturized modular LEGO-like cage scaffold system, which can be assembled and scaled manually with ease. Scalability is based on an intuitive concept of stacking modules, like conventional LEGO blocks, allowing for literally thousands of potential geometric configurations, and without the need for specialized equipment. Moreover, the modular hollow-cage design allows each unit to be loaded with biologic cargo of different compositions, thus enabling controllable and easy patterning of therapeutics within the material in 3D. In summary, the concept of miniaturized cage designs with such straight-forward assembly and scalability, as well as controllable loading properties, is a flexible platform that can be extended to a wide range of materials for improved biological performance.TOC3D printed LEGO-like hollow microcagescan be easily assembled, adjoined, and stacked-up to suit the complexity of defect tissues; aid spatial loading of cells and biomolecules; instruct cells migration three-dimensionally; and facilitate cell invasion and neovascularizationin-vivo, thus accelerating the process of tissue healing and new tissue formation.
Multi-dimensional predictions of psychotic symptoms via machine learning
Authors: Taylor Jeremy A , Larsen Kit Melissa , Garrido Marta I 
Published: March 2020

AbstractThe diagnostic criteria for schizophrenia comprise a diverse range of heterogeneous symptoms. As a result, individuals each present a distinct set of symptoms despite having the same overall diagnosis. Whilst previous machine learning studies have primarily focused on dichotomous patient-control classification, we predict the severity of each individual symptom on a continuum. We applied machine learning regression within a multi-modal fusion framework to fMRI and behavioural data acquired during an auditory oddball task in 80 schizophrenia patients. Brain activity was highly predictive of some, but not all symptoms, namely hallucinations, avolition, anhedonia and attention. Critically, each of these symptoms was associated with specific functional alterations across different brain regions. We also found that modelling symptoms as an ensemble of subscales was more accurate, specific and informative than models which predict compound scores directly. In principle, this approach is transferrable to any psychiatric condition or multi-dimensional diagnosis.
A theory of joint attractor dynamics in the hippocampus and the entorhinal cortex accounts for artificial hippocampal remapping and individual grid cell field-to-field variability
Authors: Agmon Haggai , Burak Yoram 
Published: March 2020

ABSTRACTThe representation of position in the brain is distributed across multiple neural populations. Grid cell modules in the medial entorhinal cortex (MEC) express activity patterns that span a low-dimensional manifold which remains stable across different environments. In contrast, the activity patterns of hippocampal place cells span distinct low-dimensional manifolds in different environments. It is unknown how these multiple representations of position are coordinated. Here we develop a theory of joint attractor dynamics in the hippocampus and the MEC. We show that the system exhibits a coordinated, joint representation of position across multiple environments, consistent with global remapping in place cells and grid cells. We then show that our model accounts for recent experimental observations that lack a mechanistic explanation: variability in the firing rate of single grid cells across firing fields, and artificial remapping of place cells under depolarization, but not under hyperpolarization, of layer II stellate cells of the MEC.
Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion
Authors: Nwogu Nnenna , Ortiz Luz E. , Whitehouse Adrian , Kwun Hyun Jin 
Published: March 2020

ABSTRACTMerkel cell polyomavirus (MCV) small T antigen (sT) is the main oncoprotein for the development of Merkel cell carcinoma (MCC). MCC is a rare, clinically aggressive neuroendocrine tumor of the skin with a high propensity for local, regional, and distant spread. The dysregulation of matrix metalloproteinase-9 (MMP-9) has been implicated in multiple essential roles in the development of various malignant tumor cell invasion and metastasis. Previously, MCV sT was shown to induce the migratory and invasive phenotype of MCC cells through the transcriptional activation of the Sheddase molecule, ADAM 10 (A disintegrin and metalloprotease domain-containing protein 10). In this study, we show that MCV sT protein stimulates differential expression of epithelial–mesenchymal transition (EMT) associated genes, including MMP-9 and Snail. This effect is dependent on the presence of the large T stabilization domain (LSD), which is known to be responsible for cell transformation through targeting of promiscuous E3 ligases, including FBW7, a known MMP-9 and Snail regulator. Chemical treatments of MMP-9 markedly inhibited sT-induced cell migration and invasion. These results suggest that MCV sT contributes to the activation of MMP-9 as a result of FBW7 targeting, and increases the invasive potential of cells, which can be used for targeted therapeutic intervention.IMPORTANCEMerkel cell carcinoma (MCC) is the most aggressive cutaneous tumor without clearly defined treatment. Although MCC has a high propensity for metastasis, little is known about the underlying mechanisms that drive MCC invasion and metastatic progression. MMP-9 has shown to play a detrimental role in many metastatic human cancers, including melanoma and other non-melanoma skin cancers. Our study shows that MCV sT-mediated MMP-9 activation is driven through the LSD, a known E3 ligase targeting domain, in MCC. MMP-9 may serve as the biochemical culprit to target and develop a novel approach for the treatment of metastatic MCC.
Metabolites alleviate staphylococcal bloodstream infection in a NO-dependent manner via arginase inhibition
Authors: Pang Rui , Su Yu-bin , Zhou Hua , Chen Xinhai 
Published: March 2020

AbstractStaphylococcus aureusis a notorious bacterial pathogen that often causes soft tissue and bloodstream infections and invariably garners resistance mechanisms against new antibiotics. Host innate immunity modulated by metabolites has been proved as a powerful strategy against bacterial infections. However, few studies focus on the application of this strategy againstS. aureusinfection. Here, we identified four metabolite biomarkers, L-proline, L-isoleucine, L-leucine, and L-valine (PILV), by a metabolomics study. In animal models ofS. aureusbloodstream infection, exogenous administration of each metabolite or PILV shows an anti-infective effect, while PILV treatment has higher protection than individual metabolite treatment. Each metabolite targets nitric oxide (NO) to killS. aureusvia arginase inhibition, and PILV exhibits additive inhibition of arginase activity that causes further killing. This suppression also contributes to the metabolite-mediated phagocytic killing ofS. aureusin human blood. Our finding demonstrates the metabolite-mediated innate immunity as a therapeutic intervention forS. aureusinfection.
A rapidly reversible mutation generates subclonal genetic diversity and unstable drug resistance
Authors: Dan Lufeng , Li Yuze , Chen Shuhua , Liu Jingbo , Li Fangting , Wang Yu , He Xiangwei , Carey Lucas B. 
Published: March 2020

AbstractMost genetic changes have negligible reversion rates. As most mutations that confer resistance to an adversary condition (e.g., drug treatment) also confer a growth defect in its absence, it is challenging for cells to genetically adapt to transient environmental changes. Here we identify a set of rapidly reversible drug resistance mutations inS. pombethat are caused by Microhomology mediated Tandem Duplication (MTD), and reversion back to the wild-type sequence. Using 10,000x coverage whole-genome sequencing we identify near 6000 subclonal MTDs in a single clonal population, and determine using machine learning how MTD frequency is encoded in genome. We find that sequences with the highest predicted MTD rates tend to generate insertions that maintain the correct reading frame suggesting that MTD formation has shaped the evolution of coding sequences. Our study reveals a common mechanism of reversible genetic variation that is beneficial for adaptation to environmental fluctuations and facilitates evolutionary divergence.
RNA editing in inflorescences of wild grapevine unveils association to sex and development
Authors: Ramos Miguel J. N. , Faísca-Silva David , Coito João L. , Cunha Jorge , Silva Helena Gomes , Viegas Wanda , Costa M. Manuela R. , Amâncio Sara , Rocheta Margarida 
Published: March 2020

SUMMARYRNA editing challenges the central dogma of molecular biology, by modifying the genetic information at the transcription level. Recent reports, suggesting increased levels of RNA editing in plants, raised questions on the nature and dynamics of such events during development. We here report the occurrence of distinct RNA editing patterns in wildVitisflowers during development, with twelve possible RNA editing modifications observed for the first time in plants. RNA editing events are gender and developmental stage specific, identical in subsequent years of this perennial species and with distinct nucleotide frequencies neighboring editing sites on the 5’ and 3’ flanks. The transcriptome dynamics unveils a new regulatory layer responsible for gender plasticity enhancement or underling dioecy evolution inVitis.
Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo
Authors: Best Katherine T. , Knapp Emma , Ketonis Constantinos , Jonason Jennifer H. , Awad Hani A. , Loiselle Alayna E. 
Published: March 2020

AbstractAcute tendon injuries are characterized by excessive matrix deposition that impedes regeneration and disrupts functional improvements. Inflammation is postulated to drive pathologic scar tissue formation, with nuclear factor kappa B (NF-κB) signaling emerging as a candidate pathway in this process. However, characterization of the spatial and temporal activation of canonical NF-κB signaling during tendon healingin vivo, including identification of the cell populations activating NF-κB, is currently unexplored. Therefore, we aimed to determine which cell populations activate canonical NF-κB signaling following flexor tendon repair with the goal of delineating cell-specific functions of NF-κB signaling during scar mediated tendon healing. Immunofluorescence revealed that both tendon cells and myofibroblasts exhibit prolonged activation of canonical NF-κB signaling into the remodeling phase of healing. Using cre-mediated knockout of the canonical NF-κB kinase (IKKβ), we discovered that suppression of canonical NF-κB signaling in Scleraxis-lineage cells increased myofibroblast content and scar tissue formation. Interestingly, Scleraxis-lineage specific knockout of IKKβ increased the incidence of apoptosis, suggesting that canonical NF-κB signaling may be mediating cell survival during tendon healing. These findings suggest indispensable roles for canonical NF-κB signaling during flexor tendon healing.One Sentence SummaryScleraxis-lineage specific knockdown of persistent canonical IKKβ/NF-κB drives scar formation and apoptotic signaling during flexor tendon healing.
Bayesian model selection reveals biological origins of zero inflation in single-cell transcriptomics
Authors: Choi Kwangbom , Chen Yang , Skelly Daniel A. , Churchill Gary A. 
Published: March 2020

AbstractSingle-cell RNA sequencing is a powerful tool for characterizing cellular heterogeneity in gene expression. However, high variability and a large number of zero counts present challenges for analysis and interpretation. There is substantial controversy over the origins and proper treatment of zeros and no consensus on whether zero-inflated count distributions are necessary or even useful. While some studies assume the existence of zero inflation due to technical artifacts and attempt to impute the missing information, other recent studies of argue that there is no zero inflation in scRNA-Seq data. We apply a Bayesian model selection approach to unambiguously demonstrate zero inflation in multiple biologically realistic scRNA-Seq datasets. We show that the primary causes of zero inflation are not technical but rather biological in nature. We also demonstrate that parameter estimates from the zero-inflated negative binomial distribution are an unreliable indicator of zero inflation. Despite the existence of zero inflation of scRNA-Seq counts, we recommend the generalized linear model with negative binomial count distribution (not zero-inflated) as a suitable reference model for scRNA-Seq analysis.
Predicting future drinking among young adults: using ensemble machine-learning to combine MRI with psychometrics and behaviour
Authors: Groefsema Martine M. , Luijten Maartje , Engels Rutger C.M.E. , Sescousse Guillaume , Jollans Lee 
Published: March 2020

AbstractBackgroundWhile most research into predictors of problematic alcohol use has focused on adolescence, young adults are also at elevated risk, and differ from adolescents and adults in terms of exposure to alcohol and neurodevelopment. Here we examined predictors of alcohol use among young adults at a 1-year follow-up using a broad predictive modelling approach.MethodsData in four modalities were included from 128 men aged between 18 and 25 years; functional MRI regions-of-interest from 1) a beer-incentive delay task, and 2) a social alcohol cue-exposure task, 3) grey matter data, and 4) non-neuroimaging data (i.e. psychometric and behavioural). These modalities were combined into an ensemble model to predict follow-up Alcohol Use Disorder Identification (AUDIT) scores, and were tested separately for their contribution. To reveal specificity for the prediction of future AUDIT scores, the same analyses were carried out for current AUDIT score.ResultsThe ensemble resulted in a more accurate estimation of follow-up AUDIT score than any single modality. Only removal of the social alcohol cue-exposure task and of the non-neuroimaging data significantly worsened predictions. Reporting to need a drink in the morning to start the day was the strongest unique predictor of future drinking along with anterior cingulate cortex and cerebellar activity.ConclusionsAlcohol-related task fMRI activity is a valuable predictor for future drinking among young adults alongside non-neuroimaging variables. Multi-modal prediction models best predict future drinking among young adults and may play an important part in the move towards individualized treatment and prevention efforts.
Storing and analyzing a genome on a blockchain
Authors: Gürsoy Gamze , Brannon Charlotte M , Wagner Sarah , Gerstein Mark 
Published: March 2020

AbstractThe genomic characterization of individuals promises to be immensely useful for biomedical research and healthcare. However, a critical barrier to expanding personal genome sequencing is achieving secure, high-integrity storage of raw data. While cloud storage offers solutions to access such data from any place and device, the vulnerabilities of centralized storage in relation to security, data integrity, and robustness, such as single points of failure, have not yet been addressed. Blockchain is a potential alternative to these storage modes. However, storing large-scale data on blockchain can be challenging due to slow transaction speeds, the potential for chains to reach large sizes, and limitations on querying data stored on-chain. Currently, several genomic storage applications incorporate blockchain, but likely because of these challenges, many use blockchain only to facilitate and log data-access transactions, rather than to store raw genomic data on-chain. While this secures the process of data access, it does not secure the data itself, which is often stored off-chain (i.e. in a cloud or file-hosting services). Here, we developed a novel method of storing reference-aligned reads on-chain in a private blockchain network. We also developed tools for accessing and analyzing the on-chain data. We addressed the challenges of on-chain data storage by minimizing the data inserted to the chain using reference-based data compression techniques and by binning the on-chain data by genomic location to reduce retrieval times. Our tools provide open-source blockchain-based storage and access for advanced genomic analyses such as variant calling.
Multi-contact 3C data reveal that the human genome is largely unentangled
Authors: Tavares-Cadete Filipe , Norouzi Davood , Dekker Bastiaan , Liu Yu , Dekker Job 
Published: March 2020

SUMMARYThe genome is organized into chromosome territories that are themselves spatially segregated in A and B compartments. The extent to which interacting compartment domains and chromosomes are topologically entangled is not known. We show that detection of series of co-occurring chromatin interactions using multi-contact 3C (MC-3C) reveals insights into the topological entanglement of compartment domains and territories. We find that series of co-occurring interactions and their order represent interaction percolation paths through nuclear space in single cells where fragment 1 interacts with fragment 2, which in turn interacts with fragment 3 and so on. Analysis of paths that cross two chromosome territories revealed very little mixing of chromatin from the two chromosomes. Similarly, paths that cross compartment domains show that loci from interacting domains do not mix. Polymer simulations show that such paths are consistent with chromosomes and compartment domains behaving as topologically closed polymers that are not catenated with one another. Simulations show that even low levels of random strand passage, e.g. through topoisomerase II activity, would result in entanglements and mixing of loci of different chromosomes and compartment domains with concomitant changes in interaction paths inconsistent with MC-3C data. Our results show that cells maintain a largely unentangled state of chromosomes and compartment domains.
Light-driven formation of high-valent manganese oxide by photosystem II supports evolutionary role in early bioenergetics
Authors: Chernev Petko , Fischer Sophie , Hoffmann Jutta , Oliver Nicholas , Burnap Robert L. , Zaharieva Ivelina , Nürnberg Dennis J. , Haumann Michael , Dau Holger 
Published: March 2020

AbstractWater oxidation and concomitant O2-formation by the Mn4Ca cluster of oxygenic photosynthesis has shaped the biosphere, atmosphere, and geosphere. It has been hypothesized that at an early stage of evolution, before photosynthetic water oxidation became prominent, photosynthetic formation of Mn oxides from dissolved Mn(2+) ions may have played a key role in bioenergetics and possibly facilitated early geological manganese deposits. The biochemical evidence for the ability of photosystems to form extended Mn oxide particles, lacking until now, is provided herein. We tracked the light-driven redox processes in spinach photosystem II (PSII) particles devoid of the Mn4Ca clusters by UV-vis and X-ray spectroscopy. We find that oxidation of aqueous Mn(2+) ions results in PSII-bound Mn(III,IV)-oxide nanoparticles of the birnessite type comprising 50-100 Mn ions per PSII. Having shown that even today’s photosystem-II can form birnessite-type oxide particles efficiently, we propose an evolutionary scenario, which involves Mn-oxide production by ancestral photosystems, later followed by down-sizing of protein-bound Mn-oxide nanoparticles to finally yield today’s Mn4CaO5cluster of photosynthetic water oxidation.
Spindle position dictates division site during asymmetric cell division in moss
Authors: Kozgunova Elena , Yoshida Mari W. , Reski Ralf , Goshima Gohta 
Published: March 2020

AbstractAsymmetric cell division (ACD) underlies the development of multicellular organisms. It is considered that the division site in land plants is predetermined prior to mitosis and that the localization of the mitotic spindle does not govern the division plane. This contrasts with animal ACD, in which the division site is defined by active spindle-positioning mechanisms. Here, we isolated a hypomorphic mutant of the conserved microtubule-associated protein TPX2 in the mossPhyscomitrium patensand observed abnormal spindle motility during cell division. This defect compromised the position of the division site and produced inverted daughter cell sizes in the first ACD of gametophore (leafy shoot) development. The phenotype was rescued by restoring endogenous TPX2 function and, unexpectedly, by depolymerizing actin filaments. Thus, we have identified an active spindle-positioning mechanism that, reminiscent of acentrosomal ACD in animals, involves microtubules and actin filaments and sets the division site in plants.
Mouse embryonic stem cells self-organize into trunk-like structures with neural tube and somites
Authors: Veenvliet Jesse V , Bolondi Adriano , Kretzmer Helene , Haut Leah , Scholze-Wittler Manuela , Schifferl Dennis , Koch Frederic , Pustet Milena , Heimann Simon , Buschow Rene , Wittler Lars , Timmermann Bernd , Meissner Alexander , Herrmann Bernhard G 
Published: March 2020

AbstractPost-implantation embryogenesis is a highly dynamic process comprising multiple lineage decisions and morphogenetic changes inaccessible to deep analysisin vivo. Mouse embryonic stem cells (mESCs) can form aggregates reflecting the post-occipital embryo (gastruloids), but lacking proper morphogenesis. Here we show that embedding of aggregates derived from mESCs in an extracellular matrix compound results in Trunk-Like-Structures (TLS) with a high level of organization comprising a neural tube and somites. Comparative single-cell RNA-seq analysis demonstrates that TLS execute gene-regulatory programs in an embryo-like order, and generate primordial germ cell like cells (PGCLCs). TLS lackingTbx6form ectopic neural tubes, mirroring the embryonic mutant phenotype. ESC-derived trunk-like structures thus constitute a novel powerfulin vitroplatform for investigating lineage decisions and morphogenetic processes shaping the post-implantation embryo.One sentence summaryA platform for generating trunk-like-structures with precursors of spinal cord, bone and muscle from stem cells in a dish