bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac Differentiation of Human Pluripotent Stem Cells Using Defined Extracellular Matrix Proteins Reveals Essential Role of Fibronectin
Authors: Zhang Jianhua , Tao Ran , Lalit Pratik A. , Carvalho Juliana L. , Markandeya Yogananda , Palecek Sean P. , Kamp Timothy J. 
Published: April 2021

AbstractResearch and therapeutic applications using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) require robust differentiation strategies. Efforts to improve hPSC-CM differentiation have largely overlooked the role of extracellular matrix (ECM). The present study investigates the ability of defined ECM proteins to promote hPSC cardiac differentiation. Fibronectin, laminin-111, and laminin-521 enabled hPSCs to attach and expand; however, fibronectin ECM either endogenously produced or exogenously added promoted, while laminins inhibited, cardiac differentiation in response to growth factors Activin A, BMP4, and bFGF. Inducible shRNA knockdown of fibronectin prevented Brachyury+mesoderm formation and subsequent hPSC-CM differentiation. Antibodies blocking fibronectin binding to integrin β1, but not α5, inhibited cardiac differentiation. Furthermore, inhibition of integrin-linked kinase blocked cardiac differentiation. These results identify fibronectin, laminin-111 and laminin-521 as defined substrates enabling cardiac differentiation of hPSCs and uncover the essential role of fibronectin and downstream signaling pathways in the early stage of hPSC-CM differentiation.
The Shu Complex Prevents Mutagenesis and Cytotoxicity of Single-Strand Specific Alkylation Lesions
Authors: Bonilla Braulio , Brown Alexander J. , Hengel Sarah R. , Rapchak Kyle S. , Mitchell Debra , Pressimone Catherine A. , Fagunloye Adeola A. , Luong Thong T. , Zaher Hani S. , Mosammaparast Nima , Malc Ewa P. , Mieczkowski Piotr A. , Roberts Steven A. , Bernstein Kara A. 
Published: April 2021

ABSTRACTThree-methyl cytosine (3meC) are toxic DNA lesions, blocking base pairing. Bacteria and humans, express members of the AlkB enzymes family, which directly remove 3meC. However, other organisms, including budding yeast, lack this class of enzymes. It remains an unanswered evolutionary question as to how yeast repairs 3meC, particularly in single-stranded DNA. The yeast Shu complex, a conserved homologous recombination factor, aids in preventing replication-associated mutagenesis from DNA base damaging agents such as methyl methanesulfonate (MMS). We found that MMS-treated Shu complex-deficient cells, exhibit a genome-wide increase in A:T and G:C substitutions mutations. The G:C substitutions displayed transcriptional and replicational asymmetries consistent with mutations resulting from 3meC. Ectopic expression of a human AlkB homolog in Shu-deficient yeast rescues MMS-induced growth defects and increased mutagenesis. Finally, the Shu complex exhibits increased affinity for 3meC-containing DNA. Thus, our work identifies a novel mechanism for coping with alkylation adducts.
Weak Task Synchronization of Default Mode Network in Task Based Paradigms
Authors: Tripathi Vaibhav , Garg Rahul 
Published: April 2021

AbstractDefault mode network (DMN) are the areas of the brain that get deactivated upon the presentation of externally focused, attention demanding tasks. Interestingly, these areas are consistently deactivated irrespective of the nature of the task. Recent evidence shows that the behavior of the DMN may be more nuanced than what was earlier believed. We wanted to investigate the dynamics of DMN further and utilized novel statistical approaches to study the same. We analysed four publicly available datasets (total 223 subjects) across seven tasks related to different cognitive modalities and found out that there is a large amount of variability in the presumed task-negative network across subjects, trials and regions. We designed a method called Inter Trial Temporal Synchronization Analysis (IT-TSA) and Inter Subject TSA (IS-TSA) to analyse variability across trials and subjects respectively. We found out that all task-negative regions and even weak task-positive regions have low synchronization across trials and subjects. We hypothesize that the DMN variability might be more due to neural differences rather than structural or HRF variations. We also investigated the use of non GLM technique like the Inter Subject Correlation (ISC) and found that it may only be suitable to study tightly synchronized task-positive regions. Our study challenges the understanding of DMN as a task-negative region and advances the findings that DMN acts as an active component associated with a unique set of self-referential, autobiographical processes which are deactivated differentially and non linearly across trials and subjects in the presence of extrinsic processes.HighlightsDefault Mode Network is weakly synchronized across trials and subjects in task paradigms.Inter Subject Correlation is not suited to detect task-based activations in DMN.Synchronization Analysis reveals temporal structure in fMRI data.
A unified model of the task-evoked pupil response
Authors: Burlingham Charlie S. , Mirbagheri Saghar , Heeger David J. 
Published: April 2021

ABSTRACTThe pupil dilates and re-constricts following task events. It is popular to model this task-evoked pupil response as a linear transformation of event-locked impulses, the amplitudes of which are used as estimates of arousal. We show that this model is incorrect, and we propose an alternative model based on the physiological finding that a common neural input drives saccades and pupil size. The estimates of arousal from our model agreed with key predictions: arousal scaled with task difficulty and behavioral performance but was invariant to trial duration. Moreover, the model offers a unified explanation for a wide range of phenomena: entrainment of pupil size and saccade occurrence to task timing, modulation of pupil response amplitude and noise with task difficulty, reaction-time dependent modulation of pupil response timing and amplitude, a constrictory pupil response time-locked to saccades, and task-dependent distortion of this saccade-locked pupil response.
Uncovering the modified immunopeptidome reveals insights into principles of PTM-driven antigenicity
Authors: Kacen Assaf , Javitt Aaron , Kramer Matthias P. , Morgenstern David , Tsaban Tomer , Solomon Adam , Teo Guo Ci , da Veiga Leprevost Felipe , Barnea Eilon , Yu Fengchao , Admon Arie , Eisenbach Lea , Cafri Gal , Schueler-Furman Ora , Levin Yishai , Nesvizhskii Alexey I. , Merbl Yifat 
Published: April 2021

AbstractAntigen processing and presentation are critical for modulating tumor-host interactions. While post-translational modifications (PTMs) can alter the binding and recognition of antigens, their identification remains challenging. Here we uncover the role PTMs may play in antigen presentation and recognition in human cancers by profiling 29 different PTM combinations in immunopeptidomics data from multiple clinical samples and cell lines. We established and validated an antigen discovery pipeline and showed that newly identified modified antigens from a murine cancer model are cancer-specific and can elicit T cell killing. Systematic analysis of PTMs across multiple cohorts defined new haplotype preferences and binding motifs in association with specific PTM types. By expanding the antigenic landscape with modifications, we uncover disease-specific targets, including thousands of novel cancer-specific antigens and reveal insight into PTM-driven antigenicity. Collectively, our findings highlight an immunomodulatory role for modified peptides presented on HLA I, which may have broad implications for T-cell mediated therapies in cancer and beyond.SignificanceMajor efforts are underway to identify cancer-specific antigens for personalized immunotherapy. Here, we enrich the immunopeptidome landscape by uncovering thousands of novel putative antigens that are post-translationally modified. We define unique preferences for PTM-driven alterations affecting HLA binding and TCR recognition, which in turn alter tumor-immune interactions.Conflict of interest statementAuthors declare no conflicts of interest.
Probing solution structure of the pentameric ligand-gated ion channel GLIC by small-angle neutron scattering
Authors: Lycksell Marie , Rovšnik Urška , Bergh Cathrine , Johansen Nicolai T , Martel Anne , Porcar Lionel , Arleth Lise , Howard Rebecca J , Lindahl Erik 
Published: April 2021

AbstractPentameric ligand-gated ion channels undergo subtle conformational cycling to control electrochemical signal transduction in many kingdoms of life. Several crystal structures have now been reported in this family, but the functional relevance of such models remains unclear. Here, we used small-angle neutron scattering (SANS) to probe ambient solution-phase properties of the pH-gated bacterial ion channel GLIC under resting and activating conditions. Data collection was optimized by inline paused-flow size-exclusion chromatography, and exchanging into deuterated detergent to hide the micelle contribution. Resting-state GLIC was the best-fit crystal structure to SANS curves, with no evidence for divergent mechanisms. Moreover, enhanced-sampling molecular dynamics simulations enabled differential modeling in resting versus activating conditions, with the latter corresponding to an intermediate ensemble of both the extracellular and transmembrane domains. This work demonstrates state-dependent changes in a pentameric ion channel by SANS, an increasingly accessible method for macromolecular characterization with the coming generation of neutron sources.
Investigating the Interplay Between Affective, Phonatory and Motoric Subsystems in Autism Spectrum Disorder Using a Multimodal Dialogue Agent
Authors: Kothare Hardik , Ramanarayanan Vikram , Roesler Oliver , Neumann Michael , Liscombe Jackson , Burke William , Cornish Andrew , Habberstad Doug , Sakallah Alaa , Markuson Sara , Kansara Seemran , Faerman Afik , Bensidi-Slimane Yasmine , Fry Laura , Portera Saige , Suendermann-Oeft David , Pautler David , Demopoulos Carly 
Published: April 2021

AbstractWe explore the utility of an on-demand multimodal conversational platform in extracting speech and facial metrics in children with Autism Spectrum Disorder (ASD). We investigate the extent to which these metrics correlate with objective clinical measures, particularly as they pertain to the interplay be-tween the affective, phonatory and motoric subsystems. 22 participants diagnosed with ASD engaged with a virtual agent in conversational affect production tasks designed to elicit facial and vocal affect. We found significant correlations between vocal pitch and loudness extracted by our platform during these tasks and accuracy in recognition of facial and vocal affect, as-sessed via the Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA-2) neuropsychological task. We also found significant correlations between jaw kinematic metrics extracted using our platform and motor speed of the dominant hand assessed via a standardised neuropsychological finger tapping task. These findings offer preliminary evidence for the usefulness of these audiovisual analytic metrics and could help us better model the interplay between different physiological subsystems in individuals with ASD.
Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons
Authors: Xie Ying Xue , Naseri Nima N. , Fels Jasmine , Kharel Parinati , Na Yoonmi , Burré Jacqueline , Sharma Manu 
Published: April 2021

SUMMARYConsiderable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson’s disease, the molecular-cellular mechanism(s) remain unclear. Here we show that pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis; proposing a central mechanism for exocytosis of aggregated and degradation-resistant proteins from neurons.
Correlated evolution of parental care with dichromatism, colour, and patterns in anurans
Authors: Seshadri K S , Thaker Maria 
Published: April 2021

AbstractParental care is widespread among vertebrates, with clear fitness benefits. Caring parents however incur costs that include higher predation risk. Anurans have among the most diverse forms of parental care, and we test whether the occurrence of care is associated with morphology that minimizes predation risk. We first examine whether parental care co-occurs with sexual dichromatism, testing the hypothesis that when one sex is conspicuous, the other is cryptically patterned and cares for the young. From our phylogenetic comparative analyses of 988 anurans distributed globally, we find that parental care is less likely to co-occur with dichromatism, irrespective of the caring sex. We then examine whether colour gradients and patterns that enhance crypticity are associated with the occurrence of parental care. We found that species with male-only care were more likely to have Bars-Bands, but contrary to our expectation, other colours (Green-Brown, Red-Blue-Black, Yellow) and patterns (Plain, Spots, Mottled-Patches) were not associated with caregiving behaviours. The lack of strong correlations between dorsal morphology and parental care suggests that crypticity is not the dominant strategy to minimise predation risk for care-giving anurans, and that the evolution of body colour and parental care are driven by independent selection pressures.
Linearised loop kinematics to study pathways between conformations
Authors: Hoevenaars Antonius G.L. , André Ingemar 
Published: April 2021

AbstractConformational changes are central to the function of many proteins. Characterization of these changes using molecular simulation requires methods to effectively sample pathways between protein conformational states. In this paper we present an iterative algorithm that samples conformational transitions in protein loops, referred to as the Jacobian-based Loop Transition (JaLT) algorithm. The method uses internal coordinates to minimise the sampling space, while Cartesian coordinates are used to maintain loop closure. Information from the two representations is combined to push sampling towards a desired target conformation. The innovation that enables the simultaneous use of Cartesian coordinates and internal coordinate is the linearisation of the inverse kinematics of a protein backbone. The algorithm uses the Rosetta all-atom energy function to steer sampling through low-energy regions and uses Rosetta’s side-chain energy minimiser to update side-chain conformations along the way. Because the JaLT algorithm combines a detailed energy function with a low-dimensional conformational space, it is positioned in between molecular dynamics (MD) and elastic network model (ENM) methods. As a proof of principle, we apply the JaLT algorithm to study the conformational transition between the open and occluded state in the MET20 loop of the Escherichia coli dihydrofolate reductase enzyme. Our results show that the algorithm generates semi-continuous pathways between the two states with realistic energy profiles. These pathways can be used to identify energy barriers along the transition. The effect of a single point mutation of the MET20 loop was also investigated and the predicted increase in energy barrier is consistent with the experimentally observed reduction in catalytic rate of the enzyme. Additionally, it is demonstrated how the JaLT algorithm can be used to identify dominant degrees of freedom during a transition. This can be valuable input for a more extensive characterization of the free energy pathway along a transition using molecular dynamics, which is often performed with a reduced set of degrees of freedom. This study has thereby provided the first examples of how linearisation of inverse kinematics can be applied to the analysis of proteins.
DruID: PersonalizedDrug Recommendations byIntegrating Multiple BiomedicalDatabases for Cancer
Authors: Liany Herty , Jeyasekharan Anand , Rajan Vaibhav 
Published: April 2021

AbstractAdvances in next-generation sequencing technologies have led to the development of personalized genomic profiles in diagnostic panels that inform oncologists of alterations in clinically relevant genes. While targeted therapies for some alterations may be found, an effective therapeutic strategy should consider multiple and dependent genetic interactions that affect cancer progression, a task which remains challenging. There are ongoing efforts to profile cancer cells in-vitro, both to catalog their genomic information and study their sensitivity to various drugs. There is a need for tools that can interpret the personalized genomic profile of a patient in light of information from these biological and pre-clinical studies and recommend potentially useful drugs. To address this need, we develop a new algorithmic framework called DruID, to effectively combine drug efficacy predictions from a deep neural network model with information, such as drug sensitivity, drug-drug interactions and genetic dependencies, from multiple publicly available databases. We empirically evaluate DruID on cancer cell line data on which efficacy of many drugs have been experimentally determined. We find that DruID outperforms competing approaches and promises to be a useful tool in clinical decision-making.
Virtual Parts Repository 2: Model-driven design of genetic regulatory circuits
Authors: Mısırlı Göksel , Yang Bill , James Katherine , Wipat Anil 
Published: April 2021

AbstractEngineering genetic regulatory circuits is key to the creation of biological applications that are responsive to environmental changes. Computational models can assist in understanding especially large and complex circuits where manual analysis is infeasible, permitting a model-driven design process. However, there are still few tools that offer the ability to simulate the system under design. One of the reasons for this is the lack of accessible model repositories or libraries that cater for the modular composition of models of synthetic systems that do not yet exist in nature. Here, we present the Virtual Parts Repository 2, a resource to facilitate the model-driven design of genetic regulatory circuits, which provides reusable, modular and composable models. The repository is service-oriented and can be utilized by design tools in computational workflows. Designs provided in Synthetic Biology Open Language documents are used to derive system-scale and hierarchical Systems Biology Markup Language models. We also present a rule-based modeling abstraction based on reaction networks to facilitate scalable and modular modeling of complex and large designs. This modeling abstraction incorporates design patterns such as roadblocking, distributed deployment of genetic circuits using plasmids and cellular resource dependency. The computational resources and the modeling abstraction presented in this paper allow computational design tools to take advantage of computational simulations and ultimately help facilitate more predictable applications.Graphical TOC Entry
Effect of market versus nonmarket environmental policy stringency on knowledge sourcing behavior for green technology: evidence from OECD countries
Authors: Choi Gunae , Cho Se Ho 
Published: April 2021

Purpose
The purpose of this paper is to examine firms’ knowledge-sourcing behavior in green technology development with respect to the home country’s market- vs nonmarket environmental policy stringency.

Design/methodology/approach
This paper empirically analyzes the effects of market and nonmarket environmental policy stringency on firms’ knowledge sourcing activity with patent data from OECD countries during 1991–2010, across five categories of green technologies.

Findings
When a nation establishes more stringent market environmental policies, firms likely source more international knowledge rather than domestic knowledge about green technology, up to a point. After that level, this balance shifts (inverted U-shaped curve) due to the risks associated with greater investment costs and commerciality. Nonmarket environmental policies instead should exhibit a positive, linear relationship with international relative to domestic knowledge sourcing. This study also reveals the dynamic roles of a firm’s green technological capability with market-based environmental policy stringency and a substitutive role of the capability with nonmarket-based environmental policy stringency.

Research limitations/implications
This study shows the effect of market and nonmarket environmental policy stringency on firms’ knowledge sourcing. The findings provide meaningful implications for policymakers regarding the optimal levels of market and nonmarket environmental policy stringency that will enhance their countries’ green technology development.

Originality/value
This paper enriches the literature of environmental policy and knowledge sourcing and offers the direction of future research of how environmental policy stringency influences a firm’s knowledge sourcing for green technology development.
What doesn't kill you makes you stronger: Detoxification ability as a mechanism of honesty in a sexually selected signal
Authors: G‐Santoyo Isaac , González‐Tokman Daniel , Tapia‐Rodríguez Miguel , Córdoba‐Aguilar Alex 
Published: April 2021

Abstract

Sexual selection leads to the expression and maintenance of colourful signals. The metabolic pathways to produce such signals often involve toxic byproducts that can reduce survival. However, rather than discarding these otherwise harmful byproducts, animals may use them by integrating them into sexually selected traits.

We tested this using the damselfly Hetaerina americana, where males bear a red wing spot (RWS) that has evolved by intrasexual competition.

By using confocal microscopy and several biochemical techniques, we determined that the RWS are generated by ommochrome pigments derived from tryptophan metabolism.

Second, we injected a group of males with the toxic precursor of these ommochromes, 3‐hydroxy‐kynurenine (3‐Hk), confirming the toxicity of this compound in adult males.

Finally, we showed that adult males injected with a median lethal concentration of 3‐Hk had more ommochromes in their RWS than controls but similar survival, suggesting that the deposition of ommochrome pigment in the wing counteracts the 3‐HK toxicity.

Thus, we report that sexually selected pigmented signals may involve the co‐option of excreted compounds that could otherwise have lethal effects, a hypothesis we call ‘detoxifying ability signalling’. Our results provide new insights about the evolution of sexual signals, elucidating a mechanism for the evolution of honest indicators of quality that could have arisen due to natural selection.