bluuebunny/crossref_metadata_2025_split huggingface dataset:
A preliminary assessment of allostatic load in male mantled howler monkeys
Authors: Dias Pedro Américo D. , Coyohua-Fuentes Alejandro , Chavira-Ramírez David Roberto , Canales-Espinosa Domingo , Rangel-Negrín Ariadna 
Published: February 2021

AbstractAllostatic load refers to the wear and tear of the organism associated with the repeated activation of mechanisms that allow for homeostasis. Although allostasis (i.e., maintaining stability through change) is achieved through the orchestration of multiple systems, assessments of allostatic load in wildlife have usually relied on the measurement of single or few physiological mediators. In the present study, we aimed at constructing an allostatic load index (ALI) for male mantled howler monkeys (Alouatta palliata) based on seven physiological mediators (C-peptide, triiodothyronine, glucocorticoids, testosterone, amount of activity, foraging effort, and participation in agonistic interactions). We then examined if variation in this ALI was associated with social, ecological, and abiotic challenges. For five years, we studied ten adult males belonging to two groups. We assessed physiological mediators via behavioral observations (3,364 hours of samplings), and both urine (1,500 assayed samples) and fecal (1,500 assayed samples) sampling. We calculated an ALI based on mediator specific risk scores. Seasonality, encounters with extragroup males, mating, and centrality were positively related with male allostatic load, though only the first two had significant effects on ALI. ALI reflected the physiological and behavioral responses of males to social, ecological, and abiotic challenges. It remains for future research to determine if the observed trends correspond to normal fluctuations in mechanisms that allow male mantled howler monkeys to cope with their environment.
Experimental evidence for enhanced receptor binding by rapidly spreading SARS-CoV-2 variants
Authors: Laffeber Charlie , de Koning Kelly , Kanaar Roland , Lebbink Joyce HG 
Published: February 2021

AbstractRapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 9-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation does not significantly influence the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 3-fold weaker than N501Y. The recently emerging double mutant E484K/N501Y binds as tight as N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.
Unexpected false feelings of familiarity about faces are associated with increased pupil dilations
Authors: Ziman Kirsten , Manning Jeremy R. 
Published: February 2021

AbstractOur subjective sense that something we encounter is familiar to us is reflected by changes in pupil size. Although pupil dilation effects of familiarity have been well documented, familiarity is not the only, or even the strongest, contributing factor to pupil dilation. Changes in pupil dilation also reflect changes in brightness, affective or emotional responses, hormonal release, expected value or utility, and surprise, among others. Because many factors can affect pupil dilation, important questions remain about how pupil dilation changes reflect high-order cognitive processes, like attention and memory. For example, because surprise and familiarity are often difficult to fully distinguish (since new experiences can be surprising or unexpected), it can be difficult to tease apart pupil dilation effects of surprise versus familiarity. To better understand the effects of surprise and familiarity on pupil dilation, we examined pupil responses during a recognition memory task involving photographs of faces and outdoor scenes. When participants rated novel face images as “familiar,” we observed a robust pupil dilation response.
TP-MAP - an Integrated Software Package for the Analysis of 1D and 2D Thermal Profiling Data
Authors: Feyertag Felix , Huber Kilian V.M. 
Published: February 2021

AbstractThermal profiling (TP) has emerged as a promising experimental methodology for elucidating the molecular targets of drugs and metabolites on a proteome-wide scale. Here, we present the Thermal Profiling Meltome Analysis Program (TP-MAP) software package for the analysis and ranking of 1D and 2D thermal profiling datasets. TP-MAP provides a user-friendly interface to quickly identify hit candidates and further explore targets of interest via intersection and crosslinking to public databases.
Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8
Authors: Remillard David , Savage Nikolas A. , Kedves Alexia T. , Paulk Joshiawa , Chen Xin , Garcia Francisco J. , Romanowski Michael J. , Horton Patricia A. , Murphy Jason , Schirle Markus , Harrington Edmund M. , Maxwell Matthew B. , Pham Helen Trinh , Maksimovic Igor , Thomas Jason R. , Forrester William C. 
Published: February 2021

AbstractBromodomain-containing proteins frequently reside in multisubunit chromatin complexes with tissue or cell state-specific compositions. Recent studies have revealed tumor-specific dependencies on the BAF complex bromodomain subunit BRD9 that are a result of recurrent mutations afflicting the structure and composition of associated complex members. To enable the study of ligand engaged complex assemblies, we established a chemoproteomics approach using a functionalized derivative of the BRD9 ligand BI-9564 as an affinity matrix. Unexpectedly, in addition to known interactions with BRD9 and associated BAF complex proteins, we identify a previously unreported interaction with members of the NuA4 complex through the bromodomain-containing subunit BRD8. We apply this finding, alongside homology model guided design, to develop chemical biology approaches for the study of BRD8 inhibition, and to arrive at first-in-class selective and cellularly active probes for BRD8. These tools will empower further pharmacological studies of BRD9 and BRD8 within respective BAF and NuA4 complexes.
Frequency of quorum sensing mutations inPseudomonas aeruginosastrains isolated from different environments
Authors: O’Connor Kathleen , Zhao Conan Y. , Mei Madeline , Diggle Stephen P. 
Published: February 2021

AbstractPseudomonas aeruginosauses quorum sensing (QS) to coordinate the expression of multiple genes necessary for establishing and maintaining infection. It has previously been shown thatlasRQS mutations frequently arise in cystic fibrosis (CF) lung infections, however, there has been far less emphasis on determining whether other QS system mutations arise during infection or in other environments. To test this, we utilized 852 publicly available sequencedP. aeruginosagenomes from thePseudomonasInternational Consortium Database (IPCD) to studyP. aeruginosaQS mutational signatures. To study isolates by source, we focused on a subset of 654 isolates collected from CF, wounds, and non-infection environmental isolates, where we could clearly identify their source. We also worked a small collection of isolatesin vitroto determine the impact oflasRandpqsmutations on isolate phenotypes. We found thatlasRmutations are common across all environments and are not specific to infection nor a particular infection type. We also found that thepqssystem proteins PqsA, PqsH, PqsL and MexT, a protein of increasing importance to the QS field, are highly variable. Conversely, RsaL, a negative transcriptional regulator of thelassystem, was found to be highly conserved, suggesting selective pressure to represslassystem activity. Overall, our findings suggest that QS mutations inP. aeruginosaare common and not limited to thelassystem; however, LasR is unique in the frequency of putative loss-of-function mutations.
Pulsatile contractions and pattern formation in excitable actomyosin cortex
Authors: Staddon Michael F. , Munro Edwin M. , Banerjee Shiladitya 
Published: February 2021

AbstractThe actin cortex is an active adaptive material, embedded with complex regulatory networks that can sense, generate, and transmit mechanical forces. The cortex exhibits a wide range of dynamic behaviours, from generating pulsatory contractions and travelling waves to forming organised structures. Despite the progress in characterising the biochemical and mechanical components of the actin cortex, the emergent dynamics of this mechanochemical system is poorly understood. Here we develop a reaction-diffusion model for the RhoA signalling network, the upstream regulator for actomyosin assembly and contractility, coupled to an active actomyosin gel, to investigate how the interplay between chemical signalling and mechanical forces regulate stresses and patterns in the cortex. We demonstrate that mechanochemical feedback in the cortex acts to destabilise homogeneous states and robustly generate pulsatile contractions. By tuning active stress in the system, we show that the cortex can generate propagating contraction pulses, form network structures, or exhibit topological turbulence.
Clinically-driven design of synthetic gene regulatory programs in human cells
Authors: Israni Divya V. , Li Hui-Shan , Gagnon Keith A. , Sander Jeffry D. , Roybal Kole T. , Keith Joung J. , Wong Wilson W. , Khalil Ahmad S. 
Published: February 2021

AbstractSynthetic biology seeks to enable the rational design of regulatory molecules and circuits to reprogram cellular behavior. The application of this approach to human cells could lead to powerful gene and cell-based therapies that provide transformative ways to combat complex diseases. To date, however, synthetic genetic circuits are challenging to implement in clinically-relevant cell types and their components often present translational incompatibilities, greatly limiting the feasibility, efficacy and safety of this approach. Here, using a clinically-driven design process, we developed a toolkit of programmable synthetic transcription regulators that feature a compact human protein-based design, enable precise genome-orthogonal regulation, and can be modulated by FDA-approved small molecules. We demonstrate the toolkit by engineering therapeutic human immune cells with genetic programs that enable titratable production of immunotherapeutics, drug-regulated control of tumor killingin vivoand in 3D spheroid models, and the first multi-channel synthetic switch for independent control of immunotherapeutic genes. Our work establishes a powerful platform for engineering custom gene expression programs in mammalian cells with the potential to accelerate clinical translation of synthetic systems.
Functional modules within a distributed neural network control feeding in a model medusa
Authors: Weissbourd Brandon , Momose Tsuyoshi , Nair Aditya , Kennedy Ann , Hunt Bridgett , Anderson David J. 
Published: February 2021

SummaryJellyfish are free-swimming, radially symmetric organisms with complex behaviors that arise from coordinated interactions between distinct, autonomously functioning body parts. This behavioral complexity evolved without a corresponding cephalization of the nervous system. The systems-level neural mechanisms through which such decentralized control is achieved remain unclear. Here, we address this question using the jellyfish,Clytia,and present it as a new neuroscience model. We describe a coordinated, asymmetric behavior in which food is passed from the umbrellar margin to the central mouth via directed margin folding. Using newly developed transgenic jellyfish lines to ablate or image specific neuronal subpopulations, we find, unexpectedly, that margin folding reflects the local activation of neural subnetworks that tile the umbrella. Modeling suggests that this structured ensemble activity emerges from sparse, local connectivity rules. These findings reveal how an organismal behavior can emerge from local interactions between functional modules in the absence of a central brain.
Loss of Muscleblind Splicing Factor ShortensC. elegansLifespan by Reducing the Activity of p38 MAPK/PMK-1 and Transcription Factors ATF-7 and Nrf/SKN-1
Authors: Matilainen Olli , Ribeiro Ana R. S. , Verbeeren Jens , Cetinbas Murat , Sadreyev Ruslan I. , Garcia Susana M. D. A. 
Published: February 2021

AbstractMuscleblind-like splicing regulators (MBNLs) are alternative splicing factors that have an important role in developmental processes. Dysfunction of these factors is a key contributor of different neuromuscular degenerative disorders, including Myotonic Dystrophy type 1 (DM1). Since DM1 is a multisystemic disease characterized by symptoms resembling accelerated aging, we asked whether MBNLs regulate cellular processes required to maintain normal lifespan. By utilizing the model organismCaenorhabditis elegans, we found that loss of MBL-1 (the sole ortholog of mammalian MBNLs), which is known to be required for normal lifespan, shortens lifespan by decreasing the activity of p38 MAPK/PMK-1 as well as the function of transcription factors ATF-7 and SKN-1. Furthermore, we show that mitochondrial stress caused by knockdown of mitochondrial electron transport chain components promotes the longevity ofmbl-1mutants in a partially PMK-1-dependent manner. Together, the data establish a mechanism of how DM1-associated loss of muscleblind affects lifespan. Furthermore, this study suggests that mitochondrial stress could alleviate symptoms caused by the dysfunction of muscleblind splicing factor, creating a potential approach to investigate for therapy.Reviewer token for the RNA-seq data (GEO: GSE146801):wvataksittaffcj
Connectome-based individual prediction of cognitive behaviors via the graph propagation network reveals directed brain network topology
Authors: Wu Dongya , Li Xin , Feng Jun 
Published: February 2021

AbstractThe brain connectome supports the information flow underlying human cognitions and should reflect the individual variability in human cognitive behaviors. Various studies have utilized the brain connectome to predict individual differences in human behaviors. However, traditional studies viewed the brain connectome feature as a vector of one dimension, a method which neglects topological structures of the brain connectome. To utilize topological properties of the brain connectome, we proposed that graph neural network which combines graph theory and neural network can be adopted. Different from previous node-driven graph neural networks that parameterize on the node feature transformation, we designed an edge-driven graph neural network named graph propagation network that parameterizes on the information propagation within the brain connectome. We compared various models in predicting the individual total cognition based on the resting-state functional connectome. The edge-driven graph propagation network showed the highest prediction accuracy and outperformed the node-driven graph neural network and traditional partial least square regression. The graph propagation network also revealed a directed network topology encoding the information flow, indicating that the high-level association cortices are responsible for the information integration underlying the total cognition. These results suggest that the edge-driven graph propagation network can better explore the topological structure of the brain connectome and can serve as a new method to associate the brain connectome and human behaviors.
Seven amino acid types suffice to reconstruct the core fold of RNA polymerase
Authors: Yagi Sota , Padhi Aditya K. , Vucinic Jelena , Barbe Sophie , Schiex Thomas , Nakagawa Reiko , Simoncini David , Zhang Kam Y. J. , Tagami Shunsuke 
Published: February 2021

AbstractThe extant complex proteins must have evolved from ancient short and simple ancestors. Nevertheless, how such prototype proteins emerged on the primitive earth remains enigmatic. The double-psi beta-barrel (DPBB) is one of the oldest protein folds and conserved in various fundamental enzymes, such as the core domain of RNA polymerase. Here, by reverse engineering a modern DPBB domain, we reconstructed its evolutionary pathway started by “interlacing homo- dimerization” of a half-size peptide, followed by gene duplication and fusion. Furthermore, by simplifying the amino acid repertoire of the peptide, we successfully created the DPBB fold with only seven amino acid types (Ala, Asp, Glu, Gly, Lys, Arg, and Val), which can be coded by only GNN and ARR (R = A or G) codons in the modern translation system. Thus, the DPBB fold could have been materialized by the early translation system and genetic code.
Chelator sensing and lipopeptide interplay mediates molecular interspecies interactions between soil bacilli and pseudomonads
Authors: Andric Sofija , Meyer Thibault , Rigolet Augustin , Arias Anthony Argüelles , Steels Sébastien , Hoff Grégory , Höfte Monica , De Mot René , McCann Andrea , De Pauw Edwin , Ongena Marc 
Published: February 2021

AbstractSome bacterial species are important members of the rhizosphere microbiome and confer protection to the host plant against pathogens. However, our knowledge of the multitrophic interactions determining the ecological fitness of these biocontrol bacteria in their highly competitive natural niche is still limited. In this work, we investigated the molecular mechanisms underlying interactions betweenB. velezensis,considered as model plant-associated and beneficial species in theBacillusgenus, andPseudomonasas a rhizosphere-dwelling competitor. Our data show thatB. velezensisboosts its arsenal of specialized antibacterials upon the perception of the secondary siderophore enantio-pyochelin produced by phylogenetically distinct pseudomonads and some other genera. We postulate thatB. velezensishas developed some chelator sensing systems to learn about the identity of its surrounding competitors. Illustrating the multifaceted molecular response ofBacillus, surfactin is another crucial component of the secondary metabolome mobilized in interbacteria competition. Its accumulation not only enhances motility but, unexpectedly, the lipopeptide also acts as a chemical trap that reduces the toxicity of other lipopeptides released byPseudomonaschallengers. This in turn favors the persistence ofBacilluspopulations upon competitive root colonization. Our work thus highlights new ecological roles for bacterial secondary metabolites acting as key drivers of social interactions.
A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis
Authors: L. McAlary , V.K. Shephard , G.S.A. Wright , J.J. Yerbury 
Published: February 2021

AbstractAmyotrophic lateral sclerosis (ALS)-associated mutations in Cu/Zn superoxide dismutase (SOD1) reduce folding stability, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS, however, the results have been mixed. Here, we utilise a small-molecule polytherapy of CuATSM and ebselen to mimic the metal delivery and disulfide bond promoting activity of SOD1’s cellular chaperone, the ‘copper chaperone for SOD1’ (CCS). We find that polytherapy using CuATSM and ebselen is highly effective at reducing inclusion formation in a cell model of SOD1 aggregation, reduces mutant SOD1-associated cell death, and promotes effective maturation of SOD1 beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may be an effective method of treating SOD1-associated ALS.
Collagen has a unique SEC24 preference for efficient export from the endoplasmic reticulum
Authors: Lu Chung-Ling , Ortmeier Steven , Brudvig Jon , Moretti Tamara , Cain Jacob , Boyadjiev Simeon A. , Weimer Jill M. , Kim Jinoh 
Published: February 2021

ABSTRACTSEC24 is mainly involved in cargo sorting during COPII vesicle assembly. There are four SEC24 paralogs (A to D) in mammals, which are classified into two subgroups (SEC24A/B and SEC24C/D). Pathological mutations inSEC24Dcause osteogenesis imperfecta with craniofacial dysplasia in humans.sec24dmutant fish also recapitulate the phenotypes. Consistent with the skeletal phenotypes, the secretion of collagen was severely defective in mutant fish, emphasizing the importance of SEC24D in collagen secretion. However, SEC24D patient-derived fibroblasts show only a mild secretion phenotype, suggesting tissue-specificity in the secretion process. UsingSec24dKO mice and cultured cells, we show that SEC24A and SEC24B also contribute to ER export of procollagen. In contrast, fibronectin 1 requires either SEC24C or SEC24D for ER export. On the basis of our results, we propose that procollagen interacts with multiple SEC24 paralogs for efficient export from the ER, and that this is the basis for tissue-specific phenotypes resulting from SEC24 paralog deficiency.
Visualizing multi-protein patterns at the synapse of neuronal tissue with DNA-assisted single-molecule localization microscopy
Authors: Narayanasamy Kaarjel K. , Stojic Aleksandar , Li Yunqing , Sass Steffen , Hesse Marina , Deussner-Helfmann Nina S. , Dietz Marina S. , Klevanski Maja , Kuner Thomas , Heilemann Mike 
Published: February 2021

AbstractThe development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350-400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy. Using antibodies labeled with short DNA oligonucleotides, multiple targets are visualized successively by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. The structural integrity of the tissue is maintained owing to only a single labelling step during sample preparation. Multiple targets are imaged using a single laser wavelength, minimizing chromatic aberration. This method proved robust for multi-target imaging in semi-thin tissue sections, paving the way towards structural cell biology with single-molecule super-resolution microscopy.