bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-equilibrium conditions inside rock pores drive fission, maintenance and selection of coacervate protocells
Authors: Ianeselli Alan , Tetiker Damla , Stein Julian , Kühnlein Alexandra , Mast Christof , Braun Dieter , Dora Tang T-Y 
Published: July 2021

AbstractKey requirements for the first cells on Earth include the ability to compartmentalize and evolve. Compartmentalization spatially localizes biomolecules from a dilute pool and an evolving cell which grows and divides permits mixing and propagation of information to daughter cells. Complex coacervate microdroplets are excellent candidates as primordial cells with the ability to partition and concentrate molecules into their core and support primitive and complex biochemical reactions. However, the evolution of coacervate protocells by fusion, growth and fission has not yet been demonstrated. In this work, a primordial environment initiated the evolution of coacervate-based protocells. Gas bubbles inside heated rock pores perturb the coacervate protocell distribution and drive the growth, fusion, division and selection of coacervate microdroplets. This setting provides a primordial non-equilibrium environment. Our findings describe how common gas bubbles within heated rock pores induce the early evolution processes of coacervate-based protocells, providing a compelling scenario for the evolution of membrane-free coacervate microdroplets on the early Earth.
Antibody and T cell memory immune response after two doses of the BNT162b2 mRNA vaccine in older adults with and without prior SARS-CoV-2 infection
Authors: Demaret Julie , Corroyer-Simovic Bénédicte , Alidjinou Enagnon Kazali , Goffard Anne , Trauet Jacques , Miczek Sophie , Vuotto Fanny , Dendooven Arnaud , Huvent-Grelle Dominique , Podvin Juliette , Dreuil Daniel , Faure Karine , Deplanque Dominique , Bocket Laurence , Duhamel Alain , Labreuche Julien , Sobaszek Annie , Puisieux Francois , Labalette Myriam , Lefèvre Guillaume 
Published: July 2021

AbstractWe quantified S1-specific IgG, neutralizing antibody titers, specific IFNγ secreting T cells and functionality of specific CD4+ and CD8+ T cells in 130 young adults (median age 44.0 years) and 106 older residents living in a long-term care facility (86.5 years) after 2 doses of BNT162b2. Three months after the first injection, humoral and cellular memory responses were dramatically impaired in the 54 COVID-19-naive older compared to the 121 COVID-19-naive younger adults. Notably, older participants’ neutralizing antibodies, detected in 76.5% (versus 100% in young adults,P< 0.0001), were ten times lower than the younger’s antibody titers (P< 0.0001). Antibody and T cell responses were greater among the 52 COVID-19-recovered than among the 54 COVID-19-naive older adults (P< 0.0001). Our study shows that 2 doses of BNT162b2 does not guarantee long-term protection against SARS-CoV-2 in the older. An additional dose should be considered to boost their specific memory response.
The geometry of domain-general performance monitoring in the human medial frontal cortex
Authors: Fu Zhongzheng , Beam Danielle , Chung Jeffrey M. , Reed Chrystal M. , Mamelak Adam N. , Adolphs Ralph , Rutishauser Ueli 
Published: July 2021

AbstractControlling behavior to flexibly achieve desired goals depends on the ability to monitor one’s own performance. It is unknown how performance monitoring can be both flexible to support different tasks and specialized to perform well on each. We recorded single neurons in the human medial frontal cortex while subjects performed two tasks that involve three types of cognitive conflict. Neurons encoding predicted conflict, conflict, and error in one or both tasks were intermixed, forming a representational geometry that simultaneously allowed task specialization and generalization. Neurons encoding conflict retrospectively served to update internal estimates of control demand. Population representations of conflict were compositional. These findings reveal how representations of evaluative signals can be both abstract and task-specific and suggest a neuronal mechanism for estimating control demand.
Growth temperature is the principal driver of chromatinization in archaea
Authors: Hocher Antoine , Borrel Guillaume , Fadhlaoui Khaled , Brugère Jean-François , Gribaldo Simonetta , Warnecke Tobias 
Published: July 2021

ABSTRACTAcross the tree of life, DNA in living cells is associated with proteins that coat chromosomes, constrain their structure and influence DNA-templated processes such as transcription and replication. In bacteria and eukaryotes, HU and histones, respectively, are the principal constituents of chromatin, with few exceptions. Archaea, in contrast, have more diverse repertoires of nucleoid-associated proteins (NAPs). The evolutionary and ecological drivers behind this diversity are poorly understood. Here, we combine a systematic phylogenomic survey of known and predicted NAPs with quantitative protein abundance data to shed light on the forces governing the evolution of archaeal chromatin. Our survey highlights the Diaforarchaea as a hotbed of NAP innovation and turnover. Loss of histones and Alba in the ancestor of this clade was followed by multiple lineage-specific horizontal acquisitions of DNA-binding proteins from other prokaryotes. Intriguingly, we find that one family of Diaforarchaea, the Methanomethylophilaceae, lacks any known NAPs. Comparative analysis of quantitative proteomics data across a panel of 19 archaea revealed that investment in NAP production varies over two orders of magnitude, from <0.02% to >5% of total protein. Integrating genomic and ecological data, we demonstrate that growth temperature is an excellent predictor of relative NAP investment across archaea. Our results suggest that high levels of chromatinization have evolved as a mechanism to prevent uncontrolled helix opening and runaway denaturation – rather than, for example, to globally orchestrate gene expression – with implications for the origin of chromatin in both archaea and eukaryotes.
Ultrastructural analysis of nasopharyngeal epithelial cells from patients with SARS-CoV-2 infection
Authors: Saraiva Karina Lidianne Alcântara , Vasconcelos Luydson Richardson Silva , Bezerra Matheus Filgueira , Arcoverde Rodrigo Moraes Loyo , Brandão-Filho Sinval Pinto , Ayres Constância Flávia Junqueira , de Figueiredo Regina Célia Bressan Queiroz , Pereira-Neves Antonio 
Published: July 2021

AbstractThe nasal epithelium is an initial site for SARS-CoV-2 infection, responsible for the ongoing COVID-19 pandemic. However, the pathogenicity and morphological impact of SARS-CoV-2 on the nasopharynx cells from symptomatic patients with different viral loads remain poorly understood. Here, we investigated the ultrastructure of nasal cells obtained from individuals at distinct disease days and with high and low SARS-CoV-2 loads. Squamous and ciliated cells were the main cells observed in SARS-CoV-2 negative samples. We identified virus-like particles (VLPs) and replication organelles (RO)-like structures in the squamous cells from high viral load samples after 3- and 4-days of symptoms. Ultrastructural changes were found in those cells, such as the loss of microvilli and primary cilium, the increase of multivesicular bodies and autophagosomes, and signs of cell death. No ciliated cells were found in those samples. Squamous cells from low viral load sample after 5 days of symptoms showed few microvilli and no primary cilium. VLPs and RO-like structures were found in the ciliated cells only. No ultrastructural alterations were seen in the cells from low viral load individuals after 10- and 14-days of symptoms. Our results shed light on the ultrastructural effects of SARS-CoV-2 infection on the human nasopharyngeal cells.
Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders
Authors: Woodard Jaie , Zheng Wei , Zhang Yang 
Published: July 2021

AbstractThree-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.Author summaryPharmacological chaperones are small molecule drugs that bind to proteins to help stabilize the folded state. One set of diseases for which this treatment has been effective is the lysosomal storage disorders, which are caused by defective lysosomal enzymes. However, not all genotypes are equally responsive to treatment. For instance, missense mutants that are particularly destabilized relative to WT are less likely to respond. The availability of datasets containing responsiveness data for large numbers of mutants, along with crystal structures of the protein involved in each disease, make machine learning methods incorporating sequence-based and structural data feasible. We hypothesize that data from two diseases, Fabry and Pompe disease, may be useful for predicting responsiveness of variants in the related Gaucher disease. Results suggest that many rare variants in Gaucher disease could be amenable to existing drugs. Results suggest that drug responsiveness depends on protein topology is such a way that mutations in early-to-fold residues are more likely to be non-responsive to pharmacological chaperone treatment, which is consistent with a simple kinetic model of stability rescue. This study provides an example of how machine learning can be used to inform further studies towards personalized treatment in medicine.
Peptides derived from gp43, the most antigenic protein from Paracoccidioides brasiliensis, form amyloid fibrils in vitro: implications for vaccine development
Authors: Cardim-Pires Thyago R. , Sant’Anna Ricardo , Foguel Debora 
Published: July 2021

AbstractFungal infection is an important public health problem afflicting more than a billion people worldwide. Mycoses are especially important in Latin America, and in Brazil in particular. Paracoccidioides is the genus of fungi responsible for paracoccidioidomycosis comprising two species, P. brasiliensis and P. lutzii. The lungs are the primary infection site, but oral mucosa and airways can also be affected. The glycoprotein gp43 is involved in fungi adhesion to epithelial cells and is the most studied protein of P. brasiliensis. Seminal work identified a specific stretch of 15 amino acids that spans the region 181-195 (called P10) as an important epitope of gp43, being recognized by T lymphocytes in peripheral blood mononuclear cells of mice and humans and is envisioned as a potential vaccine component. Here, we show by using thioflavin T (ThT), transmission electron microscopy and other methods that synthetic P10 forms typical amyloid aggregates in solution in very short times, a property that could hamper vaccine development. In silico, aggregation analysis reveals several aggregation-prone regions (APR) in the P10 sequence that are capable of forming amyloid cores with steric zipper architecture. Seeds of P10 obtained by fibril mechanical fragmentation were able to induce the aggregation of P4 but not P23, as evidenced by ThT binding and mass spectrometry. These two peptides, also derived from gp43, are potent modulators of local and systemic inflammation. In-silico proteolysis studies with gp43 revealed that aggregation-prone, P10-like peptides could be generated by the action of several proteases such as proteinase K, trypsin and pepsin, which suggests that P10 could be formed upon gp43 digestion in a physiological condition. Considering our data in the context of a potential vaccine development, we redesigned the sequence of the P10 peptide, maintaining the antigenic region (HTLAIR), but drastically reducing its aggregation propensity.
Heterogeneous substrate binding in a glutamate transporter homologue
Authors: Reddy Krishna D. , Ciftci Didar , Scopelliti Amanda , Boudker Olga 
Published: July 2021

ABSTRACTIntegral membrane glutamate transporters couple the concentrative substrate transport to ion gradients. There is a wealth of structural and mechanistic information about this family. Recent studies revealed transport rate heterogeneity in an archaeal homologue GltPh, inconsistent with simple kinetic models, but its structural and mechanistic determinants remain undefined. In a mutant GltPh, which exclusively populates the outward-facing state, we demonstrate the co-existence of at least two sub-states in slow equilibrium binding the substrate with different apparent affinities. Wild-type GltPh shows similar binding properties, and modulation of the sub-state equilibrium correlates with transport rates. Following binding, the low-affinity sub-state of the mutant is transient. Consistently, cryo-EM on samples frozen within seconds after substrate addition reveals the presence of structural classes with perturbed helical packing of the extracellular half of the transport domain in regions adjacent to the binding site. In contrast, an equilibrated structure does not show such classes. The structure at 2.2 Å resolution details a pattern of waters in the intracellular half of the domain and resolves classes with subtle differences in the substrate-binding site. We hypothesize that the rigid cytoplasmic half of the domain mediates substrate and ion recognition and coupling, while the extracellular labile half sets the affinity and dynamic properties.
Effects of Ionic Strength on Gating and Permeation of TREK-2 K2P channels
Authors: Conrad Linus J , Proks Peter , Tucker Stephen J 
Published: July 2021

AbstractIn addition to the classical voltage-dependent behavior mediated by voltage-sensing-domains (VSD), a growing number of voltage-dependent gating behaviors are being described in ion channels that lack canonical VSDs. A common thread in their mechanism of action is the contribution of the permeating ion to this voltage sensing process. The polymodal K2P K+channel TREK2 responds to membrane voltage through a gating process that is mediated by the interaction of K+with its selectivity filter. Recently, we have found that this action can be modulated by small molecule agonists (e.g. BL1249) which appear to have an electrostatic influence on K+binding within the inner cavity and produce an increase in the single-channel conductance of TREK-2 channels. Here, we directly probed this K+-dependent gating process by recording both macroscopic and single-channel currents of TREK-2 in the presence of high concentrations of internal K+. Surprisingly we found that the channel is inhibited by high internal K+concentrations and that this is mediated by the concomitant increase in ionic-strength. However, we were still able to determine that the increase in single channel conductance in the presence of BL1249 was blunted in high ionic-strength, whilst its activatory effect (on channel open probability) persisted. These effects are consistent with an electrostatic mechanism of action of negatively charged activators such as BL1249 on permeation, but also suggest that their influence on channel gating is more complex.
CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors
Authors: Kyung Taeyoon , Gordon Khloe S. , Perez Caleb R. , Holec Patrick V. , Ramos Azucena , Zhang Angela Q. , Liu Yunpeng , Koch Catherine , Starchenko Alina , Joughin Brian , Lauffenburger Douglas A. , Irvine Darrell J. , Hemann Michael T. , Birnbaum Michael E. 
Published: July 2021

AbstractCD19-targeted CAR therapies have successfully treated B cell leukemias and lymphomas, but many responders later relapse or experience toxicities. CAR intracellular domains (ICDs) are key to converting antigen recognition into anti-tumor effector functions. Despite the many possible immune signaling domain combinations that could be included in CARs, almost all CARs currently rely upon CD3ζ, CD28, and/or 4-1BB signaling. To explore the signaling potential of CAR ICDs, we generated a library of 700,000 CD19 CAR molecules with diverse signaling domains and developed a high throughput screening platform to enable optimization of CAR signaling for anti-tumor functions. Our strategy identifies CARs with novel signaling domain combinations that elicit distinct T cell behaviors from a clinically available CAR, including enhanced proliferation and persistence, lower exhaustion, potent cytotoxicity in anin vitrotumor rechallenge condition, and comparable tumor controlin vivo. This approach is readily adaptable to numerous disease models, cell types, and selection conditions, making it a promising tool for rapidly improving adoptive cell therapies and expanding their utility to new disease indications.
Adolescent Brain Cognitive Development (ABCD) Community MRI Collection and Utilities
Authors: Feczko Eric , Conan Greg , Marek Scott , Tervo-Clemmens Brenden , Cordova Michaela , Doyle Olivia , Earl Eric , Perrone Anders , Sturgeon Darrick , Klein Rachel , Harman Gareth , Kilamovich Dakota , Hermosillo Robert , Miranda-Dominguez Oscar , Adebimpe Azeez , Bertolero Maxwell , Cieslak Matthew , Covitz Sydney , Hendrickson Timothy , Juliano Anthony C. , Snider Kathy , Moore Lucille A. , Uriartel Johnny , Graham Alice M. , Calabro Finn , Rosenberg Monica D. , Rapuano Kristina M. , Casey BJ , Watts Richard , Hagler Donald , Thompson Wesley K. , Nichols Thomas E. , Hoffman Elizabeth , Luna Beatriz , Garavan Hugh , Satterthwaite Theodore D. , Ewing Sarah Feldstein , Nagel Bonnie , Dosenbach Nico U.F. , Fair Damien A. 
Published: July 2021

AbstractThe Adolescent Brain Cognitive Development Study (ABCD), a 10 year longitudinal neuroimaging study of the largest population based and demographically distributed cohort of 9-10 year olds (N=11,877), was designed to overcome reproducibility limitations of prior child mental health studies. Besides the fantastic wealth of research opportunities, the extremely large size of the ABCD data set also creates enormous data storage, processing, and analysis challenges for researchers. To ensure data privacy and safety, researchers are not currently able to share neuroimaging data derivatives through the central repository at the National Data Archive (NDA). However, sharing derived data amongst researchers laterally can powerfully accelerate scientific progress, to ensure the maximum public benefit is derived from the ABCD study. To simultaneously promote collaboration and data safety, we developed the ABCD-BIDS Community Collection (ABCC), which includes both curated processed data and software utilities for further analyses. The ABCC also enables researchers to upload their own custom-processed versions of ABCD data and derivatives for sharing with the research community. This NeuroResource is meant to serve as the companion guide for the ABCC. In section we describe the ABCC. Section II highlights ABCC utilities that help researchers access, share, and analyze ABCD data, while section III provides two exemplar reproducibility analyses using ABCC utilities. We hope that adoption of the ABCC’s data-safe, open-science framework will boost access and reproducibility, thus facilitating progress in child and adolescent mental health research.
Benchmarking long-read genome sequence alignment tools for human genomics applications
Authors: LoTempio Jonathan , Délot Emmanuèle , Vilain Eric 
Published: July 2021

AbstractBackgroundThe utility of long-read genome sequencing platforms has been shown in many fields including whole genome assembly, metagenomics, and amplicon sequencing. Less clear is the applicability of long reads to reference-guided human genomics, the foundation of genomic medicine. Here, we benchmark available platform-agnostic alignment tools on datasets from nanopore and single-molecule real-time platforms to understand their suitability in producing a genome representation.ResultsFor this study, we leveraged publicly-available data from sample NA12878 generated on Oxford Nanopore and sample NA24385 on Pacific Biosciences platforms. Each tool that was benchmarked, including GraphMap2, LRA, Minimap2, NGMLR, and Winnowmap2 produced the same alignment file each time. However, the different tools widely disagreed on which reads to leave unaligned, affecting the end genome coverage and the number of discoverable breakpoints. Minimap2 and winnowmap2 were computationally lightweight enough for use at scale. No alignment from one tool independently resolved all large structural variants (10,000-100,000 basepairs) present in the Database of Genome Variants (DGV) for sample NA12878 or the truthset for NA24385.ConclusionsIt should be best practice to use an analysis pipeline that generates alignments with both minimap2 and winnowmap2 as both are lightweight and yield different views of the genome. If computational resources and time are not a factor for a given case or experiment, a third representation from NGMLR will provide another view, and another chance to resolve a case. LRA, while fast, did not work on the nanopore data for our cluster, but PacBio results were promising in that those computations completed faster than Mininmap2. Graphmap2 is not an ideal tool for exploration of a whole human genome generated on a long-read sequencing platform.
Allosteric effect of nanobody binding on ligand-specific active states of the β2-Adrenergic Receptor
Authors: Chen Yue , Fleetwood Oliver , Pérez-Conesa Sergio , Delemotte Lucie 
Published: July 2021

AbstractNanobody binding stabilizes the active state of G-protein-coupled receptor (GPCR) and modulates its affinity for bound ligands. However, the atomic level basis for this allosteric regulation remains elusive. Here, we investigate the conformational changes induced by the binding of a nanobody (Nb80) on the active-like β2 adrenergic receptor (β2AR) via enhanced sampling molecular dynamics simulations. Dimensionality reduction analysis shows that Nb80 stabilizes a highly active state of the β2AR with a ~14 Å outward movement of transmembrane helix 6 and close proximity of transmembrane (TM) helices 5 and 7. This is further supported by the residues located at hotspots located on TMs 5, 6 and 7, as shown by supervised machine learning methods. Besides, ligand-specific subtle differences in the conformations assumed by intercellular loop 2 and extracellular loop 2 are captured from the trajectories of various ligand-bound receptors in the presence of Nb80. Dynamic network analysis further reveals that Nb80 binding can enhance the communication between the binding sites of Nb80 and of the ligand. We identify unique allosteric signal transmission mechanisms between the Nb80-binding site and the extracellular domains in presence of full agonist and G-protein biased partial agonist, respectively. Altogether, our results provide insights into the effect of intracellular binding partners on the GPCR activation mechanism, which could be useful for structure-based drug discovery.TOCGraphical Table of Contents