bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-organization of songbird neural sequences during social isolation
Authors: Mackevicius Emily L. , Gu Shijie , Denisenko Natalia I. , Fee Michale S. 
Published: February 2022

AbstractBehaviors emerge via a combination of experience and innate predis-positions. As the brain matures, it undergoes major changes in cellular, network and functional properties that can be due to sensory experience as well as developmental processes. In normal birdsong learning, neural sequences emerge to control song syllables learned from a tutor. Here, we disambiguate the role of experience and development in neural sequence formation by delaying exposure to a tutor. Using functional calcium imaging, we observe neural sequences in the absence of tutoring, demonstrating that experience is not necessary for the formation of sequences. However, after exposure to a tutor, pre-existing sequences can become tightly associated with new song syllables. Since we delayed tutoring, only half our birds learned new syllables following tutor exposure. The birds that failed to learn were the birds in which pre-tutoring neural sequences were most ‘crystallized’, that is, already tightly associated with their (untutored) song.
Substrate stiffness impacts early biofilm formation by modulatingPseudomonas aeruginosatwitching motility
Authors: Ho Sofia Gomez , Bureau Lionel , John Karin , Débarre Delphine , Lecuyer Sigolène 
Published: February 2022

ABSTRACTSurface-associated lifestyles dominate in the bacterial world. Large multicellular assemblies, called biofilms, are essential to the survival of bacteria in harsh environments, and are closely linked to antibiotic resistance in pathogenic strains. Biofilms stem from the surface colonization of a wide variety of substrates encountered by bacteria, from living tissues to inert materials. Here, we demonstrate experimentally that the promiscuous opportunistic pathogenPseudomonas aeruginosaexplores substrates differently based on their rigidity, leading to striking variations in biofilm structure, exopolysaccharides (EPS) distribution, strain mixing during co-colonization and phenotypic expression. Using simple kinetic models, we show that these phenotypes arise through a mechanical interaction between the elasticity of the substrate and the type IV pilus (T4P) machinery, that mediates the surface-based motility called twitching. Together, our findings reveal a new role for substrate softness in the spatial organization of bacteria in complex microenvironments, with far-reaching consequences on efficient biofilm formation.
Sexually dimorphic architecture and function of a mechanosensory circuit in C. elegans
Authors: Setty Hagar , Salzberg Yehuda , Karimi Shadi , Berent-Barzel Elisheva , Krieg Michael , Oren-Suissa Meital 
Published: February 2022

ABSTRACTHow sensory perception is processed by the two sexes of an organism is still only partially understood. Despite some evidence for sexual dimorphism in auditory and olfactory perception, whether touch is sensed in a dimorphic manner has not been addressed. Here we find that the neuronal circuit for tail mechanosensation in C. elegans is wired differently in the two sexes and employs a different combination of sex-shared sensory neurons and interneurons in each sex. Reverse genetic screens uncovered cell- and sex-specific functions of the alpha-tubulin mec-12 and the sodium channel tmc-1 in sensory neurons, and of the glutamate receptors nmr-1 and glr-1 in interneurons, revealing the underlying molecular mechanisms that mediate tail mechanosensation. Moreover, we show that only in males, the sex-shared interneuron AVG is strongly activated by tail mechanical stimulation, and accordingly is crucial for their behavioral response. Importantly, sex reversal experiments demonstrate that the sexual identity of AVG determines both the behavioral output of the mechanosensory response and the molecular pathways controlling it. Our results present for the first time extensive sexual dimorphism in a mechanosensory circuit at both the cellular and molecular levels.
Protein compactness and interaction valency define the architecture of a biomolecular condensate across scales
Authors: Polyansky Anton A. , Gallego Laura D. , Efremov Roman G. , Köhler Alwin , Zagrovic Bojan 
Published: February 2022

AbstractNon-membrane-bound biomolecular condensates have been proposed to represent an important mode of subcellular organization in diverse biological settings. However, the fundamental principles governing the spatial organization and dynamics of condensates at the atomistic level remain unclear. TheS. cerevisiaeLge1 protein is required for histone H2B ubiquitination and its N-terminal intrinsically disordered fragment (Lge11-80) undergoes robust phase separation. This study connects single- and multi-chain all-atom molecular dynamics simulations of Lge11-80with thein vitrobehavior of Lge11-80condensates. Analysis of modelled protein-protein interactions elucidates the key determinants of Lge11-80condensate formation and links configurational entropy, valency and compactness of proteins inside the condensates. A newly derived analytical formalism, related to colloid fractal cluster formation, describes condensate architecture across length scales as a function of protein valency and compactness. In particular, the formalism provides an atomistically resolved model of Lge11-80condensates on the scale of hundreds of nanometers starting from individual protein conformers captured in simulations. The simulation-derived fractal dimensions of condensates of Lge11-80and its mutants agree with theirin vitromorphologies. The presented framework enables a multiscale description of biomolecular condensates and embeds their study in a wider context of colloid self-organization.
Structural insights into the assembly and activation of IL-27 signalling complex
Authors: Jin Yibo , Fyfe Paul K. , Gardner Scott , Wilmes Stephan , Bubeck Doryen , Moraga Ignacio 
Published: February 2022

AbstractInterleukin 27 (IL-27) is a heterodimeric cytokine that elicits potent immuno-suppressive responses. Comprised of EBI3 and p28 subunits, IL-27 binds GP130 and IL-27Rα receptor chains to activate the JAK/STAT signalling cascade. However, how these receptors recognize IL-27 and form a complex capable of phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) to solve the structure of the IL-27 receptor recognition complex. Our data show how IL-27 serves as a bridge connecting IL-27Rα with GP130 to initiate signalling. While both receptors weakly bind the p28 component of the heterodimeric cytokine, EBI3 stabilizes the complex by binding a positively charged surface of IL-27Rα. We find that assembly of the IL-27 receptor recognition complex is distinct from both IL-12 and IL-6 cytokine families and provides a mechanistic blueprint for tuning IL-27 pleiotropic actions.
Furin-cleavage site is present in an antiparallel β-strand in SARS-CoV2 Spike protein
Authors: Bashir Arif , Shah Naveed Nazir 
Published: February 2022

AbstractFurin cleavage-site (CS) present between the S1/S2 junction in SARS-CoV2 spike (S) protein is critical to drive the fusion of SARS-CoV2 with the host cell. SARS-CoV2 falls in the sarbecovirus lineage that doesn’t comprise of furin CS and therefore makes its origin enigmatic. The available wild-type (Wt) SARS-CoV2 S protein with PDB ID: 6yvb lacks a stretch of amino acid including furin CS as well. All investigators till date have shown this stretch existing in the form of a loop. We are for the first time reporting that this stretch comprises of 14 amino acid residues (677QTNSPRRARSVASQ689), forming an antiparallel β-sheet comprising of PRRAR furin CS. We observed the presence of this antiparallel β-sheet in MERS spike protein as well. While switching over from Wt. SARS-CoV2 with PRRAR furin CS to B.1.1.7 variant with HRRAR furin CS, we found 3% increase in the percentage content of β stands. Interestingly, we found that the change of B.1.1.7 to B.1.617 variant comprising of RRRAR furin CS shifted the percentage secondary structure back to that found in Wt. SARS-CoV2. We anticipate that this β-sheet is used as a docking site by host cell proteases to act on furin-CS. Additionally, we studied the interaction of modeled SARS-CoV2 S protein with transmembrane protease, serine 2 (TMPRSS2), and furin proteases, which clearly highlighted that these proteases exclusively uses furin CS located in β-sheet to cleave the SARS-CoV2 S protein at its S1/S2 junction.
Hybridization and a mixture of small and large-effect loci facilitate adaptive radiation
Authors: De-Kayne Rishi , Selz Oliver M. , Marques David A. , Frei David , Seehausen Ole , Feulner Philine G. D. 
Published: February 2022

AbstractAdaptive radiations represent some of the most remarkable explosions of diversification across the tree of life. However, the constraints to rapid diversification and how they are sometimes overcome, particularly the relative roles of genetic architecture and hybridization, remain unclear. Here, we address these questions in the Alpine whitefish radiation, using a whole-genome dataset that includes multiple individuals of each of the 22 species belonging to six ecologically distinct ecomorph classes across several lake-systems. We reveal that repeated ecological and morphological diversification along a common environmental axis is associated with both genome-wide allele frequency shifts and a specific, larger effect, locus, associated with the geneedar. Additionally, we highlight the role of introgression between species from different lake-systems in facilitating the evolution and persistence of species with unique phenotypic combinations and ecology. These results highlight the role of both genome architecture and secondary contact with hybridization in fuelling adaptive radiation.
Borrowing ecological theory to infer interactions between sensitive and resistant breast cancer cell populations
Authors: Susswein Zachary , Sengupta Surojeet , Clarke Robert , Bansal Shweta 
Published: February 2022

AbstractWhile some forms of breast cancer are highly responsive to treatment, endocrine therapy-resistant breast cancers are disproportionately lethal. There has been significant progress in understanding how endocrine therapy-resistant strains evolve from therapy-susceptible strains of cancer, but little is understood about the proliferation of resistance through cancer cell populations, or the interactions that occur between populations of resistant and sensitive cells. In this study, we characterize the nature of the ecological interaction between populations of resistant and susceptible breast cancer cells to reveal novel methods of controlling drug resistance.Using in-vitro data on fluorescent-tagged resistant and susceptible cells, we use an image processing algorithm to identify and count cell growth till equilibrium. We then borrow theory from population biology to infer the type of ecological interaction that occurs between populations of resistant and sensitive cells. In particular, we use a Bayesian approach to fit single culture cell populations to infer density-dependent growth parameters (growth rate, carrying capacity) and a Generalized Lotka-Volterra model to understand how susceptible and resistant co-culture populations may be depressing or supporting growth of the other.Our results identify a net mutualistic interaction between the susceptible and resistant cancer strains, demonstrating that there are ecological dynamics to cancer resistance. Our findings also suggest that ecological dynamics change in the presence of therapy, and that an adaptive treatment protocol can induce cycling behavior suggesting that heterogeneous ecological effects contribute to empirically observed adaptive-therapeutic dynamics.
The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds
Authors: Saha Itika , Yuste-Checa Patricia , Silva Padilha Miguel Da , Guo Qiang , Körner Roman , Holthusen Hauke , Trinkaus Victoria A. , Dudanova Irina , Fernández-Busnadiego Rubén , Baumeister Wolfgang , Sanders David W. , Gautam Saurabh , Diamond Marc I. , Ulrich Hartl F. , Hipp Mark S. 
Published: February 2022

AbstractAmyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer’s disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the AAA+ chaperone VCP is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with Hsp70 and the ubiquitin-proteasome machinery. Inhibition of VCP activity stabilizes large Tau aggregates, and is accompanied by a reduction in the amount of Tau species competent of prion- like aggregate seeding in recipient cells. Thus, disaggregation by VCP generates seeding-active Tau as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.
Mural norrin/β-catenin signaling regulates Lama2 expression to promote neurovascular unit assembly
Authors: Biswas Saptarshi , Shahriar Sanjid , Giangreco Nicholas P. , Arvanitis Panos , Winkler Markus , Tatonetti Nicholas P. , Brunken William J. , Cutforth Tyler , Agalliu Dritan 
Published: February 2022

ABSTRACTNeurovascular unit (NVU) assembly and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are critical for these processes, yet which signaling pathway(s) regulate their expression remains unknown. Here we show that mural cells have active Norrin/β-catenin signaling during central nervous system development. Bulk RNA sequencing and validation using P10 and P14 wild-type versusApcdd1-/-retinas reveal that Lama2 (Laminin-α2 chain) mRNA and protein levels are increased in mutant vasculature undergoing higher Norrin/β-catenin signaling. Mural cells are the main source of Lama2, and β-catenin activation induces Lama2 expression in mural cellsin vitro. Markers of mature astrocytes including Aquaporin-4 (a water channel in astrocyte endfeet) and Integrin-α6 (a laminin receptor) are upregulated inApcdd1-/-retinas following higher Lama2 vBM deposition. Thus, the Norrin/β-catenin pathway regulates Lama2 expression in mural cells to promote NVU assembly and neurovascular barrier maturation.SUMMARYBiswaset al., demonstrate that Norrin/β-catenin signaling is active in CNS mural cells and regulates Lama2 deposition in the vascular basement membrane, promoting neurovascular unit assembly and blood-CNS barrier maturation.
Deep learning accurately quantifies plasma cell percentages on CD138-stained bone marrow samples
Authors: Fu Fred , Guenther Angela , Sakhdari Ali , McKee Trevor D. , Xia Daniel 
Published: February 2022

AbstractBackgroundThe diagnosis of plasma cell neoplasms requires accurate, and ideally precise, percentages. This plasma cell percentage is often determined by visual estimation of CD138-stained bone marrow biopsies and clot sections. While not necessarily inaccurate, estimates are by definition imprecise. For this study, we hypothesized that deep learning can be used to improve precision.MethodsWe trained a semantic segmentation-based convolutional neural network (CNN) using annotations of CD138+ and CD138− cells provided by one pathologist on small image patches of bone marrow and validated the CNN on an independent test set of images patches using annotations from two pathologists and a non-deep-learning commercial software. Once satisfied with performance, we scaled-up the CNN to evaluate whole slide images (WSIs), and deployed the system as a workflow friendly web application to measure plasma cell percentages using snapshots taken from microscope cameras.ResultsOn validation image patches, we found that the intraclass correlation coefficients for plasma cell percentages between the CNN and pathologist #1, a non-deep learning commercial software and pathologist #1, and pathologists #1 and #2 were 0.975, 0.892, and 0.994, respectively. The overall results show that CNN labels were almost as accurate pathologist labels at a cell-by-cell level. On WSIs from 10 clinical cases, the CNN continued to perform well, and identified two cases where the sign-out pathologist overestimated plasma cell percentages.ConclusionsThe high labeling accuracy of the CNN supports its eventually application as a computational second-opinion tool for the measurement of plasma cell percentages in clinical practice.
Transcriptome analysis of diverse Plasmodium falciparum clinical isolates identifies genes correlating with highly variable expression of merozoite surface protein MSPDBL2
Authors: Hocking Suzanne E. , Stewart Lindsay B. , Tarr Sarah J. , Freville Aline , Tetteh Kevin K. A. , Ahouidi Ambroise D. , Amambua-Ngwa Alfred , Diakite Mahamadou , Awandare Gordon A. , Conway David J. 
Published: February 2022

AbstractThe merozoite surface protein MSPDBL2 of Plasmodium falciparum is under strong balancing selection and is a target of naturally acquired antibodies. Remarkably, MSPDBL2 is expressed in only a minority of mature schizonts of any cultured parasite line, and mspdbl2 gene transcription increases in response to overexpression of the gametocyte development inducer GDV1, so it is important to understand its natural expression. Here, MSPDBL2 in mature schizonts was analysed in the first ex vivo culture cycle of 96 clinical isolates from four populations with varying levels of infection endemicity in different West African countries, by immunofluorescence microscopy with antibodies against a conserved region of the protein. In most isolates, less than 1% of mature schizonts were positive for MSPDBL2 (median of 0.6% overall), but the frequency distribution was highly skewed as nine isolates had more than 3% schizonts positive and one had 73% positive. To investigate whether expression of other gene loci correlated with MSPDBL2 expression, whole transcriptome sequencing was performed on schizont-enriched material from 17 of the clinical isolates with a wide range of proportions of schizonts positive. Transcripts of particular parasite genes were highly significantly positively correlated with MSPDBL2 positivity in schizonts as well as with mspdbl2 gene transcript levels, with overrepresentation of genes previously implicated as likely to be involved in gametocytogenesis, but not including the gametocytogenesis master regulator ap2g. Although MSPDBL2 is apparently not directly involved in sexual commitment, it marks a co-occurring developmental subpopulation that may be functionally distinct within blood stage infections.
The Chlamydia protein CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35
Authors: Meier Karsten , Jachmann Lana H. , Pérez Lucía , Kepp Oliver , Valdivia Raphael H. , Kroemer Guido , Sixt Barbara S. 
Published: February 2022

ABSTRACTThe obligate intracellular bacterium Chlamydia trachomatis inserts into the membrane of its vacuole (the inclusion) a family of poorly characterized Inc proteins. While the Inc CpoS was recently revealed as a critical suppressor of host cellular immune surveillance, the underlying mechanism remained unknown. By complementing a cpoS mutant with modified variants of CpoS, we found that CpoS blocks distinct cellular defense responses through distinct mechanisms. Specifically, we show that the ability of CpoS to interact with Rab GTPases is not only instrumental to its ability to mediate lipid transport to the inclusion, but also key to CpoS-mediated inhibition of type I interferon responses. Indeed, depletion of Rab35 can phenocopy the respective defect of the cpoS mutant. Unexpectedly, we found that CpoS is also essential for the formation of inclusion microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. Overall, our findings highlight the modulation of membrane trafficking as a pathogenic immune evasion strategy and the role of Inc-Inc interactions in shaping the inclusion microenvironment.
Genomewide m6A mapping uncovers dynamic changes in the m6A epitranscriptome of cisplatin-treated apoptotic HeLa cells
Authors: Akçaöz Azime , Tüncel Özge , Bengisu Gelmez Ayşe , Sağlam Buket , Vatansever İpek Erdoğan , Akgül Bünyamin 
Published: February 2022

AbstractCisplatin, which is a traditional cancer therapeutic drug, induces apoptosis by modulating a diverse array of gene regulatory mechanisms. However, cisplatin-mediated changes in the m6A methylome is unknown. We employed m6A miCLIP-seq to investigate the effect of m6A methylation events under cisplatin-mediated apoptotic conditions in HeLa cells. Our high-resolution approach revealed numerous m6A marks on 972 target mRNAs with an enrichment on 132 apoptotic mRNAs. Following validation of site-specific m6A events on candidate RNAs, we tracked the fate of candidate mRNAs under METTL3 knockdown and cisplatin treatment conditions. We detected perturbations in the translational efficiency of PMAIP1 and PHLDA1 transcripts based on the polysome profile analyses. Congruently, PMAIP1 and p53 amounts were dependent on METTL3. Additionally, cisplatin-mediated apoptosis was sensitized by METTL3 knockdown. These results suggest that apoptotic pathways are modulated by m6A methylation events and METTL3-p53-PMAIP1 axis modulates cisplatin-mediated apoptosis in HeLa cells.
Potent Neutralization of Omicron and other SARS-CoV-2 Variants of Concern by Biparatopic Human VH Domains
Authors: Chen Chuan , Saville James W. , Marti Michelle M. , Schäfer Alexandra , Cheng Mary Hongying , Mannar Dhiraj , Zhu Xing , Berezuk Alison M. , Banerjee Anupam , Sobolewski Michele D. , Kim Andrew , Treat Benjamin R. , Da Silva Castanha Priscila Mayrelle , Enick Nathan , McCormick Kevin D , Liu Xianglei , Adams Cynthia , Hines Margaret Grace , Sun Zehua , Chen Weizao , Jacobs Jana L. , Barratt-Boyes Simon M. , Mellors John W. , Baric Ralph S. , Bahar Ivet , Dimitrov Dimiter S. , Subramaniam Sriram , Martinez David R. , Li Wei 
Published: February 2022

AbstractThe emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics that are effective against a variety of strains of the virus. Herein, we characterize a human VH domain, F6, which we generated by sequentially panning large phage displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that neutralized Omicron pseudoviruses with a half-maximal neutralizing concentration (IC50) of 4.8 nM in vitro. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 VOCs - including the recently emerged Omicron variant - and highlight a vulnerable epitope within the spike protein RBD that may be exploited to achieve broad protection against circulating variants.