bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions
Authors: Rombouts Jan , Gelens Lendert 
Published: August 2020

AbstractBistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies indicate that the shape of the bistable response curve changes dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent.Author summaryMany systems in nature show bistability, which means they can evolve to one of two stable steady states under exactly the same conditions. Which state they evolve to depends on where the system comes from. Such bistability underlies the switching behavior that is essential for cells to progress in the cell division cycle. A quick switch happens when the cell jumps from one steady state to another steady state. Typical of this switching behavior is its robustness and irreversibility. In this paper, we expand this viewpoint of the dynamics of the cell cycle by considering bistable switches which themselves are changing in time. This gives the cell an extra layer of control over transitions both in time and in space, and can make those transitions more robust. Such dynamically changing bistability can appear very naturally. We show this in a model of mitotic entry, in which we include a nuclear and cytoplasmic compartment. The activity of a crucial cell cycle protein follows a bistable switch in each compartment, but the shape of its response is changing in time as proteins are imported and exported from the nucleus.
Same, Same, but Different: Molecular Analyses ofStreptococcus pneumoniaeImmune Evasion Proteins Identifies new Domains and Reveals Structural Differences between PspC and Hic Variants
Authors: Du Shanshan , Vilhena Claudia , King Samantha , Sahagun Alfredo , Hammerschmidt Sven , Skerka Christine , Zipfel Peter F. 
Published: August 2020

AbstractPspC and Hic proteins ofStreptococcus pneumoniaeare some of the most variable microbial immune evasion proteins identified to date. Due to structural similarities and conserved binding profiles it was assumed over a long time that these pneumococcal surface proteins represent a protein family, comprising eleven subgroups. Recently, however, by evaluating more proteins larger diversity of individual proteins became apparent. In contrast to previous assumptions a pattern evaluation of six PspC and five Hic variants, each representing one of the previously defined subgroups, revealed distinct structural and likely functionally regions of the proteins, and identified nine new domains and new domain alternates. Several domains are unique to PspC and Hic variants, while other domains are shared with otherS. pneumoniaeand bacterial virulent determinants. This understanding improved pattern evaluation on the level of full-length proteins, allowed a sequence comparison on the domain level and furthermore identified domains with a modular composition. This novel concept allows a better characterization of variability, and modular domain composition of individual proteins, enables a structural and functional characterization at the domain level and furthermore shows substantial structural differences between PspC and Hic proteins. Such knowledge will also be useful for molecular strain typing, characterizing PspC and Hic proteins from new clinicalS. pneumoniaestrains, including those derived from patients who present with pneumococcal hemolytic uremic syndrome. Furthermore this analysis explains the role of multifaceted intact PspC and Hic proteins in pathogen host interactions. and can provide a basis for rational vaccine design.Author SummaryThe human pathobiontStreptococcus pneumoniaeexpresses highly polymorphic PspC or Hic proteins, which bind a repertoire of host immune regulators and combine antigenic variation with conserved immune evasion features. Understanding domain composition of each protein encoded by more than 60 000pspCorhicgenes deposited in the data banks defines their diversity, a role in immune escape and can furthermore delineate structure function approach for single protein domains. PspC and Hic proteins show variable domain composition and sequence diversity, which explain differences in binding of human regulators and likely in immune escape. The results of our analyses provide insights in the domain composition of these diverse immune evasion proteins, identifies new domains, defines domains which are unique to PspC or Hic variants, and identifies domains which are shared with other bacterial immune evasion proteins. These data have implication on cell wall attachment, surface distribution and in immune escape.
Phylogenomic Discordance in the Eared Seals is best explained by Incomplete Lineage Sorting following Explosive Radiation in the Southern Hemisphere
Authors: Lopes Fernando , Oliveira Larissa R. , Kessler Amanda , Beux Yago , Crespo Enrique , Cárdenas-Alayza Susana , Majluf Patricia , Sepúlveda Maritza , Brownell Robert L. , Franco-Trecu Valentina , Páez-Rosas Diego , Chaves Jaime , Loch Carolina , Robertson Bruce C. , Acevedo-Whitehouse Karina , Elorriaga-Verplancken Fernando R. , Kirkman Stephen P. , Peart Claire R. , Wolf Jochen B. W. , Bonatto Sandro L. 
Published: August 2020

AbstractThe phylogeny and systematics of fur seals and sea lions (Otariidae) have long been studied with diverse data types, including an increasing amount of molecular data. However, only a few phylogenetic relationships have reached acceptance because of strong gene-tree species tree discordance. Divergence times estimates in the group also vary largely between studies. These uncertainties impeded the understanding of the biogeographical history of the group, such as when and how trans-equatorial dispersal and subsequent speciation events occurred. Here we used high-coverage genome-wide sequencing for 14 of the 15 species of Otariidae to elucidate the phylogeny of the family and its bearing on the taxonomy and biogeographical history. Despite extreme topological discordance among gene trees, we found a fully supported species tree that agrees with the few well-accepted relationships and establishes monophyly of the genusArctocephalus. Our data support a relatively recent trans-hemispheric dispersal at the base of a southern clade, which rapidly diversified into six major lineages between 3 to 2.5 Ma.Otariadiverged first, followed byPhocarctosand then four major lineages withinArctocephalus. However, we foundZalophusto be non-monophyletic, with California(Z. californianus)and Steller sea lions(Eumetopias jubatus)grouping closer than the Galapagos sea lion (Z. wollebaeki)with evidence for introgression between the two genera. Overall, the high degree of genealogical discordance was best explained by incomplete lineage sorting resulting from quasi-simultaneous speciation within the southern clade with introgresssion playing a subordinate role in explaining the incongruence among and within prior phylogenetic studies of the family.
The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function
Authors: Oftedal Bergithe E , Maio Stefano , Handel Adam , White Madeleine PJ , Howie Duncan , Davis Simon , Prevot Nicolas , Rota Ioanna A. , Deadman Mary E , Kessler Benedikt M , Fischer Roman , Trede Nikolaus S , Sezgin Erdinc , Maizels Rick M , Holländer Georg A 
Published: August 2020

AbstractT cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. Additionally, Th2 polarization digresses in the absence of CCT-controlled protein folding resulting paradoxically in continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
Purinergic signaling controls spontaneous activity in the auditory system throughout early development
Authors: Babola Travis A. , Li Sally , Wang Zhirong , Kersbergen Calvin , Elgoyhen Ana Belén , Coate Thomas , Bergles Dwight 
Published: August 2020

ABSTRACTSpontaneous bursts of electrical activity in the developing auditory system arise within the cochlea prior to hearing onset and propagate through future sound processing circuits of the brain to promote maturation of auditory neurons. Studies in isolated cochleae revealed that this intrinsically generated activity is initiated by ATP release from inner supporting cells (ISCs), resulting in activation of purinergic autoreceptors, K+efflux and subsequent depolarization of inner hair cells (IHCs). However, little is known about when this activity emerges or whether different mechanisms underlie distinct stages of development. Here we show that spontaneous electrical activity in mouse cochlea emerges within ISCs during the late embryonic period, preceding the onset of spontaneous correlated activity in IHCs and spiral ganglion neurons (SGNs), which begins at birth and follows a base to apex developmental gradient. At all developmental stages, pharmacological inhibition of P2Y1 metabotropic purinergic receptors dramatically reduced spontaneous activity in these three cell types. Moreover,in vivoimaging within the inferior colliculus of awake mice revealed that auditory neurons within future isofrequency zones exhibit coordinated neural activity at birth. The frequency of these discrete bursts increased progressively during the postnatal prehearing period, yet remained dependent on P2RY1. Analysis of mice with disrupted cholinergic signaling in the cochlea, indicate that this input modulates, rather than initiates, spontaneous activity before hearing onset. Thus, the auditory system uses a consistent mechanism involving ATP release from ISCs and activation of purinergic autoreceptors to elicit coordinated excitation of neurons that will process similar frequencies of sound.SIGNIFICANCE STATEMENTIn developing sensory systems, groups of neurons that will process information from similar sensory space exhibit highly correlated electrical activity that is critical for proper maturation and circuit refinement. Defining the period when this activity is present, the mechanisms responsible and the features of this activity are crucial for understanding how spontaneous activity influences circuit development. We show that, from birth to hearing onset, the auditory system relies on a consistent mechanism to elicit correlate firing of neurons that will process similar frequencies of sound. Targeted disruption of this activity will increase our understanding of how these early circuits mature and may provide insight into processes responsible for developmental disorders of the auditory system.
Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia
Authors: Ding Baojin , Tang Yu , Ma Shuaipeng , Akter Masuma , Liu Meng-Lu , Zang Tong , Zhang Chun-Li 
Published: August 2020

AbstractDYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation intorsin A(TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygousTOR1Amutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear “blebs” that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.
Temporal modulation of the NF-κB RelA network in response to different types of DNA damage
Authors: Campbell Amy , Franco Catarina Ferraz , Su Ling-I , Perkins Simon , Jones Andrew R. , Brownridge Philip J. , Perkins Neil D. , Eyers Claire E. 
Published: August 2020

ABSTRACTDifferent types of DNA damage can initiate phosphorylation-mediated signalling cascades that result in stimulus specific pro- or anti-apoptotic cellular responses. Amongst its many roles, the NF-κB transcription factor RelA is central to these DNA damage response pathways. However, we still lack understanding of the co-ordinated signalling mechanisms that permit different DNA damaging agents to induce distinct cellular outcomes through RelA. Here, we use label-free quantitative phosphoproteomics to examine the temporal effects of exposure of U2OS cells to either etoposide (ETO) or hydroxyurea (HU) by monitoring the phosphorylation status of RelA and its protein binding partners. Although few stimulus-specific differences were identified in the constituents of phosphorylated RelA interactome after exposure to these DNA damaging agents, we observed subtle, but significant, changes in their phosphorylation states, as a function of both type and duration of treatment. The DNA double strand break (DSB)-inducing ETO invoked more rapid, sustained responses than HU, with regulated targets primarily involved in transcription, cell division and canonical DSB repair. Kinase substrate prediction of ETO-regulated phosphosites suggest abrogation of CDK1 and ERK1 signalling, in addition to the known induction of ATM/ATR. In contrast, HU-induced replicative stress mediated temporally dynamic regulation, with phosphorylated RelA binding partners having roles in rRNA/mRNA processing and translational initiation, many of which contained a 14-3-3ε binding motif, and were putative substrates of the dual specificity kinase CLK1. Our data thus point to differential regulation of key cellular processes and the involvement of distinct signalling pathways in modulating DNA damage-specific functions of RelA.
Cytokine priming of naïve CD8+T lymphocytes modulates chromatin accessibility that partially overlaps with changes induced by antigen simulation
Authors: Quenum Akouavi Julite , Cloutier Maryse , Santharam Madanraj Appiya , Mayhue Marian , Ramanathan Sheela , Ilangumaran Subburaj 
Published: August 2020

AbstractBackgroundNaïve CD8+T lymphocytes undergo antigen non-specific proliferation following exposure to certain synergistic combination of inflammatory (IL-6, IL-21) and homeostatic (IL-7, IL-15) cytokines. Such cytokine-stimulated naïve CD8+T cells display increased T cell antigen receptor (TCR) sensitivity, allowing them to respond to limiting concentrations of cognate antigenic peptides and altered peptide ligands of lower affinity towards the TCR. The purpose of this study is to gain insight into the molecular mechanisms of such ‘cytokine priming’.MethodsNaïve CD8+T lymphocytes expressing the PMEL-1 transgenic TCR were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. Cells stimulated by the cognate antigenic peptide mgp10025-33were used as controls.ResultsCompared to naïve cells, cytokine-primed cells showed 212 opening and 484 closing peaks, whereas antigen-stimulated cells showed 12087 opening and 6982 closing peaks. However, a significant fraction of the opening (33%) and closing (63%) peaks of cytokine-primed cells overlapped with those of the antigenic stimulated cells. Chromatin accessibility peaks modulated in cytokine-primed cells were strongly represented in gene ontology pathways for T cell signaling, activation, regulation and effector functions. Many of the transcription factor binding motifs located close to the opening and closing peaks of cytokine-primed cells also occurred in antigen-stimulated cells.ConclusionsOur data suggest that by modulating the gene expression programs involved in TCR signaling, cytokine priming induces a poised state that lowers the TCR signaling threshold in naïve CD8+T cells and increases their antigen responsiveness.
Does retraction after misconduct have an impact on citations? A pre-post study
Authors: Candal-Pedreira Cristina , Ruano-Ravina Alberto , Fernández E , Ramos-Castaneda Jorge A. , Campos-Varela I , Pérez-Ríos Mónica 
Published: August 2020

ABSTRACTBackgroundRetracted articles continue to be cited after retraction, and this could have consequences for the scientific community and general population alike. This study was conducted to analyze the impact of retraction on citations received by retracted papers in two-time frames: during a post-retraction period equivalent to the time the article had been in print before retraction; and during the total post-retraction period.ResultsThe results indicated an increase in post-retraction citations when compared with citations received pre-retraction. There were some exceptions however: first, citations received by articles published in first-quartile journals decreased immediately after retraction (p<0.05), only to increase again after some time had elapsed; and second, post-retraction citations decreased significantly in the case of articles that had received many citations before their retraction (p<0.05).ConclusionsThe results indicate that retraction of articles has no impact on citations in the long term, since the retracted articles continue to be cited, thus circumventing their retraction. More effective mechanisms should be established to prevent the citation of retracted articles in scientific papers.MethodsQuasi-experimental, pre-post evaluation study. A total of 304 retracted original articles and literature reviews indexed in Medline fulfilled the exclusion criteria. Articles were required to have been published in Pubmed from January 2013 through December 2016 and been retracted between January 2014 and December 2016. The main outcome was the number of citations received before and after retraction. Results were broken down by journal quartile according to impact factor and the most cited papers (pre-retraction) were specifically analyzed.
Puffaligner: An Efficient and Accurate Aligner Based on the Pufferfish Index
Authors: Almodaresi Fatemeh , Zakeri Mohsen , Patro Rob 
Published: August 2020

AbstractMotivationSequence alignment is one of the first steps in many modern genomic analyses, such as variant detection, transcript abundance estimation and metagenomic profiling. Unfortunately, it is often a computationally expensive procedure. As the quantity of data and wealth of different assays and applications continue to grow, the need for accurate and fast alignment tools persists.ResultsIn this paper, we introduce PuffAligner, a fast, accurate and versatile aligner built on top of the Pufferfish index. PuffAligner is able to produce highly-sensitive alignments, similar to those of Bowtie2, but much more quickly. While exhibiting similar speed to the ultrafast STAR aligner, PuffAligner requires considerably less memory to construct its index and align reads. PuffAligner strikes a desirable balance with respect to the time, space, and accuracy tradeoffs made by different alignment tools, and provides a promising foundation on which to test new alignment ideas over large collections of sequences.AvailabilityPuffAligner is a free and open-source software. It is implemented in C++14 and can be obtained fromhttps://github.com/COMBINE-lab/pufferfish/tree/cigar-strings
Learning with uncertainty for biological discovery and design
Authors: Hie Brian , Bryson Bryan , Berger Bonnie 
Published: August 2020

AbstractMachine learning that generates biological hypotheses has transformative potential, but most learning algorithms are susceptible to pathological failure when exploring regimes beyond the training data distribution. A solution is to quantify predictionuncertaintyso that algorithms can gracefully handle novel phenomena that confound standard methods. Here, we demonstrate the broad utility of robust uncertainty prediction in biological discovery. By leveraging Gaussian process-based uncertainty prediction on modern pretrained features, we train a model on just 72 compounds to make predictions over a 10,833-compound library, identifying and experimentally validating compounds with nanomolar affinity for diverse kinases and whole-cell growth inhibition ofMycobacterium tuberculosis. We show how uncertainty facilitates a tight iterative loop between computation and experimentation, improves the generative design of novel biochemical structures, and generalizes across disparate biological domains. More broadly, our work demonstrates that uncertainty should play a key role in the increasing adoption of machine learning algorithms into the experimental lifecycle.
The chromatin remodeler ISWI acts duringDrosophiladevelopment to regulate adult sleep
Authors: Gong Naihua N. , Dilley Leela Chakravarti , Williams Charlette E. , Moscato Emilia H. , Szuperak Milan , Wang Qin , Jensen Matthew , Girirajan Santhosh , Tan Tiong Yang , Deardorff Matthew A. , Li Dong , Song Yuanquan , Kayser Matthew S. 
Published: August 2020

AbstractSleep disruptions are among the most commonly-reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From aDrosophilascreen of human NDD-associated risk genes, we identified the chromatin remodelerImitation SWItch/SNF(ISWI) to be required for adult fly sleep. Loss ofISWIalso results in disrupted circadian rhythms, memory, and social behavior, butISWIacts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically,ISWIexpression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the humanISWIhomologsSMARCA1andSMARCA5differentially rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.