bluuebunny/crossref_metadata_2025_split huggingface dataset:
Density and temperature controlled fluid extraction in a bacterial biofilm is determined by poly-γ-glutamic acid production
Authors: Morris Ryan J. , Sukhodub Tetyana , MacPhee Cait E. , Stanley-Wall Nicola R. 
Published: December 2020

ABSTRACTA hallmark of microbial biofilms is the self-production of extracellular matrix that encases the cells resident within the community. The matrix provides protection from the environment, while spatial heterogeneity of expression influences the structural morphology and colony spreading dynamics.Bacillus subtilisis a model bacterial system used to uncover the regulatory pathways and key building blocks required for biofilm growth and development. Previous reports have suggested that poly-γ-glutamic acid (PGA) production is suppressed during biofilm formation and does not play a major role in biofilm morphology of the undomesticated isolate NCIB 3610. In this work we report on the observation of multiple travelling fronts that develop during the early stage ofB. subtiliscolony biofilm formation. We find the emergence of a highly motile population of bacteria that is facilitated by the extraction of fluid from the underlying agar substrate. Motility develops behind a moving front of fluid that propagates from the boundary of the biofilm towards the interior. The extent of proliferation is strongly modulated by the presence of extracellular polysaccharides (EPS). We trace the origin of this moving front of fluid to the production of PGA. We find that PGA production is correlated with higher temperatures, resulting in a mature biofilm morphology that is distinct from the biofilm architecture typically associated withB. subtilis. Our results suggest thatB. subtilisNCIB 3610 produces distinct biofilm matrices in response to environmental conditions.
Systematic analysis of goal-related movement sequences during maternal behavior in a female mouse model for Rett syndrome
Authors: Stevenson Parker K. , Casenhiser Devin M. , Krishnan Keerthi 
Published: December 2020

Parenting is an ethologically relevant social behavior consisting of stereotypic components involving the care and nourishment of young. First-time rodent dams seek and gather wandering/scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Over the decades, qualitative observations of the behaving animal have been presented in quantitative discrete units. However, systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioral sequence, which would be ultimately essential for understanding the underlying neurobiology, is usually not analyzed. Here, we present systematic analysis of pup retrieval behavior across three days in alloparental female mice (Surrogates or Sur) of two genotypes;Mecp2Heterozygotes(Het), a female mouse model for a neuropsychiatric disorder called Rett syndrome and their wild type (WT) siblings. Additionally, we analyzed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software.We previously showed that Het are inefficient, by measuring latency and errors, at pup retrieval. Here, we show that the sequence of searching, pup-approach and good retrieval crystallizes over time for WT; this sequence does not crystallize in Het. We found that goal-related movements of Het in different phases were similar to WT, suggesting context-driven atypical dynamic patterns in Het. We also identified pup approach and pup grooming as atypical tactile interactions between pups and Het, which contribute to inefficient pup retrieval. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains in response to the growing pups. Overall, our approach 1) embraces natural variation in individual mice on different days of pup retrieval behavior, 2) establishes a “gold-standard” manually curated dataset to next build behavioral repertoires using machine learning approaches, and 3) identifies distinct atypical tactile sensory processing in a female mouse model for Rett syndrome.
The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
Authors: Avolio Elisa , Carrabba Michele , Milligan Rachel , Williamson Maia Kavanagh , Beltrami Antonio P , Gupta Kapil , Elvers Karen T , Gamez Monica , Foster Rebecca , Gillespie Kathleen , Hamilton Fergus , Arnold David , Berger Imre , Caputo Massimo , Davidson Andrew D , Hill Darryl , Madeddu Paolo 
Published: December 2020

ABSTRACTSevere coronavirus disease 2019 (COVID-19) manifests as a life-threatening microvascular syndrome. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Spike (S) protein to engage with its receptors and infect host cells. To date, it is still not known whether heart vascular pericytes (PCs) are infected by SARS-CoV-2, and if the S protein alone provokes PC dysfunction. Here, we aimed to investigate the effects of the S protein on primary human cardiac PC signalling and function. Results show, for the first time, that cardiac PCs are not permissive to SARS-CoV-2 infectionin vitro, whilst a recombinant S protein alone elicits functional alterations in PCs. This was documented as: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in thecytokine storm, and (4) production of pro-apoptotic factors responsible for EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation and rescued PC function in the presence of the S protein. In conclusion, our findings suggest that circulating S protein prompts vascular PC dysfunction, potentially contributing to establishing microvascular injury in organs distant from the site of infection. This mechanism may have clinical and therapeutic implications.Clinical perspectiveSevere COVID-19 manifests as a microvascular syndrome, but whether SARS-CoV-2 infects and damages heart vascular pericytes (PCs) remains unknown.We provide evidence that cardiac PCs are not infected by SARS-CoV-2. Importantly, we show that the recombinant S protein alone elicits cellular signalling through the CD147 receptor in cardiac PCs, thereby inducing cell dysfunction and microvascular disruptionin vitro.This study suggests that soluble S protein can potentially propagate damage to organs distant from sites of infection, promoting microvascular injury. Blocking the CD147 receptor in patients may help protect the vasculature not only from infection, but also from the collateral damage caused by the S protein.
Noise Distorts the Epigenetic Landscape and Shapes Cell Fate Decisions
Authors: Coomer Megan A. , Ham Lucy , Stumpf Michael P. H. 
Published: December 2020

AbstractThe Waddington epigenetic landscape has become an iconic representation of the cellular differentiation process. Recent single-cell transcriptomic data provide new opportunities for quantifying this originally conceptual tool, offering insight into the gene regulatory networks underlying cellular development. While many methods for constructing the landscape have been proposed, by far the most commonly employed approach is based on computing the landscape as the negative logarithm of the steady-state probability distribution. Here, we use simple models to highlight the complexities and limitations that arise when reconstructing the potential landscape in the presence of stochastic fluctuations. We consider how the landscape changes in accordance with different stochastic systems, and show that it is the subtle interplay between the deterministic and stochastic components of the system that ultimately shapes the landscape. We further discuss how the presence of noise has important implications for the identifiability of the regulatory dynamics from experimental data.
CGRP-receptor family reveals endogenous GPCR agonist bias and its significance in primary human cardiovascular cells
Authors: Clark Ashley J. , Mullooly Niamh , Safitri Dewi , Harris Matthew , de Vries Tessa , Van Den Brink Antoinette Maassen , Poyner David R. , Giani Davide , Wigglesworth Mark , Ladds Graham 
Published: December 2020

AbstractAgonist bias at G protein-coupled receptors has attracted considerable interest, although its relevance for physiologically-produced agonists is not always clear. Here, using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin-like receptor (CLR). We reveal that by switching the accessory protein: receptor activity-modifying protein (RAMP) associated with CLR we can re-route the physiological pathways activated by the stimulating peptide agonists. These results have revealed a unique role in calcium-mediated nitric oxide signalling for the little-understood peptide adrenomedullin 2 and distinct pro-proliferative effects of calcitonin-gene related peptide (CGRP) and adrenomedullin in cardiovascular cells. This work reveals that CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and its importance in endogenous GPCR signalling.
GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer
Authors: Brun Sonia , Pascussi Jean-Marc , Gifu Elena Patricia , Bestion Eloïne , Macek-Jilkova Zuzana , Wang Guanxiong , Bassissi Firas , Mezouar Soraya , Courcambeck Jérôme , Merle Philippe , Decaens Thomas , Pannequin Julie , Halfon Philippe , de Fromentel Claude Caron 
Published: December 2020

ABSTRACTPatients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and have the ability to regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmedin vivoin HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45-). Accordingly, GNS561, which was in a global phase 1b clinical trial in liver cancers that was recently successful, offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population.
Population genomics of the maize pathogenUstilago maydis: demographic history and role of virulence clusters in adaptation
Authors: Schweizer Gabriel , Haider Muhammad Bilal , Barroso Gustavo V. , Rössel Nicole , Münch Karin , Kahmann Regine , Dutheil Julien Y. 
Published: December 2020

AbstractThe tight interaction between pathogens and their hosts results in reciprocal selective forces that impact the genetic diversity of the interacting species. The footprints of this selection differ between pathosystems because of distinct life-history traits, demographic histories, or genome architectures. Here, we studied the genome-wide patterns of genetic diversity of 22 isolates of the causative agent of the corn smut disease,Ustilago maydis, originating from five locations in Mexico, the presumed center of origin of this species. In this species, many genes encoding secreted effector proteins reside in so-called virulence clusters in the genome, an arrangement that is so far not found in other filamentous plant pathogens. Using a combination of population genomic statistical analyses, we assessed the geographical, historical and genome-wide variation of genetic diversity in this fungal pathogen.We report evidence of two partially admixed subpopulations that are only loosely associated with geographic origin. Using the multiple sequentially Markov coalescent model, we inferred the demographic history of the two pathogen subpopulations over the last 0.5 million years. We show that both populations experienced a recent strong bottleneck starting around 10,000 years ago, coinciding with the assumed time of maize domestication. While the genome average genetic diversity is low compared to other fungal pathogens, we estimated that the rate of non-synonymous adaptive substitutions is three times higher in genes located within virulence clusters compared to non-clustered genes, including non-clustered effector genes. These results highlight the role that these singular genomic regions play in the evolution of this pathogen.Significance statementThe maize pathogenUstilago maydisis a model species to study fungal cell biology and biotrophic host-pathogen interactions. Population genetic studies of this species, however, were so far restricted to using a few molecular markers, and genome-wide comparisons involved species that diverged more than 20 million years ago. Here, we sequenced the genomes of 22 MexicanU. maydisisolates to study the recent evolutionary history of this species. We identified two co-existing populations that went through a recent bottleneck and whose divergence date overlaps with the time of maize domestication. Contrasting the patterns of genetic diversity in different categories of genes, we further showed that effector genes in virulence clusters display a high rate of adaptive mutations, highlighting the importance of these effector arrangements for the adaptation ofU. maydisto its host.
Cortical entrainment to hierarchical contextual rhythms recomposes dynamic attending in visual perception
Authors: Yuan Peijun , Hu Ruichen , Zhang Xue , Wang Ying , Jiang Yi 
Published: December 2020

AbstractTemporal regularity is ubiquitous and essential to guiding attention and coordinating behavior within a dynamic environment. Previous researchers have modeled attention as an internal rhythm that may entrain to first-order regularity from rhythmic events to prioritize information selection at specific time points. Using the attentional blink paradigm, here we show that higher-order regularity based on rhythmic organization of contextual features (pitch, color, or motion) may serve as a temporal frame to recompose the dynamic profile of visual temporal attention. Critically, such attentional reframing effect is well predicted by cortical entrainment to the higher-order contextual structure at the delta band as well as its coupling with the stimulus-driven alpha power. These results suggest that the human brain involuntarily exploits multiscale regularities in rhythmic contexts to recompose dynamic attending in visual perception, and highlight neural entrainment as a central mechanism for optimizing our conscious experience of the world in the time dimension.
Hyperbolic matrix factorization reaffirms the negative curvature of the native biological space
Authors: Poleksic Aleksandar 
Published: December 2020

AbstractPast research in systems biology has taken for granted the Euclidean geometry of biological space. This has not only drawn parallels to other fields but has also been convenient due to the ample statistical and numerical optimization tools available to address the core task and downstream machine learning problems. However, emerging theoretical studies now demonstrate that biological databases exhibit hierarchical topology, characterized by heterogeneous degree distribution and a high degree of clustering, thus contradicting the flat geometry assumption. Namely, since the number of nodes in hierarchical structures grows exponentially with node depth, the biological networks naturally reside in a hyperbolic space where the circle circumference and disk area are the exponential functions of the radius. To test these claims and assess potential benefits of the applications grounded in the above hypothesis, we have developed a mathematical framework and an accompanying computational procedure for matrix factorization and implied biological relationship inference in hyperbolic space. Not only does our study demonstrate a significant increase in the accuracy of hyperbolic embedding compared to Euclidean embedding, but it also shows that the latent dimension of an optimal hyperbolic embedding is by more than an order of magnitude smaller than the latent dimension of an optimal Euclidean embedding. We see this as additional evidence that hyperbolic geometry, rather than Euclidean, underlines the biological system.
Schema-induced shifts in mice navigational strategies are unveiled by a minimal behavioral model of spatial exploration
Authors: Vallianatou Christina-Anna , Alonso Alejandra , Aleman Adrian , Genzel Lisa , Stella Federico 
Published: December 2020

AbstractShifts in spatial patterns produced during the execution of a navigational task can be used to track the effects of the accumulation of knowledge and the acquisition of structured information about the environment. Here we provide a quantitative analysis of mice behavior while performing a novel goal localization task in a large, modular arena, the HexMaze. To demonstrate the effects of different forms of previous knowledge we first obtain a precise statistical characterization of animals’ paths with sub-trial resolution and over different phases of learning. The emergence of a flexible representation of the task is accompanied by a progressive improvement of performance, mediated by multiple, multiplexed time scales. We then use a generative mathematical model of the animal behavior to isolate the specific contributions to the final navigational strategy. We find that animal behavior can be accurately reproduced by the combined effect of a goal-oriented component, becoming stronger with the progression of learning, and of a random walk component, producing choices unrelated to the task and only partially weakened in time.
Design of novel Cyanovirin-N variants by modulation of binding dynamics through distal mutations
Authors: Kazan I. Can , Sharma Prerna , Rahman Mohammad Imtiazur , Bobkov Andrey , Fromme Raimund , Ghirlanda Giovanna , Ozkan S. Banu 
Published: December 2020

AbstractWe develop integrated coevolution and dynamic coupling (ICDC) approach to identify, mutate, and assess distal sites to modulate function. We validate the approach first by analyzing the existing mutational fitness data of TEM-1 β-lactamase and show that allosteric positions co-evolved and dynamically coupled with the active site significantly modulate function. We further apply ICDC approach to identify positions and their mutations that can modulate binding affinity in a lectin, Cyanovirin-N (CV-N), that selectively binds to dimannose, and predict binding energies of its variants through Adaptive BP-Dock. Computational and experimental analyses reveal that binding enhancing mutants identified by ICDC impact the dynamics of the binding pocket, and show that rigidification of the binding residues compensates for the entropic cost of binding. This work suggests a general mechanism by which distal mutations modulate function through dynamic allostery and provides a blueprint to identify candidates for mutagenesis in order to optimize protein function.
osr1maintains renal progenitors and regulates podocyte development by promotingwnt2bathrough antagonism ofhand2
Authors: Drummond Bridgette E. , Chambers Brooke E. , Wesselman Hannah M. , Ulrich Marisa N. , Gerlach Gary F. , Kroeger Paul T. , Leshchiner Ignaty , Goessling Wolfram , Wingert Rebecca A. 
Published: December 2020

ABSTRACTKnowledge about the genetic pathways that control renal cell lineage development is essential to better understand the basis of congenital malformations of the kidney and design regenerative medicine therapies. The embryonic zebrafish kidney, or pronephros, contains two nephrons that are conserved with humans. Recently, the transcription factors Osr1 and Hand2 were found to exert antagonistic influences to balance kidney specification (Perens et al., 2016). Here, we performed a forward genetic screen in zebrafish to identify nephrogenesis regulators, where whole genome sequencing of the noveloceanside(ocn) mutant revealed a nonsense mutation inosr1. ocnmutants evince severe pronephros defects including abrogation of podocytes and proximal tubule cells. Our studies reveal thatosr1is not needed to specify renal progenitors, but rather required to maintain their survival. Additionally,osr1is requisite for expression of the canonical Wnt ligandwnt2ba, wherewnt2bais expressed in the intermediate mesoderm (IM) and later restricts to podocytes. Deficiency ofwnt2bareduced podocyte progenitors, where overexpression ofwnt2bawas sufficient to rescue the podocyte lineage as well asosr1loss of function. Finally, we demonstrate that reciprocal antagonism betweenosr1andhand2mediates podocyte development specifically by controllingwnt2baexpression in the IM. Together, our data show that Osr1 is essential for a sequence of temporal functions that mediate the survival and lineage decisions of IM progenitors, and subsequently the maintenance of podocytes and proximal tubule epithelium in the embryonic nephron.
Ribosome profiling inStreptococcus pneumoniaereveals the role of methylation of 23S rRNA nucleotide G748 on ribosome stalling
Authors: Shoji Tatsuma , Takaya Akiko , Kusuya Yoko , Takahashi Hiroki , Kawashima Hiroto 
Published: December 2020

2.Abstract(1) BackgroundMany nucleotides in 23S rRNA are methylated post-transcriptionally by methyltransferases and cluster around the peptidyltransferase center (PTC) and the nascent peptidyl exit tunnel (NPET) located in 50S subunit of 70S ribosome. Biochemical interactions between a nascent peptide and the tunnel may stall ribosome movement and affect expression levels of the protein. However, no studies have shown a role for NPET on ribosome stalling using an NPET mutant.(2) ResultsA ribosome profiling assay inStreptococcus pneumoniaedemonstrates for the first time that an NPET mutant exhibits completely different ribosome occupancy compared to wild-type. We demonstrate, using RNA footprinting, that changes in ribosome occupancy correlate with changes in ribosome stalling. Further, statistical analysis shows that short peptide sequences that cause ribosome stalling are species-specific and evolutionarily selected. NPET structure is required to realize these specie-specific ribosome stalling.(3) ConclusionsResults support the role of NPET on ribosome stalling. NPET structure is required to realize the species-specific and evolutionary conserved ribosome stalling. These findings clarify the role of NPET structure on the translation process.