bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct visualization of native infectious SARS-CoV-2 and its inactivation forms using high resolution Atomic Force Microscopy
Authors: Lyonnais Sébastien , Hénaut Mathilde , Neyret Aymeric , Merida Peggy , Cazevieille Chantal , Gros Nathalie , Chable-Bessia Christine , Muriaux Delphine 
Published: October 2020

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for COVID19, a new emerging pandemic affecting humans. Here, single viruses were analyze by atomic force microscopy (AFM) operating directly in a level 3 biosafety (BSL3) facility, which appeared as a fast and powerful method to assess infectious virus morphology in its native conformation, or upon inactivation treatments, at the nanoscale level and in 3D. High resolution AFM reveals structurally intact infectious and inactivated SARS-CoV-2 upon low concentration of formaldehyde treatment. This protocol allows the preparation of intact inactivated SARS-CoV-2 particles for safe use of samples out of level 3 laboratory, as revealed by combining AFM and plaque assays, to accelerate researches against the COVID-19 pandemic. Overall, we illustrate how adapted BSL3-atomic force microscopy is a remarkable toolbox for rapid and direct virus identification and characterization.
Trehalose and α-glucan mediate distinct abiotic stress responses inPseudomonas aeruginosa
Authors: Woodcock Stuart D. , Syson Karl , Little Richard H. , Sifouna Despoina , Brown James K.M. , Bornemann Stephen , Malone Jacob G. 
Published: October 2020

AbstractAn important prelude to bacterial infection is the ability of a pathogen to survive independently of the host and to withstand environmental stress. The compatible solute trehalose has previously been connected with diverse abiotic stress tolerances, particularly osmotic shock. In this study, we combine molecular biology and biochemistry to dissect the trehalose metabolic network in the opportunistic human pathogenPseudomonas aeruginosaPA01 and define its role in abiotic stress protection. We show that trehalose metabolism in PA01 is integrated with the biosynthesis of branched α-glucan (glycogen), with mutants in either biosynthetic pathway significantly compromised for survival on abiotic surfaces. While both trehalose and α-glucan are important for abiotic stress tolerance, we show they counter distinct stresses. Trehalose is vital to the PA01 osmotic stress response, with trehalose synthesis mutants displaying severely compromised growth in elevated salt conditions. However, trehalose does not contribute directly to the PA01 desiccation response. Rather, desiccation tolerance is mediated directly by GlgE-derived α-glucan, with deletion of theglgEsynthase gene compromising PA01 survival in low humidity but having little effect on osmotic sensitivity. Desiccation tolerance is independent of trehalose concentration, marking a clear distinction between the roles of these two molecules in mediating responses to abiotic stress.
Piggybacking on niche-adaptation reduces the cost of multidrug resistance plasmids
Authors: Kloos Julia , Gama João A. , Hegstad Joachim , Samuelsen Ørjan , Johnsen Pål J. 
Published: October 2020

AbstractThe persistence of plasmids in bacterial populations represents a puzzling evolutionary problem with serious clinical implications due to their role in the ongoing antibiotic resistance crisis. Recently, major advancements have been made towards resolving this “plasmid paradox” but mainly in a non-clinical context. Here we propose an additional explanation for the maintenance of multidrug resistance (MDR) plasmids in clinicalEscherichia colistrains. After co-evolving two MDR plasmids encoding last resort carbapenem resistance with an extraintestinal pathogenicE. colistrain, we observed that chromosomal media adaptive mutations in the global regulatory systems CCR (Carbon Catabolite Repression) and ArcAB (Aerobic Respiration Control) pleiotropically mitigated the costs of both plasmids. Mechanistically, cost reductions were due to a net downregulation of plasmid gene expression. Our results suggest that global chromosomal transcriptional re-wiring during bacterial niche-adaptation may facilitate plasmid maintenance.
Spontaneous emergence of azithromycin resistance in independent lineages ofSalmonellaTyphi in Northern India
Authors: Carey Megan E. , Jain Ruby , Yousuf Mohammad , Maes Mailis , Dyson Zoe A. , Thu Trang Nguyen Hoang , Nguyen To Nguyen Thi , Dan Thanh Ho Ngoc , Nguyen Quynh Nhu Pham , Mahindroo Jaspreet , Pham Duy Thanh , Sandha Kawaljeet Singh , Baker Stephen , Taneja Neelam 
Published: October 2020

AbstractBackgroundThe emergence and spread of antimicrobial resistance (AMR) pose a major threat to the effective treatment and control of typhoid fever. The ongoing outbreak of extensively drug resistant (XDR)SalmonellaTyphi (S. Typhi) in Pakistan has left azithromycin as the only remaining broadly efficacious oral antimicrobial for typhoid in South Asia. Ominously, azithromycin resistantS. Typhi organisms have been subsequently reported in Bangladesh, Pakistan, and Nepal.MethodsHere, we aimed to understand the molecular basis of AMR in 66S. Typhi isolated in a cross-sectional study performed in a suburb of Chandigarh in Northern India using whole genome sequencing (WGS) and phylogenetic analysis.ResultsWe identified sevenS. Typhi organisms with the R717Q mutation in theacrBgene that was recently found to confer resistance to azithromycin in Bangladesh. Six out of the azithromycin-resistantS. Typhi isolates also exhibited triple mutations ingyrA(S83F and D87N) andparC(S80I) genes and were resistant to ciprofloxacin. These contemporary ciprofloxacin/azithromycin-resistant isolates were phylogenetically distinct from each other and from those reported from Bangladesh, Pakistan, and Nepal.ConclusionsThe independent emergence of azithromycin resistant typhoid in Northern India reflects an emerging broader problem across South Asia and illustrates the urgent need for the introduction of typhoid conjugate vaccines (TCVs) in the region.Key pointsWe identified ciprofloxacin/azithromycin-resistantSalmonellaTyphi (S. Typhi) in Chandigarh in Northern India. The independent emergence of ciprofloxacin/azithromycin-resistant typhoid in Bangladesh, Pakistan, Nepal, and India and the continued spread of extensively-drug resistant (XDR) typhoid in Pakistan highlight the limitations of licensed oral treatments for typhoid fever in South Asia.
Efficient long-range conduction in cable bacteria through nickel protein wires
Authors: Boschker Henricus T. S. , Cook Perran L.M. , Polerecky Lubos , Eachambadi Raghavendran Thiruvallur , Lozano Helena , Hidalgo-Martinez Silvia , Khalenkow Dmitry , Spampinato Valentina , Claes Nathalie , Kundu Paromita , Wang Da , Bals Sara , Sand Karina K. , Cavezza Francesca , Hauffman Tom , Bjerg Jesper Tataru , Skirtach Andre G. , Kochan Kamila , McKee Merrilyn , Wood Bayden , Bedolla Diana , Gianoncelli Alessandra , Geerlings Nicole M.J. , Gerven Nani Van , Remaut Han , Geelhoed Jeanine S. , Millan-Solsona Ruben , Fumagalli Laura , Nielsen Lars-Peter , Franquet Alexis , Manca Jean V. , Gomila Gabriel , Meysman Filip J. R. 
Published: October 2020

AbstractFilamentous cable bacteria display unrivalled long-range electron transport, generating electrical currents over centimeter distances through a highly ordered network of fibers embedded in their cell envelope. The conductivity of these periplasmic wires is exceptionally high for a biological material, but their chemical structure and underlying electron transport mechanism remain unresolved. Here, we combine high-resolution microscopy, spectroscopy, and chemical imaging on individual cable bacterium filaments to demonstrate that the periplasmic wires consist of a conductive protein core surrounded by an insulating shell layer. The core proteins contain a sulfur-ligated nickel cofactor, and conductivity decreases when nickel is oxidized or selectively removed. The involvement of nickel as the active metal in biological conduction is remarkable, and suggests a hitherto unknown form of electron transport that enables efficient conduction in centimeter-long protein structures.
A unified physiological framework of transitions between seizures, sustained ictal activity and depolarization block at the single neuron level
Authors: Depannemaecker Damien , Ivanov Anton , Lillo Davide , Spek Len , Bernard Christophe , Jirsa Viktor 
Published: October 2020

AbstractThe majority of seizures recorded in humans and experimental animal models can be described by a generic phenomenological mathematical model, The Epileptor. In this model, seizure-like events (SLEs) are driven by a slow variable and occur via saddle node (SN) and homoclinic bifurcations at seizure onset and offset, respectively. Here we investigated SLEs at the single cell level using a biophysically relevant neuron model including a slow/fast system of four equations. The two equations for the slow subsystem describe ion concentration variations and the two equations of the fast subsystem delineate the electrophysiological activities of the neuron. Using extracellular K+as a slow variable, we report that SLEs with SN/homoclinic bifurcations can readily occur at the single cell level when extracellular K+reaches a critical value. In patients and experimental models, seizures can also evolve into sustained ictal activity (SIA) and, depolarization block (DB), activities which are also parts of the dynamic repertoire of the Epileptor. Increasing extracellular concentration of K+in the model to values found during experimental status epilepticus and DB, we show that SIA and DB can also occur at the single cell level. Thus, seizures, SIA and DB, which have been first identified as network events, can exist in a unified framework of a biophysical model at the single neuron level and exhibit similar dynamics as observed in the Epileptor.Author SummaryEpilepsy is a neurological disorder characterized by the occurrence of seizures. Seizures have been characterized in patients in experimental models at both macroscopic and microscopic scales using electrophysiological recordings. Experimental works allowed the establishment of a detailed taxonomy of seizures, which can be described by mathematical models. We can distinguish two main types of models. Phenomenological (generic) models have few parameters and variables and permit detailed dynamical studies often capturing a majority of activities observed in experimental conditions. But they also have abstract parameters, making biological interpretation difficult. Biophysical models, on the other hand, use a large number of variables and parameters due to the complexity of the biological systems they represent. Because of the multiplicity of solutions, it is difficult to extract general dynamical rules. In the present work, we integrate both approaches and reduce a detailed biophysical model to sufficiently low-dimensional equations, and thus maintaining the advantages of a generic model. We propose, at the single cell level, a unified framework of different pathological activities that are seizures, depolarization block, and sustained ictal activity.
Transcriptional silencing ofALDH2in acute myeloid leukemia confers a dependency on Fanconi anemia proteins
Authors: Yang Zhaolin , Wei Yiliang , Wu Xiaoli S. , Iyer Shruti V. , Jung Moonjung , Adelman Emmalee R. , Klingbeil Olaf , Kramer Melissa , Demerdash Osama E. , Chang Kenneth , Goodwin Sara , Hodges Emily , McCombie W. Richard , Figueroa Maria E. , Smogorzewska Agata , Vakoc Christopher R. 
Published: October 2020

AbstractHundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitin conjugation and ligation machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T (an E2) and FANCL (an E3) as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxic effects of endogenous aldehydes. We provide evidence that DNA hypermethylation and transcriptional silencing ofALDH2occur in a recurrent manner in human AML patient samples, which is sufficient to confer FA pathway dependency in this disease. Taken together, our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
Incomplete removal of extracellular glutamate controls synaptic transmission and integration at a cerebellar synapse
Authors: Balmer Timothy S. , Borges-Merjane Carolina , Trussell Laurence O. 
Published: October 2020

AbstractSynapses of glutamatergic mossy fiber onto cerebellar unipolar brush cells (UBCs) generate slow excitatory (ON) or inhibitory (OFF) postsynaptic responses dependent on the complement of glutamate receptors expressed on the UBC’s large dendritic brush. Using brain slice recording and computational modeling of synaptic transmission, we found that substantial glutamate is maintained in the UBC synaptic cleft, sufficient to modify spontaneous firing in OFF UBCs and tonically desensitize AMPARs of ON UBC. The source of ambient glutamate was spontaneous, spike-independent exocytosis from the mossy fiber terminal, and its level was dependent on activity of glutamate transporters EAAT1-2. Changing levels of ambient glutamate shifted the polarity of evoked synaptic responses in ON UBCs and altered the phase of responses to in vivo-like synaptic activity. Unlike classical fast synapses, receptors at the UBC synapse are virtually always exposed to a significant level of glutamate, which varies in a graded manner during transmission.
Environmental enrichment enhances patterning and remodeling of synaptic nanoarchitecture revealed by STED nanoscopy
Authors: Wegner Waja , Steffens Heinz , Gregor Carola , Wolf Fred , Willig Katrin I. 
Published: October 2020

AbstractSynaptic plasticity underlies long-lasting structural and functional changes to brain circuitry and its experience-dependent remodeling can be fundamentally enhanced by environmental enrichment. It is unknown, however, whether and how environmental enrichment alters the morphology and dynamics of individual synapses. Here, we present a virtually crosstalk free, two-colorin vivoSTED microscope to simultaneously superresolve the dynamics of endogenous PSD95 of the post-synaptic density and spine geometry. With environmental enrichment, the size distributions of PSD95 and spine head sizes were sharper than in controls, indicating that synaptic strength is set more precisely with environmental enrichment. Spine head geometry and PSD95 assemblies were highly dynamic but their changes correlated only mildly. With environmental enrichment, the topography of the PSD95 nanoorganization was more dynamic; changes in size were smaller than in mice housed in standard cages and depended linearly on their original size. Thus, two-colorin vivotime-lapse imaging of synaptic nanoorganization uncovers a unique synaptic nanoplasticity associated with the enhanced learning capabilities under environmental enrichment.
Sound transmission by chamber prosthesis of the middle ear
Authors: Gambin Wiktor L. 
Published: October 2020

AbstractTests done on specimens cut from the temporal bones show, that the stapedotomy can be more effective, if instead of the piston prosthesis, the ear chamber prosthesis is used. In that case, the vibrations of the eardrum are transferred to a plate with attachment sticked to the incus. The plate is suspended on a membrane stretched on the base of conical chamber which is filled with a fluid and placed in the middle ear cave. The sound wave caused by a vibrating plate, is focused at the chamber outlet placed in a small hole drilled in the stapes footplate. As in the case of the piston prosthesis behavior of the round window membrane differs from that observed in the normal ear. The flow through a narrow outlet of the conical chamber makes a more deflection of the central part of the round window membrane. The properties of the prosthesis elements are close to those of the removed parts of the middle ear. In spite of this, one can observe a different sound transmission inside the ear. When the sound is higher than 1000 Hz, the vibration amplitude of the plate is 5-10 dB higher than that for the stapes footplate in the healthy ear. However, when the sound is lower than 1000 Hz, this amplitude is lower than that for the stapes footplate. To explain it, a simplified model of the sound propagation in the ear given in the prior work is used. To get a better agreement with the test results, the model takes into account a damping of the sound wave by the round window membrane. Next, the model is adapted to the ear with chamber prosthesis. The factors that may have an effect on the behavior of the sound wave are examined. The first is shortening of the incus. It increases the leverage of the ossicles and the force acting on the prosthesis plate compared to that in the normal ear. Next factor is a reduction of the mass of the vibrating plate what makes a growth of its resonance frequency. This slightly reduces the amplitude of the plate for the low sounds and increases it for the medium and the higher sounds. At end, the lack of the influence of the flow through the conical chamber on the sound wave energy is shown. The assumed model gives the rules for amplitudes of the chamber plate as functions of the sound frequency. Their values for the sound frequency from 400 Hz to 8000 Hz and its graphs are shown and compared with those for the stapes footplate in the normal ear. One can see that if the sound frequency is higher than 1000 Hz, then the chamber prosthesis makes higher amplitudes of the sound wave than the normal ear. To explain their drop for frequencies lower than 1000 Hz, needs more tests in this range.
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Authors: den Hoed J. , de Boer E. , Voisin N. , Dingemans A.J.M. , Guex N. , Wiel L. , Nellaker C. , Amudhavalli S.M. , Banka S. , Bena F.S. , Ben-Zeev B. , Bonagura V.R. , Bruel A.-L. , Brunet T. , Brunner H.G. , Chew H.B. , Chrast J. , Cimbalistienė L. , Coon H. ,   The DDD study, Délot E.C. , Démurger F. , Denommé-Pichon A.-S. , Depienne C. , Donnai D. , Dyment D.A. , Elpeleg O. , Faivre L. , Gilissen C. , Granger L. , Haber B. , Hachiya Y. , Abedi Y. Hamzavi , Hanebeck J. , Hehir-Kwa J.Y. , Horist B. , Itai T. , Jackson A. , Jewell R. , Jones K.L. , Joss S. , Kashii H. , Kato M. , Kattentidt-Mouravieva A.A. , Kok F. , Kotzaeridou U. , Krishnamurthy V. , Kučinskas V. , Kuechler A. , Lavillaureix A. , Liu P. , Manwaring L. , Matsumoto N. , Mazel B. , McWalter K. , Meiner V. , Mikati M.A. , Miyatake S. , Mizuguchi T. , Moey L.H. , Mohammed S. , Mor-Shaked H. , Mountford H. , Newbury-Ecob R. , Odent S. , Orec L. , Osmond M. , Palculict T.B. , Parker M. , Petersen A. , Pfundt R. , Preikšaitienė E. , Radtke K. , Ranza E. , Rosenfeld J.A. , Santiago-Sim T. , Schwager C. , Sinnema M. , Blok L. Snijders , Spillmann R.C. , Stegmann A.P.A. , Thiffault I. , Tran L. , Vaknin-Dembinsky A. , Vedovato-dos-Santos J.H. , Vergano S.A. , Vilain E. , Vitobello A. , Wagner M. , Waheeb A. , Willing M. , Zuccarelli B. , Kini U. , Newbury D.F. , Kleefstra T. , Reymond A. , Fisher S.E. , Vissers L.E.L.M. 
Published: October 2020

AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
A genomic assessment of the marine-speciation paradox within the toothed whale superfamily Delphinoidea
Authors: Westbury Michael V , Cabrera Andrea A. , Rey-Iglesia Alba , De Cahsan Binia , Duchêne David A. , Hartmann Stefanie , Lorenzen Eline D 
Published: October 2020

AbstractThe importance of post-divergence gene flow in speciation has been documented across a range of taxa in recent years, and may have been especially widespread in highly mobile, wide-ranging marine species, such as cetaceans. Here, we studied individual genomes from nine species across the three families of the toothed whale superfamily Delphinoidea (Delphinidae, Phocoenidae, Monodontidae). To investigate the role of post-divergence gene flow in the speciation process, we used a multifaceted approach, including: (i) phylogenomics, (ii) the distribution of shared derived alleles, and (iii) demographic inference. We found the divergence of lineages within Delphinoidea did not follow a process of pure bifurcation, but was much more complex. Sliding-window phylogenomics reveal a high prevalence of discordant topologies within the superfamily, with further analyses indicating these discordances arose due to both incomplete lineage sorting and gene flow. D-statistics, D-foil, andf-branch analyses supported gene flow between members of Delphinoidea, with the vast majority of gene flow occurring as ancient interfamilial events. Demographic analyses provided evidence that introgressive gene flow has likely ceased between all species pairs tested, despite reports of contemporary interspecific hybrids. Our study provides the first steps towards resolving the large complexity of speciation within Delphinoidea; we reveal the prevalence of ancient interfamilial gene flow events prior to the diversification of each family, and suggests that contemporary hybridisation events may be disadvantageous, as hybrid individuals do not appear to contribute to the parental species’ gene pools.