bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau amyloidogenesis begins with a loss of its conformational polymorphism
Authors: del Carmen Fernández-Ramírez María , Hervás Rubén , Menéndez Margarita , Laurents Douglas V. , Carrión-Vázquez Mariano 
Published: June 2020

AbstractKnowledge on the molecular bases of early amyloid assembly is fundamental to understand its structure-dysfunction relationship during disease progression. Tauopathies, a well-defined set of neurodegenerative disorders that includes Alzheimer’s disease, are characterized by the pathological amyloid aggregation of tau. However, the underlying molecular mechanisms that trigger tau aggregation and toxicity are poorly understood. Here, using a single-molecule approach, AFM-based single molecule-force spectroscopy (AFM-SMFS), combined with a protein-engineering mechanical protection strategy, we have analyzed the fluctuations of the conformational space of tau during the start of its pathological amyloid assembly. Specifically, we have analyzed the region that includes the four tau microtubule-binding repeats, known to play a key role on tau aggregation. We find that, unlike other amyloid-forming proteins, tau aggregation is accompanied by a decrease of conformational polymorphism, which is driven by amyloid-promoting factors, such as the Δ280K and P301L mutations, linked to Frontotemporal Dementia-17, or by specific chemical conditions. Such perturbations have distinct effects and lead to different tau (aggregate) structures. In addition to providing insight into how tau aggregates in a context dependent manner, these findings may help delve into how protein aggregation-based diseases, like Alzheimer’s, might be treated using monomer fluctuations as a pharmacological target.Abstract Figure
Two opposite voltage-dependent currents control the unusual early development pattern of embryonic Renshaw cell electrical activity
Authors: Boeri Juliette , Meunier Claude , Corronc Hervé Le , Branchereau Pascal , Timofeeva Yulia , Lejeune François Xavier , Mouffle Christine , Arulkandarajah Hervé , Mangin Jean Marie , Legendre Pascal , Czarnecki Antonny 
Published: June 2020

AbstractRenshaw cells (V1R) are excitable as soon as they reach their final location next to the spinal motoneurons and are functionally heterogeneous. Using multiple experimental approaches, in combination with biophysical modeling and dynamical systems theory, we analyzed, for the first time, the mechanisms underlying the electrophysiological properties of V1R during early embryonic development of the spinal cord locomotor networks (E11.5-E16.5). We found that these interneurons are subdivided into several functional clusters from E11.5 and then display an unexpected transitory involution process during which they lose their ability to sustain tonic firing. We demonstrated that the essential factor controlling the diversity of the discharge pattern of embryonic V1Ris the ratio of a persistent sodium conductance to a delayed rectifier potassium conductance. Taken together, our results reveal how a simple mechanism, based on the synergy of two voltage-dependent conductances that are ubiquitous in neurons, can produce functional diversity in V1Rand control their early developmental trajectory.
Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice
Authors: Cabana-Domínguez Judit , Martín-García Elena , Gallego-Roman Ana , Maldonado Rafael , Fernàndez-Castillo Noèlia , Cormand Bru 
Published: June 2020

ABSTRACTBackground and PurposeCocaine addiction causes serious health problems and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in thePLCB1gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution ofPLCB1gene to cocaine addictive properties in mice.Experimental approachWe used heterozygousPlcb1knockout mice (Plcb1+/-) and characterized their behavioral phenotype. Subsequently, mice were trained for operant conditioning and self-administered cocaine for 10 days.Plcb1+/- mice were assessed for cocaine motivation, followed by 26 days of extinction and finally evaluated for cue-induced reinstatement of cocaine seeking. Gene expression alterations after reinstatement were assessed in medial prefrontal cortex (mPFC) and hippocampus (HPC) by RNAseq.Key ResultsPlcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Importantly, after cocaine self-administration and extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior inPlcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex ofPlcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation.Conclusions and ImplicationsTo conclude, we found that heterozygous deletion of thePlcb1gene decreases cue-induced reinstatement of cocaine seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction.
Whole-genome sequence analysis reveals evolution of antimicrobial resistance in a Ugandan colistin resistantAcinetobacter baumannii
Authors: Aruhomukama Dickson , Sserwadda Ivan , Mboowa Gerald 
Published: June 2020

AbstractIn recent times, pan-drug resistantAcinetobacter baumanniihave emerged and continue to spread among critically ill patients, this poses an urgent risk to global and local human health. This study sought to provide the first genomic analysis of a pan-drug resistantAcinetobacter baumanniifrom Uganda and Africa, and to tell a story of mobile genetic element-mediated antibiotic resistance evolution in the isolate. It was an in-silico study in which intrinsic and acquired antibiotic resistance genes, and/or chromosomal resistance mutations were identified using PATRIC, CARD, NDARO and ResFinder. Screening for insertion sequences was done using ISfinder. Also, plasmid screening, phylogenetic analysis and sequence typing were performed using PlasmidFinder, PATRIC and Gubbin, and MLST respectively.The isolate belonged to the Sequence type 136, belonging to Clonal complex 208 and Global complex 2. This isolate shared close homology with strains from Tanzania. Resistance in the isolate was chromosomally and mobile genetic element-mediated byAcinetobacter-derived cephalosporinases and carbapenem hydrolyzing class D β-lactamses,blaOXA-2, 51, 5 88, 317,blaADC-2, 25. Colistin resistance was associated with previously documented mutants,lpxAandlpxC. Other key resistance genes identified were:aph(3”)-lb, aph(6)-ld, aph(3’)-la, aac(3)-lld, aac(3)-lla, aph(3’)-l, aph(3”)-l, aph(6)-lc, aph(6)-ld, aac(3)-II, III, IV, VI, VIII, IX, X, macA, macB, tetA, tetB, tetR, dfrA, and those of thefloRfamily. RSF1010 like IncQ broad-host-range plasmids and features of pACICU1, pACICU2, and p3ABAYEAcinetobacter baumanniiplasmids namely partitioning proteins ParA and B were present. Insertion sequences present included IS3, IS5, IS66and those of the ISLre2families.The study described for the first time a pan-drug resistantAcinetobacter baumanniifrom Uganda, and told a story of mobile genetic element-mediated antibiotic resistance evolution in the isolate despite being limited by pan-drug resistance phenotypic data. It provides a basis to track trends in antibiotic resistance and identification of emerging resistance patterns inAcinetobacter baumanniiin Uganda.
Nucleotide binding, evolutionary insights and interaction partners of the pseudokinase Unc-51-like kinase 4
Authors: Preuss Franziska , Chatterjee Deep , Mathea Sebastian , Shrestha Safal , St-Germain Jonathan , Saha Manipa , Kannan Natarajan , Raught Brian , Rottapel Robert , Knapp Stefan 
Published: June 2020

AbstractUnc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the cofactor is required for structural stability of ULK4. Here we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4 specific activation loop, which stabilizes the C-helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin associated proteins and several active kinases suggesting new roles for ULK4.HighlightsStructure of the ULK4 ATP complex reveals a unique ATP binding mode.Disease associated mutations modulate ATP binding and ULK4 stabilityDegradation of active site motifs co-occurred in evolution with an ULK4 specific activation loopBioID suggests a role of ULK4 regulating centrosomal and cytoskeletal functions
Role of misfolded tau in the onset and progression of brain toxicity after trauma
Authors: Zanier Elisa R. , Barzago Maria Monica , Vegliante Gloria , Romeo Margherita , Bertani Ilaria , Natale Carmina , Colnaghi Luca , Colombo Laura , Russo Luca , Micotti Edoardo , Fioriti Luana , Chiesa Roberto , Diomede Luisa 
Published: June 2020

ABSTRACTTraumatic brain injury (TBI) is associated with widespread tau pathology in about one third of patients. We previously found that TBI induces a transmissible tau pathology (tauTBI), with late cognitive decline and synaptic dysfunction. To understand whether tauTBIis a marker of ongoing neurodegeneration or a driver of functional decline, we employedC. elegans. Brain homogenates from chronic TBI mice, or from mice in which tauTBIhad been transmitted by intracerebral inoculation, impairedC. elegansmotility and neuromuscular synaptic transmission. Brain homogenates from tau P301L transgenic mice, or pre-aggregated recombinant tau, induced a similar toxic response. Protease digestion or pre-incubation of homogenates with anti-tau antibodies abolished toxicity, and TBI brain homogenates from tau knock-out mice had no toxic effect. These results support a vital role of abnormal tau species in chronic neurodegeneration after TBI and set the groundwork for the development of aC. elegans-based platform for screening anti-tau compounds.
Nonlinear spatial integration underlies the diversity of retinal ganglion cell responses to natural stimuli
Authors: Karamanlis Dimokratis , Gollisch Tim 
Published: June 2020

AbstractHow neurons encode natural stimuli is a fundamental question for sensory neuroscience. In the early visual system, standard encoding models assume that neurons linearly filter incoming stimuli through their receptive fields, but artificial stimuli, such as reversing gratings, often reveal nonlinear spatial processing. We investigated whether such nonlinear processing is relevant for the encoding of natural images in ganglion cells of the mouse retina. We found that standard linear receptive field models fail to capture the spiking activity for a large proportion of cells. These cells displayed pronounced sensitivity to fine spatial contrast, and local signal rectification was identified as the dominant nonlinearity. In addition, we also observed a class of nonlinear ganglion cells with opposite tuning for spatial contrast and a particular sensitivity for spatially homogeneous stimuli. Our work highlights receptive field nonlinearities as a crucial component for understanding early sensory encoding in the context of natural stimuli.
Global pleiotropic effects in adaptively evolvedEscherichia colilacking CRP reveal molecular mechanisms that define growth physiology
Authors: Pal Ankita , Iyer Mahesh S. , Srinivasan Sumana , Seshasayee Aswin S , Venkatesh K.V. 
Published: June 2020

AbstractEvolution entails the orchestration of cellular resources together with mutations to achieve fitter phenotypes. Here, we determined the system-wide pleiotropic effects that redress the significant perturbations caused by the deletion of global transcriptional regulator CRP inEscherichia coliwhen evolved in the presence of glucose. We elucidated that absence of CRP results in alterations in key metabolic pathways instrumental for the precise functioning of protein biosynthesis machinery that subsequently corroborated with intracellular metabolite profiles. Apart from acquiring mutations in the promoter of glucose transporterptsG, the evolved populations recovered the metabolic pathways to their pre-perturbed state with amelioration of protein biosynthesis machinery coupled with fine-tuned proteome re-allocation that enabled growth recovery. However, ineffective utilization of carbon towards biomass as perceived from ATP maintenance flux and costly amino acid accumulations poses a limitation. Overall, we comprehensively illustrate the genetic and metabolic adjustments underlying adaptive evolvability, fundamental for understanding the growth physiology.
A Mild Keratin 1 Decrease Leads to Cell Death and Increased Oxidative Stress in B16-F10 Melanoma Cell Lines
Authors: Li Yujia , Zhang Mingchao , Ying Weihai 
Published: June 2020

AbstractKeratins play multiple significant biological roles in epithelium. K1 / keratin 10 (K10) heterodimer is a hallmarker for keratinocyte differentiation. While keratins are absent in normal melanocyte, keratins have been found in both melanoma cell lines and human melanoma. The biological significance of the keratins in melanoma cells has remained unclear. In our current study we applied K1 siRNA to investigate the biological significance of the K1 in B16-F10 melanoma cells. We found that as low as a 16% decrease in the K1 level led to significant increases in both apoptosis and necrosis of the cells. Moreover, the mild K1 decrease led to significant increases in both dichlorofluorescein (DCF) and ethidium signals - two indicators of oxidative stress - in the cells. Collectively, our findings have provided the first evidence indicating both a critical role of the K1 in maintaining the survival of melanoma cells and an important role of the K1 in modulating the oxidative stress state of the cells. These findings have exposed new functions of keratins in cancer cells, suggesting that K1 may become a novel therapeutic target for melanoma.
Large cognitive fluctuations surrounding sleep in daily living
Authors: Huber Reto , Ghosh Arko 
Published: June 2020

AbstractIt is well recognized that cognitive output fluctuates surrounding sleep. Such fluctuations are rarely investigated in subjects’ daily living, partially due to the inaccessibility of sleep laboratory technology and cognitive testing. Here we leverage the continuous and long-term smartphone touchscreen interaction logs to study the patterns of cognitive output surrounding sleep and contrasted these to the patterns underlying physical activity captured from wrist-worn actigraphy. According to spectral density analysis, both cognitive and physical activity was dominated by diurnal (∼24 h) and infra-radian (∼7 days) rhythms. However, these rhythms differed in a domain-specific manner. The proxy measures of cognitive performance – tapping speed, unlocking speed, and app locating speed – contained lower-powered diurnal rhythm than physical activity. Still, the amount of smartphone usage showed the strongest diurnal rhythm – even when compared to the ambient luminescence levels experienced according to actigraphy. Interestingly, the cognitive rhythms were not in sync with physical activity, as cognitive measures peaked later in the day and on weekdays rather than weekends. The difference between cognitive and physical activity became vivid during bedtime and subjects routinely interacted with their smartphones during the actigraphy labelled sleep period. The cognitive measures in this period were worse in comparison to the hour before or after sleep. Therefore, smartphones can seamlessly capture the dynamic fluctuations in cognitive output including during spontaneous awakenings. We conclude that the rhythms underlying cognitive activity in the real world are distinct from physical activity and this discord may be a hallmark of modern human behaviour.
Germanium nanospheres for ultraresolution picotensiometry of kinesin motors
Authors: Sudhakar Swathi , Abdosamadi Mohammad Kazem , Jachowski Tobias Jörg , Bugiel Michael , Jannasch Anita , Schäffer Erik 
Published: June 2020

Kinesin motors are essential for transport of cellular cargo along cytoskeletal microtubule filaments. How motors step, detach, and cooperate is still unclear. To dissect the molecular motion of kinesin-1, we have developed germanium nanospheres as ultraresolution optical trapping probes. We found that single motors took 4-nm-center-of-mass steps. Furthermore, motors never detached from microtubules under native hindering load conditions. Instead, motors slid on microtubules with microsecond-long, 8-nm steps and remained in this slip state before detaching or reengaging in directed motion. Surprisingly, reengagement and, thus, rescue of directed motion was prevailing. We argue that teams of motors may be synchronized through this slip state and rescues need to be accounted for to understand long-range transport.One Sentence SummaryOptical trapping of high-refractive-index semiconductor nanoparticles shows how motors detach and walk with 4-nm steps.
Testing evolutionary explanations for the lifespan benefit of dietary restriction inDrosophila melanogaster
Authors: Savola Eevi , Montgomery Clara , Waldron Fergal M. , Monteith Katy , Vale Pedro , Walling Craig 
Published: June 2020

ABSTRACTDietary restriction (DR), limiting calories or specific nutrients, extends lifespan across diverse taxa. This lifespan extension has been explained as diet-mediated changes in the trade-off between lifespan and reproduction, with survival favoured with scarce resources. Another evolutionary hypothesis suggests the selective benefit of the response is the maintenance of reproduction. This hypothesis predicts that lifespan extension is a side effect of benign laboratory conditions, where DR individuals are frailer and unable to deal with additional stressors, and thus lifespan extension should disappear under more stressful conditions. We tested this by rearing outbred femaleDrosophila melanogasteron 10 different protein:carbohydrate diets. Flies were either infected with a bacterial pathogen (Pseudomonas entomophila), injured or unstressed. We monitored lifespan, fecundity and ageing measures. DR extended lifespan and reduced reproduction irrespective of injury and infection. These results do not support lifespan extension under DR being a side effect of benign laboratory conditions.
Learning a latent representation of human genomics using Avocado
Authors: Schreiber Jacob , Noble William 
Published: June 2020

AbstractIn the past decade, the use of high-throughput sequencing assays has allowed researchers to experimentally acquire thousands of functional measurements for each basepair in the human genome. Despite their value, these measurements are only a small fraction of the potential experiments that could be performed while also being too numerous to easily visualize or compute on. In a recent pair of publications, we address both of these challenges with a deep neural network tensor factorization method, Avocado, that compresses these measurements into dense, information-rich representations. We demonstrate that these learned representations can be used to impute with high accuracy the output of experimental assays that have not yet been performed and that machine learning models that leverage these representations outperform those trained directly on the functional measurements on a variety of genomics tasks. The code is publicly available athttps://github.com/jmschrei/avocado.
HIV-1 Gag protein with or without p6 specifically dimerizes on the viral RNA packaging signal
Authors: Sarni Samantha , Biswas Banhi , Liu Shuohui , Olson Erik D. , Kitzrow Jonathan P. , Rein Alan , Wysocki Vicki H. , Musier-Forsyth Karin 
Published: June 2020

AbstractThe HIV-1 Gag protein is responsible for genomic RNA (gRNA) packaging and immature viral particle assembly. While the presence of gRNA in virions is required for viral infectivity, in its absence, Gag can assemble around cellular RNAs and form particles resembling gRNA-containing particles. When gRNA is expressed, it is selectively packaged despite the presence of excess host RNA, but how it is selectively packaged is not understood. Specific recognition of a gRNA packaging signal (Psi) has been proposed to stimulate the efficient nucleation of viral assembly. However, the heterogeneity of Gag-RNA interactions renders capturing this transient nucleation complex using traditional structural biology approaches challenging. Here, we used native mass spectrometry to investigate RNA binding of wild-type Gag and Gag lacking the p6 domain (GagΔp6). Both proteins bind to Psi RNA primarily as dimers, but to a control RNA primarily as monomers. The dimeric complexes on Psi RNA require an intact dimer interface within Gag. GagΔp6 binds to Psi RNA with high specificityin vitroand also selectively packages gRNA in particles produced in mammalian cells. These studies provide direct support for the idea that Gag binding to Psi specifically nucleates Gag-Gag interactions at the early stages of immature viral particle assembly in a p6-independent manner.
All is fish that comes to the net: metabarcoding for rapid fisheries catch assessment
Authors: Russo Tommaso , Maiello Giulia , Talarico Lorenzo , Baillie Charles , Colosimo Giuliano , D’Andrea Lorenzo , Di Maio Federico , Fiorentino Fabio , Franceschini Simone , Garofalo Germana , Scannella Danilo , Cataudella Stefano , Mariani Stefano 
Published: June 2020

AbstractMonitoring marine resource exploitation is a key activity in fisheries science and biodiversity conservation. Since research surveys are time-consuming and costly, fishery-dependent data (i.e. derived directly from fishing vessels) are increasingly credited with a key role in expanding the reach of ocean monitoring. Fishing vessels may be seen as widely ranging data-collecting platforms, which could act as a fleet of sentinels for monitoring marine life, in particular exploited stocks. Here, we investigate the possibility of assessing catch composition of single hauls carried out by trawlers by applying DNA metabarcoding to the “slush” collected from fishing nets just after the end of hauling operations. We assess the performance of this approach in portraying β-diversity and examining the quantitative relationship between species abundances in the catch and DNA amount in the slush (reads counts generated by amplicon sequencing). We demonstrate that the assemblages identified using DNA in the slush mirror those returned by visual inspection of net content and detect a strong relationship between read counts and species abundances in the catch. We therefore argue that this approach could be upscaled to serve as a powerful source of information on the structure of demersal assemblages and the impact of fisheries.