bluuebunny/crossref_metadata_2025_split huggingface dataset:
Continuous regimens of cortico-motor integration calibrate levels of arousal during emergence from anesthesia
Authors: Gao Sijia , Calderon Diany Paola 
Published: February 2020

AbstractBackgroundRecovery to a conscious state when emerging from anesthesia requires full cortical desynchronization, initiation of movement and behavioral reactivity to sensory stimuli. However, the variety of cortical electroencephalogram (EEG) patterns associated with specific anesthetics and the paucity of behavioral descriptions during emergence from anesthesia have prevented EEG and behavior as feasible tracking methods to assess emerging from anesthesia. We propose a detailed combined analysis of motor and cortical activity to determine levels of arousal in rodents.MethodsUsing decreasing anesthetic concentrations, we simultaneously recorded local field potentials (LFPs) and movement in mice. We delineated cortical dynamics and sub-states during emergence from anesthesia by applying a smoothed-Z score to extract dominant frequencies from spectrogram. Then, we implemented KMeans to obtain cortical sub-states. Finally, we used density estimation and an abrupt change detection algorithm to segment cortical activity into periods. We used cortical sub-states obtained during isoflurane traces to supervise sub-states in sevoflurane and a pharmacologically induced-arousal model. This information together with examining videos were used to categorize behavior.ResultsWe identified five cortical periods with restored motor behavior during emergence from isoflurane anesthetic. Periods of structured sub-states denoted when specific motor behaviors occurred. No significant differences were found when comparing the combined cortical features and motor behavior using isoflurane, sevoflurane and our arousal-rodent model. We describe graded regimens of cortico-motor activity during emergence from anesthesia to assess arousal levels.ConclusionWe show cortical patterns denote gradual motor behaviors when emerging from anesthesia. Restoring motor behavior is a dynamic process that begins tens of minutes earlier than the righting reflex. Combining cortical activity and motor behavior unveils novel biomarkers to accurately track emerging from general anesthesia in rodents and likely other species.
Structural basis for the recognition of the 2019-nCoV by human ACE2
Authors: Yan Renhong , Zhang Yuanyuan , Guo Yingying , Xia Lu , Zhou Qiang 
Published: February 2020

AbstractAngiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter B0AT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 Å in the presence of B0AT1. The local resolution at the ACE2-RBD interface is 3.5 Å, allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.
Theory of Neuronal Perturbome: Linking Connectivity to Coding via Perturbations
Authors: Sadeh Sadra , Clopath Claudia 
Published: February 2020

SummaryTo unravel the functional properties of the brain, we need to untangle how neurons interact with each other and coordinate in large-scale recurrent networks. One way to address this question is to measure the functional influence of individual neurons on each other by perturbing themin vivo. Application of such single-neuron perturbations in mouse visual cortex has recently revealed feature-specificsuppressionbetween excitatory neurons, despite the presence of highly specific excitatory connectivity, which was deemed to underlie feature-specificamplification. Here, we studied which connectivity profiles are consistent with these seemingly contradictory observations, by modelling the effect of single-neuron perturbations in large-scale neuronal networks. Our numerical simulations and mathematical analysis revealed that, contrary to the prima facie assumption, neither inhibition-dominance nor broad inhibition alone were sufficient to explain the experimental findings; instead, strong and functionally specific excitatory-inhibitory connectivity was necessary, consistent with recent findings in the primary visual cortex of rodents. Such networks had a higher capacity to encode and decode natural images in turn, which was accompanied by the emergence of response gain nonlinearities at the population level. Our study provides a general computational framework to investigate how single-neuron perturbations are linked to cortical connectivity and sensory coding, and paves the road to map theperturbomeof neuronal networks in future studies.
CK1 Delta Is an mRNA Cap-Associated Protein That Drives Translation Initiation and Tumor Growth
Authors: Pal Ipsita , Grilo Andre M. Sardinha , Berchowitz Luke E. , Das Sharma Sohani , Mundi Prabhjot S. , Ali Abdullah M. , Martin M. Laura , Safari Maryam , Scotto Luigi , Malkovskiy Eli , Sawas Ahmed , Mukherjee Siddhartha , O’Connor Owen A. , Jovanovic Marko , Deng Changchun 
Published: February 2020

ABSTRACTWhether translation is differentially regulated across liquid and solid tumors remains poorly understood. Here we report the discovery that Casein Kinase 1 delta (CK1δ) plays a key role in regulating translation initiation in blood cancers, but interestingly, not in solid tumors. In lymphomas CK1δ is a key positive regulator of 4E-BP1 and p70S6K phosphorylation, assembly of eIF4F, and translation initiation. Furthermore, CK1δ is pulled down by m7GTP-agarose that mimics the mRNA m7G cap, consistent with the regulatory role of CK1δ in translation initiation. Targeting CK1δ using a small molecule inhibitor, namely SR-3029, potently kills lymphoma cell lines and primary lymphoma cells across histology subtypes. While SR-3029 shares with mTORC1 inhibitors the overlapping mechanism of repressing 4E-BP1 and p70S6K/RPS6 phosphorylation, the kinetics of repression is slow with SR-3029 and fast with mTORC1 inhibitors such as Torin-1. Remarkably, it is slower-acting SR-3029, but not fast-acting Torin-1, that kills lymphoma cells consistently across multiple histology subtypes. Proteomics and RNA sequencing studies show that SR-3029 represses the expression of many genes preferentially at the translation step, such as genes in the reactome translation initiation pathway. SR-3029 markedly represses the protein level of the C-MYC oncogene without decreasing its mRNA level. In contrast, Torin-1 fails to reduce the protein level of C-MYC in the same lymphoma cells. While SR-3029 also demonstrates potent activity in select solid tumors, its mechanism of action in the solid tumors is different. In breast cancer cells SR-3029 inhibits nuclear localization of β-catenin but at the same concentrations does not inhibit 4E-BP1 and p70S6K phosphorylation or global protein synthesis. Likewise, SR-3029 does not inhibit nuclear localization of β-catenin in lymphoma cells. Our results indicate that CK1δ is an mRNA cap-associated protein and an upstream kinase required for 4E-BP1 and p70S6K phosphorylation. CK1δ stimulates assembly of eIF4F and translation initiation, and is a critical driver for tumor growth in blood cancers across multiple histology types. CK1δ invokes the alternative mechanism of regulating β-catenin in select solid tumors. Our results indicate that CK1δ inhibition is a promising therapeutic strategy in both liquid and solid tumors, and the distinct roles of CK1δ in these malignancies may serve as biomarkers to enable precision cancer treatment.
A family of contact-dependent nuclease effectors contain an exchangeable, species-identifying domain
Authors: Sirias Denise , Utter Daniel R. , Gibbs Karine A. 
Published: February 2020

AbstractIn mixed-species communities, bacteria can deploy contact-dependent effectors to compete with other organisms, often directly injecting these proteins into neighboring cells. One current hypothesis is that the entire protein contains information specific for a single species; emergence of new effectors comes from acquiring genes. Here we have characterized a family of DNA-degrading effectors that are nucleases which cause death. Like other families of chimeric nucleases, these effectors contain two domains. One is a PD-(D/E)XK-containing domain necessary for DNA cleavage. The other domain, which does not contain known DNA-binding structures, encodes species-identifying information. We capitalized on the species-identifying domain to differentiate among low-abundance species, as well as to reveal domain architectures within these proteins, in human gut and oral microbiomes. Emerging are questions about how low-abundance strains use effectors for survival and how strain-identifying effectors evolve.
High standing genetic variation in an invasive plant allows immediate evolutionary response to climate warming
Authors: Sun Yan , Bossdorf Oliver , Grados Ramon Diaz , Liao ZhiYong , Müller-Schärer Heinz 
Published: February 2020

AbstractPredicting plant distributions under climate change is constrained by our limited understanding of potential rapid adaptive evolution. In an experimental evolution study with the invasive common ragweed, we subjected replicated populations of the same initial genetic composition to simulated climate warming. Pooled DNA sequencing of parental and offspring populations showed that warming populations experienced a greater loss of genetic diversity, and greater genetic divergence from their parents, than control populations. In a common environment, offspring from warming populations showed more convergent phenotypes in seven out of nine plant traits, with later flowering and larger biomass, than plants from control populations. For both traits, we also found a significant higher ratio of phenotypic to genetic differentiation across generations for warming than for control populations, indicating stronger selection under warming conditions. Our findings demonstrate that ragweed populations can rapidly evolve in response to climate change within a single generation.
Limited evolution despite years of measurable viremia in a cART-treated seronegative HIV-1 positive individual
Authors: Fryer Helen R. , Raghwani Jayna , Gill M John , van Marle Guido , Golbchik Tanya , Grove Joe , Lythgoe Katrina A. 
Published: February 2020

AbstractUnderstanding the role that antibodies play in controlling HIV-1 infection and in the dynamics that underpin the formation of the HIV-1 reservoir are important steps towards combatting this global disease. To address these gaps, we performed whole-genome, deep sequence analysis of longitudinal plasma HIV-1 samples from an individual who failed to develop detectable anti-HIV-1 antibodies for 4 years post infection. These analyses reveal limited evolution despite months of measurable viremia during treatment with cART. We used a mathematical model to simultaneously analyse the viral and evolutionary dynamics of this unique individual. We propose a role for antibodies in reducing viral infectivity and demonstrate how our data are consistent with a theory of rapid activation of latently infected cells prior to effective viral suppression. Our study supports and elucidates a recent finding that although the latent reservoir persists for years once virus is effectively suppressed, prior to suppression, viral strains within the reservoir turn over rapidly. The implications for a cure are significant.
Improving Metagenomic Classification using Discriminative k-mers from Sequencing Data
Authors: Storato D. , Comin M. 
Published: February 2020

AbstractThe major problem when analyzing a metagenomic sample is to taxonomically annotate its reads in order to identify the species they contain. Most of the methods currently available focus on the classification of reads using a set of reference genomes and their k-mers. While in terms of precision these methods have reached percentages of correctness close to perfection, in terms of recall (the actual number of classified reads) the performances fall at around 50%. One of the reasons is the fact that the sequences in a sample can be very different from the corresponding reference genome, e.g. viral genomes are highly mutated. To address this issue, in this paper we study the problem of metagenomic reads classification by improving the reference k-mers library with novel discriminative k-mers from the input sequencing reads. We evaluated the performance in different conditions against several other tools and the results showed an improved F-measure, especially when close reference genomes are not available.Availabilityhttps://github.com/davide92/K2Mem.git
Characterization of the dimeric interactions of dimeric and tetrameric conformations of the PvNV protrusion-domain using a mixed DFT/QTAIM approach
Authors: Astani Elahe K. , Chen Nai-Chi , Huang Yen-Chieh , Ersali Sara , Lin Pei-Ju , Guan Hong-Hsiang , Lin Chien-Chih , Chuankhayan Phimonphan , Chen Chun-Jung 
Published: February 2020

AbstractThe protrusion-domain (P-domain) ofPenaeus vannameinodavirus (PvNV) exists as two dimer-dimer conformations: one is a protein dimer and the other is a protein tetramer. We undertook a theoretical study to gain a clear understanding of the nature of the stabilizing interactions at the dimeric interfaces of the dimeric and tetrameric conformations of the PvNV P-domain (PvNVPd) using the quantum theory of atoms in molecules (QTAIM) and natural-bond orbital (NBO) analyses in the framework of the density-functional theory (DFT) approach. The QTAIM analysis characterized the presence of multiple hydrogen bonds of common types with strength ranging from electrostatic to the covalent limit inside the PvNVPd dimer-dimer interfaces. Val257-Lys335, Phe294-Val330, Gln296-Thr328, Glu296-Thr329, Thr328-Gln297, Val330-Ala293, Lys335-Asp256 and Lys335-Val257 pairs are critical residue pairs of all three dimeric interfaces of PvNVPd. They preserve these dimeric interfaces through charge-charge, charge-dipole, dipole-dipole, hydrophobic and hydrogen bond interactions. The strongest intermolecular dimer–dimer interactions belong to the dimeric interface between subunits A and B of PvNVPd in the tetrameric conformation.
The DrosophilaTARTtransposon manipulates the piRNA pathway as a counter-defense strategy to limit host silencing
Authors: Ellison Christopher E. , Kagda Meenakshi S. , Cao Weihuan 
Published: February 2020

AbstractCo-evolution between transposable elements (TEs) and their hosts can be antagonistic, where TEs evolve to avoid silencing and the host responds by reestablishing TE suppression, or mutualistic, where TEs are co-opted to benefit their host. TheTART-ATE functions as an important component of Drosophila telomeres, but has also reportedly inserted into theD. melanogasternuclear export factor genenxf2. We find that, rather than inserting intonxf2, TART-Ahas actually captured a portion ofnxf2sequence. We show that Nxf2 is involved in suppressingTART-Aactivity via the piRNA pathway and thatTART-Aproduces abundant piRNAs, some of which are antisense to thenxf2transcript. We propose that capturingnxf2sequence allowedTART-Ato target thenxf2gene for piRNA-mediated repression and that these two elements are engaged in antagonistic co-evolution despite the fact thatTART-Ais serving a critical role for its host genome.
Novel phenotype of Wolbachia strain wPip in Aedes aegypti challenges assumptions on mechanisms of Wolbachia-mediated dengue virus inhibition
Authors: Fraser Johanna E. , O’Donnell Tanya B. , Duyvestyn Johanna M. , O’Neill Scott L. , Simmons Cameron P. , Flores Heather A. 
Published: February 2020

AbstractThe bacterial endosymbiontWolbachiais a biocontrol tool that inhibits the ability of theAedes aegyptimosquito to transmit positive-sense RNA viruses such as dengue and Zika. Growing evidence indicates that whenWolbachiastrainswMel orwAlbB are introduced into local mosquito populations, human dengue incidence is reduced. Despite the success of this novel intervention, we still do not fully understand howWolbachiaprotects mosquitoes from viral infection. Here, we demonstrate that theWolbachiastrainwPip does not inhibit virus infection inAe. aegypti. We have leveraged this novel finding, and a panel ofAe. aegyptilines carrying virus-inhibitory (wMel andwAlbB) and non-inhibitory (wPip) strains in a common genetic background, to rigorously test a number of hypotheses about the mechanism ofWolbachia-mediated virus inhibition. We demonstrate that, contrary to previous suggestions, there is no association between a strain’s ability to inhibit dengue infection in the mosquito and either its typical density in the midgut or salivary glands, or the degree to which it elevates innate immune response pathways in the mosquito. These findings, and the experimental platform provided by this panel of genetically comparable mosquito lines, clear the way for future investigations to define howWolbachiapreventsAe. aegyptifrom transmitting viruses.Author summaryDengue virus, transmitted by theAedes aegyptimosquito, is one of the fastest-growing infectious diseases, causing an estimated 390 million human infections per year worldwide. Vaccines have limited efficacy and there are no approved therapeutics. This has driven the rise of novel vector control programs, in particular those that use the bacterium,Wolbachia, which prevents transmission of dengue and other human pathogenic viruses when stably introduced intoAe. aegyptipopulations. Although this is proving to be a highly effective method, the details of how this biocontrol tool works are not well understood. Here we characterise a newWolbachiastrain,wPip, and find thatAe. aegypticarryingwPip are still able to transmit dengue similar to mosquitoes that do not carryWolbachia. This finding has allowed us to begin a rigorous program of comparative studies to determine which features of aWolbachiastrain determine whether it is antiviral. Understanding these mechanisms will enable us to predict the risk of viral resistance arising againstWolbachiaand facilitate preparation of second-generation field release lines.
The Development of Active Binocular Vision under Normal and Alternate Rearing Conditions
Authors: Klimmasch Lukas , Schneider Johann , Lelais Alexander , Shi Bertram E. , Triesch Jochen 
Published: February 2020

AbstractThe development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereogramms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.
Succession ofBifidobacterium longumstrains in response to the changing early-life nutritional environment reveals specific adaptations to distinct dietary substrates
Authors: Kujawska Magdalena , La Rosa Sabina Leanti , Pope Phillip B. , Hoyles Lesley , McCartney Anne L. , Hall Lindsay J 
Published: February 2020

AbstractDiet-microbe interactions play a crucial role in infant development and modulation of the early-life microbiota. The genusBifidobacteriumdominates the breast-fed infant gut, with strains ofB. longumsubsp.longum(B. longum) andB. longumsubsp.infantis(B. infantis) particularly prevalent. Although transition from milk to a more diversified diet later in infancy initiates a shift to a more complex microbiome, specific strains ofB. longummay persist in individual hosts for prolonged periods of time. Here, we sought to investigate the adaptation ofB. longumto the changing infant diet. Genomic characterisation of 75 strains isolated from nine either exclusively breast- or formula-fed (pre-weaning) infants in their first 18 months revealed subspecies- and strain-specific intra-individual genomic diversity with respect to glycosyl hydrolase families and enzymes, which corresponded to different dietary stages. Complementary phenotypic growth studies indicated strain-specific differences in human milk oligosaccharide and plant carbohydrate utilisation profiles of isolates between and within individual infants, while proteomic profiling identified active polysaccharide utilisation loci involved in metabolism of selected carbohydrates. Our results indicate a strong link between infant diet andB. longumsubspecies/strain genomic and carbohydrate utilisation diversity, which aligns with a changing nutritional environment: i.e. moving from breast milk to a solid food diet. These data provide additional insights into possible mechanisms responsible for the competitive advantage of thisBifidobacteriumspecies and its long-term persistence in a single host and may contribute to rational development of new dietary therapies for this important developmental window.
A knock-inDrosophilamodel supports a conserved link between potassium channelopathy and involuntary movement
Authors: Kratschmer Patrick , Buhl Edgar , Chen Ko-Fan , Lowe Simon , Kullmann Dimitri M. , Hodge James J.L. , Jepson James E.C. 
Published: February 2020

ABSTRACTBackgroundGenetic and in vitro studies have linked a heterozygous gain-of-function mutation (D434G) in the hSlo1 BK (Big potassium) channel to paroxysmal dyskinesia. However, support for this linkage from in vivo models has been lacking.ObjectivesWe aimed to re-create the equivalent mutation to hSlo1 D434G in the fruit fly,Drosophila, and examine how this mutation altered movement and action potential waveforms.MethodsWe generated a knock-inDrosophilamodel of hSlo1 D434G. We used video-tracking and infra-red beam-break systems to test whether locomotion was altered in this model, and patch-clamp electrophysiology to determine how the mutation affected action potential waveforms.ResultsWe identified profound motor dysfunction and sporadic leg twitches, as well as a reduced width and an enhancement of the afterhyperpolarization phase of action potentials, in the model background.ConclusionOur results support a conserved relationship between enhanced BK channel function and disrupted motor control across distantly related species.