bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains
Authors: Turner Hannah L. , Pallesen Jesper , Lang Shanshan , Bangaru Sandhya , Urata Sarah , Li Sheng , Cottrell Christopher A. , Bowman Charles A. , Crowe James E. , Wilson Ian A. , Ward Andrew B. 
Published: October 2018

AbstractSeasonal influenza virus infections can cause significant morbidity and mortality, but the threat from emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy to decipher the mechanism of action of a potent HA head-directed monoclonal antibody bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, pre-fusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the pre-fusion conformation. The “breathing” of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.Author SummaryA transiently exposed epitope on influenza H7 hemagglutinin represents a new target for neutralizing antibodies.
Decoding voluntary movements and postural tremor based on thalamic LFPs for closed-loop stimulation for essential tremor
Authors: Tan Huiling , Debarros Jean , Pogosyan Alek , Aziz Tipu Z. , Huang Yongzhi , Wang Shouyan , Timmermann Lars , Visser-Vandewalle Veerle , Pedrosa David J. , Green Alexander L. , Brown Peter 
Published: October 2018

AbstractHigh frequency deep brain stimulation (DBS) targeting motor thalamus is an effective therapy for essential tremor (ET). However, conventional continuous stimulation may deliver unnecessary current to the brain since tremor mainly affects voluntary movements and sustained postures in ET. We recorded LFPs from the motor thalamus, surface electromyographic (EMG) signals and/or behavioural measurements in seven ET patients during temporary lead externalization after the first surgery for DBS when they performed different voluntary upper limb movements and in nine more patients during the surgery, when they were asked to lift their arms to trigger postural tremor. We show that both voluntary movements and postural tremor can be decoded based on features extracted from thalamic LFPs using a machine learning based binary classifier. This information can be used to close the loop for DBS so that stimulation could be delivered on demand, without the need for peripheral sensors or additional invasive electrodes.
Sensory experience controls dendritic structure and behavior by distinct pathways involving degenerins
Authors: Inberg Sharon , Iosilevskii Yael , Calatayud-Sanchez Alba , Setty Hagar , Oren-Suissa Meital , Krieg Michael , Podbilewicz Benjamin 
Published: October 2018

AbstractDendrites are crucial for receiving information into neurons. Sensory experience affects the structure of these tree-like neurites, which, it is assumed, modifies neuronal function, yet the evidence is scarce, and the mechanisms are unknown. To study whether sensory experience affects dendritic morphology, we use theCaenorhabditis elegans’arborized nociceptor PVD neurons, under natural mechanical stimulation induced by physical contacts between individuals. We found that mechanosensory signals induced by conspecifics and by glass beads affect the dendritic structure of the PVD. Moreover, developmentally isolated animals show a decrease in their ability to respond to harsh touch. The structural and behavioral plasticity following sensory deprivation are functionally independent of each other and are mediated by an array of evolutionarily conserved mechanosensory amiloride-sensitive epithelial sodium channels (degenerins). Calcium imaging of the PVD neurons in a micromechanical device revealed that controlled mechanical stimulation of the body wall produces similar calcium dynamics in both isolated and crowded animals. Our genetic results, supported by optogenetic, behavioral, and pharmacological evidence, suggest an activity- dependent homeostatic mechanism for dendritic structural plasticity, that in parallel controls escape response to noxious mechanosensory stimuli.Significance StatementLittle is known about how neuronal activity and sensory experience influence the structure and function of dendritic trees. Furthermore, how dendritic structures affect neuronal functions remains to a large extent a mystery despite their fundamental functions in neuronal sensory and synaptic activities in health and diseases. Here we show that complex dendritic trees of the nociceptive and proprioceptive PVD neuron inC. elegansdisplay a dynamic nature where they undergo pronounced dendritic modifications during adulthood. These modifications are determined by the received sensory signals generated by conspecific worms on the plate or by inert glass beads. We revealed functions for degenerins/Epithelial sodium channels in this phenomenon, using genetic and optogenetic approaches. We found that the degenerin MEC-10 acts cell autonomously to translate environmental mechanical signals into structural and functional modifications in the PVD.
Caring without sharing: Meta-analysis 2.0 for massive genome-wide association studies
Authors: Pourshafeie Armin , Bustamante Carlos D. , Prabhu Snehit 
Published: October 2018

AbstractGenome-wide association studies have been effective at revealing the genetic architecture of simple traits. Extending this approach to more complex phenotypes has necessitated a massive increase in cohort size. To achieve sufficient power, participants are recruited across multiple collaborating institutions, leaving researchers with two choices: either collect all the raw data at a single institution or rely on meta-analyses to test for association. In this work, we present a third alternative. Here, we implement an entire GWAS workflow (quality control, population structure control, and association) in a fully decentralized setting. Our iterative approach (a) does not rely on consolidating the raw data at a single coordination center, and (b) does not hinge upon large sample size assumptions at each silo. As we show, our approach overcomes challenges faced by meta-studies when it comes to associating rare alleles and when case/control proportions are wildly imbalanced at each silo. We demonstrate the feasibility of our method in cohorts ranging in size from 2K (small) to 500K (large), and recruited across 2 to 10 collaborating institutions.
Accurate registration of 3D time-lapse microscopy images
Authors: Kahaki Seyed M. M. , Wang Shih-Luen , Stepanyants Armen 
Published: October 2018

ABSTRACTIn vivo imaging experiments often require automated detection and tracking of changes in the specimen. This problem, however, can be hindered by variations in the position and orientation of the specimen relative to the microscope, as well as by linear and nonlinear deformations. Here, we present a feature-based registration method, coupled with translation, rigid, affine, and B-spline transformations, designed to address these issues in 3D time-lapse microscopy images. In this method, features are detected as local intensity maxima in the source and target image stacks, and their similarity matrix is used as an input to the Hungarian algorithm to establish initial correspondences. Random Sampling Consensus algorithm is then employed to eliminate outliers. The resulting set of corresponding features is used to determine the optimal transformations. Accuracy of the proposed algorithm was tested on fluorescently labeled axons imaged over a 48- day period with a two-photon laser scanning microscope. For this, multiple axons in individual stacks of images were traced semi-manually in 3D, and the distances between the corresponding traces were measured before and after the registration. The results show that there is a progressive improvement in the registration accuracy with increasing complexity of the transformations. In particular, an accuracy of less than 1 voxel (0.26 μm) was achieved with a regularized B-spline transformation. To illustrate the utility of the proposed method, registered images were used to automatically track synaptic boutons on axons over the entire duration of the experiment, yielding 99% precision and recall.
Mitochondrial type II NADH dehydrogenase ofPlasmodium falciparumis dispensable and not the functional target of putative NDH2 quinolone inhibitors
Authors: Ke Hangjun , Ganesan Suresh M. , Dass Swati , Morrisey Joanne M. , Pou Sovitj , Nilsen Aaron , Riscoe Michael K. , Mather Michael W. , Vaidya Akhil B. 
Published: October 2018

AbstractThe battle against malaria has been substantially impeded by the recurrence of drug resistance inPlasmodium falciparum, the deadliest human malaria parasite. To counter the problem, novel antimalarial drugs are urgently needed, especially those that target unique pathways of the parasite, since they are less likely to have side effects. The mitochondrial type II NADH dehydrogenase ofP. falciparum, PfNDH2 (PF3D7_0915000), has been considered a good prospective antimalarial drug target for over a decade, since malaria parasites lack the conventional multi-subunit NADH dehydrogenase, or Complex I, present in the mammalian mitochondrial electron transport chain (mtETC). Instead, Plasmodium parasites contain a single subunit NDH2, which lacks proton pumping activity and is absent in humans. A significant amount of effort has been expended to develop PfNDH2 specific inhibitors, yet the essentiality of PfNDH2 has not been convincingly verified. Herein, we knocked out PfNDH2 inP. falciparumvia a CRISPR/Cas9 mediated approach. Deletion of PfNDH2 does not alter the parasite’s susceptibility to multiple mtETC inhibitors, including atovaquone and ELQ-300. We also show that the antimalarial activity of the fungal NDH2 inhibitor HDQ and its new derivative CK-2-68 is due to inhibition of the parasite cytochromebc1complex rather than PfNDH2. These compounds directly inhibit the ubiquinol-cytochromecreductase activity of the malarialbc1complex. Our results call into question the validity of PfNDH2 as an antimalarial drug target.ImportanceFor a long time, PfNDH2 has been considered an attractive antimalarial drug target. However, the conclusion that PfNDH2 is essential was based on preliminary and incomplete data. Here we generate a PfNDH2 KO (knockout) parasite in the blood stages ofPlasmodium falciparum, showing that the gene is not essential. We also show that previously reported PfNDH2-specific inhibitors kill the parasites primarily via targeting the cytochromebc1complex, not PfNDH2. Overall, we provide genetic and biochemical data that help to resolve a long-debated issue in the field regarding the potential of PfNDH2 as an antimalarial drug target.
AIDE: annotation-assisted isoform discovery with high precision
Authors: Li Wei Vivian , Li Shan , Tong Xin , Deng Ling , Shi Hubing , Li Jingyi Jessica 
Published: October 2018

AbstractGenome-wide accurate identification and quantification of full-length mRNA isoforms is crucial for investigating transcriptional and post-transcriptional regulatory mechanisms of biological phenomena. Despite continuing efforts in developing effective computational tools to identify or assemble full-length mRNA isoforms from second-generation RNA-seq data, it remains a challenge to accurately identify mRNA isoforms from short sequence reads due to the substantial information loss in RNA-seq experiments. Here we introduce a novel statistical method, AIDE (Annotation-assisted Isoform DiscovEry), the first approach that directly controls false isoform discoveries by implementing the testing-based model selection principle. Solving the isoform discovery problem in a stepwise and conservative manner, AIDE prioritizes the annotated isoforms and precisely identifies novel isoforms whose addition significantly improves the explanation of observed RNA-seq reads. We evaluate the performance of AIDE based on multiple simulated and real RNA-seq datasets followed by a PCR-Sanger sequencing validation. Our results show that AIDE effectively leverages the annotation information to compensate the information loss due to short read lengths. AIDE achieves the highest precision in isoform discovery and the lowest error rates in isoform abundance estimation, compared with three state-of-the-art methods Cufflinks, SLIDE, and StringTie. As a robust bioinformatics tool for transcriptome analysis, AIDE will enable researchers to discover novel transcripts with high confidence.
Transection of the ventral hippocampal commissure impairs spatial reference but not contextual or spatial working memory
Authors: Jordan Jake T. , Tong Yi , Pytte Carolyn L. 
Published: October 2018

AbstractPlasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus is lateralized with the left hemisphere dominant in plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric integration of input from these pathways is essential for integrating spatial memory stored in the left CA3 with spatial working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent spatial working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing spatial working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.
Single-cell RNA-seq identifies a reversible epithelial-mesenchymal transition in abnormally specified epithelia of p63 EEC syndrome
Authors: Soares Eduardo , Xu Quan , Li Qingqing , Qu Jieqiong , Zheng Yuxuan , Raeven Henriette H. M. , Brandao Karina , Petit Isabelle , van den Akker Willem M.R. , Aberdam Daniel , Tang Fuchou , Zhou Huiqing 
Published: October 2018

AbstractMutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed distinct step-wise cell fate transitions during epidermal commitment; from multipotent simple epithelium to basal stratified epithelia, and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by mutant p63 occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified signatures of embryonic epithelial-mesenchymal transition (EMT) associated with the deviated commitment route of EEC iPSCs. Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. Our findings demonstrate that p63 is required for specification of stratified epithelia, probably by repressing embryonic EMT during epidermal commitment. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.Significance statementMutations in p63 cause several developmental disorders with defects of epithelial related organs and tissues including the epidermis. Our study is to dissect the unknown cellular and molecular pathomechanism. We utilized human induced pluripotent stem cells (iPSCs) derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations and studied transcriptome changes during differentiation of these cells to epidermal cells. Our analyses showed that the specification of the proper epithelial cell fate was affected by p63 EEC mutations, with an abnormal embryonic epithelial-mesenchymal transition (EMT). Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. This study provides insights into disease mechanisms associated with p63 mutations and suggests potential therapeutic strategies.
Genetic variability in response to Aβ deposition influences Alzheimer’s risk
Authors: Salih Dervis A. , Bayram Sevinc , Guelfi Manuel S. , Reynolds Regina , Shoai Maryam , Ryten Mina , Brenton Jonathan , Zhang David , Matarin Mar , Botia Juan , Shah Runil , Brookes Keeley , Guetta-Baranes Tamar , Morgan Kevin , Bellou Eftychia , Cummings Damian M. , Hardy John , Edwards Frances A. , Escott-Price Valentina 
Published: October 2018

AbstractGenetic analysis of late-onset Alzheimer’s disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimer’s risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimer’s disease genome-wide association studies identifies 5 other genetic risk loci for the disease (OAS1, CXCL10, LAPTM5, ITGAM and LILRB4). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimer’s risk.One Sentence SummaryIdentification of 5 new risk loci for Alzheimer’s by statistical comparison of mouse Aβ microglial response with gene-based SNPs from human GWAS
Distinct waking states for strong evoked responses in primary visual cortex and optimal visual detection performance
Authors: Neske Garrett T. , McCormick David A. 
Published: October 2018

AbstractVariability in cortical neuronal responses to sensory stimuli and in perceptual decision making performance is substantial. Moment-to-moment fluctuations in waking state or arousal can account for much of this variability. Yet, the nature of this variability across the full spectrum of waking states is often not completely characterized, leaving the characteristics of the optimal state for sensory processing unresolved. Using pupillometry in concert with extracellular multiunit and intracellular whole-cell recordings, we found that the magnitude and reliability of visually evoked responses in primary visual cortex (V1) of awake, passively behaving male mice increase as a function of arousal and are largest during sustained locomotion periods. During these high-arousal, sustained locomotion periods, cortical neuronal membrane potential was at its most depolarized and least variable. Contrastingly, behavioral performance of mice on two distinct visual detection tasks was generally best at a range of intermediate arousal levels, but worst during locomotion. These results suggest that large, reliable responses to visual stimuli in V1 occur at a distinct arousal level from that associated with optimal visual detection performance. Our results clarify the relation between neuronal responsiveness and the continuum of waking states, and suggest new complexities in the relation between primary sensory cortical activity and behavior.
Reconstitution of the equilibrium state of dynamic actin networks
Authors: Manhart Angelika , Icheva Aleksandra , Guerin Christophe , Klar Tobbias , Boujemaa-Paterski Rajaa , Thery Manuel , Blanchoin Laurent , Mogilner Alex 
Published: October 2018

AbstractPrinciples of regulation of actin network dimensions, fundamentally important for cell functions, remain unclear. We studied in vitro and in silico the effect of key parameters, actin density, ADF/Cofilin concentration and network width on the network length. In the presence of ADF/Cofilin, networks reached equilibrium and became globally treadmilling. At the trailing edge, the network disintegrated into large fragments. A mathematical model predicts the network length as a function of width, actin and ADF/Cofilin concentrations. Local depletion of ADF/Cofilin by binding to actin is significant, leading to wider networks growing longer. A single rate of breaking network nodes, proportional to ADF/Cofilin density and inversely proportional to the square of the actin density, can account for the disassembly dynamics. Selective disassembly of heterogeneous networks by ADF/Cofilin controls steering during motility. Our results establish general principles on how the dynamic equilibrium state of actin network emerges from biochemical and structural feedbacks.
Distinctive interaction between cognitive networks and the visual cortex in early blind individuals
Authors: Abboud Sami , Cohen Laurent 
Published: October 2018

AbstractIn early blind individuals, brain activation by a variety of non-perceptual cognitive tasks extends to the visual cortex, while in the sighted it is restricted to supramodal association areas. We hypothesized that such activation results from the integration of different sectors of the visual cortex into typical task-dependent networks. We tested this hypothesis with fMRI in blind and sighted subjects using tasks assessing speech comprehension, incidental long-term memory and both verbal and non-verbal executive control, in addition to collecting resting-state data. All tasks activated the visual cortex in blind relative to sighted subjects, which enabled its segmentation according to task sensitivity. We then assessed the unique brain-scale functional connectivity of the segmented areas during resting state. Language-related seeds were preferentially connected to frontal and temporal language areas; the seed derived from the executive task was connected to the right dorsal frontoparietal executive network; the memory-related seed was uniquely connected to mesial frontoparietal areas involved in episodic memory retrieval. Thus, using a broad set of language, executive, and memory tasks in the same subjects, combined with resting state connectivity, we demonstrate the selective integration of different patches of the visual cortex into brain-scale networks with distinct localization, lateralization, and functional roles.