bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-density Neural Recordings from Feline Sacral Dorsal Root Ganglia with Thin-film Array
Authors: Sperry Zachariah J. , Na Kyounghwan , Jun James , Madden Lauren R. , Socha Alec , Yoon Eusik , Seymour John P. , Bruns Tim M. 
Published: July 2020

AbstractObjective: Dorsal root ganglia (DRG) are promising sites for recording sensory activity. Current technologies for DRG recording are stiff and typically do not have sufficient site density for high-fidelity neural data techniques. Approach: In acute experiments, we demonstrate single-unit neural recordings in sacral DRG of anesthetized felines using a 4.5 μm-thick, high-density flexible polyimide microelectrode array with 60 sites and 30-40 μm site spacing. We delivered arrays into DRG with ultrananocrystalline diamond shuttles designed for high stiffness affording a smaller footprint. We recorded neural activity during sensory activation, including cutaneous brushing and bladder filling, as well as during electrical stimulation of the pudendal nerve and anal sphincter. We used specialized neural signal analysis software to sort densely packed neural signals. Main results: We successfully delivered arrays in five of six experiments and recorded single-unit sensory activity in four experiments. The median neural signal amplitude was 55 μV peak-to-peak and the maximum unique units recorded at one array position was 260, with 157 driven by sensory or electrical stimulation. In one experiment, we used the neural analysis software to track eight sorted single units as the array was retracted ~500 μm. Significance: This study is the first demonstration of ultrathin, flexible, high-density electronics delivered into DRG, with capabilities for recording and tracking sensory information that are a significant improvement over conventional DRG interfaces.
Structural basis of the dynamic human CEACAM1 monomer-dimer equilibrium
Authors: Gandhi Amit K. , Sun Zhen-Yu J. , Kim Walter M. , Huang Yu-Hwa , Kondo Yasuyuki , Bonsor Daniel A. , Sundberg Eric J. , Wagner Gerhard , Kuchroo Vijay K. , Petsko Gregory A. , Blumberg Richard S. 
Published: July 2020

AbstractHuman (h) carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) function depends upon IgV-mediated homodimerization or heterodimerization with host ligands, including hCEACAM5 and hTIM-3, and a variety of microbial pathogens. However, there is little structural information available on how hCEACAM1 transitions between monomeric and dimeric states which in the latter case is critical for initiating hCEACAM1 activities. We therefore mutated residues within the hCEACAM1 IgV GFCC’ face including V39, I91, N97 and E99 and examined hCEACAM1 IgV monomer-homodimer exchange using differential scanning fluorimetry, multi-angle light scattering, X-ray crystallography and/or nuclear magnetic resonance. From these studies, we describe hCEACAM1 homodimeric, monomeric and transition states at atomic resolution and its conformational behavior in solution through NMR assignment of the wildtype (WT) hCEACAM1 IgV dimer and N97A monomer. These studies reveal the flexibility of the GFCC’ face and its important role in governing the formation of hCEACAM1 dimers and potentially heterodimers.
Validation and tuning ofin situtranscriptomics image processing workflows with crowdsourced annotations
Authors: Vo-Phamhi Jenny M. , Yamauchi Kevin A. , Gómez-Sjöberg Rafael 
Published: July 2020

AbstractRecent advancements inin situmethods, such as multiplexedin situRNA hybridization andin situRNA sequencing, have deepened our understanding of the way biological processes are spatially organized in tissues. Automated image processing and spot-calling algorithms for analyzingin situtranscriptomics images have many parameters which need to be tuned for optimal detection. Having ground truth datasets (images where there is very high confidence on the accuracy of the detected spots) is essential for evaluating these algorithms and tuning their parameters.We present a first-in-kind open-source toolkit and framework forin situtranscriptomics image analysis that incorporates crowdsourced annotations, alongside expert annotations, as a source of ground truth for the analysis ofin situtranscriptomics images. The kit includes tools for preparing images for crowdsourcing annotation to optimize crowdsourced workers’ ability to annotate these images reliably, performing quality control (QC) on worker annotations, extracting candidate parameters for spot-calling algorithms from sample images, tuning parameters for spot-calling algorithms, and evaluating spot-calling algorithms and worker performance. These tools are wrapped in a modular pipeline with a flexible structure that allows users to take advantage of crowdsourced annotations from any source of their choice. We tested the pipeline using real and syntheticin situtranscriptomics images and annotations from the Amazon Mechanical Turk system obtained via Quanti.us. Using real images fromin situexperiments and simulated images produced by one of the tools in the kit, we studied worker sensitivity to spot characteristics and established rules for annotation QC. We explored and demonstrated the use of ground truth generated in this way for validating spot-calling algorithms and tuning their parameters, and confirmed that consensus crowdsourced annotations are a viable substitute for expert-generated ground truth for these purposes.Data AvailabilityThe iPython notebooks, input images, and In Situ Transcriptomics Annotation (INSTA) pipeline software are available fromhttps://github.com/czbiohub/instapipeline. The SpotImage software is available fromhttps://github.com/czbiohub/spotimage. The files and iPython notebooks used to generate the figures for this paper are available fromhttps://github.com/czbiohub/instapaper.
Accurate detection of circulating tumor DNA using nanopore consensus sequencing
Authors: Marcozzi Alessio , Jager Myrthe , Elferink Martin , Straver Roy , van Ginkel Joost H. , Peltenburg Boris , Chen Li-Ting , Renkens Ivo , van Kuik Joyce , Terhaard Chris , de Bree Remco , Devriese Lot A. , Willems Stefan M. , Kloosterman Wigard P. , de Ridder Jeroen 
Published: July 2020

ABSTRACTLevels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant ctDNA molecules based on somatic variants, extremely sensitive sequencing methods are required. Here, we describe a new technique, CyclomicsSeq, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule. Consensus calling of the DNA copies increased the base-calling accuracy ∼60x, enabling accurate detection ofTP53mutations at frequencies down to 0.02%. We demonstrate that aTP53-specific CyclomicsSeq assay can be successfully used to monitor tumor burden during treatment for head-and-neck cancer patients. CyclomicsSeq can be applied to any genomic locus and offers an accurate diagnostic liquid biopsy approach that can be implemented in point-of-care clinical workflows.
Diminishing effects of mechanical loading over time during rat Achilles tendon healing
Authors: Khayyeri Hanifeh , Hammerman Malin , Turunen Mikael J , Blomgran Parmis , Notermans Thomas , Guizar-Sicairos Manuel , Eliasson Pernilla , Aspenberg Per , Isaksson Hanna 
Published: July 2020

AbstractMechanical loading affects tendon healing and recovery. However, our understanding about how physical loading affects recovery of viscoelastic functions, collagen production and tissue organisation is limited. The objective of this study was to investigate how different magnitudes of loading affects biomechanical and collagen properties of healing Achilles tendons over time.Achilles tendon from female Sprague Dawley rats were cut transversely and divided into two groups; normal loading (control) and reduced loading by Botox (unloading). The rats were sacrificed at 1, 2- and 4-weeks post-injury and mechanical testing (creep test and load to failure), small angle x-ray scattering (SAXS) and histological analysis were performed.The effect of unloading was primarily seen at the early time points, with inferior mechanical and collagen properties (SAXS), and reduced histological maturation of the tissue in unloaded compared to loaded tendons. However, by 4 weeks no differences remained. SAXS and histology revealed heterogeneous tissue maturation with more mature tissue at the peripheral region compared to the center of the callus. Thus, mechanical loading advances Achilles tendon biomechanical and collagen properties earlier compared to unloaded tendons, and the spatial variation in tissue maturation and collagen organization across the callus suggests important regional (mechano-) biological activities that require more investigation.
Distinct patterns of activity in individual cortical neurons and local networks in primary somatosensory cortex of mice evoked by mechanical limb stimulation
Authors: Bandet Mischa V. , Dong Bin , Winship Ian R. 
Published: July 2020

AbstractTo distinguish between somatic stimuli, the primary somatosensory cortex should process dissimilar stimuli with distinct patterns of neuronal activation. Two-photon calcium imaging permits simultaneous optical recording of sensory evoked activity in hundreds of cortical neurons during varied sensory stimulation. Hence, it allows a visualization of patterns of activity in individual neurons and local cortical networks in response to distinct stimulation. Here, flavoprotein autofluorescence imaging was used to map the somatosensory cortex of anaesthetized C57BL/6 mice, andin vivotwo-photon Ca2+imaging was used to define patterns of neuronal activation during mechanical stimulation of the contralateral forelimb or hindlimb at various frequencies (3, 10, 100, 200, and 300 Hz). The data revealed that neurons within the limb associated somatosensory cortex exhibit stimulus-specific patterns of activity. Subsets of neurons were found to have sensory-evoked activity that is either primarily responsive to single stimulus frequencies or broadly responsive to multiple frequencies of limb movement. High frequency stimuli were shown to elicit more activation across the population, with a greater percentage of the population responding and greater percentage of cells with high amplitude responses. Stimulus-evoked cell-cell correlations within these neuronal networks varied as a function of frequency of stimulation, such that each stimulus elicited a distinct pattern that was more consistent across multiple trials of the same stimulus compared to trials at different frequencies of stimulation. The variation in cortical response to these artificial stimuli can thus be represented by the population pattern of supra-threshold Ca2+transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between responsive neurons.
Visualization of giant virus particles using BONCAT labeling and STED microscopy
Authors: Berjón-Otero Mónica , Duponchel Sarah , Hackl Thomas , Fischer Matthias 
Published: July 2020

AbstractGiant DNA viruses of the phylumNucleocytoviricotaare being increasingly recognized as important regulators of natural protist populations. However, our knowledge of their infection cycles is still very limited due to a lack of cultured virus-host systems and molecular tools to study them. Here, we apply bioorthogonal noncanonical amino acid tagging (BONCAT) to pulse label the marine heterotrophic flagellateCafeteria burkhardaeduring infection with the lytic giant virus CroV. In absence of CroV, we report efficient incorporation of the L-methionine analog L-azidohomoalanine (AHA) into newly synthesized proteins of the methionine prototrophicC. burkhardae. During CroV infection, AHA was predominantly found in viral proteins, and single CroV virions were imaged with stimulated emission depletion (STED) super-resolution microscopy. CroV particles incorporated AHA with 95-100% efficiency while retaining their infectivity, which makes BONCAT/STED a powerful tool to study viral replication cycles in this ecologically relevant marine bacterivore.SignificanceGiant DNA viruses are the dominant class of protist-infecting viruses, yet the vast majority of described giant virus-protist systems remain uncultured. One of the better studied cultured systems is composed of the stramenopileCafeteria burkhardae(previouslyC. roenbergensis), the giant Cafeteria roenbergensis virus (CroV) and the virophage mavirus.C. burkhardaeis a widespread marine phagotrophic protist that plays an important role in regulating bacterial populations. In addition to being grazed upon by larger zooplankton,C. burkhardaepopulations are controlled by the lytic giant virus CroV. In turn, CroV is parasitized by the virophage mavirus that increases host population survival in the presence of CroV and forms a mutualistic symbiosis with its host. Despite being of fundamental ecological and evolutionary interest, this tripartite host-virus-virophage system suffers from a lack of molecular tools. Here, we show that CroV particles can be fluorescently labeled and imaged by super-resolution microscopy. To achieve this we established robust procedures for analyzing protist and viral populations and implemented the use of bioorthogonal noncanonical amino acid tagging (BONCAT) in a marine unicellular flagellate.
SMPD3suppresses IDH mutant tumor growth via dual autocrine-paracrine roles
Authors: Balakrishnan Anjali , Saleh Fermisk , Adnani Lata , Chinchalongporn Vorapin , El-Sehemy Ahmed , Olender Thomas , Chen Myra J , Ahmad Shiekh Tanveer , Prokopchuk Oleksandr , Vasan Lakshmy , Touahri Yacine , Islam Rehnuma , Sujanthan Sajeevan , Zinyk Dawn , Comanita Lacrimioara C , Kan Boris , Fleming Taylor , Michael Iacovos P , Morshead Cindi M , Leong Hon S , Okawa Satoshi , Brand Marjorie , Wallace Valerie A , Chan Jennifer A , Schuurmans Carol 
Published: July 2020

AbstractIsocitrate dehydrogenase (IDH) mutant gliomas, including oligodendroglioma (IDH-O) and astrocytoma (IDH-A), have signature slow-growth rates that are poorly understood. Here, we reveal thatSMPD3,a ceramide-producing sphingomyelinase implicated as a tumor suppressor gene and involved in extracellular vesicle biogenesis, suppresses IDH-mutant tumor growth via autocrine and paracrine actions. In patients with IDH-mutant gliomas, higherSMPD3expression levels correlate with longer survival, consistent with ceramide acting as an anti-oncometabolite.SMPD3knock-down in patient-derived IDH-O cells enhances proliferation cell-autonomously in 2D-culture and 3D-human cerebral organoids, and accelerates tumor growth in mouse orthotopic xenografts. Supporting paracrine actions, IDH-O-derived extracellular vesicles, enriched in ribosomal proteins, induce astrocytic deathin vitro. Furthermore, non-neoplastic glia in IDH-O tumors proliferate abnormally yet undergo apoptosis, concomitant with the acquisition of a translation-enriched transcriptional signature by tumor-associated oligodendrocytes.SMPD3thus suppresses IDH-mutant glioma growth cell-autonomously and phenotypically alters normal glia via extracellular vesicle biogenesis and paracrine actions.
Predictive pre-activation of orthographic and lexical-semantic representations facilitates visual word recognition
Authors: Eisenhauer Susanne , Gagl Benjamin , Fiebach Christian J. 
Published: July 2020

AbstractTo a crucial extent, the efficiency of reading results from the fact that visual word recognition is faster in predictive contexts. Predictive coding models suggest that this facilitation results from pre-activation of predictable stimulus features across multiple representational levels before stimulus onset. Still, it is not sufficiently understood which aspects of the rich set of linguistic representations that are activated during reading – visual, orthographic, phonological, and/or lexical-semantic – contribute to context-dependent facilitation. To investigate in detail which linguistic representations are pre-activated in a predictive context and how they affect subsequent stimulus processing, we combined a well-controlled repetition priming paradigm, including words and pseudowords (i.e., pronounceable nonwords), with behavioral and magnetoencephalography measurements. For statistical analysis, we used linear mixed modeling, which we found had a higher statistical power compared to conventional multivariate pattern decoding analysis. Behavioral data from 49 participants indicate that word predictability (i.e., context present vs. absent) facilitated orthographic and lexical-semantic, but not visual or phonological processes. Magnetoencephalography data from 38 participants show sustained activation of orthographic and lexical-semantic representations in the interval before processing the predicted stimulus, suggesting selective pre-activation at multiple levels of linguistic representation as proposed by predictive coding. However, we found more robust lexical-semantic representations when processing predictable in contrast to unpredictable letter strings, and pre-activation effects mainly resembled brain responses elicited when processing the expected letter string. This finding suggests that pre-activation did not result in ‘explaining away’ predictable stimulus features, but rather in a ‘sharpening’ of brain responses involved in word processing.
Molecular and cellular pathology of monogenic Alzheimer’s disease at single cell resolution
Authors: Marinaro Federica , Haneklaus Moritz , Zhang Zhechun , Strano Alessio , Evans Lewis , Handfield Louis-François , Ryan Natalie S. , Fox Nick C. , Hemberg Martin , Ramanathan Sharad , Livesey Frederick J. 
Published: July 2020

AbstractCell and molecular biology analyses of sporadic Alzheimer’s disease brain are confounded by clinical variability, ageing and genetic heterogeneity. Therefore, we used single-nucleus RNA sequencing to characterize cell composition and gene expression in the cerebral cortex in early-onset, monogenic Alzheimer’s disease. Constructing a cellular atlas of frontal cortex from 8 monogenic AD individuals and 8 matched controls, provided insights into which neurons degenerate in AD and responses of different cell types to AD at the cellular and systems level. Such responses are a combination of positively adaptive and deleterious changes, including large-scale changes in synaptic transmission and marked metabolic reprogramming in neurons. The nature and scale of the transcriptional changes in AD emphasizes the global impact of the disease across all brain cell types.One Sentence SummaryAlzheimer’s disease brain atlas provides insights into disease mechanisms
A tropane-based ibogaine analog rescues folding-deficient SERT and DAT
Authors: Bhat Shreyas , Guthrie Daryl A. , Kasture Ameya , El-Kasaby Ali , Cao Jianjing , Bonifazi Alessandro , Ku Therese , Giancola JoLynn B. , Hummel Thomas , Freissmuth Michael , Newman Amy Hauck 
Published: July 2020

AbstractMissense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutants, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild type transporters, and for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG601,602AA and DAT-PG584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperonein vivo, in Drosophila harboring DAT-PG584,585AA and rescued six out of 13 disease-associated human DAT mutantsin vitro.Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutants.
Adult newborn granule cells confer emotional-state-dependent plasticity in memory retrieval
Authors: Lei Bo , Kang Bilin , Lin Wantong , Chen Haichao , Hao Yuejun , Ma Jian , Shi Songhai , Zhong Yi 
Published: July 2020

SummaryAchieving optimal behavior requires animals to flexibly retrieve prior knowledge. Here we show that adult newborn granule cells (anbGCs) mediate emotional-state-dependent plasticity of memory retrieval. We find that acute social reward (aSR) enhances memory retrieval by increasing the reactivation of engram cells, while acute social stress (aSS) weakens retrieval and reduces the reactivation. Such bidirectional regulation relies on the activation of distinct populations of anbGCs by aSR and aSS, triggering opposing modifications of dDG activity, which is sufficient to regulate and predict the performance of memory retrieval. Concordantly, in emotional disorder models, aSR-dependent memory plasticity is impaired, while the effect of aSS remains intact. Together, our data revealed that anbGCs mediate plasticity of memory retrieval, allowing animals to flexibly retrieve memory according to the current emotional state, and suggested the essential roles of anbGCs in translating emotional information to the regulation of memory expression.
The representation of bodies in high level visual, prefrontal and inferior parietal cortex varies with explicit vs. implicit expression perception
Authors: Marrazzo Giuseppe , Vaessen Maarten J. , de Gelder Beatrice 
Published: July 2020

AbstractRecent studies provide an increasingly understanding of how visual objects categories like faces or bodies are represented in the brain but also raised the question whether a category based or more network inspired models are more powerful. Two important and so far sidestepped issues in this debate concern, first, how major category attributes like the emotional expression directly influence category representation and second, whether category and attribute representation are sensitive to task demands. This study investigated the impact of a crucial category attribute like emotional expression on category activity and whether this varies with the participants’ task. Using (fMRI) we measured BOLD responses while participants viewed whole body expressions and performed either an explicit (emotion) or an implicit (shape) recognition task. Our results based on multivariate methods show that the type of task is the strongest determinant of brain activity and can be decoded in EBA, VLPFC and IPL. Brain activity was higher for the explicit task condition in VLPFC and was not emotion specific. This pattern suggests that during explicit recognition of the body expression, body category representation may be strengthened, and emotion and action related activity suppressed. Taken together these results stress the importance of the task and of the role of category attributes for understanding the functional organization of high level visual cortex.