bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis
Authors: Kelly Jenna N. , Laloli Laura , V’kovski Philip , Holwerda Melle , Portmann Jasmine , Thiel Volker , Dijkman Ronald 
Published: April 2020

AbstractRespiratory viruses, such as the 2009 pandemic strain of influenza A virus (IAV, H1N1pdm09), target cells found in the human respiratory epithelium. These cells, which form a pseudostratified epithelial layer along the airways, constitute the first line of defence against respiratory pathogens and play a crucial role in the host antiviral response. However, despite their key role in host defence, it remains unknown how distinct cell types in the respiratory epithelium respond to IAV infection and how these responses may contribute to IAV-induced pathogenesis and overall disease outcome. Here, we used single cell RNA-sequencing (scRNA-seq) to dissect the host response to IAV infection in its natural target cells. scRNA-seq was performed on human airway epithelial cell (hAEC) cultures infected with either wild-type pandemic IAV (WT) or with a mutant version of IAV (NS1R38A) that induced a robust innate immune response. We then characterized both the host and viral transcriptomes of more than 19,000 single cells across the 5 major cell types populating the human respiratory epithelium. For all cell types, we observed a wide spectrum of viral burden among single infected cells and a disparate host response between infected and bystander populations. Interestingly, we also identified multiple key differences in the host response to IAV among individual cell types, including high levels of pro-inflammatory cytokines and chemokines in secretory and basal cells and an important role for luminal cells in sensing and restricting incoming virus. Multiple infected cell types were shown to upregulate interferons (IFN), with type III IFNs clearly dominating the antiviral response. Transcriptional changes in genes related to cell differentiation, cell migration, and tissue repair were also identified. Strikingly, we also detected a shift in viral host cell tropism from non-ciliated cells to ciliated cells at later stages of infection and observed major changes in the cellular composition. Microscopic analysis of both WT and NS1R38Avirus-infected hAECs at various stages of IAV infection revealed that the transcriptional changes we observed at 18 hpi were likely driving the downstream histopathological alterations in the airway epithelium. To our knowledge, this is the first study to provide a comprehensive analysis of the cell type-specific host antiviral response to a respiratory virus infection in its natural target cells – namely, the human respiratory epithelium.
Melatonin alters fluid phase co-existence in POPC/DPPC/cholesterol membranes
Authors: Mei Nanqin , Robinson Morgan , Davis James H. , Leonenko Zoya 
Published: April 2020

ABSTRACTThe structure and biophysical properties of lipid biomembranes are important for normal function of plasma and organelle membranes, which is essential for proper functioning of living cells. In Alzheimer’s disease (AD) the structure of neuronal membranes becomes compromised by the toxic effect of amyloid-β(Aβ) protein which accumulates at neuron synapses, resulting in membrane perforation and dysfunction, oxidative stress and cell death. Melatonin is an important pineal gland hormone that has been shown to be protective against Aβtoxicity in cellular and animal studies, but the molecular mechanism of this protection is not well understood. It has been shown that melatonin can interact with model lipid membranes and alter the membrane biophysical properties, such as membrane molecular order and dynamics. This effect of melatonin has been previously studied in simple model bilayers with one or two lipid components, we consider a more complex ternary lipid mixture as our membrane model. In this study, we used2H-NMR to investigate the effect of melatonin on lipid phase behaviour of a three-component model lipid membranes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and cholesterol. We used deuterium labelled palmitoyl-d31in POPC-d31and DPPC-d62separately, to probe the changes in hydrocarbon chain order as a function of temperature and varying concentrations of melatonin. We found that melatonin concentration influences phase separation in these ternary mixtures somewhat differently depending on whether POPC-d31or DPPC-d62was used. At 5 mol% melatonin we observed phase separation in samples with POPC-d31, but not with DPPC-d62. However, at 10 mol% melatonin phase separation was observed in both samples with either POPC-d31or DPPC-d62. These results indicate that melatonin can have a strong effect on membrane structure and physical properties, which may provide some clues to understanding how melatonin protects against Aβ.SIGNIFICANCEMelatonin has been shown to be protective against Aβpathology in animal and cellular studies. Although the mechanism of this protection is not well-understood, melatonin’s membrane-active properties may be important in this regard. In this work solid-state deuterium nuclear magnetic resonance was used to study the effect of melatonin on the POPC/DPPC/cholesterol model membranes. Specifically, we showed that melatonin modifies lipid hydrocarbon chain order to promote phase separation. This knowledge helps to explain the role of melatonin in lipid domain formation and may provide a deeper understanding of the mechanism of melatonin neuroprotection in AD.
Mice carrying paternal knockout of imprintedGrb10do not show compulsive behaviour
Authors: Rienecker Kira DA , Chavasse Alexander T , Moorwood Kim , Ward Andrew , Humby Trevor , Isles Anthony R 
Published: April 2020

ABSTRACTMice lacking paternal expression of imprintedGrb10show a number of social behaviour deficits, including an enhanced allogrooming phenotype. However, this could also index compulsive behaviour, and the increased whisker barbering seen inGrb10+/pmice has been suggested to be indicative of a trichotillomania-type behaviour. Here we test whether compulsive behaviour is a more general phenotype inGrb10+/pmice by examining marble burying. We also examined the mice for potentially confounding anxiety phenotypes using the elevated plus maze (EPM).Grb10+/pmice showed no difference from wild-type littermate controls on any measure in the marble burying test at any age. However,Grb10+/pmice were more willing to enter, spend time on, and head-dip on the open arm of the EPM than wild-type mice. These data suggest thatGrb10+/pmice are not generally more compulsive, and that the enhanced allogrooming is probably indicative of altered social behaviour. Furthermore, the altered behaviours seen on the EPM adds to other published findings suggesting thatGrb10has a role in mediating risk-taking.
Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures
Authors: Karkampouna S. , De Filippo M.R. , Ng C.Y. , Klima I. , Zoni E. , Spahn M. , Stein F. , Haberkant P. , Thalmann G.N. , de Julio M.Kruithof 
Published: April 2020

ABSTRACTProstate cancer (PCa) is the second leading cause of cancer-associated death in men with therapy resistance acquisition to androgen deprivation treatment and metastasis progression. Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. The main objective of the current study is to determine, using transcriptomic and proteomic analyses on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern, and how this information could be applied in prognostics. Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis). Using organism-specific reference databases, the human-specific transcriptome, representing the tumor, was identified and separated from the mouse-specific transcriptome (representing the contributing stroma counterpart) from the same PDX tumor samples. To identify proteome changes in the tumor (human) versus the stroma (mouse), we performed human and mouse cell separation using the MACS mouse depletion sorting kit, and subjected protein lysates to quantitative TMT labeling and mass spectrometry. We show that tenascin C is one of the most abundant stromal genes in bone metastasis PCa PDXs, is modulated by androgen levelsin vivoand is highly expressed in castration resistant LAPC9 PDX compared to castration sensitive BM18 PDX. Tissue microarray of primary PCa samples (N=210) was used to evaluate the potential of TNC to act as a metastasis prognosis marker. Low number of TNC-positive cells were associated with statistically significant clinical progression to local recurrence or metastasis, compared to high TNC-positive group. Our data showed that metastatic PCa PDXs that differ in androgen sensitivity trigger a differential stroma response suggesting that stroma was influenced by tumor cues. Selected stromal markers of osteoblastic PCa induced bone metastases, were induced in the microenvironment of the host organism in metastatic xenografts, although implanted in a non-bone site, indicating a conserved mechanism of tumor cells to induce a stromal pre-metastatic signature with high potential prognostic or diagnostic value.
Membrane Elastic Properties During Neural Progenitor/Neural Stem Cell Differentiation
Authors: Soares Juliana , de S. Araujo Glauber R. , Santana Cintia , Matias Diana , Moura-Neto Vivaldo , Farina Marcos , Frases Susana , Viana Nathan B. , Romão Luciana , Nussenzveig H. Moysés , Pontes Bruno 
Published: April 2020

ABSTRACTNeural stem cells differentiate into several cell types that display distinct functions. However, little is known about how cell surface mechanics vary during the differentiation process. Here, by precisely measuring membrane tension and bending modulus, we map their variations and correlate them with changes in cell morphology along differentiation into neurons, astrocytes and oligodendrocytes. Both neurons and undifferentiated cells reveal a decrease in membrane tension over the first hours of differentiation followed by stabilization, with no change in bending modulus. Astrocytes membrane tension initially decreases and then increases after 72h, accompanied by consolidation of GFAP expression and striking actin reorganization, while bending modulus increases following observed alterations. For oligodendrocytes, the changes in membrane tension are less abrupt over the first hours but their values subsequently decrease, correlating with a shift from O4 to MBP expressions and a remarkable actin reorganization, while bending modulus remains constant. Oligodendrocytes at later differentiation stages show membrane vesicles with similar membrane tension but higher bending modulus as compared to the cell surface. Altogether, our results display an entire spectrum of how membrane elastic properties are varying, contributing to a better understanding of neural stem cell differentiation from a mechanobiological perspective.
Real-time biomedical knowledge synthesis of the exponentially growing world wide web using unsupervised neural networks
Authors: Wagner Tyler , Awasthi Samir , Wittenberg Gayle , Venkatakrishnan AJ , Tarjan Dan , Anyanwu-Ofili Anuli , Badley Andrew , Halamka John , Flores Christopher , Khan Najat , Barve Rakesh , Soundararajan Venky 
Published: April 2020

AbstractDecoding disease mechanisms for addressing unmet clinical need demands the rapid assimilation of the exponentially growing biomedical knowledge. These are either inherently unstructured and non-conducive to current computing paradigms or siloed into structured databases requiring specialized bioinformatics. Despite the recent renaissance in unsupervised neural networks for deciphering unstructured natural languages and the availability of numerous bioinformatics resources, a holistic platform for real-timesynthesisof the scientific literature and seamless triangulation with deep omic insights and real-world evidence has not been advanced. Here, we introduce the nferX platform that makes the highly unstructured biomedical knowledge computable and supports the seamless visualtriangulationwith statistical inference from diverse structured databases. The nferX platform will accelerate and amplify the research potential of subject-matter experts as well as non-experts across the life science ecosystem (https://academia.nferx.com/).
The primary donor of far-red Photosystem II: ChlD1or PD2?
Authors: Judd Martyna , Morton Jennifer , Nürnberg Dennis , Fantuzzi Andrea , Rutherford A. William , Purchase Robin , Cox Nicholas , Krausz Elmars 
Published: April 2020

ABSTRACTFar-red light (FRL) Photosystem II (PSII) isolated fromChroococcidiopsis thermalisis studied using parallel analyses of low-temperature absorption, circular dichroism (CD) and magnetic circular dichroism (MCD) spectroscopies in conjunction with fluorescence measurements. This extends earlier studies (Nurnberget al2018 Science 360 (2018) 1210-1213). We confirm that the chlorophyll absorbing at 726 nm is the primary electron donor. At 1.8 K efficient photochemistry occurs when exciting at 726 nm and shorter wavelengths; but not at wavelengths longer than 726 nm. The 726 nm absorption peak exhibits a 21 ± 4 cm−1electrochromic shift due to formation of the semiquinone anion, QA•-. Modelling indicates that no other FRL pigment is located among the 6 central reaction center chlorins: PD1, PD2ChlD1, ChlD2, PheoD1and PheoD2. Two of these chlorins, ChlD1and PD2, are located at a distance and orientation relative to QA•-so as to account for the observed electrochromic shift. Previously, ChlD1was taken as the most likely candidate for the primary donor based on spectroscopy, sequence analysis and mechanistic arguments. Here, a more detailed comparison of the spectroscopic data with exciton modelling of the electrochromic pattern indicates that PD2is at least as likely as ChlD1to be responsible for the 726 nm absorption. The correspondence in sign and magnitude of the CD observed at 726 nm with that predicted from modelling favors PD2as the primary donor. The pros and cons of PD2vs ChlD1as the location of the FRL-primary donor are discussed.TOC GraphicHighlightsPrimary Donor confirmed at 726 nmDetermination of far-red chl pigment Qyexcitation positions, widths, CD and MCD amplitudesQuantification of electrochromic shifts and QA•-photoconversion yieldElectrochromic shift consistent with primary donor at either ChlD1or PD2The CD amplitude favors the primary donor at PD2
Genomic Epidemiology with Mixed Samples
Authors: Mäklin Tommi , Kallonen Teemu , Alanko Jarno , Samuelsen Ørjan , Hegstad Kristin , Mäkinen Veli , Corander Jukka , Heinz Eva , Honkela Antti 
Published: April 2020

AbstractGenomic epidemiology is a tool for tracing transmission of pathogens based on whole-genome sequencing. We introduce the mGEMS pipeline for genomic epidemiology with plate sweeps representing mixed samples of a target pathogen, skipping the colony pick step. The pipeline includes the novel mGEMS read binner for probabilistic assignments of sequencing reads, and the scalable pseudoaligner Themisto. We demonstrate the effectiveness of our approach using closely related samples in a nosocomial setting, obtaining results that are comparable to those based on colony picks. Our results lend firm support to more widespread consideration of genomic epidemiology with mixed infection samples.
Multi-dimensional tuning in motor cortical neurons during active behavior
Authors: Yuan Rachel C. , Bottjer Sarah W. 
Published: April 2020

ABSTRACTA region within songbird cortex, AId (dorsal intermediate arcopallium), is functionally analogous to motor cortex in mammals and has been implicated in vocal learning during development. AId thus serves as a powerful model for investigating motor cortical contributions to developmental skill learning. We made extracellular recordings in AId of freely behaving juvenile zebra finches and evaluated neural activity during diverse motor behaviors throughout entire recording sessions, including song production as well as hopping, pecking, preening, fluff-ups, beak interactions with cage objects, scratching, and stretching. A large population of single neurons showed significant modulation of activity during singing relative to quiescence. In addition, AId neurons demonstrated heterogeneous response patterns that were evoked during multiple movements, with single neurons often demonstrating excitation during one movement type and suppression during another. Lesions of AId do not disrupt vocal motor output or impair generic movements, suggesting that the responses observed during active behavior do not reflect direct motor drive. Consistent with this idea, we found that some AId neurons showed differential activity during pecking movements depending on the context in which pecks occurred, suggesting that AId circuitry encodes diverse inputs beyond generic motor parameters. Moreover, we found evidence of neurons that did not respond during discrete movements but were nonetheless modulated during active behavioral states compared to quiescence. Taken together, our results support the idea that AId neurons are involved in sensorimotor integration of external sensory inputs and/or internal feedback cues to help modulate goal-directed behaviors.SIGNIFICANCE STATEMENTMotor cortex across taxa receives highly integrated, multi-modal information and has been implicated in both execution and acquisition of complex motor skills, yet studies of motor cortex typically employ restricted behavioral paradigms that target select movement parameters, preventing wider assessment of the diverse sensorimotor factors that can affect motor cortical activity. Recording in AId of freely behaving juvenile songbirds that are actively engaged in sensorimotor learning offers unique advantages for elucidating the functional role of motor cortical neurons. The results demonstrate that a diverse array of factors modulate motor cortical activity and lay important groundwork for future investigations of how multi-modal information is integrated in motor cortical regions to contribute to learning and execution of complex motor skills.
A Mechanistic Investigation into Ischemia-Driven Distal Recurrence of Glioblastoma
Authors: Curtin Lee , Hawkins-Daarud Andrea , Porter Alyx B. , van der Zee Kristoffer G. , Owen Markus R. , Swanson Kristin R. 
Published: April 2020

AbstractGlioblastoma (GBM) is the most aggressive primary brain tumor with a short median survival. Tumor recurrence is a clinical expectation of this disease and usually occurs along the resection cavity wall. However, previous clinical observations have suggested that in cases of ischemia following surgery, tumors are more likely to recur distally. Through the use of a previously established mechanistic model of GBM, the Proliferation Invasion Hypoxia Necrosis Angiogenesis (PIHNA) model, we explore the phenotypic drivers of this observed behavior. We have extended the PIHNA model to include a new nutrient-based vascular efficiency term that encodes the ability of local vasculature to provide nutrients to the simulated tumor. The extended model suggests sensitivity to a hypoxic microenvironment and the inherent migration and proliferation rates of the tumor cells are key factors that drive distal recurrence.
Sleep spindles preferentially consolidate weakly encoded memories
Authors: Denis Dan , Mylonas Dimitrios , Poskanzer Craig , Bursal Verda , Payne Jessica D. , Stickgold Robert 
Published: April 2020

AbstractSleep has been shown to be critical for memory consolidation, with some research suggesting that certain memories are prioritized for consolidation. Initial strength of a memory appears to be an important boundary condition in determining which memories are consolidated during sleep. However, the role of consolidation-mediating oscillations, such as sleep spindles and slow oscillations, in this preferential consolidation has not been explored. Here, 54 human participants (76% female) studied pairs of words to three distinct encoding strengths, with recall being tested immediately following learning and again six hours later. Thirty-six had a two-hour nap opportunity following learning, whilst the remaining 18 remained awake throughout. Results showed that across six hours awake, weakly encoded memories deteriorated the fastest. In the nap group however, this effect was attenuated, with forgetting rates equivalent across encoding strengths. Within the nap group, consolidation of weakly encoded items was associated with fast sleep spindle density during non-rapid eye movement sleep. Moreover, sleep spindles that were coupled to slow oscillations predicted the consolidation of weak memories independently of uncoupled sleep spindles. These relationships were unique to weakly encoded items, with spindles not correlating with memory for intermediate or strong items. This suggests that sleep spindles facilitate memory consolidation, guided in part by memory strength.Significance statementGiven the countless pieces of information we encode each day, how does the brain select which memories to commit to long-term storage? Sleep is known to aid in memory consolidation, and it appears that certain memories are prioritized to receive this benefit. Here, we found that compared to staying awake, sleep was associated with better memory for weakly encoded information. This suggests that sleep helps attenuate the forgetting of weak memory traces. Fast sleep spindles, a hallmark oscillation of non-rapid eye movement sleep, mediate consolidation processes. We extend this to show that fast spindles were uniquely associated with the consolidation of weakly encoded memories. This provides new evidence for preferential sleep-based consolidation and elucidate a physiological correlate of this benefit.
The lateral entorhinal cortex is a hub for local and global dysfunction in pre-tauopathy states
Authors: Mandino Francesca , Yeow Ling Yun , Bi Renzhe , Sejin Lee , Bae Han Gyu , Baek Seung Hyun , Lee Chun-Yao , Mohammad Hasan , Teoh Chai Lean , Horien Corey , Lee Jasinda H. , Lai Mitchell K. P. , Jung Sangyong , Fu Yu , Olivo Malini , Gigg John , Grandjean Joanes 
Published: April 2020

AbstractFunctional network activity alterations are one of the earliest hallmarks of Alzheimer’s disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.