bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfer Learning for Predicting Conversion from Mild Cognitive Impairment to Dementia of Alzheimer’s Type based on 3D-Convolutional Neural Network
Authors: Bae Jinhyeong , Stocks Jane , Heywood Ashley , Jung Youngmoon , Jenkins Lisanne , Katsaggelos Aggelos , Popuri Karteek , Beg M. Faisal , Wang Lei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2019

AbstractDementia of Alzheimer’s Type (DAT) is associated with a devastating and irreversible cognitive decline. As a pharmacological intervention has not yet been developed to reverse disease progression, preventive medicine will play a crucial role for patient care and treatment planning. However, predicting which patients will progress to DAT is difficult as patients with Mild Cognitive Impairment (MCI) could either convert to DAT (MCI-C) or not (MCI-NC). In this paper, we develop a deep learning model to address the heterogeneous nature of DAT development. Structural magnetic resonance imaging was utilized as a single biomarker, and a three-dimensional convolutional neural network (3D-CNN) was developed. The 3D-CNN was trained using transfer learning from the classification of Normal Control and DAT scans at the source task. This was applied to the target task of classifying MCI-C and MCI-NC scans. The model results in 82.4% classification accuracy, which outperforms current models in the field. Furthermore, by implementing an occlusion map approach, we visualize key brain regions that significantly contribute to the prediction of MCI-C and MCI-NC. Results show the hippocampus, amygdala, cerebellum, and pons regions as significant to prediction, which are consistent with current understanding of disease. Finally, the model’s prediction value is significantly correlated with rates of change in clinical assessment scores, indicating the model is able to predict an individual patient’s future cognitive decline. This information, in conjunction with the identified anatomical features, will aid in building a personalized therapeutic strategy for individuals with MCI. This model could also be useful for selection of participants for clinical trials.
Metastasis-specific gene expression in autochthonous and allograft mouse mammary tumor models: stratification and identification of targetable signatures
Authors: Ross Christina , Szczepanek Karol , lee Maxwell , Yang Howard , Peer Cody J. , Kindrick Jessica , Shankarappa Priya , Lin Zhi-Wei , Sanford Jack , Figg William D. , Hunter Kent 
Published: December 2019

AbstractBreast cancer is a leading cause of cancer-related death of women in the U.S., which is ultimately due to metastasis rather than primary tumor burden. Therefore, increased understanding of metastasis to develop novel therapies is critical in reducing breast cancer-related mortality. Indeed, a major hurdle in advancing metastasis-targeted intervention is the genotypic and phenotypic heterogeneity that exists between primary and secondary lesions. To identify targetable metastasis-specific gene expression profiles we performed RNA sequencing of breast cancer metastasis mouse models. We analyzed metastases from models of various oncogenic drivers and routes, including orthotopic injection, tail vein injection, intracardiac injection, and genetically engineered mouse models (GEMMs). Herein, we analyzed samples from 176 mice and tissue culture samples, resulting in 338 samples total. Using these data, we contrasted the different breast cancer metastasis models, and also identified common, targetable metastasis specific gene expression signatures.Principal component analysis revealed that mouse model (Allograft v. GEMM) rather than tissue source (PT v metastatic nodule) shaped the transcriptomes of our samples. Allograft models exhibited more mesenchymal-like gene expression than GEMM models, and primary culturing of GEMM-derived metastatic tissue induced more mesenchymal-like gene expression. Furthermore, metastasis-specific gene expression differed between tail vein and orthotopic injection models of the same cell line, the degree of which was cell line dependent. Finally, we examined metastasis-specific gene expression common to models of spontaneous metastasis (orthotopic injection and GEMMs). Pathway analysis identified upregulation of the sildenafil response, and nicotine degradation pathways. The influence of these pathways on metastatic spread was assessed by treatment of allograft models with clinically relevant dosing of sildenafil or nicotine. Sildenafil significantly reduced pulmonary metastasis while nicotine administration significantly increased metastasis, and neither regimen altered primary tumor mass. Taken together our data reveals critical differences between pre-clinical models of metastatic breast cancer. Additionally, this strategy has identified clinically targetable metastasis-specific pathways integral to metastatic spread.
Multiplexed imaging of nucleome architectures in single cells of mammalian tissue
Authors: Liu Miao , Lu Yanfang , Yang Bing , Chen Yanbo , Radda Jonathan S.D. , Hu Mengwei , Katz Samuel G. , Wang Siyuan 
Published: December 2019

AbstractThe three-dimensional architecture of the genome affects genomic functions. Multiple genome architectures at different length scales, including chromatin loops, domains, compartments, and regions associated with nuclear lamina and nucleoli, have been discovered. However, how these structures are arranged in the same cell and how they are correlated with each other in different cell types in mammalian tissue are largely unknown. Here, we developed Multiplexed Imaging of Nucleome Architectures that measures multiscale chromatin folding, copy numbers of numerous RNA species, and associations of numerous genomic regions with nuclear lamina, nucleoli and surface of chromosomes in the same, single cells. We applied this method in mouse fetal liver, and identifiedde novocell-type-specific chromatin architectures associated with gene expression, as well as chromatin organization principles independent of cell type. Polymer simulation showed that both intra-chromosomal phase-separating interactions and extra-chromosomal interactions are necessary to establish the observed organization. Our experiments and modeling provide a multiscale and multi-faceted picture of chromatin folding and nucleome architectures in mammalian tissue and illustrate physical principles for maintaining chromatin organization.
QuantifiableIn VivoImaging Biomarkers of Retinal Regeneration by Photoreceptor Cell Transplantation
Authors: Liu Ying V. , Sodhi Simrat , Xue Gilbert , Teng Derek , Agakishiev Dzhalal , McNally Minda M. , Harris-Bookman Sarah , McBride Caitlin , Konar Gregory , Singh Mandeep S. 
Published: December 2019

AbstractPurposeShort-term improvements in retinal anatomy are known to occur in preclinical models of photoreceptor transplantation. However, correlative changes over the long term are poorly understood. We aimed to develop a quantifiable imaging biomarker grading scheme, using non-invasive multimodal confocal scanning laser ophthalmoscopy (cSLO) imaging, to enable serial evaluation of photoreceptor transplantation over the long term.MethodsYellow-green fluorescent microspheres were transplanted into the vitreous cavity and/or subretinal space ofC57/BL6Jmice. Photoreceptor cell suspensions or sheets from rhodopsin-green fluorescent protein mice were transplanted subretinally, into eitherNOD.CB17-Prkdcscid/JorC3H/HeJ-Pde6brd1mice. Multimodal cSLO imaging was performed serially for up to three months after transplantation. Imaging biomarkers were scored, and a grade was defined for each eye by integrating the scores. Image grades were correlated with immunohistochemistry (IHC) data.ResultsMultimodal imaging enabled the extraction of quantitative imaging biomarkers including graft size, GFP intensity, graft length, on-target graft placement, intra-graft lamination, hemorrhage, retinal atrophy, and peri-retinal proliferation. Migration of transplanted material was observed. Changes in biomarker scores and grades were detected in 13/16 and 7/16 eyes, respectively. A high correlation was found between image grades and IHC parameters.ConclusionsSerial evaluation of multiple imaging biomarkers, when integrated into a per-eye grading scheme, enabled comprehensive tracking of longitudinal changes in photoreceptor cell grafts over time. The application of systematic multimodalin vivoimaging could be useful in increasing the efficiency of preclinical retinal cell transplantation studies in rodents and other animal models.
The psychological correlates of distinct neural states occurring during wakeful rest
Authors: Karapanagiotidis Theodoros , Vidaurre Diego , Quinn Andrew J. , Vatansever Deniz , Poerio Giulia L. , Turnbull Adam , Ho Nerissa Siu Ping , Leech Robert , Bernhardt Boris C. , Jefferies Elizabeth , Margulies Daniel S. , Nichols Thomas E. , Woolrich Mark W. , Smallwood Jonathan 
Published: December 2019

AbstractWhen unoccupied by an explicit external task, humans engage in a wide range of different types of self-generated thinking. These are often unrelated to the immediate environment and have unique psychological features. Although contemporary perspectives on ongoing thought recognise the heterogeneity of these self-generated states, we lack both a clear understanding of how to classify the specific states, and how they can be mapped empirically. In the current study, we capitalise on advances in machine learning that allow continuous neural data to be divided into a set of distinct temporally re-occurring patterns, or states. We applied this technique to a large set of resting state data in which we also acquired retrospective descriptions of the participants’ experiences during the scan. We found that two of the identified states were predictive of patterns of thinking at rest. One state highlighted a pattern of neural activity commonly seen during demanding tasks, and the time individuals spent in this state was associated with descriptions of experience focused on problem solving in the future. A second state was associated with patterns of activity that are commonly seen under less demanding conditions, and the time spent in it was linked to reports of negative rumination. Finally, we found that these two neural states tended to fall at either end of a neural hierarchy that is thought to reflect the brain’s response to cognitive demands. Together, these results demonstrate that approaches which take advantage of time-varying changes in neural function can play an important role in understanding the repertoire of self-generated states. Moreover, they establish that important features of self-generated ongoing experience are related to variation along a similar vein to those seen when the brain responds to cognitive task demands.
Visual self-motion cues are impaired in Parkinson’s disease yet over-weighted during visual-vestibular integration
Authors: Yakubovich Sol , Israeli-Korn Simon , Halperin Orly , Yahalom Gilad , Hassin-Baer Sharon , Zaidel Adam 
Published: December 2019

AbstractBackgroundParkinson’s disease (PD) is prototypically a movement disorder. Although perceptual and motor functions are interdependent, much less is known about perceptual dysfunction in PD. Perceptual deficits can impact activities of daily living, and contribute to motor symptoms, but might go unnoticed if not tested directly. Posture, gait and balance, affected in PD, rely on veridical perception of one’s own motion in space. Yet it is unknown whether self-motion perception is impaired in PD.ObjectivesTo test self-motion perception in PD, separately for visual and vestibular cues (unisensory), and multisensory integration thereof.MethodsParticipants (19 early stage PD, 23 age-matched and 20 young adult controls) experienced vestibular (motion platform), visual (optic flow), and combined visual-vestibular self-motion stimuli, and discriminated whether the stimulus headings were rightward or leftward of straight ahead. PD participants and age-matched controls were tested on two visits (PD on and off medication).ResultsPD participants had significantly impaired visual self-motion perception, both on and off medication. This deficit correlated significantly with clinical disease severity. By contrast, their vestibular performance was unimpaired. Remarkably, despite impaired visual self-motion perception, PD participants significantly over-weighted visual cues during multisensory (visual-vestibular) integration.ConclusionsSelf-motion perception is affected already in early stage PD, specifically by impaired visual (vs. vestibular) function, and by suboptimal visual-vestibular integration. This may contribute to impaired balance and gait control. Future investigation into this connection might open up new avenues for alternative therapies to better treat these symptoms. Furthermore, these results may also impact early PD diagnosis and subtyping.
Role of HP1β during spermatogenesis and DNA replication
Authors: Charaka Vijaya , Tiwari Anjana , Pandita Raj K , Hunt Clayton R , Pandita Tej K. 
Published: December 2019

AbstractMaintaining genomic stability in a continually dividing cell population requires accurate DNA repair, especially in male germ cells. Repair and replication protein access to DNA, however, is complicated by chromatin compaction. The HP1β chromatin protein, encoded byCbx1, is associated with chromatin condensation but its role in meiosis is not clear. To investigate the role ofCbx1 in male germ cells, we generated testis specificCbx1 deficient transgenic mice by crossingCbx1flox/flox(Cbx1f/f) mice with Stra8Cre+/−mice. Loss ofCbx1 in testes adversely affected sperm maturation andCbx1 deletion increased seminiferous tubule degeneration and basal level DNA damage., We observed thatCbx1−/−MEF cells displayed reduced resolution of stalled DNA replication forks as well as decreased fork restart, indicating defective DNA synthesis. Taken together, these results suggest that loss ofCbx1 in growing cells leads to DNA replication defects and associated DNA damage that impact cell survival.
SCSA: a cell type annotation tool for single-cell RNA-seq data
Authors: Cao Yinghao , Wang Xiaoyue , Peng Gongxin 
Published: December 2019

AbstractCurrently most methods take manual strategies to annotate cell types after clustering the single-cell RNA sequencing (scRNA-seq) data. Such methods are labor-intensive and heavily rely on user expertise, which may lead to inconsistent results. We present SCSA, an automatic tool to annotate cell types from scRNA-seq data, based on a score annotation model combining differentially expressed genes (DEGs) and confidence levels of cell markers from both known and user-defined information. Evaluation on real scRNA-seq datasets from different sources with other methods shows that SCSA is able to assign the cells into the correct types at a fully automated mode with a desirable precision.
Multimodal Learning of Pheromone Locations
Authors: Pardasani Meenakshi , Marathe Shruti D. , Purnapatre Maitreyee Mandar , Dalvi Urvashi , Abraham Nixon M. 
Published: December 2019

AbstractMemorizing pheromonal locations is critical for many mammalian species as it involves finding mates and avoiding competitors. In rodents, pheromonal information is perceived by the main and accessory olfactory systems. However, the role of somatosensation in context dependent learning and memorizing of pheromone locations remains unexplored. We addressed this problem by training female mice on a multimodal task to locate pheromones by sampling volatiles emanating from male urine through the orifices of varying dimensions or shapes that are sensed by their vibrissae. In this novel pheromone location assay, female mice’ preference towards male urine scent decayed over time when they were permitted to explore pheromones v/s neutral stimuli, water. On training them for the associations involving olfactory and whisker systems, it was established that they were able to memorize the location of opposite sex pheromones, when tested 15 days later. This memory was not formed either when the somatosensory inputs through whisker pad were blocked or when the pheromonal cues were replaced with that of same sex. The association between olfactory and somatosensory systems were further confirmed by the enhanced expression of the Activity regulated cytoskeleton protein. Further, the activation of main olfactory bulb circuitry by pheromone volatiles did not cause any modulation in learning and memorizing non-pheromonal volatiles. Our study thus provides the evidence for associations formed between different sensory modalities facilitating the long-term memory formation relevant to social and reproductive behaviors.
Exaptation of two ancient immune proteins into a new dimeric pore-forming toxin in snails
Authors: Giglio M.L. , Ituarte S. , Milesi V. , Dreon M.S. , Brola T.R. , Caramelo J. , Ip J.C.H. , Maté S. , Qiu J.W. , Otero L.H. , Heras H. 
Published: December 2019

AbstractThe Membrane Attack Complex-Perforin (MACPF) family is ubiquitously found in all kingdoms. They have diverse cellular roles but MACPF but pore-forming toxic function are very rare in animals. Here we present the structure of PmPV2, a MACPF toxin from the poisonous apple snail eggs, that can affect the digestive and nervous systems of potential predators. We report the three-dimensional structure of PmPV2, at 15 Å resolution determined by negative stain electron microscopy (NS-EM) and its solution structure by small angle X-ray scattering (SAXS). We found that PV2s differ from nearly all MACPFs in two respects: it is a dimer in solution and protomers combine two immune proteins into an AB toxin. MACPF chain is linked by a single disulfide bond to a tachylectin chain, and two heterodimers are arranged head-to-tail by non-covalent forces in the native protein. MACPF domain is fused with a putative new Ct-accessory domain exclusive to invertebrates. Tachylectin is a six-bladed β-propeller, similar to animal tectonins. We experimentally validated the predicted functions of both subunits and demonstrated for the first time that PV2s are true pore-forming toxins. The tachylectin..B..delivery subunit would bind to target membranes, and then its MACPF..A..toxic subunit disrupt lipid bilayers forming large pores altering the plasma membrane conductance. These results indicate that PV2s toxicity evolved by linking two immune proteins where their combined preexisting functions give rise to a new toxic entity with a novel role in defense against predation. This structure is an unparalleled example of protein exaptation.
Field evaluation of DNA amplification of human filarial and malaria parasites using mosquito excreta/feces
Authors: Minetti Corrado , Pilotte Nils , Zulch Michael , Canelas Tiago , Tettevi Edward J. , Veriegh Francis B. D. , Osei-Atweneboana Mike Yaw , Williams Steven A. , Reimer Lisa J. 
Published: December 2019

AbstractBackgroundWe recently developed a superhydrophobic cone-based method for the collection of mosquito excreta/feces (E/F) for the molecular xenomonitoring of vector-borne parasites showing higher throughput compared to the traditional approach. To test its field applicability, we used this platform to detect the presence of filarial and malaria parasites in two villages of Ghana and compared results to those for detection in mosquito carcasses and human blood.Methodology and principal findingsWe compared the molecular detection of three parasites (Wuchereria bancrofti, Plasmodium falciparumandMansonella perstans) in mosquito E/F, mosquito carcasses and human blood collected from the same households in two villages in the Savannah Region of the country. We successfully detected the parasite DNA in mosquito E/F from indoor resting mosquitoes, includingW. bancroftiwhich had a very low community prevalence (2.5-3.8%). Detection in the E/F samples was concordant with detection in insect whole carcasses and people, and laboratory tests showed that the risk of mosquito carcass cross-contamination with positive excreta when insects are held together in the device is minimal.ConclusionsOur approach to collect and test mosquito E/F successfully detected a variety of parasites at varying prevalence in the human population under field conditions, including a pathogen (M. perstans) which is not transmitted by mosquitoes. The method shows promise for further development and applicability for the early detection and surveillance of a variety of pathogens carried in human blood.Author summaryMolecular xenomonitoring of parasites or viruses using mosquitoes as “flying syringes” is a promising and non-invasive tool for early detection and surveillance of various pathogens, particularly in low prevalence settings, but there is a need for cost-effective and higher throughput alternatives. We recently developed a novel approach based on the collection of mosquito excreta/feces (E/F) using a superhydrophobic cone that directs the sample into a tube at the bottom of the collection cup. We tested this method’s ability to detect the presence of lymphatic filariasis, malaria, and mansonellosis from households in two endemic rural communities of Ghana and compared it to the molecular detection from blood and mosquito carcass samples from corresponding households. The detection of parasite DNA in mosquito E/F was successful for all three pathogens, and it showed good concordance with the detection in the insects’ whole carcasses. Given the successful detection ofMansonella perstans, which is not transmitted by mosquitoes, our tool shows promise for use as an alternative method for the early and non-invasive detection and surveillance of various pathogens in human blood, including those not strictly mosquito-borne, in endemic settings.
A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition
Authors: Cocco Mario , Care Matthew A , Al-Maskari Muna , Doody Gina , Tooze Reuben 
Published: December 2019

AbstractThe activated B-cell (ABC) to plasmablast transition is the cusp of antibody secreting cell (ASC) differentiation but is incompletely defined. We apply expression time-courses, parsimonious gene correlation network analysis, and ChIP-seq to explore this in human cells. The transition initiates with input signal loss leading within hours from cell growth dominant programs to enhanced proliferation, accompanied from 24h by ER-stress response, secretory optimization and upregulation of ASC features. Clustering of genomic occupancy for ASC transcription factors (TFs) IRF4, BLIMP1 and XBP1 with CTCF and histone marks defines distinct patterns for each factor in plasmablasts. Integrating TF-associated clusters and modular gene expression identifies a dichotomy: XBP1 and IRF4 significantly link to gene modules induced in plasmablasts, but not to modules of repressed genes, while BLIMP1 links to modules of ABC genes repressed in plasmablasts but is not significantly associated with modules induced in plasmablasts. Pharmacological inhibition of the G9A (EHMT2) histone-methytransferase, a BLIMP1 co-factor that catalyzes repressive H3K9me2 marks, leaves functional ASC differentiation intact but de-represses ABC-state genes. Thus, in human plasmablasts IRF4 and XBP1 emerge as the dominant association with ASC gene expression, while BLIMP1 links to repressed modules with particular focus in repression of the B-cell activation state.