bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Audibility of Low Vision Devices with Speech Output Used by Older Adults with Dual Sensory Impairment
Authors: St-Amour Lorie , Jarry Jonathan , Wittich Walter 
Published: May 2019

SIGNIFICANCE
The successful uptake, integration, and use of vision rehabilitation devices with speech output depend to a large part on their audibility. However, individuals with combined vision and hearing impairments are at a disadvantage when using devices that do not consider multiple impairments.

PURPOSE
Sensory rehabilitation for individuals with combined vision and hearing impairment often relies on the use of assistive technology devices that use speech outputs (e.g., talking clock), but in individuals with dual impairment, their use is likely compromised by a concurrent hearing loss. The goal of this study was to evaluate the audibility of these devices in a population of individuals with acquired dual sensory impairment.

METHODS
We measured the ability to correctly repeat speech output presented by three assistive technology devices (talking watch, calculator, scanner) and confidence levels in response accuracy in 24 participants with visual impairment only and in 22 individuals with dual sensory loss. Stimuli were presented at three volumes that were repeated one or four times. Participants were placed at a fixed distance of 74 cm from the sound source.

RESULTS
The pattern of results was similar across the different devices, whereby an interaction of volume and repetition indicated that participants' accuracy to repeat a phrase and their confidence in their response improved with increasing volume, but more so at higher numbers of repetition (P < .05; ω2, from 0.005 to 0.298). Participants with dual sensory loss generally had lower accuracy and confidence.

CONCLUSIONS
Scores and confidence levels being very low across devices and users suggest that even participants with normal hearing for their age experienced a certain level of difficulty understanding speech output, confirming the need for better assistive technology device design.
Palmitoylation controls the stability of 190 kDa Ankyrin-G in dendritic spines and is regulated by ZDHHC8 and lithium
Authors: Piguel Nicolas H. , Shaun S. Sanders , DeSimone Francesca I. , Martin-de-Saavedra Maria D. , McCoig Emmarose , Dionisio Leonardo E. , Smith Katharine R. , Thomas Gareth M. , Penzes Peter 
Published: May 2019

AbstractAnkG, encoded by theANK3gene, is a multifunctional scaffold protein with complex isoform expression: the 480 kDa and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. TheANK3gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorders and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown. Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium. Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDDHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.
Spliced peptides and cytokine driven changes in the immunopeptidome of melanoma
Authors: Faridi Pouya , Woods Katherine , Ostrouska Simone , Deceneux Cyril , Aranha Ritchlynn , Duscharla Divya , Wong Stephen Q. , Chen Weisan , Ramarathinam Sri , Lim Kam Sian Terry C.C. , Croft Nathan P. , Li Chen , Ayala Rochelle , Cebon Jonathan , Purcell Anthony W. , Schittenhelm Ralf B. , Behren Andreas 
Published: May 2019

SummaryAntigen-recognition by CD8+ T cells is governed by the pool of peptide antigens presented on the cell surface in the context of HLA class I complexes. Recent studies have shown not only a high degree of plasticity in the immunopeptidome, but also that a considerable fraction of all presented peptides is generated through proteasome-mediated splicing of non-contiguous regions of proteins to form novel peptide antigens. Here we used high-resolution mass-spectrometry combined with new bioinformatic approaches to characterize the immunopeptidome of melanoma cells in the presence or absence of interferon-γ. In total, we identified more than 60,000 peptides from a single patient derived cell line (LM-MEL-44) and demonstrated that interferon-γ induced marked changes in the peptidome with an overlap of only ∼50% between basal and treated cells. Around 6-8% of the peptides were identified as cis-spliced peptides, and 2213 peptides (1827 linear, 386 cis-spliced peptides) were derived from known melanoma-associated antigens. These peptide antigens were equally distributed between the constitutive and interferon-γ induced peptidome. We next examined additional HLA-matched patient derived cell lines to investigate how frequently these peptides were identified and found that a high proportion of both linear and spliced peptides were conserved between individual patient tumors, drawing on data amassing to over 100,000 peptide sequences from these extended data sets. Moreover, several of these peptides showed in vitro immunogenicity across multiple melanoma patients. These observations highlight the breadth and complexity of the repertoire of immunogenic peptides that can be exploited therapeutically and suggest that spliced peptides are a major new class of tumor antigens.
APOL1 is not expressed in proximal tubules and is not filtered
Authors: Blessing Natalya A. , Wu Zhenzhen , Madhavan Sethu , Shin Myung K. , Hoek Maarten , Sedor John R. , O’Toole John F. , Bruggeman Leslie A. 
Published: May 2019

AbstractThe kidney expression pattern of APOL1 was examined using both protein and mRNAin situmethods onAPOL1bacterial artificial chromosome transgenic mice, with and without proteinuria. APOL1 was detected in podocytes and endothelial cells of the kidney, but was not expressed in tubular epithelia, nor was plasma APOL1 protein filtered and reabsorbed by the proximal tubule. APOL1 expression in podocytes and endothelia should remain the focus for mechanistic studies of APOL1-mediated pathogenesis.
Yeast surface display of full-length human microtubule-associated protein tau
Authors: Wang Shiyao , Cho Yong Ku 
Published: May 2019

AbstractMicrotubule-associated protein tau is an intrinsically-disordered, highly soluble protein found primarily in neurons. Under normal conditions, tau regulates the stability of axonal microtubules and intracellular vesicle transport. However, in patients of neurodegeneration such as Alzheimer’s disease (AD), tau forms neurofibrillary deposits, which correlates well with the disease progression. Identifying molecular signatures in tau, such as post-translational modification, truncation, and conformational change has great potential to detect earliest signs of neurodegeneration, and develop therapeutic strategies. Here we show that full-length human tau, including the longest isoform found in the adult brain can be robustly displayed on the surface of yeastSaccharomyces cerevisiae. Yeast-displayed tau binds to anti-tau antibodies that cover epitopes ranging from the N-terminus to the 4R repeat region. Unlike tau expressed in the yeast cytosol, surface-displayed tau was not phosphorylated at sites found in AD patients (probed by antibodies AT8, AT270, AT180, PHF-1). However, yeast-displayed tau showed clear binding to paired helical filament (PHF) tau conformation-specific antibodies Alz-50, MC-1, and Tau-2. Although the tau possessed a conformation found in PHFs, oligomerization or aggregation into larger filaments were undetected. Taken together, yeast-displayed tau enables robust measurement of protein interactions, and is of particular interest for characterizing conformational change.
Reduced Permeability to Rifampicin by Capsular Thickening as a Mechanism of Antibiotic Persistence inMycobacterium tuberculosis
Authors: Sebastian Jees , Swaminath Sharmada , Ajitkumar Parthasarathi 
Published: May 2019

ABSTRACTPersisters constitute a subpopulation of bacteria that can tolerate lethal concentrations of antibiotics. Multiple mechanisms have been suggested for bacterial persistence against antibiotics. With mycobacteria being no exception to this behaviour, we had reported thede novoemergence of genetically antibiotic-resistantMycobacterium tuberculosisfrom persister cells upon prolonged exposure to microbicidal concentrations of the anti-tuberculosis drugs, rifampicin and moxifloxacin. Here, we present evidence for reduced permeability to rifampicin as a mechanism for persistence ofMycobacterium tuberculosis in vitro. We observed that rifampicin persistentM. tuberculosiscells developed a thick outer layer (TOL) capsule. The TOL restricted the entry of fluorochrome-conjugated rifampicin, 5-carboxyfluorescein-rifampicin (5-FAM-rifampicin), which retained only 2.5% of its original bactericidal activity, but high levels of permeability, on actively growing mid-log phase cells. Gentle mechanical removal of TOL significantly enhanced 5-FAM-rifampicin entry into the persister cells. The level of 5-FAM-rifampicin in the persister cells was not affected by the pre-incubation of the cells with verapamil, a drug efflux pump inhibitor, ruling out the involvement of efflux pumps in the reduced intracellular concentration of 5-FAM-rifampicin. GC-MS analysis of TOL showed the presence of ∼7-fold, ∼5-fold and ∼2- fold higher levels of α-D-glucopyranoside, 1,2,5-linked-mannitol, and 3,4-linked mannose, respectively, among ∼2-fold higher levels of derivatives of several other types of sugars such as arabinose and galactose. Taken together, the present study reveals that rifampicin-persistentM. tuberculosiscells develop TOL that enables the bacilli to restrict entry of rifampicin and thereby remain tolerant to the antibioticin vitro.
Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia
Authors: Kaiser Tobias , Feng Guoping 
Published: May 2019

AbstractMicroglia are specialized brain-resident macrophages with important functions in health and disease. To improve our understanding of these cells, the research community needs genetic tools to identify and control them in a manner that distinguishes them from closely related cell-types. We have targeted the recently discovered microglia-specific Tmem119 gene to generate knock-in mice expressing EGFP (JAX#031823) or CreERT2 (JAX#031820) for the identification and manipulation of microglia, respectively. Genetic characterization of the locus and qPCR-based analysis demonstrate correct positioning of the transgenes and intact expression of endogenous Tmem119 in the knock-in mouse models. Immunofluorescence analysis further shows that parenchymal microglia, but not other brain macrophages, are completely and faithfully labeled in the EGFP-line at different time points of development. Flow cytometry indicates highly selective expression of EGFP in CD11b+CD45lo microglia. Similarly, immunofluorescence and flow cytometry analyses using a Cre-dependent reporter mouse line demonstrate activity of CreERT2 primarily in microglia upon tamoxifen administration with the caveat of activity in leptomeningeal cells. Finally, flow cytometric analyses reveal absence of EGFP expression and minimal activity of CreERT2 in blood monocytes of the Tmem119-EGFP and Tmem119-CreERT2 lines, respectively. These new transgenic lines extend the microglia toolbox by providing the currently most specific genetic labeling and control over these cells in the myeloid compartment of mice.Visual abstractSignificance statementTools that specifically label and manipulate only microglia are currently unavailable, but are critically needed to further our understanding of this cell type. Complementing and significantly extending recently introduced microglia-specific immunostaining methods that have quickly become a new standard in the field, we generated two mouse lines that label and control gene expression in microglia with high specificity and made them publicly available. Using these readily accessible mice, the research community will be able to study microglia biology with improved specificity.
Prostate-Specific Antigen Dynamics Predict Individual Responses to Intermittent Androgen Deprivation
Authors: Brady Renee , Nagy John D. , Gerke Travis A. , Zhang Tian , Wang Andrew Z. , Zhang Jingsong , Gatenby Robert A. , Enderling Heiko 
Published: May 2019

AbstractBackgroundIntermittent androgen deprivation therapy (IADT) is an attractive treatment approach for biochemically recurrent prostate cancer (PCa), whereby cycling treatment on and off can reduce cumulative dose, limit toxicities, and delay development of treatment resistance. To optimize treatment within the context of ongoing intratumoral evolution, underlying mechanisms of resistance and actionable biomarkers need to be identified.MethodsWe have developed a quantitative framework to simulate enrichment of prostate cancer stem cell (PCaSC) dynamics during treatment as a plausible mechanism of resistance evolution.ResultsSimulated dynamics of PCaSC and non-stem cancer cells demonstrate that stem cell proliferation patterns correlate with longitudinal serum prostate-specific antigen (PSA) measurements in 70 PCa patients undergoing multiple cycles of IADT. By learning the dynamics from each treatment cycle, individual model simulations predict evolution of resistance in the subsequent IADT cycle with a sensitivity and specificity of 57% and 94%, respectively and an overall accuracy of 90%. Additionally, we evaluated the potential benefit of docetaxel for IADT in biochemically recurrent PCa. Model simulations based on response dynamics from the first IADT cycle identify patients who would or would not benefit from concurrent docetaxel in subsequent cycles.ConclusionOur results demonstrate the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics continuously updated with each treatment cycle.Translational RelevanceCompared to continuous androgen deprivation therapy, intermittent androgen deprivation (IADT) has been shown to reduce toxicity and delay time to progression in prostate cancer. While numerous mathematical models have been developed to study the response to both continuous and intermittent androgen deprivation, very few have identified actionable biomarkers of resistance and exploited them to predict how patients will or will not respond to subsequent treatment. Here, we identify prostate-specific antigen (PSA) dynamics as the first such biomarker. Mechanistic mathematical modeling of prostate cancer stem cell dynamics that dictate prostate-specific antigen serum levels predicts individual responses to IADT with 90% overall accuracy and can be used to develop patient-specific adaptive treatment protocols, and potentially identify patients that may benefit from concurrent chemotherapy. Model results demonstrate the feasibility and potential value of adaptive clinical trials guided by patient-specific mathematical models of intratumoral evolutionary dynamics continuously updated with each treatment cycle.
Mammalian NSUN2 introduces 5-methylcytidines into mitochondrial tRNAs
Authors: Shinoda Saori , Kitagawa Sho , Nakagawa Shinichi , Wei Fan-Yan , Tomizawa Kazuhito , Araki Kimi , Araki Masatake , Suzuki Takeo , Suzuki Tsutomu 
Published: May 2019

ABSTRACTPost-transcriptional modifications in mitochondrial tRNAs (mt-tRNAs) play critical roles in mitochondrial protein synthesis, which produces respiratory chain complexes. In this study, we used mass spectrometric analysis to map 5-methylcytidine (m5C) at positions 48–50 in eight mouse and six human mt-tRNAs. We also confirmed the absence of m5C in mt-tRNAs isolated fromNsun2knockout (KO) mice, as well as fromNSUN2KO human culture cells. In addition, we successfully reconstituted m5C at positions 48–50 of mt-tRNAin vitrowith NSUN2 protein in the presence ofS-adenosylmethionine (SAM). Although NSUN2 is predominantly localized to the nucleus and introduces m5C into cytoplasmic tRNAs and mRNAs, structured illumination microscopy (SIM) clearly revealed NSUN2 foci inside mitochondria. These observations provide novel insights into the role of NSUN2 in the physiology and pathology of mitochondrial functions.
Simulations of particle tracking in the oligociliated mouse node and implications for left-right symmetry breaking mechanics
Authors: Gallagher M.T. , Montenegro-Johnson T.D. , Smith D.J. 
Published: May 2019

AbstractThe concept of internal anatomical asymmetry is familiar; usually in humans the heart is on the left and the liver is on the right, however how does the developing embryo know to produce this consistent laterality? Symmetry breaking initiates with left-right asymmetric cilia-driven fluid mechanics in a small fluid-filled structure called the ventral node in mice. However the question of what converts this flow into left-right asymmetric development remains unanswered. A leading hypotheses is that flow transports morphogen containing vesicles within the node, the absorption of which results in asymmetrical gene expression. To investigate how vesicle transport might result in the situs patterns observed in wildtype and mutant experiments, we extend the open source Stokes flow package, NEAREST, to consider the hydrodynamic and Brownian motion of particles in a mouse model with flow driven by one, two, and 112 beating cilia.Three models for morphogen-containing particle released are simulated to assess their compatibility with observed results in oligociliated and wildtype mouse embryos: uniformly random release, localised cilium stress induced release, and localised release from motile cilia themselves. Only the uniformly random release model appears consistent with the data, with neither localised-release model resulting in significant transport in the oligociliated embryo.
Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression
Authors: Co Marissa , Hickey Stephanie L. , Kulkarni Ashwinikumar , Harper Matthew , Konopka Genevieve 
Published: May 2019

AbstractGenetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper-layer neurons and interneurons. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to neurodevelopmental disorders.
Bacteria isolated from bengal cat (Felis catus×Prionailurus bengalensis) anal sac secretions produce volatile compounds associated with animal signaling
Authors: Yamaguchi Mei S. , Ganz Holly H. , Cho Adrienne W. , Zaw Thant H. , Jospin Guillaume , McCartney Mitchell M. , Davis Cristina E. , Eisen Jonathan A. , Coil David A. 
Published: May 2019

AbstractAnal sacs are an important odor producing organ found across the mammalian Order Carnivora. Secretions from the anal sac may be used as chemical signals by animals for behaviors ranging from defense to species recognition to signaling reproductive status. In addition, a recent study suggests that domestic cats utilize short-chain free fatty acids in anal sac secretions for individual recognition. The fermentation hypothesis is the idea that symbiotic microorganisms living in association with animals contribute to odor profiles used in chemical communication and that variation in these chemical signals reflects variation in the microbial community. Here we examine the fermentation hypothesis by characterizing volatile organic compounds (VOC) and bacteria isolated from anal sac secretions collected from a male bengal cat, a cross between a domestic cat and wild leopard cat (Felis catus×Prionailurus bengalensis).Both left and right anal sacs of a male bengal cat were manually expressed (emptied) and collected. Half of the material was used to culture bacteria or to extract bacterial DNA and other half was used for VOC analysis. DNA was extracted from the anal sac secretions and used for a 16S rRNA gene sequence based characterization of the microbial community. Additionally, some of the material was plated out in order to isolate bacterial colonies. The same three taxa,Bacteroides fragilis,Tessaracoccus, andFinegoldia magnawere abundant in the 16S rRNA gene sequence data and also isolated by culturing. Using Solid Phase Microextraction (SPME) gas chromatography-mass spectrometry (GC-MS), we tentatively identified 52 compounds from bengal cat anal sac secretions and 67 compounds from cultures of the three bacterial isolates chosen for further analysis.. Among 67 compounds tentatively identified from bacteria isolates, 52 were also found in the anal sac secretion.We show that the bacterial community in the anal sac consists primarily of only a few abundant taxa and that isolates of these taxa produce numerous volatiles that are found in the combined anal sac volatile profile. Many of these volatiles are found in anal sac secretions from other carnivorans, and are also associated with known bacterial biosynthesis pathways. This supports the fermentation hypothesis and the idea that the anal sac is maintained at least in part to house bacteria that produce volatiles for the host.
Uncovering the subtype-specific temporal order of cancer pathway dysregulation
Authors: Khakabmamaghani Sahand , Ding Dujian , Snow Oliver , Ester Martin 
Published: May 2019

AbstractCancer is driven by genetic mutations that dysregulate pathways important for proper cell function. Therefore, discovering these cancer pathways and their dysregulation order is key to understanding and treating cancer. However, the heterogeneity of mutations between different individuals makes this challenging and requires that cancer progression is studied in a subtype-specific way. To address this challenge, we provide a mathematical model, called Subtype-specific Pathway Linear Progression Model (SPM), that simultaneously captures cancer subtypes and pathways and order of dysregulation of the pathways within each subtype. Experiments with synthetic data indicate the robustness of SPM to problem specifics including noise compared to an existing method. Moreover, experimental results on glioblastoma multiforme and colorectal adenocarcinoma show the consistency of SPM’s results with the existing knowledge and its superiority to an existing method in certain cases. The implementation of our method is available at https://github.com/Dalton386/SPM.