bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective Combination Immunotherapy using Oncolytic Viruses to Deliver CAR Targets to Solid Tumors
Authors: Park Anthony K. , Fong Yuman , Chen Nanhai G. , Jeang Brook , Tilakawardane Dileshni , Murad John P. , Kim Sang-In , Lu Jianming , Thomas Sandra H. , Forman Stephen J. , Priceman Saul J. 
Published: November 2019

AbstractChimeric antigen receptor (CAR)-engineered T cell therapy for solid tumors is limited by the lack of tumor-restricted and homogeneous expression of tumor antigens1,2. Therefore, we engineered an oncolytic virus to express a non-signaling, truncated CD19 (CD19t) protein for tumor-selective delivery, enabling targeting by CD19-specific CAR T cells. Infecting tumor cells with a chimeric oncolytic vaccinia virus coding for CD19t (OV19t) producedde novoCD19 surface-antigen expression prior to virus-mediated tumor lysis. Co-cultured CD19-CAR T cells secreted cytokines and elicited potent cytolytic activity against infected tumors. Using multiple mouse tumor models, intratumoral delivery of OV19t induced tumor expression of CD19t and improved tumor control following CD19-CAR T cell administration. CAR T cell–mediated tumor killing also promoted release of virus from dying tumor cells, which propogated tumor expression of CD19t. These data demonstrate a novel immunotherapy approach utilizing oncolytic viruses to promotede novoCAR T cell targeting of solid tumors.One Sentence SummaryWe describe a novel and effective combination immunotherapy utilizing oncolytic viruses to deliver de novo cell surface expression of CD19 antigen promoting CD19-CAR T cell anti-tumor responses against solid tumors.
Reduction of cybersickness during and immediately following noisy galvanic vestibular stimulation
Authors: Weech Séamas , Wall Travis , Barnett-Cowan Michael 
Published: November 2019

AbstractThe mechanism underlying cybersickness during virtual reality (VR) exposure is still poorly understood, although research has highlighted a causal role for visual-vestibular sensory conflict. Recently established methods for reducing cybersickness include galvanic vestibular stimulation (GVS) to mimic absent vestibular cues in VR, or vibration of the vestibular organs to add noise to the sensory modality. Here, we examined if applying noise to the vestibular system using noisy-current GVS also affects sickness severity in VR. Participants were exposed to one of two VR games that were classified as either moderate or intense with respect to their nauseogenic effects. The VR content lasted for 50 minutes and was broken down into 3 blocks: 30 minutes of gameplay during exposure to either noisy GVS (±1750 μA) or sham stimulation (0 μA), and 10 minutes of gameplay before and after this block. We characterized the effects of noisy GVS in terms of post-minus-pre-exposure cybersickness scores. For the intense VR content, we found a main effect of noisy vestibular stimulation. Participants reported lower cybersickness scores during and directly after exposure to GVS. However, this difference was quickly extinguished (∼3-6 min) after further exposure to VR, indicating that sensory adaptation did not persist after stimulation was terminated. In contrast, there were no differences between the sham and GVS group for the moderate VR content. The results show the potential for reducing cybersickness with simple non-invasive sensory stimulation. We discuss the prospect that noise-induced sensory re-weighting is responsible for the observed effects, and address other possible mechanisms.
Resist or perish: fate of a microbial population subjected to a periodic presence of antimicrobial
Authors: Marrec Loïc , Bitbol Anne-Florence 
Published: November 2019

AbstractThe evolution of antimicrobial resistance can be strongly affected by variations of antimicrobial concentration. Here, we study the impact of periodic alternations of absence and presence of antimicrobial on resistance evolution in a microbial population, using a stochastic model that includes variations of both population composition and size, and fully incorporates stochastic population extinctions. We show that fast alternations of presence and absence of antimicrobial are inefficient to eradicate the microbial population and strongly favor the establishment of resistance, unless the antimicrobial increases enough the death rate. We further demonstrate that if the period of alternations is longer than a threshold value, the microbial population goes extinct upon the first addition of antimicrobial, if it is not rescued by resistance. We express the probability that the population is eradicated upon the first addition of antimicrobial, assuming rare mutations. Rescue by resistance can happen either if resistant mutants preexist, or if they appear after antimicrobial is added to the environment. Importantly, the latter case is fully prevented by perfect biostatic antimicrobials that completely stop division of sensitive microorganisms. By contrast, we show that the parameter regime where treatment is efficient is larger for biocidal drugs than for biostatic drugs. This sheds light on the respective merits of different antimicrobial modes of action.Author summaryAntimicrobials select for resistance, which threatens to make antimicrobials useless. Understanding the evolution of antimicrobial resistance is therefore of crucial importance. Under what circumstances are microbial populations eradicated by antimicrobials? Conversely, when are they rescued by resistance? We address these questions employing a stochastic model that incorporates variations of both population composition and size. We consider periodic alternations of absence and presence of antimicrobial, which may model a treatment. We find a threshold period above which the first phase with antimicrobial fully determines the fate of the population. Faster alternations strongly select for resistance, and are inefficient to eradicate the microbial population, unless the death rate induced by the treatment is large enough. For longer alternation periods, we calculate the probability that the microbial population gets eradicated. We further demonstrate the different merits of biostatic antimicrobials, which prevent sensitive microbes from dividing, and of biocidal ones, which kill sensitive microbes.
Evaluation of primer pairs for microbiome profiling across a food chain from soils to humans within the One Health framework
Authors: Wasimuddin  , Schlaeppi Klaus , Ronchi Francesca , Leib Stephen L , Erb Matthias , Ramette Alban 
Published: November 2019

AbstractThe “One Health” framework emphasizes the ecological relationships between soil, plant, animal and human health. Microbiomes play important roles in these relationships, as they modify the health and performance of the different compartments and influence the transfer of energy, matter and chemicals between them. Standardized methods to characterize microbiomes along food chains are, however, currently lacking. To address this methodological gap, we evaluated the performance of DNA extractions kits and commonly recommended primer pairs targeting different hypervariable regions (V3-V4, V4, V5-V6, V5-V6-V7) of the 16S rRNA gene, on microbiome samples along a model food chain, including soils, maize roots, cattle rumen, and cattle and human faeces. We also included faeces from gnotobiotic mice colonized with defined bacterial taxa and mock communities to confirm the robustness of our molecular and bioinformatic approaches on these defined low microbial diversity samples. Based on Amplicon Sequence Variants, the primer pair 515F-806R led to the highest estimates of species richness and diversity in all sample types and offered maximum diversity coverage of reference databases in in silico primer analysis. The influence of the DNA extraction kits was negligible compared to the influence of the choice of primer pairs. Comparing microbiomes using 515F-806R revealed that soil and root samples have the highest estimates of species richness and inter-sample variation. Species richness decreased gradually along the food chain, with the lowest richness observed in human faeces. Primer pair choice directly influenced the estimation of community changes (beta diversity) within and across compartments and may give rise to preferential detection of specific taxa. This work demonstrates why a standardized approach is necessary to analyse microbiomes within and between source compartments along food chains in the context of the One Health framework.
Narrative and Gaming Experience Interact to Affect Presence and Cybersickness in Virtual Reality
Authors: Weech Séamas , Kenny Sophie , Lenizky Markus , Barnett-Cowan Michael 
Published: November 2019

AbstractResearch has established a link between presence and cybersickness in virtual environments, but there is significant disagreement regarding the directionality of the relationship (positive or negative) between the two factors, and if the relationship is modulated by other top-down influences. Several studies have revealed a negative association between the factors, highlighting the prospect that manipulating one factor might affect the other. Here we examined if a top-down factor (narrative context) enhances presence, and whether this effect is associated with a decrease in cybersickness. We analyzed the association between responses to questionnaire measures of cybersickness and presence, as well as the degree to which their relationship was affected by the administration of an ‘enriched’ or ‘minimal’ verbal narrative context. The results of the first experiment, conducted in a controlled laboratory environment, revealed that enriched narrative was associated with increased presence, but that the reductive effect of narrative on cybersickness depended on video gaming experience. We also observed the expected negative association between presence and cybersickness, but only in the enriched narrative group. In a second experiment, conducted with a diverse sample at a public museum, we confirmed our previous finding that presence and cybersickness are negatively correlated, specifically when participants experienced an enriched narrative. We also confirmed the interaction between narrative and gaming experience with respect to cybersickness. These results highlight the complexity of the presence-cybersickness relationship, and confirm that both factors can be modulated in a beneficial manner for virtual reality users by means of top-down interventions.
Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination
Authors: Mammel Anna E. , Delgado Katherine C. , Chin Andrea L. , Condon Alec F. , Hill Jo Q. , Aicher Sue A. , Wang Yingming , Fedorov Lev M. , Robinson Fred L. 
Published: November 2019

ABSTRACTThe form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also calledSET Binding Factor 1; SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused byMTMR2orMTMR13(SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS). MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2. In the mouse PNS, Mtmr2 was required to maintain wild type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 in mice led to perinatal lethality, indicating that the two proteins have partially redundant functions during embryogenesis. Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adultMtmr5-/-mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects. Mtmr5 levels were highest during axon radial sorting, whereas Mtmr13 levels rose as myelin formed, and remained high through adulthood. Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2. This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease.
Functional Organization of Mouse Primary Auditory Cortex in adult C57BL/6 and F1 (CBAxC57) mice
Authors: Bowen Zac , Winkowski Daniel E. , Kanold Patrick O. 
Published: November 2019

AbstractThe primary auditory cortex (A1) plays a key role for sound perception since it represents one of the first cortical processing stations for sounds. Recent studies have shown that on the cellular level the frequency organization of A1 is more heterogeneous than previously appreciated. However, many of these studies were performed in mice on the C57BL/6 background which develop high frequency hearing loss with age making them a less optimal choice for auditory research. In contrast, mice on the CBA background retain better hearing sensitivity in old age. Since potential strain differences could exist in A1 organization between strains, we performed comparative analysis of neuronal populations in A1 of adult (~10 weeks) C57BL/6 mice and CBAxC57 F1 mice. We used in vivo 2-photon imaging of pyramidal neurons in cortical layers L4 and L2/3 of awake mouse primary auditory cortex (A1) to characterize the populations of neurons that were active to tonal stimuli. Pure tones recruited neurons of widely ranging frequency preference in both layers and strains with neurons in CBA mice exhibiting a wider range of frequency preference particularly to higher frequencies. Frequency selectivity was slightly higher in C57BL/6 mice while neurons in CBA mice showed a greater sound-level sensitivity. The spatial heterogeneity of frequency preference was present in both strains with CBA mice exhibiting higher tuning diversity across all measured length scales. Our results demonstrate that the tone evoked responses and frequency representation in A1 of adult C57BL/6 and CBAxC57 F1 mice is largely similar.
Integrated Genomic Analysis Reveals Key Features of Long Undecoded Transcript Isoform (LUTI)-based Gene Repression
Authors: Tresenrider Amy , Jorgensen Victoria , Chia Minghao , Liao Hanna , van Werven Folkert J. , Ünal Elçin 
Published: November 2019

SUMMARYLong Undecoded Transcript Isoforms (LUTIs) represent a class of non-canonical mRNAs that downregulate gene expression through the combined act of transcriptional and translational repression. While single gene studies revealed some important aspects of LUTI-based repression, how these features impact gene regulation at a global scale is unknown. By using transcript leader and direct RNA sequencing, here we identify 74 LUTI candidates that are expressed specifically during meiotic prophase. Translational repression of these candidates is ubiquitous and dependent on upstream open reading frames. However, LUTI-based transcriptional repression is highly variable. In only 50% of the cases, LUTI transcription causes downregulation of the protein-coding transcript isoform. Higher LUTI expression, enrichment of histone 3 lysine 36 trimethylation, and changes in nucleosome position are the strongest predictors of LUTI-based transcriptional repression. We conclude that LUTIs downregulate gene expression in a manner that integrates translational repression, chromatin state changes, and the magnitude of LUTI expression.
RNA Sequencing by Direct Tagmentation of RNA/DNA Hybrids
Authors: Di Lin , Fu Yusi , Sun Yue , Li Jie , Liu Lu , Yao Jiacheng , Wang Guanbo , Wu Yalei , Lao Kaiqin. , Lee Raymond W. , Zheng Genhua , Xu Jun , Oh Juntaek , Wang Dong , Xie X. Sunney , Huang Yanyi , Wang Jianbin 
Published: November 2019

AbstractTranscriptome profiling by RNA sequencing (RNA-seq) has been widely used to characterize cellular status but it relies on second strand cDNA synthesis to generate initial material for library preparation. Here we use bacterial transposase Tn5, which has been increasingly used in various high-throughput DNA analyses, to construct RNA-seq libraries without second strand synthesis. We show that Tn5 transposome can randomly bind RNA/DNA heteroduplexes and add sequencing adapters onto RNA directly after reverse transcription. This method, Sequencing HEteRo RNA-DNA-hYbrid (SHERRY), is versatile and scalable. SHERRY accepts a wide range of starting materials, from bulk RNA to single cells. SHERRY offers a greatly simplified protocol, and produces results with higher reproducibility and GC uniformity compared with prevailing RNA-seq methods.Significance StatementRNA sequencing is widely used to measure gene expression in biomedical research; therefore, improvements in the simplicity and accuracy of the technology are desirable. All existing RNA sequencing methods rely on the conversion of RNA into double-stranded DNA through reverse transcription followed by second strand synthesis. The latter step requires additional enzymes and purification, and introduces sequence-dependent bias. Here, we show that Tn5 transposase, which randomly binds and cuts double-stranded DNA, can directly fragment and prime the RNA/DNA heteroduplexes generated by reverse transcription. The primed fragments are then subject to PCR amplification. This provides a new approach for simple and accurate RNA characterization and quantification.
Dynamic Brain-Body Coupling of Breath-by-Breath O2-CO2Exchange Ratio with Resting State Cerebral Hemodynamic Fluctuations
Authors: Chan Suk-tak , Evans Karleyton C. , Song Tian-yue , Selb Juliette , van der Kouwe Andre , Rosen Bruce R. , Zheng Yong-ping , Ahn Andrew C. , Kwong Kenneth 
Published: November 2019

ABSTRACTThe origin of low frequency cerebral hemodynamic fluctuations (CHF) in resting state remains unknown. Here we studied the contribution of respiratory gas exchange (RGE) metrics to CHF during spontaneous breathing. RGE metrics include the breath-by-breath changes of partial pressure of oxygen (ΔPO2) and carbon dioxide (ΔPCO2) between end inspiration and end expiration, and their ratio breath-by-breath O2-CO2exchange ratio (bER). We used transcranial Doppler sonography to evaluate CHF changes during spontaneous breathing by measuring the cerebral blood flow velocity (CBFv) in the middle cerebral arteries. The regional CHF changes during spontaneous breathing were mapped with blood oxygenation level dependent (BOLD) signal changes using functional magnetic resonance imaging (fMRI) technique. We found that prominent oscillations with periods of 0.5 to 2 minutes characterized ΔPO2, ΔPCO2and bER. The oscillations of bER were coherent with CHF during spontaneous breathing at the frequency range of 0.008-0.03Hz which is consistent with the low frequency resting state CHF. CHF had strong correlation with bER, followed by ΔPO2and then by ΔPCO2. Brain regions with the strongest bER-CHF coupling overlapped with many areas of default mode network. Although the physiological mechanisms underlying the strong correlation between bER and CHF are not completely understood, our findings suggest the contribution of bER to low frequency resting state CHF. It also provides a novel insight of brain-body interaction via CHF and oscillations of RGE metrics.
Synergistic and Antagonistic Drug Interactions in the Treatment of Systemic Fungal Infections
Authors: Wambaugh Morgan A. , Denham Steven T. , Brammer Brianna , Stonhill Miekan , Brown Jessica C. S. 
Published: November 2019

SummaryInvasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited number of efficacious drugs and poor drug availability. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits fungal cell growth instead of killing fungal cells, necessitating long treatments. To improve fluconazole treatments, we used our novel high-throughput method, the overlap2method (O2M), to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. Although serendipitous identification of these interactions is rare, O2M allows us to screen molecules five times faster than testing combinations individually and greatly enriches for interactors. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole.In vivo, this combination doubled the time-to-endpoint of mice with disseminatedCryptococcus neoformansinfections. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.
Proteolytic Cleavage by Matriptase Exacerbating Kidney Injury: a Novel Therapeutic Target
Authors: Ozawa Shota , Matsubayashi Masaya , Nanaura Hitoki , Yanagita Motoko , Mori Kiyoshi , Asanuma Katsuhiko , Kajiwara Nobuyuki , Hayashi Kazuyuki , Ohashi Hiroshi , Kasahara Masato , Yokoi Hideki , Kataoka Hiroaki , Mori Eiichiro , Nakagawa Takahiko 
Published: November 2019

AbstractChronic kidney disease (CKD) is a progressive disease, and podocyte injury is a potential mechanism. We found that Matriptase was activated at podocytes in CKD patients and mice while a Matriptase inhibitor slowed the progression of mouse kidney disease. The mechanism could be accounted for by an imbalance favoring Matriptase over its cognate inhibitor, hepatocyte growth factor activator inhibitor type 1 (HAI-1), as conditional depletion of HAI-1 in podocytes accelerates podocyte injury. Intriguingly, the N-terminal of Podocin (Podocin-N), as a consequence of Matriptase cleavage of Podocin, translocates to nucleoli. These results suggest that aberrant activation of Matriptase would cause podocyte injury, and a targeting Matriptase could be a novel therapeutic strategy for CKD patients.Significant statementChronic kidney disease (CKD) is a progressive disease. If podocytes, which are specialized cells of the kidney glomerulus that wrap around capillaries, are injured, kidney injury is exacerbated. Thus, a therapeutic strategy to addressing CKD would be to block podocyte injury. The present study provides evidence that Matriptase cleaves Podocin, a component of podocyte slit membrane, and the N-terminal of podocin translocates to nucleoli, causing kidney injury. Our findings show that the N-terminal of Podocin plays an efficient role for cell fate in podocytes. In addition, the inhibition of Matriptase would be a potential therapeutic target for CKD.