bluuebunny/crossref_metadata_2025_split huggingface dataset:
An ultrasensitive GRAB sensor for detecting extracellular ATPin vitroandin vivo
Authors: Wu Zhaofa , He Kaikai , Chen Yue , Li Hongyu , Pan Sunlei , Li Bohan , Liu Tingting , Wang Huan , Du Jiulin , Jing Miao , Li Yulong 
Published: February 2021

SUMMARYThe purinergic transmitter ATP (adenosine 5’-triphosphate) plays an essential role in both the central and peripheral nervous systems, and the ability to directly measure extracellular ATP in real time will increase our understanding of its physiological functions. We developed an ultrasensitiveGPCRActivation‒Based ATP sensor called GRABATP1.0, with a robust fluorescence response to extracellular ATP when expressed in several cell types. This sensor has sub-second kinetics, ATP affinity in the range of tens of nanomolar, and can be used to localize ATP release with subcellular resolution. Using this sensor, we monitored ATP release under a variety ofin vitroandin vivoconditions, including primary hippocampal neurons, a zebrafish model of injury-induced ATP release, and LPS-induced ATP-release events in individual astrocytes in the mouse cortex measured usingin vivotwo-photon imaging. Thus, the GRABATP1.0sensor is a sensitive, versatile tool for monitoring ATP release and dynamics under both physiological and pathophysiological conditions.
Disrupted circadian core-clock oscillations in Type 2 Diabetes are linked to altered rhythmic mitochondrial metabolism
Authors: Gabriel Brendan M. , Altıntaş Ali , Smith Jonathon A.B. , Sardon-Puig Laura , Zhang Xiping , Basse Astrid L. , Laker Rhianna C. , Gao Hui , Liu Zhengye , Dollet Lucile , Treebak Jonas T. , Zorzano Antonio , Huo Zhiguang , Rydén Mikael , Lanner Johanna T. , Esser Karyn A. , Barrès Romain , Pillon Nicolas J. , Krook Anna , Zierath Juleen R. 
Published: February 2021

SummaryCircadian rhythms are generated by an auto-regulatory feedback loop composed of transcriptional activators and repressors. Disruption of circadian rhythms contributes to Type 2 diabetes (T2D) pathogenesis. We elucidated whether altered circadian rhythmicity of clock genes is associated with metabolic dysfunction in T2D. Transcriptional cycling of core clock genesARNTL, CLOCK,CRY1andNR1D1was altered in skeletal muscle from individuals with T2D and this was coupled with reduced number and amplitude of cycling genes and disturbed circadian oxygen consumption. Mitochondrial associated genes were enriched for differential circadian amplitudes in T2D, and positively correlated with insulin sensitivity. ChIP- sequencing identified CLOCK and BMAL1 binding to circadian mitochondrial genes associated with insulin sensitivity, implicating regulation by the core clock. Mitochondria disruption altered core-clock gene expression and free-radical production, phenomena that were restored by resveratrol treatment. We identify bi-directional communication between mitochondrial function and rhythmic gene expression, processes which are disturbed in diabetes.
Selection of active defensive behaviors relies on extended amygdala dopamine D2 receptors
Authors: Castell Laia , Gall Valentine Le , Cutando Laura , Puighermanal Emma , Jercog Daniel , Tarot Pauline , Tassou Adrien , Harrus Anne-Gabrielle , Rubinstein Marcelo , Nouvian Régis , Rivat Cyril , Herry Cyril , Valjent Emmanuel 
Published: February 2021

SummaryThe ability to efficiently switch from one defensive strategy to another maximizes an animal’s chance of survival. Here, we demonstrate that the selection of active defensive behaviors requires the coordinated activation of dopamine D2 receptor (D2R) signaling within the central extended amygdala (EA) comprising the nucleus accumbens, the oval bed nucleus stria terminals and the central amygdala. We find that discriminative learning between predictive and non-predictive threat auditory stimuli is unaltered in mice carrying a temporally-controlled deletion of D2R within output neurons of the EA. In contrast, intact EA D2R signaling is required for active avoidance learning and innate flight responses triggered by a visual threat stimulus (looming). Consequently, conditional D2R knockout mice biased defensive responses toward passive defensive strategies. Altogether, these findings identify EA D2R signaling as an important mechanism by which DA regulates the switch from passive to active defensive behaviors, regardless whether of learned or innate threat.
Rapid adaptation and remote delivery of undergraduate research training during the COVID 19 Pandemic
Authors: Yowler Joanna Yang , Knier Kit , WareJoncas Zachary , Ehlers Shawna L. , Ekker Stephen C. , Reyes Fabiola Guasp , Horazdovsky Bruce F. , Mueller Glenda , Gomez Adriana Morales , Sood Amit , Sussman Caroline R. , Scholl Linda M. , Weavers Karen M. , Pierret Chris 
Published: February 2021

AbstractCOVID-19 continues to alter daily life around the globe. Education is particularly affected by shifts to distance learning. This change has poignant effects on all aspects of academic life, including the consequence of increased mental stress reported specifically for students. COVID-19 cancellations of many summer fellowships and internships for undergraduates across the country increased students’ uncertainty about their educational opportunities and careers. When the pandemic necessitated elimination of on-campus programming at Mayo Clinic, a new program was developed for remote delivery. Summer Foundations in Research (SFIR) was drafted around 4 aims: 1) support the academic trajectory gap in research science created by COVID-19; 2) build sustainable scientific relationships with mentors, peers, and the community; 3) create opportunities for participants to share and address concerns with their own experiences in the pandemic; and 4) provide support for individual wellbeing. SFIR included research training, but also training in communication through generative Dialogue and resilience through Amit Sood’s SMART program. 170 participants were followed for outcomes in these spaces. Knowledge of and interest in careers involving biomedical research rose significantly following SFIR. Participants’ mean confidence levels in 12 Key areas of research rose between 0.08 to 1.32 points on a 7-point scale. The strongest gains in mean confidence levels were seen in designing a study and collaborating with others. SFIR participants demonstrated gains in perceived happiness, and measured resilience and a reduction in stress. Participants’ qualitative responses indicated exceptionally positive mentor relationships and specific benefit of both the SMART program and Dialogue.
Efficient Agony Based Transfer Learning Algorithms for Survival Forecasting
Authors: Tamaskar Abhinav , Bannon James , Mishra Bud 
Published: February 2021

AbstractProgression modeling is a mature subfield of cancer bioinformatics, but it has yet to make a proportional clinical impact. The majority of the research in this area has focused on the development of efficient algorithms for accurately reconstructing sequences of (epi)genomic events from noisy data. We see this as the first step in a broad pipeline that will translate progression modeling to clinical utility, with the subsequent steps involving inferring prognoses and optimal therapy programs for different cancers and using similarity in progression to enhance decision making. In this paper we take some initial steps in completing this pipeline. As a theoretical contribution, we introduce a polytime-computable pairwise distance between progression models based on the graph-theoretic notion of “agony”. Focusing on a particular progression model we can then use this agony distance to cluster (dis)similarities viamulti-dimensional scaling. We recover known biological similarities and dissimilarities. Finally, we use the agony distance to automate transfer learning experiments and show a large improvement in the ability to forecast time to death.
Binocular vs. monocular recovery experience differentially promote recovery from visual deficits in a mouse model of amblyopia
Authors: Martinez Jessy D. , Donnelly Marcus J. , Popke Donald S. , Torres Daniel , Sheskey Sarah , Clawson Brittany C. , Jiang Sha , Aton Sara J. 
Published: February 2021

AbstractAltered visual experience during monocular deprivation (MD) profoundly changes in ocular dominance (OD) in the developing primary visual cortex (V1). MD-driven changes in OD are an experimental model of amblyopia, where early-life alterations in vision lead visual disruption in adulthood. Current treatments for amblyopia include patching of the dominant eye, and more recently-developed binocular therapies. However, the relative impact of monocular vs. binocular recovery experiences on recovery of function in V1 is not well understood. Using single-unit recording, we compared how binocular recovery [BR] or reverse occlusion [RO] of identical duration and content affects OD and visual response recovery in mouse binocular V1 after a period of MD. We also tested how BR and RO affected MD-driven alterations of parvalbumin expression, and visually-driven expression of cFos in parvalbumin-positive and negative neurons. Finally, we tested how BR and RO affected recovery of normal visual acuity for the two eyes in the context of visually-driven behavior. We find that BR is quantitatively superior with respect to normalization of V1 neurons’ OD, visually-driven cFos expression, and visual acuity for the two eyes. However, MD-driven changes in the firing rate and response properties of V1 principal neuron and fast-spiking interneuron populations do not recover fully after either BR or RO. Binocular matching of orientation preference also remains disrupted in V1 neurons after both forms of recovery experience. Thus BR and RO, analogs of differing treatment regimens for amblyopia, differentially impact various aspects of visual recovery in a mouse model for amblyopia.Significance StatementAmblyopia resulting from altered childhood eye function is a leading cause of lifelong vision loss. Treatment typically involves patching of the dominant eye (forcing monocular visual experience), and produces only partial recovery of vision. Using a well-established mouse model of amblyopia, we directly compared how two types of visual experiences influence recovery of visual function. Our findings suggest that binocular vs. monocular visual experience differentially effect restoration of normal visual responses in cortical neurons, visually-driven neuronal gene expression, and visual acuity. Understanding how the quality of recovery experience impacts visual system recovery in amblyopia should provide critical insights for clinical strategies for its treatment.
Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression
Authors: Cheung Phyllis F , Yang JiaJin , Krengel Kirsten , Althoff Kristina , Yip Chi Wai , Siu Elaine HL , Ng Linda WC , Lang Karl S , Cham Lamin , Engel Daniel R , Soun Camille , Cima Igor , Scheffler Björn , Striefler Jana K , Sinn Marianne , Bahra Marcus , Pelzer Uwe , Oettle Helmut , Markus Peter , Smeets Esther MM , Aarntzen Erik HJG , Savvatakis Konstantinos , Liffers Sven-Thorsten , Neander Christian , Bazarna Anna , Zhang Xin , Merkler Doron , Paschen Annette , Crawford Howard C. , Chan Anthony WH , Cheung Siu Tim , Siveke Jens T 
Published: February 2021

ABSTRACTImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.STATEMENT OF SIGNIFICANCEImmune evasion is a key property of PDAC, rendering it refractory to immunotherapy. Here we demonstrate that tumor-derived PGRN promotes autophagy-dependent MHCI degradation, while anti-PGRN increases intratumoral CD8 infiltration and blocks tumor progression. With recent advances in T cell-mediated approaches, PGRN represents a pivotal target to enhance tumor antigen-specific cytotoxicity.
Examining the quality and fertilization competence of bovine ejaculate with low progressive motility – should we give it a chance?
Authors: Li Y. , Kalo D. , Komsky-Elbaz A. , Zeron Y. , Roth Z. 
Published: February 2021

AbstractSpermatozoa progressive motility is positively correlated with fertilization competence. Bulls’ ejaculates with progressive motility lower than 50% are routinely rejected through the process of straw preparation, designated for artificial insemination of dairy cows. We examined the quality and fertility competence of ejaculates with relative low progressive motility (55–60%, n = 5; control) with those of very low progressive motility i.e. below the lower threshold, (20-45%, n = 5; rejected). Analysis revealed a lower volume for the control vs. rejected samples. Dip-Quick staining revealed a higher proportion of spermatozoa with abnormal morphology in the rejected group, in particular those with detached heads. Activation of spermatozoa with calcium ionophore, resulted by a lower proportion of activated spermatozoa in the rejected group. In addition, a higher proportion of spermatozoa with DNA damage were recorded in the rejected vs. the control samples. Following in-vitro fertilization, the proportion of oocytes that developed to the 2- and 4-cell stage embryos did not differ between groups. However, the proportion of embryos that further developed to blastocysts, was higher in the control group. Transcript abundance of selected genes in the blastocysts and the apoptotic index did not differ between groups, suggesting that the forming blastocysts were of the same quality. It is suggested that in specific cases, for example genetically superior bulls, ejaculates with very low progressive motility can be used forin vitroproduction of embryo. Furtherin vivoexaminations, i.e. artificial insemination or transferring of embryos derived from these inferior ejaculates, might clarified this point.
Determinants of ligand-functionalized DNA nanostructure-cell interactions
Authors: Cremers Glenn A.O. , Rosier Bas J.H.M. , Meijs Ab , Tito Nicholas B. , van Duijnhoven Sander M.J. , van Eenennaam Hans , Albertazzi Lorenzo , de Greef Tom F.A. 
Published: February 2021

AbstractSynthesis of ligand-functionalized nanomaterials with control over size, shape and ligand orientation, facilitates the design of tailored nanomedicines for therapeutic purposes. DNA nanotechnology has emerged as a powerful tool to rationally construct two- and three-dimensional nanostructures, enabling site-specific incorporation of protein ligands with control over stoichiometry and orientation. To efficiently target cell surface receptors, exploration of the parameters that modulate cellular accessibility of these nanostructures is essential. In this study we systematically investigate tunable design parameters of antibody-functionalized DNA nanostructures binding to therapeutically relevant receptors. We show that, although the native affinity of antibody-functionalized DNA nanostructures remains unaltered, the absolute number of bound surface receptors is lower compared to soluble antibodies and is mainly governed by nanostructure size and DNA handle location. The obtained results provide key insights in the ability of ligand-functionalized DNA nanostructures to bind surface receptors and yields design rules for optimal cellular targeting.
Csf1r-GCaMP5 Reporter Mice Reveal Immune Cell Communication in Vitro and in Vivo
Authors: Taghdiri N , Calcagno D , Fu Z , Huang K , Kohler RH , Weissleder R , Coleman TP , Kevin KR 
Published: February 2021

ABSTRACTInterconnected cells are responsible for emergent functions ranging from cognition in the brain to cyclic contraction in the heart. In electrically excitable cells, methods for studying cell communication are highly advanced, but in non-excitable cells, generalized methods for studying cell communication are less mature. Immune cells have generally been classified as non-excitable cells with diverse pathophysiologic roles that span every tissue in the body, yet little is known about their interconnectedness because assays are destructive and have low temporal resolution. In this work, we hypothesize that non-excitable immune cells are functionally interconnected in previously unrecognized cell communication networks. To test the hypothesis, we created a hematopoietic calcium reporter mouse (Csf1r-Cre × GCaMP5) and non-destructively quantified the spatiotemporal dynamics of intracellular calciumin vitroandin vivo.In vitro, bone marrow derived macrophages calcium reporters reveal that fatal immune stimulatory DNA-sensing induces rapid intercellular communication to neighboring cells.In vivo, using intravital microscopy through a dorsal window chamber in the context of MC38-H2B-mCherry tumors, Csf1r-GCaMP5 reporters exhibit spatiotemporal dynamics consistent with cell communication. We present a theoretical framework and analysis pipeline for identifying spatiotemporal locations of “excess synchrony” of calcium spiking as a means of inferring previously unrecognized cell communication events. Together, these methods provide a toolkit for investigating known and as-yet-undiscovered cell communication eventsin vitroandin vivo.
A 48-Channel Receive Array Coil for Mesoscopic Diffusion-Weighted MRI of Humanex vivoBrain Imaging on the 3T Connectome Scanner
Authors: Scholz Alina , Etzel Robin , May Markus W , Mahmutovic Mirsad , Tian Qiyuan , Ramos-Llordén Gabriel , Bilgiç Berkin , Witzel Thomas , Stockmann Jason P , Mekkaoui Choukri , Wald Lawrence L , Huang Susie Y , Yendiki Anastasia , Keil Boris 
Published: February 2021

AbstractIn vivodiffusion-weighted magnetic resonance imaging is limited in signal-to-noise-ratio (SNR) and acquisition time, which constrains spatial resolution to the macroscale regime.Ex vivoimaging, which allows for arbitrarily long scan times, is critical for exploring human brain structure in the mesoscale regime without loss of SNR. Standard head array coils designed for patients are sub-optimal for imagingex vivowhole brain specimens. The goal of this work was to design and construct a 48-channelex vivowhole brain array coil for high-resolution and highb-value diffusion-weighted imaging on a 3T Connectome scanner. The coil was validated with bench measurements and characterized by imaging metrics on an agar brain phantom and anex vivohuman brain sample. The two-segment coil former was constructed for a close fit to a whole human brain, with small receive elements distributed over the entire brain. Imaging tests including SNR and G-factor maps were compared to a 64-channel head coil designed forin vivouse. There was a 2.9-fold increase in SNR in the peripheral cortex and a 1.3-fold gain in the center when compared to the 64-ch head coil. The 48-channelex vivowhole brain coil also decreases noise amplification in highly parallel imaging, allowing acceleration factors of approximately one unit higher for a given noise amplification level. The acquired diffusion-weighted images in a wholeex vivobrain specimen demonstrate the applicability of the developed coil for high-resolution and highb-value diffusion-weightedex vivobrain MRI studies.
Quantitative analysis of neuronal mitochondrial movement reveals patterns resulting from neurotoxicity of rotenone and 6-hydroxydopamine
Authors: Simões Rui F. , Pino Rute , Moreira-Soares Maurício , Kovarova Jaromira , Neuzil Jiri , Travasso Rui , Oliveira Paulo J. , Cunha-Oliveira Teresa , Pereira Francisco B. 
Published: February 2021

AbstractAlterations in mitochondrial dynamics, including their trafficking, can present early manifestation of neuronal degeneration. However, current methodologies used to study mitochondrial trafficking events rely on parameters that are mostly altered in later stages of neurodegeneration. Our objective was to establish a reliable computational methodology to detect early alterations in neuronal mitochondrial trafficking. We propose a novel quantitative analysis of mitochondria trajectories based on innovative movement descriptors, including straightness, efficiency, anisotropy, and kurtosis. Using biological data from differentiated SH-SY5Y cells treated with mitochondrial toxicants 6-hydroxydopamine and rotenone, we evaluated time and dose-dependent alterations in trajectory descriptors. Mitochondrial movement was analyzed by total internal reflection fluorescence microscopy followed by computer modelling to describe the process. The stacks of individual images were analyzed by an open source MATLAB algorithm (www.github.com/kandelj/MitoSPT) and to characterize mitochondria trajectories, we used the Python package trajpy (https://github.com/ocbe-uio/trajpy/). Our results confirm that this computational approach is effective and accurate in order to study mitochondrial motility and trajectories in the context of healthy and diseased neurons in different stages.
Bacteriophage self-counting in the presence of viral replication
Authors: Coleman Seth , Yao Tianyou , Nguyen Thu Vu Phuc , Golding Ido , Igoshin Oleg 
Published: February 2021

SUMMARYWhen host cells are in low abundance, temperate bacteriophages opt for dormant (lysogenic) infection. Phage lambda implements this strategy by increasing the frequency of lysogeny at higher multiplicity of infection (MOI). However, it remains unclear how the phage reliably counts infecting viral genomes even as their intracellular number increases due to replication. By combining theoretical modeling with single-cell measurements of viral copy number and gene expression, we find that, instead of hindering lambda’s decision, replication facilitates it. In a nonreplicating mutant, viral gene expression simply scales with MOI rather than diverging into lytic (virulent) and lysogenic trajectories. A similar pattern is followed during early infection by wildtype phage. However, later in the infection, the modulation of viral replication by the decision genes amplifies the initially modest gene expression differences into divergent trajectories. Replication thus ensures the optimal decision—lysis upon single-phage infection, lysogeny at higher MOI.