bluuebunny/crossref_metadata_2025_split huggingface dataset:
GENE EXPRESSION WITHIN A HUMAN CHOROIDAL NEOVASCULAR MEMBRANE USING SPATIAL TRANSCRIPTOMICS
Authors: Voigt Andrew P. , Mullin Nathaniel K. , Navratil Emma M. , Flamme-Wiese Miles J. , Lin Li-Chun , Scheetz Todd E. , Han Ian C. , Stone Edwin M. , Tucker Budd A. , Mullins Robert F. 
Published: June 2023

ABSTRACTMacular neovascularization is a relatively common and potentially visually devastating complication of age-related macular degeneration. In macular neovascularization, pathologic angiogenesis can originate from either the choroid or the retina, but we have limited understanding of how different cell types become dysregulated in this dynamic process. In this study, we performed spatial RNA sequencing on a human donor eye with macular neovascularization as well as a healthy control donor. We identified genes enriched within the area of macular neovascularization and used deconvolution algorithms to predict the originating cell type of these dysregulated genes. Within the area of neovascularization, endothelial cells were predicted to increase expression of genes related to Rho family GTPase signaling and integrin signaling. Likewise, VEGF and TGFB1 were identified as potential upstream regulators that could drive the observed gene expression changes produced by endothelial and retinal pigment epithelium cells in the macular neovascularization donor. These spatial gene expression profiles were compared to previous single-cell gene expression experiments in human age-related macular degeneration as well as a model of laser-induced neovascularization in mice. As a secondary aim, we also investigated spatial gene expression patterns within the macular neural retina and between the macular and peripheral choroid. We recapitulated previously described regional-specific gene expression patterns across both tissues. Overall, this study spatially analyzes gene expression across the retina, retinal pigment epithelium, and choroid in health and describes a set of candidate molecules that become dysregulated in macular neovascularization.
TooManyCellsInteractive: a visualization tool for dynamic exploration of single-cell data
Authors: Klamann Conor , Lau Christie , Schwartz Gregory W. 
Published: June 2023

AbstractAs single-cell sequencing data sets grow in size, visualizations of large cellular populations become difficult to parse and require extensive processing to identify subpopulations of cells. Managing many of these charts is laborious for technical users and unintuitive for non-technical users. To address this issue, we developed TooManyCellsInteractive (TMCI), a browser-based JavaScript application for visualizing hierarchical cellular populations as an interactive radial tree. TMCI allows users to explore, filter, and manipulate hierarchical data structures through an intuitive interface while also enabling batch export of high-quality custom graphics. Here we describe the software architecture and illustrate how TMCI has identified unique survival pathways among drug-tolerant persister cells in a pan-cancer analysis. TMCI will help guide increasingly large data visualizations and facilitate multi-resolution data exploration in a user-friendly way.
Collective pooling of foraging information in animal fission-fusion dynamics
Authors: Ramos-Fernandez Gabriel , Smith Aguilar Sandra E. 
Published: June 2023

1AbstractIn animal species with fission-fusion dynamics, individuals can split from or follow others during collective movements. In spider monkeys (Ateles geoffroyi) this decision depends in part on the information they have about the location of available feeding trees. Foraging widely and continuously splitting and joining from others, individuals could be pooling their partial information such that the group as a whole has a more complete picture of a heterogeneous foraging environment. Here we use individual utilization areas over a realistic foraging landscape to infer the sets of potentially known trees by each individual. Then we measure the spatial entropy of these areas, considering tree species diversity and spatial distribution. We measure how complementary pairs of areas are, by decomposing the spatial entropy into redundant and unique components. We find that the areas uniquely known by each pair member still contain considerable amounts of information, but there is also a high redundancy in the information that a pair has about the foraging landscape. The networks joining individuals based on the unique information components seem to be structured efficiently for information transmission. Distributed foraging in fission-fusion dynamics would be an example of adaptive pooling of information and thus, collective intelligence.
The AusTraits Plant Dictionary
Authors: Wenk Elizabeth H. , Sauquet Hervé , Gallagher Rachael V. , Brownlee Rowan , Boettiger Carl , Coleman David , Yang Sophie , Auld Tony , Barrett Russell , Brodribb Timothy , Choat Brendan , Dun Lily , Ellsworth David , Gosper Carl , Guja Lydia , Jordan Gregory J. , Breton Tom Le , Leigh Andrea , Lu-Irving Patricia , Medlyn Belinda , Nolan Rachael , Ooi Mark , Sommerville Karen D. , Vesk Peter , White Mathew , Wright Ian J. , Falster Daniel S. 
Published: June 2023

AbstractTraits with intuitive names, a clear scope and explicit description are essential for all trait databases. Reanalysis of data from a single database, or analyses that integrate data across multiple databases, can only occur if researchers are confident the trait concepts are consistent within and across sources. The lack of a unified, comprehensive resource for plant trait definitions has previously limited the utility of trait databases. Here we describe the AusTraits Plant Dictionary (APD), which extends the trait definitions included in the new trait database AusTraits. The development process of the APD included three steps: review and formalisation of the scope of each trait and the accompanying trait description; addition of trait meta-data; and publication in both human and machine-readable forms. Trait definitions include keywords, references and links to related trait concepts in other databases, and the traits are grouped into a hierarchy for easy searching. As well as improving the usability of AusTraits, the Dictionary will foster the integration of trait data across global and regional plant trait databases.
Transcriptome data from silica-preserved leaf tissue reveals gene flow patterns in a Caribbean bromeliad
Authors: Ruiz-Vargas Natalia , Ramanauskas Karolis , Tyszka Alexa S. , Mason-Gamer Roberta J. , Walker Joseph F. 
Published: June 2023

SummaryTranscriptome sequencing is a cost-effective approach that allows researchers to study a broad range of questions. However, to preserve RNA for transcriptome sequencing, tissue is often kept under special conditions, such as immediate ultracold freezing. Here, we demonstrate that RNA can be obtained from six-month-old, field collected samples stored in silica gel at room temperature. Using these transcriptomes, we explore the evolutionary relationships of the genusPitcairnia(Bromeliaceae) in the Dominican Republic and infer barriers to gene flow.We extracted RNA from silica-dried leaf tissue from 19Pitcairniaindividuals collected across the Dominican Republic. We used a series of macro-and micro-evolutionary approaches to examine the relationships and patterns of gene flow among individuals.We produced high-quality transcriptomes from silica-dried material and demonstrated that evolutionary relationships on the island match geography more closely than species delimitation methods. A population genetic examination indicates that a combination of ecological and geographic features are barriers to gene flow inPitcairnia.High-quality transcriptomes can be obtained from silica-preserved tissue. The genetic diversity amongPitcairniapopulations does not warrant classification as separate species, but the Dominican Republic contains several barriers to gene flow, notably the Cordillera Central mountain range.
Proteins containing 6-crossing knot types and their folding pathways
Authors: Sikora Maciej , Flapan Erica , Wong Helen , Rubach Pawel , Garstka Wojciech , Niewieczerzal Szymon , Rawdon Eric J , Sulkowska Joanna I. 
Published: June 2023

AbstractStudying complex protein knots can provide new insights into potential knot folding mechanisms and other fundamental aspects of why and how proteins knot. This paper presents results of a systematic analysis of the 3D structure of proteins with 6-crossings knots predicted by the artificial intelligence program AlphaFold 2. Furthermore, using a coarse-grained native based model, we found that three representative proteins can self tie to a 63knot, the most complex knot found in a protein thus far. Because it is not a twist knot, the 63knot cannot be folded via a simple mechanism involving the threading of a single loop. Based on successful trajectories for each protein, we determined that the 63knot is formed after folding a significant part of the protein backbone to the native conformation. Moreover, we found that there are two distinct knotting mechanisms, which are described here. Also, building on aloop flipping theorydeveloped earlier, we present two new theories of protein folding involving the creation and threading of two loops, and explain how our theories can describe the successful folding trajectories for each of the three representative 63-knotted proteins.
Simultaneous assessment of human genome and methylome data in a single experiment using limited deamination of methylated cytosine
Authors: Yan Bo , Wang Duan , Ettwiller Laurence 
Published: June 2023

AbstractMulti-omics requires concerted recording of independent information, ideally from a single experiment. In this study, we introduce RIMS-seq2, a high-throughput technique to simultaneously sequence genomes and overlay methylation information while requiring only a small modification of the experimental protocol for high throughput DNA sequencing to include a controlled deamination step. Importantly, the rate of deamination of 5mC is negligible and thus, do not interfere with standard DNA sequencing and data processing. Thus, RIMS-seq2 libraries from whole or targeted genome sequencing show the same germline variation calling accuracy and sensitivity as compared to standard DNA-seq. Additionally, regional methylation levels provide an accurate map of the human methylome.
Forecasting histone methylation by Polycomb complexes with minute-scale precision
Authors: Lundkvist Moa J. , Lizana Ludvig , Schwartz Yuri B. 
Published: June 2023

AbstractAll animals use the Polycomb system to epigenetically repress developmental genes. The repression requires tri-methylation of Lysine 27 of histone H3 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2), but the dynamics of this process is poorly understood. To bridge the gap, we developed a computational model that forecasts H3K27 methylation inDrosophilawith high temporal resolution and spatial accuracy of contemporary experimental techniques. Using this model, we show that pools of methylated H3K27 in dividing cells are defined by the effective concentration of PRC2 and the replication frequency. We find that the allosteric stimulation by pre-existing H3K27me3 makes PRC2 better in methylating developmental genes as opposed to indiscriminate methylation throughout the genome. Applied toDrosophiladevelopment, our model argues that, in this organism, the intergenerationally inherited H3K27me3 does not “survive” rapid cycles of embryonic chromatin replication and is unlikely to transmit the memory of epigenetic repression to the offspring. We foresee that our model is adaptable to other organisms, including mice and humans.
Context-specific GITR agonism potentiates anti-PD-L1 and CD40-based immuno-chemotherapy combination in heterogeneous pancreatic tumors
Authors: Ragulan Chanthirika , Desai Krisha , Lawrence Patrick Varun , Ikami Yuta , Aalam Mohammed Musheer , Ps Hari , Kannan Nagarajan , Cunningham David , Starling Naureen , Sadanandam Anguraj 
Published: June 2023

AbstractImmunotherapy has shown limited success in pancreatic adenocarcinoma (PDAC) patients. To improve clinical management of cancer, it is crucial to identify alternative immunostimulatory targets associated with mechanisms of tumor evolution to facilitate the development of novel combination immunotherapies. Here we categorized PDACs and other cancers (n>7,500) into subgroups based on immunostimulatory glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related ligand (GITRL) and receptor (GITR) expression:GITRLhigh+GITRhighandGITRLhigh/low+GITRlow. We characterized immune evasion mechanisms using immunotherapy preclinical trials in four representative immunocompetent mouse models, finding that the GITR agonist, DTA-1 significantly improved responses in GITRLhigh(+GITRhigh) tumors (n=2). Further characterization revealed increased activation of CD8+T-cells (but not T-regulatory; Tregs cells) and enhanced interferon-γ, immunoproteosome, antigen presentation, and T-cell receptor (TCR) gene expression in DTA-1 responders.In vivoclonal tracking using DNA barcoding showed that GITR agonist therapy significantly reduced tumor burden by targeting expansion of heterogeneous PDAC clones and not clone-initiating cells (representing potential resistance). However, emerging GITRLhigh+GITRhighepithelial-like oligoclones from the responder model escaped immune surveillance to GITR agonist treatment via increased PD-L1, offering a combined anti-PD-L1, CD40 agonist and DTA-1 immunotherapy regimens (with/without chemotherapy) that further improved responses by decreasing PD-L1+myeloid cells. Conversely, mesenchymal-enriched GITRLlowmodels exhibited primary (intrinsic) resistance to GITR agonist treatment due to reduced T-cells and increased myeloid and/or PD-L1+non-immune cells. These results provide pre-clinical context for GITR+PD-L1+CD40- based personalized immuno-chemotherapy combinations for PDAC.
Effects of dopamine and opioid receptor antagonism on the neural processing of social and non-social rewards
Authors: Massaccesi Claudia , Korb Sebastian , Götzendorfer Sebastian , Chiappini Emilio , Willeit Matthaeus , Lundström Johan N. , Windischberger Christian , Eisenegger Christoph , Silani Giorgia 
Published: June 2023

AbstractRewards are a broad category of stimuli inducing approach behavior to aid survival. Extensive evidence from animal research has shown that wanting (the motivation to pursue a reward) and liking (the pleasure associated with its consumption) are mostly regulated by dopaminergic and opioidergic activity in dedicated brain areas. However, less is known about the neuroanatomy of dopaminergic and opioidergic regulation of reward processing in humans, especially when considering different types of rewards (i.e., social and non-social). To fill this gap of knowledge, we combined dopaminergic and opioidergic antagonism (via amisulpride and naltrexone administration) with functional neuroimaging to investigate the neurochemical and neuroanatomical bases of wanting and liking of matched non-social (food) and social (interpersonal touch) rewards, using a randomized, between-subject, placebo-controlled, double-blind design. While at the behavioral level no drug effect was observed, brain activity was modulated by the administered compounds. In particular, opioid antagonism, compared to placebo, was associated with reduced activity in the medial orbitofrontal cortex during consumption of the most valued social and non-social rewards. Dopamine antagonism, however, had no clear effects on brain activity in response to rewards anticipation. These findings provide insights into the neurobiology of human reward processing and suggest a similar opioidergic regulation of the neural responses to social and non-social reward consumption.
Design of four component T=4 tetrahedral, octahedral, and icosahedral protein nanocages through programmed symmetry breaking
Authors: Lee Sangmin , Kibler Ryan D. , Hsia Yang , Borst Andrew J. , Philomin Annika , Kennedy Madison A. , Stoddard Barry , Baker David 
Published: June 2023

AbstractFour, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral (T-sym), octahedral (O-sym) or icosahedral (I-sym) point group symmetry to generate closed cage-like structures1,2. Generating more complex closed structures requires breaking perfect point group symmetry. Viruses do this in the icosahedral case using quasi-symmetry or pseudo-symmetry to access higher triangulation number architectures3–9, but nature appears not to have explored higher triangulation number tetrahedral or octahedral symmetries. Here, we describe a general design strategy for building T = 4 architectures starting from simpler T = 1 structures through pseudo-symmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (T-sym), 96 (O-sym), and 240 (I-sym) subunits, each with four distinct chains and six different protein-protein interfaces, and diameters of 33nm, 43nm, and 75nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen displaying vaccine candidates10,11and targeted delivery vehicles12,13.
PARP12 is required to repress the replication of a Mac1 mutant coronavirus in a cell and tissue specific manner
Authors: Kerr Catherine M. , Parthasarathy Srivatsan , Schwarting Nancy , O’Connor Joseph J. , Giri Emily , More Sunil , Orozco Robin C. , Fehr Anthony R. 
Published: June 2023

ABSTRACTADP-ribosyltransferases (ARTs) mediate the transfer of ADP-ribose from NAD+to protein or nucleic acid substrates. This modification can be removed by several different types of proteins, including macrodomains. Several ARTs, also known as PARPs, are stimulated by interferon, indicating ADP-ribosylation is an important aspect of the innate immune response. All coronaviruses (CoVs) encode for a highly conserved macrodomain (Mac1) that is critical for CoVs to replicate and cause disease, indicating that ADP-ribosylation can effectively control coronavirus infection. Our siRNA screen indicated that PARP12 might inhibit the replication of a MHV Mac1 mutant virus in bone-marrow derived macrophages (BMDMs). To conclusively demonstrate that PARP12 is a key mediator of the antiviral response to CoVs both in cell culture andin vivo, we produced PARP12−/−mice and tested the ability of MHV A59 (hepatotropic/neurotropic) and JHM (neurotropic) Mac1 mutant viruses to replicate and cause disease in these mice. Notably, in the absence of PARP12, Mac1 mutant replication was increased in BMDMs and in mice. In addition, liver pathology was also increased in A59 infected mice. However, the PARP12 knockout did not restore Mac1 mutant virus replication to WT virus levels in all cell or tissue types and did not significantly increase the lethality of Mac1 mutant viruses. These results demonstrate that while PARP12 inhibits MHV Mac1 mutant virus infection, additional PARPs or innate immune factors must contribute to the extreme attenuation of this virus in mice.IMPORTANCEOver the last decade, the importance of ADP-ribosyltransferases (ARTs), also known as PARPs, in the antiviral response has gained increased significance as several were shown to either restrict virus replication or impact innate immune responses. However, there are few studies showing ART-mediated inhibition of virus replication or pathogenesis in animal models. We found that the CoV macrodomain (Mac1) was required to prevent ART-mediated inhibition of virus replication in cell culture. Here, using knockout mice, we found that PARP12, an interferon-stimulated ART, was required to repress the replication of a Mac1 mutant CoV both in cell culture and in mice, demonstrating that PARP12 represses coronavirus replication. However, the deletion of PARP12 did not fully rescue Mac1 mutant virus replication or pathogenesis, indicating that multiple PARPs function to counter coronavirus infection.
Characterization of human lightness discrimination thresholds for independent spectral variations
Authors: Reynolds Devin , Singh Vijay 
Published: June 2023

ABSTRACTThe lightness of an object is an intrinsic property that depends on its surface reflectance spectrum. The visual system estimates an object’s lightness from the light reflected off its surface. The light reflected also depends on object extrinsic properties of the scene. For stable perception, the visual system needs to discount variations due to extrinsic properties. We characterize this perceptual stability for variation in two spectral properties of the scene: the reflectance spectra of background objects and the intensity of light sources. We use a two-alternative forced-choice task to measure human observers’ thresholds of discriminating computer-generated images of 3D scenes based on the lightness of a spherical target object in the scene. We measured how the discrimination thresholds changed as we varied the reflectance spectra of the objects and the intensity of the light sources in the scene, both individually and simultaneously. For small amounts of extrinsic variations, the thresholds of discrimination remained constant indicating that the thresholds were dominated by observers’ intrinsic representation of lightness. As extrinsic variation increased, it started affecting observers’ lightness judgment and the thresholds increased. We estimated that the effects of extrinsic variations were comparable to observers’ intrinsic variation in the representation of object lightness. Moreover, for simultaneous variation of these spectral properties, the increase in threshold square compared to no variation condition was a linear sum of the corresponding increase in threshold squares for the individual properties, indicating that the variation from these independent sources combines linearly.
Development and deployment of improvedAnopheles gambiaes.l. field surveillance by adaptive spatial sampling design
Authors: Monteiro Gabriel M. , Djogbénou Luc S. , Donnelly Martin J. , Sedda Luigi 
Published: June 2023

AbstractAccurate assessments of vector occurrence and abundance, particularly in widespread vector-borne diseases such as malaria, is essential for efficient deployment of disease surveillance and control interventions. This study emphasizes the need for flexible spatial sampling designs that can capture the dynamic relationships between disease vector species and the environment. Although previous studies have examined the benefits of adaptive sampling for disease hotspot identification (mostly by simulations), limited research has been conducted on field surveillance of malaria vectors. Here, an adaptive spatial sampling design targeting potential and uncertainAn. gambiaehotspots, a major malaria vector in sub-Saharan Africa, is presented. The first phase of the proposed design involved ecological zone delineation and a proportional lattice with close pairs sampling design to maximise spatial coverage, representativeness of ecological zones and vector spatial autocorrelation (by the employment of close pairs). In the second phase, a spatial adaptive sampling design targeted high-risk areas with the largest uncertainty. For the second phase, the sample size was reduced compared to the first phase, but predictions improved for out-of-sample and training data. However, the overall model uncertainty increased, highlighting the trade-off in multi-criteria adaptive sampling designs. It is important that future research focuses on these trade-offs to reduce the timescale for effective malaria control and elimination efforts.