bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral vector eluting lenses for single-step targeted expression of genetically-encoded activity sensors for in vivo microendoscopic calcium imaging
Authors: Jons Carolyn K. , Cheng David , Dong Changxin , Meany Emily L. , Nassi Jonathan J. , Appel Eric A. 
Published: November 2023

AbstractOptical methods for studying the brain offer powerful approaches for understanding how neural activity underlies complex behavior. These methods typically rely on genetically encoded sensors and actuators to monitor and control neural activity. For microendoscopic calcium imaging, injection of a virus followed by implantation of a lens probe is required to express a calcium sensor and enable optical access to the target brain region. This two-step process poses several challenges, chief among them being the risks associated with mistargeting and/or misalignment between virus expression zone, lens probe and target brain region. Here, we engineer an adeno-associated virus (AAV)-eluting polymer coating for gradient refractive index (GRIN) lenses enabling expression of a genetically encoded calcium indicator (GCaMP) directly within the brain region of interest upon implantation of the lens. This approach requires only one surgical step and guarantees alignment between GCaMP expression and lens in the brain. Additionally, the slow virus release from these coatings increases the working time for surgical implantation, expanding the brain regions and species amenable to this approach. These enhanced capabilities should accelerate neuroscience research utilizing optical methods and advance our understanding of the neural circuit mechanisms underlying brain function and behavior in health and disease.
A NRF2/β3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress
Authors: Michel Lauriane Y. M. , Esfahani Hrag , Verdoy Roxane , de Mulder Delphine , Ambroise Jérôme , Roelants Véronique , Bouchard Bertrand , Savary Jérôme , Dewulf Joseph P. , Doumont Thomas , Bouzin Caroline , Haufroid Vincent , Luiken Joost J.F.P. , Nabben Miranda , Singleton Michael L. , Bertrand Luc , Ruiz Matthieu , Des Rosiers Christine , Balligand Jean-Luc 
Published: November 2023

AbstractBackgroundCardiac β3-adrenergic receptors (β3AR) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR and β2AR. β3AR agonists were recently shown to protect from myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. The underlying mechanisms, however, remain elusive.MethodsTo dissect functional, transcriptional and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a humanADRB3transgene (β3AR-Tg) and subjected to transverse aortic constriction (TAC) were assessed using echocardiography, RNAseq, PET scan, metabolomics, seahorse and metabolic flux analysis. Subsequently, signaling and metabolic pathways were investigated furtherin vivoin β3AR-Tg andin vitroin neonatal rat ventricular myocytes adenovirally infected to express β3AR and subjected to neurohormonal stress. These results were completed with an analysis of single nucleus RNAseq data from human cardiac myocytes from heart failure patients.ResultsCompared with WT littermate, β3AR-Tg mice were protected from hypertrophy after transaortic constriction (TAC), while systolic function was preserved. β3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the Pentose-Phosphate Pathway (PPP) in β3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the PPP, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, while downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in β3AR-Tg post-TAC compared to WT, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as upstream transcription factor which was functionally verified in β3AR-expressing cardiac myocytes where its translocation and nuclear activity was dependent on β3AR activation of nitric-oxide synthase (NOS) NO production.ConclusionModerate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts antioxidant effects through activation of the PPP and NRF2 pathway, thereby preserving myocardial oxidative metabolism, function and integrity under pathophysiological stress.
Assessing the capacity of high-resolution commercial satellite imagery for grapevine downy mildew detection and surveillance in New York state
Authors: Kanaley Kathleen , Combs David B. , Paul Angela , Jiang Yu , Bates Terry , Gold Kaitlin M. 
Published: November 2023

AbstractGrapevine downy mildew (GDM), caused by the oomycetePlasmopara viticola,can cause 100% yield loss and vine death under conducive conditions. Growers currently rely on frequent fungicide applications for control, but this practice has led to widespread resistance. Rapid remote detection and surveillance of GDM outbreaks would enable precision pesticide applications to target effective but resistance-prone fungicides where and when most needed, while relying on less resistance-prone protectants elsewhere. High resolution commercial satellite platforms offer the opportunity to track rapidly spreading diseases like GDM over large, heterogeneous fields. Here, we investigate the capacity of PlanetScope (3 m) and SkySat (50 cm) imagery for season-long GDM detection and surveillance. A team of trained scouts rated GDM severity and incidence in two acres of Chardonnay grapevines in Geneva, NY, USA in June-August of 2020, 2021, and 2022. Satellite imagery acquired within 72 hours of scouting was processed to extract single-band reflectance and vegetation indices (VIs). Random forest models trained on spectral bands and VIs derived from both image datasets could classify areas of high and low GDM incidence and severity with maximum accuracies of 0.88 (SkySat) and 0.94 (PlanetScope). However, we do not observe significant differences between VIs of high and low damage classes until late July-early August. We identify cloud cover, image co-registration, and low spectral resolution as key challenges to operationalizing satellite-based GDM surveillance. This work establishes the capacity of spaceborne multispectral sensors to detect late-stage GDM and outlines steps towards incorporating satellite remote sensing in grapevine disease surveillance systems.
PriOmics: integration of high-throughput proteomic data with complementary omics layers using mixed graphical modeling with group priors
Authors: Kosch Robin , Limm Katharina , Staiger Annette M. , Kurz Nadine S. , Seifert Nicole , Oláh Bence , Solbrig Stefan , Ziepert Marita , Chteinberg Emil , Spang Rainer , Siebert Reiner , Zacharias Helena U. , Ott German , Oefner Peter J. , Altenbuchinger Michael 
Published: November 2023

ABSTRACTMass spectrometry (MS)-based high-throughput proteomics data cover abundances of 1,000s of proteins and facilitate the study of co- and post-translational modifications (CTMs/PTMs) such as acetylation, ubiquitination, and phosphorylation. Yet, it remains an open question how to holistically explore such data and their relationship to complementary omics layers or phenotypical information. Network inference methods aim for a holistic analysis of data to reveal relationships between molecular variables and to resolve underlying regulatory mechanisms. Among those, graphical models have received increased attention as they can distinguish direct from indirect relationships, aside from their generalizability to diverse data types. We propose PriOmics as a graphical modeling approach to integrate proteomics data with complementary omics layers and pheno- and genotypical information. PriOmics models intensities of individual peptides and incorporates their protein affiliation as prior knowledge in order to resolve statistical relationships between proteins and CTMs/PTMs. We show in simulation studies that PriOmics improves the recovery of statistical associations compared to the state of the art and demonstrate that it can disentangle regulatory effects of protein modifications from those of respective protein abundances. These findings are substantiated in a dataset of Diffuse Large B-Cell Lymphomas (DLBCLs) where we integrate SWATH-MS-based proteomics data with transcriptomic and phenotypic information.GRAPHICAL ABSTRACT
Characterization and Phylogenetic Insights into the First Viral Major Vault Proteins (MVPs), Identified in Bacteriophages from the Human Gut
Authors: Santos Thiago M. , Galvão Emerson , Gomes Helena , Del-Bem Luiz-Eduardo 
Published: November 2023

ABSTRACTThe Major Vault Protein (MVP) is the principal component of the enigmatic vault complex, dome-shaped cytoplasmic ribonucleoproteins found in eukaryotes. Although vaults have been associated with several minor functions, including amino acid storage and cargo transport, their overall function remains to be fully understood. While MVPs are widely distributed among most higher eukaryotes and have homologs in prokaryotes, no similar protein have been reported in viral species until now. In this study, we explored the NCBI viral protein database for MVP homologs and identified two putative MVPs from distinct tailed bacteriophage isolates from the ClassCaudoviricetes, ctOa11 and ctRi15, of human gut metagenomic samples. Furtherin silicoanalysis were conducted to describe and characterize these unprecedent phage proteins. Phylogenetic topologies indicate that viral MVPs are closely related to bacterial MVP homologs. Tridimensional protein models of viral MVPs were generated to perform protein structure comparisons with eukaryotic and prokaryotic MVPs, indicating a significant similarity to bacterial proteins. For the functional significance of MVPs in phage infectivity, we suggest that they may have an unknown metabolic role enhancing phage fitness. While this work provides new insights into the genetic phage diversity and phylogenetic distribution of MVPs, complementary functional studies are necessary to fully elucidate their function in viral and bacterial species.
S100A8-enriched microglia populate the brain of tau-seeded and accelerated aging mice
Authors: Gruel Roxane , Bijnens Baukje , Van Den Daele Johanna , Thys Sofie , Willems Roland , Wuyts Dirk , Van Dam Debby , Verstraelen Peter , Verboven Rosanne , Roels Jana , Vandamme Niels , Mancuso Renzo , Pita-Almenar Juan Diego , De Vos Winnok H. 
Published: November 2023

AbstractLong considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (senescence accelerated mouse prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genesS100a8andS100a9. In 9-months-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction.Graphical abstract
eIF4A1 is essential for reprogramming the translational landscape of Wnt-driven colorectal cancers
Authors: Waldron Joseph A. , Kanellos Georgios , Smith Rachael C. L. , Knight John R. P. , Munro June , Alexandrou Constantinos , Vlahov Nikola , Pardo-Fernandez Luis , Moore Madeleine , Gillen Sarah L. , Strathdee Douglas , Stevenson David , Warrander Fiona C. , Gilroy Kathryn , Nixon Colin , Cadden Barbara , Powley Ian , Officer-Jones Leah , Ballantyne Fiona , Hay Jennifer , Pennel Kathryn , Edwards Joanne , Campbell Andrew D. , Ridgway Rachel A. , Coffelt Seth B. , Norman Jim , Quesne John Le , Bushell Martin , Sansom Owen J. 
Published: November 2023

AbstractDysregulated translation is a hallmark of cancer. Targeting the translational machinery represents a therapeutic avenue which is being actively explored. eIF4A inhibitors target both eIF4A1, which promotes translation as part of the eIF4F complex, and eIF4A2, which can repress translation via the CCR4–NOT complex. While high eIF4A1 expression is associated with poor patient outcome, the role of eIF4A2 in cancer remains unclear. Furthermore, the on-target toxicity of targeting specific eIF4A paralogues in healthy tissue is under-explored. We show that while loss of either paralogue is tolerated in the wild-type intestine, eIF4A1 is specifically required to support the translational demands of oncogenic Wnt signalling. Intestinal tumourigenesis is suppressed in colorectal cancer models following loss of eIF4A1 but accelerated following loss of eIF4A2, while eIF4A inhibition with eFT226 mimics loss of eIF4A1 in these models.
Disruption of IL-17 signaling in the respiratory mucosa results in invasive streptococcal infection
Authors: Mills Jamie-Lee , Lepletier Ailin , Ozberk Victoria , Dooley Jessica , Kaden Jacqualine , Calcutt Ainslie , Huo Yongbao , Hicks Allan , Zaid Ali , Good Michael F. , Pandey Manisha 
Published: November 2023

ABSTRACTStreptococcus pyogenesinfection of the upper respiratory tract and skin can lead to severe invasive streptococcal disease (ISD). Previous studies have demonstrated that the deficiency of IL-17 in mice (IL-17-/-) reduces mucosal immunity againstS. pyogenes. However, the impact of IL-17 deficiency on the development of ISD is unknown. Here, we model single or repeated non-lethal, intranasal (IN)S. pyogenesM1 strain infections in immunocompetent and IL-17-/-mice to assess bacterial dissemination following a final IN or skin challenge. Immunocompetent mice that received a singleS. pyogenesIN infection displayed long-lasting mucosal immunity and no systemic infection. However, in the absence of IL-17, a single IN infection resulted in the dissemination ofS. pyogenesto the spleens, which was further exacerbated by repeated IN infections. Interestingly, immunity following skin challenge did not show a correlation with IL-17 and was instead associated with the activation of germinal center responses and the accumulation of neutrophils in the spleen. Our results highlight the critical role of IL-17 in preventing ISD followingS. pyogenesinfection of the respiratory mucosa.
Tonic dopamine and biases in value learning linked through a biologically inspired reinforcement learning model
Authors: Romero Pinto Sandra , Uchida Naoshige 
Published: November 2023

AbstractA hallmark of various psychiatric disorders is biased future predictions. Here we examined the mechanisms for biased value learning using reinforcement learning models incorporating recent findings on synaptic plasticity and opponent circuit mechanisms in the basal ganglia. We show that variations in tonic dopamine can alter the balance between learning from positive and negative reward prediction errors, leading to biased value predictions. This bias arises from the sigmoidal shapes of the dose-occupancy curves and distinct affinities of D1- and D2-type dopamine receptors: changes in tonic dopamine differentially alters the slope of the dose-occupancy curves of these receptors, thus sensitivities, at baseline dopamine concentrations. We show that this mechanism can explain biased value learning in both mice and humans and may also contribute to symptoms observed in psychiatric disorders. Our model provides a foundation for understanding the basal ganglia circuit and underscores the significance of tonic dopamine in modulating learning processes.
Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer
Authors: Zhou Yufan , Li Tian , He Zhijing , Choppavarapu Lavanya , Hu Xiaohui , Cao Ruifeng , Leone Gustavo W. , Kahn Michael , Jin Victor X. 
Published: November 2023

AbstractThe therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the β-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.
Optical segmentation-based compressed readout of neuronal voltage dynamics
Authors: Kim Seonghoon , Ko Gwanho , Kang Iksung , Tian He , Fan Linlin Z. , Li Yixin , Cohen Adam E. , Wu Jiamin , Dai Qionghai , Choi Myunghwan 
Published: November 2023

AbstractFunctional imaging of biological dynamics generally begins with acquiring time-series images, followed by quantifying spatially averaged intensity traces for the regions of interest (ROIs). The conventional pipeline discards a substantial portion of the acquired data when quantifying intensity traces, indicative of inefficient data acquisition. Here we propose a conceptually novel acquisition pipeline that assigns each ROI to a single pixel in the detector, enabling optimally compressed acquisition of the intensity traces. As a proof-of-principle, we implemented a detection module composed of a pair of spatial light modulators and a microlens array, which segments the original image into multiple subimages by introducing distinct angular shifts to each ROI. Each subimage exclusively encodes the signal for the corresponding ROI, facilitating the compressed readout of its intensity trace using a single pixel. This spatial compression allowed for maximizing the temporal information without compromising the spatial information on ROIs. Harnessing our novel approach, we demonstrate the recording of circuit-scale neuronal voltage dynamics at over 5 kHz sampling rate, revealing the individual action potential waveforms within subcellular structures, as well as their submillisecond-scale temporal delays.
Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release
Authors: Bodt Skylar M. L. , Ge Jinghua , Ma Wen , Rasicci David V. , Desetty Rohini , McCammon J. Andrew , Yengo Christopher M. 
Published: November 2023

AbstractInherited mutations in human beta-cardiac myosin (M2β) can lead to severe forms of heart failure. The E525K mutation in M2β is associated with dilated cardiomyopathy (DCM) and was found to stabilize the interacting heads motif (IHM) and autoinhibited super-relaxed (SRX) state in dimeric heavy meromyosin. However, in monomeric M2β subfragment 1 (S1) we found that E525K enhances (3-fold) the maximum steady-state actin-activated ATPase activity (kcat) and decreases (6-fold) the actin concentration at which ATPase is one-half maximal (KATPase). We also found a 3 to 4-fold increase in the actin-activated power stroke and phosphate release rate constants at 30 μM actin, which overall enhanced the duty ratio 3-fold. Loaded motility assays revealed that the enhanced intrinsic motor activity translates to increased ensemble force in M2β S1. Glutamate 525, located near the actin binding region in the so-called activation loop, is highly conserved and predicted to form a salt-bridge with another conserved residue (lysine 484) in the relay helix. Enhanced sampling molecular dynamics simulations predict that the charge reversal mutation disrupts the E525-K484 salt-bridge, inducing conformations with a more flexible relay helix and a wide phosphate release tunnel. Our results highlight a highly conserved allosteric pathway associated with actin activation of the power stroke and phosphate release and suggest an important feature of the autoinhibited IHM is to prevent this region of myosin from interacting with actin. The ability of the E525K mutation to stabilize the IHM likely overrides the enhanced intrinsic motor properties, which may be key to triggering DCM pathogenesis.Significance StatementHeart disease can be caused by inherited mutations in beta-cardiac myosin, the molecular motor that powers systolic contraction in the ventricles of the heart. However, it remains unclear how these mutations lead to contractile dysfunction and pathogenic remodeling of the heart. We investigated a unique dilated cardiomyopathy mutation (E525K) that dramatically stabilizes the autoinhibited state while enhancing intrinsic motor function. Thus, we examined how this mutation impacts transient kinetic steps of the ATPase cycle, motile properties, and structural changes associated with the power stroke and phosphate release. Our results provide a kinetic and structural basis for how beta-cardiac myosin mutations may disrupt molecular-level contractile function in complex ways, which may inform the development of targeted therapeutics.