bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-15 enhances anti-tumor immunity of sipuleucel-T by activating lymphocyte subsets and reversing immunoresistance
Authors: Saeed Muhammad A. , Peng Bo , Kim Kevin , Borkowski Ariel , Tine Brian Van , Sheikh Nadeem , Vu Tuyen , Thorek Daniel LJ , Fehniger Todd , Pachynski Russell K. 
Published: July 2023

AbstractEngineered cell therapies have emerged as a potent therapeutic option for the hematologic malignancies, however solid tumor responses to similar approaches have been modest. The outlier is Sipuleucel-T (sip-T), an FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report the first high dimensional cellular analyses of sip-T using mass cytometry (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B-cells, and natural killer (NK) and NKT cells.We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate cancer. Of cytokines tested, IL-15 treated sip-T showed the most significant activation and proliferation of effector lymphocytes, as well as augmentation of tumor cytotoxicity in vitro. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner. Adoptive transfer of IL-15 treated sip-T into NSG mice resulted in potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2 to 14-fold higher influx of sip-T and a significant increase in interferon (IFN)-γ producing CD8+ T and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward the first evidence that IL-15 treatment can enhance the functional anti-tumor efficacy of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat mCRPC patients.Graphical AbstractOne sentence summaryIL-15 treatment can enhance the efficacy/anti-tumor immunity of sipuleucel-T by modulating CD8+ T-cell and CD56+ NKT subsets.
Skyline fossilized birth-death model is robust to violations of sampling assumptions in total-evidence dating
Authors: Zhang Chi , Ronquist Fredrik , Stadler Tanja 
Published: July 2023

AbstractSeveral total-evidence dating studies under the fossilized birth-death (FBD) model have produced very old age estimates, which are not supported by the fossil record. This phenomenon has been termed “deep root attraction (DRA)”. For two specific data sets, involving divergence time estimation for the early radiations of ants, bees and wasps (Hymenoptera) and of placental mammals (Eutheria), it has been shown that the DRA effect can be greatly reduced by accommodating the fact that extant species in these trees have been sampled to maximize diversity, so called diversified sampling. Unfortunately, current methods to accommodate diversified sampling only consider the extreme case where it is possible to identify a cut-off time such that all splits occurring before this time are represented in the sampled tree but none of the younger splits. In reality, the sampling bias is rarely this extreme, and may be difficult to model properly. Similar modeling challenges apply to the sampling of the fossil record. This raises the question of whether it is possible to find dating methods that are more robust to sampling biases. Here, we show that the skyline FBD (SFBD) process, where the diversification and fossil-sampling rates can vary over time in a piecewise fashion, provides age estimates that are more robust to inadequacies in the modeling of the sampling process and less sensitive to DRA effects. In the SFBD model we consider, rates in different time intervals are either considered to be independent and identically distributed, or assumed to be autocorrelated following an Ornstein-Uhlenbeck (OU) process. Through simulations and reanalyses of the Hymenoptera and Eutheria data, we show that both variants of the SFBD model unify age estimates under random and diversified sampling assumptions. The SFBD model can resolve DRA by absorbing the deviations from the sampling assumptions into the inferred dynamics of the diversification process over time. Although this means that the inferred diversification dynamics must be interpreted with caution, taking sampling biases into account, we conclude that the SFBD model represents the most robust approach available currently for addressing DRA in total-evidence dating.
Microglia Regulate Sleep via Calcium-Dependent Modulation of Norepinephrine Transmission
Authors: Ma Chenyan , Li Bing , Silverman Daniel , Ding Xinlu , Li Anan , Xiao Chi , Huang Ganghua , Worden Kurtresha , Muroy Sandra , Chen Wei , Xu Zhengchao , Tso Chak Foon , Huang Yixuan , Zhang Yufan , Luo Qingming , Saijo Kaoru , Dan Yang 
Published: July 2023

AbstractSleep interacts reciprocally with immune system activity, but its specific relationship with microglia – the resident immune cells in the brain – remains poorly understood. Here we show that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+signaling, and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging showed that P2Y12/Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine. Furthermore, imaging of norepinephrine activity with its biosensor showed that microglia P2Y12/Gi activation significantly reduced norepinephrine, partly by increasing the adenosine concentration. Thus, microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.
Microglial cannabinoid receptor type 1 mediates social memory deficits produced by adolescent THC exposure and 16p11.2 duplication
Authors: Hasegawa Yuto , Kim Juhyun , Ursini Gianluca , Jouroukhin Yan , Zhu Xiaolei , Miyahara Yu , Xiong Feiyi , Madireddy Samskruthi , Obayashi Mizuho , Lutz Beat , Sawa Akira , Brown Solange P. , Pletnikov Mikhail V. , Kamiya Atsushi 
Published: July 2023

AbstractAdolescent cannabis use increases the risk for cognitive impairments and psychiatric disorders. Cannabinoid receptor type 1 (Cnr1) is expressed not only in neurons and astrocytes, but also in microglia, which shape synaptic connections during adolescence. Nonetheless, until now, the role of microglia in mediating the adverse cognitive effects of delta-9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, has been unexplored. Here, we report that adolescent THC exposure produces microglial apoptosis in the medial prefrontal cortex (mPFC), which was exacerbated in the mouse model of 16p11.2 duplication, a representative copy number variation (CNV) risk factor for psychiatric disorders. These effects are mediated by microglial Cnr1, leading to reduction in the excitability of mPFC pyramidal-tract neurons and deficits in social memory in adulthood. Our findings highlight the importance of microglial Cnr1 to produce the adverse effect of cannabis exposure in genetically vulnerable individuals.
ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma
Authors: Laing Sarah , Kruspig Björn , Shaw Robin , Officer-Jones Leah , Edwards Sarah , McKinven Danielle , Hsieh Ya-Ching , Powley Ian , Brady Nicola , Pennie Rachel , Kwan Ryan , Lima Anthony , Myrta Szymon , Periyasamy Manikandan , Dye Isabel C , Nixon Colin , Clark Graeme , Junttila Melissa R. , Maddalo Danilo , Miller Crispin , Ali Simak , Fuchter Matthew J. , Nickles Dorothee , Kirschner Kristina , Brown Robert B. , Le Quesne John , Strathdee Douglas , Coffelt Seth B. , Roberts Ed , Murphy Daniel J. 
Published: July 2023

ABSTRACTImmunotherapy is increasingly viewed as treatment of choice for lung cancer, however, clinical responses to immune checkpoint blockade remain highly unpredictable and are largely transient. A deeper mechanistic understanding of the dynamics of tumour:immune interactions is needed to drive rational development of improved treatment strategies. Progress is hampered by a paucity of autochthonous model systems in which to interrogate the 2-way interactions of immune responses to evolving tumours and vice-versa. Specifically, commonly used genetically engineered mouse models typically lack the genetic diversity needed to drive an adaptive immune response. APOBEC mutagenesis signatures are prominent in lung cancer and APOBEC activity is predicted to drive immune visibility through Cytidine deaminase activity, coupled with inaccurate DNA-repair responses. We therefore generated a CRE-inducibleAPOBEC3Ballele, interbred with multiple oncogenic drivers of lung adenocarcinoma, and used the resulting mice to investigate the response to PD1 blockade at single cell resolution.SIGNIFICANCEUsing our novel immune-visible model of KRas-driven autochthonous lung adenocarcinoma, we uncovered a surprising increase in tumour-cell expression of EGFR/ERBB ligands following treatment with α-PD1 and present evidence that transient ERBB blockade can restore immune surveillance in KRas mutant LuAd and combine effectively with immune checkpoint blockade.
Macroecological patterns in experimental microbial communities
Authors: Shoemaker William R. , Sánchez Álvaro , Grilli Jacopo 
Published: July 2023

AbstractEcology has historically benefited from the characterization of statistical patterns of biodiversity within and across communities, an approach known as macroecology. Within microbial ecology, macroecological approaches have identified universal patterns of diversity and abundance that can be captured by effective models. Experimentation has simultaneously played a crucial role, as the advent of high-replication community time-series has allowed researchers to investigate underlying ecological forces. However, there remains a gap between experiments performed in the laboratory and macroecological patterns documented in natural systems, as we do not know whether these patterns can be recapitulated in the lab and whether experimental manipulations produce macroecological effects. This work aims at bridging the gap between experimental ecology and macroecology. Using high-replication time-series, we demonstrate that microbial macroecological patterns observed in nature exist in a laboratory setting, despite controlled conditions, and can be unified under the Stochastic Logistic Model of growth (SLM). We find that demographic manipulations (e.g., migration) impact observed macroecological patterns. By modifying the SLM to incorporate said manipulations alongside experimental details (e.g., sampling), we obtain predictions that are consistent with macroecological outcomes. By combining high-replication experiments with ecological models, microbial macroecology can be viewed as a predictive discipline.
Venom tradeoff shapes interspecific interactions, physiology and reproduction
Authors: Surm Joachim M. , Birch Sydney , Macrander Jason , Jaimes-Becerra Adrian , Fridrich Arie , Aharoni Reuven , Rozenblat Rotem , Sharabany Julia , Appelbaum Lior , Reitzel Adam M. , Moran Yehu 
Published: July 2023

AbstractThe ability of an animal to effectively capture prey and defend against predators is pivotal for its survival. Venom, a mixture of many toxin proteins, shapes predator-prey interactions. Here, we use the sea anemoneNematostella vectensisto test how toxin genotypes impact predator-prey interactions. We developed a new genetic manipulation tool which significantly reduces both RNA and protein levels of Nv1, a major neurotoxin. In concert we recently discovered a native population ofNematostellathat has lost Nv1.We demonstrate that these anemones lacking Nv1, have reduced ability to defend themselves against grass shrimp, a native predator. Additionally, secreted Nv1 can act indirectly in defense by attracting mummichog fish, which are known to prey on grass shrimp. This unravels a tritrophic interaction acting in animal defense at the molecular level. Additionally, our work reveals an evolutionary tradeoff, as the reduction of Nv1 levels causes faster growth and increased sexual and asexual reproductive rates.
Disease-specific tau filaments assemble via polymorphic intermediates
Authors: Lövestam Sofia , Li David , Wagstaff Jane L. , Kotecha Abhay , Kimanius Dari , McLaughlin Stephen H. , Murzin Alexey G. , Freund Stefan M.V. , Goedert Michel , Scheres Sjors H.W. 
Published: July 2023

AbstractIntermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention. However, structural information about intermediate species has been scarce and the molecular mechanisms by which amyloids assemble remain largely unknown. Here, we use time-resolved electron cryo-microscopy (cryo-EM) to study thein vitroassembly of recombinant truncated tau (amino acids 297-391) into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy. We report the formation of a shared first intermediate amyloid (FIA), with an ordered core comprising amino acids 302-316. Nuclear magnetic resonance indicates that the same amino acids adopt rigid, β-strand-like conformations in monomeric tau. At later time points, the FIAs disappear and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain. Our results provide structural insights into the processes of primary and secondary nucleation of amyloid assembly, with implications for the design of novel therapies.
Impaired cholesterol transport from aged astrocytes to neurons can be rescued by cannabinoids
Authors: Allende Leandro G. , Natalí Lautaro , Cragnolini Andrea B. , Musri Melina M. , Mendoza Diego de , Martín Mauricio G. 
Published: July 2023

SummaryCholesterol is crucial for the proper functioning of eukaryotic cells, especially neurons, which rely on cholesterol to maintain their complex structure and facilitate synaptic transmission. However, brain cells are isolated from peripheral cholesterol by the blood-brain barrier and mature neurons primarily uptake the cholesterol synthesized by astrocytes for proper function. This study aimed to investigate the effect of aging on cholesterol trafficking in astrocytes and its delivery to neurons. Using in vitro and in vivo models of aging, we found that aged astrocytes accumulated high levels of cholesterol in the lysosomal compartment, and this cholesterol buildup can be attributed to the simultaneous occurrence of two events: decreased levels of the ABCA1 transporter which impairs ApoE-cholesterol export from astrocytes, and reduced expression of NPC1, which hinders cholesterol release from lysosomes. We show that these two events are accompanied by increased microR33 in aged astrocytes, which is known to downregulate ABCA1 and NPC1. In addition, we demonstrate that the microR33 increase is triggered by oxidative stress, one of the hallmarks of aging.By co-culture experiments we also show that aging in vitro impairs the cholesterol delivery from astrocytes to neurons. Remarkably, we found that this altered transport of cholesterol could be alleviated through treatment with endocannabinoids as well as cannabidiol or CBD. Given that reduced neuronal cholesterol affects synaptic plasticity, the ability of cannabinoids to restore cholesterol transport from aged astrocytes to neurons holds significant implications in the field of aging.
Denoising Diffusion MRI: Considerations and implications for analysis
Authors: Manzano-Patron Jose-Pedro , Moeller Steen , Andersson Jesper L.R. , Ugurbil Kamil , Yacoub Essa , Sotiropoulos Stamatios N. 
Published: July 2023

ABSTRACTDevelopment of diffusion MRI (dMRI) denoising approaches has experienced considerable growth over the last years. As noise can inherently reduce accuracy and precision in measurements, its effects have been well characterised both in terms of uncertainty increase in dMRI-derived features and in terms of biases caused by the noise floor, the smallest measurable signal given the noise level. However, gaps in our knowledge still exist in objectively characterising dMRI denoising approaches in terms of both of these effects and assessing their efficacy. In this work, we reconsider what a denoising method should and should not do and we accordingly define criteria to characterise the performance. We propose a comprehensive set of evaluations, including i) benefits in improving signal quality and reducing noise variance, ii) gains in reducing biases and the noise floor and improving, iii) preservation of spatial resolution, iv) agreement of denoised data against a gold standard, v) gains in downstream parameter estimation (precision and accuracy), vi) efficacy in enabling noise-prone applications, such as ultra-high-resolution imaging. We further provide newly acquired complex datasets (magnitude and phase) with multiple repeats that sample different SNR regimes to highlight performance differences under different scenarios. Without loss of generality, we subsequently apply a number of exemplar patch-based denoising algorithms to these datasets, including Non-Local Means, Marchenko-Pastur PCA (MPPCA) in the magnitude and complex domain and NORDIC, and compare them with respect to the above criteria and against a gold standard complex average of multiple repeats. We demonstrate that all tested denoising approaches reduce noise-related variance, but not always biases from the elevated noise floor. They all induce a spatial resolution penalty, but its extent can vary depending on the method and the implementation. Some denoising approaches agree with the gold standard more than others and we demonstrate challenges in even defining such a standard. Overall, we show that dMRI denoising performed in the complex domain is advantageous to magnitude domain denoising with respect to all the above criteria.
CellSNAP: A fast, accurate algorithm for 3D cell segmentation in quantitative phase imaging
Authors: Raj Piyush , Paidi Santosh , Conway Lauren , Chatterjee Arnab , Barman Ishan 
Published: July 2023

AbstractQuantitative phase imaging (QPI) has rapidly emerged as a complementary tool to fluorescence imaging, as it provides an objective measure of cell morphology and dynamics, free of variability due to contrast agents. In particular, three-dimensional (3D) tomographic imaging of live cells has opened up new directions of investigation by providing systematic and correlative analysis of various cellular parameters without limitations of photobleaching and phototoxicity. While current QPI systems allow the rapid acquisition of tomographic images, the pipeline to analyze these raw 3D tomograms is not well-developed. This work focuses on a critical, yet often underappreciated, step of the analysis pipeline, that of 3D cell segmentation from the acquired tomograms. The current method employed for such tasks is the Otsu-based 3D watershed algorithm, which works well for isolated cells; however, it is very challenging to draw boundaries when the cells are clumped. This process is also memory intensive since the processing requires computation on a 3D stack of images. We report the CellSNAP (Cell Segmentation via Novel Algorithm for Phase Imaging) algorithm for the segmentation of QPI images, which outstrips the current gold standard in terms of speed, robustness, and implementation, achieving cell segmentation under 2 seconds per cell on a single-core processor. The implementation of CellSNAP can easily be parallelized on a multi-core system for further speed improvements. For the cases where segmentation is possible with the existing standard method, our algorithm displays an average difference of 5% for dry mass and 8% for volume measurements. We also show that CellSNAP can handle challenging image datasets where cells are clumped and marred by interferogram drifts, which pose major difficulties for all QPI-focused segmentation tools. We envision our work will lead to the broader adoption of QPI imaging for high-throughput analysis, which has, in part, been stymied by a lack of suitable image segmentation tools.
Primary human lung fibroblasts exhibit trigger- but not disease-specific cellular senescence and impair alveolar epithelial cell progenitor function
Authors: Bramey Nora , Melo-Narvaez Maria Camila , See Fenja , Ballester-Lllobell Beatriz , Steinchen Carina , Jain Eshita , Hafner Kathrin , Yildirim Ali Önder , Königshoff Melanie , Lehmann Mareike 
Published: July 2023

AbstractAging is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are increased in different cell types such as fibroblasts in the lungs of these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H2O2and bleomycin treatment induced a senescent phenotype in phLF whereas TGF-β1 only had a pro-fibrotic effect. Interestingly, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin. However, exposure to different stimuli resulted in different senescent programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of alveolar epithelial progenitor cells. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacityin vitro.