bluuebunny/crossref_metadata_2025_split huggingface dataset:
SysQuan: repurposing SILAC mice for the affordable absolute quantitation of the human proteome
Authors: Mohammed Yassene , Richard Vincent R. , Reyes Madlangsakay M. Immanuel , Lao Ying , Spicer Victor , Popp Robert , Gaither Claudia , Henneken Laura , Kleinekofort Wolfgang , Zahedi René P. , Borchers Christoph H. 
Published: November 2024

AbstractRelative quantitation, used by most MS-based proteomics laboratories to determine proteinfold-changes, requires samples being processed and analyzed together for best comparability through minimizing batch differences. This limits the adoption of MS-based proteomics in population-wide studies, and the detection of subtle but relevant changes in heterogeneous samples. Absolute quantitation circumvents these limitations and enables comparison of results across laboratories, studies, and longitudinally. However, high costs of the essential stable isotope labeled (SIL) standards prevents widespread access and limits the number of quantifiable proteins.Our new approach, called “SysQuan”, repurposes SILAC mouse tissues/biofluids as system-wide internal standards for matched human samples to enable absolute quantitation of, theoretically, two-thirds of the human proteome using 157,086 shared tryptic peptides. We demonstrate that SysQuan enables quantification of 70% and 31% of the liver and plasma proteomes, respectively. We demonstrate for 14 metabolic proteins that abundant SIL mouse tissues enable cost-effective reverse absolute quantitation in, theoretically, 1000s of human samples. Moreover, 10,000s of light/heavy doublets in untargeted SysQuan datasets enable unique post-acquisition absolute quantitation.SysQuan empowers researchers to replace relative quantitation with affordable absolute quantitation at scale, making data comparable across laboratories, diseases and tissues, enabling completely novel study designs and increasing reusability of data in repositories.TOC Graphic
Optimizing Angiopep-2 Density on Polymeric Nanoparticles for Enhanced Blood-Brain Barrier Penetration and Glioblastoma Targeting: Insights from In Vitro and In Vivo Experiments
Authors: Zhang Weisen , Refaat Ahmed , Li Haoqin , Zhu Douer , Tong Ziqiu , Nicolazzo Joseph A. , Peng Bo , Bai Hua , Esser Lars , Voelcker Nicolas H. 
Published: November 2024

AbstractThe blood-brain barrier (BBB) poses a formidable challenge to efficient drug delivery into the brain. One promising approach involves leveraging receptor-mediated transcytosis facilitated by Angiopep-2 peptide (Ang-2)-conjugated nanoparticles. However, the precise impact of Ang-2 density on BBB penetration remains poorly understood. In this study, we developed a versatile polymeric nanoparticle system with tuneable Ang-2 surface density and systemically examined its influence on BBB penetration through variousin vitroassays and anin vivostudy. Our findings revealed a nuanced relationship between Ang-2 surface density and BBB penetration across the different experimental setups. In 2D cell culture, we observed a positive correlation between Ang-2 surface density and cellular association in hCMEC/D3 cells, characterized by a distinctive inflection point. Conversely, in the Transwell model, higher Ang-2 density correlated negatively with BBB penetration, whereas the BBB-GBM-on-a-chip showed the opposite trend. These disparities may arise from differences in avidity under static versus dynamic conditions, potentially modulating nanoparticle interactions due to fluidic forces.In vivostudies revealed that higher Ang-2 densities facilitated nanoparticle transport across the BBB, consistent with the findings of the BBB-GBM-on-a-chip model. Furthermore, loading doxorubicin into nanoparticles with optimal Ang-2 density resulted in controlled pH-responsive release and enhanced anticancer effect against U87 GBM cells in both 2D cell cultures and a 3D BBB-GBM-on-a-chip model. These results underscore the critical importance of optimizing Ang-2 surface density for efficient BBB penetration and emphasize the utility of dynamic models in preclinicalin vitroassessment of novel nanoparticle formulations for targeted delivery to the brain.
Harnessing micrometer-scale tPA beads for high plasmin generation and accelerated fibrinolysis
Authors: Osmond Matthew J. , Dabertrand Fabrice , Quillinan Nidia , Su Enming J. , Lawrence Daniel A. , Marr David W.M. , Neeves Keith B. 
Published: November 2024

AbstractRapid restoration of blood flow is critical in treating acute ischemic stroke. Current fibrinolytic therapies using tissue plasminogen activator (tPA) are limited by low recanalization rates and risks of off-target bleeding. Here, we present a strategy using tPA immobilized on micrometer-scale beads to enhance local plasmin generation. We synthesized tPA-functionalized beads of varying sizes (0.1 μm and 1.0 μm) and evaluated their efficacy.In vitroassays demonstrated that 1.0 μm tPA-beads generated higher plasmin generation compared to free tPA and 0.1 μm beads, overcoming antiplasmin inhibition and promoting a self-propagating wave of fibrinolysis. In a murine model of acute ischemic stroke, intravenous administration of 1.0 μm tPA-beads at doses nearly two orders of magnitude lower than the standard free tPA dose led to rapid and near-complete thrombus removal within minutes. This approach addresses kinetic and transport limitations of current therapies and may reduce the risk of hemorrhagic complications.TeaserMicrometer-scale tPA beads improve stroke treatment by enhancing local clot-dissolving action.
Behavioral and neural evidence for perceptual predictions in social interactions
Authors: Lu Juanzhi , Riecke Lars , de Gelder Beatrice 
Published: November 2024

AbstractThe ability to predict others’ behavior is crucial for social interactions. The goal of the present study was to test whether predictions are derived during observation of social interactions and whether these predictions influence how the whole-body emotional expressions of the agents are perceived. Using a novel paradigm, we induced social predictions in participants by presenting them with a short video of a social interaction in which a person approached another person and greeted him by touching the shoulder in either a neutral or an aggressive fashion. The video was followed by a still image showing a later stage in the interaction and we measured participants’ behavioral and neural responses to the still image, which was either congruent or incongruent with the emotional valence of the touching. We varied the strength of the induced predictions by parametrically reducing the saliency of emotional cues in the video.Behaviorally, we found that reducing the emotional cues in the video led to a significant decrease in participants’ ability to correctly judge the appropriateness of the emotional reaction in the image. At the neural level, EEG recordings revealed that observing an angry reaction elicited significantly larger N170 amplitudes than observing a neutral reaction. This emotion effect was only found in the high prediction condition (where the context in the preceding video was intact and clear), not in the mid and low prediction conditions. We further found that incongruent conditions elicited larger N300 amplitudes than congruent conditions only for the neutral images. Our findings provide evidence that viewing the initial stages of social interactions triggers predictions about their outcome in early cortical processing stages.
Effects of live yeasts and their metabolic products on bumble bee microcolony development
Authors: Rukowski Danielle , Weston Makena , Vannette Rachel L. 
Published: November 2024

AbstractBumble bees can benefit from fungi, though the mechanisms underlying these benefits remain unknown and could include nutrition, resource supplementation, or pathogen protection. We tested how adding living yeasts or their metabolic products toBombus impatiensdiets in a factorial experiment affects microcolony performance, including survival, reproduction, and pathogen presence. We additionally assessed effects of yeast treatments on diet (nectar and pollen) chemical composition using untargeted metabolomics. Yeasts impacted microcolony reproduction and survival, but effects depended on source colony. Colonies containing the putative pathogenAspergillusshowed reduced reproduction, but yeast treatments reducedAspergillusprevalence. Yeast treatments altered chemical composition of nectar and pollen, but most distinguishing compounds were unidentified. Our results suggest limited direct effects of yeasts via nutrition, resource supplementation, or modification of diets, instead suggesting that yeasts may benefit bees through interactions with the pathogens includingAspergillus. Overall, the effects of yeast supplementation are context-dependent, and more research is necessary to better understand the factors important in determining their impacts on bee hosts.
Interplay between autophagy, the unfolded protein response and the cytoplasmic heat stress response during heat stress in maize
Authors: Tang Jie , Li Zhaoxia , Bassham Diane C 
Published: November 2024

AbstractHigh temperatures can substantially reduce plant survival and reproduction, and therefore decrease crop productivity. Plants activate several pathways in response to high temperatures, including the endoplasmic reticulum (ER) unfolded protein response (UPR), the cytoplasmic heat stress response, and autophagy, which together aid in stress tolerance by refolding or degrading misfolded and unfolded proteins. The relationship between the UPR and autophagy is known, as ER stress activates the UPR, and a key activator of the UPR, Inositol-requiring enzyme type 1 (IRE1B), upregulates autophagy. To assess the relationship between the distinct responses to heat stress in maize, we analyzed the effect of disruption of the UPR, via abzip60mutant, on autophagy. We found that genes related to autophagy are upregulated in thebzip60mutant, and that autophagy is activated in this mutant even in the absence of stress. We in turn analyzed the effect of loss of autophagy on the UPR. ThebZIP60mRNA spliced form, a marker for the UPR, was increased in mutants inATG10, a core component of the autophagy machinery, during ER stress. By contrast,bZIP60splicing was unaffected inatg10mutants in response to heat, whereas cytoplasmic heat stress components were increased. Loss of autophagy therefore differentially affects other heat stress response pathways, depending on the specific stress conditions leading to the activation of the pathways.
Evolutionarily guided transcription factor design programs novel T cell states
Authors: Takacsi-Nagy Oliver , Hartman Austin , Chen Andy Y. , Yin Yajie , Reeder Gabriella C. , Kernick Courtney , Lu Johnathan , McClellan Alison K. , Raposo Colin J. , Theberath Nicole E. , Yan Patrick K. , Eyquem Justin , Roth Theodore L. , Satpathy Ansuman T. 
Published: November 2024

AbstractProtein-coding genes in the human genome evolved via modular rearrangement of domains from ancestral genes1. Here, we develop a scalable, evolutionarily guided method to assemble novel protein-coding genes from constituent domains within a protein family, termed DESynR (Domain Engineered via Synthesis and Recombination) genes. Using primary human chimeric antigen receptor T cells as a model system, we find that the expression of DESynR Activator Protein-1 (AP-1) transcription factors (TFs) significantly outperforms the overexpression of natural AP-1 TFs in multiple functional assaysin vitroandin vivo. Top DESynR AP-1 TFs exhibit non-intuitive architectures of constituent domains, including from TFs that are not canonically expressed in T cells. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming of T cells and, in some cases, lead to the development of non-natural T cell states, engaging gene expression modules from disparate human cell types. Taken together, we demonstrate that novel configurations of existing protein domains may uncover non-evolved genes that program cell states with therapeutically relevant functions.
The circadian clock regulates receptor-mediated immune responses to an herbivore-associated molecular pattern
Authors: Guayazán Palacios Natalia , Imaizumi Takato , Steinbrenner Adam D. 
Published: November 2024

SummaryPlants activate induced defenses through the recognition of molecular patterns. Like pathogen-associated molecular patterns (PAMPs), herbivore-associated molecular patterns (HAMPs) can be recognized by cell surface pattern recognition receptors leading to defensive transcriptional changes in host plants. Herbivore-induced defensive outputs are regulated by the circadian clock, but the underlying molecular mechanisms remain unknown. To investigate how the plant circadian clock regulates transcriptional reprogramming of a specific HAMP-induced pathway, we characterized the daytime and nighttime transcriptional response to caterpillar-derived In11 peptide, in the legume crop cowpea (Vigna unguiculata). Using diurnal and free-running conditions, we found that daytime In11 elicitation resulted in stronger late-induced gene expression than nighttime. Plants with a conditional arrhythmic phenotype in constant light (LL) conditions lost time-of-day dependent responses to In11 treatment, and this was associated with arrhythmic expression of circadian clock core transcription factorLate Elongated Hypocotyl VuLHY1andVuLHY2. Reporter assays with VuLHY homologs indicated that they interact with the promoter of daytime In11-inducedKunitz Trypsin Inhibitor(VuKTI) via a canonical and a polymorphic CCA1/LHY Binding Site (CBS), consistent with a mechanism of direct regulation by circadian clock transcription factors. This study improves our understanding of the time-dependent mechanisms that regulate herbivore-induced gene expression.
Stress from environmental change drives clearance of a persistent enteric virus
Authors: Herrmann Christin , Zaldana Kimberly , Agostino Eva L , Koralov Sergei B , Cadwell Ken 
Published: November 2024

AbstractPersistent viral infections are associated with long-term health issues and prolonged transmission. How external perturbations after initial exposure affect the duration of infection is unclear. We discovered that murine astrovirus, an enteric RNA virus, persists indefinitely when mice remain unperturbed but is cleared rapidly after cage change. Besides eliminating the external viral reservoir, cage change also induced a transcriptional defense response in the intestinal epithelium. We further identified that displacing infected animals initially caused a temporary period of immune suppression through the stress hormone corticosterone, which was followed by an immune rebound characterized by an increase in CD8 T cells responsible for the epithelial antiviral responses. Our findings show how viral persistence can be disrupted by preventing re-exposure and activating immunity upon stress recovery, indicating that external factors can be manipulated to shorten the duration of a viral infection.
Acetic acid induces osmotic imbalances in drug-resistant bacteria synergistically enhancing cobalt-doped carbon quantum dots bactericidal efficiency
Authors: Truskewycz Adam , Choi Benedict , Pedersen Line , Han Jianhua , Halberg Nils 
Published: November 2024

AbstractWhen pathogenic bacteria colonise a wound, they can create an alkaline ecological niche which selects for their survival by creating an inflammatory environment which restricts healthy wound healing to proceed. To aid healing, wound acidification has been exploited to disrupt this process and stimulate fibroblast growth, increase wound oxygen concentrations, minimise proteolytic activity and re-stimulate the host immune system. Within this study, we have developed unique cobalt doped carbon quantum dot nanoparticles which work together with mild acetic acid creating a potent synergistic antimicrobial therapy. The acidic environment alters the osmotic balance of microorganisms forcing them to swell and speed up the internalisation of the ultra-small particles. The particles hyperpolarise the bacterial membranes and generate damaging peroxidase species resulting in cellular lysis. In mice, cobalt doped carbon quantum dots remove MRSA infection while allowing wounds to heal at equivalent rates to uninfected wounds. This work demonstrates how synergistic antimicrobial treatment strategies can be successfully used to combat antimicrobial resistant infections.
Tardigrade Dsup: Interactions with DNA and protection of cells from oxidative stress
Authors: Ni Gavin Shuyang , Su Hetian , Zhu Yingqi , Dhiman Anshika , Zhou Huan-Xiang , Lin Wei , Hao Nan 
Published: November 2024

AbstractThe remarkable capability of Tardigrade to survive under extreme conditions has been partially attributed to Dsup, an intrinsically disordered, highly positively charged protein. Dsup has been shown to bind to DNA in vitro, a property that has been associated with the capability of Dsup to exhibit stress-protective effects when expressed in mammalian cells. However, DNA binding of Dsup has not been visualized in living cells and expression of Dsup in different cell types was associated with either protective or detrimental effects. In addition, the effect of Dsup expression has not been clearly demonstrated at the organism level. Here we combined molecular dynamics (MD) simulations and fluorescence lifetime imaging microscopy (FLIM)-Förster resonance energy transfer (FRET) to interrogate Dsup-DNA interactions and demonstrated Dsup binding to DNA in living mammalian cells. Furthermore, Dsup expression in both HEK293T cells and yeast enhanced cell survival in the presence of hydrogen peroxide, suggesting that the presence of Dsup allows both mammalian and yeast cells to better cope with oxidative stress conditions. This study provides a better understanding of the property and functional role of Dsup and lays a foundation to explore new approaches to enhance stress resistance.
An ocean of opsins
Authors: De Vivo Giacinto , Pelettier Eric , Feuda Roberto , D’Aniello Salvatore 
Published: November 2024

AbstractIn this study, we explored the diversity and evolution of opsins using meta-omic data from the TARA Oceans and TARA Polar Circle expeditions, one of the largest marine datasets available. By using molecular clustering and phylogenetic analyses, we identified and characterized opsins across various taxonomic groups and gene subfamilies. Our results indicate that the majority of opsin sequences belong to arthropods and vertebrates. However, we also detected sequences from all major opsin subfamilies, including r-opsin, c-opsin, xenopsin, and Group-4 opsins. Despite the broad taxonomic scope, no novel opsin gene families were discovered, suggesting a comprehensive understanding of opsin diversity in marine ecosystems. Additionally, we present novel opsin sequences from less-studied taxa, which may serve as a valuable resource for future research into opsin function and diversity.
Greening rates are sensitive to methodology and biology; comment to Sustained greening of the Antarctic Peninsula observed from satellites
Authors: Bokhorst S. , Huisman S. , de Jonge I.K. , Janssen T.A.J. , Cornelissen J.H.C. , Hughes K. A. , Convey P. 
Published: November 2024

AbstractRoland et al.1claim to provide evidence for a ‘greening trend’ throughout the Antarctic Peninsula region over the last four decades, based on satellite remote sensing data. However, the early period vegetation cover estimates do not match with the likely extent of vegetated areas in this region at that time, raising doubts about the magnitude of any greening trend. Furthermore, growth rates of mosses and higher plants in Antarctica are insufficient to explain the 14-fold green cover expansion claimed, and neither have such changes been observed at long-term monitoring sites or from field warming studies. The reported satellite time series analyses of the presented trend seems biased by satellite image availability, lack of consistency in the areas covered by imagery and processing pitfalls. Antarctic terrestrial ecosystems are indeed predicted to become greener with climate change, but at much slower rates than reported by Roland et al.1.
"Transcriptional Regulation of human NMNAT2: Insights from 3D Genome Sequencing and Bioinformatics"
Authors: Chang Yu Chen , Yang Sen , Cho Minyoung , Nho Kwangsik , Baizabal José-Manuel , Lu Hui-Chen 
Published: November 2024

AbstractNicotinamide mononucleotide adenylyl transferases 2 (NMNAT2) is a crucial nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme essential for neuronal health. In the Religious Orders Study/Memory and Aging Project (ROSMAP), human brain levels of NMNAT2 mRNA positively correlated with cognitive capabilities in older adults. NMNAT2 mRNA abundance is significantly reduced following various insults or proteinopathies. To elucidate the transcriptional regulation of NMNAT2, we employed circular chromosome conformation capture followed by high-throughput sequencing (4C-seq) to identify potential NMNAT2 enhancer and silencer regions by determining genomic regions interacting with the NMNAT2 promoter in human SH-SY5Y cells. We discovered distinct NMNAT2 promoter interactomes in undifferentiated versus neuron-like SH-SY5Y cells. Utilizing bioinformatics analyses, we identified putative transcriptional factors and NMNAT2-associated genes. Notably, the mRNA levels of many of these genes showed a significant correlation with NMNAT2 mRNA levels in ∼400 single-nuclei RNA-seq datasets from ROSMAP. Additionally, using CRISPR-Cas9 strategies, we confirmed the requirement of two specific genomic regions within the interactomes and four transcription factors in regulating NMNAT2 transcription. In summary, our study identifies genomic loci containing NMNAT2 regulatory elements and predicts associated genes and transcription factors through computational analyses.
YY1 Enhances the Stability of HIF-1α Protein by Interacting with NUSAP1 in Macrophages within the Prostate Cancer Microenvironment
Authors: Li Wenchao , Chen SaiSai , Lu Jian , Mao Weipu , Zheng Shiya , Zhang Minhao , Wu Tiange , Chen Yurui , Lu Kai , Chu Chunyan , Shu Chuanjun , Hou Yue , Yang Xue , Shi Naipeng , Chen Zhijun , Zhang Lihua , Zhang Lei , Na Rong , Chen Ming , Ju Shenghong , Zhang Dingxiao , Ma Yi , Xu Bin 
Published: November 2024

AbstractImmune checkpoint therapy for prostate cancer (PCa) has failed in clinical trials; however, the precise underlying mechanisms involved remain elusive. PCa, a classic "immune-cold” tumor, is characterized by an immunosuppressive tumor microenvironment. Within this milieu, macrophages, the predominant immune cell population, have a propensity to infiltrate the hypoxic zones of tumors. In a previous study, we showed that Yin Yang 1 (YY1) is highly expressed in macrophages in PCa tissues. Here, through multiplexed imaging mass cytometry (IMC) of a PCa tissue microarray, we further demonstrate that YY1+macrophages aggregate in hypoxic areas of tumors and that hypoxia promotes the phase separation of YY1 in the nucleus by increasing YY1 tyrosine phosphorylation in macrophages. Furthermore, YY1 binds to NUSAP1 and promotes the SUMOylation of HIF-1α, which promotes phase separation and stabilization of the HIF-1α protein. We also demonstrated that either treatment with a small molecule inhibitor (tenapanor) to decrease the YY1–NUSAP1–HIF-1α interaction or myeloid-specific YY1 gene knockout impairs subcutaneous PCa tumor formation. Furthermore, we present a first-generation tetrahedral DNA nanostructure (TDN) based on the proteolysis targeting chimera (PROTAC) technique, named YY1-DcTAC, which targets and degrades YY1 in tumor-associated macrophages. In a PCa mouse model, YY1-DcTAC exhibited prolonged drug efficacy, robust macrophage-specific responsiveness, potent antitumor effects, and increased CD8+T cell tumor infiltration. In summary, our findings underscore the pivotal role of YY1 within the hypoxia/HIF-1α pathway in tumor-associated macrophages and affirm the therapeutic potential of targeting YY1 for treating PCa.