bluuebunny/crossref_metadata_2025_split huggingface dataset:
Olfactory impairment and the risk of major adverse cardiovascular outcomes in older adults
Authors: Chamberlin Keran W. , Yuan Yaqun , Li Chenxi , Luo Zhehui , Reeves Mathew , Kucharska-Newton Anna , Pinto Jayant M. , Ma Jiantao , Simonsick Eleanor M. , Chen Honglei 
Published: October 2023

AbstractBackgroundOlfactory impairment is common in older adults and may be associated with adverse cardiovascular health; however, empirical evidence is sparse.ObjectiveTo examine olfaction and the risk of coronary heart disease (CHD), stroke, and congestive heart failure (CHF).MethodsThis study included 2,537 older adults (aged 75.6±2.8 years) from the Health ABC Study with olfaction assessed by the 12-item Brief Smell Identification Test in 1999-2000, defined as poor (score ≤8), moderate (9-10), or good (11-12). The outcomes were incident CHD, stroke, and CHF.ResultsDuring up to 12-year follow-up, 353 incident CHD, 258 stroke, and 477 CHF events were identified. Olfaction was associated with incident CHF, but not with CHD or stroke. After adjusting for demographics, the cause-specific hazard ratio (HR) of CHF was 1.35 (95% confidence interval (CI): 1.08, 1.70) for moderate and 1.39 (95%CI: 1.09, 1.76) for poor olfaction. With additional adjustment for lifestyle, chronic diseases, and biomarkers of CHF, the HR was modestly attenuated to 1.32 (95%CI: 1.05, 1.66) for moderate and 1.28 (95%CI: 1.01, 1.64) for poor olfaction. These associations were robust in pre-planned subgroup analyses by age, sex, race, and prevalent CHD/stroke. However, the associations appeared to be evident among participants who reported very-good-to-excellent health (HR=1.47 (95%CI: 1.02, 2.13) for moderate and 1.76, (95%CI: 1.20, 2.57) for poor olfaction). In contrast, null association with CHF was found among those with fair-to-poor self-reported health.ConclusionsIn community-dwelling older adults, a single olfaction test was associated with a long-term risk for incident CHF, particularly among those reporting very-good-to-excellent health.
Transcriptome Profiling and Characterization of Peritoneal Metastasis Ovarian Cancer Xenografts in Humanized Mice
Authors: Kang Sung Wan , Lee Ji-young , Kang Ok-Ju , Kim Yong-Man , Choi Eun Kyung , Lee Shin-Wha 
Published: October 2023

ABSTRACTBackgroundAlthough immunotherapy has not yet been as successful in ovarian cancer (OC), it remains a potential therapeutic strategy. Preclinical models of OC are necessary to evaluate the efficacy of immuno-oncology (IO) drugs targeting human cancer and immune components but have been underutilized. Developing mouse models with a humanized (Hu) immune system can help understand the human immune response to IO drugs, including immune checkpoint inhibitors (ICIs), which have demonstrated limited effectiveness in OC patients.MethodsWe established OC xenograft Hu-mouse models by intraperitoneally injecting luciferase-expressing SKOV-3 Luc and OVCAR-3 Luc OC cells into CD34+Hu-mice. Tumor growth was monitored through bioluminescence imaging (BLI). We assessed the efficacy of PD-1 blockade with pembrolizumab in the SKOV-3 Luc Hu-mouse model. The immune profiles of the tumors were characterized using colorimetric immunostaining and flow cytometry. Additionally, we analyzed RNA-seq data to investigate the gene expression signature of pembrolizumab refractory tumors.ResultsWe confirmed tumor development in both OC cell lines within CD34+Hu-mice. In these models, human lymphocyte and myeloid cell subsets were present in the tumors, draining lymph nodes, blood, and spleens. The SKOV-3 Luc tumor-bearing Hu-mice did not respond to pembrolizumab monotherapy. These tumors exhibited a high presence of tumor-infiltrating macrophages. Tumors in Hu-mice unresponsive to pembrolizumab showed a lower abundance of CD8+T-cells, memory B cells, plasma cells, and a higher proportion of naïve M0 macrophages and mast cells compared to the PBS control. Furthermore, we identified 43 significantly enriched gene sets in these tumors. The differentially expressed genes (DEGs) were predominantly enriched in HDAC class I, RB1, KLF1/3, TCF21, MYD88, SMARCE1 target genes, and genes associated with epithelial-mesenchymal transition (EMT) and fibroblasts.ConclusionOur xenograft Hu-mouse model of OC provides a valuable tool for investigating the efficacy of IO drugs. The insights gained from this model offer potential avenues to explore mechanisms of resistance to PD-1/PD-L1 blockade in OC.
Docking for molecules that bind in a symmetric stack with SymDOCK
Authors: Smith Matthew S. , Knight Ian S. , Kormos Rian C. , Pepe Joseph G. , Kunach Peter , Diamond Marc I. , Shahmoradian Sarah H. , Irwin John J. , DeGrado William F. , Shoichet Brian K. 
Published: October 2023

AbstractDiscovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of much current interest. In recent structures, ligands bind in stacks in the tau fibrils to reflect the rotational and translational symmetry of the fibril itself; in these structures the ligands make few interactions with the protein but interact extensively with each other. To exploit this symmetry and stacking, we developed SymDOCK, a method to dock molecules that follow the protein’s symmetry. For each prospective ligand pose, we apply the symmetry operation of the fibril to generate a self-interacting and fibril-interacting stack, checking that doing so will not cause a clash between the original molecule and its image. Absent a clash, we retain that pose and add the ligand-ligand van der Waals energy to the ligand’s docking score (here using DOCK3.8). We can check these geometries and energies using an implementation of ANI, a neural network-based quantum-mechanical evaluation of the ligand stacking energies. In retrospective calculations, symmetry docking can reproduce the poses of three tau PET tracers whose structures have been determined. More convincingly, in aprospectivestudy SymDOCK predicted the structure of the PET tracer MK-6240 bound in a symmetrical stack to AD PHF tau before that structure was determined; the docked pose was used to determine how MK-6240 fit the cryo-EM density. In proof-of-concept studies, SymDOCK enriched known ligands over property-matched decoys in retrospective screens without sacrificing docking speed, and can address large library screens that seek new symmetrical stackers. Future applications of this approach will be considered.
Cell surface architecture of the cultivated DPANN archaeonNanobdella aerobiophila
Authors: Kato Shingo , Tahara Yuhei O. , Nishimura Yuki , Uemastu Katsuyuki , Arai Takahiro , Nakane Daisuke , Ihara Ayaka , Nishizaka Takayuki , Iwasaki Wataru , Itoh Takashi , Miyata Makoto , Ohkuma Moriya 
Published: October 2023

AbstractThe DPANN archaeal clade includes obligately ectosymbiotic species. Their cell surfaces potentially play an important role in the symbiotic interaction between the ectosymbionts and their hosts. However, little is known about the mechanism of the ectosymbiosis. Here, we show cell surface structures of the cultivated DPANN archaeonNanobdella aerobiophilastrain MJ1Tand its hostMetallosphaera sedulastrain MJ1HA, using a variety of electron microscopy techniques, i.e., negative-staining transmission electron microscopy (TEM), quick-freeze deep-etch (QFDE) TEM, and 3D electron tomography. The thickness, unit size, and lattice symmetry of the S-layer of strain MJ1Twere different from those of the host archaeon strain MJ1HA. Genomic and transcriptomic analyses highlighted the most highly expressed MJ1Tgene for a putative S-layer protein with multiple glycosylation sites and immunoglobulin-like folds, which has no sequence homology to known S-layer proteins. In addition, genes for putative pectin lyase- or lectin-like extracellular proteins, which are potentially involved in symbiotic interaction, were found in the MJ1T genome based on in silico 3D protein structure prediction. Live cell imaging at the optimum growth temperature of 65°C indicated that cell complexes of strains MJ1Tand MJ1HA were motile, but sole MJ1Tcells were not. Taken together, we propose a model of the symbiotic interaction and cell cycle ofNanobdella aerobiophila.ImportanceDPANN archaea are widely distributed in a variety of natural and artificial environments, and may play a considerable role in the microbial ecosystem. All of the cultivated DPANN archaea so far need host organisms for their growth, i.e., obligately ectosymbiotic. However, the mechanism of the ectosymbiosis by DPANN archaea is largely unknown. To this end, we performed a comprehensive analysis of the cultivated DPANN archaeon,Nanobdella aerobiophila, using electron microscopy, live cell imaging, transcriptomics, and genomics including 3D protein structure prediction. Based on the results, we propose a reasonable model of the symbiotic interaction and cell cycle ofNanobdella aerobiophila, which will enhance our understanding of the enigmatic physiology and ecological significance of DPANN archaea.
The proteomic toolbox for identification, quantification, and characterization of polyclonal antibodies
Authors: Tang Weize , Drabovich Andrei P. 
Published: October 2023

SUMMARYRecent advances in proteomics and mass spectrometry facilitated the in-depth characterization of monoclonal antibodies and enabled innovative approaches for the quantification of polyclonal antibodies generated against numerous antigens. Human respiratory syncytial virus (RSV) is a contagious respiratory pathogen often manifested as a common cold infection in adults and more serious symptoms in infants and the elderly population. Here, we used a reference IgG1κ monoclonal antibody NISTmAb 8671 and its affinity interaction with an RSV fusion glycoprotein F as a model to develop the proteomic toolbox for identification, quantification, and characterization of polyclonal antibodies. Our toolbox integrated a variety of proteomic and mass spectrometry approaches for accurate mass measurements of antibody fragments, antibody digestion with the complimentary proteases (trypsin, asparaginase, and proalanase), immunoaffinity enrichments, and bottom-up or middle-down proteomics. We measured absolute concentrations of anti-RSV antibody isotypes and subclasses in 69 serum samples of healthy individuals and revealed IgG1 (2,580 ng/mL), IgA1 (280 ng/mL), and IgM (180 ng/mL) as the most abundant isotypes. Interestingly, we also identified the presence of IgG2 (74 ng/ml), IgG4 (4.9 ng/mL) and IgA2 (5.5 ng/mL) antibodies. Interactome measurements detected the consistent co-precipitation of C1q complement complexes. Repertoire profiling of the variable regions of polyclonal antibodies revealed the frequent use of IGHV3 subgroup genes, while IGHV5-51 was the most abundant single gene of the anti-RSV polyclonal antibody response. The presented toolbox will facilitate the in-depth characterization of polyclonal antibodies and pave the way to quantitative approaches in serological studies and precision immunology.
Inhibition ofPseudomonas aeruginosaquorum sensing by chemical induction of the MexEF-oprN efflux pump
Authors: Kristensen Rasmus , Andersen Jens Bo , Rybtke Morten , Jansen Charlotte Uldahl , Fritz Blaine Gabriel , Kiilerich Rikke Overgaard , Uhd Jesper , Bjarnsholt Thomas , Qvortrup Katrine , Tolker-Nielsen Tim , Givskov Michael , Jakobsen Tim Holm 
Published: October 2023

ABSTRACTThe cell-to-cell communication system quorum sensing (QS), used by various pathogenic bacteria to synchronize gene expression and increase host invasion potentials, is studied as a potential target for persistent infection control. To search for novel molecules targeting the QS system in the Gram-negative opportunistic pathogenPseudomonas aeruginosaa chemical library consisting of 3280 small compounds from LifeArc was screened. A series of ten conjugated phenones that have not previously been reported to target bacteria were identified as inhibitors of QS inP. aeruginosa. Two lead compounds (ethylthio enynone and propylthio enynone) were resynthesized for verification of activity and further elucidation of the mode of action. The isomeric pure Z-ethylthio enynone was used for RNA sequencing revealing a strong inhibitor of QS-regulated genes and the QS-regulated virulence factors rhamnolipid and pyocyanin were significantly decreased by treatment with the compounds. A transposon mutagenesis screen performed in a newly constructedlasB-gfpmonitor strain identified the target of Z-ethylthio enynone inP. aeruginosato be the MexEF-OprN efflux pump, which was further established using definedmexknockout mutants. Our data indicate that the QS inhibitory capabilities of Z-ethylthio enynone were caused by the drainage of intracellular signal molecules as a response to chemical-induced stimulation of the MexEF-oprN efflux pump thereby inhibiting the auto-generated positive feedback and its enhanced signal-molecule synthesis.
Spatially resolved distribution of pancreatic hormones proteoforms by MALDI-imaging mass spectrometry
Authors: Sisnande Tháyna , Brum Felipe Lopes , Matias Daiane O. , Ribeiro Fernando de Sá , Moulin Thayana Beninatto , Mohana-Borges Ronaldo , de Magalhães Mariana T. Q. , Lima Luís Maurício T. R. 
Published: October 2023

ABSTRACTZinc plays crucial role in the immune system and endocrine processes. Dietary zinc restriction leads to the degeneration of the endocrine pancreas resulting in hormonal imbalance in β-cell. Proteostasis may vary depending on the stage of a pathophysiological process, motivating the development of tools aimed at the direct analysis of biological status. Among proteomics methods, MALDI-ToF-MS can serve as a rapid peptidomics tool from analysis of extracts or by histological imaging. Here we report the optimization of MALDI imaging mass spectrometry analysis of thin histological sections from mouse pancreas, allowing the identification of major islet peptide hormones and major accumulated precursors and/or proteolytic products of peptide hormones. Cross-validation of the identified peptide hormones was performed by LC-ESI-MS from pancreatic islet extracts. Mice fed a zinc-restricted diet had a relatively lower amount of peptide intermediates in comparison with the control group. These data provide evidence for complex modulation of proteostasis by an imbalance of micronutrients, directly accessed by MALDI-MSI.
Computational mechanism underlying switching of motor actions
Authors: Zhong Shan , Pouratian Nader , Christopoulos Vassilios 
Published: October 2023

AbstractSurviving in a constantly changing environment requires not only the ability to select actions, but also the flexibility to stop and switch actions when necessary. Extensive research has been devoted to understanding how the brain switches actions, yet the computations underlying switching and how it relates to selecting and stopping processes remain elusive. A central question is whether switching is an extension of the stopping process or involves different mechanisms. To address this question, we modeled action regulation tasks with a neurocomputational theory and evaluated its predictions on individuals performing reaches in a dynamic environment. Our findings suggest that, unlike stopping, switching does not necessitate a proactive pause mechanism to delay movement onset. However, switching engages a pause mechanism after movement onset, if the new target location is unknown prior to switch signal. These findings offer a new understanding of the action-switching computations, opening new avenues for future neurophysiological investigations.
Molecular mechanism of NAD+binding to the Nudix homology domains of DBC1
Authors: Ou Liming , Zhao Xuechen , Wu Ivy (Jing) , Xiong Zhiyuan , Ruan Zhi , Zhou Guangyu , Chen Wen 
Published: October 2023

AbstractDBC1 (deleted in breast cancer 1) is a human nuclear protein that modulates the activities of various proteins. NAD+(oxidized form of nicotinamide adenine dinucleotide) is thought to potentially bind to the Nudix homology domains (NHDs) of DBC1, thereby regulating DBC1-PARP1 [poly (adenosine diphosphate–ribose) polymerase] interactions, the modulation of which may restore DNA repair to protect against cancer, radiation, and aging. Therefore, our study comprehensively employed methods including NMR (Nuclear Magnetic Resonance), ITC (isothermal titration calorimetry), genetic mutation, and computer biology to thoroughly investigate the molecular mechanism of the binding interaction between NAD+and its precursor NMN with the NHD domain of DBC1 (DBC1354-396). The results from NMR and ITC indicate that NAD+likely interacts with DBC1354-396through hydrogen bonding, with a binding affinity nearly twice that of NMN. The key binding sites are primarily E363 and D372. Molecular Docking further revealed the importance of conventional hydrogen bonds and carbon-hydrogen bonds in the binding process. These findings may lead to a better understanding of how NAD+regulates the physiological functions of DBC1, thereby offering guiding principles for the development of targeted therapies and drug research focused on tumor diseases associated with DBC1.
A normalization method that controls for total RNA abundance affects the identification of differentially expressed genes, revealing bias toward morning-expressed responses
Authors: Laosuntisuk Kanjana , Vennapusa Amaranatha , Somayanda Impa M. , Leman Adam R. , Jagadish SV Krishna , Doherty Colleen J. 
Published: October 2023

AbstractRNA-Sequencing is widely used to investigate changes in gene expression at the transcription level in plants. Most plant RNA-Seq analysis pipelines base the normalization approaches on the assumption that total transcript levels do not vary between samples. However, this assumption has not been demonstrated. In fact, many common experimental treatments and genetic alterations affect transcription efficiency or RNA stability, resulting in unequal transcript abundance. The addition of synthetic RNA controls is a simple correction that controls for variation in total mRNA levels. However, adding spike-ins appropriately is challenging with complex plant tissue, and carefully considering how they are added is essential to their successful use. We demonstrate that adding external RNA spike-ins as a normalization control produces differences in RNA-Seq analysis compared to traditional normalization methods, even between two times of day in untreated plants. We illustrate the use of RNA spike-ins with 3’ RNA-Seq and present a normalization pipeline that accounts for differences in total transcriptional levels. We evaluate the effect of normalization methods on identifying differentially expressed genes in the context of identifying the effect of the time of day on gene expression and response to chilling stress in sorghum.
Deciphering the biology and chemistry of the mutualistic partnership betweenBacillus velezensisand the arbuscular mycorrhizal fungusRhizophagus irregularis
Authors: Anckaert Adrien , Stéphane Declerck , Poussart Laure-Anne , Lambert Stéphanie , Catherine Helmus , Boubsi Farah , Steels Sebastien , Arias Anthony Argüelles , Calonne-Salmon Maryline , Ongena Marc 
Published: October 2023

AbstractArbuscular mycorrhizal (AM) fungi (e.g.Rhizophagus irregularis) recruit specific bacterial species in their hyphosphere. However, the chemical interplay and the mutual benefit of this intricate partnership have not yet been investigated especially as it involves bacteria known as strong producers of antifungal compounds such asBacillus velezensis. Here, we show that the soil dwellingB. velezensismigrates along the hyphal network of the AM fungusR. irregularis, forming biofilms and inducing metabolic fluxes that contributes to host plant root colonization by the bacterium. During hyphosphere colonization,R. irregularismodulates the biosynthesis of specific lipopeptides and antimicrobial compounds inB. velezensisas a mechanism toward-off mycoparasitic fungi and bacteria to ensure stable coexistence. These mutual benefits are extended into a tripartite context via the provision of enhanced protection to the host plant through the induction of systemic resistance.
Haematopoietic stem cell numbers are not solely determined by niche availability
Authors: Takeishi Shoichiro , Marchand Tony , Koba Wade R. , Borger Daniel K. , Xu Chunliang , Guha Chandan , Bergman Aviv , Frenette Paul S. , Gritsman Kira , Steidl Ulrich 
Published: October 2023

AbstractHaematopoietic stem cells (HSCs) reside in specialized microenvironments, also referred to as niches, and it has been widely believed that HSC numbers are determined by the niche size alone1–5. However, the vast excess of the number of niche cells over that of HSCs raises questions about this model. We initially established a mathematical model of niche availability and occupancy, which predicted that HSC numbers are restricted at both systemic and local levels. To address this question experimentally, we developed a femoral bone transplantation system, enabling us to increase the number of available HSC niches. We found that the addition of niches does not alter total HSC numbers in the body, regardless of whether the endogenous (host) niche is intact or defective, suggesting that HSC numbers are limited at the systemic level. Additionally, HSC numbers in transplanted wild-type femurs did not increase beyond physiological levels when HSCs were mobilized from defective endogenous niches to the periphery, indicating that HSC numbers are also constrained at the local level. Our study demonstrates that HSC numbers are not solely determined by niche availability, thereby rewriting the long-standing model for the regulation of HSC numbers.
Comprehensive analysis of the Aquaporin genes inEucalyptus grandissuggests potential targets for drought stress tolerance
Authors: Seidel Dayana S. , Claudino Paulo H. , Sperotto Gabriela , Wendt Simone N. , Shomo Zachery D. , Mural Ravi V. , Dias Henrique M. 
Published: October 2023

AbstractThis study delves into the comprehensive analysis ofAQPgenes inEucalyptus grandis, providing insights into their genomic abundance, diversification, expression patterns across tissues, and responses to drought stress. We identified 53AQPgenes in theEucalyptus grandisgenome, categorized into four subfamilies:AQP-NIP,AQP-SIP,AQP-PIP, andAQP-TIP. This abundance ofAQPgenes is a reflection of gene duplications, both tandem and whole-genome, which have shaped their expansion. The chromosomal distribution of these genes reveals their widespread presence across the genome, with some subfamilies exhibiting more tandem duplications, suggesting distinct roles and evolutionary pressures. Sequence analysis uncovered characteristic motifs specific to different AQP subfamilies, demonstrating the diversification of protein and targeting. The expression profiles ofAQPgenes in various tissues in bothArabidopsis thalianaandEucalyptus grandisshowcased variations, with root tissues showing higher expression levels. Notably,AQP-PIPgenes consistently exhibited robust expression across tissues, highlighting their importance in maintaining water regulation within plants. Furthermore, the study investigated the response ofAQPgenes to drought stress and rehydration, revealing differential expression patterns.EgAQP-NIPandEgAQP-TIPgenes were up-regulated during drought stress, emphasizing their role in osmotic equilibrium and water transport. Conversely,EgAQP-PIPgenes showed down-regulation during drought stress but were up-regulated upon rehydration, indicating their involvement in water movement across cell membranes. Overall, this research contributes to our understanding ofAQPgenes inEucalyptus grandis, shedding light on their genomic evolution, expression patterns, and responses to environmental challenges, particularly drought stress. This information can be valuable for future studies aimed at enhancing the drought resilience of woody perennial plants likeEucalyptus grandis.