bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-resident regulatory T cells in pancreatic cancer express the αvβ5 integrin as a targetable activation marker
Authors: Suzuki Kodai , Kunisada Yuki , Miyamura Norio , Eikawa Shingo , Hurtado de Mendoza Tatiana , Mose Evangeline S. , Lu Caisheng , Kuroda Yukihito , Ruoslahti Erkki , Lowy Andrew M. , Sugahara Kazuki N. 
Published: May 2023

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) has abundant immunosuppressive regulatory T cells (Tregs), which contribute to a microenvironment resistant to immunotherapy. Here, we report that Tregs in the PDAC tissue, but not those in the spleen, express the αvβ5 integrin in addition to neuropilin-1 (NRP-1), which makes them susceptible to the iRGD tumor-penetrating peptide, which targets cells positive for αv integrin- and NRP-1. As a result, long-term treatment of PDAC mice with iRGD leads to tumor-specific depletion of Tregs and improved efficacy of immune checkpoint blockade. αvβ5 integrin+Tregs are induced from both naïve CD4+T cells and natural Tregs upon T cell receptor stimulation, and represent a highly immunosuppressive subpopulation of CCR8+Tregs. This study identifies the αvβ5 integrin as a marker for activated tumor-resident Tregs, which can be targeted to achieve tumor-specific Treg depletion and thereby augment anti-tumor immunity for PDAC therapy.
A novel approach to modeling side chain ensembles of the bifunctional spin label RX
Authors: Tessmer Maxx H. , Stoll Stefan 
Published: May 2023

AbstractWe introduce a novel approach to modeling side chain ensembles of bifunctional spin labels. This approach utilizes rotamer libraries to generate side chain conformational ensembles. Because the bifunctional label is constrained by two attachment sites, the label is split into two monofunctional rotamers which are first attached to their respective sites, then rejoined by a local optimization in dihedral space. We validate this method against a set of previously published experimental data using the bifunctional spin label, RX. This method is relatively fast and can readily be used for both experimental analysis and protein modeling, providing significant advantages over modeling bifunctional labels with molecular dynamics simulations. Use of bifunctional labels for site directed spin labeling (SDSL) electron paramagnetic resonance (EPR) spectroscopy dramatically reduces label mobility, which can significantly improve resolution of small changes in protein backbone structure and dynamics. Coupling the use of bifunctional labels with side chain modeling methods allows for improved quantitative application of experimental SDSL EPR data to protein modeling.Statements and DeclarationsThe authors declare no competing interests.
Oxic microbial electrosynthesis can be more energy efficient for biomass production than knallgas or photosynthesis based processes
Authors: Rominger Leonie , Hackbarth Max , Jung Tobias , Scherzinger Marvin , Horn Harald , Kaltschmitt Martin , Gescher Johannes 
Published: May 2023

AbstractData on the efficiency and development of continuous processes are scarce in the emerging field of oxic microbial electrosynthesis (OMES). Therefore, the recently isolated knallgas bacteriumKyrpidia spormanniiwas observed in a bioelectrochemical flow cell setup to study biomass formation and energy efficiency of cathode dependent growth. The study revealed that a potential of -500 mV vs. the standard hydrogen electrode (SHE) caused differences in the structure of the biofilm developing on the cathode, but had almost no impact on biomass growth behavior compared to -375 mV vs. SHE. No growth was observed at 0 mV vs SHE. Coulombic efficiency (CE) was calculated for the cultivation at -500 mV vs. SHE. The process can be conducted with the same electron efficiency as traditional gas fermentation. The solar energy demand with 67.89 kWh kg-1dry biomass is highly competitive to alternative and already established processes for converting (solar) energy to biomass. Additionally, with suggestions for a biomass harvesting method and subsequent recultivation, proof of principle for a continuously operable process was provided. The results pave the way for a new concept in carbon dioxide-based biotechnology.Significance statementTo mitigate global climate change, it is imperative to transition the human economy to a different resource foundation, moving away from fossil fuels and reducing atmospheric carbon dioxide levels. Biotechnological production based on CO2necessitates a supply of energy and electrons. This study reveals that an oxic process, wherein bacteria are directly cultivated as a biofilm on the cathode surface of a bioelectrochemical system, can exhibit higher energy efficiency than plant-based systems or systems reliant on hydrogen generated through water electrolysis. This technology could be instrumental in establishing carbon dioxide and renewable energy as the foundation for feed, food, and platform chemical production.
Cell type deconvolution of bulk blood RNA-Seq to reveal biological insights of neuropsychiatric disorders
Authors: Boltz Toni , Schwarz Tommer , Bot Merel , Hou Kangcheng , Caggiano Christa , Lapinska Sandra , Duan Chenda , Boks Marco P. , Kahn Rene S. , Zaitlen Noah , Pasaniuc Bogdan , Ophoff Roel 
Published: May 2023

AbstractGenome-wide association studies (GWAS) have uncovered susceptibility loci associated with psychiatric disorders like bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome with unknown causal mechanisms of the link between genetic variation and disease risk. Expression quantitative trait loci (eQTL) analysis of bulk tissue is a common approach to decipher underlying mechanisms, though this can obscure cell-type specific signals thus masking trait-relevant mechanisms. While single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell type proportions and cell type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-Seq from 1,730 samples derived from whole blood in a cohort ascertained for individuals with BP and SCZ this study estimated cell type proportions and their relation with disease status and medication. We found between 2,875 and 4,629 eGenes for each cell type, including 1,211 eGenes that are not found using bulk expression alone. We performed a colocalization test between cell type eQTLs and various traits and identified hundreds of associations between cell type eQTLs and GWAS loci that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on cell type expression regulation and found examples of genes that are differentially regulated dependent on lithium use. Our study suggests that computational methods can be applied to large bulk RNA-Seq datasets of non-brain tissue to identify disease-relevant, cell type specific biology of psychiatric disorders and psychiatric medication.
NSC95397 is a Novel HIV-1 Latency Reversing Agent
Authors: Nichols Doyle Randilea , Yang Vivian , Kayode Yetunde I. , Damoiseaux Robert , Taylor Harry E. , Fregoso Oliver I. 
Published: May 2023

The latent viral reservoir represents one of the major barriers of curing HIV-1. Focus on the “kick and kill” approach, in which virus expression is reactivated then cells producing virus are selectively depleted, has led to the discovery of many latency reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ∼4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair – highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, that shows potential for synergy with known LRAs, and that may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency.ImportanceOne of the largest barriers to curing HIV-1 is the latent viral reservoir – this is when the virus incorporates itself into long-lived cells in the body, ready to reactivate and re-seed infection. Destroying dormant HIV-1 is one potential pathway to a cure, yet no therapeutics have been discovered to work well in patients. In our study, we identified a compound, NSC95397, that can awaken dormant HIV-1 on its own through novel mechanisms not previously linked to HIV-1 latency. Moreover, NSC95397 improves the abilities of previously identified compounds to reactivate latent HIV-1. Thus, our study has identified a compound that can help towards the better understanding of an HIV-1 cure.
The Australian Eye and Ear Health Survey (AEEHS): study protocol for a population-based cross-sectional study
Authors: Kha Richard , Macken Oonagh , Mitchell Paul , Liew Gerald , Keay Lisa , Waddell Colina , Yang Eleanor , Do Vu , Fricke Tim , Newall John , Gopinath Bamini 
Published: May 2023

AbstractIntroductionVision and hearing impairments are highly prevalent and have a significant impact on physical, psychological and social wellbeing. There is a need for accurate, contemporary national data on the prevalence, risk factors and impacts of vision and hearing loss in Australian adults.ObjectivesThe Australian Eye and Ear Health Survey (AEEHS) aims to determine the prevalence, risk factors and impacts of vision and hearing loss in both Aboriginal and Torres Strait Islander and non-Indigenous older adults.Methods and analysisThe AEEHS is a population-based cross-sectional survey which will include 5,000 participants (3250 non-Indigenous aged 50 years or older and 1750 Aboriginal and Torres Strait Islander people aged 40 years or older) from 30 sites covering urban and rural/regional geographic areas, selected using a multi-stage, random cluster sampling strategy. Questionnaires will be administered to collect data on socio-demographic, medical, ocular and otological history. The testing battery includes assessment of blood pressure, blood sugar, anthropometry, visual acuity (presenting, unaided, pinhole and best-corrected), refraction, tonometry, slit lamp and dilated eye examination, ocular imaging including optical coherence tomography (OCT), OCT-angiography and retinal photography, and automated visual fields. Audiometry, tympanometry and video otoscopy will also be performed. The primary outcomes are age-standardised prevalence of cause-specific vision and hearing impairment. Secondary outcomes are prevalence of non-blinding eye diseases (including dry eye disease), patterns in health service utilisation, universal health coverage metrics, risk factors for vision and hearing impairment, and impact on quality of life.EthicsThe protocol for this study was approved by the University of Sydney Human Research Ethics Committee (HREC-2020/818) and Australian Institute of Aboriginal and Torres Strait Islander Studies (AIATSIS) Research Ethics Committee (HREC-EO303-20211008).Dissemination of resultsOur findings will be disseminated through presentation at meetings and peer-reviewed publications. Findings will also be widely disseminated by project partners with the aim of improving public health policy directives and equitable service delivery to prevent avoidable vision and hearing impairment in Australia.
IAMSAM : Image-based Analysis of Molecular signatures using the Segment-Anything Model
Authors: Lee Dongjoo , Park Jeongbin , Cook Seungho , Yoo Seongjin , Lee Daeseung , Choi Hongyoon 
Published: May 2023

AbstractSpatial transcriptomics is a cutting-edge technique that combines gene expression data with spatial information, allowing researchers to study gene expression patterns within tissue architecture. Here, we present IAMSAM, a user-friendly web-based tool for analyzing spatial transcriptomics data focusing on morphological features. IAMSAM accurately segments tissue images using the Segment-anything model, allowing for the semi-automatic selection of regions of interest based on morphological signatures. Furthermore, IAMSAM provides downstream analysis, such as identifying differentially expressed genes, enrichment analysis, and cell type prediction within the selected regions. With its simple interface, IAMSAM empowers researchers to explore and interpret heterogeneous tissues in a streamlined manner.
Characterizing physical interactions between male and female mosquitoes (Aedes aegypti) in relation to female receptivity and insemination outcomes using a hydrophobic fluorescent dye
Authors: Cramer Monica M. , Gabel Thomas M. , Duvall Laura B. 
Published: May 2023

ABSTRACTAedes aegypti, the yellow fever mosquito, presents a major threat to human health across the globe as a vector of disease-causing pathogens. Females of this species generally mate only once. From this single mating event, the female stores sufficient sperm to fertilize the multiple clutches of eggs produced during her lifetime. Mating causes dramatic changes in the female’s behavior and physiology, including a lifetime suppression of her mating receptivity. Female rejection behaviors include male avoidance, abdominal twisting, wing-flicking, kicking, and not opening vaginal plates or extruding the ovipositor. Many of these events occur on a scale that is too miniscule or fast to see by eye, so high-resolution videography has been used to observe these behaviors instead. However, videography can be labor intensive, require specialized equipment, and often requires restrained animals. We used an efficient, low-cost method to record physical contact between males and females during attempted and successful mating, determined by recording spermathecal filling after dissection. A hydrophobic oil-based fluorescent dye can be applied to the abdominal tip of one animal and can be subsequently transferred to the genitalia of animals of the opposite sex when genital contact occurs. Our data indicate that male mosquitoes make high levels of contact with both receptive and unreceptive females and that males attempt to mate with more females than they successfully inseminate. Female mosquitoes with disrupted remating suppression mate with and produce offspring from multiple males, transferring dye to each. These data suggest that physical copulatory interactions occur independently of the female’s receptivity to mate and that many of these interactions represent unsuccessful mating attempts that do not result in insemination.
Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs inDrosophila melanogaster
Authors: Sklias Athena , Cruciani Sonia , Marchand Virginie , Spagnuolo Mariangela , Lavergne Guillaume , Bourguignon Valérie , Dreos René , Novoa Eva Maria , Motorin Yuri , Roignant Jean-Yves 
Published: May 2023

AbstractDuring their maturation, ribosomal RNAs (rRNAs) are decorated by hundreds of chemical modifications that participate in proper folding of rRNA secondary structures and therefore in ribosomal function. Along with pseudouridine, methylation of the 2′-hydroxyl ribose moiety (Nm) is the most abundant modification of rRNAs. The majority of Nm modifications in eukaryotes are placed by Fibrillarin, a conserved methyltransferase belonging to a ribonucleoprotein complex guided by C/D box small nucleolar RNAs (C/D box snoRNAs). These modifications impact interactions between rRNAs, tRNAs and mRNAs, and some are known to fine tune translation rates and efficiency. In this study, we built the first comprehensive map of Nm sites inDrosophila melanogasterrRNAs using two complementary approaches (RiboMethSeq and Nanopore direct RNA sequencing) and identified their corresponding C/D box snoRNAs by whole-transcriptome sequencing. Wede novoidentified 61 Nm sites, from which 55 are supported by both sequencing methods, we validated the expression of 106 C/D box snoRNAs and we predicted new or alternative rRNA Nm targets for 31 of them. Comparison of methylation level upon different stresses show only slight but specific variations, indicating that this modification is relatively stable inD. melanogaster. This study paves the way to investigate the impact of snoRNA-mediated 2′-O-methylation on translation and proteostasis in a whole organism.
Tyramine promotes colon cancer risk and development by inducing DNA damage and inflammation
Authors: Glymenaki Maria , Curio Sophie , Shrestha Smeeta , El-Bahrawy Mona , Wang Yulan , Gooderham Nigel J. , Guerra Nadia , Li Jia V. 
Published: May 2023

AbstractHigh dietary consumption of processed meat is associated with increased colorectal cancer (CRC) risk, but mechanistic links remain largely unknown. Tyramine is a biogenic amine found in processed food and a gut bacterial product from tyrosine. However, the impact of tyramine on gut health has not been studied. We found that tyramine induced necrosis and promoted cell proliferation and DNA damage in HCT116 cells. Ingestion of tyramine increased colonic tumor size, intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and a higher number of Ly6G+ neutrophils) inApcMin/+mice. Furthermore, tyramine-treated wild-type mice exhibited visible adenomas and significantly enhanced intestinal tissue DNA damage, together with altered gene pathways involved in epithelial barrier function. In addition, natural killer cell numbers were lower and polymorphonuclear-myeloid derived suppressor cells were higher in tumors from tyramine-treatedApcMin/+mice, suggesting a suppressive anti-tumor immune response. Thus, tyramine not only increases CRC risk, but also facilitates tumor development. Modulating the levels of tyramine in food and monitoring high-risk individuals could aid in better prognosis and management of CRC.
Roles of Lipopolysaccharide Glycosyltransferases in Maintenance ofHelicobacter pyloriMorphology, Cell Wall Permeability, and Antimicrobial Susceptibilities
Authors: Tang Xiaoqiong , Yang Tiankuo , Shen Yalin , Song Xiaona , Benghezal Mohammed , Marshall Barry J. , Tang Hong , Li Hong 
Published: May 2023

AbstractHelicobacter pyloriunique lipopolysaccharide structure is essential in maintaining the cell envelop integrity and renders the bacterium natural resistance to cationic antimicrobial peptides (CAMPs). Our group has recently elucidated the complete set of LPS glycosyltransferase genes inH. pylorireference strain G27. Here, with a series of 8 systematically constructed LPS glycosyltransferase gene mutants (G27ΔHP1578, G27ΔHP1283, G27ΔHP0159, G27ΔHP0479, G27ΔHP0102, G27ΔwecA, G27ΔHP1284and G27ΔHP1191), we investigated the roles ofH. pyloriLPS glycosyltransferases in maintenance of cell morphology, cell wall permeability, and antimicrobial susceptibilities. We demonstrated that deletion of these LPS glycosyltransferase genes did not interfere with bacterial cell wall permeability, but resulted in significant morphological changes (coccoid, coiled “c”-shape, and irregular shapes) after 48 h growth as compared to the rod-like cell shape of the wild-type strain. Moreover, as compared with the wild-type, none of the LPS mutants had altered susceptibility against clarithromycin, levofloxacin, amoxicillin, tetracycline, and metronidazole. However, the deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, our findings suggest that the LPS glycosyltransferases play critical roles in the maintenance of the typical spiral morphology ofH. pylori, as well as resistance to CAMPs and rifampicin. The LPS glycosyltransferases could be promising targets for developing novel anti-H. pyloridrugs.ImportanceH. pyloritypical helical morphology, cell wall integrity, as well as resistance to cationic CAMPs and antimicrobials are significant factors for its long-term colonization and persistent infection in human gastric mucosa. Our results show that each of the 8 LPS glycosyltransferase genes (HP1578,HP1283,HP0159,HP0479,HP0102,wecA,HP1284andHP1191) deletion did not interfere with bacterial cell wall permeability, but resulted in significant loss ofH. pyloritypical helical shape. Furthermore, deletion of the conserved LPS glycosyltransferases, especially the O-antigen initiating enzyme WecA displayed a dramatic increase in susceptibility to the CAMP polymyxin B and rifampicin. Taken together, we believe that the LPS glycosyltransferases are good targets for developing novel anti-H. pyloridrugs.
Inclusion of “managing flexibility” valuations in the pricing of PPP projects: a multi-objective decision-making method
Authors: Guo Yubo , Su Yangyang , Chen Chuan , Martek Igor 
Published: May 2023

PurposeThe Public–Private Partnership (PPP) modality plays an important role in the procurement of global infrastructure projects. Regarding PPP's complex transaction structure, pricing of a PPP project is critical to both parties where the government pursues a high value for money (VFM) and the investor strives to maximize its financial gains. Despite the straightforward win–win principle, a formidable compromise is often the case to end up with a fairly acceptable price, subject to many determinants such as the risk profile, expected return, technological innovation and capacities of both parties. Among them, this study chooses to examine the “managing flexibility” (MF) capacity of investors in pricing of a PPP project, in light of the widely recognized importance of a real-option perspective toward the long term, complex and uncertain PPP arrangement. This study addresses two major questions: (1) how is MF in PPP projects to be valued and (2) how are PPP projects to be priced when considering a project's MF value.Design/methodology/approachA binomial tree model is used to evaluate the MF value in PPP projects. Based on the developed MF pricing model, net present value (NPV) and adjusted VFM value are then calculated. Finally, a multi-objective decision-making method (MODM) was adopted to determine the optimal level of returns based on invested capital (ROIC), return on operation maintenance (ROOM) and concession period.FindingsThe applicability and functionality of the proposed model is investigated using a real project case. For a given return, extended NPV and adjusted VFM value were calculated and analyzed using sensitivity analysis. Factor influence is shown by the model to be dependent on factor impact on cash flow. Subsequently, a multi-objective decision-making (MODM) model was adopted to determine the optimal level of returns, where the solution approximates the real-world bidding price. Results confirm that the pricing model provides a reliable and practical PPP proposal pricing tool.Originality/valueThis study proposes an integrated framework for valuing MF in PPP projects and thus more accurately determine optimal pricing of PPP projects than revealed in extant research. The model offers a practical tool to aid in the valuation of PPP projects.