bluuebunny/crossref_metadata_2025_split huggingface dataset:
Research progress of Chinese herbal medicines and classic prescriptions in the treatment of COPD based on the TCM theory and medicinal characteristics
Authors: Luo Qian , Peng Bo , Wei Xiaolu , Liu Yan , Li Wei , Liu Wei , Waqas Ahmed , Wang Caixia , Ye Zuguang , Zhang Guangping , Hou Hongping 
Published: May 2024

Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a complex pathogenesis, which causes the lack of precise and personalized prevention, control, and treatment approaches in clinical practice. Traditional Chinese medicine (TCM) with multiple components acting on multiple targets plays a role in the prevention and treatment of COPD. After evaluating the treatment of cough, dyspnea, and lung distension based on syndrome differentiation in TCM, we summarized the commonly used TCM preparations for treating COPD. These preparations are mainly composed of medicines for clearing interior heat and releasing exterior, tonifying, activating blood and resolving stasis, resolving phlegm, relieving cough and breathlessness, and regulating Qi movement. Because all of them contain a variety of active ingredients such as flavonoids, terpenoids, and phenols, we analyzed the mechanisms of the classic prescriptions alone or in combination with other medicines or therapeutic methods. These mechanisms involve counteracting inflammation, oxidative stress, and fibrosis, inhibiting apoptosis, alleviating airway remodeling, and enhancing immunity. Meantime, we summarized the existing problems in the treatment of COPD by TCM. This review provides a scientific basis for the research and treatment of COPD in the future.
Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition
Authors: Lin Chuwei , Sniezek Catherine M. , McGann Christopher D. , Karki Rashmi , Giglio Ross M. , Garcia Benjamin A. , McFaline-Figeroa José L. , Schweppe Devin K. 
Published: May 2024

SummaryEpigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogenous and dependent on factors such as the genetic background, metabolic state, and on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line or using a small number of compounds. To more comprehensively profile the effects of small-molecule perturbations and their influence on these heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models
Mechanical forces instruct division plane orientation of cambium stem cells during radial growth inArabidopsis thaliana
Authors: Höfler Mathias , Liu Xiaomin , Greb Thomas , Alim Karen 
Published: May 2024

AbstractPrecise regulation of cell division is central for the formation of complex multicellular organisms and a hallmark of stem cell activity. In plants, due to the absence of cell migration, correct placement of newly produced cell walls during cell division is of eminent importance for generating functional tissues and organs. In particular, during radial growth of plant shoots and roots, concerted cell divisions in the cambium are essential to produce adjacent xylem and phloem tissues in a strictly bidirectional manner. While several intercellular signaling cascades have been identified to instruct tissue organization during radial growth, a role of mechanical forces in guiding cambium stem cell activity has been frequently proposed but, so far, not been functionally investigated on the cellular level. Here, we coupled anatomical analyses with a cell-based vertex model to analyze the role of mechanical stress in radial plant growth at the cell and tissue scale. Simulations based on segmented cellular outlines of radially growingArabidopsishypocotyls revealed a distinct stress pattern with circumferential stresses in cambium stem cells which coincided with the orientation of cortical microtubules. Integrating stress patterns as a cue instructing cell division orientation was sufficient for the emergence of typical cambium-derived cell files and agreed with experimental results for stress-related tissue organization in confining mechanical environments. Our work thus underlines the significance of mechanical forces in tissue organization through self-emerging stress patterns during the growth of plant organs.
Distinct Tumor-TAM Interactions in IDH-Stratified Glioma Microenvironments unveiled by Single-Cell and Spatial Transcriptomics
Authors: Motevasseli Meysam , Darvishi Maryam , Khoshnevisan Alireza , Zeinalizadeh Mehdi , Saffar Hiva , Bayat Shiva , Najafi Ali , Abbaspour Mohammad Javad , Mamivand Ali , Olson Susan B. , Tabrizi Mina 
Published: May 2024

ABSTRACTTumor-associated macrophages (TAMs) residing in the tumor microenvironment (TME) are characterized by their pivotal roles in tumor progression, antitumor immunity, and TME remodeling. However, a thorough comparative characterization of tumor-TAM crosstalk across IDH-defined categories of glioma remains elusive. We delineated the phenotypic heterogeneity of TAMs across IDH-stratified gliomas. Notably, two TAM subsets with a mesenchymal phenotype were enriched in IDH-WT glioblastoma (GBM) and correlated with poorer patient survival and reduced response to anti-PD1 immune checkpoint inhibitor (ICI). We proposed SLAMF9 receptor as a potential therapeutic target. Inference of gene regulatory networks identified PPARG, ELK1, and MXI1 as master transcription factors of mesenchymal BMD-TAMs. Analyses of reciprocal tumor-TAM interactions, revealed distinct crosstalk in IDH-WT tumors, including ANXA1-FPR1/3, FN1-ITGAVB1, VEGFA-NRP1, and TNFSF12-TNFRSF12A. Furthermore, we demonstrated significant upregulation ofANXA1, FN1, NRP1, andTNFRSF12Agenes in IDH-WT tumors using bulk RNA-seq and RT-qPCR. Longitudinal expression analysis of candidate genes revealed no difference between primary and recurrent tumors. Collectively, our study offers insights into the unique cellular composition and communication of TAMs in glioma TME, revealing novel vulnerabilities for therapeutic interventions in IDH-WT GBM.
Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells
Authors: Tan Jingyu , Dong Xinlin , Liu Haiwen 
Published: May 2024

AbstractCellular oxidative stress mediated by intrinsic and/or extrinsic reactive oxygen species (ROS) is associated with disease pathogenesis. Oxidative DNA damage can naturally be substituted by mitochondrial DNA (mtDNA), leading to base lesion/strand break formation, copy number changes, and mutations. In this study, we devised a single test for the sensitive quantification of acute mtDNA damage, repair, and copy number changes using supercoiling-sensitive quantitative PCR (ss-qPCR) and examined how oxidative stress-related mtDNA damage responses occur in oral cancer cells. We observed that exogenous hydrogen peroxide (H2O2) induced dynamic mtDNA damage responses, as reflected by early structural DNA damage, followed by DNA repair if damage did not exceed a particular threshold. However, high oxidative stress levels induced persistent mtDNA damage and caused a 5–30-fold depletion in mtDNA copy numbers over late responses. This dramatic depletion was associated with significant growth arrest and apoptosis, suggesting persistent functional consequences. Moreover, oral cancer cells responded differentially to oxidative injury when compared with normal cells, and different ROS species triggered different biological consequences under stress conditions. In conclusion, we developed a new method for the sensitive detection of mtDNA damage and copy number changes, with exogenous H2O2inducing dynamic mtDNA damage responses associated with functional changes in stressed cancer cells. Finally, our method can help characterize oxidative DNA damage in cancer and other human diseases.
Memoization on Shared Subtrees Accelerates Computations on Genealogical Forests
Authors: Hübner Lukas , Stamatakis Alexandros 
Published: May 2024

AbstractThe field of population genetics attempts to advance our understanding of evolutionary processes. It has applications, for example, in medical research, wildlife conservation, and – in conjunction with recent advances in ancient DNA sequencing technology – studying human migration patterns over the past few thousand years. The basic toolbox of population genetics includes genealogical tress, which describe the shared evolutionary history among individuals of the same species. They are calculated on the basis of genetic variations. However, in recombining organisms, a single tree is insufficient to describe the evolutionary history of the whole genome. Instead, a collection of correlated trees can be used, where each describes the evolutionary history of a consecutive region of the genome. The current corresponding state of-the-art data structure, tree sequences, compresses these genealogical trees via edit operations when moving from one tree to the next along the genome instead of storing the full, often redundant, description for each tree. We propose a new data structure, genealogical forests, which compresses the set of genealogical trees into a DAG. In this DAG identical subtrees that are shared across the input trees are encoded only once, thereby allowing for straight-forward memoization of intermediate results. Additionally, we provide a C++ implementation of our proposed data structure, calledgfkit, which is 2.1 to 11.2 (median 4.0) times faster than the state-of-the-art tool on empirical and simulated datasets at computing important population genetics statistics such as the Allele Frequency Spectrum, Patterson’sf, the Fixation Index, Tajima’sD, pairwise Lowest Common Ancestors, and others. On Lowest Common Ancestor queries with more than two samples as input,gfkitscales asymptotically better than the state-of-the-art, and is thus up to 990 times faster. In conclusion, our proposed data structure compresses genealogical trees by storing shared subtrees only once, thereby enabling straight-forward memoization of intermediate results, yielding a substantial runtime reduction and a potentially more intuitive data representation over the state-of-the-art. Our improvements will boost the development of novel analyses and models in the field of population genetics and increases scalability to ever-growing genomic datasets.2012 ACM Subject ClassificationApplied computing → Computational genomics; Applied computing → Molecular sequence analysis; Applied computing → Bioinformatics; Applied computing → Population genetics
Neisseria gonorrhoeae induces local secretion of IL-10 at the human cervix to promote asymptomatic colonization
Authors: Dai Yiwei , Yu Qian , Edwards Vonetta , Tettelin Hervé , Stein Daniel C. , Song Wenxia 
Published: May 2024

AbstractGonorrhea, caused by the human-restricted pathogenNeisseria gonorrhoeae, is a commonly reported sexually transmitted infection. Since most infections in women are asymptomatic, the true number of infections is likely much higher than reported. How gonococci (GC) colonize women’s vaginocervix without triggering symptoms remains elusive. Using a human cervical tissue explant model, we found that GC inoculation increased the local secretion of both pro- (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines during the first 24-h. Cytokine induction required GC expression of an Opa isoform that binds the host receptors carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). GC inoculation induced NF-κB activation in both cervical epithelial and subepithelial cells. However, inhibition of NF-κB activation, which reduced GC-induced IL-1β and TNF-α, did not affect GC colonization. Neutralizing IL-10 or blocking IL-10 receptors by antibodies reduced GC colonization by increasing epithelial shedding and epithelial cell-cell junction disassembly. Inhibition of the CEACAM downstream signaling molecule SHP1/2, which reduced GC colonization and increased epithelial shedding, reduced GC-induced IL-10 secretion. These results show that GC induce local IL-10 secretion at the cervix by engaging the host CEACAMs to prevent GC-colonizing epithelial cells from shedding while suppressing inflammation activation, providing a potential mechanism for GC asymptomatic infection in women.
Targeting both GD2 and B7-H3 using bispecific antibody improves tumor selectivity for GD2-positive tumors
Authors: Rosenkrans Zachary T. , Erbe Amy K. , Clemons Nathan B. , Feils Arika S. , Medina-Guevara Yadira , Jeffery Justin J. , Barnhart Todd E. , Engle Jonathan W. , Sondel Paul M. , Hernandez Reinier 
Published: May 2024

AbstractObjectivesDisialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated.MethodsDifferential expression of human B7-H3 (hB7-H3) was transduced into GD2+B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2+/hB7-H3-B78 cells relative to GD2+/hB7-H3+B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t1/2= 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2+/hB7-H3+and GD2+/hB7-H3-B78 tumor models.ResultsFlow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2+/hB7-H3+B78 cells with high avidity but not GD2+/hB7-H3+B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2+/hB7-H3-and GD2+/hB7-H3+B78 murine tumor showed similar biodistribution in normal tissues for [89Zr]Zr-Df-INV34-6, [89Zr]Zr-Df-bsAb CTRL, and [89Zr]Zr-Df-DINU. Importantly, [89Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2+/hB7-H3+B78 over GD2+/hB7-H3-B78 tumors, and substantially higher to GD2+/hB7-H3+B78 than the non-targeted [89Zr]Zr-Df-bsAb CTRL control. [89Zr]Zr-Df-DINU displayed similar uptake in both GD2+tumor models, with uptake comparable to [89Zr]Zr-Df-INV34-6 in the GD2+/hB7-H3+B78 model.ConclusionThe GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.Graphical Abstract
Comprehensive gene expression analysis of organoid-derived healthy human colonic epithelium and cancer cell line by stimulated with live probiotic bacteria
Authors: Sen Akira , Imai Atsuki , Yanagisawa Kota , Miyauchi Eiji , Oda Tsukasa , Sasaki Fuki , Uchida Shintaro , Okada Takuhisa , Yokobori Takehiko , Saeki Hiroshi , Odamaki Toshitaka , Sasaki Nobuo 
Published: May 2024

AbstractThe large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells.In vitrohost cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 cells are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer cells derived from healthy Human Colonic Organoid (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria,Bifidobacterium longumsubsp.longumdifferentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 cells represented absorptive cells in the small intestinal epithelium, and MHCO cells showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured liveBifidobacterium longumand Caco-2 or MHCO cells.B. longum-stimulated MHCO cells exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication.
The CSF transcriptome in pneumococcal meningitis reveals compartmentalised host inflammatory responses associated with mortality
Authors: Guerra-Assunção José Afonso , Chakravarty Probir , Pollara Gabriele , Venturini Cristina , Mlozowa Veronica S , Denis Brigitte , Nyirenda Mulinda , Lalloo David G , Noursadeghi Mahdad , Brown Jeremy S , Heyderman Robert S , Wall Emma C 
Published: May 2024

AbstractBackgroundPneumococcal meningitis (PM) has persistently poor clinical outcomes, especially in sub- Saharan Africa. To better characterise the inflammatory response and identify factors associated with mortality we compared paired peripheral blood and cerebrospinal fluid (CSF) transcriptomes before the initiation of antibiotics in Malawian adults with proven PM.ResultsBlood transcriptional profiles were obtained in 28 patients with PM, with simultaneous paired with CSF profiles available for 13 patients. 15/28 (52%) patients died. Comparison of the transcriptome between CSF and blood compartments showed upregulation of 2293 differentially expressed genes in CSF and 909 in blood; enriched pathways in CSF included inflammasome activity and neutrophil migration/activation in the CSF, contrasting with enrichment for pathways including platelet and endothelial activation, cell cycle, cytokine release and oxidative stress in the blood transcriptome. Comparison of CSF profiles between survivors and non-survivors revealed 1829 differentially expressed genes, non- survivor CSF was enriched for multiple innate inflammatory pathways, including IL-17A and Type 1 interferons and proteolysis. In contrast, minimal transcriptomic differences between outcome groups were detected in blood.ConclusionInflammation in PM is characterised by compartmentalised responses in blood and CSF. Poorer outcomes are associated with an dysregulated innate immune host response toS. pneumoniaein the CSF compartment.
Deciphering cis-regulatory elements using REgulamentary
Authors: Riva Simone G. , Georgiades Emily , Herrmann Jennifer C. , Gür E. Ravza , Sanders Edward , Sergeant Martin , Baxter Matthew , Hughes Jim R. 
Published: May 2024

AbstractWith the boom in Genome-Wide Association Studies (GWAS), it has become apparent that many disease-associated genetic variants lie in the non-coding regions of the genome. In order to prioritise these variants and disentangle their functional significance, it is important to be able to accurately classify cis-regulatory elements within these non-coding regions of the genome. Historically, the classification of cis-regulatory elements relied purely on the presence of characteristic histone marks, with recent advancements in their classification using more sophisticated Hidden Markov Model (HMM)-based approaches. The limitation of the HMM-based approaches is that the output of these models is an arbitrary chromatin state, which then requires the user to manually assign these states to a particular class of cis-regulatory elements. Here we present a new tool, REgulamentary, which enablesde novogenome-wide annotation of cis-regulatory elements in a cell-type specific manner. We benchmarked REgulamentary against GenoSTAN, the most popular existing published chromatin annotation and regulatory element identification tool, to demonstrate the advancements REgulamentary can provide in assigning chromatin states. Finally, as an example of REgulamentary’s utility in solving complex disease traitloci, we applied REgulamentary to published GWAS data to demonstrate how this tool can be used to prioritise likely causal variants.
Effective recognition of double-stranded RNA does not require activation of cellular inflammation
Authors: Drazkowska Karolina , Cieslicka Julia , Pastucha Anna , Markiewicz Lukasz , Goryca Krzysztof , Kowalczyk Tomasz , Cysewski Dominik , Bausch Andreas , Sikorski Pawel J. 
Published: May 2024

SummaryExcess double-stranded RNA (dsRNA) is present in the cytoplasm of human cells, usually following viral infections. Recognition of dsRNAs activates innate immune pathways, leading to cellular inflammation and inhibition of cell growth. Here, we show that an effective dsRNA response may occur without the onset of inflammation. Interestingly, pro-inflammatory (RLR-dependent pathway) and cell growth inhibitory mechanisms (OAS/RNase L- and PKR-dependent pathways) can act independently. We found that the 5′ ends of dsRNA direct the onset of cellular inflammation, whereas RNA duplex activates the OAS/RNase L and PKR pathways. Unexpectedly, three of the most common human RNA epitranscriptomic markers –i.e. N6-methyladenosine, 5-methylcytosine, and pseudouridine – did not affect the immunogenicity of dsRNA; however, the presence ofN6-methyladenosine inhibited the OAS/RNase L pathway. Our observations demonstrate how precisely innate immunity is fine-tuned in cells to take appropriate countermeasures when a specific threat arises.