Origin Of Heterogeneity Research Articles

STEM-01. SHARED ASTROCYTE-LIKE GLIOMA STEM CELLS DRIVE HETEROGENEITY AND IMMUNE DYNAMICS IN ADULT-TYPE DIFFUSE GLIOMAS

Abstract Adult-type diffuse gliomas present significant treatment challenges due to their complex cellular composition and evolving nature. Understanding this heterogeneity is critical for the development of effective, targeted therapies. We conducted single-cell and single-nucleus RNA sequencing on a unique cohort of 66 tumours (single surgery) and 54 paired samples (two surgeries). This comprehensive dataset of approximately 900,000 cells allows us to dissect conserved cellular landscapes and dynamic evolution across diverse glioma subtypes. Using a novel phylogeny-based approach, we identified an astrocyte-like glioma stem cell (GSC) as the root of diverse glioma lineages. This discovery transforms our understanding of glioma development, pinpointing the GSC as a potential therapeutic target. The GSC’s similarity to healthy adult neural stem cells provides clues as to the origin of glioma heterogeneity and the shared basis of intratumoural diversity. Our analysis uncovered a shared cellular architecture across astrocytomas, oligodendrogliomas, and glioblastomas (GBMs). This architecture encompasses seven recurring malignant cell states: neuro-, oligo-, neuro-oligo-lineage, cycling (G1/S, G2/M), hypoxia-associated, and a quiescent astrocyte-like GSC. Importantly, these cell state proportions vary significantly between glioma subtypes. Additionally, we demonstrate that GBMs display substantially higher T-cell and myeloid cell infiltration than IDH-mutant gliomas. Counterintuitively, this correlates with a poorer prognosis, implying profound T-cell dysfunction and intricate myeloid cell-tumour interactions. Longitudinal analysis further highlights the dynamic nature of glioma cell populations and the immune landscape. Subtype-specific T-cell and myeloid gene expression profiles were identified, including potential targets such as PARD6G (GBM) and CXCL13 (IDH-mutant-astrocytoma), laying the groundwork for tailored immunotherapies and prognostic biomarkers. This study presents a comprehensive model of glioma heterogeneity and evolution. The model reveals a shared astrocyte-like GSC that fuels cellular diversity, coupled with distinct, dynamic immune landscapes in different glioma subtypes. These findings hold extraordinary potential for developing transformative treatment strategies. Future research functionally validating the GSC and its impact on tumour dynamics will be essential for translating these insights into improved patient outcomes.

Risk factors for incidence of interstitial lung disease in patients with rheumatoid arthritis: a systematic review and meta-analysis

ObjectivesThis study aimed at identifying risk factors for the incidence of interstitial lung disease in patients with rheumatoid arthritis (RA-ILD) by a systematic review and meta-analysis.MethodsInformation sources: studies published by March 2021 were searched in PubMed, Web of Science, MEDLINE, EMBASE, Cochrane Library and Scopus databases.Eligibility criteria: cohort studies or nested case-control studies that reported OR or HR of risk factors for RA-ILD were included. Two researchers independently screened the studies and extracted data.Synthesis of results: the relative risks (RRs) were introduced to measure the association across studies.Risk bias: quality assessments of included studies were performed using the Newcastle-Ottawa Scale. Based on the result of heterogeneity, the random-effects model or fixed-effects model was chosen in the meta-analysis. Furthermore, a sensitivity analysis was conducted to identify the origins of heterogeneity, and publication bias was evaluated for the factors with no less than five included studies by funnel plots and Egger’s test.ResultsAmong 3075 identified articles, 12 studies met the inclusion criteria. 17 risk factors were included in the meta-analysis. Male (RR 1.94, 95% CI 1.33 to 2.85, p<0.001), elder age (>60 years, RR 1.42, 95% CI 1.05 to 1.94, p=0.02), older RA onset age (RR 1.05, 95% CI 1.01 to 1.10, p=0.02), smoking (RR 1.37, 95% CI 1.09 to 1.71, p=0.006), lung complications (RR 2.72, 95% CI 1.24 to 5.95, p=0.01), rheumatoid nodule (RR 1.85, 95% CI 1.36 to 2.51, p<0.001), leflunomide usage (RR 1.41, 95% CI 1.02 to 1.96, p=0.04) were identified as risk factors of RA-ILD.ConclusionPhysicians should be aware that patients with RA with the above risk factors are likely to develop RA-ILD, and perform close ILD screening during follow-ups so that the patients can be early diagnosed and treated, and achieve improved prognosis.

Microbial Community Analysis Offers Insight into the Complex Origins of Plant Disease in a Smallholder Farm Context

Classical approaches to plant disease diagnosis assume a single pathogen/single disease paradigm. Here, we revisit the presumed role of Fusarium oxysporum as the causal agent of wilting and yellowing of chickpea plants on smallholder farms in Ethiopia. Contrary to expectations, detection of Fusarium DNA using conserved PCR primers failed to associate the pathogen with symptomatic plants. Instead, culture-independent sequencing of microbial communities nominated unexpected pathogens and revealed patchiness in the assembly of common microbial consortia. Surprisingly, tests of differential enrichment identified Phytophthora as the most common disease-associated taxon. More generally, across all field sites, multilevel pattern analysis identified indicator taxa whose patterns of co-occurrence demarcate discrete microbial communities and are consistent with a range of specific interactions, including mutualism and antagonism. Taken together, these data indicate that soilborne chickpea disease in Ethiopia has heterogeneous origins and that despite decades of emphasis and disease resistance breeding, the role of Fusarium as the frequent agent of chickpea disease in Ethiopia remains enigmatic.

Methodological aspects of correlative, multimodal, multiparametric breast cancer imaging: from data acquisition to image processing for AI-based radioproteomics in a preclinical setting

Preclinical high-field magnetic resonance imaging (MRI) systems offer a diverse array of MRI techniques, providing rich multiparametric MRI (mpMRI) platforms for studying numerous biological parameters. mpMRI platforms prove particularly indispensable when investigating tumors that exhibit profound intratumoral heterogeneity, such as breast cancer. A thoughtful comprehension of the origins of intratumoral heterogeneity is imperative for the judicious assessment of new targeted therapies and treatment interventions. Furthermore, when data from mpMRI are complemented with data from other in vivo imaging modalities, such as positron emission tomography (PET), and correlated with data from ex vivo modalities, such as matrix-assisted laser desorption imaging mass spectrometry (MALDI IMS), the in vivo parameters can be further elucidated at a molecular level and microscopic scale. Nevertheless, extracting meaningful scientific insights from such complex datasets necessitates the utilization of machine learning (ML) approaches to discern region-specific radiomic features. The development of correlative, multimodal imaging (CMI) workflows, such as one incorporating MRI, PET and MALDI IMS, is inherently challenging, given the many technological and methodological challenges related to multimodal data acquisition as well as the physiological limitations of the laboratory mice of the investigation. Standardization efforts in image acquisition and processing are required to increase the reproducibility and translatability of CMI data. To address the challenges of developing standardized CMI workflows and stimulate dialog regarding this area of need, we present a practical workflow to investigate tumor heterogeneity in breast cancer xenografts across various spatial scales. Our workflow entails simultaneous functional MRI and PET acquisitions in living mice, followed by correlation with post-imaging MALDI IMS and histologic data. Additionally, we propose data preprocessing steps for potential ML applications. We illustrate the feasibility of this workflow through two examples, showcasing its effectiveness in comparing in vivo and ex vivo images to evaluate tumor metabolism and hypoxia in mice with breast cancer xenografts.

Defect-Mediated Formation of Oriented Phase Domains in a Lithium-Ion Insertion Electrode.

The performance and robustness of electrodes are closely related to transformation-induced nanoscale structural heterogeneity during (de)lithiation. As a result, it is critical to understand at atomic scale the origin of such structural heterogeneity and ultimately control the transformation microstructure, which remains a formidable task. Here, by performing in situ studies on a model intercalation electrode material, anatase TiO2, we reveal that defects─both preexisting and as-formed during lithiation─can mediate the local anisotropic volume expansion direction, resulting in the formation of multiple differently oriented phase domains and eventually a network structure within the lithiated matrix. Our results indicate that such a mechanism operated by defects, if properly harnessed, could not only improve lithium transport kinetics but also facilitate strain accommodation and mitigate chemomechanical degradation. These findings provide insights into the connection of defects to the robustness and rate performance of electrodes, which help guide the development of advanced lithium-ion batteries via defect engineering.

Macrophage variants in laboratory research: most are well done, but some are RAW.

Macrophages play a pivotal role in the innate immune response. While their most characteristic function is phagocytosis, it is important not to solely characterize macrophages by this activity. Their crucial roles in body development, homeostasis, repair, and immune responses against pathogens necessitate a broader understanding. Macrophages exhibit remarkable plasticity, allowing them to modify their functional characteristics in response to the tissue microenvironment (tissue type, presence of pathogens or inflammation, and specific signals from neighboring cells) swiftly. While there is no single defined "macrophage" entity, there is a diverse array of macrophage types because macrophage ontogeny involves the differentiation of progenitor cells into tissue-resident macrophages, as well as the recruitment and differentiation of circulating monocytes in response to tissue-specific cues. In addition, macrophages continuously sense and respond to environmental cues and tissue conditions, adjusting their functional and metabolic states accordingly. Consequently, it is of paramount importance to comprehend the heterogeneous origins and functions of macrophages employed in in vitro studies, as each available in vitro macrophage model is associated with specific sets of strengths and limitations. This review centers its attention on a comprehensive comparison between immortalized mouse macrophage cell lines and primary mouse macrophages. It provides a detailed analysis of the strengths and weaknesses inherent in these in vitro models. Finally, it explores the subtle distinctions between diverse macrophage cell lines, offering insights into numerous factors beyond the model type that can profoundly influence macrophage function.

Classification of solid and liquid structures using a deep neural network unveils origin of dynamical heterogeneities in supercooled liquids

As the temperature decreases, the dynamics of supercooled liquids significantly slow down and become increasingly heterogeneous in space. Many previous studies have found that static structures also become heterogeneous and are spatially correlated with the dynamical heterogeneity. However, there are still debates on whether the dynamical heterogeneity is controlled by the structures, and which structural order parameters should be used to describe the structural heterogeneities (if exist) in amorphous systems. The appropriate order parameter depends on the specific details of the system and needs to be determined for each system. To address this difficulty, here, we use a machine-learning-based method that was trained solely by the static structures. This method combines convolutional neural networks and gradient-weighted class activation mapping, providing interpretable characteristic structures, which can quantify the degrees of liquid-like and solid-like structures in every local part of the system. We apply this method to a canonical glass-forming system and demonstrate that particles in the liquid-like structures are mobile, while those in the solid-like structures are immobile. The present work develops a novel approach to accurately characterize amorphous structures, which will be particularly useful for systems where appropriate structural order parameters have not yet been identified.

Multienzymatic Orthogonal Activation of DNA Codec Enables Tumor-Specific Imaging of Base Excision Repair Activity.

Accurate monitoring of base excision repair (BER) activity in cancer cells is critical for advancing the comprehension of DNA repair processes, gaining insights into cancer development, and guiding treatment strategies. However, current assay techniques for assessing BER activity in cancer cells face challenges due to the heterogeneous origins and diversity of BER enzymes. In this work, we present a highly reliable triple loop-interlocked DNA codec (GATED) that enables precise assessment of BER activity in cancer cells through signal amplification mediated by multienzyme orthogonal activation. The GATED device features a dumbbell-shaped DNA probe to encode two BER enzymes for BER-related signal conversion as well as two bound circular DNA to decode the apurinic/apyrimidinic sites for apurinic/apyrimidinic endonuclease 1 (APE1)-mediated signal amplification. Importantly, GATED is orthogonally activated by multiple target BER enzymes (i.e., uracil DNA glycosylase, thymine DNA glycosylase, and APE1), resulting in a unified fluorescent signal that significantly improves the detection specificity and sensitivity to BER enzymes. Additionally, we demonstrate that the GATED has exceptional biostability within complex biological systems, where it was successfully employed to monitor BER activity in cancer cells with high specificity and enabled cell-based high-throughput screening for BER inhibitors. The GATED provides a much-needed tool for the real-time monitoring of BER activity and the screening of BER inhibitors in cancer cells, potentially advancing both the investigation and clinical application of BER biology.

The heterogeneous origins of religion as a category in law in the United Kingdom: Implications for education

This paper examines the origins of ‘religion or belief’ as a protected characteristic as it came to be enshrined in the Equality Act 2010. In relation to the Equality Act 2010, heteronomous definitions, derived from race relations legislation can tend toward a conflation of race and religion. An example of this is the Mandla v Park Grove School case (1978) which determined the right of a Sikh boy to wear a turban to school through the application of the Race Relations Act 1976. Later jurisprudence including Begum v Denbigh High School (2006) and legislation such as the Racial and Religious Hatred Act 2006 further draws upon the language of race to treat of religion or belief, resulting in a heterogeneous (mis)representation of religion which tends both toward essentialism and a deficit model of religiosity. With reference to education, a Christian welfarist orientation toward ‘religious instruction’ can be traced back to 1788, in the 20th century this begins to be supplanted by a concern for ‘religious neutrality’ derived from colonial practices of governance in India. Drawing on these, it is possible to recover a more positive and authentic definition of the role of religion in UK law.

Moral Boundaries

This article reviews the growing economics literature that studies the politico-economic impacts of heterogeneity in moral boundaries across individuals and cultures. The so-called universalism-versus-particularism cleavage has emerged as a main organizing principle behind various salient features of contemporary political competition, including individual-level and spatial variation in voting, the realignment of rich liberals and poor conservatives, the internal structure of ideology, and the moral content of political messaging. A recurring theme is that the explanatory power of universalism for left-wing policy views and voting is considerably larger than that of traditional economic variables. Looking at the origins of heterogeneity in universalism, an emerging consensus is that cross-group variation is partly economically functional and reflects that morality evolved to support cooperation in economic production. This insight organizes much work on how kinship systems, market exposure, political institutions, and ecology have shaped universalism through their impacts on the relative benefits of localized and impersonal interactions.

Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Identities from Microglia.

Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206 + microglia precursors in the YS. We found that brain-engrafted MDMs exhibit transcriptional and epigenetic characteristics akin to meningeal macrophages, likely due to environmental imprinting within the meningeal space. Utilizing parabiosis and skull transplantation, we demonstrated that monocytes from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains. Our results reveal the heterogeneous origins and cellular dynamics of brain parenchymal macrophages at baseline and in models of microglia depletion.

Heterogeneous Evolution of Breast Cancer Cells-An Endogenous Molecular-Cellular Network Study.

Breast cancer heterogeneity presents a significant challenge in clinical therapy, such as over-treatment and drug resistance. These challenges are largely due to its obscure normal epithelial origins, evolutionary stability, and transitions on the cancer subtypes. This study aims to elucidate the cellular emergence and maintenance of heterogeneous breast cancer via quantitative bio-process modeling, with potential benefit to therapeutic strategies for the disease. An endogenous molecular-cellular hypothesis posits that both pathological and physiological states are phenotypes evolved from and shaped by interactions among a number of conserved modules and cellular factors within a biological network. We hereby developed a model of core endogenous network for breast cancer in accordance with the theory, quantifying its intrinsic dynamic properties with dynamic modeling. The model spontaneously generates cell states that align with molecular classifications at both the molecular and modular level, replicating four widely recognized molecular subtypes of the cancer and validating against data extracted from the TCGA database. Further analysis shows that topologically, a singular progression gateway from normal breast cells to cancerous states is identified as the Luminal A-type breast cancer. Activated positive feedback loops are found to stabilize cellular states, while negative feedback loops facilitate state transitions. Overall, more routes are revealed on the cellular transition between stable states, and a traceable count explains the origin of breast cancer heterogeneity. Ultimately, the research intended to strength the search for therapeutic targets.

ETMR-14. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES AN ONCOGENIC PHOTORECEPTOR PROGRAM AS A TUMORIGENIC VULNERABILITY UNIFYING DISTINCT EMBRYONAL CNS TUMOR ENTITIES

Abstract BACKGROUND Pineoblastoma (PB) is a rare and aggressive childhood brain tumor with highly variable outcomes. PB is diagnostically characterized by expression of the photoreceptor identity transcription factor CRX, while tumors can be further classified into molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1), each marked by unique clinico-molecular features. However, developmental origins of PB subgroup heterogeneity and mechanisms governing malignancy remain unknown. METHODS We assembled a single-nucleus RNA-sequencing cohort (n=25) of primary PB tumors, including cases from all subgroups. A single-cell transcriptional atlas of the mouse pineal gland, covering 11 developmental stages (E11-P21), was created as a reference to map PB subgroup origins. Developmental trajectory analysis in the pineal gland showed a progression from pinealocyte progenitors to an early-, mid- and mature stage of pinealocyte differentiation. RESULTS Cross-species bioinformatics identified significant associations between PB subgroups and pinealocyte progenitors, mitotic cells expressing Crx, Otx2 and Neurod1. Single-nuclei gene regulatory networks in PB tumors identified CRX, OTX2, and NEUROD1 as master regulators of an oncogenic photoreceptor program conserved across PB subgroups. Surprisingly, this photoreceptor program was also highly expressed in retinoblastoma (RETB) and Group3 medulloblastoma (G3-MB). The molecular association between PB, RETB and G3-MB was further supported by DNA methylation and bulk RNA-seq, suggesting up-regulation of the oncogenic photoreceptor program is a unifying molecular connection of distinct CNS tumor entities. Querying this photoreceptor program across the developing pineal gland, retina, and cerebellum, identified conserved yet transient expression within each developmental lineage, suggesting the photoreceptor program may be a developmental vulnerability. In-vivo dependency assays for Otx2 and Neurod1 performed in a novel genetically engineered mouse model of the PB-RB subgroup confirmed their selective essentiality in photoreceptor-positive tumors. CONCLUSIONS Collectively, these findings uncover the photoreceptor program as a shared oncogenic dependency underlying anatomically distinct embryonal CNS tumors and provide a path towards rational clinical translation.

Extracellular Vesicle Preparation and Analysis: A State-of-the-Art Review.

In recent decades, research on Extracellular Vesicles (EVs) has gained prominence in the life sciences due to their critical roles in both health and disease states, offering promising applications in disease diagnosis, drug delivery, and therapy. However, their inherent heterogeneity and complex origins pose significant challenges to their preparation, analysis, and subsequent clinical application. This review is structured to provide an overview of the biogenesis, composition, and various sources of EVs, thereby laying the groundwork for a detailed discussion of contemporary techniques for their preparation and analysis. Particular focus is given to state-of-the-art technologies that employ both microfluidic and non-microfluidic platforms for EV processing. Furthermore, this discourse extends into innovative approaches that incorporate artificial intelligence and cutting-edge electrochemical sensors, with a particular emphasis on single EV analysis. This review proposes current challenges and outlines prospective avenues for future research. The objective is to motivate researchers to innovate and expand methods for the preparation and analysis of EVs, fully unlocking their biomedical potential.

Unfolding the role of cell state on stress granule heterogeneity and function in pancreatic cancer.

e16357 Background: A major impediment to cancer therapy is the reality that cancer is a heterogeneous disease. A single tumor can consist of many genotypic or phenotypic profiles, which are marked by degrees of sensitivity to different therapeutics. Identifying and targeting origins of cancer cell heterogeneity is critical for predicting patient outcome and enhancing treatment efficacy. We observe a novel source of cancer cell heterogeneity that involves one of the largest stress-sensing platforms described to date: the stress granule (SG). Stress granules are non-membranous, cytoplasmic organelles that assemble in response to stress, and promote cell survival. Deregulation of SGs has been linked to several pathological conditions, including cancer, neurodegeneration, ischemia, and viral infections. SGs have been shown to promote tumor growth and metastasis, as well as contribute to mechanisms of chemo-resistance. Thus, these signaling hubs are emerging as a potential target in cancer. Methods: To induce SG formation, human pancreatic ductal adenocarcinoma (PDAC) cell lines were treated with sodium arsenite, thapsigargin, or exposed to hypoxic conditions. Immunoflourescent staining of core SG proteins was then conducted. To investigate cell cycle-driven mechanisms of SG heterogeneity, cell cycle stage was identified by expression of a Fluorescent ubiquitination-based cell cycle indicator (Fucci) lentiviral system. To investigate cPLA2’s role in SG formation, the chemical inhibitor Pyrrophenone, an shRNA targeting cPLA2, and an exogenous full-length or cleaved form of cPLA2, were used. In vivo, ES149 cells expressing Luciferase and the Fucci system were orthotopically implanted into C57BL/6 mice. Established tumors were treated every 3 days with Vehicle, Oxaliplatin, Pyrrophenone, or a combination of the latter. Tumor size was tracked via IVIS Spectrum. Fucci flourescence was used to identify cell cycle phase. SGs and cell death were assessed by immunoflourescent staining of tumors. Results: Cancer cells show a high degree of heterogeneity in their production of SGs. Cell cycle phase dictates SG heterogeneity. G2 phase cells have significantly higher levels of SG formation as compared cells in G1/S. This process is regulated by cleavage of the cPLA2 protein. Oxaliplatin administration increases G2 phase content in tumors. Co-treatment with Oxaliplatin and Pyrrophenone significantly decreases SG formation, increases cell death, and leads to tumor regressions in vivo. Conclusions: G2 phase cancer cells develop higher levels of SGs when exposed to stressful stimuli, as compared to G1/S phase counterparts. The cPLA2 protein is cleaved into a catalytically dead form that is present in G1/S phases, but absent in G2 phase. Oxaliplatin treatment in vivo leads to an increase in G2 phase tumor cells. When paired with cPLA2 inhibition, this results in increased cancer cell death and decreased tumor growth.

A strategy integrating GC–MS, UPLC profiling, and DNA metabarcoding for characterization and discrimination of the medicinal and culinary pieces from four Curcuma species

Curcumae pieces prepared in ready-to-use forms, consumed extensively for their significant medicinal and culinary benefits, present a challenge in discrimination due to their heterogeneous origins, analogous morphologies, and varied components. This study explored the metabolites of nine Curcumae pieces (NCPs) by Gas Chromatography-Mass Spectrometry (GC–MS) and Ultra-Performance Liquid Chromatography/Ultra High-Performance Liquid Chromatography–Quadrupole Time of Flight–Mass Spectrometry (UPLC/UHPLC–QTOF–MS) technologies, augmented by multivariate statistical analysis (Principal Component Analysis, PCA; Orthogonal Partial Least Squares Discriminant Analysis, OPLS–DA) and machine learning algorithms (Random Forest, RF). Twenty-six key differential markers in volatile and non-volatile metabolites each were found subsequently. Additionally, DNA metabarcoding was employed to develop specific Single Nucleotide Polymorphism (SNP) markers for the precise identification of Curcuma species in single and mixed samples, and for CRa even contained in Chinese patent prescriptions. The integration of these three methodologies facilitates a more reliable authentication of NCPs, enhancing the overall strategy for their global discrimination. This research contributes to the advancement of quality control and the development of functional foods or products derived from Curcumae pieces, tailored to meet specific health and dietary requirements.

Investigation on Fluorescence Origin and Spectral Heterogeneity in Carbon Dots: A Dynamic Perspective

AbstractHeterogeneity in the fluorescence of carbon dots (CDs) has been hard to figure out so far. This could potentially be related to structural factors, size or intermediate fluorophores, especially when employing the bottom‐up synthesis. Herein, we unveil the origin of fluorescence and spectral heterogeneity of CDs using a simple dynamic method. This work reports the room light‐excited green fluorescence and dual‐emissive N‐doped CDs synthesized using a hydrothermal method. Studies were carried out considering the factors of fluorescence phenomena, such as excitation‐independent emission, fluorescent impurities, aggregation and solvation dynamics. The new steady‐state, Excitation‐resolved area‐normalized emission spectroscopy (ERANES) and ensemble measurements, including time‐resolved studies reveal that a heterogeneous environment exists in the ground state. Eventually, the results show the existence of core, edge and surface states in the CDs. Additionally, the fluorescence characteristics depend on the structural functionalization that occurs in both the intrinsic and extrinsic states of the CDs and it is proven that this does not violate the Kasha‐Vavilov rule. Although a highly purified material could still exhibit heterogeneity due to the ensemble emissive states and structural variations. Our results provide insights into the enduring debates about fluorescence and a deeper understanding of the structure‐ property relationship of CDs.

Integrating bulk RNA-seq and scRNA-seq analyses revealed the function and clinical value of thrombospondins in colon cancer

BackgroundActing as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of matricellular glycoproteins, are key regulators in cancer biology with multifaceted roles. Although TSPs have been implicated in anti-tumor immunity and epithelial-mesenchymal transition (EMT) in several malignancies, their specific roles to colon cancer remain elusive. Addressing this knowledge gap is essential, as understanding the function of TSPs in colon cancer could identify new therapeutic targets and prognostic markers. MethodsAnalyzing 1981 samples from 10 high-throughput datasets, including six bulk RNA-seq, three scRNA-seq, and one spatial transcriptome dataset, our study investigated the prognostic relevance, risk stratification value, immune heterogeneity, and cellular origin of TSPs, as well as their influence on cancer-associated fibroblasts (CAFs). Utilizing survival analysis, unsupervised clustering, and functional enrichment, along with multiple correlation analyses of the tumor-microenvironment (TME) via Gene Set Variation Analysis (GSVA), spatial localization, Monocle2, and CellPhoneDB, we provided insights into the clinical and cellular implications of TSPs. ResultsFirst, we observed significant upregulation of THBS2 and COMP in colon cancer, both of which displayed significant prognostic value. Additionally, we detected a significant positive correlation between TSPs and immune cells, as well as marker genes of EMT. Second, based on TSPs expression, patients were divided into two clusters with distinct prognoses: the high TSPs expression group (TSPs-H) was characterized by pronounced immune and stromal cell infiltration, and notably elevated T-cell exhaustion scores. Subsequently, we found that THBS2 and COMP may be associated with the differentiation of CAFs into pan-iCAFs and pan-dCAFs, which are known for their heightened matrix remodeling activities. Moreover, THBS2 enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. CAFs expressing THBS2 (THBS2+ CAFs) demonstrated higher scores across multiple signaling pathways, including angiogenic, EMT, Hedgehog, Notch, Wnt, and TGF-β, when compared to THBS2- CAFs. These observations suggest that THBS2 may be associated with stronger pro-carcinogenic activity in CAFs. ConclusionsThis study revealed the crucial role of TSPs and the significant correlation between THBS2 and CAFs interactions in colon cancer progression, providing valuable insights for targeting TSPs to mitigate cancer progression.

Time-calibration of carbonate diagenesis and regional tectonism in the Norwegian Barents Sea

Diagenesis plays a crucial role in carbonate reservoir properties, for example through the dissolution or precipitation of carbonate minerals, with burial history and fluid migration thought to play an important role in the timing of these events. To better understand these relationships and the local manifestation of regional events, we study carbonate sedimentary rocks and associated diagenetic cements from the Loppa High and Finnmark Platform using in-situ U–Pb carbonate geochronology and C–O stable isotope ratios, combined with burial history modelling. The results indicate a complex history of diagenesis: analyzed dolomicrite samples from the Loppa High typically yield ages that are older than their biostratigraphic age, in contrast to dolomicrite samples from the Finnmark Platform that yielded younger ages; this regional offset may be reflective of different styles of early diagenesis, as well as heterogeneous and re-deposited origin of some studied materials. While many diagenetic calcite cements coincide with modelled burial or uplift events, other events have no cements associated with them, although the possibility that some diagenetic carbonate phases were unsampled cannot be ruled out. Some calcite cements are not associated with burial events at all and may instead be related to hydrocarbon ‘charging’, supported by strongly negative δ13C values recorded in these cements. Broadly, these results highlight the value of integrating petrographic observations, burial history modelling, carbonate U–Pb geochronology, and C–O isotope ratios, as well as the complexity of untangling diagenetic histories.

18F-FDG PET/MR for diagnosis of primary central nervous system lymphoma: protocol for a systematic review and meta-analysis

BackgroundPrimary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin’s lymphoma with poor prognosis. 18F-flourodeoxyglucose positron emission tomography (PET)/magnetic resonance (MR) combines the advantages of PET and...