Cohesin-Dependent Loop Extrusion: Molecular Mechanics and Role in Cell Physiology.

The most prominent representatives of multisubunit SMC complexes, cohesin and condensin, are best known as structural components of mitotic chromosomes. It turned out that these complexes, as well as their bacterial homologues, are molecular motors, the ATP-dependent movement of these complexes along DNA threads leads to the formation of DNA loops. In recent years, we have witnessed an avalanche-like accumulation of data on the process of SMC dependent DNA looping, also known as loop extrusion. This review briefly summarizes the current understanding of the place and role of cohesin-dependent extrusion in cell physiology and presents a number of models describing the potential molecular mechanism of extrusion in a most compelling way. We conclude the review with a discussion of how the capacity of cohesin to extrude DNA loops may be mechanistically linked to its involvement in sister chromatid cohesion.

Identification of memory mechanism in tissue-resident stem cells via ANGPTL4 beyond immune cells upon viral antigen exposure.

Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus [HPV]) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo. Importantly, endometrial stem cells exhibited robust memory functions following consecutive HPV antigen exposures, whereas fully differentiated cells such as fibroblasts and vesicular cells did not show corresponding changes in response to the same antigen exposures. Deficiency of angiopoietin-like 4 (ANGPTL4) achieved through small hairpin RNA knockdown in vitro and knockout (KO) mice in vivo highlighted the critical role of ANGPTL4 in governing memory functions associated with various stem cell processes. This regulation occurred through histone H3 methylation alterations and PI3K/Akt signaling pathways in response to successive HPV antigen exposures. Furthermore, memory functions associated with various stem cell functions that were evident in wild-type mice following consecutive exposures to HPV antigen were not observed in ANGPTL4 KO mice. In summary, our findings strongly support the presence of memory mechanism in non-immune cells, particularly tissue-resident stem cells.

Targeted Metabolomics on Rare Primary Cells.

Cellular function critically depends on metabolism, and the function of the underlying metabolic networks can be studied by measuring small molecule intermediates. However, obtaining accurate and reliable measurements of cellular metabolism, particularly in rare cell types like hematopoietic stem cells, has traditionally required pooling cells from multiple animals. A protocol now enables researchers to measure metabolites in rare cell types using only one mouse per sample while generating multiple replicates for more abundant cell types. This reduces the number of animals that are required for a given project. The protocol presented here involves several key differences over traditional metabolomics protocols, such as using 5 g/L NaCl as a sheath fluid, sorting directly into acetonitrile, and utilizing targeted quantification with rigorous use of internal standards, allowing for more accurate and comprehensive measurements of cellular metabolism. Despite the time required for the isolation of single cells, fluorescent staining, and sorting, the protocol can preserve differences among cell types and drug treatments to a large extent.

Potential therapeutic strategy for cancer: Multi-dimensional cross-talk between circRNAs and parental genes.

In many ways, circular RNAs (circRNAs) have been demonstrated to be crucial in the onset and advancement of cancer throughout the last ten years and have become a new focus of intense research in the field of RNAs. Accumulating studies have demonstrated that circRNAs can regulate parental gene expression via a variety of biological pathways. Furthermore, research into the complex interactions between circRNAs and their parental genes will shed light on their biological roles and open up new avenues for circRNAs' potential clinical translational uses. However, to date, multi-dimensional cross-talk between circRNAs and parental genes have not been systematically elucidated. Particularly intriguing is circRNA's exploration of tumor targeting, and potential therapeutic uses based on the parental gene regulation perspective. Here, we discuss their biogenesis, take a fresh look at the molecular mechanisms through which circRNAs control the expression of their parental genes in cancer. We further highlight We further highlight the latest circRNA clinical translational applications, including prognostic diagnostic markers, cancer vaccines, gDNA, and so on. Demonstrating the potential benefits and future applications of circRNA therapy.

Cross-talk between Helicobacter pylori and gastric cancer: a scientometric analysis.

Background: Helicobacter pylori (HP) is considered a leading risk factor for gastric cancer (GC). The aim of this article is to conduct bibliometric and visual analysis to assess scientific output, identify highly cited papers, summarize current knowledge, and explore recent hotspots and trends in HP/GC research. Methods: A bibliographic search was conducted on October 24, 2023, to retrieve relevant studies on HP/GC research between 2003 and 2022. The search terms were attached to HP and GC. The main data were from the Web of Science Core Collection (WoSCC). Data visualization was performed using Biblioshiny, VOSviewer, and Microsoft Excel. Results: In HP/GC research, 1970 papers were retrieved. The total number of papers (Np) in HP/GC was growing from 2003 to 2022. China and Japan were in the leading position and made the most contributions to HP/GC. Vanderbilt University and the US Department of Veterans Affairs had the highest Np. The most productive authors were Peek Jr Richard M. and Piazuelo M Blanca. Helicobacter received the most Np, while Gastroenterology had the most total citations (TC). High-cited publications and keyword clustering were used to identify the current status and trends in HP/GC research, while historical citation analysis provided insight into the evolution of HP/GC research. The hot topics included the effect of HP on gastric tumorigenesis and progression, the pathogenesis of HP-induced GC (HP factors), and the mechanisms by which HP affects GC (host factors). Research in the coming years could focus on topics such as autophagy, gut microbiota, immunotherapy, exosomes, epithelial-mesenchymal transition (EMT), and gamma-glutamyl transpeptidase (GGT). Conclusion: This study evaluated the global scientific output in HP/GC research and its quantitative characteristics, identified the essential works, and collected information on the current status, main focuses and emerging trends in HP/GC research to provide academics with guidance for future paths.

Aneuploidy-induced cellular behaviors: Insights from Drosophila.

A balanced gene complement is crucial for proper cell function. Aneuploidy, the condition of having an imbalanced chromosome set, alters the stoichiometry of gene copy numbers and protein complexes and has dramatic consequences at the cellular and organismal levels. In humans, aneuploidy is associated with different pathological conditions including cancer, microcephaly, mental retardation, miscarriages, and aging. Over the last century, Drosophila has provided a valuable system for studying the consequences of systemic aneuploidies. More recently, it has contributed to the identification and molecular dissection of aneuploidy-induced cellular behaviors and their impact at the tissue and organismal levels. In this perspective, we review this active field of research, first by comparing knowledge from yeast, mouse, and human cells, then by highlighting the contributions of Drosophila. The aim of these discussions was to further our understanding of the functional interplay between aneuploidy, cell physiology, and tissue homeostasis in human development and disease.

Proteomics: Unraveling the Cross Talk Between Innate Immunity and Disease Pathophysiology, Diagnostics, and Treatment Options.

Inflammation is crucial in diseases, and proteins play a key role in the interplay between innate immunity and pathology. This review explores how proteomics helps understanding this relationship, focusing on diagnosis and treatment. We explore the dynamic innate response and the significance of proteomic techniques in deciphering the complex network of proteins involved in prevalent diseases, including infections, cancer, autoimmune and neurodegenerative disorders. Proteomics identifies key proteins in host-pathogen interactions, shedding light on infection mechanisms and inflammation. These discoveries hold promise for diagnostic tools, therapies, and vaccines. In cancer research, proteomics reveals innate signatures associated with tumor development, immune evasion, and therapeutic response. Additionally, proteomic analysis has unveiled autoantigens and dysregulation of the innate immune system in autoimmunity, offering opportunities for early diagnosis, disease monitoring, and new therapeutic targets. Moreover, proteomic analysis has identified altered protein expression patterns in neurodegenerative diseases like Alzheimer's and Parkinson's, providing insights into potential therapeutic strategies. Proteomics of the innate immune system provides a comprehensive understanding of disease mechanisms, identifies biomarkers, and enables effective interventions in various diseases. Despite still in its early stages, this approach holds great promise to revolutionize innate immunity research and significantly improve patient outcomes across a wide range of diseases.

Ketone bodies in cell physiology and cancer.

Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' posttranslational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including fasting-mimicking diets (FMDs) and KDs, can prevent cancer and affect tumor progression.

CellularPotts.jl: simulating multiscale cellular models in Julia.

SUMMARY: CellularPotts.jl is a software package written in Julia to simulate biological cellular processes such as division, adhesion, and signaling. Accurately modeling and predicting these simple processes is crucial because they facilitate more complex biological phenomena related to important disease states like tumor growth, wound healing, and infection. Here we take advantage of Cellular Potts Modeling to simulate cellular interactions and combine them with differential equations to model dynamic cell signaling patterns. These models are advantageous over other approaches because they retain spatial information about each cell while remaining computationally efficient at larger scales. Users of this package define three key inputs to create valid model definitions: a 2- or 3-dimensional space, a table describing the cells to be positioned in that space, and a list of model penalties that dictate cell behaviors. Models can then be evolved over time to collect statistics, simulated repeatedly to investigate how changing a specific property impacts cellular behavior, and visualized using any of the available plotting libraries in Julia. AVAILABILITY AND IMPLEMENTATION: The CellularPotts.jl package is released under the MIT license and is available at https://github.com/RobertGregg/CellularPotts.jl. An archived version of the code (v0.3.2) at time of submission can also be found at https://doi.org/10.5281/zenodo.10407783.

Integration of single-nucleus RNA sequencing and network disturbance to elucidate crosstalk between multicomponent drugs and trigeminal ganglia cells in migraine.

ETHNOPHARMACOLOGICAL RELEVANCE: Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) plays an important role. TG is composed of multiple neuronal and non-neuronal cell types, which is related to "neuro-inflammation-vascular" disorder in migraine. Tou Tong Ning capsule (TTNC), a CFDA-approved traditional Chinese medicine for treating migraine, has the characteristics of "multicomponents, multitargets, multipathways". AIM OF THE STUDY: To clarify the mechanism of TTNC and elucidate crosstalk between multicomponent drugs and neuronal and non-neuronal functions and cells in migraine. MATERIALS AND METHODS: We integrated single-nucleus RNA sequencing and a quantitative evaluation algorithm of the disturbance of multitarget drugs on the disease network and explored the specific pathology of migraine and corresponding compounds. A cerebrovascular smooth muscle spasmolytic activity experiment was carried out to verify the results of the bioinformatics analysis. RESULTS: TTNC exhibited its regulation activities in neuronal and non-neuronal aspects based on drugs attack to four subnetworks and cell specific networks, which explored the MoA of TTNC in comprehensive and refined perspectives. Compared to neuronal regulation, TTNC showed more significant attack score on non-neuronal biological function (smooth muscle and vessel). And TTNC compound clusters C1, C6 and C7, targeting non-neuronal function and cells, had larger group area than C10, C4 and C6 for neuronal function and cell, which implied that TTNC may mainly regulate the non-neuronal function, e.g., vessel smooth muscle contraction. Contraction of cerebrovascular smooth muscle of mice ex vivo confirmed the vasodilation activity of TTNC and active compounds from C1, C6, C9 (Emodin, Luteolin and Levistilide A). Literature mining confirmed the vasospasmodolytic activity and neuroprotective effect of TTNC. CONCLUSIONS: The study found that TTNC may primarily alleviate non-neuronal functional disorders in migraine by relaxing cerebral vascular smooth muscle cell spasm to alleviate migraine. Integrating single-nucleus RNA sequencing data and network disturbance tools provides a new strategy for the pharmacological mechanism of multicomponent drugs through cell subtyping.

Membrane transporters in cell physiology, cancer metabolism and drug response.

By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Measuring neuron-regulated immune cell physiology via the alpha-2 adrenergic receptor in an ex vivo murine spleen model.

The communication between the nervous and immune systems plays a crucial role in regulating immune cell function and inflammatory responses. Sympathetic neurons, which innervate the spleen, have been implicated in modulating immune cell activity. The neurotransmitter norepinephrine (NE), released by sympathetic neurons, influences immune cell responses by binding to adrenergic receptors on their surface. The alpha-2 adrenergic receptor (α2AR), expressed predominantly on sympathetic neurons, has received attention due to its autoreceptor function and ability to modulate NE release. In this study, we used fast-scan cyclic voltammetry (FSCV) to provide the first subsecond measurements of NE released in the white pulp region of the spleen and validated it with yohimbine, a known antagonist of α2AR. For further application of FSCV in neuroimmunology, we investigated the extent to which subsecond NE from sympathetic neurons is important for immune cell physiology and cytokine production, focusing on tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interleukin-6 (IL-6). Our findings provide insights into the regulatory mechanisms underlying sympathetic-immune interactions and show the significance of using FSCV, a traditional neurochemistry technique, to study these neuroimmune mechanisms.

Recent Advances in Molecular and Cellular Functions of S100A10.

S100A10 (p11, annexin II light chain, calpactin light chain) is a multifunctional protein with a wide range of physiological activity. S100A10 is unique among the S100 family members of proteins since it does not bind to Ca2+, despite its sequence and structural similarity. This review focuses on studies highlighting the structure, regulation, and binding partners of S100A10. The binding partners of S100A10 were collated and summarized.

Defining and identifying cell sub-crosstalk pairs for characterizing cell-cell communication patterns.

Current cell-cell communication analysis focuses on quantifying intercellular interactions at cell type level. In the tissue microenvironment, one type of cells could be divided into multiple cell subgroups that function differently and communicate with other cell types or subgroups via different ligand-receptor-mediated signaling pathways. Given two cell types, we define a cell sub-crosstalk pair (CSCP) as a combination of two cell subgroups with strong and similar intercellular crosstalk signals and identify CSCPs based on coupled non-negative matrix factorization. Using single-cell spatial transcriptomics data of mouse olfactory bulb and visual cortex, we find that cells of different types within CSCPs are significantly spatially closer with each other than those in the whole single-cell spatial map. To demonstrate the utility of CSCPs, we apply 13 cell-cell communication analysis methods to sampled single-cell transcriptomics datasets at CSCP level and reveal ligand-receptor interactions masked at cell type level. Furthermore, by analyzing single-cell transcriptomics data from 29 breast cancer patients with different immunotherapy responses, we find that CSCPs are useful predictive features to discriminate patients responding to anti-PD-1 therapy from non-responders. Taken together, partitioning a cell type pair into CSCPs enables fine-grained characterization of cell-cell communication in tissue and tumor microenvironments.

Adverse Crosstalk between Extracellular Matrix Remodeling and Ferroptosis in Basal Breast Cancer.

(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in women and causes a high number of mortality among this population due to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy, and inhibit distant metastases, potentially impacting the tumor microenvironment. (2) Methods: Through data mining, the ferroptosis/extracellular matrix remodeling literature text-mining results were integrated into the breast cancer transcriptome cohort, taking into account patients with distant relapse-free survival (DRFS) under adjuvant therapy (anthracyclin + taxanes) with validation in an independent METABRIC cohort, along with the MDA-MB-231 and HCC338 transcriptome functional experiments with ferroptosis activations (GSE173905). (3) Results: Ferroptosis/extracellular matrix remodeling text-mining identified 910 associated genes. Univariate Cox analyses focused on breast cancer (GSE25066) selected 252 individual significant genes, of which 170 were found to have an adverse expression. Functional enrichment of these 170 adverse genes predicted basal breast cancer signatures. Through text-mining, some ferroptosis-significant adverse-selected genes shared citations in the domain of ECM remodeling, such as TNF, IL6, SET, CDKN2A, EGFR, HMGB1, KRAS, MET, LCN2, HIF1A, and TLR4. A molecular score based on the expression of the eleven genes was found predictive of the worst prognosis breast cancer at the univariate level: basal subtype, short DRFS, high-grade values 3 and 4, and estrogen and progesterone receptor negative and nodal stages 2 and 3. This eleven-gene signature was validated as regulated by ferroptosis inductors (erastin and RSL3) in the triple-negative breast cancer cellular model MDA-MB-231. (4) Conclusions: The crosstalk between ECM remodeling-ferroptosis functionalities allowed for defining a molecular score, which has been characterized as an independent adverse parameter in the prognosis of breast cancer patients. The gene signature of this molecular score has been validated to be regulated by erastin/RSL3 ferroptosis activators. This molecular score could be promising to evaluate the ECM-related impact of ferroptosis target therapies in breast cancer.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.

Whole-genome doubling in tissues and tumors.

The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD+) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD+ cells.

Acidosis-induced regulation of adipocyte G0S2 promotes crosstalk between adipocytes and breast cancer cells as well as tumor progression.

Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.

Modulation of cell physiology by bispecific nanobodies enabling changes in the intracellular localization of organelle proteins.

Proteins localize to their respective organelles in cells. This localization is changed by activation or repression in response to signal transduction. Therefore, the appropriate intracellular localization of proteins is important for their functions to be exerted. However, difficulties are associated with controlling the localization of endogenous proteins. In the present study, we developed a conceptually new method of controlling the intracellular localization of endogenous proteins using bispecific nanobodies (BiNbs). BiNbs recognize proteins expressed in the inner membrane, cytoskeleton, nucleus, and peroxisomes, but not in mitochondria or endoplasmic reticulum. BiNbs designed to recognize ß-CATENIN and the intrinsic cytosolic protein VIMENTIN (3 × Flag ß-CAT-VIM BiNbs) decreased the ß-CATENIN-mediated transactivation of target genes by preventing its nuclear localization. Furthermore, 3 × Flag ß-CAT-VIM BiNbs suppressed the proliferation and invasion of the VIMENTIN-expressing breast cancer cell line MDA-MB-231, but not MDA-MB-468, in which the expression of VIMENTIN was defective. The present results revealed that changes in the intracellular localization of specific proteins by BiNbs modulated the physiology and functions of cells. The development of BiNbs to recognize proteins specifically expressed in target cells may be a useful approach for eliciting cell-selective effects.