Intercellular Signaling Research Articles

Pattern Formation and Bistability in a Synthetic Intercellular Genetic Toggle.

Differentiation within multicellular organisms is a complex process that helps to establish spatial patterning and tissue formation within the body. Often, the differentiation of cells is governed by morphogens and intercellular signaling molecules that guide the fate of each cell, frequently using toggle-like regulatory components. Synthetic biologists have long sought to recapitulate patterned differentiation with engineered cellular communities, and various methods for differentiating bacteria have been invented. Here, we couple a synthetic corepressive toggle switch with intercellular signaling pathways to create a "quorum-sensing toggle". We show that this circuit not only exhibits population-wide bistability in a well-mixed liquid environment but also generates patterns of differentiation in colonies grown on agar containing an externally supplied morphogen. If coupled to other metabolic processes, circuits such as the one described here would allow for the engineering of spatially patterned, differentiated bacteria for use in biomaterials and bioelectronics.

Single-nucleus RNA sequencing reveals cell types, genes, and regulatory factors influencing melanogenesis in the breast muscle of Xuefeng black-bone chicken

The black-bone chicken, known for its high melanin content, holds significant economic value due to this unique trait. Particularly notable is the prominent melanin deposition observed in its breast muscle. However, the molecular mechanisms governing melanin synthesis and deposition in the breast muscle of black-bone chickens remain largely unknown. This study employed a single-nucleus transcriptome assay to identify genes associated with melanin deposition in the breast muscle of black-bone chickens, which are presumed to influence pigmentation levels. A comprehensive analysis of the nuclear transcriptome was conducted on the breast muscle of Xuefeng black-bone chickens, encompassing 18 distinct cell types, including melanocytes. Our findings revealed that STIMATE, LRRC7, ENSGALG00000049990, and GLDC play pivotal regulatory roles in melanin deposition within the breast muscle. Further exploration into the molecular mechanisms unveiled transcription factors and protein interactions suggesting that RARB, KLF15, and PRDM4 may be crucial regulators of melanin accumulation in the breast muscle. Additionally, HPGDS, GSTO1, and CYP1B1 may modulate melanin production and deposition in the breast muscle by influencing melanocyte metabolism. Our findings also suggest that melanocyte function in the breast muscle may be intertwined with intercellular signaling pathways such as PTPRK-WNT5A, NOTCH1-JAG1, IGF1R-IGF1, IDE-GCG, and ROR2-WNT5A. Leveraging advanced snRNA-seq technology, we generated a comprehensive single-cell nuclear transcriptome atlas of the breast muscle of Xuefeng black-bone chickens. This facilitated the identification of candidate genes, regulatory factors, and cellular signals potentially influencing melanin deposition and melanocyte function. Overall, our study provides crucial insights into the molecular basis of melanin deposition in chicken breast muscle, laying the groundwork for future breeding programs aimed at enhancing black-bone chicken cultivation.

Biologics Agents in Periodontal Regeneration:A Review

The field of periodontology and dental implantology has witnessed significant advancements in the use of molecular mediators and biologic agents over the past decade. Periodontal regeneration, which involves the complete restoration of cementum, bone, and connective tissue following removal of epithelial tissues, is considered superior to tissue repair. Recent research has focused on utilizing biologic materials as complementary therapies to enhance regeneration by accelerating wound healing. These biologic agents were investigated using the following search terms: tissue engineering, intercellular signaling molecules, and biological factors. Enamel matrix derivative (EMD), platelet-derived growth factor (PDGF), platelet-rich plasma, bone morphogenetic proteins (BMPs), fibroblast growth factor (FGF), and parathyroid hormone (PTH) have demonstrated the capacity to stimulate both hard and soft tissue regeneration. However, no single biologic agent is universally effective, necessitating a case-by-case evaluation for optimal treatment selection. Currently, EMD and PDGF are the only biologic therapies approved by the FDA for periodontal regeneration, while BMP-2 is indicated for bone augmentation. Due to a lack of FDA approval for periodontal applications, the clinical use of FGF and PTH in this context is not recommended.

Activity-dependent transcriptional programs in memory regulate motor recovery after stroke

Stroke causes death of brain tissue leading to long-term deficits. Behavioral evidence from neurorehabilitative therapies suggest learning-induced neuroplasticity can lead to beneficial outcomes. However, molecular and cellular mechanisms that link learning and stroke recovery are unknown. We show that in a mouse model of stroke, which exhibits enhanced recovery of function due to genetic perturbations of learning and memory genes, animals display activity-dependent transcriptional programs that are normally active during formation or storage of new memories. The expression of neuronal activity-dependent genes are predictive of recovery and occupy a molecular latent space unique to motor recovery. With motor recovery, networks of activity-dependent genes are co-expressed with their transcription factor targets forming gene regulatory networks that support activity-dependent transcription, that are normally diminished after stroke. Neuronal activity-dependent changes at the circuit level are influenced by interactions with microglia. At the molecular level, we show that enrichment of activity-dependent programs in neurons lead to transcriptional changes in microglia where they differentially interact to support intercellular signaling pathways for axon guidance, growth and synaptogenesis. Together, these studies identify activity-dependent transcriptional programs as a fundamental mechanism for neural repair post-stroke.

The Role of Extracellular Vesicles in Bone Regeneration and Associated Bone Diseases.

Extracellular vesicles (EVs) are nanoscale particles with a lipid bilayer membrane structure secreted by various cell types. Nearly all human cells secrete EVs, primarily mediating intercellular communication. In recent years, scientists have discovered that EVs can carry multiple biological cargos, such as DNA, non-coding RNAs (ncRNAs), proteins, cytokines, and lipids, and mediate intercellular signal transduction. Bone is a connective tissue with a nerve supply and high vascularization. The repair process after injury is highly complex, involving interactions among multiple cell types and biological signaling pathways. Bone regeneration consists of a series of coordinated osteoconductive and osteoinductive biological processes. As mediators of intercellular communication, EVs can promote bone regeneration by regulating osteoblast-mediated bone formation, osteoclast-mediated bone resorption, and other pathways. This review summarizes the biogenesis of EVs and the mechanisms by which EV-mediated intercellular communication promotes bone regeneration. Additionally, we focus on the research progress of EVs in various diseases related to bone regeneration. Finally, based on the above research, we explore the clinical applications of engineered EVs in the diagnosis and treatment of bone regeneration-related diseases.

Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling.

Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns cell polarity along the tissue plane and drives polarized cell behaviors during tissue morphogenesis. Accumulating evidence indicates that the vertebrate PCP pathway is regulated by noncanonical, β-catenin-independent Wnt signaling; however, the signaling components and mechanisms are incompletely understood. In the mouse hearing organ, both PCP and noncanonical Wnt (ncWnt) signaling are required in the developing auditory sensory epithelium to control cochlear duct elongation and planar polarity of resident sensory hair cells (HCs), including the shape and orientation of the stereociliary hair bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K pathway that coordinates HC planar polarity and intercellular PCP signaling. Here, we identify Wnt7b as a ncWnt ligand acting in concert with Wnt5a to promote tissue elongation in diverse developmental processes. In the cochlea, Wnt5a and Wnt7b are redundantly required for cochlear duct coiling and elongation, HC planar polarity, and asymmetric localization of core PCP proteins Fzd6 and Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple, a nonreceptor guanine nucleotide exchange factor for Gαi, and activates PI3K/AKT and ERK signaling, which promote asymmetric Fzd6 localization. Thus, ncWnt and PCP signaling pathways have distinct mutant phenotypes and signaling components, suggesting that they act as separate, parallel pathways with nonoverlapping functions in cochlear morphogenesis. NcWnt signaling drives tissue elongation and reinforces intercellular PCP signaling by regulating the trafficking of PCP-specific Frizzled receptors.

The BioRECIPE Knowledge Representation Format.

The BioRECIPE (Biological system Representation for Evaluation, Curation, Interoperability, Preserving, and Execution) knowledge representation format was introduced to standardize and facilitate human-machine interaction while creating, verifying, evaluating, curating, and expanding executable models of intra- and intercellular signaling. This format allows a human user to easily preview and modify any model component, while it is at the same time readable by machines and can be processed by a suite of model development and analysis tools. The BioRECIPE format is compatible with multiple representation formats, natural language processing tools, modeling tools, and databases that are used by the systems and synthetic biology communities.

Unveiling the multifaceted role of adropin in various diseases (Review).

Adropin is a secreted peptide encoded by the energy homeostasis‑associated gene, which also functions as a membrane‑bound protein facilitating intercellular communication. This peptide has been detected in various tissues and body fluids, including the brain, liver, kidney, heart, pancreas, small intestine, endothelial cells and colostrum. Notably, the amino acid sequences of adropin are identical in humans, mice and rats. Previous studies have demonstrated that adropin levels fluctuate under different physiological and pathological conditions. Adropin plays a role in regulating carbohydrate metabolism, lipid metabolism and intercellular molecular signaling pathways, implicating its involvement in the progression of numerous diseases, such as acute myocardial infarction, lung injury, non‑alcoholic fatty liver disease/non‑alcoholic steatohepatitis, kidney disease, polycystic ovary syndrome, obesity, and diabetes, atherosclerosis, systemic sclerosis and cancer. Despite its significance, the precise role and mechanism of this protein remain inadequately understood and studied. To elucidate the function of adropin and its clinical research status, a systematic review of recent studies on adropin across various diseases was conducted. Additionally, several challenges and limitations associated with adropin research in both animal and clinical contexts were identified, aiming to offer valuable insights for future investigation.

The therapeutic use of exosomes in children with adenoid hypertrophy accompanied by otitis media with effusion (AHOME): a protocol study

BackgroundThe adenoids act as a reservoir of bacterial pathogens and immune molecules, and they are significantly involved in children with otitis media with effusion (OME). As an essential carrier of intercellular substance transfer and signal transduction, exosomes with different biological functions can be secreted by various types of cells. There remains significant uncertainty regarding the clinical relevance of exosomes to OME, especially in its pathophysiologic development. In this study, we will seek to determine the biological functions of exosomes in children with adenoid hypertrophy accompanied by OME (AHOME).MethodsThe diagnostic criteria for OME in children aged 4–10 years include a disease duration of at least 3 months, type B or C acoustic immittance, and varying degrees of conductive hearing loss. Adenoidal hypertrophy is diagnosed when nasal endoscopy shows at least 60% adenoidal occlusion in the nostrils or when nasopharyngeal lateral X-ray shows A/N > 0.6. Children who meet the indications for adenoidectomy surgery undergo adenoidectomy. Peripheral blood, nasopharyngeal swab, and adenoid tissue will be collected from patients, and the exosomes will be isolated from the samples. Following the initial collection, patients will undergo adenoidectomy and peripheral blood and nasopharyngeal swabs will be collected again after 3 months.Expected resultsThis study aims to identify differences in exosomes from preoperative adenoid tissue and peripheral blood samples between children with AHOME and those with adenoid hypertrophy alone. Additionally, it seeks to determine changes in microbial diversity in adenoid tissue between these groups.ConclusionsThe findings are expected to provide new insights into the diagnosis and treatment of OME, to identify novel biomarkers, and to enhance our understanding of the pathophysiology of OME, potentially leading to the development of innovative diagnostic and therapeutic approaches.

Isolation and characterization of NGFFYamide neuropeptide from Patiria pectinifera pyloric caeca extract

Neuropeptides are small molecules that mediate intercellular signaling and regulate physiological processes. Starfish possess various myoactive neuropeptides, including starfish myorelaxant peptide (SMP) and a calcitonin-type peptide with apical muscle relaxing properties. In this study, we report the purification of a neuropeptide from starfish (Patiria pectinifera) pyloric caeca extract using high-performance liquid chromatography (HPLC) and an in vitro bioassay to screen for fractions and peptides with relaxing effects on P. pectinifera apical muscle preparations. A series of HPLC steps using reversed-phase and cation-exchange columns yielded a purified peptide with muscle-relaxing effects. The purified peptide's structure was determined by LC-MS and Edman degradation, revealing a pentapeptide with an amidated C-terminus (NGFFYamide) and a molecular mass of 646.2930 Da. This is the first report of NGFFYamide purification from P. pectinifera through biochemical methods. The nucleotide sequence encoding the NGFFYamide precursor was determined, showing the presence of a conserved neurophysin domain in the C-terminal region. RT-qPCR results confirmed high expression in radial nerves cord, consistent with previous findings on NG peptides in echinoderms. In vitro pharmacological studies on muscle preparations from P. pectinifera and Asterias amurensis revealed differential relaxing activity of NGFFYamide on apical muscles, while its effects on tube foot preparations were similar in both species. NGFFYamide also induced potent contraction in P. pectinifera cardiac stomach. Comparison of three NG peptides (NGFFYamide, NGFFFamide, and NGIWYamide) on P. pectinifera cardiac stomach revealed varying potency, suggesting class-specific receptor interactions. Tachyphylaxis was observed in P. pectinifera apical muscle but not in A. amurensis, warranting further investigation. Based on these results, it is plausible that NGFFYamide could be involved in regulating locomotion and feeding behavior in P. pectinifera, consistent with findings in Asterias rubens.

Carbon Nanotube Sensor Platforms for the Detection of Cellular Nitric Oxide Efflux Gradients

Cell communication is the ability to receive, process, and transmit signals from the environment and within cells to ensure functional coordination during physiological events. Cells communicate between themselves using waves of chemical concentration that change in both direction and time. Nitric oxide (NO) is a gaseous, ubiquitous, intra - and inter-cellular signaling molecule. NO’s small size and lipophilic nature allows it to diffuse through cell membranes and reach intracellular compartments of nearby cells. However, NO detection in biological systems represents a challenge due to NO’s short half-life (in the range of seconds) before breaking down into different subproducts. The lack of spatial NO detection, not an upstream or downstream indicator of NO, has hindered understanding of the extracellular NO dynamic signaling during both physiological and pathological events. However, single wall carbon nanotube (SWNT)-based fluorescent sensors allow for the detection of NO, and when immobilized onto a glass substrate, they can be used to quantify extracellular NO in a spatial-temporal manner. We detected changes in extracellular NO efflux from different macrophage cell lines known for their NO production under inflammatory responses, specifically human THP-1 monocytes and murine macrophage RAW 264.7. The cells were seeded on the SWNT platform and treated with Liposaccharides (LPS) 24 h to increase their NO release. The SWNT platform’s sensing response to NO was detected by changes in fluorescence intensity. Fluorescence data was collected on a custom-built hyperspectral microscope to give us near infrared (nIR) signal quantification with spatial resolution. Images were collected before and after the respective NO induction method. To analyze the extracellular NO mappings, bright field images of the cells were used to extract the cell coordinates and translate them to fluorescent images. Hyperspectral image analysis was performed with MATLAB to determine SWNT fluorescence below each cell and its surrounding area. To validate that the change in the fluorescence response was attributed to NO and not from cellular interaction with the SWNT sensor, we added 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a NO scavenger, after visualizing the SWNT quenching to recover the initial fluorescence signal, showing that the cells didn’t affect SWNT functionality. Through fluorescence intensity changes with pixel specificity on the image acquisition, we were able to spatially quantify NO released by cells with dynamic diffusion gradients. The newly developed platform provides the means to quantify extracellular NO. In this study, only two cell lines were studied, but the platforms will allow for the quantification of NO for other cell types as well. By comparing extracellular NO concentrations for different types of cells, we will be able to better understand physiological and pathological patterns of NO release, leading to a better understanding of cellular signaling.

Phosphodiesterase-5 inhibition collaborates with vaccine-based immunotherapy to reprogram myeloid cells in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and inducible NOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors, including head and neck cancers. We show for the first time to our knowledge that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-programmed cell death protein 1, and anti-cytotoxic T lymphocyte-associated protein 4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA-sequencing analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid/T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid/T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.

Single-nucleus multiomics reveals the disrupted regulatory programs in three brain regions of sporadic early-onset Alzheimer's disease.

Sporadic early-onset Alzheimer's disease (sEOAD) represents a significant but less-studied subtype of Alzheimer's disease (AD). Here, we generated a single-nucleus multiome atlas derived from the postmortem prefrontal cortex, entorhinal cortex, and hippocampus of nine individuals with or without sEOAD. Comprehensive analyses were conducted to delineate cell type-specific transcriptomic changes and linked candidate cis-regulatory elements (cCREs) across brain regions. We prioritized seven conservative transcription factors in glial cells in multiple brain regions, including RFX4 in astrocytes and IKZF1 in microglia, which are implicated in regulating sEOAD-associated genes. Moreover, we identified the top 25 altered intercellular signaling between glial cells and neurons, highlighting their regulatory potential on gene expression in receiver cells. We reported 38 cCREs linked to sEOAD-associated genes overlapped with late-onset AD risk loci, and sEOAD cCREs enriched in neuropsychiatric disorder risk loci. This atlas helps dissect transcriptional and chromatin dynamics in sEOAD, providing a key resource for AD research.

CRABP1-complexes in exosome secretion

BackgroundCellular retinoic acid binding protein 1 (CRABP1) mediates rapid, non-canonical activity of retinoic acid (RA) by forming signalosomes via protein-protein interactions. Two signalosomes have been identified previously: CRABP1-MAPK and CRABP1-CaMKII. Crabp1 knockout (CKO) mice exhibited altered exosome profiles, but the mechanism of CRABP1 action was unclear. This study aimed to screen for and identify novel CRABP1 signalosomes that could modulate exosome secretion by using a combinatorial approach involving biochemical, bioinformatic and molecular studies.MethodsImmunoprecipitation coupled with mass spectrometry (IP-MS) identified candidate CRABP1-interacting proteins which were subsequently analyzed using GO Term Enrichment, Functional Annotation Clustering; and Pathway Analysis. Gene expression analysis of CKO samples revealed altered expression of genes related to exosome biogenesis and secretion. The effect of CRABP1 on exosome secretion was then experimentally validated using CKO mice and a Crabp1 knockdown P19 cell line.ResultsIP-MS identified CRABP1-interacting targets. Bioinformatic analyses revealed significant association with actin cytoskeletal dynamics, kinases, and exosome secretion. The effect of CRABP1 on exosome secretion was experimentally validated by comparing circulating exosome numbers of CKO and wild type (WT) mice, and secreted exosomes from WT and siCRABP1-P19 cells. Pathway analysis identified kinase signaling and Arp2/3 complex as the major pathways where CRABP1-signalosomes modulate exosome secretion, which was validated in the P19 system.ConclusionThe combinatorial approach allowed efficient screening for and identification of novel CRABP1-signalosomes. The results uncovered a novel function of CRABP1 in modulating exosome secretion, and suggested that CRABP1 could play roles in modulating intercellular communication and signal propagation.

Murine exosomal miR-30a aggravates cardiac function after acute myocardial infarction via regulating cell fate of cardiomyocytes and cardiac resident macrophages

After acute myocardial infarction (AMI), intercellular communication is crucial for maintaining cardiac homeostasis and patient survival. Exosomes secreted by cardiomyocytes serve as carriers for transporting microRNA(miRNAs), participating in intercellular signaling and the regulation of cardiac function. This study aims to investigate the role of exosomal microRNA-30a(miR-30a) during AMI and its underlying mechanisms. AMI was induced by permanent ligation of the left anterior descending (LAD) artery in C57BL/6 mice. The expression of miR-30a in mice was respectively enhanced and inhibited by administering agomiR-30a and antagomiR-30a. Using HL-1 cardiomyocytes and RAW264.7 macrophages for in vitro experiments, HL-1 cardiomyocytes were cultured under hypoxic conditions to induce ischemic injury. Following isolation and injection of exosomals, a variety of validation methods were utilized to assess the expression of miR-30a, and investigate the effects of enriched exosomal miR-30a on the state of cardiomyocytes. After AMI, the level of exosomal miR-30a in the serum of mice significantly increased and was highly enriched in cardiac tissue. Cardiomyocytes treated with agomiR-30a and miR-30a-enriched exosomes exhibited inhibition of cell autophagy, increased cell apoptosis, mice showed an larger myocardial infarct area and poorer cardiac function. Exosomes released from hypoxic cardiomyocytes transferred miR-30a to cardiac resident macrophages, promoting the polarization into pro-inflammatory M1 macrophages. In conclusion, murine exosomal miR-30a exacerbates cardiac dysfunction post-AMI by disrupting the autophagy-apoptosis balance in cardiomyocytes and polarizing cardiac resident macrophages into pro-inflammatory M1 macrophages. Modulating the expression of miR-30a may reduce cardiac damage following AMI, and targeting exosomal miR-30a could be a potential therapeutic approach for AMI.

Cell-Cell Interactions: How Coupled Boolean Networks Tend to Criticality.

Biological cells are usually operating in conditions characterized by intercellular signaling and interaction, which are supposed to strongly influence individual cell dynamics. In this work, we study the dynamics of interacting random Boolean networks, focusing on attractor properties and response to perturbations. We observe that the properties of isolated critical Boolean networks are substantially maintained also in interaction settings, while interactions bias the dynamics of chaotic and ordered networks toward that of critical cells. The increase in attractors observed in multicellular scenarios, compared to single cells, allows us to hypothesize that biological processes, such as ontogeny and cell differentiation, leverage interactions to modulate individual and collective cell responses.

Something to talk about; crosstalk disruption at the neurovascular unit during HIV infection of the CNS

Abstract Although treatable with antiretroviral therapy, HIV infection persists in people living with HIV (PLWH). It is well known that the HIV virus finds refuge in places for which antiretroviral medications do not reach therapeutic levels, mainly the CNS. It is clear that as PLWH age, the likelihood of developing HIV-associated neurological deficits increases. At the biochemical level neurological dysfunction is the manifestation of altered cellular function and ineffective intercellular communication. In this review, we examine how intercellular signaling in the brain is disrupted in the context of HIV. Specifically, the concept of how the blood-brain barrier can be a convergence point for crosstalk, is explored. Crosstalk between the cells of the neurovascular unit (NVU) (endothelium, pericytes, astrocytes, microglia and neurons) is critical for maintaining proper brain function. In fact, the NVU allows for rapid matching of neuronal metabolic needs, regulation of blood-brain barrier (BBB) dynamics for nutrient transport and changes to the level of immunosurveillance. This review invites the reader to conceptually consider the BBB as a router or convergence point for NVU crosstalk, to facilitate a better understanding of the intricate signaling events that underpin the function of the NVU during HIV associated neuropathology.

Comparing the roles of sex chromosome-encoded protein homologs in gene regulation.

The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.

TAZ downregulated ANXA1 expression to modulate myeloma cell interactions with bone marrow mesenchymal stromal cells

We and others have previously shown that TAZ plays a tumor suppressive role in multiple myeloma. However, recent reports suggest that molecular crosstalk between the myeloma cells and bone marrow stromal components contributes to the myeloma cell survival and drug resistance. These reports further point to reciprocal interaction via adhesion molecules as the most prominent mechanism of intercellular crosstalk between myeloma cells and bone marrow mesenchymal stromal cells (BM-MSCs). YAP/TAZ silencing/expression has been shown to correlate across all cancers with a set of adhesion/extracellular matrix proteins. Therefore, we hypothesized that TAZ may regulate myeloma cell interaction with BM stromal cells by influencing the expression of distinct cell adhesion signatures. We used previously established TAZ myeloma cell line models, including DELTA47-pLENTI or TAZ knockout DELTA47 cells cocultured with or without BM-MSCs, as our study models. Using RNA sequencing analysis, we performed the first comprehensive screen for cell adhesion-related transcriptional targets of TAZ in multiple myeloma (MM). In doing so, we uncovered an enrichment of cell adhesion-related genes in TAZ knockout DELTA47 cells relatively to pLENTI-DELTA47 cells, including 11 genes with log2 fold change > 2 (p < 0.05), namely, ANXA1, ADGRL2, NCAM1, NCAM2, ADGRL3, CXADR, ALCAM, JAM2, KIRREL1, KIRREL2, and ADGRG7, suggesting possible relationship with TAZ. We validated ANXA1 as a bona fide target of TAZ in MM. We show that TAZ represses myeloma cell migration and interaction with BM-MSCs by transcriptionally downregulating ANXA1 expression via TEAD-dependent mechanism. Our data provide new insights into the understanding of the role of TAZ in the intercellular communication signals between myeloma cells and BM-MSCs. Our findings also suggest that ANXA1 represents a putative cell adhesion target to attenuate BM-MSC driven, tumor-promoting interaction with myeloma cells.

Stimulation and imaging of neural cells via photonic nanojets

Various neuromodulation techniques have been developed to modulate the peak activity of neurons, thereby regulating brain function and alleviating neurological disorders. Additionally, neuronal stimulation and imaging have significantly contributed to the understanding and treatment of these diseases. Here, we propose utilizing photonic nanojets for optical stimulation and imaging of neural cells. The application of resin microspheres as microlenses enhances fluorescence imaging of neural lysosomes, mitochondria, and actin filaments by generating photonic nanojets. Moreover, optical tweezers can precisely manipulate the microlenses to locate specific targets within the cell for real-time stimulation and imaging. The focusing capabilities of these microlenses enable subcellular-level spatial precision in stimulation, allowing highly accurate targeting of neural cells while minimizing off-target effects. Furthermore, fluorescent signals during neural cell stimulation can be detected in real-time using these microlenses. The proposed method facilitates investigation into intercellular signal transmission among neural cells, providing new insights into the underlying mechanisms of neuronal cell activities at a subcellular level.