Regulation Of Cell Differentiation Research Articles

CHAF1B promotes the progression of lung squamous-cell carcinoma by inhibiting SETD7 expression.

The p60 subunit of the chromatin assembly factor-1 complex, that is, chromatin assembly factor-1 subunit B (CHAF1B), is a histone H3/H4 chaperone crucial for the transcriptional regulation of cell differentiation and self-renewal. CHAF1B is overexpressed in several cancers and may represent a potential target for cancer therapy. However, its expression and clinical significance in lung squamous-cell carcinoma (LUSC) remain unclear. In this study, we performed weighted gene correlation network analysis to analyze the Gene Expression Omnibus GSE68793 LUSC dataset and identified CHAF1B as one of the most important driver gene candidates. Immunohistochemical analysis of 126 LUSC tumor samples and 80 adjacent normal lung tissues showed the marked upregulation of CHAF1B in tumor tissues and the negative association of its expression level with patient survival outcomes. Silencing of CHAF1B suppressed LUSC proliferation in vitro and LUSC tumor growth in vivo. Furthermore, bulk RNA sequencing of CHAF1B knockdown cells indicated SET domain containing 7 (SETD7) as a significant CHAF1B target gene. In addition, CHAF1B competitively binds to the SETD7 promoter region and represses its transcription. Altogether, these results imply that CHAF1B plays a vital role in LUSC tumorigenesis and may represent a potential molecular target for this deadly disease.

Long non-coding RNA NEAT1 promotes ovarian granulosa cell proliferation and cell cycle progression via the miR-29a-3p/IGF1 axis

BackgroundGranulosa cell proliferation and survival are essential for normal ovarian function and follicular development. Long non-coding RNAs (lncRNAs) have emerged as important regulators of cell proliferation and differentiation. Nuclear paraspeckle assembly transcript 1 (NEAT1) has been implicated in various cellular processes, but its role in granulosa cell function remains unclear.MethodsWe investigated the function of lncRNA NEAT1 in human ovarian granulosa-like tumor cells (KGN). The effects of NEAT1 overexpression or silencing on cell proliferation and cell cycle were evaluated using CCK-8 assays and flow cytometry. The interaction between NEAT1, miR-29a-3p, and IGF1 was examined using dual-luciferase reporter assays, qRT-PCR, and Western blot analysis.ResultsNEAT1 promoted granulosa cell proliferation and cell cycle progression by indirectly upregulated IGF1 expression through acting as a molecular sponge for miR-29a-3p. Cell proliferation and G2/M phase proportions were increased by overexpression of NEAT1, whereas cell proliferation and G2/M phase proportions decreased with NEAT1 silencing. The effects of NEAT1 on cell proliferation and cell cycle-related proteins (CCNB1 and CDK2) were partially reversed by miR-29a-3p mimic, while miR-29a-3p inhibitor rescued the effects of NEAT1 silencing.ConclusionLncRNA NEAT1 could promote ovarian granulosa cell proliferation and cell cycle progression via the miR-29a-3p/IGF1 axis in polycystic ovary syndrome. Further investigation of this mechanism in clinical samples may have implications for understanding ovarian physiology and pathology.

Near-infrared DNA biosensors based on polysulfonate coatings for the sensitive detection of microRNAs.

MicroRNAs (miRNAs) play crucial roles in the regulation of immune cell differentiation and the immune response during allergic rhinitis (AR). Studies have shown that miRNA-155 is significantly upregulated in AR pathogenesis. Therefore, miRNA-155 can be used as a biomarker for AR diagnosis. Although fluorescent biosensors based on upconversion nanoparticles (UCNPs) have made significant advances in the detection of miRNAs, developing UCNPs with polymer coatings, efficient surface passivation, and DNA functionalization for hybrid sensing in biological media remains challenging. Herein, hairpin DNA1 (H1) is modified into a thin polysulfonic acid layer on UCNPs by sulfonamide bonds, and the fluorescence of the UCNPs is quenched by the fluorescence resonance energy transfer (FRET) process of BHQ3 carried by H1. When the target miRNA-155 is present, the hairpin structure of H1 is opened, allowing BHQ3 to move away from the UCNP surface, and the fluorescence of UCNP is restored. At the same time, hairpin DNA1 (H2) can combine with H1 to replace the miRNA-155 that is bound to H1 with the help of the opening stem ring structure of H1, and the replaced miRNA-155 can continue to react with H1 to amplify the fluorescence signal. Under the optimal experimental conditions, the linear range of miRNA-155 is 0.01-3 nM, with a detection limit of 1.14 pM. Furthermore, the constructed biosensor has been applied to determine miRNA-155 in serum samples, and the spiked recoveries range from 99.8% to 104.8%, which indicates that the developed assay has potential applications in monitoring allergic rhinitis or other miRNA related diseases.

SCPL48 regulates the vessel cell programmed cell death during xylem development in Arabidopsis thaliana.

Secondary cell wall (SCW) deposition is tightly coordinated with programmed cell death (PCD) during xylem development and plays a crucial role in plant stress responses. In this study, we characterized a serine carboxypeptidase-like gene, SCPL48, which exhibits xylem cell-specific expression patterns in stem xylem during vascular development. The scpl48 plants exhibited reduced stem xylem cell numbers, particularly vessel cells, accompanied by delayed organelle degradation during PCD and increased secondary wall thickness in xylem vessel cells. In contrast, SCPL48 overexpression resulted in increased vessel cell abundance and accelerated degradation of vessel cell contents, suggesting its critical role in xylem vessel cell differentiation. Notably, SCPL48 expression was significantly up-regulated in response to ABA treatment and drought stress, with SCPL48 overexpression lines demonstrating enhanced drought resistance. Further molecular analyses revealed that SCPL48 was directly targeted and transcriptionally activated by key SCW regulators VND6, and MYB46. Furthermore, the expression of PCD-related protease genes, including XCP1, XSP1, RNS3, MC9, γVPE, and CEP1, showed compensatory changes in both scpl48 mutants and SCPL48 overexpression lines. Collectively, our findings demonstrate that SCPL48 functions as a key regulator in xylem vessel cell differentiation, PCD and drought stress responses.

Notch Signaling in Central Nervous System: From Cellular Development to Multiple Sclerosis Disease.

Multiple sclerosis (MS), is characterized by autoimmune-driven neuroinflammation, axonal degeneration, and demyelination. This study aimed to explore the therapeutic potential of targeting Notch signaling within the central nervous system (CNS) in the context of MS. Understanding the intricate roles of Notch signaling could pave the way for targeted interventions to mitigate MS progression. A comprehensive literature review was conducted using databases such as PubMed, Web of Science, and Scopus. Keywords such as "Notch signaling," "neuroglial interactions," and "MS" were used. The selection criteria included relevance to neuroglial interactions, peer-reviewed publications, and studies involving animal models of MS. This review highlights the diverse functions of Notch signaling in CNS development, including its regulation of neural stem cell differentiation into neurons, astrocytes, and oligodendrocytes. In the context of MS, Notch signaling has emerged as a promising therapeutic target, exhibiting positive impacts on neuroprotection and remyelination. However, its intricate nature within the CNS necessitates precise modulation for therapeutic efficacy. This study provides a comprehensive overview of the potential therapeutic role of Notch signaling in MS. The findings underscore the significance of Notch modulation for neuroprotection and remyelination, emphasizing the need for precision in therapeutic interventions. Further research is imperative to elucidate the specific underlying mechanisms involved, which will provide a foundation for targeted therapeutic strategies for the management of MS and related neurodegenerative disorders.

Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes.

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (p < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.

Anticancer Effects of MAPK6 siRNA-Loaded PLGA Nanoparticles in the Treatment of Breast Cancer.

siRNA-loaded nanoparticles open new perspectives for cancer treatment. MAPK6 is upregulated in breast cancer and is involved in cell growth, differentiation and cell cycle regulation. Herein, we aimed to investigate the anticancer effects of MAPK6 knockdown by using MAPK6 siRNA-loaded PLGA nanoparticles (siMAPK6-PLGA-NPs) in MCF-7 breast cancer cells. After the synthesis and characterisation of nanoparticles, treatment concentrations were determined with cytotoxicity assay. Subsequently, MAPK6 knockdown and anticancer effects of siMAPK6-PLGA-NPs were evaluated by invitro assays. siMAPK6-PLGA-NPs have been determined to suppress MAPK6 expression efficiently. Invitro studies revealed that siMAPK6-PLGA-NPs significantly reduced the migration, proliferation and colony-forming ability and enhanced the apoptosis in MCF-7 cells. Taken together, siMAPK6-PLGA-NPs exhibited robust and promising anticancer effects against MCF-7 cells. Our findings demonstrated that siRNA-loaded PLGA nanoparticles have great potential for breast cancer treatment and MAPK6 gene may be the therapeutic target in breast cancer.

The Complexity and Significance of Fibroblast Growth Factor (FGF) Signaling for FGF-Targeted Cancer Therapies.

Fibroblast growth factors (FGFs) have diverse functions in the regulation of cell proliferation and differentiation in development, tissue maintenance, wound repair, and angiogenesis. The goal of this review paper is to (i) deliberate on the role of FGFs and FGF receptors (FGFRs) in different cancers, (ii) present advances in FGF-targeted cancer therapies, and (iii) explore cell signaling mechanisms that explain how FGF expression becomes dysregulated during cancer development. FGF is often mutated and overexpressed in cancer and the different FGF and FGFR isoforms have unique expression patterns and distinct roles in different cancers. Among the FGF members, the FGF 15/19 subfamily is particularly interesting because of its unique protein structure and role in endocrine function. The abnormal expression of FGFs in different cancer types (breast, colorectal, hepatobiliary, bronchogenic, and others) is examined and correlated with patient prognosis. The classification of FGF ligands based on their mode of action, whether autocrine, paracrine, endocrine, or intracrine, is illustrated, and an analysis of the binding specificity of FGFs to FGFRs is also provided. Moreover, the latest advances in cancer therapeutic strategies involving small molecules, ligand traps, and monoclonal antibody-based FGF inhibitors are presented. Lastly, we discuss how the dysregulation of FGF and FGFR expression affects FGF signaling and its role in cancer development.

Primary Cilia Regulate the Homeostasis and Regeneration of the Stem Cell Niche in the Tooth.

Primary cilia, functioning as crucial hubs for signal sensing and transduction, are integral to the development and maintenance of homeostasis across various organs. However, their roles in tooth homeostasis and repair remain inadequately understood. In this study, we reveal an indispensable role for primary cilia in regulating the homeostasis and regeneration of teeth, primarily through the regulation of cell proliferation. Using cilium-deficient mice, we demonstrate that disruption of ciliary homeostasis leads to abnormal tooth morphology, stunted growth and notably impaired tooth repair. RNA sequencing reveals a dysregulation in genes associated with various biological processes such as cell proliferation, differentiation, and cycle regulation. Furthermore, we show that cilium-deficient mice display reduced cell proliferation. Our findings highlight a critical function for primary cilia in the regulation of tooth homeostasis and regeneration and have important implications for the development of tooth regeneration therapies.

Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells.

Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s, which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-β (TGF-β) as a cell-autonomous driver for NK cell tissue residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-β was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-β was redundant in tumors, our study revealed that NK cell-derived TGF-β allowed the expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-β1, which is relevant for antiviral immunity.

The aberrantly activated AURKB supports and complements the function of AURKA in CALR mutated cells through regulating the cell growth and differentiation.

Aurora kinase B (AURKB) was reported to assist Aurora kinase A (AURKA) to regulate cellular mitosis. AURKA has been found activated in myeloproliferative neoplasms (MPNs) patients with CALR gene mutation, however, it's unclear whether AURKB displays a compensatory function of AURKA in regulation of CALR mutant cell growth and differentiation. Here, we found that AURKB, similar with AURKA, was aberrantly activated in CALR mutant patients, and displayed a more tolerance to the aurora kinase inhibitor. Inhibition of AURKA decreased cell growth and colony formation, induced cell differentiation and apoptosis, while, this inhibitive degree was further enhanced when AURKB was blocked by incremental inhibitor. Transcriptomic analyses revealed a more significant gene enrichment in cells with knockdown of AURKB than that of AURKA, mainly reflecting in oxidative phosphorylation, mitosis, proliferation and apoptosis signaling pathway. Moreover, downregulation of AURKB enhanced cell growth arrest and apoptosis more obviously than that of AURKA, and additionally promoted cell differentiation and metabolism-oxygen consumption rate (OCR). Otherwise, overexpression of AURKA or AURKB facilitated the cell proliferation of CALR mutant cells, and made cells more sensitive to the aurora kinase inhibitor. These results suggest that activated AURKB not only supports the functions of AURKA in promoting the growth of CALR mutated cells, but also has impeded the differentiation of these cells.

ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF.

Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc-finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 depletion system in mouse embryonic stem cells. Our results show that ZNF143/ZFP143 degradation has no effect on chromatin looping. Systematic analysis of ZNF143/ZFP143 occupancy data revealed that a commonly used antibody cross-reacts with CTCF, leading to its incorrect association with chromatin loops. Nevertheless, ZNF143/ZFP143 specifically activates nuclear-encoded mitochondrial genes, and its loss leads to severe mitochondrial dysfunction. Using an invitro embryo model, we find that ZNF143/ZFP143 is an essential regulator of organismal development. Our results establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by safeguarding mitochondrial activity.

Tyrosine Hydroxylase-positive Nucleus Accumbens Neurons Influence Delay Discounting in a Mouse T-maze Task.

Delay discounting (DD) is a phenomenon where individuals devalue a reward associated with a temporal delay, with the rate of devaluation being representative of impulsive-like behavior. Here we first sought to develop and validate a mouse DD task to study brain circuits involved in DD decision-making within short developmental time windows, given widespread evidence of developmental regulation of impulse control and risk-taking. We optimized a T-maze DD task for mice that enables training and DD trials within two weeks. Mice learned to choose between a large and a small reward located at opposite arms of a T-maze. Once training criteria were met, mice underwent DD whereby the large reward choice was associated with a temporal delay. Task validation showed that adolescent C57BL/6J mice display increased preference for the small reward upon a temporal delay, confirming increased impulsivity compared to adults. We next used this DD task to explore the neural basis of decision-making. We used tyrosine hydroxylase transgenic mice (TH-Cre) to target TH-positive neurons in the nucleus accumbens (NAc) and ventral tegmental area (VTA) with Cre-dependent excitatory or inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Inhibition of transduced neurons in the NAc decreased preference for the small but immediate reward during DD. Inhibition of TH+ neurons in the ventral tegmental area (VTA) did not affect impulsive choice in this DD task. These results uncover a novel role for NAc TH-positive neurons in DD behavior and expand the repertoire of behavioral tasks available for studying decision-making across the lifespan.Significance Statement Delay discounting (DD) tasks are used in rodents to study impulsive choice, whereby subjects display a preference for an immediate, smaller reward when access to a larger reward is contingent on a temporal delay. Research implicates the nucleus accumbens (NAc) brain region in impulsive behavior, with recent evidence of specialization among NAc neuronal subtypes in impulsive choice. Here we interrogated the neural requirements of impulsive choice in mice. We found that inhibition of a subset of NAc neurons expressing tyrosine hydroxylase decreases impulsive choice. We also saw increased impulsive choice in adolescent mice compared to adults, consistent with reported developmental changes in impulsivity. Together, our data identify cell-specific NAc regulation of impulsive choice with important implications for neurodevelopment.

Iodine activates NLRP3 inflammasomes in PBMCs of patients with autoimmune thyroiditis and regulates Th1 and Th17 cell differentiation.

Inflammasomes are associated with various autoimmune diseases. Herein, we aimed to study the occurrence of inflammasomes in peripheral blood mononuclear cells (PBMCs) from patients with autoimmune thyroiditis (AIT), and the relationship between their abundance and the inflammatory response index of AIT. Furthermore, we examined the effect of iodine on inflammasomes containing NLR family pyrin domain-containing 3 (NLRP3) and inflammasome activation of helper T (Th) cell differentiation regulation in cultured PBMCs. We collected PBMCs and serum samples from 50 patients with AIT with normal thyroid function and 50 controls matched for age and sex. In PBMCs, the mRNA and protein expressions of certain inflammasome constituents (e.g., NLRP1, NLRP3, absent in melanoma 2 (AIM2) and caspase-1), interleukin (IL)-1β and IL-18 were assessed using qRT-PCR and western blotting. Enzyme-linked immunosorbent assays (ELISAs) assessed the serum levels of IL-1β and IL-18. Flow cytometry was employed to examine NLRP3 expression on CD14+ monocytes and Th1 and Th17 cell percentages in the groups. AIT- or healthy control-derived PBMCs were stimulated using sodium iodide, with or without lipopolysaccharide (LPS) for 72 h. PBMCs from patients with AIT had significantly higher levels of pro-IL-18, pro-IL-1β and NLRP3 than did the PBMCs from the healthy controls (P < 0.05). Compared with those from the controls, AIT-derived PBMCs had enhanced levels of active IL-18 and active caspase-1 p20 (P < 0.05), whereas their abundance of active IL-1β was similar (P > 0.05). In serum, the AIT group had enhanced levels of IL-18 compared with the healthy controls (P < 0.05) but had similar levels of IL-1β (P > 0.05). NLRP3 expression on CD14+ monocytes from AIT patients was significantly augmented compared with the healthy controls (P< 0.01). Significantly increased percentages of Th1 and Th17 cells were detected in AIT patients compared with those in the healthy participants (P < 0.001). Sodium iodide treatment upregulated NLRP3 expression in PBMCs during 72 h of culture (P < 0.001). The percentage of Th1 and Th17 cells in AIT patients increased in an iodine-dependent manner (P < 0.01). Iodine had no significant effect on the number of these cells in the healthy control group (P > 0.05). AIT-derived PBMC NLRP3 activity and expression increased. Iodine might regulate the immune and inflammatory response of patients with AIT by activating NLRP3 and promoting Th1 and Th17 cell differentiation.

Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) among them. The KEAP1 gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The STK11 gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The STK11 gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of STK11 or KEAP1 abnormalities with the KRAS mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of STK11 and KEAP1 genes mutations with the KRAS gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with STK11-, KEAP1- and KRAS-mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.

Cell-specific regulation of insulin action and hepatic fibrosis by CEACAM1.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides in vivo evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.

SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections

Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing.

Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, function and regeneration.

RNA-binding proteins are critically involved in the post-transcriptional control of gene expression during embryonic development and in adult life, contributing to regulating cell differentiation and maintaining tissue homeostasis. Compared to the relatively well documented functions of transcription factors, the regulatory roles of RNA-binding proteins in muscle development and function remain largely elusive. However, deficiency of many RNA-binding proteins has been associated with muscular defects, neuromuscular disorders and heart diseases, such as myotonic dystrophy, amyotrophic lateral sclerosis, and cardiomyopathy. Rbm24 is highly conserved among vertebrates and is one of the best characterized RNA-binding proteins with crucial implication in the myogenic and cardiomyogenic programs. It presents the distinctive particularity of displaying highly restricted expression in both skeletal and cardiac muscles, with changes in subcellular localization during the process of differentiation. Functional analyses using different vertebrate models have clearly demonstrated its requirement for skeletal muscle differentiation and regeneration as well as for myocardium organization and cardiac function, by regulating the expression of both common and distinct target genes in these tissues. The challenge remains to decipher the dynamic feature of post-transcriptional circuits regulated by Rbm24 during skeletal myogenesis, cardiomyogenesis, and muscle repair. This review discusses current understanding of its function in striated muscles and its possible implication in human disease, with the aim of identifying research gaps for future investigation.

CDA Formulations: Potentially the Standard Care of Breast, Lung and Liver Cancers

Breast and lung cancers are very common, which are the top two leading causes of death from cancer. Hepatomas are not as common. But hepatomas are not responding well to therapies currently available. Cancer incidence and mortality keep on increasing ever since these statistics became public records, which are an indication of the failure of the health profession to control cancer. Cancer therapies approved in the past are mostly based on killing of cancer cells which are wrong to solve only a fraction of cancer problems. To effectively solve cancer, we must eliminate all factors contributing to the evolution of cancer. Cancer evolves due to wound unhealing because of the collapse of chemo-surveillance. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs), which are embryonic stem cells to initiate the development of organs and tissues. Methylation enzymes (MEs) play a pivotal role on the regulation of cell replication and differentiation. Because of this pivotal role, MEs are exceptionally subjected to double allosteric regulations, on the individual enzymes by steroid hormone and on the enzyme complex by telomerase and chemo-surveillance. MEs of embryonic stem cells (ESCs) including PSCs are abnormal due to association with telomerase, which are important for the functions of these cells for the development of fetus and wound healing. The build-up of normal stem cells with abnormal MEs is strictly under regulations by contact inhibition, ten-eleven translocator -1 (TET-1) enzyme to direct lineage transitions and chemo-surveillance to destabilize abnormal MEs. When such safety mechanisms fail, clinical symptoms arise. Obviously, the most appropriate solution of diseases due to wound unhealing is to restore safety mechanisms created by the nature. Cell differentiation agent -2 (CDA-2) is our creation of cancer drug to target on abnormal MEs. CDA-2 was approved by the Chinese FDA as an adjuvant to supplement cytotoxic therapy of cancer against breast, non-small cell lung cancers and primary hepatomas in 2004, and as a mono-therapeutic agent for the therapy of myelodysplastic syndromes (MDSs) in 2017. MDSs are diseases attributable entirely to cancer stem cells (CSCs). CDA-2 was the best drug for the therapy of MDSs, and therefore should be considered the standard care of MDSs. Breast, non-small cell lung cancers and primary hepatomas responded well to CDA-2. The therapeutic end point of CDA-2 is the terminal differentiation of cancer cells which cannot make tumor to disappear. Evidently, terminal differentiation of CSCs is the only option to solve CSCs. The solution of CSCs is very critical to the success of cancer therapy. Therefore, CDA formulations are potentially the standard care of breast and lung cancers and primary hepatomas.

Developmental Stage and Cellular Context Determine Oncogenic and Molecular Outcomes of Ezh2 Y641F Mutation in Hematopoiesis.

Mutations in the histone methyltransferase EZH2, particularly the Y641 hotspot mutation, have been implicated in hematologic malignancies, yet the effect of timing and cellular context on their oncogenic potential has remained unknown. In this study, we utilized a conditional allele with tissue-specific Cre drivers to investigate the effects of Ezh2 Y641F mutations at various stages of development, with a focus on the hematopoietic system. We found that ubiquitous heterozygous Ezh2 Y641F expression at birth, or conditional expression in hematopoietic or mesenchymal stem cells, led to decreased survival due to hematopoietic defects and bone marrow failure, with no evidence of malignancy. In contrast, Ezh2 Y641F expression in committed B cells drives lymphoma formation, highlighting the lineage-specific oncogenic activity of the mutation. Transcriptomic analysis of B cell progenitors revealed key pathway alterations between Cre models such as altered IL2-Stat5 signaling pathway, differential expression of E2F targets, and altered GTPase pathway expression driven by upregulation of Guanylate Binding Proteins (GBPs) in Mx1-Cre Ezh2 Y641F pro-B cells. We further found that the GBP locus is regulated by Ezh2-mediated H3K27me3, it is associated with poorer survival in Acute Myeloid Leukemia patients and has variable effects on apoptosis in human lymphoma and leukemia cell lines. These findings suggest that the Ezh2 Y641F mutation may alter immune regulatory pathways, cell differentiation and apoptosis, with potential implications for disease progression. Our results highlight the critical role of mutation timing and cellular context in EZH2-driven hematopoietic disease, resulting in distinct downstream changes that shape the oncogenic impact of EZH2.