Transcription Signaling Pathway Research Articles

What a tangled web we weave: crosstalk between JAK–STAT and other signalling pathways during development in Drosophila

The Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling pathway is a key player in animal development and physiology. Although it functions in a variety of processes, the net output of JAK–STAT signalling depends on its spatiotemporal activation, as well as extensive crosstalk with other signalling pathways. Drosophila, with its relatively simple signal transduction pathways and plethora of genetic analysis tools, is an ideal system for dissecting JAK–STAT signalling interactions. In this review, we explore studies in Drosophila revealing that JAK–STAT signalling lies at the nexus of a complex network of interlinked pathways, including epidermal growth factor receptor (EGFR), c‐Jun N‐terminal kinase (JNK), Notch, Insulin, Hippo, bone morphogenetic protein (BMP), Hedgehog (Hh) and Wingless (Wg). These pathways can synergise with or antagonise one another to produce a variety of outcomes. Given the conserved nature of signal transduction pathways, we conclude with our perspective on the implication of JAK–STAT signalling dysregulation in human diseases, and how studies in Drosophila have the potential to inform and influence clinical research.

Urolithin B suppresses phenotypic switch in vascular smooth muscle cells induced by PDGF-BB via inhibiting the PI3K-AKT pathway.

Atherosclerosis (AS) is a prevalent cardiovascular condition, and the growth and phenotypic switch of vascular smooth muscle cells (VSMCs) play a crucial role in its development. Studies have revealed that the activation of certain transcription factors and signaling pathways can trigger these cellular changes. Consequently, targeting these pathways and pivotal molecules has emerged as a promising strategy for AS treatment. Drugs that can reverse the cellular changes in VSMCs may offer new therapeutic options for AS, marking a significant advancement. While previous research has suggested that urolithin B (Uro B) possesses anti-atherosclerotic properties, its exact mechanism remains to be fully understood, especially the effect of Uro B in VSMCs. This study discovered that Uro B can impede the proliferation and migration of VSMCs prompted by PDGF-BB, as well as their phenotypic changes, indicating that Uro B could potentially prevent AS by inhibiting the phenotypic switch of VSMCs.

Transdifferentiation of rat keratinocyte progenitors to corneal epithelial cells by limbal niche via the STAT3/PI3K/AKT signaling pathway

PurposeTo develop a method for enriching keratinocyte progenitor cells (KPCs) and establish a limbal niche (LN)-mediated transdifferentiation protocol of KPCs into corneal epithelial cells.MethodsLimbal niche cells (LNCs) were isolated from limbal tissues through enzymatic digestion and characterized. Conditioned medium from LNCs cultures was collected. KPCs were enriched by rapid adhesion of Matrigel and subsequently cultured in either an LNCs-conditioned medium supplemented with KSFM (LN-KS) or SHEM (LN-SH) for 14 days. Corneal-specific marker expression was assessed to evaluate transdifferentiation efficiency. Key transcription factors and signaling pathways involved in the transdifferentiation process were identified through single-cell and RNA sequencing, and were validated by western blot and quantitative real-time PCR.ResultsBoth LN-KS and LN-SH protocols successfully induced corneal epithelial cell transdifferentiation from KPCs, with LN-KS demonstrating higher efficiency in generating CK12 + and p63 + cells (p < 0.001). RNA sequencing analysis and western blot have revealed significant activation of STAT3 and PI3K/AKT signaling pathways. Inhibition of STAT3 blocked the activation of PI3K/AKT signaling pathway and impaired corneal epithelial cell transdifferentiation.ConclusionsThis study demonstrates the ability of LN to promote KPCs transdifferentiation into corneal epithelial cells in vitro, and this process is partially mediated by the STAT3/PI3K/AKT signaling pathway.Graphical abstract

Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are pivotal in regulating various physiological processes including growth, development, and metabolism. The biological actions of thyroid hormones are primarily initiated by binding to nuclear thyroid hormone receptors (TRs). These receptors, belonging to the superfamily of nuclear receptors, act as ligand-dependent transcription factors. Transcriptional regulation by TRs is mediated by the recruitment of coregulators, governing activation and repression of target genes, thereby modulating cellular responses to thyroid hormones. Beyond this canonical genomic pathway, TH can regulate the expression of genes not directly bound by TRs through cross-talk mechanisms with other transcription factors and signaling pathways. Thyroid hormones can also elicit rapid non-genomic effects, potentially mediated by extranuclear TR proteins or by interactions with membrane receptors such as integrin αvβ3. This non-genomic mode of action adds another layer of complexity to the diverse array of physiological responses orchestrated by thyroid hormones, expanding our understanding of their multifaceted actions.

Phosphorylation of SNW1 protein associated with equine melanocytic neoplasm identified in serum and feces

Equine melanocytic neoplasm (EMN) represents a form of skin tumor observed predominantly in grey horses aged over 15 years. Despite its prevalence, current therapeutic and preventive strategies for EMN have been subject to limited investigation. This study endeavors to shed light on potential phosphoproteins present in equine serum and fecal samples, potentially linked to EMN, with a specific focus on functional interactions in EMN pathogenesis. We examined 50 samples (25 serum, 25 feces), divided into three groups based on EMN severity: normal (n = 16), mild (n = 18), and severe EMN (n = 16). Equine phosphoproteome analysis identified 2,359 annotated serum phosphoproteins and 2002 annotated fecal phosphoproteins through differentially expressed proteins (DEPs). KEGG analysis emphasized the role of environmental information processing. Notably, the integrin NF-kappaB binding P-TEFb to stimulate transcriptional elongation signaling pathway, involving SNW1 protein, was implicated in early stage of EMN development in both serum and fecal samples. This highlights SNW1’s potential role in mediating transcriptional processes, offering a novel marker within environmental information processing. This study enhances understanding of EMN mechanisms in horses, suggesting early detection through non-invasive methods and identifying a functional pathway involving SNW1, which could inform future treatment and prevention strategies.

The molecular mechanisms of cardiac development and related diseases.

Cardiac development is a complex and intricate process involving numerous molecular signals and pathways. Researchers have explored cardiac development through a long journey, starting with early studies observing morphological changes and progressing to the exploration of molecular mechanisms using various molecular biology methods. Currently, advancements in stem cell technology and sequencing technology, such as the generation of human pluripotent stem cells and cardiac organoids, multi-omics sequencing, and artificial intelligence (AI) technology, have enabled researchers to understand the molecular mechanisms of cardiac development better. Many molecular signals regulate cardiac development, including various growth and transcription factors and signaling pathways, such as WNT signaling, retinoic acid signaling, and Notch signaling pathways. In addition, cilia, the extracellular matrix, epigenetic modifications, and hypoxia conditions also play important roles in cardiac development. These factors play crucial roles at one or even multiple stages of cardiac development. Recent studies have also identified roles for autophagy, metabolic transition, and macrophages in cardiac development. Deficiencies or abnormal expression of these factors can lead to various types of cardiac development abnormalities. Nowadays, congenital heart disease (CHD) management requires lifelong care, primarily involving surgical and pharmacological treatments. Advances in surgical techniques and the development of clinical genetic testing have enabled earlier diagnosis and treatment of CHD. However, these technologies still have significant limitations. The development of new technologies, such as sequencing and AI technologies, will help us better understand the molecular mechanisms of cardiac development and promote earlier prevention and treatment of CHD in the future.

Spatial transcriptome profiling identifies DTX3L and BST2 as key biomarkers in esophageal squamous cell carcinoma tumorigenesis

BackgroundUnderstanding the stepwise progression of esophageal squamous cell carcinoma (ESCC) is crucial for developing customized strategies for early detection and optimal clinical management. Herein, we aimed to unravel the transcriptional and immunologic alterations occurring during malignant transformation and identify clinically significant biomarkers of ESCC.MethodsDigital spatial profiling (DSP) was performed on 11 patients with early-stage ESCC (pT1) to explore the transcriptional alterations in epithelial, immune cell, and non-immune cell stromal compartments across regions of distinct histology, including normal tissues, low- and high-grade dysplasia, and cancerous tissues. Furthermore, single-cell spatial transcriptomics was performed using the CosMx Spatial Molecular Imaging (SMI) system on 4 additional patients with pT1 ESCC. Immunohistochemical (IHC) analysis was performed on consecutive histological sections of 20 pT1 ESCCs. Additionally, public bulk and single-cell RNA-sequencing (scRNA-seq) datasets were analyzed, and in vitro and in vivo functional studies were conducted.ResultsSpatial transcriptional reprogramming and dynamic cell signaling pathways that determined ESCC progression were delineated. Increased infiltration of macrophages from normal tissues through dysplasia to cancerous tissues occurred. Macrophage subtypes were characterized using the scRNA-seq dataset. Cell–cell communication analysis of scRNA-seq and SMI data indicated that the migration inhibitory factor (MIF)-CD74 axis may exhibit pro-tumor interactions between macrophages and epithelial cells. DSP, SMI, and IHC data demonstrated that DTX3L expression in epithelial cells and BST2 expression in stromal cells increased gradually with ESCC progression. Functional studies demonstrated that DTX3L or BST2 knockdown inhibited ESCC proliferation and migration and decreased M2 polarization of tumor-associated macrophages.ConclusionsSpatial profiling comprehensively characterized the molecular and immunological hallmarks from normal tissue to ESCC, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease and contributing to the prevention of ESCC. Within this exploration, we uncovered biomarkers that exhibit a robust correlation with ESCC progression, offering potential new avenues for insightful therapeutic approaches.

Angiogenic and neurogenic potential of dental-derived stem cells for functional pulp regeneration: A narrative review.

Dental pulp tissue engineering is expected to become an ideal treatment for irreversible pulpitis and apical periodontitis. However, angiogenesis and neurogenesis for functional pulp regeneration have not yet met the standard for large-scale clinical application, and need further research. This review focused on the potential mechanisms of angiogenesis and neurogenesis in pulp regeneration, including stem cell types, upstream and downstream regulatory molecules and cascade signalling pathways, thereby providing a theoretical basis and inspiring new ideas to improve the effectiveness of dental pulp tissue engineering. An electronic literature search was carried out using the keywords of 'pulp regeneration', 'stem cell transplantation', 'dental pulp stem cells', 'angiogenesis' and 'neurogenesis'. The resulting literature was screened and reviewed. Stem cells used in dental pulp tissue engineering can be classified as dental-derived and non-dental-derived stem cells, amongst which dental pulp stem cells (DPSC) have achieved promising results in animal experiments and clinical trials. Multiple molecules and signalling pathways are involved in the process of DPSC-mediated angiogenic and neurogenetic regeneration. In order to promote angiogenesis and neurogenesis in pulp regeneration, feasible measures include the addition of growth factors, the modulation of transcription factors and signalling pathways, the use of extracellular vesicles and the modification of bioscaffold materials. Dental pulp tissue engineering has had breakthroughs in preclinical and clinical studies invivo. Overcoming difficulties in pulpal angiogenesis and neurogenesis, and achieving functional pulp regeneration will lead to a significant impact in endodontics.

Transcriptional regulation in the absence of inositol trisphosphate receptor calcium signaling.

The activation of IP3 receptor (IP3R) Ca2+ channels generates agonist-mediated Ca2+ signals that are critical for the regulation of a wide range of biological processes. It is therefore surprising that CRISPR induced loss of all three IP3R isoforms (TKO) in HEK293 and HeLa cell lines yields cells that can survive, grow and divide, albeit more slowly than wild-type cells. In an effort to understand the adaptive mechanisms involved, we have examined the activity of key Ca2+ dependent transcription factors (NFAT, CREB and AP-1) and signaling pathways using luciferase-reporter assays, phosphoprotein immunoblots and whole genome transcriptomic studies. In addition, the diacylglycerol arm of the signaling pathway was investigated with protein kinase C (PKC) inhibitors and siRNA knockdown. The data showed that agonist-mediated NFAT activation was lost but CREB activation was maintained in IP3R TKO cells. Under base-line conditions transcriptome analysis indicated the differential expression of 828 and 311 genes in IP3R TKO HEK293 or HeLa cells, respectively, with only 18 genes being in common. Three main adaptations in TKO cells were identified in this study: 1) increased basal activity of NFAT, CREB and AP-1; 2) an increased reliance on Ca2+- insensitive PKC isoforms; and 3) increased production of reactive oxygen species and upregulation of antioxidant defense enzymes. We suggest that whereas wild-type cells rely on a Ca2+ and DAG signal to respond to stimuli, the TKO cells utilize the adaptations to allow key signaling pathways (e.g., PKC, Ras/MAPK, CREB) to transition to the activated state using a DAG signal alone.

Identification of Transcriptional Regulators and Signaling Pathways Mediating Postnatal Rumen Growth and Functional Maturation in Cattle.

The rumen plays an essential role in the physiology and health of ruminants. The rumen undergoes substantial changes in size and function from birth to adulthood. The cellular and molecular mechanisms underlying these changes are not clear. This study was aimed to identify the transcription factors and signaling pathways mediating these changes in cattle. We found that the ratios of the emptied rumen, reticulum, omasum, and abomasum to body weight in adult steers were 4.8 (P < 0.01), 3.1 (P < 0.01), 6.0 (P < 0.01), and 0.8 (P = 0.9) times those in neonatal calves, respectively. The length of rumen papillae and the thickness of rumen epithelium, tunica mucosa and submucosa, tunica muscularis, and tunica serosa increased 7.4-, 2.0-, 3.0-, 2.9-, and 4.6-fold (P < 0.01 for all), respectively, from neonatal calves to adult steers. However, the density of rumen papillae was lower in adult steers than in neonatal calves (P < 0.05). The size of rumen epithelial cells was not different between neonatal calves and adult steers (P = 0.57). RNA sequencing identified 2,922 genes differentially expressed in the rumen between neonatal calves and adult steers. Functional enrichment analyses revealed that organ development, blood vessel development, Ras signaling, and Wnt signaling were among the functional terms enriched in genes downregulated in adult steers vs. neonatal calves and that fatty acid metabolism, immune responses, PPAR signaling, and Rap1 signaling were among those enriched in genes upregulated in adult steers vs. neonatal calves. Serum response factor (SRF), interferon regulatory factor 4, and purine-rich single-stranded DNA-binding protein alpha were among the major candidate transcription factors controlling the expression of genes upregulated, while TCF4, inhibitor of DNA binding 4, and snail family transcriptional repressor 2 were among those controlling the expression of genes downregulated in adult steers vs. neonatal calves. Taken together, these results suggest that the rumen grows by increasing the number, not the size, of cells from birth to adulthood, that the absorptive, metabolic, immune, and motility functions of the rumen are acquired or significantly enhanced during the postnatal life, and that the changes in rumen size and function from birth to adulthood are mediated by many candidate transcription factors, including SRF and TCF4, and many candidate signaling pathways, including the PPAR and Wnt signaling pathways.

Interplay of Chromatin Remodeling BAF Complexes in Mouse Embryonic and Epiblast Stem Cell Conversion and Maintenance.

Mouse embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) are pluripotent stem cells derived from pre-implantation and post-implantation embryos, respectively. These cells are capable of interconversion through manipulation of key transcription factors and signaling pathways. While BAF chromatin remodeling complexes are known to play crucial roles in ESC self-renewal and pluripotency, their roles in EpiSCs and their interconversion with ESCs remain unclear. This study demonstrates that the LIF/STAT3 and Wnt signaling pathways, in conjunction with canonical BAF (cBAF) and PRC2 complexes, inhibit EpiSC gene expression, thereby preventing ESCs from converting to EpiSCs. Upon removal of LIF, the reduced LIF/STAT3 signaling lifts this inhibition, increasing TGF/Nodal pathway activity. Subsequently, the cBAF complex facilitates ESC to EpiSC conversion by promoting EpiSC gene expression. Furthermore, unlike cBAF, inhibition of the ncBAF complex downregulates TGF-β signaling, thereby hindering both ESC to EpiSC conversion and EpiSC maintenance. Moreover, this study revealed the dual mechanisms, methylating histone or non-histone protein STAT3, by which PRC2 components participate in the regulation of ESCs to EpiSCs. This research elucidates the interplay between distinct BAF complexes and specific signaling pathways in regulating the conversion and maintenance of ESCs and EpiSCs.

Identification of Novel Proteins Mediating Causal Association Between Smoking and Essential Hypertension: A Mendelian Randomization Study.

Smoking is a factor for hypertension. We aim to reveal novel plasma proteins mediating the relationship of smoking with hypertension and identify potential drug targets for hypertension on the basis of Mendelian randomization design. Data for smoking were selected from the largest genome-wide association study meta-analysis performed by the Genome-Wide Association Study and Sequencing Consortium of Alcohol and Nicotine Use. Data for plasma proteins were selected from the deCODE Health study and the UK Biobank Pharma Proteomics Project. Data for hypertension were extracted from the FinnGen Study. Moreover, proteome-wide Mendelian randomization and colocalization analyses, 2-step Mendelian randomization, and gene function and network prediction, as well as druggability assessment were performed. We finally identified 8 proteins (ANXA4 [annexin A4], DLK1 [protein delta homolog 1], KLB [β-klotho], MMP8 [matrix metallopeptidase 8], PLAT [tissue-type plasminogen activator], POSTN [periostin], SAT2 [thialysine N-ε-acetyltransferase], and IFNLR1 [interferon λ receptor 1]) mediating association of smoking with hypertension. PLAT and IFNLR1 were identified to be involved in the complement and coagulation cascades and the Janus kinase/signal transducer and activator of transcription signaling pathway. ANXA4, KLB, MMP8, PLAT, and IFNLR1 had druggability. Moreover, IFNLR1 had strong evidence of genetic colocalization, because the posterior probability for H4 of IFNLR1 was 91.3%. This study identified the 8 proteins that mediate causal association between smoking and essential hypertension. Interferon λ receptor agonist targeting IFNLR1 may open a new avenue for treating hypertension. Our discoveries provide new insights into protein pathogenesis of hypertension and to better guide hypertension prevention and treatment among smokers.

Neuroprotective Effect of Maresin-1 in Rotenone-Induced Parkinson’s Disease in Rats: The Putative Role of the JAK/STAT Pathway

Exposure to rotenone results in similar pathophysiological features as Parkinson’s disease. Inflammation and oxidative stress are essential to PD pathogenesis. Maresin-1 has potent anti-inflammatory properties and promotes the regression of inflammation function. The current study aimed to evaluate the protective effects of Maresin-1 (MaR1) in rotenone (ROT)-induced PD and whether this protective role is associated with the initiation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT) signaling pathway. Thirty male Wister rats were classified into control, ROT-treated, and ROT + MaR1-treated groups. Rats underwent rotarod, open field, grip strength, and stepping tests as part of their motor behavioral evaluation. Serum glial cell-derived neurotrophic factor (GDNF) and striatal dopamine, acetylcholine, malondialdehyde (MDA), reduced glutathione (GSH), TNF-α, IL-6, and IL-1β were evaluated. Expression of JAK1 and STAT3 genes was assessed in striatum. Then, the tissue was subjected to histological and immunohistochemical evaluation for caspase-3, GFAP, and NF-kB. The administrated group with rotenone showed significant motor behavioral impairment. This was accompanied by reduced levels of GDNF and dopamine and increased levels of acetylcholine, as well as augmented oxidative stress and inflammatory biomarkers and reduced antioxidant activity. Inflammatory pathways (JAK1/STAT3, caspase-3, and NF-kB) were upregulated. Histopathological changes and upregulation in GFAP immunopositive reaction were observed. Remarkably, MaR1 treatment effectively alleviated behavior, histopathological changes, and biochemical alterations induced by ROT. MaR1 exerts protective effects against ROT-induced PD by its anti-inflammatory, antiapoptotic, and antioxidant properties. MaR1 mechanisms of action may involve modulation of pathways such as JAK/STAT.

Inhibitory DNA Aptamer Tools against SOCS3-gp130 Interactions.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a crucial role in transmembrane signal transduction, enabling cells to communicate with the extracellular environment, which requires precise regulation to prevent abnormal signaling outcomes. Within this complex pathway, suppressor of cytokine signaling 3 (SOCS3) acts as a pivotal negative regulator via binding to cytokine receptors. However, our understanding of the regulatory mechanisms governing SOCS3 interactions has been limited by the lack of suitable chemical probes. Aptamers, a notable category of chemical tools, have emerged as a viable avenue for the development of chemical inhibitors. In this study, we successfully identified specific inhibitory aptamers that bind to SOCS3 and effectively disrupt the interaction between SOCS3 and glycoprotein 130, a common cytokine receptor for interleukin-6 and leukemia inhibitory factor, which regulates the survival of normal human endometrial stromal cells. These aptamers not only provide a valuable chemical tool to advance our understanding of the regulatory dynamics of the JAK/STAT signaling pathway by SOCS3 but also hold great promise for the future development of therapeutic interventions.

MDM2 interacts with PTEN to inhibit endothelial cell development and promote deep vein thrombosis via the JAK/STAT signaling pathway.

Deep vein thrombosis (DVT) is a prevalent clinical condition, which markedly affects patients' quality of life, commonly leading to post‑thrombotic syndrome. The present study aimed to elucidate the intricate interplay between murine double minute‑2 (MDM2) and phosphatase and tensin homolog (PTEN), thus shedding new light on their role in the pathogenesis of DVT. The results showed that both MDM2 and PTEN were upregulated in venous blood samples obtained from patients with DVT. However, MDM2 or PTEN knockdown markedly increased the proliferation, migration, invasion, apoptosis and angiogenesis of oxidized low‑density lipoprotein‑treated human umbilical vein endothelial cells (HUVECs). Furthermore, MDM2 silencing downregulated PTEN. The association between MDM2 and PTEN was verified through comprehensive analyses, including Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis and co‑immunoprecipitation assays. The effect of PTEN on DVT was evaluated by Kyoto Encyclopedia of Genes and Genomes and STRING analysis, which demonstrated that PTEN displayed an inhibitory role in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Notably, treatment with AG‑490, an inhibitor of JAK/STAT signaling, reversed the protective effect of PTEN knockdown on the behavior of HUVECs. In summary, the results of the current study indicated that both MDM2 and PTEN were upregulated in patients with DVT. The interaction between MDM2 and PTEN was also verified, thus providing novel insights into their potential collaborative role in the development of DVT. Overall, MDM2 and PTEN may interact to inhibit endothelial cell development and promote the occurrence of DVT via inhibiting the JAK/STAT signaling pathway.

Computing hematopoiesis plasticity in response to genetic mutations and environmental stimulations.

Cell plasticity (CP), describing a dynamic cell state, plays a crucial role in maintaining homeostasis during organ morphogenesis, regeneration, and trauma-to-repair biological process. Single-cell-omics datasets provide an unprecedented resource to empower CP analysis. Hematopoiesis offers fertile opportunities to develop quantitative methods for understanding CP. In this study, we generated high-quality lineage-negative single-cell RNA-sequencing datasets under various conditions and introduced a working pipeline named scPlasticity to interrogate naïve and disturbed plasticity of hematopoietic stem and progenitor cells with mutational or environmental challenges. Using embedding methods UMAP or FA, a continuum of hematopoietic development is visually observed in wild type where the pipeline confirms a low proportion of hybrid cells ( P hc , with bias range: 0.4∼0.6) on a transition trajectory. Upon Tet2 mutation, a driver of leukemia, or treatment of DSS, an inducer of colitis, P hc is increased and plasticity of hematopoietic stem and progenitor cells was enhanced. We prioritized several transcription factors and signaling pathways, which are responsible for P hc alterations. In silico perturbation suggests knocking out EGR regulons or pathways of IL-1R1 and β-adrenoreceptor partially reverses P hc promoted by Tet2 mutation and inflammation.

Epigenetic characterization of adult rhesus monkey spermatogonial stem cells identifies key regulators of stem cell homeostasis.

Spermatogonial stem cells (SSCs) play crucial roles in the preservation of male fertility. However, successful ex vivo expansion of authentic human SSCs remains elusive due to the inadequate understanding of SSC homeostasis regulation. Using rhesus monkeys (Macaca mulatta) as a representative model, we characterized SSCs and progenitor subsets through single-cell RNA sequencing using a cell-specific network approach. We also profiled chromatin status and major histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K9me3), and subsequently mapped promoters and active enhancers in TSPAN33+ putative SSCs. Comparing the epigenetic changes between fresh TSPAN33+ cells and cultured TSPAN33+ cells (resembling progenitors), we identified the regulatory elements with higher activity in SSCs, and the potential transcription factors and signaling pathways implicated in SSC regulation. Specifically, TGF-β signaling is activated in monkey putative SSCs. We provided evidence supporting its role in promoting self-renewal of monkey SSCs in culture. Overall, this study outlines the epigenetic landscapes of monkey SSCs and provides clues for optimization of the culture condition for primate SSCs expansion.

The Knob Domain of the Fiber-1 Protein Affects the Replication of Fowl Adenovirus Serotype 4.

Fowl adenovirus serotype 4 (FAdV-4) outbreaks have caused significant economic losses in the Chinese poultry industry since 2015. The relationships among viral structural proteins in infected hosts are relatively unknown. To explore the role of different parts of the fiber-1 protein in FAdV-4-infected hosts, we truncated fiber-1 into fiber-1-Δ1 (73-205 aa) and fiber-1-Δ2 (211-412 aa), constructed pEF1α-HA-fiber-1-Δ1 and pEF1α-HA-fiber-1-Δ2 and then transfected them into leghorn male hepatocyte (LMH) cells. After FAdV-4 infection, the roles of fiber-1-Δ1 and fiber-1-Δ2 in the replication of FAdV-4 were investigated, and transcriptome sequencing was performed. The results showed that the fiber-1-Δ1 and fiber-1-Δ2 proteins were the shaft and knob domains, respectively, of fiber-1, with molecular weights of 21.4 kDa and 29.6 kDa, respectively. The fiber-1-Δ1 and fiber-1-Δ2 proteins were mainly localized in the cytoplasm of LMH cells. Fiber-1-Δ2 has a greater ability to inhibit FAdV-4 replication than fiber-1-Δ1, and 933 differentially expressed genes (DEGs) were detected between the fiber-1-Δ1 and fiber-1-Δ2 groups. Functional analysis revealed these DEGs in a variety of biological functions and pathways, such as the phosphoinositide 3-kinase-protein kinase b (PI3K-Akt) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, cytokine-cytokine receptor interactions, Toll-like receptors (TLRs), the Janus tyrosine kinase-signal transducer and activator of transcription (Jak-STAT) signaling pathway, the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) signaling pathway, and other innate immune pathways. The mRNA expression levels of type I interferons (IFN-α and INF-β) and proinflammatory cytokines (IL-1β, IL-6 and IL-8) were significantly increased in cells overexpressing the fiber-1-Δ2 protein. These results demonstrate the role of the knob domain of the fiber-1 (fiber-1-Δ2) protein in FAdV-4 infection and provide a theoretical basis for analyzing the function of the fiber-1 protein of FAdV-4.

Exploration of common pathogenesis and candidate hub genes between HIV and monkeypox co-infection using bioinformatics and machine learning

This study explored the pathogenesis of human immunodeficiency virus (HIV) and monkeypox co-infection, identifying candidate hub genes and potential drugs using bioinformatics and machine learning. Datasets for HIV (GSE 37250) and monkeypox (GSE 24125) were obtained from the GEO database. Common differentially expressed genes (DEGs) in co-infection were identified by intersecting DEGs from monkeypox datasets with genes from key HIV modules screened using Weighted Gene Co-Expression Network Analysis (WGCNA). After gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and construction of protein-protein interaction (PPI) network, candidate hub genes were further screened based on machine learning algorithms. Transcriptional factors (TFs) and miRNA-candidate hub gene networks were constructed to understand regulatory mechanisms and protein-drug interactions to identify potential therapeutic drugs. Seven candidate hub genes—MX2, ADAR, POLR2H, RPL5, IFI16, IFIT2, and RPS5—were identified. TFs and miRNAs associated with these hub genes, playing a key role in regulating viral infection and inflammation due to the activation of antiviral innate immunity, were also identified through network analysis. Potential therapeutic drugs were screened based on these hub genes: AZT, a nucleotide reverse transcriptase inhibitor, suppressed viral replication in HIV and monkeypox co-infection, while mefloquine inhibited inflammation due to the activation of antiviral innate immunity. In conclusion, the study identified candidate hub genes, their transcriptional regulation, signaling pathways, and small-molecule drugs in HIV and monkeypox co-infection, contributing to understanding the pathogenesis of HIV and monkeypox co-infection and informing precise therapeutic strategies.

The Role of JAK Inhibitors in the Treatment of Cutaneous Lupus Erythematosus: A Review.

Cutaneous lupus erythematosus (CLE), a manifestation of the chronic autoimmune disease lupus erythematosus (LE), showcases diverse clinical, immunologic, and histologic attributes. CLE can be further categorized into subtypes -- acute (ACLE), subacute (SCLE), or chronic (CCLE) -- with each class characterized by distinct features, including the degree of cutaneous involvement, lesion duration, and associated laboratory findings. While conventional treatments, including photoprotective strategies, topical corticosteroids, and antimalarial agents, have proven effective for some, recent immunomodulatory therapies offer alternative avenues. Janus kinase (JAK) inhibitors, in particular, have gained attention due to their demonstrated efficacy in the management of various autoimmune disorders. Dysregulation of the JAK/signal transducer and activator of transcription (STAT) signaling pathway has been implicated in the pathogenesis of CLE, further underscoring the promise of JAK inhibitors as an adjunctive therapy alongside systemic immunosuppression. This systematic review aims to discuss the diagnosis and categorization of CLE and its subtypes, elucidate the intricacies of intracellular signaling within the JAK/STAT pathway, and discuss the current applications of JAK inhibitors in the treatment of autoimmune disease. Supported by cases, randomized control trials, basic science articles, and other reviews in the literature, this review provides evidence for the use of the JAK/STAT pathway as a therapeutic target. Nevertheless, the role of JAK inhibitors and their therapeutic properties warrant further scrutiny through rigorous investigation and comprehensive randomized control trials to ascertain safety and efficacy. J Drugs Dermatol. 2024;23(12):1100-1107. doi:10.36849/JDD.8045.