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Development is a complex process that occurs throughout the life cycle. F-actin, a major component of the cytoskeleton, is essential for the morphogenesis of tissues and organs during development. F-actin is formed by the polymerization of G-actin, and the dynamic balance of polymerization and depolymerization ensures proper cellular function. Disruption of this balance results in various abnormalities and defects or even embryonic lethality. Here, we reviewed recent findings on the structure of G-actin and F-actin and the polymerization of G-actin to F-actin. We also focused on the functions of actin isoforms and the underlying mechanisms of actin polymerization/depolymerization in cellular and organic morphogenesis during development. This information will extend our understanding of the role of actin polymerization in the physiologic or pathologic processes during development and may open new avenues for developing therapeutics for embryonic developmental abnormalities or tissue regeneration.

Abstract Backgrounds and aims As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt‐related transcription factor 2 (Runx2) is associated with the development of non‐alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive. Approach and results In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl4‐induced, 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine‐induced or methionine‐choline deficient (MCD)‐induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV‐Runx2 or VA‐Lip‐Runx2 injection exacerbated CCl4‐induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA‐seq and Runx2 ChIP‐seq analysis demonstrated that Runx2 could promote integrin alpha‐V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2‐induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF‐β1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC. Conclusions Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis.

Inflammation is an immune response that the host organism eliminates threats from foreign objects or endogenous signals. It plays a key role in the progression, prognosis as well as therapy of diseases. Chronic inflammatory diseases have been regarded as the main cause of death worldwide at present, which greatly affect a vast number of individuals, producing economic and social burdens. Thus, developing drugs targeting inflammation has become necessary and attractive in the world. Currently, accumulating evidence suggests that small leucine-rich proteoglycans (SLRPs) exhibit essential roles in various inflammatory responses by acting as an anti-inflammatory or pro-inflammatory role in different scenarios of diseases. Of particular interest was a well-studied member, termed fibromodulin (FMOD), which has been largely explored in the role of inflammatory responses in inflammatory-related diseases. In this review, particular focus is given to the role of FMOD in inflammatory response including the relationship of FMOD with the complement system and immune cells, as well as the role of FMOD in the diseases associated with inflammation, such as skin wounding healing, osteoarthritis (OA), tendinopathy, atherosclerosis, and heart failure (HF). By conducting this review, we intend to gain insight into the role of FMOD in inflammation, which may open the way for the development of new anti-inflammation drugs in the scenarios of different inflammatory-related diseases.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in “cold tumors” with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

IntroductionPeriapical alveolar bone loss is the common consequence of apical periodontitis (AP) caused by persistent local inflammation around the apical area. Human stem cells from apical papilla (hSCAPs) play a crucial role in the restoration of bone lesions during AP. Studies have recently identified the critical role of microRNAs (miRNAs) involved in AP pathogenesis, but little is known about their function and potential molecular mechanism, especially in the osteogenesis of hSCAPs during AP. Here, we investigated the role of clinical sample-based specific miRNAs in the osteogenesis of hSCAPs.MethodsDifferential expression of miRNAs were detected in the periapical tissues of normal and patients with AP via transcriptomic analysis, and the expression of miR-199a-5p was confirmed by qRT-PCR. Treatment of hSCAPs with miR-199a-5p mimics while loaded onto beta-tricalcium phosphate (β-TCP) ceramic particle scaffold to explore its effect on osteogenesis in vivo. RNA binding protein immunoprecipitation (RIP) and Luciferase reporter assay were conducted to identify the target gene of miR-199a-5p.ResultsThe expression of miR-199a-5p was decreased in the periapical tissues of AP patients, and miR-199a-5p mimics markedly enhanced cell proliferation and osteogenic differentiation of hSCAPs, while miR-199a-5p antagomir dramatically attenuated hSCAPs osteogenesis. Moreover, we identified and confirmed Interferon Induced Protein with Tetratricopeptide Repeats 2 (IFIT2) as a specific target of miR-199a-5p, and silencing endogenous IFIT2 expression alleviated the inhibitory effect of miR-199a-5p antagomir on the osteogenic differentiation of hSCAPs. Furthermore, miR-199a-5p mimics transfected hSCAPs loaded onto beta-tricalcium phosphate (β-TCP) scaffolds induced robust subcutaneous ectopic bone formation in vivo.DiscussionThese results strengthen our understanding of predictors and facilitators of the key AP miRNAs (miR-199a-5p) in bone lesion repair under periapical inflammatory conditions. And the regulatory networks will be instrumental in exploring the underlying mechanisms of AP and lay the foundation for future regenerative medicine based on dental mesenchymal stem cells.

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.

Two nodes with similar social behavior mean that they contact each other frequently. Therefore, forwarding packets to them can efficiently improve the performance of routing algorithms in mobile opportunistic networks (MONs). Previous works use different factors to evaluate the similarity between nodes. However, they neglect the importance of nodes, which has a big influence on the system performance. How to use social importance to compute node similarity is still an open issue in MONs. This paper proposes SSR, a social similarity-based routing algorithm combining the context of social importance. First, nodes record the social importance of encounters in their buffer. Second, whenever two nodes are in contact, a dynamic time warping algorithm is used to determine the similarity of the two nodes' social importance sequences. The more similar the two sequences are, the more similar the social behavior of the two nodes is. Finally, the packet is always forwarded to the relay node with the most similar social behavior to the destination node to ensure the delivery efficiency. The simulation results show that compared with the traditional social routing algorithm, SSR significantly improves the packet delivery rate and reduces the delivery delay, cost, and hops.

Exposure to the widely-used phthalate plasticizer di-(2-ethylhexyl)-phthalate (DEHP) has been shown to be closely related to an increased prevalence of allergic diseases in infants and juveniles. Earlier work in our laboratory found that DEHP-related anaphylactic responses could be ascribed to T-follicular helper (Tfh) cell hyperfunction directly. The Tfh cell, a newly identified CD4+ TH cell subset, until recently has been considered as a key player in humoral immunity. Tfh cells can respond to stimulation through various receptors. Signaling lymphocytic activation molecule family member-1 (SLAMF1, CD150) is a surface co-stimulatory receptor that can bind to an intracytoplasmic adaptor signaling lymphocytic activation molecule-associated protein (SAP) to initiate downstream signaling cascades, regulating some events of immune response. The present study explored the role of SLAMF1 in Tfh cell differentiation and cytokine secretion under the condition of DEHP exposure. Using a weanling mice model of DEHP gavage with ovalbumin (OVA) sensitization, it was found that DEHP acted as an immunoadjuvant to elevate SLAMF1 and SAP expression in host Tfh cells. Ex vivo studies of effects from DEHP exposure on Tfh cells from OVA-sensitized hosts showed that DEHP acted in an adjuvant-like manner to promote the expression of adaptor protein SAP, transcription factors Bcl-6 and c-MAF, and cytokines interleukin (IL)-21 and IL-4 in Tfh cells. Transfection of these Tfh cells with Slamf1 small interfering RNA prior to exposure to the DEHP attenuated the over-expression of these molecules that was caused by the DEHP. In conclusion, this study demonstrated that DEHP, via a SLAMF1-mediated pathway, can impact on Tfh cell differentiation and their ability to form select cytokines.

Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)β signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.

The performance of mobile opportunistic networks mainly relies on collaboration among nodes. Thus far, researchers have ignored the influence of node sociality on the incentive process, leading to poor network performance. Considering the fact that followers always imitate the behavior of superstars, this paper proposes FollowMe, which integrates the social importance of nodes with evolutionary game theory to improve the collaborative behavior of nodes. First, we use the prisoner’s dilemma model to establish the matrix of game gains between nodes. Second, we introduce the signal reference as a game rule between nodes. The number of nodes choosing different strategies in a game round is used to calculate the cumulative income of the node in combination with the probability formula. Finally, the Fermi function is used to determine whether the node updates the strategy. The simulation results show that, compared with the random update rule, the proposed strategy is more capable of promoting cooperative behavior between nodes to improve the delivery rate of data packets.

Mobile edge computing is a new communication paradigm, which stores content close to the end users, so as to reduce the backhaul delay and alleviate the traffic load of the backbone networks. Crowd participation is one of the most striking features of this technology, and it enables numerous interesting applications. The dynamics of crowd participation offer unprecedented opportunities for both content caching and data forwarding. In this paper, we investigate the influence of the dynamics of crowd participation, from the perspective of opportunistic caching and forwarding, and discuss how we can exploit such opportunities to allocate content and select relays efficiently. Some existing issues in this emerging research area are also discussed.

Acinetobacter baumannii (A. baumannii) poses a serious public health challenge due to its notorious antimicrobial resistance, particularly carbapenem-resistant A. baumannii (CRAB). In this study, we isolated a virulent phage, named P1068, from medical wastewater capable of lysing CRAB, primarily targeting the K3 capsule type. Basic characterization showed that P1068 infected the A. baumannii ZWAb014 with an optimal MOI of 1, experienced a latent period of 10 min and maintained stability over a temperature range of 4-37 °C and pH range of 3-10. Phylogenetic and average nucleotide identity analyses indicate that P1068 can be classified as a novel species within the genus Obolenskvirus of the Caudoviricetes class as per the most recent virus classification released by the International Committee on Taxonomy of Viruses (ICTV). Additionally, according to classical morphological classification, P1068 is identified as a T4-like phage (Myoviridae). Interestingly, we found that the tail fiber protein (TFP) of P1068 shares 74% coverage and 88.99% identity with the TFP of a T7-like phage (Podoviridae), AbKT21phiIII (NC_048142.1). This finding suggests that the TFP gene of phages may undergo horizontal transfer across different genera and morphologies. In vitro antimicrobial assays showed that P1068 exhibited antimicrobial activity against A. baumannii in both biofilm and planktonic states. In mouse models of intraperitoneal infection, P1068 phage protected mice from A. baumannii infection and significantly reduced bacterial loads in various tissues such as the brain, blood, lung, spleen, and liver compared to controls. In conclusion, this study demonstrates that phage P1068 might be a potential candidate for the treatment of carbapenem-resistant and biofilmforming A. baumannii infections, and expands the understanding of horizontal transfer of phage TFP genes. [ABSTRACT FROM AUTHOR]

Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein. [ABSTRACT FROM AUTHOR]

Objective: The glucocorticoid dexamethasone (DEX) can induce palatal cleft; however, the mechanism involved remains unclear. E-cadherin is an important cell adhesion molecule, and it can significantly affect cell fate and embryonic development. Recent studies have indicated that E-cadherin expression in palatal epithelial cells is suppressed in normal palate fusion. This study aimed to determine whether the change in E-cadherin expression is related to the incidence of cleft palate in DEX-induced mice., Methods: Mice were divided into the experimental group and the control group. Pregnant mice were injected with DEX on E10.0-E12.0, whereas mice in the control group were injected with normal saline. Hematoxylin and eosin (HE) staining, immunohistochemistry, and real-time quantitative polymerase chain reaction were employed to evaluate the effect of DEX on fetal mouse palatal processes, particularly the changes in E-cadherin and β-catenin expression levels in the phases of the experimental and control groups., Results: Data indicated that the incidence of cleft palate in the DEX group was 43.59% (17/39), whereas that in the control group was only 3.03% (1/33). The results of HE staining showed that the obviously shortened palatal processes could not contact and fuse with one another in the DEX-treated mice model compared with those in the control group. The ectopic expression of E-cadherin in embryonic palatal mesenchymal cells was also analyzed. The expression levels of E-cadherin and β-catenin in the experimental group were higher than those in the control group., Conclusion: These findings indicated that DEX could induce E-cadherin gene upregulation and ectopic expression, as well as high β-catenin expression, thereby inhibiting the growth of mesenchyme cells and cleft palate.