Building a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression.

Despite the remarkable success of chimeric antigen receptor (CAR) T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous interferon (IFN)-γ promoter for transgenic interleukin (IL)-15 expression. We demonstrate that IFN-γ expression is tightly regulated by T cell receptor signaling. By introducing an internal ribosome entry site IL15 into the 3' UTR of the IFN-γ gene via homology directed repair-mediated knock-in, we confirm that IL-15 expression can co-express with IFN-γ in an antigen stimulation-dependent manner. Importantly, the insertion of transgenes does not compromise endogenous IFN-γ expression. In vitro and in vivo data demonstrate that IL-15 driven by the IFN-γ promoter dramatically improves CAR T cells' antitumor activity, suggesting the effectiveness of IL-15 expression. Last, as a part of our efforts toward clinical translation, we have developed an innovative two-gene knock-in approach. This approach enables the simultaneous integration of CAR and IL-15 genes into TRAC and IFN-γ gene loci using a single AAV vector. CAR T cells engineered to express IL-15 using this approach demonstrate enhanced antitumor efficacy. Overall, our study underscores the feasibility of utilizing endogenous promoters for transgenic cytokines expression in CAR T cells.

TAF1 is needed for the proliferation and maturation of thyroid follicle cells via Notch signaling.

Thyroid dysgenesis (TD) is the common pathogenic mechanism of congenital hypothyroidism (CH). In addition, known pathogenic genes are limited to those that are directly involved in thyroid development. To identify additional candidate pathogenetic genes, we performed forward genetic screening for TD in zebrafish, followed by positional cloning. The candidate gene was confirmed in vitro using the Nthy-ori 3.1 cell line and in vivo using a zebrafish model organism. We obtained a novel zebrafish line with thyroid dysgenesis and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1) by positional cloning. Further molecular studies revealed that taf1 was needed for the proliferation of thyroid follicular cells by binding to the NOTCH1 promoter region. Knockdown of TAF1 impaired the proliferation and maturation of thyroid cells, thereby leading to thyroid dysplasia. This study showed that TAF1 promoted Notch signaling and that this association played a pivotal role in thyroid development.NEW & NOTEWORTHY In our study, we obtained a novel zebrafish line with thyroid dysgenesis (TD) and identified the candidate pathogenetic mutation TATA-box binding protein associated Factor 1 (taf1). Further researches revealed that taf1 was required for thyroid follicular cells by binding to the NOTCH1 promoter region. Our findings revealed a novel role of TAF1 in thyroid morphogenesis.

NAT10 inhibition promotes ac4C-dependent ferroptosis to counteract sorafenib resistance in nasopharyngeal carcinoma.

Sorafenib, an anticancer drug, has been shown to induce ferroptosis in cancer cells. However, resistance to sorafenib greatly limits its therapeutic efficacy, and the exact mechanism of resistance is not fully understood. This study investigated the role of N-Acetyltransferase 10 (NAT10) in influencing the anticancer activity of sorafenib in nasopharyngeal carcinoma (NPC) and its molecular mechanism. NAT10 expression was significantly upregulated in NPC. Mechanistically, NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib-induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In vivo knockout of NAT10 inhibited the growth of sorafenib-resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib.

Naturally Derived Injectable Dual-Cross-Linked Adhesive Hydrogel for Acute Hemorrhage Control and Wound Healing.

Developing biocompatible injectable hydrogels with high mechanical strength and rapid strong tissue adhesion for hemostatic sealing of uncontrolled bleeding remains a prevailing challenge. Herein, we engineer an injectable and photo-cross-linkable hydrogel based on naturally derived gelatin methacrylate (GelMA) and N-hydroxysuccinimide-modified poly(γ-glutamic acid) (γPGA-NHS). The chemically dual-cross-linked hydrogel rapidly forms after UV light irradiation and covalently bonds to the underlying tissue to provide robust adhesion. We demonstrate a significantly improved hemostatic efficacy of the hydrogel using various injury models in rats compared to the commercially available fibrin glue. Notably, the hydrogel can achieve hemostasis in porcine liver and spleen incision, and femoral artery puncture models. Moreover, the hydrogel is used for sutureless repair of the liver defect in a rat model with a significantly suppressed inflammatory response, enhanced angiogenesis, and superior healing efficacy compared to fibrin glue. Together, this study offers a promising bioadhesive for treating severe bleeding and facilitating wound repair.

Association of periodontitis with cardiovascular and all-cause mortality in hypertensive individuals: insights from a NHANES cohort study.

BACKGROUND: The objective of this research is to clarify the impact of periodontitis on overall and cardiovascular-related death rates among hypertensive individuals. METHOD: A total of 5665 individuals with hypertension were included from the National Health and Nutrition Examination Survey (NHANES) data spanning 2001-2004 and 2009-2014. These individuals were divided into two groups based on the presence or absence of periodontitis and further stratified by the severity of periodontitis. We employed weighted multivariate Cox proportional hazards regression and Kaplan-Meier curves (log-rank test) to evaluate the impact of periodontitis on all-cause and cardiovascular mortality. Additional analyses, including adjustments for various covariates, subgroups, and sensitivity analyses, were conducted to ensure the robustness and reliability of our results. RESULT: Over an average follow-up duration of 10.22 years, there were 1,122 all-cause and 297 cardiovascular deaths. Individuals with periodontitis exhibited an elevated risk of all-cause mortality (HR = 1.33, 95% CI 1.18-1.51; p < 0.0001) and cardiovascular mortality (HR = 1.48, 95% CI 1.15-1.89; p = 0.002). Moreover, we observed a progressive increase in both all-cause mortality and cardiovascular mortality (p for trend are both lower than 0.001) and correlating with the severity of periodontitis. These associations remained consistent across various subgroup and sensitivity analyses. CONCLUSION: Our findings suggest a significant association between periodontitis and increased risks of all-cause and cardiovascular mortality among hypertensive individuals. Notably, the severity of periodontitis appears to be a critical factor, with moderate to severe cases exerting a more pronounced impact on all-cause mortality. Additionally, cardiovascular disease mortality significantlly increases in individuals with varying degrees of periodontitis.

LEP and LEPR are possibly a double-edged sword for wound healing.

Wound healing is a complex and error-prone process. Wound healing in adults often leads to the formation of scars, a type of fibrotic tissue that lacks skin appendages. Hypertrophic scars and keloids can also form when the wound-healing process goes wrong. Leptin (Lep) and leptin receptors (LepRs) have recently been shown to affect multiple stages of wound healing. This effect, however, is paradoxical for scarless wound healing. On the one hand, Lep exerts pro-inflammatory and profibrotic effects; on the other hand, Lep can regulate hair follicle growth. This paper summarises the role of Lep and LepRs on cells in different stages of wound healing, briefly introduces the process of wound healing and Lep and LepRs, and examines the possibility of promoting scarless wound healing through spatiotemporal, systemic, and local regulation of Lep levels and the binding of Lep and LepRs.

Hypoxic nasopharyngeal carcinoma-derived exosomal miR-455 increases vascular permeability by targeting ZO-1 to promote metastasis.

Nasopharyngeal carcinoma (NPC), the most frequent reason for treatment failure in head and neck tumors, has the greatest incidence of distant metastases. Increased vascular permeability facilitates metastasis. Exosomal microRNAs (miRNAs) have been implicated in the development of the premetastatic niche and are emerging as prospective biomarkers in cancer patients. We discovered that a higher level of miR-455 was connected to a larger propensity for NPC metastasis based on deep sequencing and RT-qPCR. We found that hypoxia promoted NPC exosomes release and increased miR-455 expression in a way that was hypoxia-inducible factor 1-alpha (HIF-1α) dependent. Exosomes from NPC cells with high levels of miR-455 were found to specifically target zonula occludens 1 (ZO-1), increasing the permeability of endothelial monolayers in vitro vascular permeability and transendothelial invasion experiments. Additional in vivo studies showed that zebrafish with sustained miR-455-overexpressing NPC cell xenografts displayed increased tumor cell mass throughout the body. In vivo, zebrafish vascular tight junction integrity was disrupted by exosomes produced by NPC cells with elevated miR-455 expression. Mice-bearing xenografts further supported the finding that exosomes containing miR-455 might reduce ZO-1 expression in addition to promote NPC cell growth. These findings suggest that in a hypoxic microenvironment, exosomal miR-455 released by NPC cells enhances vascular permeability and promotes metastasis by targeting ZO-1. The HIF-1α-miR-455-ZO-1 signaling pathway may be a promising predictor and potential therapeutic target for NPC with metastasis.

Glucose metabolic reprogramming and its therapeutic potential in obesity-associated endometrial cancer.

Endometrial cancer (EC) is a common gynecological cancer that endangers women health. Although substantial progresses of EC management have been achieved in recent years, the incidence of EC still remains high. Obesity has been a common phenomenon worldwide that increases the risk of EC. However, the mechanism associating obesity and EC has not been fully understood. Metabolic reprogramming as a remarkable characteristic of EC is currently emerging. As the primary factor of metabolic syndrome, obesity promotes insulin resistance, hyperinsulinemia and hyperglycaemia. This metabolic disorder remodels systemic status, which increases EC risk and is related with poor prognosis. Glucose metabolism in EC cells is complex and mediated by glycolysis and mitochondria to ensure energy requirement. Factors that affect glucose metabolism may have an impact on EC initiation and progression. In this study, we review the glucose metabolic reprogramming of EC not only systemic metabolism but also inherent tumor cell metabolism. In particular, the role of glucose metabolic regulation in malignant properties of EC will be focused. Understanding of metabolic profile and glucose metabolism-associated regulation mechanism in EC may provide novel perspective for treatment.

Bioinspired Adhesive Antibacterial Hydrogel with Self-Healing and On-Demand Removability for Enhanced Full-Thickness Skin Wound Repair.

Adhesive-caused injury is a great threat for extensive full-thickness skin trauma because extra-strong adhesion can incur unbearable pain and exacerbate trauma upon removal. Herein, inspired by the mussel, we designed and fabricated an adhesive antibacterial hydrogel dressing based on dynamic host-guest interaction that enabled on-demand stimuli-triggered removal to effectively care for wounds. In contrast with most hard-to-removable dressing, this adhesive antibacterial hydrogel exhibited strong adhesion property (85 kPa), which could achieve painless and noninvasive on-demand separation within 2 s through a host-guest competition mechanism (amantadine). At the same time, the hydrogel exhibited rapid self-healing properties, and the broken hydrogel could be completely repaired within 5 min. The hydrogel also had excellent protein adsorption properties, mechanical properties, antibacterial properties, and biocompatibility. This on-demand removal was facilitated by the introduction of amantadine as a competitive guest, without any significant adverse effects on cell activity (>90%) or wound healing (98.5%) in vitro. The full-thickness rat-skin defect model and histomorphological evaluation showed that the hydrogel could significantly promote wound healing and reduce scar formation by regulating inflammation, accelerating skin re-epithelialization, and promoting granulation tissue formation. These results indicate that the developed adhesive antibacterial hydrogel offers a promising therapeutic strategy for the healing of extensive full-layer skin injuries.

A Choline Phosphoryl-Conjugated Chitosan/Oxidized Dextran Injectable Self-Healing Hydrogel for Improved Hemostatic Efficacy.

The development of injectable hydrogels with good biocompatibility, self-healing, and superior hemostatic properties is highly desirable in emergency and clinical applications. Herein, we report an in situ injectable and self-healing hemostatic hydrogel based on choline phosphoryl functionalized chitosan (CS-g-CP) and oxidized dextran (ODex). The CP groups were hypothesized to accelerate hemostasis by facilitating erythrocyte adhesion and aggregation. Our results reveal that the CS-g-CP/ODex hydrogels exhibit enhanced blood clotting and erythrocyte adhesion/aggregation capacities compared to those of the CS/ODex hydrogels. The CS-g-CP50/ODex75 hydrogel presents rapid gelation time, good mechanical strength and tissue adhesiveness, satisfactory bursting pressure, and favorable biocompatibility. The hemostatic ability of the CS-g-CP50/ODex75 hydrogel was significantly improved compared to that of the CS/ODex hydrogel and commercial fibrin sealant in the rat tail amputation and liver/spleen injury models. Our study highlights the positive and synergistic effects of CP groups on hemostasis and strongly supports the CS-g-CP50/ODex75 hydrogel as a promising adhesive for hemorrhage control.

Novel prospects for scarless wound healing: The roles of myofibroblasts and adipocytes.

Disturbances or defects in the process of wound repair can disrupt the delicate balance of cells and molecules necessary for complete wound healing, thus leading to chronic wounds or fibrotic scars. Myofibroblasts are one of the most important cells involved in fibrotic scars, and reprogramming provides a potential avenue to increase myofibroblast clearance. Although myofibroblasts have long been recognized as terminally differentiated cells, recent studies have shown that myofibroblasts have the capacity to be reprogrammed into adipocytes. This review intends to summarize the potential of reprogramming myofibroblasts into adipocytes. We will discuss myofibroblast lineage tracing, as well as the known mechanisms underlying adipocyte regeneration from myofibroblasts. In addition, we investigated different changes in myofibroblast gene expression, transcriptional regulators, signalling pathways and epigenetic regulators during skin wound healing. In the future, myofibroblast reprogramming in wound healing will be better understood and appreciated, which may provide new ideas for the treatment of scarless wound healing.

Insight into the role of dermal white adipose tissue loss in dermal fibrosis.

The loss of dermal white adipose tissue (dWAT) is vital to the formation of dermal fibrosis (DF), but the specific mechanism is not well understood. A few studies are reviewed to explore the role of dWAT in the formation of DF. Recent findings indicated that the adipocytes-to-myofibroblasts transition in dWAT reflects the direct contribution to the DF formation. While adipose-derived stem cells (ADSCs) contained in dWAT express antifibrotic cytokines, the loss of ADSCs leads to skin protection decreased, which indirectly exacerbates DF and tissue damage. Therefore, blocking or reversing the adipocytes-to-myofibroblasts transition or improving the survival of ADSCs in dWAT and the expression of antifibrotic cytokines may be an effective strategy for the treatment of DF.

Enabling Fog-Blockchain Computing for Autonomous-Vehicle-Parking System: A Solution to Reinforce IoT-Cloud Platform for Future Smart Parking.

With the advent of modern technologies, including the IoT and blockchain, smart-parking (SP) systems are becoming smarter and smarter. Similar to other automated systems, and particularly those that require automation or minimal interaction with humans, the SP system is heuristic in delivering performances, such as throughput in terms of latency, efficiency, privacy, and security, and it is considered a long-term cost-effective solution. This study looks ahead to future trends and developments in SP systems and presents an inclusive, long-term, effective, and well-performing smart autonomous vehicle parking (SAVP) system that explores and employs the emerging fog-computing and blockchain technologies as robust solutions to strengthen the existing collaborative IoT-cloud platform to build and manage SP systems for autonomous vehicles (AVs). In other words, the proposed SAVP system offers a smart-parking solution, both indoors and outdoors, and mainly for AVs looking for vacant parking, wherein the fog nodes act as a middleware layer that provides various parking operations closer to IoT-enabled edge devices. To address the challenges of privacy and security, a lightweight integrated blockchain and cryptography (LIBC) module is deployed, which is functional at each fog node, to authorize and grant access to the AVs in every phase of parking (e.g., from the parking entrance to the parking slot to the parking exit). A proof-of-concept implementation was conducted, wherein the overall computed results, such as the average response time, efficiency, privacy, and security, were examined as highly efficient to enable a proven SAVP system. This study also examined an innovative pace, with careful considerations to combatting the existing SP-system challenges and, therefore, to building and managing future scalable SP systems.

Emerging Effects of Resveratrol on Wound Healing: A Comprehensive Review.

Resveratrol (RSV) is a natural extract that has been extensively studied for its significant anti-inflammatory and antioxidant effects, which are closely associated with a variety of injurious diseases and even cosmetic medicine. In this review, we have researched and summarized the role of resveratrol and its different forms of action in wound healing, exploring its role and mechanisms in promoting wound healing through different modes of action such as hydrogels, fibrous scaffolds and parallel ratio medical devices with their anti-inflammatory, antioxidant, antibacterial and anti-ageing properties and functions in various cells that may play a role in wound healing. This will provide a direction for further understanding of the mechanism of action of resveratrol in wound healing for future research.

Recent Development of Electrocatalytic CO2 Reduction Application to Energy Conversion.

Carbon dioxide (CO2 ) emission has caused greenhouse gas pollution worldwide. Hence, strengthening CO2 recycling is necessary. CO2 electroreduction reaction (CRR) is recognized as a promising approach to utilize waste CO2 . Electrocatalysts in the CRR process play a critical role in determining the selectivity and activity of CRR. Different types of electrocatalysts are introduced in this review: noble metals and their derived compounds, transition metals and their derived compounds, organic polymer, and carbon-based materials, as well as their major products, Faradaic efficiency, current density, and onset potential. Furthermore, this paper overviews the recent progress of the following two major applications of CRR according to the different energy conversion methods: electricity generation and formation of valuable carbonaceous products. Considering electricity generation devices, the electrochemical properties of metal-CO2 batteries, including Li-CO2 , Na-CO2 , Al-CO2 , and Zn-CO2 batteries, are mainly summarized. Finally, different pathways of CO2 electroreduction to carbon-based fuels is presented, and their reaction mechanisms are illustrated. This review provides a clear and innovative insight into the entire reaction process of CRR, guiding the new electrocatalysts design, state-of-the-art analysis technique application, and reaction system innovation.

Exosomal ERp44 derived from ER-stressed cells strengthens cisplatin resistance of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in head and neck. Platinum-based chemotherapy is an important treatment for NPC. However, the molecular mechanism of resistance to platinum drug remains unknown. Endoplasmic reticulum resident protein 44(ERp44), an unfolded protein response (UPR)-induced endoplasmic reticulum(ER) protein, is induced during ER stress. This research explored the mechanism of ERp44 in strengthening cisplatin resistance in NPC. METHODS: Western blot and immunohistochemistry were used to investigate the expression of ERp44 and Glucose-Regulated Protein 78(GRP78) in NPC. We took CCK8 to detect the role of ERp44 on cell chemosensitivity. Flow cytometric analysis and western blot were taken to analyze cell apoptosis. We performed differential centrifugation to isolate exosomes from serum or conditioned media of cells and analyzed the impact of exosomal ERp44 on cells cisplatin sensitivity. Finally, the results were confirmed in vivo. RESULTS: We found the increased expression of ERp44 and GRP78 in NPC and ERp44 was highly expressed in ER-stressed tissues. Cell proliferation was inhibited after cisplatin treatment when ERp44 was knocked down and ERp44 strengthened cisplatin resistance by influencing cell apoptosis and pyroptosis. Then we also collected exosomes and cell viability was increased after the addition of NPC-derived-exosomes with cisplatin treatment. More importantly, our results showed under ERS, NPC cells secreted exosomes containing ERp44 and could transfer them to adjacent cells to strengthen chemoresistance. CONCLUSION: Our data suggested that exosomal ERp44 derived from ER-stressed NPC cells took an inevitable role in NPC chemoresistance and might act as a treatment target.

Localization with Transfer Learning Based on Fine-Grained Subcarrier Information for Dynamic Indoor Environments.

Indoor localization provides robust solutions in many applications, and Wi-Fi-based methods are considered some of the most promising means for optimizing indoor fingerprinting localization accuracy. However, Wi-Fi signals are vulnerable to environmental variations, resulting in data across different times being subjected to different distributions. To solve this problem, this paper proposes an across-time indoor localization solution based on channel state information (CSI) fingerprinting via multi-domain representations and transfer component analysis (TCA). We represent the format of CSI readings in multiple domains, extending the characterization of fine-grained information. TCA, a domain adaptation method in transfer learning, is applied to shorten the distribution distances among several CSI readings, which overcomes various CSI distribution problems at different time periods. Finally, we present a modified Bayesian model averaging approach to integrate the multi-domain outcomes and give the estimated positions. We conducted test-bed experiments in three scenarios on both personal computer (PC) and smartphone platforms in which the source and target fingerprinting data were collected across different days. The experimental results showed that our method outperforms state-of-the-art methods in localization accuracy.

Intuitive Development to Examine Collaborative IoT Supply Chain System Underlying Privacy and Security Levels and Perspective Powering through Proactive Blockchain.

Undoubtedly, the supply chain management (SCM) system is an important part of many organizations worldwide; over time, the technologies used to manage a supply chain ecosystem have, therefore, a great impact on businesses' effectiveness. Among others, numerous developments have been made that targeted to have robust supply chain systems to efficiently manage the growing demands of various supplies, considering the underlying requirements and main challenges such as scalability, specifically privacy and security, of various business networks. Internet of things (IoT) comes with a solution to manage a complex, scalable supply chain system, but to provide and attain enough security during information exchange, along with keeping the privacy of its users, is the great inherent challenge of IoT. To fulfill these limitations, this study designs and models a scaled IoT-based supply chain (IoT-SC) system, comprising several operations and participants, and deploys mechanisms to leverage the security, mainly confidentially, integrity, authentication (CIA), and a digital signature scheme to leverage potentially secured non-repudiation security service for the worst-case scenario, and to leverage privacy to keep users sensitive personal and location information protected against adversarial entities to the IoT-SC system. Indeed, a scaled IoT-SC system certainly opens new challenges to manage privacy and security while communicating. Therefore, in the IoT-SC system, each transaction writes from edge computing nodes to the IoT-SC controller is thoroughly examined to ensure the proposed solutions in bi-directional communication, and their robustness against adversarial behaviors. Future research works, employing blockchain and its integrations, are detailed as paces to accelerate the privacy and security of the IoT-SC system, for example, migrating IoT-centric computing to an immutable, decentralized platform.