A photoinduced SET process enables the direct B−H bond activation of NHC–boranes. In contrast to common hydrogen atom transfer (HAT) strategies, this photoinduced reaction simply takes advantage of ...the beneficial redox potentials of NHC–boranes, thus obviating the need for extra radical initiators. The resulting NHC–boryl radical was used for the borylation of a wide range of α‐trifluoromethylalkenes and alkenes with diverse electronic and structural features, providing facile access to highly functionalized borylated molecules. Labeling and photoquenching experiments provide insight into the mechanism of this photoinduced SET pathway.
A photoinduced SET process enables the direct B−H bond activation of NHC–boranes. The resulting NHC–boryl radical was used for the borylation of a wide range of α‐trifluoromethylalkenes and alkenes with diverse electronic and structural features, providing facile access to highly functionalized borylated molecules.
COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and ...immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.
Necroptosis is an alternative form of programmed cell death that generally occurs under apoptosis‐deficient conditions. Our previous work showed that connexin32 (Cx32) promotes the malignant progress ...of hepatocellular carcinoma (HCC) by enhancing the ability of resisting apoptosis in vivo and in vitro. Whether triggering necroptosis is a promising strategy to eliminate the apoptosis‐resistant HCC cells with high Cx32 expression remains unknown. In this study, we found that Cx32 expression was positively correlated with the expression of necroptosis protein biomarkers in human HCC specimens, cell lines, and a xenograft model. Treatment with shikonin, a well‐used necroptosis inducer, markedly caused necroptosis in HCC cells. Interestingly, overexpressed Cx32 exacerbated shikonin‐induced necroptosis, but downregulation of Cx32 alleviated necroptosis in vitro and in vivo. Mechanistically, Cx32 was found to bind to Src and promote Src‐mediated caspase 8 phosphorylation and inactivation, which ultimately reduced the activated caspase 8‐mediated proteolysis of receptor‐interacting serine‐threonine protein kinase 1/3, the key molecule for necroptosis activation. In conclusion, we showed that Cx32 contributed to the activation of necroptosis in HCC cells through binding to Src and then mediating the inactivation of caspase 8. The present study suggested that necroptosis inducers could be more favorable than apoptosis inducers to eliminate HCC cells with high expression of Cx32.
Connexin32 promotes shikonin‐induced necroptosis in hepatocellular carcinoma by interacting with Src and enhancing Src‐mediated caspase 8 phosphorylation on Tyr380. We identified the novel role of connexin32 in necroptosis and elucidated connexin32 as a potential target for pronecroptosis therapy in hepatocellular carcinoma.
CXCL3 belongs to the CXC‐type chemokine family and is known to play a multifaceted role in various human malignancies. While its clinical significance and mechanisms of action in uterine cervical ...cancer (UCC) remain unclear. This investigation demonstrated that the UCC cell line HeLa expressed CXCL3, and strong expression of CXCL3 was detected in UCC tissues relative to nontumor tissues. In addition, CXCL3 expression was strongly correlated with CXCL5 expression in UCC tissues. In vitro, HeLa cells overexpressing CXCL3, HeLa cells treated with exogenous CXCL3 or treated with conditioned medium from WPMY cells overexpressing CXCL3, exhibited enhanced proliferation and migration activities. In agreement with these findings, CXCL3 overexpression was also associated with the generation of HeLa cell tumor xenografts in athymic nude mice. Subsequent mechanistic studies demonstrated that CXCL3 overexpressing influenced the expression of extracellular signal‐regulated kinase (ERK) signaling pathway associated genes, including ERK1/2, Bcl‐2, and Bax, whereas the CXCL3‐induced proliferation and migration effects were attenuated by exogenous administration of the ERK1/2 blocker PD98059. The data of the current investigation support that CXCL3 appears to hold promise as a potential tumor marker and interference target for UCC.
CXCL3 was significantly overexpressed in uterine cervical cancer (UCC), and its upregulation was positively related to the clinical stage. In vitro and in vivo, CXCL3 may act as a tumor promoter involved in the malignant processes of UCC through the Bcl‐2/Bax and ERK pathways.
Beyond citations, the impact of scientific publications is often measured by usage metrics, such as downloads, save counts and sharing counts. However, the motivations behind the utilization of these ...publications and their influencing factors have not yet been well studied. Therefore, it remains questionable whether and to what extent usage metrics can reflect the impact of publications. Based on expectancy-value theory, the aim of the present study was to examine the differences in behavioral characteristics and driving factors between article downloading, sharing, and saving, especially document characteristics. For the present study, survey data from 480 respondents across Chinese universities were collected and investigated in terms of the frequency and purpose of three literature usage behaviors, namely, downloading, sharing, and saving. Additionally, 11 document characteristics were used to construct three variables in the research models: intrinsic interest value, attainment value, and utility value. Their effects on three usage behaviors were examined based on path analysis via SmartPLS. The results showed that the overall frequency of article downloading and saving was greater than that of article sharing. The primary purposes of downloading and saving were closely related to scientific research, such as for review and citing. The sharing of articles on social media was mainly for agreeing with their opinions. Both intrinsic interest value and utility value exhibited a significant positive influence on article-downloading, whereas attainment value and intrinsic interest value showed a significant relationship with sharing and saving, respectively. In conclusion, different literature usage behaviors can be triggered and driven by the distinct values of research articles. The results obtained in this study could help to clarify the determinants of different usage behaviors; additionally, they might promote the reasonable application of usage metrics or altmetrics in scientific evaluation.
Photocatalytic micromotors that exhibit wireless and controllable motion by light have been extensively explored for cancer treatment by photodynamic therapy (PDT). However, overexpressed glutathione ...(GSH) in the tumor microenvironment can down‐regulate the reactive oxygen species (ROS) level for cancer therapy. Herein, we present dendrite‐shaped light‐powered hematite microrobots as an effective GSH depletion agent for PDT of prostate cancer cells. These hematite microrobots can display negative phototactic motion under light irradiation and flexible actuation in a defined path controlled by an external magnetic field. Non‐contact transportation of micro‐sized cells can be achieved by manipulating the microrobot's motion. In addition, the biocompatible microrobots induce GSH depletion and greatly enhance PDT performance. The proposed dendrite‐shaped hematite microrobots contribute to developing dual light/magnetic field‐powered micromachines for the biomedical field.
Dendrite‐shaped hematite microrobots have been developed as an effective GSH depletion agent for photodynamic therapy (PDT) of prostate cancer cells. These single‐component microrobots with dual light/magnetic field actuation can induce GSH depletion, greatly enhancing in vitro PDT performance and accomplishing the non‐contact transportation of micro‐sized objects.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing ...evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.
Endothelium (EC) is a key component of blood-brain barrier (BBB), and has an important position in the neurovascular unit. Its dysfunction and death after cerebral ischemic/reperfusion (I/R) injury ...not only promote evolution of neuroinflammation and brain edema, but also increase the risk of intracerebral hemorrhage of thrombolytic therapies. However, the mechanism and specific interventions of EC death after I/R injury are poorly understood. Here we showed that necroptosis was a mechanism underlying EC death, which promoted BBB breakdown after I/R injury. Treatment of rats with receptor interacting protein kinase 1 (RIPK1)-inhibitor, necrostatin-1 reduced endothelial necroptosis and BBB leakage. We furthermore showed that perivascular M1-like microglia-induced endothelial necroptosis leading to BBB disruption requires tumor necrosis factor-α (TNF-α) secreted by M1 type microglia and its receptor, TNF receptor 1 (TNFR1), on endothelium as the primary mediators of these effects. More importantly, anti-TNFα (infliximab, a potent clinically used drug) treatment significantly ameliorate endothelial necroptosis, BBB destruction and improve stroke outcomes. Our data identify a previously unexplored role for endothelial necroptosis in BBB disruption and suggest infliximab might serve as a potential drug for stroke therapy.
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not ...fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4
effector-GNLY (granulysin), CD8
effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
Living organisms evolve complex genetic networks to interact with the environment. Due to the rapid development of synthetic biology, various modularized genetic parts and units have been identified ...from these networks. They have been employed to construct synthetic genetic circuits, including toggle switches, oscillators, feedback loops and Boolean logic gates. Building on these circuits, complex genetic machines with capabilities in programmable decision-making could be created. Consequently, these accomplishments have led to novel applications, such as dynamic and autonomous modulation of metabolic networks, directed evolution of biological units, remote and targeted diagnostics and therapies, as well as biological containment methods to prevent release of engineered microorganisms and genetic materials. Herein, we outline the principles in genetic circuit design that have initiated a new chapter in transforming concepts to realistic applications. The features of modularized building blocks and circuit architecture that facilitate realization of circuits for a variety of novel applications are discussed. Furthermore, recent advances and challenges in employing genetic circuits to impart microorganisms with distinct and programmable functionalities are highlighted. We envision that this review gives new insights into the design of synthetic genetic circuits and offers a guideline for the implementation of different circuits in various aspects of biotechnology and bioengineering.
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