Femtosecond laser direct writing annular small-period long-period fiber gratings for simultaneous refractive index and temperature sensing.

A new type of small-period long-period fiber grating (SP-LPFG) consisting of a series of annuli inscribed by a femtosecond laser in a single-mode fiber is proposed and demonstrated. The effects of the annuli radii and the number of annuli in each period on the transmission spectrum are studied. The transmission spectrum of the annular SP-LPFG exhibits both strong Bragg resonances and cladding mode resonances, which have similar temperature sensitivities of 9.26 and 9.75 pm/°C, respectively. The Bragg resonances are insensitive to the change of environment refractive index (RI), while the cladding mode resonances show a RI sensitivity of 141.89 nm/RIU. The proposed sensor offers a potential solution for biomolecular sensing applications by effectively eliminating the issue of temperature cross-sensitivity. Its compact design and ease of spectral acquisition enhance its practicality and convenience.

Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immunotherapy combined with molecular targeted therapy is increasingly popular in patients with advanced hepatocellular carcinoma (HCC). However, immune-related adverse events(irAEs) brought on by immunotherapy increase the likelihood of side effects, thus it is important to look into ways to address this issue. METHODS: Different metabolite patterns were established by analyzing metabolomics data in liver tissue samples from 10 patients(divided into severe and mild liver injury) before and after immuno-targeted therapy. After establishing a subcutaneous tumor model of HCC, the mice were divided into PBS group, ascorbic acid(AA) group, and anti-PD1 + tyrosine kinase inhibitor (TKI) group, anti-PD1 + TKI + AA group. Liver tissue were stained with hematoxylin-eosin staining(HE) and the content of aspartate transaminase (AST) and alanine transaminase(ALT) in blood were determined. The mechanism was confirmed by western blotting, mass cytometry, and other techniques. RESULTS: Through metabolomics analysis, AA was significantly reduced in the sample of patients with severe liver injury caused by immuno-targeted therapy compared to patients with mild liver injury. The addition of AA in vivo experiments demonstrated a reduction in liver injury in mice. In the liver tissues of the anti-PD1 + TKI + AA group, the protein expressions of SLC7A11,GPX4 and the level of glutathione(GSH) were found to be higher compared to the anti-PD1 + TKI group. Mass cytometry analysis revealed a significant increase in the CD11b+CD44+ PD-L1+ cell population in the AA group when compared to the PBS group. CONCLUSIONS: AA could reduce liver injury by preventing hepatocyte SLC7A11/GPX4 ferroptosis and improve the immunotherapy effect of anti-PD1 by boosting CD11b+CD44+PD-L1+cell population in HCC.

HNRNPD regulates the biogenesis of circRNAs and the ratio of mRNAs to circRNAs for a set of genes.

Exonic circular RNAs (ecircRNAs) in animal cells are generated by backsplicing, and the biogenesis of ecircRNAs is regulated by an array of RNA binding proteins (RBPs). HNRNPD is a heterogeneous nuclear ribonucleoprotein family member with both cytoplasmic and nuclear roles, and whether HNRNPD regulates the biogenesis of circRNAs remains unknown. In this study, we examine the role of HNRNPD in the biogenesis of ecircRNAs. The levels of ecircRNAs are primarily increased upon depletion of HNRNPD. HNRNPD preferentially binds to motifs enriched with A and U nucleotides, and the flanking introns of ecircRNAs tend to have more numbers and higher intensity of HNRNPD binding sites. The levels of mRNAs are generally not significantly altered in HNRNPD knockout cells. For a small set of genes, the circRNA:mRNA ratio is substantially affected, and the mRNA levels of some of these genes demonstrate a significant decrease in HNRNPD knockout cells. CDK1 is identified as a key gene modulated by HNRNPD in the context of circRNA biogenesis. HNRNPD suppresses the biogenesis of circCDK1 and favours the generation of CDK1 mRNA, and the CDK1 protein is a critical regulator of the cell cycle and apoptosis. HNRNPD can participate in cellular physiology, including the cell cycle and apoptosis, and plays roles in clear cell renal cell carcinoma (ccRCC) by modulating circRNA biogenesis and the mRNA levels of key genes, such as CDK1.

New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization (TACE) being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

Circular RNA ARHGAP5 inhibits cisplatin resistance in cervical squamous cell carcinoma by interacting with AUF1.

Cervical squamous cell carcinoma (CSCC) is one of the leading causes of cancer death in women worldwide. Patients with advanced cervical carcinoma always have a poor prognosis once resistant to cisplatin due to the lack of effective treatment. It is urgent to investigate the molecular mechanisms of cisplatin resistance. Circular RNAs (circRNAs) are known to exert their regulatory functions in a series of malignancies. However, their effects on CSCC remain to be elucidated. Here, we found that cytoplasmic circARHGAP5, derived from second and third exons of the ARHGAP5 gene, was downregulated in cisplatin-resistant tissues compared with normal cervix tissues and untreated cervical cancer tissues. In addition, experiments from overexpression/knockdown cell lines revealed that circARHGAP5 could inhibit cisplatin-mediated cell apoptosis in CSCC cells both in vitro and in vivo. Mechanistically, circARHGAP5 interacted with AU-rich element RNA-binding protein (AUF1) directly. Overexpression of AUF1 could also inhibit cell apoptosis mediated by cisplatin. Furthermore, we detected the potential targets of AUF1 related to the apoptotic pathway and found that bcl-2-like protein 11 (BIM) was not only negatively regulated by AUF1 but positively regulated by circARHGAP5, which indicated that BIM mRNA might be degraded by AUF1 and thereby inhibited tumor cell apoptosis. Collectively, our data indicated that circARHGAP5 directly bound to AUF1 and prevented AUF1 from interacting with BIM mRNA, thereby playing a pivotal role in cisplatin resistance in CSCC. Our study provides insights into overcoming cancer resistance to cisplatin treatment.

High-performance vector torsion sensor based on high polarization-dependent in-fiber Mach-Zehnder interferometer.

We propose a high-performance vector torsion sensor based on an in-fiber Mach-Zehnder interferometer (MZI), which consists of a straight waveguide inscribed in the core-cladding boundary of the SMF by a femtosecond laser in only one step. The length of the in-fiber MZI is 5 mm, and the whole fabrication time does not exceed 1 min. The asymmetric structure makes the device have high polarization dependence, and the transmission spectrum shows a strong polarization-dependent dip. Since the polarization state of the input light entering the in-fiber MZI varies with the twist of the fiber, torsion sensing can be achieved by monitoring the polarization-dependent dip. Torsion can be demodulated by both the wavelength and intensity of the dip, and vector torsion sensing can be achieved by setting the appropriate polarization state of the incident light. The torsion sensitivity based on intensity modulation can reach 5763.96 dB/(rad/mm). The response of dip intensity to strain and temperature is weak. Furthermore, the in-fiber MZI retains the fiber coating, so it maintains the robustness of the complete fiber structure.

An Impedance-Based Approach for Sensing Cyclodextrin-Mediated Modulation of Membrane Cholesterol.

Cyclodextrin molecules are increasingly being used in biological research and as therapeutic agents to alter membrane cholesterol content, yet there is much to learn about their interactions with cell membranes. We present a biomembrane-based organic electronic platform capable of detecting interactions of cell membrane constituents with methyl-ß-cyclodextrin (MßCD). This approach enables label-free sensing and quantification of changes in membrane integrity resulting from such interactions. In this work, we employ cholesterol-containing supported lipid bilayers (SLBs) formed on conducting polymer-coated electrodes to investigate how MßCD impacts membrane resistance. By examining the outcomes of MßCD interactions with SLBs of varying cholesterol content, we demonstrate that changes in membrane permeability or resistance can be used as a functional measure for predicting cyclodextrin-mediated cholesterol extraction from cellular membranes. Furthermore, we use the SLB platforms to electronically monitor cholesterol delivery to membranes following exposure to MßCD pre-loaded with cholesterol, observing that cholesterol enrichment is commensurate with an increase in resistance. This biomembrane-based bioelectronic sensing system offers a tool to quantify the modulation of membrane cholesterol content using membrane resistance and provides information regarding MßCD-mediated changes in membrane integrity. Given the importance of membrane integrity for barrier function in cells, such knowledge is essential for our fundamental understanding of MßCD as a membrane cholesterol modulator and therapeutic delivery vehicle.

Femtosecond laser-inscribed off-axis high-order mode long-period grating for independent sensing of curvature and temperature.

We propose and demonstrate a novel curvature and temperature sensor based on an off-axis small-period long-period fiber grating (SP-LPG) which is inscribed in a single mode fiber by a femtosecond laser in one step. The total length of the SP-LPG is only 2.1 mm. The period of the SP-LPG is 30 µm, which is smaller than that of conventional long period fiber gratings. Essentially, the SP-LPG is a high-order mode long period fiber grating. Due to the off-axis structure, the SP-LPG can be used for two-dimensional vector bending sensing. The curvature can be demodulated by the intensity variation of the dips in the transmission spectrum. When the incident light is polarized, the instantaneous curvature sensitivity of the SP-LPG can exceed 20 dB/m-1. Meanwhile, a series of Bragg resonant peaks can be observed in the reflection spectrum, which can be used to monitor the fluctuation of temperature. The transmission dip is insensitive to temperature and the reflection peak is insensitive to curvature, which allows the SP-LPG to measure curvature and temperature independently. The characteristics of high curvature sensitivity, two-dimensional bending direction identification, real-time temperature measurement, and compact structure make the device expected to be applied in the field of structural health monitoring and intelligent robotics.

Clinical characteristics and prognosis of ovarian clear cell carcinoma: a 10-year retrospective study.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a special pathological type of epithelial ovarian carcinoma (EOC). We conducted this research to investigate the clinical characteristics and outcomes of OCCC and to provide additional supporting evidence to aid in the clinical diagnosis and management. METHODS: This was a retrospective study investigating the clinical characteristics and survival outcomes of 86 patients with OCCC treated at our center between January 2010 and March 2020. Survival analysis was also performed on 179 patients with OCCC obtained from the Surveillance, Epidemiology and End Results (SEER) cancer registry database. RESULTS: The median age of participants was 49.21 ± 9.91 years old, and 74.42% of them were diagnosed at early stage. The median CA125 level was 601.48 IU/mL, while 19.77% of the patients had normal CA125 levels. Sixteen patients (18.60%) had co-existing endometriosis and 8 patients (9.3%) developed venous thromboembolism (VTE). There were 5 patients received suboptimal cytoreduction. Sixty-six patients (76.74%) underwent lymphadenectomy, and only 3 (4.55%) patients had positive lymph nodes. Patients diagnosed at an early stage had higher 3-year overall survival (OS) and progression-free survival (PFS) rates than those with advanced stage OCCC. CA19-9 (P = 0.025) and ascites (P = 0.001) were significantly associated with OS, while HE4 (P = 0.027) and ascites (P = 0.001) were significantly associated with PFS. Analysis of data from the SEER database showed that positive lymph nodes is also an independent prognostic factor for OS (P = 0.001). CONCLUSIONS: OCCC often presents at an early stage and young age with a mildly elevated CA125. CA19-9, HE4, massive ascites, and positive lymph node are independent prognostic factors.

lncRNA PART1 and MIR17HG as ΔNp63α direct targets regulate tumor progression of cervical squamous cell carcinoma.

Cervical cancer (CC) remains one of the leading causes of mortality of female cancers worldwide, with more than 90% being cervical squamous cell carcinoma (CSCC). ΔNp63α is the predominant isoform expressed in cervical epithelial tissues and exerts its antitumor function in CSCC. In this study, we have identified 39 long noncoding RNAs as ΔNp63α targets in CSCC through RNA sequencing and chromatin immunoprecipitation sequencing, in which we further confirmed and focused on the two tumor-related long noncoding RNAs, PART1 (lncPART1) and MIR17HG (lncMIR17HG). Experiments from stable overexpression/knockdown cell lines revealed that lncPART1 and lncMIR17HG regulated cell proliferation, migration, and invasion. In vivo experiments further showed that lncPART1 suppresses tumor growth in CSCC-derived tumors. Examinations of clinical tissues indicated that the expression of lncPART1 was positively correlated with ΔNp63α expression, while lncMIR17HG was negatively correlated with ΔNp63α expression, suggesting that ΔNp63α plays a central role via regulating its direct targets in the progression of CSCC. These findings provide novel insights in targeted therapy of cervical cancers.

Self-Assembly of Mammalian-Cell Membranes on Bioelectronic Devices with Functional Transmembrane Proteins.

Transmembrane proteins (TMPs) regulate processes occurring at the cell surface and are essential gatekeepers of information flow across the membrane. TMPs are difficult to study, given the complex environment of the membrane and its influence on protein conformation, mobility, biomolecule interaction, and activity. For the first time, we create mammalian biomembranes supported on a transparent, electrically conducting polymer surface, which enables dual electrical and optical monitoring of TMP function in its native membrane environment. Mammalian plasma membrane vesicles containing ATP-gated P2X2 ion channels self-assemble on a biocompatible polymer cushion that transduces the changes in ion flux during ATP exposure. This platform maintains the complexity of the native plasma membrane, the fluidity of its constituents, and protein orientation critical to ion channel function. We demonstrate the dual-modality readout using microscopy to characterize protein mobility by single-particle tracking and sensing of ATP gating of P2X2 using electrical impedance spectroscopy. This measurement of TMP activity important for pain sensing, neurological activity, and sensory activity raises new possibilities for drug screening and biosensing applications.

Biomembrane-based organic electronic devices for ligand-receptor binding studies.

We present a simple, rapid method for forming supported lipid bilayers on organic electronic devices composed of conducting polymer electrodes using a solvent-assisted lipid bilayer formation method. These supported bilayers present protein recognition elements that are mobile, critical for multivalent binding interactions. Because these polymers are transparent and conducting, we demonstrate, by optical and electrical detection, the specific interactions of proteins with these biomembrane-based bioelectronic devices. This work paves the way for easy formation of biomembrane mimetics for sensing and detection of binding events in a label-free manner on organic electronic devices of more sophisticated architectures. Graphical abstract.

Effects of LncRNA Lnc-LIF-AS on cell proliferation, migration and invasion in a human cervical cancer cell line.

This study explored the effect of LncRNA Lnc-LIF-AS on cell proliferation, migration and invasion in the human cervical cancer (HCC) cell line SiHa. SiHa cells had the lowest expression of Lnc-LIF-AS in the 4 human cervical cancer cell lines (SiHa, ME-180, C-33A and HeLa) and were transfected and divided into the SiHa/con (transfected with pMIGRI) cell group, SiHa/Lnc-LIF-AS (transfected with pMIGRI-Lnc-LIF-AS) cell group, and SiHa/Lnc-LIF-AS-DN (transfected with pMIGRI-Lnc-LIF-AS-DN, in which the sequences overlapping with LIF mRNA was deleted) cell group. Overexpression of Lnc-LIF-AS could promote the proliferation, colony formation, invasion and migration in SiHa and ME-180 cells. And the low expression of Lnc-LIF-AS suppress the proliferation, colony formation invasion and migration in HeLa cells when the Lnc-LIF-AS expression has been suppressed. In the SiHa/Lnc-LIF-AS cells group, the cell cycle was mainly halted in the S phase and overexpression of Lnc-LIF-AS had no effect on the apoptosis of SiHa cells. Overexpression of Lnc-LIF-AS could promote the secretion of LIF in SiHa cells, and the supernatant from SiHa/Lnc-LIF-AS cells could promote cell proliferation in the SiHa/con cells. The STAT3 inhibitor could inhibit cell proliferation in the SiHa/Lnc-LIF-AS cells. The expression level of Lnc-LIF-AS in cervical cancer tissues was higher than that in normal tissues and the expression level of Lnc-LIF-AS was positively correlated with the level of LIF. In the SiHa/con and SiHa/Lnc-LIF-AS-DN cell groups, there were no significant differences in cell proliferation, cell migration and cell invasion. The overexpression of Lnc-LIF-AS can promote cell proliferation, migration and invasion in cervical cancer cells, and the core function domain of this lncRNA was located in the overlapping a 3'-UTR base sequence of LIF mRNA.

Biologically Complex Planar Cell Plasma Membranes Supported on Polyelectrolyte Cushions Enhance Transmembrane Protein Mobility and Retain Native Orientation.

Reconstituted supported lipid bilayers (SLB) are widely used as in vitro cell-surface models because they are compatible with a variety of surface-based analytical techniques. However, one of the challenges of using SLBs as a model of the cell surface is the limited complexity in membrane composition, including the incorporation of transmembrane proteins and lipid diversity that may impact the activity of those proteins. Additionally, it is challenging to preserve the transmembrane protein native orientation, function, and mobility in SLBs. Here, we leverage the interaction between cell plasma membrane vesicles and polyelectrolyte brushes to create planar bilayers from cell plasma membrane vesicles that have budded from the cell surface. This approach promotes the direct incorporation of membrane proteins and other species into the planar bilayer without using detergent or reconstitution and preserves membrane constituents. Furthermore, the structure of the polyelectrolyte brush serves as a cushion between the planar bilayer and rigid supporting surface, limiting the interaction of the cytosolic domains of membrane proteins with this surface. Single particle tracking was used to analyze the motion of GPI-linked yellow fluorescent proteins (GPI-YFP) and neon-green fused transmembrane P2X2 receptors (P2X2-neon) and shows that this platform retains over 75% mobility of multipass transmembrane proteins in its native membrane environment. An enzyme accessibility assay confirmed that the protein orientation is preserved and results in the extracellular domain facing toward the bulk phase and the cytosolic side facing the support. Because the platform presented here retains the complexity of the cell plasma membrane and preserves protein orientation and mobility, it is a better representative mimic of native cell surfaces, which may find many applications in biological assays aimed at understanding cell membrane phenomena.

NSUN4 mediated RNA 5-methylcytosine promotes the malignant progression of glioma through improving the CDC42 mRNA stabilization.

5-Methylcytosine (m5C) methylation is a significant post-transcriptional modification that play a crucial role in the development and progression of numerous cancers. Whereas the functions and molecular mechanisms underlying m5C methylation in gliomas remain unclear. This study dedicated to explore changes of m5C levels and the clinical significance of the m5C writer NSUN4 in gliomas. We found that high m5C levels were negatively related to prognosis of patients with glioma. Moreover, gain- and loss-of-function experiments revealed the role of NSUN4 in enhancing m5C modification of mRNA to promote the malignant progression of glioma. Mechanistically speaking, NSUN4-mediated m5C alterations regulated ALYREF binding to CDC42 mRNA, thereby impacting the mRNA stability of CDC42. We also demonstrated that CDC42 promoted glioma proliferation, migration, and invasion by activating the PI3K-AKT pathway. Additionally, rescue experiments proved that CDC42 overexpression weaken the inhibitory effect of NSUN4 knockdown on the malignant progression of gliomas in vitro and in vivo. Our findings elucidated that NSUN4-mediated high m5C levels promote ALYREF binding to CDC42 mRNA and regulate its stability, thereby driving the malignant progression of glioma. This provides theoretical support for targeted the treatment of gliomas.

Ascites exosomal lncRNA PLADE enhances platinum sensitivity by inducing R-loops in ovarian cancer.

Cisplatin resistance is a major cause of therapeutic failure in patients with high-grade serous ovarian cancer (HGSOC). Long noncoding RNAs (lncRNAs) have emerged as key regulators of human cancers; however, their modes of action in HGSOC remain largely unknown. Here, we provide evidence to demonstrate that lncRNA Platinum sensitivity-related LncRNA from Ascites-Derived Exosomes (PLADE) transmitted by ascites exosomes enhance platinum sensitivity in HGSOC. PLADE exhibited significantly decreased expression in ascites exosomes and tumor tissues, as well as in the corresponding metastatic tumors from patients with HGSOC cisplatin-resistance. Moreover, HGSOC patients with higher PLADE expression levels exhibited longer progression-free survival. Gain- and loss-of-function studies have revealed that PLADE promotes cisplatin sensitivity by suppressing cell proliferation, migration and invasion, and enhancing apoptosis in vitro and in vivo. Furthermore, the functions of PLADE in increasing cisplatin sensitivity were proven to be transferred by exosomes to the cultured recipient cells and to the adjacent tumor tissues in mouse models. Mechanistically, PLADE binds to and downregulates heterogeneous nuclear ribonucleoprotein D (HNRNPD) by VHL-mediated ubiquitination, thus inducing an increased amount of RNA: DNA hybrids (R-loop) and DNA damage, consequently promoting cisplatin sensitivity in HGSOC. Collectively, these results shed light on the understanding of the vital roles of long noncoding RNAs in cancers.

Dendritic cell targeting peptide plus Salmonella FliCd flagellin fused outer membrane protein H (OmpH) demonstrated increased efficacy against infections caused by different Pasteurella multocida serogroups in mouse models.

As the major outer membrane protein (OMP) presents in the Pasteurella multocida envelope, OmpH was frequently expressed for laboratory assessments of its immunogenicity against P. multocida infections, but the results are not good. In this study, we modified OmpH with dendritic cell targeting peptide (Depeps) and/or Salmonella FliCd flagellin, and expressed three types of recombinant proteins with the MBP tag (rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, rFliC-OmpH-MBP). Assessments in mouse models revealed that vaccination with rDepeps-FliC-OmpH-MBP, rDepeps-OmpH-MBP, or rFliC-OmpH-MBP induced significant higher level of antibodies as well as IFN-γ and IL-4 in murine sera than vaccination with rOmpH-MBP (P < 0.5). Vaccination with the three modified proteins also provided increased protection (rDepeps-FliC-OmpH-MBP, 70 %; rDepeps-OmpH-MBP, 50 %; rFliC-OmpH-MBP, 60 %) against P. multocida serotype D compared to vaccination with rOmpH-MBP (30 %). In mice vaccinated with different types of modified OmpHs, a significantly decreased bacterial strains were recovered from bloods, lungs, and spleens compared to rOmpH-MBP-vaccinated mice (P < 0.5). Notably, our assessments also demonstrated that vaccination with rDepeps-FliC-OmpH-MBP provided good protection against infections caused by a heterogeneous group of P. multocida serotypes (A, B, D). Our above findings indicate that modification with DCpep and Salmonella flagellin could be used as a promising strategy to improve vaccine effectiveness.

Make-Your-Video: Customized Video Generation Using Textual and Structural Guidance.

Creating a vivid video from the event or scenario in our imagination is a truly fascinating experience. Recent advancements in text-to-video synthesis have unveiled the potential to achieve this with prompts only. While text is convenient in conveying the overall scene context, it may be insufficient to control precisely. In this paper, we explore customized video generation by utilizing text as context description and motion structure (e.g. frame- wise depth) as concrete guidance. Our method, dubbed Make-Your-Video, involves joint-conditional video generation using a Latent Diffusion Model that is pre-trained for still image synthesis and then promoted for video generation with the introduction of temporal modules. This two-stage learning scheme not only reduces the computing resources required, but also improves the performance by transferring the rich concepts available in image datasets solely into video generation. Moreover, we use a simple yet effective causal attention mask strategy to enable longer video synthesis, which mitigates the potential quality degradation effectively. Experimental results show the superiority of our method over existing baselines, particularly in terms of temporal coherence and fidelity to users' guidance. In addition, our model enables several intriguing applications that demonstrate potential for practical usage. The code, model weights, and videos are publicly available at our project page: https://doubiiu.github.io/projects/Make-Your-Video/.

Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism.

Viral genetic diversity presents significant challenges in developing antivirals with broad-spectrum activity and high barriers to resistance. Here we report development of proteolysis targeting chimeras (PROTACs) targeting the dengue virus envelope (E) protein through coupling of known E fusion inhibitors to ligands of the CRL4CRBN E3 ubiquitin ligase. The resulting small molecules block viral entry through inhibition of E-mediated membrane fusion and interfere with viral particle production by depleting intracellular E in infected Huh 7.5 cells. This activity is retained in the presence of point mutations previously shown to confer partial resistance to the parental inhibitors due to decreased inhibitor-binding. The E PROTACs also exhibit broadened spectrum of activity compared to the parental E inhibitors against a panel of mosquito-borne flaviviruses. These findings encourage further exploration of targeted protein degradation as a differentiated and potentially advantageous modality for development of broad-spectrum direct-acting antivirals.

GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing.

Despite substantial breakthroughs in the treatment of hepatocellular carcinoma (HCC) in recent years, many patients are diagnosed in the middle or late stages, denying them the option for surgical excision. Therefore, it is of great importance to find effective therapeutic targets of HCC. In this study, it is found that Gap junction protein beta-2 (GJB2) is highly enriched in malignant cells based on single-cell RNA sequencing and higher expression of GJB2 indicates a worse prognosis. The localization of GJB2 in HCC cancer cells is changed compared with normal liver tissue. In cancer cells, GJB2 tends to be located in the cytoplasm and nucleus, while in normal tissues, GJB2 is mainly located on the cell membrane. GJB2 is related to glycolysis, promoting NF-κB pathway via inducing the ubiquitination degradation of IκBa, and activating HIF-1α/GLUT-1/PD-L1 pathway. In addition, GJB2 knockdown reshapes tumor immune microenvironment and Salvianolic acid B inhibits the activity of GJB2. In conclusion, GJB2 promotes HCC progression by activating glycolysis through cytoplasmic translocation and generating a suppressive tumor microenvironment. Salvianolic acid B inhibits the expression of GJB2 and enhances the sensitivity of anti-PD1 therapy, which may provide insights into the development of novel combination therapeutic strategies for HCC.