Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

Impact of third-order dispersion on the dynamics of dissipative solitons in an ultrafast fiber laser.

Dissipative solitons (DSs), due to the complex interplay among dispersion, nonlinear, gain and loss, illustrate abundant nonlinear dynamics behaviors. Especially, dispersion plays an important role in the research of DS dynamics in ultrafast fiber lasers. Previous studies have mainly focused on the effect of even-order dispersion, i.e., group velocity dispersion (GVD) and fourth-order dispersion. In fact, odd-order dispersions, such as third-order dispersion (TOD), also significantly influences the dynamics of DSs. However, due to the lack of dispersion engineering tools, few experimental researches in this domain have been reported. In this work, by employing a pulse shaper in ultrafast fiber laser, an in-depth exploration of the DS dynamics influenced by TOD was conducted. With the increase of TOD value, the stable single DS undergoes a splitting into two solitons and then enters explosion state, and ultimately evolves into a chaotic state. The laser operation state is correlated to dispersion profile, which could be controlled by TOD. Here, the positive dispersion at long-wavelength side will be gradually shifted to negative dispersion by increasing the TOD, where soliton effect will drive the transitions. These findings offer valuable insights into the nonlinear dynamics of ultrafast lasers and may also foster applications involving higher-order dispersion.

Rapid, Massive, and Green Synthesis of Polyoxometalate-Based Metal-Organic Frameworks to Fabricate POMOF/PAN Nanofiber Membranes for Selective Filtration of Cationic Dyes.

Developing high-efficiency membrane materials for the rapid removal of organic dyes is crucial but remains a challenge. Polyoxometalates (POMs) clusters with anionic structures are promising candidates for the removal of cationic dyes via electrostatic interactions. However, their shortcomings, such as their solubility and inability to be mass-produced, hinder their application in water pollution treatment. Here, we propose a simple and green strategy utilizing the room temperature stirring method to mass produce nanoscale polyoxometalate-based metal-organic frameworks (POMOFs) with porous rhomboid-shaped dodecahedral and hexagonal prism structures. The products were labeled as POMOF1 (POMOF-PW12) and POMOF2 (POMOF-PMo12). Subsequently, a series of x wt% POMOF1/PAN (x = 0, 3, 5, and 10) nanofiber membranes (NFMs) were prepared using electrospinning technology, where polyacrylonitrile (PAN) acts as a "glue" molecule facilitating the bonding of POMOF1 nanoparticles. The as-prepared samples were comprehensively characterized and exhibited obvious water stability, as well as rapid selective adsorption filtration performance towards cationic dyes. The 5 wt% POMOF1/PAN NFM possessed the highest removal efficiency of 96.7% for RhB, 95.8% for MB, and 86.4% for CV dyes, which realized the selective separation over 95% of positively charged dyes from the mixed solution. The adsorption mechanism was explained using FT-IR, SEM, Zeta potential, and adsorption kinetics model, which proved that separation was determined via electrostatic interaction, hydrogen bonding, and π-π interactions. Moreover, the POMOF1/PAN membrane presented an outstanding recoverable and stable removal rate after four cycles. This study provides a new direction for the systematic design and manufacture of membrane separation materials with outstanding properties for contaminant removal.

A continuous ultra-narrow impulse synchronizer using a monolithic field programmable gate array for fast deployment and scalability.

Ultra-narrow pulses serve as critical components in numerous applications. These pulses have ultra-fast leading edges that typically function as precision trigger signals to synchronize various instruments. Ultra-narrow pulses inherently exhibit an ultra-wide bandwidth, gaining significant attention in diverse electronic systems encompassing communications, radar imaging, electronic warfare, and others. Although several techniques have been explored for generating ultra-narrow pulses, field programmable gate arrays (FPGAs) offer a promising alternative in terms of flexibility and integration. This study introduces a scalable delay pulse synchronizer method with a resolution of 23 ps. A programmable, successive, narrow pulse sequence operating at a 1-GHz repetition frequency is implemented within a monolithic FPGA. The performance of the proposed method is evaluated using an existing board with a general commercial FPGA in the laboratory. This new method presents a convenient and efficient approach of achieving ultra-narrow pulse synchronization, being applicable across various fields.

Selective anchoring of Pt NPs on covalent triazine-based frameworks via in situ derived bridging ligands for boosting photocatalytic hydrogen evolution.

The efficient and stable production of hydrogen (H2) through Pt-containing photocatalysts remains a great challenge. Herein, we develop an effective strategy to selectively and uniformly anchor Pt NPs (∼1.2 nm) on a covalent triazine-based framework photocatalyst via in situ derived bridging ligands. Compared to Pt/CTF-1, the obtained Pt/AT-CTF-1 exhibits a considerable photocatalytic H2 evolution rate of 562.9 µmol g-1 h-1 under visible light irradiation. Additionally, the strong interaction between the Pt NPs and in situ derived bridging ligands provides remarkable stability to Pt/AT-CTF-1. Experimental investigations and photo/chemical characterization reveal the synergy of the in situ derived bridging ligands in Pt/AT-CTF-1, which can selectively anchor the Pt NPs with homogeneous sizes and efficiently improve the transmission of charge carriers. This work provides a new perspective toward stabilizing ultrasmall nanoclusters and facilitating electron transfer in photocatalytic H2 evolution materials.

Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation.

Capsid assembly is critical in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. Capsid assembly is the target for new anti-viral therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and leads to hepatocyte cell death. This study aimed to identify the mechanism of action of CAM-A modulators leading to HBV-infected hepatocyte elimination where CAM-A-mediated hepatitis B surface antigen (HBsAg) reduction was evaluated in a stable HBV replicating cell line and in AAV-HBV-transduced C57BL/6, C57BL/6 SCID, and HBV-infected chimeric mice with humanized livers. Results showed that in vivo treatment with CAM-A modulators induced pronounced reductions in hepatitis B e antigen (HBeAg) and HBsAg, associated with a transient alanine amino transferase (ALT) increase. Both HBsAg and HBeAg reductions and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute. However, CD8+ T cell depletion in transduced wild-type mice did not impact antigen reduction, indicating that CD8+ T cell responses are not essential. Transient ALT elevation in AAV-HBV-transduced mice coincided with a transient increase in endoplasmic reticulum stress and apoptosis markers, followed by detection of a proliferation marker. Microarray data revealed antigen presentation pathway (major histocompatibility complex class I molecules) upregulation, overlapping with the apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A-mediated HBsAg reduction is dependent on de novo core protein translation. To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure. IMPORTANCE: Treatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.

Association between periodontitis treatment and dementia in Taiwanese adults.

BACKGROUND: The chronic systemic inflammatory response in periodontitis may be a potential risk factor for dementia, especially in adults. This study determined the association between periodontal treatment and dementia in adults and evaluated the effect of regular scaling treatment on the risk of dementia in this population. METHODS: This case-control study identified 18,930 patients with a dementia-related diagnosis from the Taiwan National Health Insurance Research Database. Scaling and periodontal emergency treatments were evaluated after 1 year and 3 years. Using multivariable logistic regression analysis to evaluate the association between periodontal emergency treatment and dementia risk. RESULTS: The results showed that scaling treatment rates were lower in the dementia cohort than the non-dementia cohort after 1 and 3 years. Patients who received periodontal emergency treatment within 3 years had a significantly increased risk of dementia. Furthermore, patients with periodontitis who did not receive scaling treatment within 3 years had a higher risk of dementia than patients without periodontitis (OR, 1.22; 95% CI, 1.10-1.35). CONCLUSION: This study demonstrated that periodontitis and dementia are associated, and that periodontitis is a risk factor for dementia in adults. The risk of dementia was dependent on the periodontal health status of adults, and our findings suggest that regular scaling can reduce the incidence of dementia in adults. Therefore, regular and routine scaling treatment is suggested for adults.

Anti-phase pulsation of counter-propagating dissipative solitons in a bidirectional fiber laser.

Due to its unique geometric structure, the bidirectional ultrafast fiber laser is an excellent light source for dual-comb applications. However, sharing the same gain between the counter-propagating solitons also gives rise to complex dynamics. Herein, we report the anti-phase pulsation of counter-propagating dissipative solitons in a bidirectional fiber laser. The in-phase and anti-phase soliton pulsation can be manipulated by adjusting the intracavity birefringence. The periodic modulation of polarization-dependent gain (PDG) caused by polarization hole burning (PHB) in the gain fiber can be responsible for anti-phase pulsation of bidirectional dissipative solitons. These findings offer new, to the best of our knowledge, insights into the complex dynamics of solitons in dissipative optical systems and performance improvement of bidirectional ultrafast fiber lasers.

Effectiveness and safety of REBACIN as a non-invasive intervention for persistent high-risk human papillomavirus infection: A real-world prospective multicenter cohort study.

BACKGROUND: We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. METHODS: According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. RESULTS: The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. CONCLUSION: This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry Registration Number: ChiCTR1800015617 http://www.chictr.org.cn/showproj.aspx?proj=26529 Date of Registration: 2018-04-11.

Apoptosis pathways and osteoporosis: An approach to genomic analysis.

BACKGROUND: Osteoporosis is a disease of the bone system that causes a decrease in skeletal density and degrades skeletal tissue. Decreased bone quality, so that bones are easily broken, damaged and fractured, is an important public health problem. Previous studies have shown that the maintenance of adult bone mass is not only due to changes in bone marrow and bone cells. By regulating apoptosis, they change the lifespan of each individual. This study influences understanding of the function of apoptosis in the pathogenesis of osteoporosis and the importance of controlling the mechanisms of osteoporosis. METHODS: On the National Institute of Biotechnology Information website, Gene Expression Omnibus (GEO) microarray data and GSE551495 GEO profiles were collected. The gene set enrichment analysis tool was used to confirm the enrichment of genetic sets in relation to the gene set. The collection of C2 gene sets is compiled from the KEGG (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://www.kegg.jp/kegg/) online database and REACTOME (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://reactome.org/) pathway analysis. The Search Tool for the Retrieval of Interaction Genes (STRING) website was used to construct and select proteins and genes. The comparative toxicological genomic database (CTD) tools can be used to predict the relationship between apoptosis, osteoporosis-related genes and interactions between central genes and osteoporosis. RESULTS: These results generally expand our understanding of the path of apoptosis in osteoporosis. We have discovered genes CASP9, CASP8, CASP3, BAX and TP53 associated with osteoporosis. In activation of KEGG apoptosis and REACTOME, caspase activation through the extrinsic apoptotic signaling pathway is characterized by the identification of a subcollection of C2. Other STRINGs show the formation of protein networks and central gene selection, and CTD can accurately predict the relationship between these apoptosis pathways and central genes. CONCLUSIONS: Our research has highlighted the importance of the osteoporosis pathway associated with osteoporosis apoptosis with several analytical approaches. These results have broadened our understanding of the pathways of osteoporosis apoptosis. It is particularly possible to predict the sensitivity and vulnerability to osteoporosis.

A Tunable Terahertz Absorber Based on Double-Layer Patterned Graphene Metamaterials.

Graphene is widely used in tunable photonic devices due to its numerous exotic and exceptional properties that are not found in conventional materials, such as high electron mobility, ultra-thin width, ease of integration and good tunability. In this paper, we propose a terahertz metamaterial absorber that is based on patterned graphene, which consists of stacked graphene disk layers, open ring graphene pattern layers and metal bottom layers, all separated by insulating dielectric layers. Simulation results showed that the designed absorber achieved almost perfect broadband absorption at 0.53-1.50 THz and exhibited polarization-insensitive and angle-insensitive characteristics. In addition, the absorption characteristics of the absorber can be adjusted by changing the Fermi energy of graphene and the geometrical parameters of the structure. The above results indicate that the designed absorber can be applied to photodetectors, photosensors and optoelectronic devices.

Purple Sweet Potato Powder Containing Anthocyanin Mitigates High-Fat-Diet-Induced Dry Eye Disease.

Purple sweet potato (PSP) powder with anthocyanins possesses the ability to reduce oxidative stress and inflammation. Studies have presumed a positive correlation between body fat and dry eye disease (DED) in adults. The regulation of oxidative stress and inflammation has been proposed as the mechanism underlying DED. This study developed an animal model of high fat diet (HFD)-induced DED. We added 5% PSP powder to the HFD to evaluate the effects and underlying mechanisms in mitigating HFD-induced DED. A statin drug, atorvastatin, was also added to the diet separately to assess its effect. The HFD altered the structure of lacrimal gland (LG) tissue, reduced LG secretory function, and eliminated the expression of proteins related to DED development, including α-smooth muscle actin and aquaporin-5. Although PSP treatment could not significantly reduce body weight or body fat, it ameliorated the effects of DED by preserving LG secretory function, preventing ocular surface erosion, and preserving LG structure. PSP treatment increased superoxide dismutase levels but reduced hypoxia-inducible factor 1-α levels, indicating that PSP treatment reduced oxidative stress. PSP treatment increased ATP-binding cassette transporter 1 and acetyl-CoA carboxylase 1 levels in LG tissue, signifying that PSP treatment regulated lipid homeostasis maintenance to reduce the effects of DED. In conclusion, PSP treatment ameliorated the effects of HFD-induced DED through the regulation of oxidative stress and lipid homeostasis in the LG.

Spectral Characteristics and Functional Responses of Phospholipid Bilayers in the Terahertz Band.

Understanding the vibrational information encoded within the terahertz (THz) spectrum of biomolecules is critical for guiding the exploration of its functional responses to specific THz radiation wavelengths. This study investigated several important phospholipid components of biological membranes-distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylcholine (DPPC), sphingosine phosphorylcholine (SPH), and lecithin bilayer-using THz time-domain spectroscopy. We observed similar spectral patterns for DPPC, SPH, and the lecithin bilayer, all of which contain the choline group as the hydrophilic head. Notably, the spectrum of DSPE, which has an ethanolamine head group, was different. Interestingly, density functional theory calculations confirmed that the absorption peak common to DSPE and DPPC at approximately 3.0 THz originated from a collective vibration of their similar hydrophobic tails. Accordingly, the cell membrane fluidity of RAW264.7 macrophages with irradiation at 3.1 THz was significantly enhanced, leading to improved phagocytosis. Our results highlight the importance of the spectral characteristics of the phospholipid bilayers when studying their functional responses in the THz band and suggest that irradiation at 3.1 THz is a potential non-invasive strategy to increase the fluidity of phospholipid bilayers for biomedical applications such as immune activation or drug administration.

Fractionated FLASH radiation in xenografted lung tumors induced FLASH effect at a split dose of 2 Gy.

PURPOSE: To explore the minimum split dose of FLASH radiotherapy (FLASH). MATERIAL AND METHODS: Lungs of nude mice were used to verify the capacity of normal tissue sparing of FLASH, while tumor-bearing nude mice were used to evaluate the curative power. Xenografted tumor models were established in Balb/c-nu mice using A549 cells at a concentration of 5×106/100 µL. With the same total dose (20 Gy), the dose rate of FLASH was 200 Gy/s when conventional radiotherapy(CONV) was 0.033 Gy/s. Two schemes of FLASH irradiations were applied: single pulse (FLASH1) and ten pulses (FLASH10). Then, according to the different tissue types and irradiation schemes, mice were divided into eight groups: Control-T, CONV-T, FLASH1-T, FLASH10-T (T for tumor) and Control-L, CONV-L, FLASH1-L, FLASH10-L (L for lung). Evaluation of FLASH effect was based on the changes in tumor volume and pathological analysis of tumor and lung tissues before and after irradiation. RESULTS: Compared to control group, the mean volume of tumors in nude mice increased slowly or decreased after irradiation with both FLASH and CONV (Control-T: 233.6±55.19 mm3, CONV-T: 146.1±50.62 mm3, FLASH1-T: 148±18.83 mm3, FLASH10-T: 119.1±50.62 mm3, p ≤ .05) . Tumor cells of irradiated groups had similar degrees of dissolution damage and inflammation, while the acute radiation pneumonia induced by FLASH was less severe. The pulmonary pathology of FLASH1-L and FLASH10-L were similar, and only a few neutrophils were observed. In addition to inflammatory cells, slight thickening of alveolar septum and obvious interstitial hemorrhage were also observed in the CONV-L group. CONCLUSION: The FLASH effect was successfully reproduced in both single and fractionated irradiation, with 2 Gy being the minimum split dose to achieve the FLASH effect in existing experiments. It is suggested that the transient oxygen depletion might not be the only mechanism behind the FLASH effect.

Airborne antibiotic resistome and human health risk in railway stations during COVID-19 pandemic.

Antimicrobial resistance is recognized as one of the greatest public health concerns. It is becoming an increasingly threat during the COVID-19 pandemic due to increasing usage of antimicrobials, such as antibiotics and disinfectants, in healthcare facilities or public spaces. To explore the characteristics of airborne antibiotic resistome in public transport systems, we assessed distribution and health risks of airborne antibiotic resistome and microbiome in railway stations before and after the pandemic outbreak by culture-independent and culture-dependent metagenomic analysis. Results showed that the diversity of airborne antibiotic resistance genes (ARGs) decreased following the pandemic, while the relative abundance of core ARGs increased. A total of 159 horizontally acquired ARGs, predominantly confering resistance to macrolides and aminoglycosides, were identified in the airborne bacteria and dust samples. Meanwhile, the abundance of horizontally acquired ARGs hosted by pathogens increased during the pandemic. A bloom of clinically important antibiotic (tigecycline and meropenem) resistant bacteria was found following the pandemic outbreak. 251 high-quality metagenome-assembled genomes (MAGs) were recovered from 27 metagenomes, and 86 genera and 125 species were classified. Relative abundance of ARG-carrying MAGs, taxonomically assigned to genus of Bacillus, Pseudomonas, Acinetobacter, and Staphylococcus, was found increased during the pandemic. Bayesian source tracking estimated that human skin and anthropogenic activities were presumptive resistome sources for the public transit air. Moreover, risk assessment based on resistome and microbiome data revealed elevated airborne health risks during the pandemic.

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies.

Background/Purpose: Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT). Materials/Methods: Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration. Results: Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group. Conclusions: FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.

REBACIN® inhibits E6/E7 oncogenes in clearance of human papillomavirus infection.

Previous studies have demonstrated that REBACIN® intervention eliminates persistent high-risk human papillomavirus (hrHPV) infection. The initial establishment and subsequent progression of cervical cancer mainly depends on two major oncogenes, E6/E7, and previous studies have proposed E6/E7 oncogenes as a target for therapeutic drug development. The aim of this study was to investigate in vitro and in vivo whether REBACIN® inhibits E6/E7 oncogenes for elucidating the mechanism of REBACIN® in the clearance of persistent hrHPV infection. In vitro, after REBACIN® treatment, the growth of both Ca Ski and HeLa cervical cancer cells containing the E6/E7 oncogenes was prevented. In line with this finding is that E6/E7 expression was inhibited, which can be counteracted by the co-application of anti-REBACIN® antibody. These studies demonstrated that REBACIN® can effectively inhibit the growth of cervical cancer cells via targeting HPV E6/E7 expression. To further verify this finding in clinic, 108 volunteer patients with persistent hrHPV infections were randomly divided into REBACIN®, recombinant human interferon alpha-2b (Immunological drug control), or no-treatment blank control groups, received intravaginal administration of REBACIN®, interferon or no-treatment every other day for three months, and then followed up for E6/E7 mRNA assay. In REBACIN® group, 68.57% of patients showed complete clearance of HPV E6/E7 mRNA, which was significantly higher compared to 25.00% in the interferon immunological drug control group and 20.00% in blank control group, confirming that REBACIN® is potently efficacious on clearing persistent hrHPV infections via inhibition of HPV E6/E7 oncogenes. Clinical trial registration: http://www.chictr.org.cn/historyversionpuben.aspx?regno=ChiCTR2100045911, identifier ChiCTR2100045911.

Overcoming Electrostatic Interaction via Strong Complexation for Highly Selective Reduction of CN- into N2.

Limited by the electrostatic interaction, the oxidation reaction of cations at the anode and the reduction reaction of anions at the cathode in the electrocatalytic system nearly cannot be achieved. This study proposes a novel strategy to overcome electrostatic interaction via strong complexation, realizing the electrocatalytic reduction of cyanide (CN- ) at the cathode and then converting the generated reduction products into nitrogen (N2 ) at the anode. Theoretical calculations and experimental results confirm that the polarization of the transition metal oxide cathodes under the electric field causes the strong chemisorption between CN- and cathode, inducing the preferential enrichment of CN- to the cathode. CN- is hydrogenated by atomic hydrogen at the cathode to methylamine/ammonia, which are further oxidized into N2 by free chlorine derived from the anode. This paper provides a new idea for realizing the unconventional and unrealizable reactions in the electrocatalytic system.

Mechanisms of FLASH effect.

FLASH radiotherapy (FLASH-RT) is a novel radiotherapy technology defined as ultra-high dose rate (≥ 40 Gy/s) radiotherapy. The biological effects of FLASH-RT include two aspects: first, compared with conventional dose rate radiotherapy, FLASH-RT can reduce radiation-induced damage in healthy tissue, and second, FLASH-RT can retain antitumor effectiveness. Current research shows that mechanisms of the biological effects of FLASH-RT are related to oxygen. However, due to the short time of FLASH-RT, evidences related to the mechanisms are indirect, and the exact mechanisms of the biological effects of FLASH-RT are not completely clear and some are even contradictory. This review focuses on the mechanisms of the biological effects of FLASH-RT and proposes future research directions.

FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy.

DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8+ T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8+ T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.