Inactivated influenza virus vaccines expressing COBRA hemagglutinin elicited broadly reactive, long-lived protective antibodies.

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

YAP promotes the early development of temporomandibular joint bony ankylosis by regulating mesenchymal stem cell function.

To explore the role of YAP, a key effector of the Hippo pathway, in temporomandibular joint (TMJ) ankylosis. The temporal and spatial expression of YAP was detected via immunohistochemistry and multiplex immunohistochemistry on postoperative Days 1, 4, 7, 9, 11, 14 and 28 in a sheep model. Isolated mesenchymal stem cells (MSCs) from samples of the Day 14. The relative mRNA expression of YAP was examined before and after the osteogenic induction of MSCs. A YAP-silenced MSC model was constructed, and the effect of YAP knockdown on MSC function was examined. YAP is expressed in the nucleus of the key sites that determine the ankylosis formation, indicating that YAP is activated in a physiological state. The expression of YAP increased gradually over time. Moreover, the number of cells coexpressing of RUNX2 and YAP-with the osteogenic active zone labelled by RUNX2-tended to increase after Day 9. After the osteogenic induction of MSCs, the expression of YAP increased. After silencing YAP, the osteogenic, proliferative and migratory abilities of the MSCs were inhibited. YAP is involved in the early development of TMJ bony ankylosis. Inhibition of YAP using shRNA might be a promising way to prevent or treat TMJ ankylosis.

In-situ precipitation zero-valent Co on Co2VO4 to activate oxygen vacancies and enhance bimetallic ions redox for efficient detection toward Hg(II).

Despite the widespread utilization of variable valence metals in electrochemistry, it is still a formidable challenge to enhance the valence conversion efficiency to achieve excellent catalytic activity without introducing heterophase elements. Herein, the in-situ precipitation of Co particles on Co2VO4 not only enhanced the concentration of oxygen vacancies (Ov) but also generated a greater number of low-valence metals, thereby enabling efficient reduction towards Hg(II). The electroanalysis results demonstrate that the sensitivity of Co/Co2VO4 towards Hg(II) was measured at an impressive value of 1987.74 µA µM-1 cm-2, significantly surpassing previously reported results. Further research reveals that Ov acted as the main adsorption site to capture Hg(II). The redox reactions of Co2+/Co3+ and V3+/V4+ played a synergistic role in the reduction of Hg(II), accompanied by the continuous supply of electrons from zero-valent Co to expedite the valence cycle. The Co/Co2VO4/GCE presented remarkable selectivity towards Hg(II), with excellent stability, reproducibility, and anti-interference capability. The electrode also exhibited minimal sensitivity fluctuations towards Hg(II) in real water samples, underscoring its practicality for environmental applications. This study elucidates the mechanism underlying the surface redox reaction of metal oxides facilitated by zero-valent metals, providing us with new strategies for further design of efficient and practical sensors.

Development and validation of Chinese compensatory health beliefs scale.

Compensatory Health Beliefs (CHBs), the notion that healthy behaviors can offset the negative effects of unhealthy actions, have been widely explored in Western contexts. Yet, their relevance within the Chinese cultural milieu remains underexplored. The primary objective of this research was to develop and validate a Chinese version of the CHBs scale (CHBs-C), addressing the gap in the literature regarding the applicability of CHBs within the Chinese cultural context. A multi-stage translation (from English to Chinese) was first completed, and exploratory factor analysis was conducted (n = 476), yielding the 14-item scale (CHBs-C scale). Confirmatory factor analysis was conducted to assess the validity, and the 2-week test-retest reliability, internal consistency and convergent validity of the scale were also assessed (n = 308). Predict validity was verified through testing the relationships between CHBs and health behaviors and habits (n = 274). Factor analysis showed a different factor structure in Chinese context, with only one factor identical to the original version. The fitness index of the new factor structure was good. However, while the scale exhibited acceptable internal consistency and high test-retest reliability, its convergent validity and predictive validity was found to be limited on a general level. Despite this, significant correlations at the subscale level were identified, highlighting nuanced interactions between CHBs and specific health behaviors within the Chinese population. This study not only establishes the CHBs-C scale as a valid and reliable instrument for assessing compensatory health beliefs in China but also lays the groundwork for further exploration of its applications and the potential cultural adaptability of CHBs.

miR-4429 inhibits ccRCC proliferation, migration, and invasion by directly targeting CD274.

Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive urological malignancies and a highly immunogenic cancer. Yet, its pathogenesis is still not fully understood. This study analyzed the role of the miR-320 family in ccRCC using bioinformatics algorithms and a series of in vitro experiments. miR-4429 was found to be significantly down-regulated in ccRCC tissues and cell lines, while overexpression of miR-4429 significantly inhibited renal cancer cell proliferation, migration, and invasion in vitro. In addition, the UALCAN database, immunohistochemistry, and protein blotting results showed that CD274 expression was up-regulated in ccRCC tissues and correlated with higher histologic grading. Dual luciferase assay indicated that CD274 was a direct target of miR-4429. Overexpression of miR-4429 in 786-O, Caki-2 cells significantly inhibited CD274 expression. KEGG results indicated that the potential target function of miR-4429 was associated with the PI3K/AKT signaling pathway, and protein blotting verified the results. In summary, this data shows that miR-4429 targets CD274 and inhibits ccRCC proliferation, migration, and invasion by regulating PI3K/AKT signaling, thus potentially providing a promising therapeutic target and prognostic biomarker for renal cell carcinoma patients.

Acupoint Autohemotherapy Attenuates DNCB-Induced Atopic Dermatitis and Activates Regulatory T Cells in BALB/c Mice.

Purpose: Acupoint autohemotherapy (A-AHT) has been proposed as an alternative and complementary treatment for atopic dermatitis (AD), yet the exact role of its blood component in terms of therapeutic efficacy and mechanism of action is still largely unknown. Methods: This study aimed to evaluate the therapeutic efficacies and action mechanisms of intramuscular injections of autologous whole blood (AWB) and mouse immunoglobulin G (IgG) (autologous or heterologous) at acupoints on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse models. Serum levels of total immunoglobulin E (IgE), IgG, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) were measured, as well as mRNA expression levels of Forkhead box P3 (FoxP3), IL-10 and IFN-γ in dorsal skin lesions, and IL-10+, IFN-γ+ and FoxP3+CD4+T cells in murine spleen. Results: It showed that repeated acupoint injection of AWB, autologous total IgG (purified from autologous blood in AD mice) or heterologous total IgG (purified from healthy blood in normal mice) effectively reduced the severity of AD symptoms and decreased epidermal and dermal thickness as well as mast cells in skin lesions. Additionally, AWB acupoint injection was found to upregulate FoxP3+, IL-10+ and IFN-γ+ CD4+T cells in murine spleen, suppressing the production of IgE antibodies and increasing that of IgG antibodies in the serum. Furthermore, both AWB and autologous total IgG administrations significantly elevated FoxP3 expression, mRNA levels of IL-10 and IFN-γ in dorsal skin lesions. However, acupoint injection of heterologous total IgG had no effect on regulatory T (Treg) and Th1 cells modulation. Conclusion: These findings suggest that the therapeutic effects of A-AHT on AD are mediated by IgG-induced activation of Treg cells.

Bouncing Dynamics of Drops' Successive Off-Center Impact.

Bouncing dynamics of a trailing drop off-center impacting a leading drop with varying time intervals and Weber numbers are investigated experimentally. Whether the trailing drop impacts during the spreading or receding process of the leading drop is determined by the time interval. For a short time interval of 0.15 ≤ Δt* ≤ 0.66, the trailing drop impacts during the spreading of the leading drop, and the drops completely coalesce and rebound; for a large time interval of 0.66 < Δt* ≤ 2.21, the trailing drop impacts during the receding process, and the drops partially coalesce and rebound. Whether the trailing drop directly impacts the surface or the liquid film of the leading drop is determined by the Weber number. The trailing drop impacts the surface directly at moderate Weber numbers of 16.22 ≤ We ≤ 45.42, while it impacts the liquid film at large Weber numbers of 45.42 < We ≤ 64.88. Intriguingly, when the trailing drop impacts the surface directly or the receding liquid film, the contact time increases linearly with the time interval but independent of the Weber number; when the trailing drop impacts the spreading liquid film, the contact time suddenly increases, showing that the force of the liquid film of the leading drop inhibits the receding of the trailing drop. Finally, a theoretical model of the contact time for the drops is established, which is suitable for different impact scenarios of the successive off-center impact. This study provides a quantitative relationship to calculate the contact time of drops successively impacting a superhydrophobic surface, facilitating the design of anti-icing surfaces.

Fully Integrated Multiplexed Wristwatch for Real-Time Monitoring of Electrolyte Ions in Sweat.

Considerable progress has already been made in sweat sensors based on electrochemical methods to realize real-time monitoring of biomarkers. However, realizing long-term monitoring of multiple targets at the atomic level remains extremely challenging, in terms of designing stable solid contact (SC) interfaces and fully integrating multiple modules for large-scale applications of sweat sensors. Herein, a fully integrated wristwatch was designed using mass-manufactured sensor arrays based on hierarchical multilayer-pore cross-linked N-doped porous carbon coated by reduced graphene oxide (NPCs@rGO-950) microspheres with high hydrophobicity as core SC, and highly selective monitoring simultaneously for K+, Na+, and Ca2+ ions in human sweat was achieved, exhibiting near-Nernst responses almost without forming an interfacial water layer. Combined with computed tomography, solid-solid interface potential diffusion simulation results reveal extremely low interface diffusion potential and high interface capacitance (598 µF), ensuring the excellent potential stability, reversibility, repeatability, and selectivity of sensor arrays. The developed highly integrated-multiplexed wristwatch with multiple modules, including SC, sensor array, microfluidic chip, signal transduction, signal processing, and data visualization, achieved reliable real-time monitoring for K+, Na+, and Ca2+ ion concentrations in sweat. Ingenious material design, scalable sensor fabrication, and electrical integration of multimodule wearables lay the foundation for developing reliable sweat-sensing systems for health monitoring.

Targeted Restoration of GPX3 Attenuates Renal Ischemia/Reperfusion Injury by Balancing Selenoprotein Expression and Inhibiting ROS-mediated Mitochondrial Apoptosis.

BACKGROUND: Renal ischemia/reperfusion (IR) injury is the leading cause of acute kidney injury in both autologous and transplanted kidneys. Low-level glutathione peroxidase 3 (GPX3) is associated with renal IR injury. The exact mechanism of targeted GPX3 restoration in renal IR injury has yet to be determined. METHODS: The distribution of GPX3 in different tissues and organs of the body was investigated. The level of GPX3 in renal IR injury was assessed. To confirm the action of GPX3 and its mechanisms, IR models were used to introduce adeno-associated virus 9 containing GPX3, as well as hypoxia/reoxygenation-exposed normal rat kidney cells that consistently overexpressed GPX3. Reverse molecular docking was used to confirm whether GPX3 was a target of ebselen. RESULTS: GPX3 is abundant in the kidneys and decreases in expression during renal IR injury. GPX3 overexpression reduced renal IR injury and protected tubular epithelial cells from apoptosis. Proteomics analysis revealed a strong link between GPX3 and mitochondrial signaling, cellular redox state, and different expression patterns of selenoproteins. GPX3 inhibited reactive oxygen species-induced mitochondrial apoptosis and balanced the disordered expression of selenoproteins. GPX3 was identified as a stable selenoprotein that interacts with ebselen. Ebselen enhanced the level of GPX3 and reduced IR-induced mitochondrial damage and renal dysfunction. CONCLUSIONS: Targeted restoration of GPX3 attenuates renal IR injury by balancing selenoprotein expression and inhibiting reactive oxygen species-mediated mitochondrial apoptosis, indicating that GPX3 could be a potential therapeutic target for renal IR injury.

Photosynthetic carbon allocation in native and invasive salt marshes undergoing hydrological change.

Biogeochemical processes mediated by plants and soil in coastal marshes are vulnerable to environmental changes and biological invasion. In particular, tidal inundation and salinity stress will intensify under future rising sea level scenarios. In this study, the interactive effects of flooding regimes (non-waterlogging vs. waterlogging) and salinity (0, 5, 15, and 30 parts per thousand (ppt)) on photosynthetic carbon allocation in plant, rhizodeposition, and microbial communities in native (Phragmites australis) and invasive (Spartina alterniflora) marshes were investigated using mesocosm experiments and 13CO2 pulse-labeling techniques. The results showed that waterlogging and elevated salinity treatments decreased specific root allocation (SRA) of 13C, rhizodeposition allocation (RA) 13C, soil 13C content, grouped microbial PLFAs, and the fungal 13C proportion relative to total PLFAs-13C. The lowest SRA, RA, and fungal 13C proportion occurred under the combined waterlogging and high (30 ppt) salinity treatments. Relative to S. alterniflora, P. australis displayed greater sensitivity to hydrological changes, with a greater reduction in rhizodeposition, soil 13C content, and fungal PLFAs. S. alterniflora showed an earlier peak SRA but a lower root/shoot 13C ratio than P. australis. This suggests that S. alterniflora may transfer more photosynthetic carbon to the shoot and rhizosphere to facilitate invasion under stress. Waterlogging and high salinity treatments shifted C allocation towards bacteria over fungi for both plant species, with a higher allocation shift in S. alterniflora soil, revealing the species-specific microbial response to hydrological stresses. Potential shifts towards less efficient bacterial pathways might result in accelerated carbon loss. Over the study period, salinity was the primary driver for both species, explaining 33.2-50.8 % of 13C allocation in the plant-soil-microbe system. We propose that future carbon dynamics in coastal salt marshes under sea-level rise conditions depend on species-specific adaptive strategies and carbon allocation patterns of native and invasive plant-soil systems.

Phosphorylation of Mad1 at serine 18 by Mps1 is required for the full virulence of rice blast fungus, Magnaporthe oryzae.

The spindle assembly checkpoint (SAC) proteins are conserved among eukaryotes safeguarding chromosome segregation fidelity during mitosis. However, their biological functions in plant-pathogenic fungi remain largely unknown. In this study, we found that the SAC protein MoMad1 in rice blast fungus (Magnaporthe oryzae) localizes on the nuclear envelope and is dispensable for M. oryzae vegetative growth and tolerance to microtubule depolymerizing agent treatment. MoMad1 plays an important role in M. oryzae infection-related development and pathogenicity. The monopolar spindle 1 homologue in M. oryzae (MoMps1) interacts with MoMad1 through its N-terminal domain and phosphorylates MoMad1 at Ser-18, which is conserved within the extended N termini of Mad1s from fungal plant pathogens. This phosphorylation is required for maintaining MoMad1 protein abundance and M. oryzae full virulence. Similar to the deletion of MoMad1, treatment with Mps1-IN-1 (an Mps1 inhibitor) caused compromised appressorium formation and decreased M. oryzae virulence, and these defects were dependent on its attenuating MoMad1 Ser-18 phosphorylation. Therefore, our study indicates the function of Mad1 in rice blast fungal pathogenicity and sheds light on the potential of blocking Mad1 phosphorylation by Mps1 to control crop fungal diseases.

Highly Accurate Determination of the Total Amount of Pb2+ and Pb(OH)+ in a Natural Water Environment Revealed by Dynamic Simulation and DFT Calculation: Benefit from the Electron Inverse Effect of Pt Nanoclusters over Defective g-C3N4.

Although utilizing nanomaterial-modified electrodes for lead ion detection has achieved great success, most of them are carried out under acidic conditions and ignore the variation of Pb(II) speciation at different pH conditions, leading to the potential inaccuracy of Pb(II) detection in a neutral natural water environment. Thus, designing a novel catalyst with high accuracy for the detection of various forms of the total amount of Pb(II) (Pb2+ and Pb(OH)+) in neutral waters is significant. Herein, Pt nanoclusters (Pt NCs) were elaborately constructed and stabilized on the Co single-atom-doped g-C3N4 with abundant N vacancies (Pt NCs/VN-C3N4), which achieved the ultrasensitive detection (102.16 µM µA-1) of Pb(II) in neutral conditions. The dynamic simulation and theoretical calculations reveal that the parallel deposition of Pb2+ and Pb(OH)+ occurs on the electrode surface modified by Pt NCs/VN-C3N4, and the current peaks of Pb(II) are cocontributed by Pb2+ and Pb(OH)+ species. An "electron inverse" phenomenon in Pt NCs/VN-C3N4 from the VN-C3N4 substrate to Pt NCs endows Pt NCs in an electron-rich state, serving as active centers to promote rapid and efficient reduction for both Pb2+ and Pb(OH)+, facilitating the accurate detection of the total amount of Pb(II) in all forms in the actual water environment.

Accurate prediction bioaccessibility of PAHs in soil-earthworm system by novel magnetic solid phase extraction technique.

Conventional chemical extraction methods may lead to overestimate or underestimate bioaccessibility due to their inability to provide realistic kinetic information regarding PAHs in soils. In this study, we propose the use of magnetic solid phase extraction (MSPE) technique for assessing the bioaccessibility of PAHs in the soil-earthworm system. Firstly, a novel polydopamine-coated magnetic core-shell microspheres (Fe3O4-C16@PDA) was developed by a one-pot sol-gel and self-polymerization method. The PDA coatings not only enhance the hydrophilicity of material surfaces but also exhibit excellent biocompatibility. The maximum adsorption capacity of Fe3O4-C16@PDA for 16 PAHs was 52.72 mg g-1, indicating that the proposed material fulfills the assessment requirements for highly contaminated soil. To compare the measurement of PAHs and their uptake by earthworms (Eisenia fetida), experiments were conducted using four different soils with varying properties. The desorption kinetics data obtained from these experiments demonstrated that the capability of the MSPE in accurately predicting the bioavailable portions of PAHs. After a 28-day exposure, the best predictor of bioavailable PAHs in earthworms was MSPE method exhibited the highest correlation coefficient (R2 > 0.90), and its slopes in the four soils were 0.972, 0.961, 1.012, and 0.962, respectively, all close to 1. These results demonstrate that the MSPE method successfully mimics the conditions encountered in soil-earthworm systems and effectively assess bioaccessibility of PAHs in soils.

Unified Strategy Enables the Collective Syntheses of Structurally Diverse Indole Alkaloids.

Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.

Inactivated recombinant influenza vaccine: the promising direction for the next generation of influenza vaccine.

INTRODUCTION: Vaccination is the most effective method to control the prevalence of seasonal influenza and the most widely used influenza vaccine is the inactivated influenza vaccine (IIV). Each season, the influenza vaccine must be updated to be most effective against current circulating variants. Therefore, developing a universal influenza vaccine (UIV) that can elicit both broad and durable protection is of the utmost importance. AREA COVERED: This review summarizes and compares the available influenza vaccines in the market and inactivation methods used for manufacturing IIVs. Then, we discuss the latest progress of the UIV development in the IIV format and the challenges to address for moving these vaccine candidates to clinical trials and commercialization. The literature search was based on the Centers for Disease Control and Prevention (CDC) and the PubMed databases. EXPERT OPINION: The unmet need for UIV is the primary aim of developing the next generation of influenza vaccines. The IIV has high antigenicity and a refined manufacturing process compared to most other formats. Developing the UIV in IIV format is a promising direction with advanced biomolecular technologies and next-generation adjuvant. It also inspires the development of universal vaccines for other infectious diseases.

Cyclin-dependent kinase inhibitor 1A inhibits pyroptosis to enhance human lung adenocarcinoma cell radioresistance by promoting DNA repair.

Purpose: One of the best anticancer treatments available is radiotherapy, which can be used either alone or in conjunction with other forms of treatment including chemotherapy and surgery. Nevertheless, a number of biochemical and physiological processes that react to ionizing radiation might provide tumor cells radioresistance, which makes radiotherapy ineffective. It has been found that CDKN1A regulates DNA damage repair, which contributes to tumor radioresistance. However, the precise mechanism is still unknown. Therefore, this study aimed to explore the mechanisms underlying CDKN1A-enhanced radioresistance in tumor cells. Methods: Cells were irradiated with 4 Gy after CDKN1A overexpression or knockdown. CDKN1A expression was measured using real-time PCR, cell viability was evaluated using cell counting kit-8 and colony formation assays, and cytotoxicity was assessed using a lactate dehydrogenase assay. Pyroptosis in cells was analyzed using caspase-1 activity assay, enzyme-linked immunosorbent assay, and flow cytometry. Inflammation activation was detected through a co-immunoprecipitation assay. Activation of pyroptosis-related proteins was analyzed using immunohistochemistry, Western blot, and immunofluorescence. Tumor radioresistance in vivo was evaluated in a mouse xenograft model. Results: Radiotherapy upregulated CDKN1A expression, which promoted lung adenocarcinoma cell survival. CDKN1A influenced radiation-induced pyroptosis in A549, which mainly depended on inhibiting the activation of the AIM2 inflammasome by promoting DNA repair. Additionally, CDKN1A upregulation enhanced A549 xenograft tumor radioresistance by inhibiting radiation-induced pyroptosis in vivo. Conclusions: CDKN1A inhibits pyroptosis to enhance the radioresistance of lung adenocarcinoma cells by promoting DNA repair. This study may serve as a reference for developing novel targeted therapies against cancer.

Multi-COBRA hemagglutinin formulated with cGAMP microparticles elicit protective immune responses against influenza viruses.

Influenza viruses cause a common respiratory disease known as influenza. In humans, seasonal influenza viruses can lead to epidemics, with avian influenza viruses of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against seasonal and pre-pandemic influenza virus strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines that promotes type I interferons production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in a mouse model for antibody responses and protection against viral challenge. Serological analysis showed that cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccines elicited robust antigen-specific antibody responses after a prime-boost vaccination and antibody titers were further enhanced after second boost. Compared to COBRA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI antibody responses against COBRA vaccination. The HAI antibody titers were not significantly different between cGAMP MPs adjuvanted monovalent and multivalent COBRA vaccine groups for most of the viruses tested in panels. The cGAMP MPs adjuvanted COBRA vaccines groups had higher antigen-specific IgG2a binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated disease caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.

MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.

BACKGROUND: Proteasome inhibitors (PIs) are one of the most important classes of drugs for the treatment of multiple myeloma (MM). However, almost all patients with MM develop PI resistance, resulting in therapeutic failure. Therefore, the mechanisms underlying PI resistance in MM require further investigation. METHODS: We used several MM cell lines to establish PI-resistant MM cell lines. We performed RNA microarray and EccDNA-seq in MM cell lines and collected human primary MM samples to explore gene profiles. We evaluated the effect of MUC20 on cuproptosis of PI-resistant MM cells using Co-immunoprecipitation (Co-IP), Seahorse bioenergetic profiling and in vivo assay. RESULTS: This study revealed that the downregulation of Mucin 20 (MUC20) could predict PI sensitivity and outcomes in MM patients. Besides, MUC20 attenuated PI resistance in MM cells by inducing cuproptosis via the inhibition of cyclin-dependent kinase inhibitor 2 A expression (CDKN2A), which was achieved by hindering MET proto-oncogene, receptor tyrosine kinase (MET) activation. Moreover, MUC20 suppressed MET activation by repressing insulin-like growth factor receptor-1 (IGF-1R) lactylation in PI-resistant MM cells. This study is the first to perform extrachromosomal circular DNA (eccDNA) sequencing for MM, and it revealed that eccDNA induced PI resistance by amplifying kinesin family member 3 C (KIF3C) to reduce MUC20 expression in MM. CONCLUSION: Our findings indicated that MUC20 regulated by eccDNA alleviates PI resistance of MM by modulating cuproptosis, which would provide novel strategies for the treatment of PI-resistant MM.

BRASSINOSTEROID-SIGNALING KINASE1 associates with and is required for cysteine protease RESPONSE TO DEHYDRATION 19-mediated disease resistance in Arabidopsis.

The receptor-like cytoplasmic kinase BRASSINOSTEROID-SIGNALING KINASE1 (BSK1) interacts with pattern recognition receptor (PRR) FLAGELLIN SENSING2 (FLS2) and positively regulates plant innate immunity in Arabidopsis thaliana. However, the molecular components involved in BSK1-mediated immune signaling remain largely unknown. To further explore the molecular mechanism underlying BSK1-mediated disease resistance, we screened two cysteine proteases, RESPONSE TO DEHYDRATION 19 (RD19) and RD19-LIKE 2 (RDL2), as BSK1-binding partners. Overexpression of RD19, but not RDL2, displayed an autoimmune phenotype, presenting programmed cell death and enhanced resistance to multiple pathogens. Interestingly, RD19-mediated immune activation depends on BSK1, as knockout of BSK1 in RD19-overexpressing plants rescued their autoimmunity and abolished the increased resistance. Furthermore, we found that BSK1 plays a positive role in maintaining RD19 protein abundance in Arabidopsis. Our results provide new insights into BSK1-mediated immune signaling and reveal a potential mechanism by which BSK1 stabilizes RD19 to promote effective immune output.