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Selective inhibition of the transcription elongation factor (P‐TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9‐targeted therapies are observed in vitro across various KRAS‐mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK‐MYC signaling, accompanied by the recovery of proto‐oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r‐C3‐C3a cascade, and induction of tumor immunosuppression. The "paradoxical" regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosphorylation and pause‐release of RNA polymerase II (Pol II). Co‐targeting of CDK9 and KRAS/MAPK signaling pathways eliminates ERK‐MYC activation and prevents feedback activation mediated by receptor tyrosine kinases, leading to more effective control of KRAS‐mutant cancers and overcoming KRASi resistance. Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS‐mutant patients. [ABSTRACT FROM AUTHOR]

Fruits and vegetables are an important part of the human diet, but during transportation and storage, microbial pathogens attack and spoil fruits and vegetables, causing huge economic losses to agriculture. Traditionally used chemical fungicides leave chemical residues, leading to environmental pollution and health risks. With the emphasis on food safety, biocontrol agents are attracting more and more attention due to their environmental friendliness. Endophytic fungi are present in plant tissues and do not cause host disease. The volatile organic compounds (VOCs) they produce are used to control postharvest diseases due to their significant antifungal activity, as well as their volatility, safety and environmental protection characteristics. This review provides the concept and characterization of endophytic fungal VOCs, concludes the types of endophytic fungi that release antifungal VOCs and their biological control mechanisms, as well as focuses on the practical applications and the challenges of applying VOCs as fumigants. Endophytic fungal VOCs can be used as emerging biocontrol resources to control postharvest diseases that affect fruits and vegetables. [ABSTRACT FROM AUTHOR]

Lifelong treatment is required for people living with HIV as current antiretroviral therapy (ART) does not eradicate HIV infection. Latently infected cells are essentially indistinguishable from uninfected cells and cannot be depleted by currently available approaches. This study evaluated antibody mediated transient CD4+ T cell depletion as a strategy to reduce the latent HIV reservoir. Anti-CD4 antibodies effectively depleted CD4+ T cells in the peripheral blood and tissues of humanized mice. We then demonstrate that antibody-mediated CD4+ T cell depletion of HIV infected ART-suppressed animals results in substantial reductions in cell-associated viral RNA and DNA levels in peripheral blood cells over the course of anti-CD4 antibody treatment. Recovery of CD4+ T cells was observed in all tissues analyzed except for the lung 26 days after cessation of antibody treatment. After CD4+ T cell recovery, significantly lower levels of cell-associated viral RNA and DNA were detected in the tissues of anti-CD4 antibody-treated animals. Further, an 8.5-fold reduction in the levels of intact HIV proviral DNA and a 3.1-fold reduction in the number of latently infected cells were observed in anti-CD4-antibody-treated animals compared with controls. However, there was no delay in viral rebound when ART was discontinued in anti-CD4 antibody-treated animals following CD4+ T cell recovery compared with controls. Our results suggest that transient CD4+ T cell depletion, a long-standing clinical intervention that might have an acceptable safety profile, during suppressive ART can reduce the size of the HIV reservoir in humanized mice. Author summary: Current long-term antiretroviral therapy does not eradicate cells latently infected with HIV. Latently HIV-infected cells are essentially indistinguishable from uninfected cells and cannot be easily targeted by currently available strategies. CD4+ T cells represent the most well-characterized and largest HIV reservoir. Anti-CD4 antibody mediated CD4+ T cells depletion has been proved to be reversible and well-tolerated in humans. In this study, we evaluated the effect of transient depletion of human CD4+ T cells with an anti-CD4 antibody on the size of the HIV reservoir in HIV-infected ART-suppressed humanized mice. CD4+ T cells in the peripheral blood and tissues of humanized mice were effectively depleted. Importantly, the size of the HIV reservoir was significantly decreased in anti-CD4 antibody treated animals following CD4+ T cell recovery compared with untreated controls. [ABSTRACT FROM AUTHOR]

Aims Heavy metal pollution is a serious and difficult environmental problem. With increasing heavy metal content in industrial wastewater, an environmentally friendly and efficient treatment method must be identified. Methods and results Considering the ability of endophytic bacteria to adsorb metal ions, this paper explored the heavy metal resistance, adsorption, and adsorption mechanisms and performance of S. succinus H3, an endophytic bacterium. S. succinus H3 exhibited metal resistance at 4 mM Cu2+ and 5 mM Mg2+. The adsorption rate of Cu2+ and Mg2+ ions by the live/dead strain was approximately 70%, and the adsorption capacity was positively correlated with the metal ion concentration. The kinetics and isothermal models were used to study the process of S. succinus H3 adsorption on Cu2+. It exhibits a good correlation with the Freundlich isothermal model. The N-H group, protein C=O group, polysaccharide C-O group, O-H group and some lipids are the main functional groups in the cell wall. S. succinus H3 may bond with the amine group to adsorb Mg2+ through complexation/coordination and may form a copper complex after adsorbing Cu2+. S. succinus H3 has a live adsorption rate of 15% in eight mixed metal ion systems at a 50 mg/L concentration. The study results can lay a foundation for expanding the bacterial resource pool of pollutant treatment and improving the efficiency for sewage treatment. The high heavy metal adsorption capacity of microorganisms has a decisive role in industrial wastewater treatment by microorganisms. Such microorganisms with high metal resistance and adsorption capacity to heavy metals can thrive in industrial wastewater, remove heavy metals efficiently, and greatly improve the efficiency of wastewater treatment. Conclusion The study results can lay a theoretical foundation for the use of S. succinus H3 to biologically treat heavy metal wastewater in the future. [ABSTRACT FROM AUTHOR]

[Objective] The Artemisia annua essential oil and its monomer eucalyptol were used to control postharvest diseases of Lanzhou lily to provide reference for prolonging the storage period of Lanzhou lily. [Method] This study selected fresh Lanzhou lily, Artemisia annua essential oil and its monomer eucalyptol as materials and used pathogenic bacteria Bacillus mojavensis (B-6), Trichoderma lixii (F-2), and Talaromyces tumuli (F-3) and Fusarium annulatum (F-6) as targets. The minimum inhibitory concentration and minimum bactericidal concentration of Artemisia annua essential oil and its monomer eucalyptol against Lanzhou lily pathogen B-6 were determined by the multiple dilution method. The inhibition rates were determined by fumigation method and virulence regression equations were established. Scanning electron microscope was used to observe the effect of Artemisia annua essential oil and monomer on cell wall of pathogenic bacteria. Lily with suspension of pathogenic bacteria and fungal spore was treated with Artemisia annua essential oil and monomer eucalyptol to determine the best fresh-keeping concentration. Free radical scavenging rate, browning degree, total phenol and flavonoid content, total soluble sugar content, tnalon-dialdehyde content and other post-harvest physiology biochemical indicators were also determined. [Result] Bacteriostatic results showed that Artemisia annua essential oil and its monomer 1, 8-cineole had strong in-hibitory effect on Lanzhou lily pathogenic bacteria B-6 with MIC of 1.25 mL/L and MBC of 1.25 and 5. 00 mL/L, respectively. The EC50 of essential oil of Artemisia annua to F-2, F-3 and F-6 were 0.314, 0.336 and 0. 357 mL/L, respectively. The EC50 of 1, 8-cineole to F-2, F-3 and F-6 were 0.280, 0.289 and 0. 420 mL/L, respectively. SEM showed that the essential oil of Artemisia annua and its monomer 1, 8-cineole destroyed cell wall membrane, and exudation of cell contents led to changes of mycelium morphology. The optimal control concentrations of Artemisia annua essential oil and 1, 8-cineole to Lanzhou lily inoculated with pathogens were 15.38 µ L/L. Physiological and biochemical indexes showed that Artemisia annua essential oil and its monomer 1, 8-cineole could inhibit the decline of antioxidant activity of Lanzhou lily, reduce browning rate and MDA accumulation of Lanzhou lily, increase SOD enzyme activity, and inhibit POD and PPO enzyme activities. [Conclusion] The essential oil of Artemisia annua and 1, 8-cineole had good bacteri-ostatic ability and antioxidant activity, and the best fresh-keeping concentration for Lanzhou lily was 15. 38 µL/L. [ABSTRACT FROM AUTHOR]