Probing the hierarchical dynamics of DNA-sperm nuclear transition protein complexes through fuzzy interaction and mesoscale condensation.

Nuclear transition protein TNP1 is a crucial player mediating histone-protamine exchange in condensing spermatids. A unique combination of intrinsic disorder and multivalent properties turns TNP1 into an ideal agent for orchestrating the formation of versatile TNP-DNA assemblies. Despite its significance, the physicochemical property and the molecular mechanism followed by TNP1 for histone replacement and DNA condensation are still poorly understood. This study reports the first-time in vitro expression and purification of human TNP1 and investigates the hierarchical dynamics of TNP1-DNA interaction using a combination of computational simulations, biochemical assays, fluorescence imaging, and atomic force microscopy. We explored three crucial facets of TNP1-DNA interactions. Initially, we delve into the molecular binding process that entails fuzzy interactions between TNP1 and DNA at the atomistic scale. Subsequently, we analyze how TNP1 binding affects the electrostatic and mechanical characteristics of DNA and influences its morphology. Finally, we study the biomolecular condensation of TNP1-DNA when subjected to high concentrations. The findings of our study set the foundation for comprehending the potential involvement of TNP1 in histone replacement and DNA condensation in spermatogenesis.

Computational insights into the conformational transition of STING: Mechanistic, energetic considerations, and the influence of crucial mutations.

STING (stimulator of interferon genes) is a crucial protein in the innate immune system's response to viral and bacterial infections. In this study, we investigated the mechanistic and energetic mechanism of the conformational transition process of STING activated by cGAMP binding. We found that the STING connector region undergoes an energetically unfavorable rotation during this process, which is compensated by the favorable interaction between cGAMP and the STING ligand binding domain. We further studied several disease-causing mutations and found that the V155 M mutation facilitates a smoother transition in the STING connector region. However, the V147L mutation exhibits unfavorable conformational transition energy, suggesting it may hinder STING activation pathway that relies on connector region rotation. Despite being labeled as hyperactive, the widespread prevalence of V147L/V147I mutations across species implies a neutral character, indicating complexity in its role. Overall, our analysis deepens the understanding of STING activation within the connector region, and targeting this region with compounds may provide an alternative approach to interfering with STING's function.

Injectable hydrogels doped with PDA nanoparticles for photothermal bacterial inhibition and rapid wound healing in vitro.

The difficulty of wound healing due to skin defects has been a great challenge due to the complex inflammatory microenvironment. Delayed wound healing severely affects the quality of life of patients and represents a significant economic burden for public health systems worldwide. Therefore, there is an urgent need for the development of novel wound dressings that can efficiently resist drug-resistant bacteria and have superior wound repair capabilities in clinical applications. In this study, we designed an adhesive antimicrobial hydrogel dressing (GMH) based on methacrylic-anhydride-modified gelatin and oxidized hyaluronic acid formed by Schiff base and UV-induced double cross-linking for infected wound repair. By inserting PDA nanoparticles into the hydrogel (GMH/PDA), the hydrogel has the capability of photothermal conversion and exhibits good photothermal antimicrobial properties under near-infrared (NIR) light irradiation, which helps to reduce the inflammatory response and avoid bacterial infections during the wound healing process. In addition, GMH/PDA hydrogel exhibits excellent injectability, allowing the hydrogel dressings to be adapted to complex wound surfaces, making them promising candidates for wound therapy. In conclusion, the multifunctional injectable GMH/PDA hydrogel possesses high antimicrobial efficiency, antioxidant properties and good biocompatibility, making them promising candidates for the treatment of infected skin wounds.

Functional mechanism of baicalein in alleviating severe acute pancreatitis-acute lung injury by blocking the TLR4/MyD88/TRIF signaling pathway.

Severe acute pancreatitis-acute lung injury (SAP-ALI) is a disease with high mortality. This study aims to explore the mechanism of baicalein on SAP-ALI in rats by blocking toll-like receptor-4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-ß (TRIF) signal pathway. The SAP-ALI rat model was established by intraperitoneal injection of 3% pentobarbital sodium (30 mg/kg), with pancreas and intestines turned over, injected with 3.5% sodium taurocholate backward into the bile-pancreatic duct at 0.1 mL/100 g for 12h, and treated with baicalein, lipopolysaccharide (LPS), miR-182 agomir, or miR-182 antagomir. The TLR4/MyD88/TRIF pathway was activated using LPS in SAP-ALI rats after baicalein treatment. Baicalein attenuated inflammatory cell infiltration, alveolar wall edema, decreased W/D ratio and levels of TLR4, MyD88, and TRIF in the lung tissues, reduced levels of inflammatory factors in pancreatic and lung tissues and BALF, diminished ROS, and elevated GSH, SOD and CAT in pancreatic and lung tissues of SAP-ALI rats. Activation of the TLR4/MyD88/TRIF pathway partly abrogated baicalein-mediated improvements in inflammation and oxidative stress in SAP-ALI rats. miR-182 targeted TLR4. miR-182 suppressed inflammation and oxidative stress in SAP-ALI rats by targeting TLR4. Inhibition of miR-182 partly nullified baicalein-mediated attenuation on inflammation and oxidative stress in SAP-ALI rats. In conclusion, baicalein can inhibit the TLR4/MyD88/TRIF pathway and alleviate inflammatory response and oxidative stress in SAP-ALI rats by upregulating miR-182 and suppressing TLR4, thus ameliorating SAP-ALI.

Electrospray Nano-Micro Composite Sodium Alginate Microspheres with Shape-Adaptive, Antibacterial, and Angiogenic Abilities for Infected Wound Healing.

Nonhealing infectious wounds, characterized by bacterial colonization, wound microenvironment destruction, and shape complexity, present an intractable problem in clinical practice. Inspired by LEGOs, building-block toys that can be assembled into desired shapes, we proposed the use of electrospray nano-micro composite sodium alginate (SA) microspheres with antibacterial and angiogenic properties to fill irregularly shaped wounds instantly. Specifically, porous poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) encapsulating basic fibroblast growth factor (bFGF) were produced by a water-in-oil-in-water double-emulsion method. Then, bFGF@MSs were blended with the SA solution containing ZIF-8 nanoparticles. The resultant solution was electrosprayed to obtain nano-micro composite microspheres (bFGF@MS/ZIF-8@SAMSs). The composite MSs' size could be regulated by PLGA MS mass proportion and electrospray voltage. Moreover, bFGF, a potent angiogenic agent, and ZIF-8, bactericidal nanoparticles, were found to release from bFGF@MS/ZIF-8@SAMSs in a controlled and sustainable manner, which promoted cell proliferation, migration, and tube formation and killed bacteria. Through experimentation on rat models, bFGF@MS/ZIF-8@SAMSs were revealed to adapt to wound shapes and accelerate infected wound healing because of the synergistic effects of antibacterial and angiogenic abilities. In summation, this study developed a feasible approach to prepare bioactive nano-micro MSs as building blocks that can fill irregularly shaped infected wounds and improve healing.