Advances in disilylation reactions to access cis/trans-1,2-disilylated and gem-disilylated alkenes.

Organosilane compounds are widely used in both organic synthesis and materials science. Particularly, 1,2-disilylated and gem-disilylated alkenes, characterized by a carbon-carbon double bond and multiple silyl groups, exhibit significant potential for subsequently diverse transformations. The versatility of these compounds renders them highly promising for applications in materials, enabling them to be valuable and versatile building blocks in organic synthesis. This review provides a comprehensive summary of methods for the preparation of cis/trans-1,2-disilylated and gem-disilylated alkenes. Despite notable advancements in this field, certain limitations persist, including challenges related to regioselectivity in the incorporation and chemoselectivity in the transformation of two nearly identical silyl groups. The primary objective of this review is to outline synthetic methodologies for the generation of these alkenes through disilylation reactions, employing silicon reagents, specifically disilanes, hydrosilanes, and silylborane reagents. The review places particular emphasis on investigating the practical applications of the C-Si bond of disilylalkenes and delves into an in-depth discussion of reaction mechanisms, particularly those reactions involving the activation of Si-Si, Si-H, and Si-B bonds, as well as the C-Si bond formation.

Emerging Human Pluripotent Stem Cell-Based Human-Animal Brain Chimeras for Advancing Disease Modeling and Cell Therapy for Neurological Disorders.

Human pluripotent stem cell (hPSC) models provide unprecedented opportunities to study human neurological disorders by recapitulating human-specific disease mechanisms. In particular, hPSC-based human-animal brain chimeras enable the study of human cell pathophysiology in vivo. In chimeric brains, human neural and immune cells can maintain human-specific features, undergo maturation, and functionally integrate into host brains, allowing scientists to study how human cells impact neural circuits and animal behaviors. The emerging human-animal brain chimeras hold promise for modeling human brain cells and their interactions in health and disease, elucidating the disease mechanism from molecular and cellular to circuit and behavioral levels, and testing the efficacy of cell therapy interventions. Here, we discuss recent advances in the generation and applications of using human-animal chimeric brain models for the study of neurological disorders, including disease modeling and cell therapy.

[Molecular dynamics simulation of force-regulated interaction between talin and Rap1b].

The binding of talin-F0 domain to ras-related protein 1b (Rap1b) plays an important role in the formation of thrombosis. However, since talin is a force-sensitive protein, it remains unclear whether and how force regulates the talin-F0/Rap1b interaction. To explore the effect of force on the binding affinity and the dynamics mechanisms of talin-F0/Rap1b, molecular dynamics simulation was used to observe and compare the changes in functional and conformational information of the complex under different forces. Our results showed that when the complex was subjected to tensile forces, there were at least two dissociation pathways with significantly different mechanical strengths. The key event determining the mechanical strength difference between the two pathways was whether the ß4 sheet of the F0 domain was pulled away from the original ß1-ß4 parallel structure. As the force increased, the talin-F0/Rap1b interaction first strengthened and then weakened, exhibiting the signature of a transition from catch bonds to slip bonds. The mechanical load of 20 pN increased the interaction index of two residue pairs, ASP 54-ARG 41 and GLN 18-THR 65, which resulted in a significant increase in the affinity of the complex. This study predicts the regulatory mechanism of the talin-F0/Rap1b interaction by forces in the intracellular environment and provides novel ideas for the treatment of related diseases and drug development.

Spatiotemporal characteristics of P-selectin-induced ß2 integrin activation of human neutrophils under flow.

Activation of integrins is crucial for recruitment of flowing leukocytes to inflammatory or injured vascular sites, but their spatiotemporal characteristics are incompletely understood. We discovered that ß2-integrin activation over the entire surface of neutrophils on immobilized P-selectin occurred via mitogen-activated protein kinase (MAPK) or non-MAPK signaling with a minute-level timescale in a force-dependent manner. In flow, MAPK signaling required intracellular Ca2+ release to activate integrin within 2 min. Integrin activation via non-MAPK signaling occurred first locally in the vicinity of ligated P-selectin glycoprotein ligand-1 (PSGL-1) within sub-seconds, and then over the entire cell surface within 1 min in an extracellular Ca2+ influx-dependent manner. The transition from a local (but rapid) to global (but slow) activation mode was triggered by ligating the freshly activated integrin. Lipid rafts, moesin, actin, and talin were involved in non-MAPK signaling. Fluid loads had a slight effect on local integrin activation with a second-level timescale, but served as enhancers of global integrin activation.

Tension Enhances the Binding Affinity of ß1 Integrin by Clamping Talin Tightly: An Insight from Steered Molecular Dynamics Simulations.

Integrin activation is a predominant step for cell-cell and cell-ECM interactions. Talin and Kindlin are mechanosensitive adaptor proteins that bind to the integrin cytoplasmic tail and mediate integrin activation, cytoskeleton rearrangement, and focal adhesion assembly. However, knowledge about how Talin and Kindlin synergistically assist integrin activation remains unclear. Here, we performed so-called "ramp-clamp" SMD simulations, which modeled the mechanosignaling from Kindlin, to investigate the effect of tension on the interaction of the ß1 integrin cytoplasmic tail with the Talin-F3 domain. The present results showed that mild but not excessive stretching enhanced the binding of integrin with Talin. This mechanical regulation on integrin affinity to Talin referred to an event cascade, in which under stretching, the integrin cytoplasmic tail adopted allostery in response to the mechanical stimulus, remodeling of integrin in favor of Talin-association ensued, and finally, a stable, close-knit complex was formed. In the cascade, the torsion angle transition of integrin was the cue for the stable interaction of the complex under tensile force. The present work suggested a model for Talin and Kindlin to synergistically activate integrin. It should help understand integrin activation and its mechanochemical regulation mechanism, integrin-related innate cellular immune responses, cell adhesion, cell-cell interaction, and integrin-related drug development.

The effect of stenosis rate and Reynolds number on local flow characteristics and plaque formation around the atherosclerotic stenosis.

PURPOSE: Atherosclerosis causes plaque to build-up in arteries. Effect of the specific local hemodynamic environment around an atherosclerotic plaque on the thrombosis formation does not remain quite clear but is believed to be crucial. The aim of this study is to uncover the flow effects on plaques formation. METHODS: To study the mechanically regulated plaque formation, the flow fields in artery blood vessels with different stenosis rates at various Reynolds numbers were simulated numerically with the two-dimensional axisymmetric models, and the hemodynamic characteristics around the plaque were scaled with stenosis rate and Reynolds number. RESULTS: The results showed that increases of both Reynolds number and stenosis rate facilitated the occurrence of flow separation phenomenon, extended recirculation zone, and upregulated the maximum normalized wall shear stress near the plaque throat section while downregulated the minimal normalized wall shear stress at the front shoulder of plaque, as it should be; in the atherosclerotic plaque leeside of the recirculation zone, an obvious catch bond region of wall shear stress might exist especially under low Reynolds number with stenosis rate smaller than 30%. This catch bond region in the plaque leeside might be responsible for the LBF (low blood flow)-enhanced formation of the atherosclerotic plaque. CONCLUSIONS: This work may provide a novel insight into understanding the biomechanical effects behind the formation and damage of atherosclerotic plaques and propose a new strategy for preventing atherosclerotic diseases.

Anticancer property of Hemp Bioactive Peptides in Hep3B liver cancer cells through Akt/GSK3ß/ß-catenin signaling pathway.

Foodborne protein hydrolysates exhibit biological activity that may be therapeutic in a number of human disease settings. Hemp peptides (HP) generated by controlled hydrolysis of hemp proteins have a number of health benefits and are of pharmaceutical value. In the present study, we produce small molecular weight HP from hemp seed and investigate its anticancer properties in Hep3B human liver cancer cells. We demonstrate that HP treatment increased apoptosis, reduced cell viability, and reduced cell migration in Hep3B human liver cancer cells without affecting the normal liver cell line L02. We correlate these phenotypes with increased cellular ROS levels, upregulation of cleaved caspase 3 and Bad, and downregulation of antiapoptotic Bcl-2. HP treatment led to increased Akt and GSK-3ß phosphorylation, with subsequent downregulation of ß-catenin, suggesting ß-catenin signaling modulation as a critical mechanism by which HP exhibits anticancer properties. Our findings suggest HP are of potential therapeutic interest for liver cancer treatment.