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Mechanical stress can directly activate chemical reactions by reducing the reaction energy barrier. A possible mechanism of such mechanochemical activation is structural deformation of the reactant species. However, the effect of deformation on the reaction energetics is unclear, especially, for shear stress-driven reactions. Here, we investigated shear stress-driven oligomerization reactions of cyclohexene on silica using a combination of reactive molecular dynamics simulations and ball-on-flat tribometer experiments. Both simulations and experiments captured an exponential increase in reaction yield with shear stress. Elemental analysis of ball-on-flat reaction products revealed the presence of oxygen in the polymers, a trend corroborated by the simulations, highlighting the critical role of surface oxygen atoms in oligomerization reactions. Structural analysis of the reacting molecules in simulations indicated the reactants were deformed just before a reaction occurred. Quantitative evidence of shear-induced deformation was established by comparing bond lengths in cyclohexene molecules in equilibrium and prior to reactions. Nudged elastic band calculations showed that the deformation had a small effect on the transition state energy but notably increased the reactant state energy, ultimately leading to a reduction in the energy barrier. Finally, a quantitative relationship was developed between molecular deformation and energy barrier reduction by mechanical stress.

Mechanochemical activation has created new opportunities for applications such as solvent-free chemical synthesis, polymer processing, and lubrication. However, mechanistic understanding of these processes is still limited because the mechanochemical response of a system is a complex function of many variables, including the direction of applied stress and the chemical features of the reactants in non-equilibrium conditions. Here, we studied shear-activated reactions of simple cyclic organic molecules to isolate the effect of chemical structure on reaction yield and pathway. Reactive molecular dynamics simulations were used to model methylcyclopentane, cyclohexane, and cyclohexene subject to pressure and shear stress between silica surfaces. Cyclohexene was found to be more susceptible to mechanochemical activation of oxidative chemisorption and subsequent oligomerization reactions than either methylcyclopentane or cyclohexane. The oligomerization trend was consistent with shear-driven polymerization yield measured in ball-on-flat sliding experiments. Analysis of the simulations showed the distribution of carbon atom sites at which oxidative chemisorption occurred and identified the double bond in cyclohexene as being the origin of its shear susceptibility. Lastly, the most common reaction pathways for association were identified, providing insight into how the chemical structures of the precursor molecules determined their response to mechanochemical activation.

Background: Knee osteoarthritis (KOA) is a widespread chronic condition. Depression frequently occurs among patients with KOA. The objective of this meta-analysis was to identify risk factors associated with comorbid depression in patients with KOA. Materials and Methods: A comprehensive search of the PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science databases was conducted for studies related to comorbid depression in patients with KOA. We conducted statistical analyses to obtain relevant results, followed by heterogeneity tests and assessment for publication bias. Results: The prevalence of comorbid depression among patients with KOA was 34% (95% CI, 28%–41%). Notable risk factors linked to comorbid depression in patients with KOA included female sex (relative risk [RR], 1.17; 95% CI, 1.11–1.23), obesity (mean difference [MD], 1.30; 95% CI, 0.88–1.71), use of analgesics (RR, 1.50; 95% CI, 1.38–1.63), comorbidities (MD, 0.20; 95% CI, 0.10–0.31), unmarried or widowed status (RR, 1.72; 95% CI, 1.56–1.91), bilateral knee pain (RR, 1.38; 95% CI, 1.11–1.71), high total Western Ontario and Mc-Master Universities Arthritis Index (WOMAC) score (MD, 14.92; 95% CI, 10.02–19.82), high WOMAC pain score (MD, 5.76; 95% CI, 2.86–8.67), low gait velocity (MD, −0.12; 95% CI, −0.16 to −0.09), and extended duration in the Timed Up and Go Test (MD, 1.56; 95% CI, 0.87–2.25). Conclusion: Based on the current evidence, female sex, obesity, use of analgesics, comorbidities, unmarried or widowed status, bilateral knee pain, high total WOMAC score, high WOMAC pain score, low gait velocity, and prolonged time on the Timed Up and Go Test were identified as risk factors for depression in patients with KOA. Focus should be given to these aspects when preventing depression among these patients. [Orthopedics. 2024;47(5):e225–e232.] [ABSTRACT FROM AUTHOR]

Background: Proteome‐wide Mendelian randomization studies have been increasingly utilized to identify potential drug targets for diseases. We aimed to identify potential therapeutic targets for migraine and its subtypes through the application of Mendelian randomization and co‐localization analysis methods. Methods: We utilized cis‐protein quantitative trait loci data for 1378 plasma proteins available from two studies with 7213 individuals and 35,559 individuals, respectively. Summary data for migraine and its subtypes were obtained from a genetic study involving up to 1,339,303 individuals. Proteins that passed both the discovery and validation Mendelian randomization analysis, sensitivity analysis, heterogeneity test, and pleiotropy test, were associated with ≥2 outcomes, and received strong support from co‐localization analysis (PP.H4.abf ≥0.80) and were classified as tier 1 proteins. Results: We identified three tier 1 proteins (LRP11, ITIH1, and ADGRF5), whose genes have not been previously identified as causal genes for migraine in genetic studies. LRP11 was significantly associated with the risk of any migraine (OR [odds ratio] = 0.968, 95% CI [confidence interval] = 0.955–0.981, p = 1.27 × 10−6) and significantly/suggestively associated with three migraine subtypes. ITIH1 was significantly associated with the risk of any migraine (OR = 1.044, 95% CI = 1.024–1.065, p = 1.08 × 10−5) and migraine with visual disturbances. ADGRF5 was significantly associated with the risk of any migraine (OR = 0.964, 95% CI = 0.946–0.982, p = 8.74 × 10−5) and suggestively associated with migraine with aura. The effects of LRP11 and ADGRF5 were further replicated using cerebrospinal fluid protein data. Apart from ADGRF5, there was no evidence of potential adverse consequences when modulating the plasma levels. We also identified another four proteins (PLCG1, ARHGAP25, CHGA, and MANBA) with no potential adverse consequences when modulating the plasma levels, and their genes were not reported by previous genetic studies. Conclusions: We found compelling evidence for two proteins and suggestive evidence for four proteins that could be promising targets for migraine treatment without significant adverse consequences. The corresponding genes were not reported in previous genetic studies. Future studies are needed to confirm the causal role of these proteins and explore the underlying mechanisms. [ABSTRACT FROM AUTHOR]