Mechanistic Insights Research Articles

Regioselective Copolymerization of Glucose-Derived Allopyranoside Epoxide with Cyclic Anhydrides: Developing Precise Sugar-Functionalized Polyesters with Unique Altrose Linkages.

Uniform sugar-functionalized polyesters combine the benefits of sugar's structural diversity, biocompatibility, and biodegradability with precise postfunctionalization capabilities, making them a highly valuable class of materials with extensive application potential. However, the irregular placement of hydroxyl groups has limited the synthesis of these polyesters. Here, we present the first platform for uniform sugar-functionalized polyesters via regioselective ring-opening copolymerizations (ROCOPs) of allopyranoside anhydrosugar epoxide (1, derived from d-glucose) with cyclic anhydrides, followed by complete selective deprotection. This method yields polyesters with controlled molecular weights, narrow molecular weight distributions (D̵ < 1.19), high glass transition temperatures (up to 188 °C), and uniform hydroxyl functionality. Furthermore, the degradation of the polyesters offers an efficient route for producing the highly valuable d-altrose. Mechanistic insights, supported by DFT calculations, as well as NMR and HPLC analyses, confirm the regioselective nucleophilic attack at the C2 position of the pyranose ring. Kinetic studies reveal a first-order dependence on 1 and a zero-order dependence on the cyclic anhydrides. Additionally, these uniform sugar-functionalized polyesters can be incorporated into triblock terpolymers through one-pot/one-step or one-pot/two-step procedures, forming uniform sugar-functionalized multiblock copolymers.

Recent Advances in Single‐Atom Catalyst for Solar Energy Conversion: A Comprehensive Review and Future Outlook

AbstractSingle‐atom catalysts (SACs) are becoming increasingly recognized as highly promising catalytic materials, distinguished by their exceptional atomic efficiency, superior selectivity, and elevated activity levels. This review offers a detailed and comprehensive overview of the recent advancements in SACs, focusing on synthesis strategies, photocatalytic energy conversion applications, and advanced characterization techniques. Various synthetic approaches for fabricating atomically dispersed catalysts are elaborated concisely, emphasizing the importance of achieving precise atomic regulation on compatible supports to ensure strong metal–support interactions. Furthermore, the advanced characterization techniques by analytical tools are illustrated for a deep exploration of catalytic activity and mechanistic insights into uniformly dispersed SACs. Specifically, different kinds of support materials such as metal–organic frameworks (MOFs), their subset zeolitic imidazolate frameworks, and graphitic carbon nitride (g‐C3N4) with diverse coordination and electronic environments are examined. Further, advances in computational techniques and machine learning are transforming SACs development by improving predictive accuracy and reducing trial‐and‐error methods, thereby accelerating the discovery of stable and active catalysts. Finally, current challenges and prospects of SACs based on MOFs, and g‐C3N4 are addressed, providing valuable insights for the continued development and application of these catalysts in various industrial processes and environmental remediation efforts.

Mechanistic Insights into Sulfamethazine Degradation by Defect-Rich MnO2-Activated Peracetic Acid

Mechanistic Insights into Sulfamethazine Degradation by Defect-Rich MnO₂-Activated Peracetic Acid

Mechanistic insights into waterjet-guided laser grooving of silicon: Impact of ablation dynamics, oxide formation, and thermal stress

Waterjet-guided laser machining of silicon offers precision with minimal heat-affected zones (HAZs), but understanding the mechanisms behind laser-material interactions remains essential. This study first utilizes orthogonal experiments to reveal fundamental relationships between processing parameters (scanning cycle, laser fluence, scanning velocity, and waterjet pressure) on groove depth and the depth-to-HAZ ratio. These findings guide the in-depth investigation of laser-material mechanisms. The results indicate that the ablation rate decreases with increasing scanning cycles, a phenomenon primarily attributed to the different absorption rates of 532 nm laser light between silicon and silicon dioxide. This conclusion is supported by x-ray photoelectron spectroscopy(XPS) results, which reveal that the accumulation of silicon dioxide occurs as the scanning cycles increase. Additionally, a near-linear relation between the ablation rate and laser fluence is observed, as the ablated area is continuously exposed to high laser intensity regions. However, increasing laser fluence also leads to diminished processing quality due to greater thermal deformation in non-ablating regions. Last, increased scanning velocity is found to cause rougher surfaces, as insufficient heat diffusion leads to higher thermal stress and results in micro-crack formations. The results provide a detailed understanding of the laser-induced transformations in the material and highlight optimal conditions for reducing thermal damage while maintaining machining efficiency. This study advances the field of laser processing by offering insights into the mechanisms governing oxide formation, thermal cracking, and material deformation during silicon grooving, providing the foundation for future exploration of laser-material interaction dynamics.

Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson’s disease and parkinsonism-dementia of Guam

Mitochondrial dysfunction is a central aspect of Parkinson’s disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscores the role of α-Syn’s mitochondrial localization in inducing TOM40 degradation. PDe-related etiological factors, such as 6-hydroxydopamine or ROS/metal ions stress, which promotes α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.

COVID-19 Exacerbates Neurovascular Uncoupling and Contributes to Endothelial Dysfunction in Patients with Mild Cognitive Impairment

Mild cognitive impairment (MCI) affects nearly 20% of older adults worldwide, with no targetable interventions for prevention. COVID-19 adversely affects cognition, with &gt;70% of older adults with Long COVID presenting with cognitive complaints. Neurovascular coupling (NVC), an essential mechanism of cognitive function, declines with aging and is further attenuated in neurocognitive disorders. The effect of COVID-19 on NVC responses has yet to be addressed in older adults who are vulnerable to dementia progression. Participants with MCI and a history of COVID-19 (COV+, N = 31) and MCI participants with no history of infection (COV− N = 11) participated in this cross-sectional study to determine if COVID-19 affects cerebrocortical NVC responses and vascular function. Functional near-infrared spectroscopy was used to measure cerebrocortical NVC responses, and endothelial function was assessed via insonation of the brachial artery during a flow-mediated dilation protocol. NVC responses were elicited by the working memory n-back paradigm. NVC in the left dorsolateral prefrontal cortex and endothelial function was decreased in the COV+ group compared to the COV− group. These data provide mechanistic insight into how COVID-19 may exacerbate long-term cognitive sequela seen in older adults, highlighting the urgent need for further research and clinical trials to explore novel therapeutic interventions aimed at preserving/restoring NVC.

Influence mechanism insight of BiVO4 microstructure on its photocatalytic performance

Influence mechanism insight of BiVO4 microstructure on its photocatalytic performance

Immunotherapy for Type 1 Diabetes: Mechanistic Insights and Impact of Delivery Systems.

Type 1 Diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, leading to hyperglycemia and various complications. Despite insulin replacement therapy, there is a need for therapies targeting the underlying autoimmune response. This review aims to explore the mechanistic insights into T1D pathogenesis and the impact of delivery systems on immunotherapy. Genetic predisposition and environmental factors contribute to T1D development, triggering an immune-mediated attack on β-cells. T cells, particularly CD4+ and CD8+ T cells, play a central role in β-cell destruction. Antigen- specific immunotherapy is a unique way to modify the immune system by targeting specific antigens (substances that trigger the immune system) for immunotherapy. It aims to restore immune tolerance by targeting autoantigens associated with T1D. Nanoparticle-based delivery systems offer precise antigen delivery, promoting immune tolerance induction. Various studies have demonstrated the efficacy of nanoparticle-mediated delivery of autoantigens and immunomodulatory agents in preclinical models, and several patents have been made in T1D. Combining antigen-specific immunotherapy with β-cell regeneration strategies presents a promising approach for T1D treatment. However, challenges remain in optimizing delivery systems for targeted immune modulation while ensuring safety and efficacy.

Unraveling Copper Imbalance in Autism Spectrum Disorder: Mechanistic Insights from the Valproic Acid Mouse Model.

Abnormal copper (Cu) levels are often closely associated with neurological disorders including neurodevelopmental conditions, such as autism spectrum disorder (ASD). However, the mechanisms underlying the disruption of Cu homeostasis in critical organs, such as the brain, remain unclear. In this study, we elucidated the molecular mechanisms of Cu imbalance in the brain of a valproic acid (VPA) mouse model along with the changes in specific metabolites. Significant alterations occurred in proteins associated with primary Cu-related metabolism in specific regions of the brain (prefrontal cortex, amygdala, cerebellum, and hippocampus), resulting in a direct elevation of Cu ions within the brain tissues (control: 5.05 ± 0.61 μg/g vs model: 6.28 ± 0.81 μg/g, p = 0.015). Furthermore, the brain metabolic profiles revealed significant upregulation of lipids, particularly phospholipid metabolites. Typical neurotransmitters, for example, dopamine (DA) (p < 0.0001) and serotonin (5-HT) (p = 0.02) were upregulated in amygdala. Other small metabolites like glutathione (GSH) (p = 0.0004) also exhibited notable variation in brain. The potential impact of Cu toxicity on the signaling pathways of key metabolites was then evaluated, providing new insights into the role of Cu in metabolism of neurotransmitters in the brain. Our finding sheds molecular aberrations associated with essential element metabolism in the brain, providing new elemental perspectives for understanding the pathogenic mechanisms underlying ASD.

Maternal lipid mobilization is essential for embryonic development in the malaria vector Anopheles gambiae.

Lipid metabolism is an essential component in reproductive physiology. While lipid mobilization has been implicated in the growth of Plasmodium falciparum malaria parasites in their Anopheles vectors, the role of this process in the reproductive biology of these mosquitoes remains elusive. Here, we show that impairing lipolysis in Anopheles gambiae, the major malaria vectors, leads to embryonic lethality. Embryos derived from females in which we silenced the triglyceride lipase AgTL2 or the lipid storage droplet AgLSD1 develop normally during early embryogenesis but fail to hatch due to severely impaired metabolism. Embryonic lethality is efficiently recapitulated by exposing adult females to broad-spectrum lipase inhibitors prior to blood feeding, unveiling lipolysis as a potential target for inducing mosquito sterility. Our findings provide mechanistic insights into the importance of maternal lipid mobilization in embryonic health that may inform studies on human reproduction.

Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation.

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and in vitro studies, we show the spatiotemporal formation and material properties of p53 condensates that might dictate its function. In particular, p53 forms liquid-like condensates in the nucleus of cells, which can bind to DNA and perform transcriptional activity. However, cancer-associated mutations promote misfolding and partially rigidify the p53 condensates with impaired DNA binding ability. Irrespective of wild-type and mutant forms, the partitioning of p53 into cytoplasm leads to the condensate formation, which subsequently undergoes rapid solidification. In vitro studies show that abundant nuclear components such as RNA and nonspecific DNA promote multicomponent phase separation of the p53 core domain and maintain their liquid-like property, whereas specific DNA promotes its dissolution into tetrameric functional p53. This work provides mechanistic insights into how the life cycle and DNA binding properties of p53 might be regulated by phase separation.

Deciphering the Comprehensive Structure-Activity Relationship of Sunshinamide for Breast Cancer Therapy through Dual Modulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4 Inhibition.

Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure-activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.

A BOIMPY Dye Enables Multi-Photoinduced Electron Transfer Catalysis: Reaching Super-Reducing Properties.

An established concept to create radical intermediates is photoexcitation of a catalyst to a higher energy intermediate, subsequently leading to a photoinduced electron transfer (PET) with a reaction partner. The known concept of consecutive photoinduced electron transfer (con-PET) leads to catalytically active species even higher in energy by the uptake of two photons. Generally speaking, increased photon uptake leads to a more potent reductant. Here, we report the concept of multi-photoinduced electron transfer catalysis (>2 photons), termed multi-PET, which is enabled by photoinduced one-electron reductions of an organic dye. Further irradiation of the doubly reduced species leads to a photoexcited dianionic super-reductant, which is more potent than Li metal - one of the strongest chemical reductants known. This multi-photon process which is enabled by 390 nm LEDs allows the cleavage of strong carbon-fluorine bonds and reduction of other halides even in very electron-rich substrates. The resulting radicals are quenched by hydrogen atoms or engaged in carbon-carbon and carbon-phosphorus bond formations, highlighting the utility of multi-PET for organic chemistry. In addition, multi-PET enabled Birch-type reductions. Spectroscopic, chemical and computational investigations are presented to gain mechanistic insights.

Mechanistic Insights into Lignin's Inhibition of Gluten Digestibility: Evidence from In Vitro Static Digestion.

This study investigates the inhibitory effects of lignin on gluten digestibility and elucidates the underlying mechanism using static in vitro digestion protocols involving pepsin and pancreatin. Gluten digestibility was evaluated based on the degree of protein hydrolysis (DH), peptides' profile, and free amino acids (AAs) content. The interactions between lignin and gluten under digestive conditions and their impact on proteolytic enzyme activities were examined through various analytical techniques, including scanning electron microscopy (SEM), viscosity measurements, ζ-potential analysis, and enzyme kinetics. Results reveal that lignin significantly impairs gluten digestibility by inducing the formation of protein aggregates, leading to distinct intermediate peptides and reduced levels of key AAs such as aspartic acid, phenylalanine, proline, and histidine. These findings offer valuable insights into gluten-lignin interactions and highlight lignin's potential applications in the food industry, particularly as a functional additive to modulate nutrient digestibility.

Mechanistic Investigation of a Photoredox Cycloaddition Chain Reaction.

Photoredox catalysis is important in modern organic chemistry and the development of new synthetic methods. Mechanistic insights, particularly with photoredox chain reactions, are underdeveloped. This study combines quantum yield (QY) measurements, transient absorption spectroscopy (TAS), and electrochemical analysis to rigorously characterize the mechanism and rate constants of a ruthenium-catalyzed photoredox chain [4 + 2] cyclization between trans-anethole and isoprene. TAS and steady-state photochemical measurements (QY studies) reveal the role of oxygen in chain propagation as a secondary electron acceptor. The key kinetic competition between chain propagation and termination is identified by TAS and explored with kinetic modeling.

Mechanistic Insights into Succinic Acid as an Adjuvant for Ciprofloxacin in Treating Pseudomonas aeruginosa Growing Within Cystic Fibrosis Airway Mucus

Pseudomonas aeruginosa is a major cause of chronic respiratory infections in patients with cystic fibrosis (CF), with biofilm formation contributing to its persistence and antibiotic resistance. This study aimed to gain insights into the mechanistic action of succinic acid as a ciprofloxacin adjuvant against clinically relevant CF isolates, including small colony variants and mucoid strains, and a ciprofloxacin-resistant strain grown within CF dense mucus. Time-kill assays in artificial CF mucus, along with planktonic and surface-attached biofilm experiments, were used to assess the activity of succinic acid alone and in combination with sublethal ciprofloxacin concentrations. Succinic acid demonstrated an adjuvant effect of ciprofloxacin against P. aeruginosa grown within CF mucus at pH levels below pKa1 during the early bacterial growth stages. In examining planktonic growth and biofilms under these conditions, we found that succinic acid demonstrated strong antibacterial and antibiofilm properties. Conversely, succinic acid activity decreased at later growth stages, though it enhanced the ciprofloxacin effect, especially against mucoid biofilms. Moreover, we noted that, in dense CF mucus, succinic acid activity was attenuated compared to a non-CF environment, indicating diffusion challenges. These findings underscore the potential of succinic acid as a therapeutic adjuvant for improving antibiotic treatment outcomes and overcoming biofilm-associated resistance in CF.

Development of anti-cancer drugs for tumor-associated macrophages: a comprehensive review and mechanistic insights

This review provides an in-depth summary of the development of anti-cancer drugs for tumor-associated macrophages (TAMs), with a particular focus on the development and tissue specialization of macrophages, and factors influencing the polarization of M1 and M2 macrophages, and mechanistic insights underlying the targeting therapeutic approaches. TAMs, pivotal in the tumor microenvironment, exhibit notable plasticity and diverse functional roles. Influenced by the complex milieu, TAMs polarize into M1-type, which suppresses tumors, and M2-type, which promotes metastasis. Notably, targeting M2-TAMs is a promising strategy for tumor therapy. By emphasizing the importance of macrophages as a therapeutic target of anti-cancer drugs, this review aims to provide valuable insights and research directions for clinicians and researchers.

Exploring β-caryophyllene: a non-psychotropic cannabinoid's potential in mitigating cognitive impairment induced by sleep deprivation.

Sleep deprivation or sleep loss, a prevalent issue in modern society, is linked to cognitive impairment, leading to heightened risks of errors and accidents. Chronic sleep deprivation affects various cognitive functions, including memory, attention, and decision-making, and is associated with an increased risk of neurodegenerative diseases, cardiovascular issues, and metabolic disorders. This review examines the potential of β-caryophyllene, a dietary non-psychotropic cannabinoid, and FDA-approved flavoring agent, as a therapeutic solution for sleep loss-induced cognitive impairment. It highlights β-caryophyllene's ability to mitigate key contributors to sleep loss-induced cognitive impairment, such as inflammation, oxidative stress, neuronal death, and reduced neuroplasticity, by modulating various signaling pathways, including TLR4/NF-κB/NLRP3, MAPK, Nrf2/HO-1, PI3K/Akt, and cAMP/PKA/CREB. As a naturally occurring, non-psychotropic compound with low toxicity, β-caryophyllene emerges as a promising candidate for further investigation. The review underscores the therapeutic potential of β-caryophyllene for sleep loss-induced cognitive impairment and provides mechanistic insights into its action on crucial pathways, suggesting that β-caryophyllene could be a valuable addition to strategies aimed at combating cognitive impairment and other health issues due to sleep loss.

Smooth Muscle Mechanosensitivity Generates and Maintains Pressure Gradients Across the Intestine.

The gut, the ureter, or the Fallopian tube all transport biological fluids by generating trains of propagating smooth muscle constrictions collectively known as peristalsis. These tubes connect body compartments at different pressures. We extend here Poiseuille's experiments on liquid flow in inert tubes to an active, mechanosensitive tube: the intestine. We use as a miniature myogenic peristaltic pump model, the fetal chicken gut, and measured the flow and contractile wave propagation as a function of the initially applied pressures and pressure gradients. We dissect the molecular pathways of smooth muscle mechanosensitivity by measuring the force generated by gut rings in different pharmacological conditions. We demonstrate that smooth muscle contractions in response to stretch or pressure is mediated by L-type Ca2+ channels and IP3 receptors. We show that this positive-feedback mechanosensitive behavior can spontaneously generate pressure gradients across gut segments initially subject to equal pressure; this same mechanism tends to stabilize initially applied pressure gradients; it can act jointly or compete with the pressure gradient induced by directional peristaltic waves. We demonstrate that high pressure differentials can reverse the physiological propagation direction of contractile waves imparted by interstitial cell of Cajal pacemaker activity. We find that flow rate increases with tube length, but that the maximum pressure differential generated depends solely on smooth muscle contractile force and on the initial resting pressure applied inside the organ. We provide fundamental mechanical and hydrodynamic insight into the myogenic mechanisms of transport in the gastrointestinal tract. We scale up our results to other human peristaltic organs and discuss their implications for pathophysiology of intestinal obstruction, vesicoureteral reflux and endometriosis.

From high-dimensional committors to reactive insights.

Transition path theory (TPT) offers a powerful formalism for extracting the rate and mechanism of rare dynamical transitions between metastable states. Most applications of TPT either focus on systems with modestly sized state spaces or use collective variables to try to tame the curse of dimensionality. Increasingly, expressive function approximators such as neural networks and tensor networks have shown promise in computing the central object of TPT, the committor function, even in very high-dimensional systems. That progress prompts our consideration of how one could use such a high-dimensional function to extract mechanistic insights. Here, we present and illustrate a straightforward but powerful way to track how individual dynamical coordinates evolve during a reactive event. The strategy, which involves marginalizing the reactive ensemble, naturally captures the evolution of the dynamical coordinate's distribution, not just its mean reactive behavior.