Chronic pain accelerates cognitive impairment by reducing hippocampal neurogenesis may via CCL2/CCR2 signaling in APP/PS1 mice.

Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD), but the mechanism underlying this association remains unclear. This was addressed in the present study by investigating the effect of chronic neuropathic pain on hippocampal neurogenesis and cognitive impairment using amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice subjected to spared-nerve injury (SNI). The Von Frey test was performed to determine the mechanical threshold of mouse hind limbs after SNI. The Morris water maze test was used to evaluate spatial learning and memory. Doublecortin-positive (DCX+), 5-bromo-2'-deoxyuridine (BrdU)+, BrdU+/neuronal nuclei (NeuN)+, and C-C motif chemokine ligand 2 (CCL2)+ neurons in the dentate gyrus of the hippocampus were detected by immunohistochemistry and immunofluorescence analysis. CCL2 and C-C chemokine receptor type 2 (CCR2) protein levels in the mouse hippocampus were analyzed by western blotting. The results showed that APP/PS1 mice with chronic neuropathic pain induced by SNI had significant learning and memory impairment. This was accompanied by increased CCL2 and CCR2 expression and decreases in the number of DCX+, BrdU+, and BrdU+/NeuN+ neurons. These results suggest that chronic neuropathic pain is associated with cognitive impairment, which may be caused by CCL2/CCR2 signaling-mediated inhibition of hippocampal neurogenesis. Thus, therapeutic strategies that alleviate neuropathic pain can potentially slow cognitive decline in patients with AD and other neurodegenerative diseases.

Cross-Binding of Four Adenosine/ATP Aptamers to Caffeine, Theophylline, and Other Methylxanthines.

The classical DNA aptamer for adenosine and ATP was selected twice using ATP as the target in 1995 and 2005, respectively. In 2022, this motif appeared four more times from selections using adenosine, ATP, theophylline, and caffeine as targets, suggesting that this aptamer can also bind methylxanthines. In this work, using thioflavin T fluorescence spectroscopy, this classical DNA aptamer showed Kd values for adenosine, theophylline, and caffeine of 9.5, 101, and 131 µM, respectively, and similar Kd values were obtained using isothermal titration calorimetry. Binding to the methylxanthines was also observed for the newly selected Ade1301 aptamer but not for the Ade1304 aptamer. The RNA aptamer for ATP also had no binding to the methylxanthines. Molecular dynamics simulations were performed using the classical DNA and RNA aptamers based on their NMR structures, and the simulation results were consistent with the experimental observations, explaining the selectivity profiles. This study suggests that a broader range of target analogues need to be tested for aptamers. For the detection of adenosine and ATP, the Ade1304 aptamer is a better choice due to its better selectivity.

Molecular dynamics study of the recognition of ATP by nucleic acid aptamers.

Despite their great success in recognizing small molecules in vitro, nucleic acid aptamers are rarely used in clinical settings. This is partially due to the lack of structure-based mechanistic information. In this work, atomistic molecular dynamics simulations are used to study the static and dynamic supramolecular structures relevant to the process of the wild-type (wt) nucleic acid aptamer recognition and binding of ATP. The effects brought about by mutation of key residues in the recognition site are also explored. The simulations reveal that the aptamer displays a high degree of rigidity and is structurally very little affected by the binding of ATP. Interaction energy decomposition shows that dispersion forces from π-stacking between ATP and the G6 and A23 nucleobases in the aptamer binding site plays a more important role in stabilizing the supramolecular complex, compared to hydrogen-bond interaction between ATP and G22. Moreover, metadynamics simulations show that during the association process, water molecules act as essential bridges connecting ATP with G22, which favors the dynamic stability of the complex. The calculations carried out on three mutated aptamer structures confirm the crucial role of the hydrogen bonds and π-stacking interactions for the binding affinity of the ATP nucleic acid aptamer.

In Vitro Light-Up Visualization of a Subunit-Specific Enzyme by an AIE Probe via Restriction of Single Molecular Motion.

Enzymes contain several subunits to maintain different biological functions. However, it remains a great challenge for specific discrimination of one subunit over another. Toward this end, the fluorescent probe TPEMA is now presented for highly specific detection of the B subunit of cytosolic creatine (CK) kinase isoenzyme (CK-B). Owing to its aggregation-induced emission property, TPEMA shows highly boosted emission toward CK-B with a fast response time and very low interference from other analytes, including the M subunit of CK (CK-M). With the aid of a Job plot assay, ITC assay and molecular dynamics simulation, it was directly confirmed that the remarkably enhanced fluorescence of TPEMA in the presence of CK-B results from the restriction of single molecular motion in the cavity. Selective wash-free fluorescence imaging of CK-B in macrophages under different treatments was successfully demonstrated.

Leader-follower game-theoretic method towards carbon-economy trade-off in a key construction project group.

Due to rapid urbanization and modernization, the construction sector now generates one third of all greenhouse gas emissions in China. Using an equilibrium strategy combined with the carbon allowance allocation, this study presents a synergistic Stackelberg model based on a construction project planning framework to deal with cumulative CO2 emissions. The bi-level model simultaneously considers the sequential decision-making relationship between the authority (leader) and the enterprises' interactive objectives and constraints. Unlike previous research, this bi-level model gives a holistic analysis of the interactivity of multiple stakeholders, thereby enabling the inherent conflicts and equilibrium between environmental protection and decision makers' profits to be reconciled and balanced. To deal with the bi-level model complexity, an interactive solution method that integrates an evolutionary mechanism and improved particle swarm optimization (IPSO) is designed for solving a construction supply planning problem. The robustness and practicality of the proposed methodology are then validated in a real world case, and sensitivity analyses under different carbon emissions quotas are also given. The results indicate that the methodology can systematically reduce carbon emissions in the Chinese construction sector, and when the authority has a strict emissions reduction altitude, construction practitioners are able to attain high carbon efficiencies; therefore, the model provides valuable strategy guidance for policymakers and business executives.