Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer’s disease through the antagonism of adenosine A2A receptors (A2AR). To test if A2AR activation in hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-MAPK (but not cGMP) levels in HEK293 cells, which was abolished by a point mutation at the C-terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and phospho-MAPK signaling in HEK293 cells, of pMAPK in nucleus accumbens, of c-Fos/pCREB in hippocampus and similarly enhanced long-term potentiation in hippocampus. Remarkably, optoA2AR activation triggered a preferential phospho-CREB signaling in hippocampus and impaired spatial memory performance while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops, prompts the possibility of targeting the intracellular A2AR interacting partners to selectively control different neuropsychiatric behaviors.

This study aims at improving the effectiveness of failure mode and effect analysis (FMEA) technique. FMEA is a widely used technique for identifying and eliminating known or potential failures from system, design, and process. However, in conventional FMEA, risk factors of Severity (S), Occurrence (O), and Detection difficulty (D) are simply multiplied to obtain a crisp risk priority number without considering the subjectivity and vagueness in decision makers' judgments. Besides, the weights for risk factors S, O, and D are also ignored. As a result, the effectiveness and accuracy of the FMEA are affected. To solve this problem, a novel FMEA approach for obtaining a more rational rank of failure modes is proposed. Basically, two stages of evaluation process are described: the determination of risk factors' weights and ranking the risk for the failure modes. A rough group 'Technique for Order Performance by Similarity to Ideal Solution' (TOPSIS) method is used to evaluate the risk of failure mode. The novel approach integrates the strength of rough set theory in handling vagueness and the merit of TOPSIS in modeling multi-criteria decision making. Finally, an application in steam valve system is provided to demonstrate the potential of the methodology under vague and subjective environment.

Ponseti clubfoot treatment has become more popular during the last decade because of its high initial correction rate. But the most common problem affecting the long-term successful outcome is relapse of the deformity. Non-compliance with Ponseti brace protocol is a major problem associated with relapse. Although more comfortable braces have been reported to improve the compliance, they all have the same design and no significant changes have been made to the protocols. After refinement in the Ponseti method and emphasizing the importance of brace to parents, the relapse rate has been markedly decreased. Nevertheless, there are patients who do not have any recurrence although they are not completely compliant with the brace treatment, whereas other patients have a recurrence even though they are strictly compliant with the brace treatment. The aim of this article is to review the relapse of clubfoot and the function of the brace and to develop an individualized brace protocol for each patient by analyzing the mechanism of the brace and the biomechanical properties of muscles, tendons, and ligaments.

A main obstacle to overcome during the treatment of tumors is drug resistance to chemotherapy; emerging studies indicate that a key factor contributing to this problem is the acidic tumor microenvironment. Here, we found that LASS2 expression was significantly lower in drug-resistant Michigan Cancer Foundation-7/adriamycin (MCF-7/ADR) human breast cancer cells than the drug-sensitive MCF-7 cells, and low expression of LASS2 was associated with poor prognosis in patients with breast cancer. Our results showed that the overexpression of LASS2 in MCF-7/ADR cells increased the chemosensitivity to multiple chemotherapeutic agents, including doxorubicin (Dox), whereas LASS2 knockdown in MCF-7 cells decreased the chemosensitivity. Cell-cycle analysis revealed a corresponding increase in apoptosis in the LASS2-overexpressing cells following Dox exposure, showing that the overexpression of LASS2 increased the susceptibility to Dox cytotoxicity. This effect was mediated by a significant increase in pHe (extracellular pH) and lysosomal pH, and more Dox entered the cells and stayed in the nuclei of cells. In nude mice, the combination of LASS2 overexpression and Dox significantly inhibited the growth of xenografts. Our findings suggest that LASS2 is involved in chemotherapeutic outcomes and low LASS2 expression may predict chemoresistance.