Sympathy and Reflection in Hume's Philosophy: Mind, Morals, Art and Politics

Hume, as an “anatomist” of human nature, believes that “the science of man is the only solid foundation for the other sciences”. The naturalistic and experimental analysis of human nature, as it informs his epistemology, is the basis for other areas. Thus, in order fully to understand his philosophy, we need to shed light on the connection between Hume’s experimental analysis of human nature in epistemology, and his naturalistic account in ethics, aesthetics, and political philosophy. However, too often, writers on the latter are not always fully informed on his general philosophy and vice versa. A principal aim of this research is to bring together investigation of his naturalistic epistemology, and his ethics, aesthetics and political philosophy. This project brings close attention to bear on all of these areas, focusing on three key concepts: sympathy, general rule, and reflection. First, I examine the nature of sympathy. I argue against recent interpreters who use his concept of sympathy to construct a solution to the Problem of Other Minds. On my interpretation, Hume employs the concept of sympathy for his ethics, aesthetics and political philosophy, not for his epistemology. Second, I show that the concept of general rule plays an essential role in his philosophy. On my interpretation, Hume first establishes the general rules of human nature. He then establishes the general rules of his ethics, aesthetics and political philosophy. Third, I uncover the role of reflection in his philosophy. According to him, it is wrong to apply abstract reasoning to matters of fact; Instead, we should adopt the experimental reasoning that he terms “reflection” to observe and generalise matters of fact, thus establishing general rules in ethics, aesthetics and political philosophy. In this way, we can see the intimate connections between these diverse aspects of his philosophical writings

Degenerative suspensory ligament desmitis as a systemic disorder characterized by proteoglycan accumulation

BACKGROUND: Degenerative suspensory ligament desmitis (DSLD) is a debilitating disorder thought to be limited to suspensory ligaments of Peruvian Pasos, Peruvian Paso crosses, Arabians, American Saddlebreds, American Quarter Horses, Thoroughbreds, and some European breeds. It frequently leads to persistent, incurable lameness and need to euthanize affected horses. The pathogenesis remains unclear, though the disease appears to run in families. Treatment and prevention are empirical and supportive, and not effective in halting the progression of the disease. Presently, the presumptive diagnosis of DSLD is obtained from patient signalment and history, clinical examination, and ultrasonographic examination of clinically affected horses, and is confirmed at post mortem examination. Presently, there are no reliable methods of diagnosing DSLD in asymptomatic horses. The goal of this study was to characterize and define the disorder in terms of tissue involvement at the macroscopic and microscopic levels. RESULTS: We examined tissues and organs from 28 affected horses (22 Peruvian Pasos, 6 horses of other breeds) and from 8 control horses. Histopathological examination revealed the presence of excessive amounts of proteoglycans in the following tissues removed from DSLD-affected horses: suspensory ligaments, superficial and deep digital flexor tendons, patellar and nuchal ligaments, cardiovascular system, and sclerae. Electron microscopy demonstrated changes in diameters of collagen fibrils in the tendon, and in smooth muscle cells of the media of the aorta compatible with increased cell permeability in DSLD-affected cells. Separation of tendon extracts by gel chromatography revealed the presence of additional proteoglycan(s) in extracts from affected, but not control extracts. CONCLUSION: This study demonstrates for the first time that DSLD, a disease process previously thought to be limited to the suspensory ligaments of the distal limbs of affected horses, is in fact a systemic disorder involving tissues and organs with significant connective tissue component. Abnormal accumulation of proteoglycans between collagen and elastic fibers rather than specific collagen fibril abnormalities is the most prominent histological feature of DSLD. Because of this observation and because of the involvement of many other tendons and ligaments beside the suspensory ligament, and of non-ligamentous tissue we, therefore, propose that equine systemic proteoglycan accumulation or ESPA rather than DSLD is a more appropriate name for this condition

pH-responsive high-density lipoprotein-like nanoparticles to release paclitaxel at acidic pH in cancer chemotherapy

Jae-Yoon Shin,1,* Yoosoo Yang,1,* Paul Heo,1 Ji-Chun Lee,1 ByoungJae Kong,1 Jae Youl Cho,1 Keejung Yoon,1 Cheol-Su Shin,2 Jin-Ho Seo,3 Sung-Gun Kim,4 Dae-Hyuk Kweon11Department of Genetic Engineering, College of Biotechnology and Bioengineering, and Center for Human Interface Nano Technology, Sungkyunkwan University, 2APTech Research Center, Suwon, 3Department of Agricultural Biotechnology, Seoul National University, Seoul, 4Department of Biomedical Science, Youngdong University, Chungbuk, South Korea*These authors contributed equally to this workBackground: Nanoparticles undergoing physicochemical changes to release enclosed drugs at acidic pH conditions are promising vehicles for antitumor drug delivery. Among the various drug carriers, high-density lipoprotein (HDL)-like nanoparticles have been shown to be beneficial for cancer chemotherapy, but have not yet been designed to be pH-responsive.Methods and results: In this study, we developed a pH-responsive HDL-like nanoparticle that selectively releases paclitaxel, a model antitumor drug, at acidic pH. While the well known HDL-like nanoparticle containing phospholipids, phosphatidylcholine, and apolipoprotein A-I, as well as paclitaxel (PTX-PL-NP) was structurally robust at a wide range of pH values (3.8–10.0), the paclitaxel nanoparticle that only contained paclitaxel and apoA-I selectively released paclitaxel into the medium at low pH. The paclitaxel nanoparticle was stable at physiological and basic pH values, and over a wide range of temperatures, which is a required feature for efficient cancer chemotherapy. The homogeneous assembly enabled high paclitaxel loading per nanoparticle, which was 62.2% (w/w). The molar ratio of apolipoprotein A-I and paclitaxel was 1:55, suggesting that a single nanoparticle contained approximately 110 paclitaxel particles in a spherical structure with a 9.2 nm diameter. Among the several reconstitution methods applied, simple dilution following sonication enhanced the reconstitution yield of soluble paclitaxel nanoparticles, which was 0.66. As a result of the pH responsiveness, the anticancer effect of paclitaxel nanoparticles was much more potent than free paclitaxel or PTX-PL-NP.Conclusion: The anticancer efficacy of both paclitaxel nanoparticles and PTX-PL-NP was dependent on the expression of scavenger receptor class B type I, while the killing efficacy of free paclitaxel was independent of this receptor. We speculate that the pH responsiveness of paclitaxel nanoparticles enabled efficient endosomal escape of paclitaxel before lysosomal break down. This is the first report on pH-responsive nanoparticles that do not contain any synthetic polymer.Keywords: pH responsiveness, nanoparticle, apolipoprotein A-I, paclitaxe

Sensitivity Analysis of High-Pressure Methanol—Steam Reformer Using the Condensation Enthalpy of Water Vapor

A methanol–steam reformer (MSR) can safely provide hydrogen-rich fuel for a fuel cell system. Since the operating temperature of an MSR is relatively low, convective heat transfer is typically used to provide thermal energy to the endothermic reactions in the MSR. In this study, the use of phase change heat transfer to provide thermal energy to the endothermic reactions was investigated, which enhanced the temperature uniformity longitudinally along the MSR. ANSYS Fluent® software was used to investigate the performance of the reforming reactions. A comparative analysis using sensible heat and latent heat as the heat supply sources was performed. Using latent heat as a heat source achieved a lesser temperature drop than sensible heat that was under 5.29 K in the outer pipe. Moreover, a sensitivity analysis of methanol–steam-reforming reactions that use phase change heat transfer in terms of the carbon ratio, gas hourly velocity (for the inner and outer pipes of the MSR), inlet temperature (inner and outer pipes), reactor length, and operating pressure (inner pipe) was performed. When the phase change energy of water vapor is used, the wall temperature of the MSR is conveniently controlled and is uniformly distributed along the channel (standard deviation: 0.81 K). Accordingly, the methanol conversion rate of an MSR that uses phase change energy is ~4% higher than that of an MSR that employs convective heat transfer

Whole Transcriptome Analysis of Myeloid Dendritic Cells Reveals Distinct Genetic Regulation in Patients with Allergies

Dendritic cells (DCs) play critical roles in atopic diseases, orchestrating both innate and adaptive immune systems. Nevertheless, limited information is available regarding the mechanism through which DCs induce hyperresponsiveness in patients with allergies. This study aims to reveal novel genetic alterations and future therapeutic target molecules in the DCs from patients with allergies using whole transcriptome sequencing. Transcriptome sequencing of human BDCA-3+/CD11c+ DCs sorted from peripheral blood monocytes obtained from six patients with allergies and four healthy controls was conducted. Gene expression profile data were analyzed, and an ingenuity pathway analysis was performed. A total of 1638 differentially expressed genes were identified at p-values < 0.05, with 11 genes showing a log2-fold change ≥1.5. The top gene network was associated with cell death/survival and organismal injury/abnormality. In validation experiments, amphiregulin (AREG) showed consistent results with transcriptome sequencing data, with increased mRNA expression in THP-1-derived DCs after Der p 1 stimulation and higher protein expression in myeloid DCs obtained from patients with allergies. This study suggests an alteration in the expression of DCs in patients with allergies, proposing related altered functions and intracellular mechanisms. Notably, AREG might play a crucial role in DCs by inducing the Th2 immune response

Identification of Hit Compounds Using Artificial Intelligence for the Management of Allergic Diseases

This study aimed to identify and evaluate drug candidates targeting the kinase inhibitory region of suppressor of cytokine signaling (SOCS) 3 for the treatment of allergic rhinitis (AR). Utilizing an artificial intelligence (AI)-based new drug development platform, virtual screening was conducted to identify compounds inhibiting the SH2 domain binding of SOCS3. Luminescence assays assessed the ability of these compounds to restore JAK-2 activity diminished by SOCS3. Jurkat T and BEAS-2B cells were utilized to investigate changes in SOCS3 and STAT3 expression, along with STAT3 phosphorylation in response to the identified compounds. In an OVA-induced allergic rhinitis mouse model, we measured serum levels of total IgE and OVA-specific IgE, performed real-time PCR on nasal mucosa samples to quantify Th2 cytokines and IFN-γ expression, and conducted immunohistochemistry to analyze eosinophil levels. Screening identified 20 hit compounds with robust binding affinities. As the concentration of SOCS3 increased, a corresponding decrease in JAK2 activity was observed. Compounds 5 and 8 exhibited significant efficacy in restoring JAK2 activity without toxicity. Treatment with these compounds resulted in reduced SOCS3 expression and the reinstatement of STAT3 phosphorylation in Jurkat T and BEAS-2B cells. In the OVA-induced allergic rhinitis mouse model, compounds 5 and 8 effectively alleviated nasal symptoms and demonstrated lower levels of immune markers compared to the allergy group. This study underscores the promising nonclinical efficacy of compounds identified through the AI-based drug development platform. These findings introduce innovative strategies for the treatment of AR and highlight the potential therapeutic value of targeting SOCS3 in managing AR

Soft-Test/Repair of CCD-Based Digital X-Ray Instrumentation

Modern x-ray imaging systems evolve toward digitization for reduced cost, faster time-to-diagnosis and improved diagnostic confidence. For the digital x-ray systems, CCD (Charge Coupled Device) technology is commonly used to detect and digitize optical x-ray image. This paper presents a novel soft-test/repair approach to overcome the defective pixel problem in CCD (Charge Coupled Device)-based digital x-ray system through theoretical modeling and analysis of the test/repair process. There are two possible solutions to cope with the defective pixel problem in CCD; one is the hard-repair approach and another is the proposed soft-test/repair approach. Hard-repair approach employs a high-yield, expensive reparable CCD to minimize the impact of hard-defects on the CCD, which occur in the form of noise propagated through AID converter to the frame memory, Therefore, less work is needed to filter and correct the image at the end-user level while it maybe exceedingly expensive to practice. On the other hand, the proposed soft-test/repair approach is to detect and tolerate defective pixels at the digitized image level; thereby it is inexpensive to practice and on-line repair can be done for non-interrupted service. It tests the images to detect the detective pixels and filter noise at the frame memory level, and caches them in a flash memory in the controller for future repair. The controller cache keeps accumulating all the noise coordinates, and preprocesses the incoming image data from the A/D converter by repairing them. The proposed soft-test/repair approach is particularly devised to facilitate hardware level implementation ultimately for real-time tele-diagnosis. Parametric simulation results demonstrate the speed and virtual yield enhancement by using the proposed approach; thereby highly reliable, yet inexpensive soft-test/repair of CCD-based digital x-ray systems can be ultimately realized

Fault Tolerant Memory Design for HW/SW Co-Reliability in Massively Parallel Computing Systems

A highly dependable embedded fault-tolerant memory architecture for high performance massively parallel computing applications and its dependability assurance techniques are proposed and discussed in this paper. The proposed fault tolerant memory provides two distinctive repair mechanisms: the permanent laser redundancy reconfiguration during the wafer probe stage in the factory to enhance its manufacturing yield and the dynamic BIST/BISD/BISR (built-in-self-test-diagnosis-repair)-based reconfiguration of the redundant resources in field to maintain high field reliability. The system reliability which is mainly determined by hardware configuration demanded by software and field reconfiguration/repair utilizing unused processor and memory modules is referred to as HW/SW Co-reliability. Various system configuration options in terms of parallel processing unit size and processor/memory intensity are also introduced and their HW/SW Co-reliability characteristics are discussed. A modeling and assurance technique for HW/SW Co-reliability with emphasis on the dependability assurance techniques based on combinatorial modeling suitable for the proposed memory design is developed and validated by extensive parametric simulations. Thereby, design and Implementation of memory-reliability-optimized and highly reliable fault-tolerant field reconfigurable massively parallel computing systems can be achieved