Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance.

Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.

Molecular Evaluation of Traditional Chicken Farm-Associated Bioaerosols for Methicillin-Resistant Staphylococcus aureus Shedding.

The outbreak of airborne pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) through bioaerosol, and their molecular characterization around domestic poultry farming areas, was not completely understood. This imposes risk of a MRSA-associated health threat for the relevant livestock food production units. To address this issue, the present study investigated the role of bioaerosol in transmitting MRSA strains in poultry house settings by combining molecular typing, phylogenetic classification, antibiotic susceptibility, and virulence gene distribution patterns. The present study highlights that all 18 bioaerosol and stool samples collected were MRSA positive, with a unique set of virulence factors. Out of 57 isolated MRSA isolates, 68.4% and 19.3% consisted of SCCmec I and IV elements, respectively, which are commonly linked with hospital-acquired and livestock-associated MRSA strains. It is worth noting that the exfoliative toxin eta and etb genes were carried by 100% and 70.2% of all isolates, respectively. Only 17.5% of strains showed the presence of enterotoxin entC. These MRSA isolates were resistant to chloramphenicol (C), ciprofloxacin (CIP), clindamycin (DA), erythromycin (E), and tetracycline (T), signifying their multi-drug resistance traits. A cluster of phylogenetic analysis described that 80.7% and 15.8% of total isolates belonged to Staphylococcus aureus protein A (spa) type t002 and t548. Whereas 3.5% were reflected as a new spa type. Additionally, as per the chi-squared test score value, these two spa types (t002 and t548) have a distribution correlation with HA-MRSA and LA-MRSA in all the samples (p < 0.005, chi-squared test; degree of freedom = 1). Ultimately, this study highlights the prevalence of MRSA colonization in the conventional poultry farm environment, showing the risk of bioaerosol transmission, which needs epidemiological attention and prevention strategies.

Association between the Severity of Nonalcoholic Fatty Liver Disease and the Risk of Coronary Artery Calcification.

Background and Objectives: There are limited data on the association between severity of non-alcoholic fatty liver disease (NAFLD) and coronary artery calcification. This study investigated sonographic diagnosed NAFLD and coronary artery calcium score (CAC) as detected by cardiac multidetector computed tomography in general populations. Materials and Methods: A total of 545 patients were enrolled in this study. NAFLD was diagnosed by ultrasonography examination and CAC score were evaluated by cardiac multidetector computed tomography. The association between NAFLD and artery calcium score stage was determined by logistic regression analysis and Spearman correlation coefficient analysis. Results: Of all the participants, 437 (80.2%) had ultrasonography-diagnosed NAFLD and 242 (44%) had coronary artery calcification (CAC > 0). After adjustment for cardiovascular risk factors, the risk of developing coronary artery calcification was 1.36-fold greater in the patients with different severity of NAFLD compared to those without NAFLD (OR = 1.36, 95% CI = 1.07-1.77, p = 0.016). The highest OR for separate coronary artery calcification was 1.98 (OR = 1.98, 95% CI = 1.37-2.87, p < 0.001) in the left main artery, and the risk was still 1.71-fold greater after adjustments (OR = 1.71, 95% CI = 1.16-2.54, p = 0.007). Conclusions: This cross-sectional study demonstrated that the severity of NAFLD was associated with the presence of significant coronary artery calcification, especially in the left main coronary artery, suggesting increasing the cardiovascular risk.

AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1.

The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida-knockout mice. The PKA-AIDA-UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.

Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation.

To determine the cortical mechanism that underlies the cognitive impairment and motor disability in hereditary spastic paraplegia (HSP), nine HSP patients from a Chinese family were examined using clinical evaluation, cognitive screening, and genetic testing. Controls were matched healthy subjects. White-matter fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD; tract-based spatial statistics), cortical thickness (FreeSurfer), and subcortical gray matter (FIRST) based on T1-weighted MRI and diffusion tensor imaging were analyzed. A novel mutation in the SPAST gene (NM_014946.3, c.1321+2T>C) was detected. Patients had motor disability and low Montreal Cognitive Assessment (MoCA) scores. Patients showed significantly decreased total gray- and white-matter volumes, corpus callosum volume, cortical thickness, and subcortical gray-matter volume as well as significantly lower FA and AD values and significantly higher MD and RD values in the corpus callosum and corticospinal tract. Cortical thickness, subcortical gray-matter volume, and MoCA score were negatively correlated with disease duration. Cortical thickness in the right inferior frontal cortex was negatively correlated with Spastic Paraplegia Rating Scale score. Cortical thickness and right hippocampus volume were positively correlated with the MoCA score and subscores. In conclusion, brain damage is not restricted to the white matter in SPG4-HSP patients, and widespread gray-matter damage may account for the disease progression, cognitive impairment, and disease severity in SPG4-HSP.

Bendable InGaN Light-Emitting Nanomembranes with Tunable Emission Wavelength.

The integration of light-emitting diodes (LEDs) into the flexible devices has exhibited a great potential in the next-generation consumer electronics. In this study, we have demonstrated an exfoliated InGaN nanomembrane LED (NM-LED) separated from a GaN/sapphire substrate through an electrochemically wet etching process. The peak wavelengths blue-shifted phenomenon of the photoluminescence (PL) and the electroluminescence spectra were observed on the free-standing NM-LED compared to the nontreated LED with the same structure, which can be ascribed to the partial strain relaxation of the LED structure confirmed by the Raman spectra and the X-ray diffraction curves. A small divergent angle of the PL emission light has also been observed on the NM-LED. Moreover, the peak emission wavelength of this NM-LED can be even modulated from a red shift (521.7 nm) to a blue shift (500.4 nm) compared with that of the flat state (509.4 nm) while being curved convexly from top p-GaN:Mg side to bottom n-GaN:Si side. Our study provides an elegant way to develop a bendable light source with variable emission wavelengths through the mechanical deformation method.

Covariate-adjusted heatmaps for visualizing biological data via correlation decomposition.

Motivation: Heatmap is a popular visualization technique in biology and related fields. In this study, we extend heatmaps within the framework of matrix visualization (MV) by incorporating a covariate adjustment process through the estimation of conditional correlations. MV can explore the embedded information structure of high-dimensional large-scale datasets effectively without dimension reduction. The benefit of the proposed covariate-adjusted heatmap is in the exploration of conditional association structures among the subjects or variables that cannot be done with conventional MV. Results: For adjustment of a discrete covariate, the conditional correlation is estimated by the within and between analysis. This procedure decomposes a correlation matrix into the within- and between-component matrices. The contribution of the covariate effects can then be assessed through the relative structure of the between-component to the original correlation matrix while the within-component acts as a residual. When a covariate is of continuous nature, the conditional correlation is equivalent to the partial correlation under the assumption of a joint normal distribution. A test is then employed to identify the variable pairs which possess the most significant differences at varying levels of correlation before and after a covariate adjustment. In addition, a z-score significance map is constructed to visualize these results. A simulation and three biological datasets are employed to illustrate the power and versatility of our proposed method. Availability and implementation: GAP is available to readers and is free to non-commercial applications. The installation instructions, the user's manual, and the detailed tutorials can be found at http://gap.stat.sinica.edu.tw/Software/GAP. Supplementary information: Supplementary Data are available at Bioinformatics online.

[Sharing Perspectives on Home Healthcare].

The baby boom after World War II, coupled with the rapid advances in medical technology and public health, has led to the current rapid aging in the world's population. Countries in Asia are experiencing a faster rate of aging than most other countries around the world. Taiwan is expected to advance from an aged society to a super-aged society in the next 7~10 years. Consequently, the demand for long-term care is increasing. The focus of healthcare has changed from acute to chronic, from disease-oriented to function-oriented and from cure to care. Families, once the cornerstone of care, have become overwhelmed by the effects of the declining birthrate and aging. Encountering the public demand for a balance between healthcare and quality of life has led to the increasing role of home-based care in the medical system. The elderly-care profession is diverse and growing. The trend of transdisciplinary team which integrating care professions, nursing professions, family medicine, geriatric medicine, rehabilitation medicine, telemedicine, and medical aids with the resource of social welfare enables home health care services to better provide well-rounded medical care. Before end of life, hospice home care services increase the likelihood of dying at home in accordance with the patient's preference, easing the symptoms of terminal illness and reducing the sorrow experienced by family members. The single insurer model used by the National Health Insurance system will inevitably replace some hospital and institutional services with home health care services that more effectively and flexibly use medical resources and attenuate the increase in medical costs.

Stimulatory effect of Echinacea purpurea extract on the trafficking activity of mouse dendritic cells: revealed by genomic and proteomic analyses.

BACKGROUND: Several Echinacea species have been used as nutraceuticals or botanical drugs for "immunostimulation", but scientific evidence supporting their therapeutic use is still controversial. In this study, a phytocompound mixture extracted from the butanol fraction (BF) of a stem and leaf (S+L) extract of E. purpurea ([BF/S+L/Ep]) containing stringently defined bioactive phytocompounds was obtained using standardized and published procedures. The transcriptomic and proteomic effects of this phytoextract on mouse bone marrow-derived dendritic cells (BMDCs) were analyzed using primary cultures. RESULTS: Treatment of BMDCs with [BF/S+L/Ep] did not significantly influence the phenotypic maturation activity of dendritic cells (DCs). Affymetrix DNA microarray and bioinformatics analyses of genes differentially expressed in DCs treated with [BF/S+L/Ep] for 4 or 12 h revealed that the majority of responsive genes were related to cell adhesion or motility (Cdh10, Itga6, Cdh1, Gja1 and Mmp8), or were chemokines (Cxcl2, Cxcl7) or signaling molecules (Nrxn1, Pkce and Acss1). TRANSPATH database analyses of gene expression and related signaling pathways in treated-DCs predicted the JNK, PP2C-α, AKT, ERK1/2 or MAPKAPK pathways as the putative targets of [BF/S+L/Ep]. In parallel, proteomic analysis showed that the expressions of metabolic-, cytoskeleton- or NF-κB signaling-related proteins were regulated by treatment with [BF/S+L/Ep]. In vitro flow cytometry analysis of chemotaxis-related receptors and in vivo cell trafficking assay further showed that DCs treated with [BF/S+L/Ep] were able to migrate more effectively to peripheral lymph node and spleen tissues than DCs treated as control groups. CONCLUSION: Results from this study suggest that [BF/S+L/Ep] modulates DC mobility and related cellular physiology in the mouse immune system. Moreover, the signaling networks and molecules highlighted here are potential targets for nutritional or clinical application of Echinacea or other candidate medicinal plants.

Enhanced light collection of GaN light emitting devices by redirecting the lateral emission using nanorod reflectors.

We demonstrate a method of utilizing self-assembled nanorod array reflectors to collect the laterally propagating guided modes from a light emitting diode (LED). We measure an enhancement factor of 12.2% and 18.4%, respectively, from the sidewall emission of GaN-based LEDs encompassed with 10 and 20 microm thick nanorod array reflectors. Such enhancement is found to be omnidirectional due to a broken symmetry from a randomized distribution of the nanorod array placed along the periphery of the LED's mesa. These observations indicate that the use of nanorod reflectors can efficiently redirect the propagation of the laterally guided modes to the surface normal direction.

Genomics and proteomics of immune modulatory effects of a butanol fraction of echinacea purpurea in human dendritic cells.

BACKGROUND: Echinacea spp. extracts and the derived phytocompounds have been shown to induce specific immune cell activities and are popularly used as food supplements or nutraceuticals for immuno-modulatory functions. Dendritic cells (DCs), the most potent antigen presenting cells, play an important role in both innate and adaptive immunities. In this study, we investigated the specific and differential gene expression in human immature DCs (iDCs) in response to treatment with a butanol fraction containing defined bioactive phytocompounds extracted from stems and leaves of Echinacea purpurea, that we denoted [BF/S+L/Ep]. RESULTS: Affymetrix DNA microarray results showed significant up regulation of specific genes for cytokines (IL-8, IL-1beta, and IL-18) and chemokines (CXCL 2, CCL 5, and CCL 2) within 4 h after [BF/S+L/Ep] treatment of iDCs. Bioinformatics analysis of genes expressed in [BF/S+L/Ep]-treated DCs revealed a key-signaling network involving a number of immune-modulatory molecules leading to the activation of a downstream molecule, adenylate cyclase 8. Proteomic analysis showed increased expression of antioxidant and cytoskeletal proteins after treatment with [BF/S+L/Ep] and cichoric acid. CONCLUSION: This study provides information on candidate target molecules and molecular signaling mechanisms for future systematic research into the immune-modulatory activities of an important traditional medicinal herb and its derived phytocompounds.

GaN nanorod light emitting diode arrays with a nearly constant electroluminescent peak wavelength.

A practical process to fabricate InGaN/GaN multiple quantum well light emitting diodes (LEDs) with a self-organized nanorod structure is demonstrated. The nanorod array is realized by using nature lithography of surface patterned silica spheres followed by dry etching. A layer of spin-on-glass (SOG), which intervening the rod spacing, serves the purpose of electric isolation to each of the parallel nanorod LED units. The electroluminescence peak wavelengths of the nanorod LEDs nearly remain as constant for an injection current level between 25mA and 100mA, which indicates that the quantum confined stark effect is suppressed in the nanorod devices. Furthermore, from the Raman light scattering analysis we identify a strain relaxation mechanism for lattice mismatch layers in the nanostructure.

Methods for simultaneously identifying coherent local clusters with smooth global patterns in gene expression profiles.

BACKGROUND: The hierarchical clustering tree (HCT) with a dendrogram 1 and the singular value decomposition (SVD) with a dimension-reduced representative map 2 are popular methods for two-way sorting the gene-by-array matrix map employed in gene expression profiling. While HCT dendrograms tend to optimize local coherent clustering patterns, SVD leading eigenvectors usually identify better global grouping and transitional structures. RESULTS: This study proposes a flipping mechanism for a conventional agglomerative HCT using a rank-two ellipse (R2E, an improved SVD algorithm for sorting purpose) seriation by Chen 3 as an external reference. While HCTs always produce permutations with good local behaviour, the rank-two ellipse seriation gives the best global grouping patterns and smooth transitional trends. The resulting algorithm automatically integrates the desirable properties of each method so that users have access to a clustering and visualization environment for gene expression profiles that preserves coherent local clusters and identifies global grouping trends. CONCLUSION: We demonstrate, through four examples, that the proposed method not only possesses better numerical and statistical properties, it also provides more meaningful biomedical insights than other sorting algorithms. We suggest that sorted proximity matrices for genes and arrays, in addition to the gene-by-array expression matrix, can greatly aid in the search for comprehensive understanding of gene expression structures. Software for the proposed methods can be obtained at http://gap.stat.sinica.edu.tw/Software/GAP.

Human kallikrein 8 protease confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.

The human kallikrein 8 (KLK8) gene, a member of the human tissue kallikrein gene family, encodes a serine protease. The KLK8 protein (hK8) is known to be a favorable prognostic marker in ovarian cancer, but the biological basis of this is not understood. We found that overexpressing the KLK8 gene in highly invasive lung cancer cell lines suppresses their invasiveness. This role in invasiveness was further confirmed by the fact that inhibition of endogenous KLK8 expression with a specific short hairpin RNA reduced cancer cell invasiveness. In situ degradation and cell adhesion assays showed that proteins produced from KLK8 splice variants modify the extracellular microenvironment by cleaving fibronectin. DNA microarray experiments and staining of cells for actin filaments revealed that the degradation of fibronectin by hK8 suppresses integrin signaling and retards cancer cell motility by inhibiting actin polymerization. In addition, studies in a mouse model coupled with the detection of circulating tumor cells by quantitative PCR for the human Alu sequence showed that KLK8 suppresses tumor growth and invasion in vivo. Finally, studies of clinical specimens from patients with non-small cell lung cancer showed that the time to postoperative recurrence was longer for early-stage patients (stages I and II) with high KLK8 expression (mean, 49.9 months) than for patients with low KLK8 expression (mean, 22.9 months). Collectively, these findings show that KLK8 expression confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.