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Brain‐derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ‐synuclein, prions, and TDP‐43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood–brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non‐genetic/lifestyle factors impact this multi‐ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non‐genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under‐investment in clinical research for Asians.We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease.We describe culturally appropriate recruitment strategies and data collection protocol.ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities.We aim to implement a successful recruitment program that enrolls across three Asian subcommunities. [ABSTRACT FROM AUTHOR]

Background: Animals develop skin regional specificities to best adapt to their environments. Birds are excellent models in which to study the epigenetic mechanisms that facilitate these adaptions. Patients suffering from SATB2 mutations exhibit multiple defects including ectodermal dysplasia‐like changes. The preferential expression of SATB2, a chromatin regulator, in feather‐forming compared to scale‐forming regions, suggests it functions in regional specification of chicken skin appendages by acting on either differentiation or morphogenesis. Results: Retrovirus mediated SATB2 misexpression in developing feathers, beaks, and claws causes epidermal differentiation abnormalities (e.g. knobs, plaques) with few organ morphology alterations. Chicken β‐keratins are encoded in 5 sub‐clusters (Claw, Feather, Feather‐like, Scale, and Keratinocyte) on Chromosome 25 and a large Feather keratin cluster on Chromosome 27. Type I and II α‐keratin clusters are located on Chromosomes 27 and 33, respectively. Transcriptome analyses showed these keratins (1) are often tuned up or down collectively as a sub‐cluster, and (2) these changes occur in a temporo‐spatial specific manner. Conclusions: These results suggest an organizing role of SATB2 in cluster‐level gene co‐regulation during skin regional specification. Key Findings: SATB2 switches sub‐cluster expressions of α‐ and β‐keratin.SATB2 causes ectodermal dysplasia‐like changes in feathers, beaks, and claws.SATB2 represses MMPs and activate collagen synthesis. [ABSTRACT FROM AUTHOR]

A series of new six (anilido)‐five (thiazole) membered ring boron difluoride dyes, namely BFs, have been synthesized from the corresponding para‐ and meta‐substituted 2‐(2'‐methylaminophenyl) benzothiazoles through complexation with boron trifluoride. Depending on the substituent effect, the derivatives can switch the emission properties from fluorescence with 100 % emission yield to slim fluorescence but >90 % triplet state population and peak wavelength tuning from 490 nm to 610 nm. Compared with non‐complexed precursors, the rigid, highly planar structure and significantly red‐shifted absorption and emission for BFs indicate that the boron center facilitates the formation of a bridge leading to increased rigidity, and is also involved in π‐conjugation, increasing the transition dipole and suppressing the non‐radiative internal conversion. Together with optical ∼100 % transparent window around 325–375 nm, BFs may find unique applications, among which the fluorescence up‐conversion via triplet‐triplet annihilation is demonstrated. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) involves many risk and protective factors encompassing genetics and lived experiences. Despite disease heterogeneity, inclusion of Asian ancestry lags. In the National Alzheimer's Coordinating Center (NACC) registry, only 2.5% of patients are of Asian ancestry. Lack of inclusion is even greater in the Alzheimer Disease Genetic Consortium, where Asian‐Americans represent only 0.7% of the population, 7‐fold less than the population (5%) of Asian‐Americans over 65. Cumulatively, disparity in research negatively impacts understanding of AD risk and protective factors and led to the formation of the Asian Cohort for Alzheimer's Disease (ACAD) to address this lack of inclusion. Method: Given the paucity of Asian American and Canadian older adults in AD research, ACAD applies a community‐based participatory research (CBPR) program to recruit participants, involving research‐community‐medicine partnerships to facilitate both better health outcomes and inclusion in research. A comprehensive program of brain health education, destigmatization, and bridging access to care are important aspects developed through ACAD Outreach and in Toronto. Extensive partnerships also help drive greater awareness about AD and related dementias to ensure a thriving dialog in the community. Result: Since September 2021, the Toronto site has had interest from over 300 individuals of Chinese descent, successfully prescreened 2/3 of those and have thus far enrolled half in the study. Of completed participants, ∼50% are cognitively healthy, 20% with AD and 27% MCI, and 2/3 of participants have provided blood, despite societal reticence for blood donations. To achieve recruitment, we conducted multiple community events, including 15 virtual seminars, in addition to working with medical, long‐term care and community center partners, and using traditional print and social media. Tools to effectively community brain health education and ACAD were developed, including overcoming challenges to participation ensuring participant comfort. This has led to high referral rates (20%) indicating strong traction in the community. Conclusion: ACAD has demonstrated feasibility in recruitment of voluntary participants to study the risk and protective factors of AD amongst Asian populations and will continue to recruit as well as analyze data, providing this information back to the community as part of the CBPR tenet. [ABSTRACT FROM AUTHOR]

Background: Despite investments in AD research to combat this public health crisis, racial/ethnic minorities such as Asian Americans and Asian Canadians (ASACs) remain underrepresented in AD research including clinical trials, biomarker, and genome‐wide association studies. The Asian Cohort for Alzheimer's Disease (ACAD) is the first large AD cohort for ASACs with a focus on recruiting Chinese, Korean and Vietnamese. We present the outreach and recruitment strategies employed by the ACAD Recruitment and Outreach Workgroup (Workgroup) during the ACAD's pilot phase. Method: Community‐Based Participatory Research (CBPR) principles are embedded through all activities as a fundamental strategy to increase research participant engagement of ASACs. CBPR engages the community in all phases of research (i.e., recruitment; resource sharing; study design; data interpretation). The Workgroup was tasked with a) coordinating and monitoring recruitment activities across all 8 recruiting sites in the US and Canada; b) developing and disseminating recruitment and community outreach/education materials; c) convening the community advisory board (CAB) to elicit feedback on participant referrals, study processes, outreach/recruitment materials and to address community partner needs; d) collaborating with academic and community partners on outreach; and e) developing best practices for community outreach. Result: The Workgroup developed multilingual and culturally adapted ACAD‐wide outreach, recruitment and retention materials including study flyers, presentation template materials, animated videos, e‐cards, social media accounts and ads. ACAD CAB provided valuable input regarding study procedures and materials as well as promoting ACAD to their respective communities and networks. During the ACAD pilot phase, 26 outreach activities were conducted across sites. Given that ACAD was launched during the COVID‐19 pandemic, many (n = 16) activities were conducted online and some at community centers, clinics, senior apartments, and outdoor events, with an estimated reach of 3,500+ community members. Many (62.5%) events were conducted in English (n = 17), and others in Asian languages such as Cantonese (n = 5), Korean (n = 2), Mandarin (n = 9) and Vietnamese (n = 2). Conclusion: ACAD's multifaceted approach to outreach and recruitment aims to optimize community engagement and a step towards representation of ASACs in AD studies. The Workgroup will continue to monitor outreach/recruitment metrics and provide support for overall and site‐specific community engagement needs. [ABSTRACT FROM AUTHOR]

A turn on fluorescence probe for the rapid detection of hypochlorite (ClO−) was prepared successfully. The detection performances of this probe were studied by virtue of ultraviolet absorption and fluorescence spectroscopy. The results demonstrated that this probe displayed excellent colorimetric and noteworthy fluorescence enhancement after interaction with hypochlorite (ClO−) and showed good selectivity and sensitivity for ClO− over other analytes in solution. Due to the short reaction time, high selectivity and sensitivity, this probe was successfully used in the detection of ClO− in living cells and water samples. [ABSTRACT FROM AUTHOR]

Introduction: Precision medicine methodologies and approaches have advanced our understanding of the clinical presentation, development, progression, and management of Alzheimer's disease (AD) dementia. However, sex and gender have not yet been adequately integrated into many of these approaches. Methods: The Society for Women's Health Research Interdisciplinary Network on AD, comprised of an expert panel of scientists and clinicians, reviewed ongoing and published research related to sex and gender differences in AD. Results: The current review is a result of this Network's efforts and aims to: (1) highlight the current state‐of‐the‐science in the AD field on sex and gender differences; (2) address knowledge gaps in assessing sex and gender differences; and (3) discuss 12 priority areas that merit further research. Discussion: The exclusion of sex and gender has impeded faster advancement in the detection, treatment, and care of AD across the clinical spectrum. Greater attention to these differences will improve outcomes for both sexes. [ABSTRACT FROM AUTHOR]

Abstract: Toll‐like receptors (TLRs) are important sensors that recognize pathogen‐associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV‐induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side‐by‐side comparison of TLR9 and cyclic GMP‐AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV‐induced immune activation. The significance of TLR9 in DENV‐induced immune response is also confirmed in examination with the bone marrow‐derived DCs prepared from Tlr9‐knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen species (ROS) induction had been previously reported in 4β‐hydroxywithanolide (4βHWE)‐induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8‐oxo‐2′deoxyguanosine [8‐oxodG]) were detected in 4βHWE‐treated oral cancer (Ca9‐22) and/or normal (HGF‐1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N‐acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE‐treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine‐DNA glycolyase (Fpg)‐based comet assay and 8‐oxodG‐based flow cytometry, the 8‐oxodG expressions were higher in 4βHWE‐treated oral cancer cells than in oral normal cells. All the 4βHWE‐induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS‐mediated selective killing of oral cancer cells. [ABSTRACT FROM AUTHOR]

Taiwan has high-tech export-oriented industries, such as semiconductors and electronic equipment. The capital city area is home to the main industrial complex and has a major fault line running through it. Three out of four nuclear power stations in Taiwan are located close to the capital. Using a single-country computable general equilibrium model, we simulate a compound disaster consisting of a major earthquake and a power crisis induced by nuclear power shutdown in northern Taiwan to quantify its impact on the Taiwanese economy. Simulation results show that Taiwan's flagship industries, such as semiconductors and electronic equipment, would be severely affected by capital and labor losses in an earthquake but not in a power crisis. This implies that no policy intervention to allocate power to these industries is needed, although we are often tempted to do so in emergencies. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a leading cause of death worldwide. Despite the global impact, clinical research in AD and, in particular, clinical trials, biomarker and genome‐wide association studies are underrepresented for racial/ethnic minorities such as Asian Americans and Asian Canadians (ASAC). The Asian Cohort for Alzheimer's Disease (ACAD) is the first large AD cohort for ASAC to address this disparity, building on best practices in community recruitment and outreach strategies with the goal of identifying genetic and non‐genetic risk factors of AD in populations of Asian descent. ACAD will include individuals of Chinese, Korean and Vietnamese ancestry, representing the first multi‐cultural Asian cohort analysis for AD. Method: Community‐Based Participatory Research (CBPR) principles are embedded through all activities as a fundamental strategy to increase research participant engagement of ASAC. CBPR engages the community in all phases of research (i.e., recruitment; resource sharing; study design; data interpretation) as a collaborative process between the community and researchers that leverages each other's strengths/assets, and requires commitment to sustainability. ACAD's Recruitment and Outreach Workgroup aims to: a) coordinate and monitor recruitment activities across all 8 recruiting sites in the US and Canada; b) develop and disseminate recruitment and community outreach/education material; c) work with ACAD's community advisory board (CAB) to address community partner needs; d) work with AD and Asian community partners; and e) develop best practices for community outreach in Asian and immigrant populations. Result: We have gathered local/regional/national leaders representing the three target ASAC cultural groups (Chinese, Korean, and Vietnamese) of ACAD as our CAB. Four significant activities thus far include: curation of information for public use; translation of ACAD educational/outreach materials; development and dissemination of social media information; and, identifying outreach and enrollment metrics as enduring documents for the research and community stakeholders. Conclusion: The overarching goal of ACAD is to include this underserved and underrepresented group, reducing health disparities, while increasing our knowledge about the risk of AD among ASAC. Our multifaceted outreach and recruitment strategies will help to optimize ACAD's success in recruitment and engagement with the ASAC community. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a global health crisis on multiple levels. A major impediment to AD research is the availability of socio‐culturally and language appropriate study materials and instruments and inclusion of under‐represented minorities. To fulfill this need, we apply best practices and lessons learned to translate study materials for use in the Asian Cohort for Alzheimer's Disease's (ACAD) study of AD in Asian Americans and Asian Canadians (ASAC) with the overarching goal in inclusivity of these populations to better understand the etiology of AD. Method: Our multi‐stag translation process is guided by the World Health Organization's (WHO) process of translation (forward and reverse translation, consensus verification and reconciliation) to achieve parity with the English materials for our target groups (Chinese (simplified and traditional; Mandarin and Cantonese), Korean and Vietnamese). ACAD's collective experience partnering with aging Asian adults has revealed not only a language barrier, but also issues with socio‐cultural communication traits, and literal translations that stigmatize AD and dementia. Consequently, we have taken into account the varying perceptions and expressions of words in a social context. The translation process was implemented by a team of multi‐lingual researchers/clinicians/community leaders with extensive practical translation experience. Since language influences how a speaker views the world, we employed a cross‐section of translators and emphasized conceptual (vs. literal) culturally appropriate translations for the community. Results: To date, we have developed Asian language versions of ACAD documents (informed consent, data collection, community and social media outreach materials, website) for all our target groups and continue the process of beta‐testing our study materials (including the cognitive assessment instruments). Conclusion: The multi‐stage translation process accounts for distinctive Asian socio‐cultural‐language backgrounds, providing an important guideline for AD researchers to promote health literacy in the health and general community in an effort to reduce health disparities in underrepresented groups, like Asians. In order to ensure fidelity across languages, we will continue validating the original English version in Chinese, Korean, and Vietnamese versions in the ACAD study. [ABSTRACT FROM AUTHOR]

Background: Asian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. Roughly 21% of ASACs will be 65 years or older by 2060, underscoring the importance to understand how dementia and Alzheimer's disease (AD) affect these large sectors of the populace. By comparison, ASACs are under‐sampled in AD research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed. Method: The Asian Cohort for Alzheimer's Disease (ACAD) will be the first large dementia genetics cohort to examine genetic/non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history, experience and leadership in AD research. The National Institute on Aging (NIA) has resourced our study, which will leverage national AD research resources and facilitate collaborations with international cohorts. Result: ACAD consists of 8 recruiting sites (6 US and 2 Canada), a coordinating site, an analysis site, and 4 active workgroups. ACAD has developed a data collection packet (DCP) and pre‐screening/sample collection procedures. The Data Management Workgroup has implemented them into a central REDCap database. The Outreach Workgroup has translated the forms and are conducting an outreach campaign into Chinese (Mandarin and Cantonese), Vietnamese and Korean. The Training Workgroup has developed a training curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment. We will recruit cases of dementia, mild cognitive impairment, subjective cognitive complaint, and controls without cognitive impairment in collaboration with community partners, clinics, and nursing homes that serve Asian communities. We will collect saliva or blood for DNA/genetics and biomarker studies. Conclusion: After launching ACAD in November 2020, we built foundation materials to initiate recruitment in Spring 2021. ACAD will provide guidance for future studies to explore ASAC risk factors for AD and related dementias. In collaboration with ongoing consortium efforts in Alzheimer's Disease Genetics Consortium, trans‐ethnic insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. Our long‐term goal will be to extend ACAD to South Asians, Filipinos, and Japanese. [ABSTRACT FROM AUTHOR]

Background: As the first large Alzheimer's Disease (AD) genetics cohort for Asians in the United States and Canada, the Asian Cohort for Alzheimer's Disease (ACAD) has adapted existing instruments to collect data on sex, genetics, medical history, and lifestyle risk factors. We hypothesize that any and all of these factors impact AD risk differently for Asians. Initially ACAD focuses on US and Canadian participants of Chinese, Korean, and Vietnamese ancestry. Method: ACAD's Clinical Workgroup reviewed commonly used dementia research questionnaires, including the NACC Uniform Data Set, Religious Order Study, and NIA‐Late‐Onset AD to select, and in some cases adapt, questions that are most appropriate for ACAD. A combination of AD clinical researchers and community outreach specialists reviewed the data collection packet, administration procedures, and consensus diagnosis process for cultural sensitivity without sacrificing scientific rigor to gather non‐genetic and lifestyle risk factor data. Result: We designed the ACAD Data Collection Packet (DCP) to create a friendly dialogue with participants through a socio‐culturally and linguistically sensitive 3‐part process. The DCP consists of some instruments already validated in Chinese, Vietnamese and Korean languages to screen for cognitive impairment (Cognitive Abilities Screening Instrument (CASI) and Modified Mini‐Mental State (3MS)). Part A collects origins, Mediterranean diet compliance, and Clinical Dementia Rating scores. The self‐administered Part B uses an adaptation of the Rush Cognitive Activity Questionnaire on early‐life enrichment. Part C structures the collection of medical history and cognitive testing with CASI vs 3MS, the Common Objects Memory Test, Category (not Letter) Fluency, and the 15‐item Clock Drawing Task. This assessment is designed to be administered either remotely or face to face. Conclusion: Over the next year, we will pilot the ACAD Data Collection Packet, to set a community standard for dementia screening among Asian Americans and Canadians that can support data harmonization across epidemiological studies. While ACAD translation accommodates Chinese, Korean, and Vietnamese at this stage, we look forward to implementing additional major Asian languages. [ABSTRACT FROM AUTHOR]

Galectin-9 (Gal-9) exerts immunosuppressive effects by inducing apoptosis in T cells that produce interferon-γ and interleukin ( IL)-17. However, Gal-9 can be pro-inflammatory in lipopolysaccharide-stimulated monocytes. Using microarray analysis, we observed that Gal-9 was up-regulated in human dendritic cells ( DCs) after dengue virus ( DV) infection. The investigation into the immunomodulatory effects and mechanisms of Gal-9 in DCs exposed to DV revealed that DV infection specifically increased mRNA and protein levels of Gal-9 but not those of Gal-1 or Gal-3. Blocking p38, but not c-Jun N-terminal kinase or extracellular signal-regulated kinase ( ERK), inhibited DV-induced expression of Gal-9. Reduction in Gal-9 by small interference RNA treatment suppressed DV-stimulated migration of DCs towards the chemoattractants CCL19 and CCL21. In addition, DV-induced IL-12p40 production was reduced after knockdown of Gal-9 in DCs. Furthermore, Gal-9 deficiency suppressed DV-induced activation of nuclear factor-κB. Inhibition of DV-induced DC migration under conditions of Gal-9 deficiency was mediated through suppressing ERK activation but not by regulating the expression of CCR7, the receptor for CCL19 and CCL21. Both the reduction in IL-12 production and the suppression of ERK activity might account for the inhibition of DV-induced DC migration after knockdown of Gal-9. In summary, this study reveals the roles of Gal-9 in DV-induced migration of DCs. The findings indicate that Gal-9 might be a therapeutic target for preventing immunopathogenesis induced by DV infection. [ABSTRACT FROM AUTHOR]

A magnetic separator attached in a zig zag flow channel assembly has been fabricated to detect myoglobin on the micro particles. An anti-myoglobin conjugated magnetic hybrid and myoglobin conjugated silica micro particles were prepared and used for myoglobin detection on channel. For the detections, the competitive assay principle was followed based on affinity interaction of anti-myoglobin-myoglobin. The caliberation curve was plotted based on the deposit percentage of myoglobin conjugated silica micro particles. The calibration curve of the myoglobin showed the linear range between 1 × 10−8 - 5 × 10−11 (M) (R2 = 0.9944). The minimum detectable concentration was 300 pg/mL. Hence all that concludes that, the application of zig zag flow channel with magnetic separator has offered new, simple and rapid approach for detecting myoglobin in whole blood samples with in 30 min. [ABSTRACT FROM AUTHOR]

PEG is used to reinforce chitosan-based hydrogels through the formation of ester and amide linkages. The reinforced PEG/chitosan (RPC) hydrogels exhibit significant enhancements in tensile modulus and elongation compared with neat chitosan. Other properties are thoroughly investigated and indicate that the physicochemical and in vitro degradation properties of the RPC hydrogels depend on the amount and molecular weight of the PEG. The RPC hydrogels can control evaporative water loss at a suitable rate to maintain a moist environment. In terms of in vitro biological properties, 3T3 fibroblasts show good viability with the RPC hydrogels, which indicates that the RPC hydrogels may be used as wound dressing materials. [ABSTRACT FROM AUTHOR]

Objective Accelerated severe lupus nephritis (ASLN), with an acute onset of severe clinical manifestations and histopathologic renal lesions, may represent transformation of mild LN to a severe form of glomerulonephritis. Abnormal activation of T and B cells and/or oxidative stress may play a major role in the pathogenesis of ASLN. This study tested the hypothesis that antroquinonol, a purified compound and major effective component of Antrodia camphorata with antiinflammatory and antioxidant activities, might prevent the transformation of mild LN into higher-grade (severe) nephritis in a murine lupus model. Methods Experimental ASLN was induced in (NZB × NZW)F1 mice by twice weekly intraperitoneal injections of Salmonella-type lipopolysaccharide (LPS). Starting 2 days after the first dose of LPS, mice were treated daily with antroquinonol, administered by gavage, for different durations up to 5 weeks. Results Antroquinonol administration significantly ameliorated the proteinuria, hematuria, impairment of renal function, and development of severe renal lesions, especially cellular crescent formation, neutrophil infiltration, fibrinoid necrosis, and T cell proliferation in the glomerulus, as well as periglomerular interstitial inflammation. Mechanistic analyses revealed that antroquinonol 1) inhibited T cell activation/proliferation, but enhanced Treg cell suppression and reduced renal production of interleukin-18 (IL-18); 2) inhibited production of reactive oxygen species and nitric oxide, but increased activation of Nrf2 in the kidney; and 3) suppressed renal inflammation via blocking of NF-κB activation. Conclusion Antroquinonol may have therapeutic potential for the early treatment of ASLN via its differential regulation of T cell function and lowering of IL-18 production, but also via the promotion of Nrf2 activation. [ABSTRACT FROM AUTHOR]

A term 'bone-breaking fever' is used in Chinese medicine to describe the symptoms of patients infected with dengue virus (DV). We examined the significance of the COX-prostaglandin pathway in human DC infected by DV. We show that DV infection induced the expression of COX-2 and the production of prostaglandin E (PGE) in DC, and stimulated the DNA binding of NF-κB and the kinase activity of both IκBα kinase (IKK) α and β. DV infection also activated MAPK and AP-1 signaling. Both IκBα kinase-NF-κB and MAPK-AP-1 were upstream of COX-2 activation. Our investigation into the significance of COX-2-PGE pathway also revealed that DV infection enhances DC migration by inducing CC chemokine receptor 7 (CCR7) expression, and that blocking COX-2 or MAPK activity suppresses DV-induced DC migration. Our data also suggest that PGE can induce CCR7 expression on DC and that antagonists of the PGE receptors EP2 and EP4 suppress DV-induced DC migration. We further show that the increased CCR7 expression was observed in both DV-infected and bystander DC, suggesting the presence of secondary effects in inducing CCR7 expression. Collectively, this study reveals not only the pathways involved in COX-2 synthesis in DV-infected DC but also the autocrine action of PGE on the migration of DV-infected DC. [ABSTRACT FROM AUTHOR]

Alzheimer's disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer's disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points--during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder of unknown etiology. It has been suggested that metalloproteinases (MMPs) play important roles in the development and complications of autoimmune disorders. This article presents our research on the expression or activities of MMPs in Taiwanese T1DM patients. Methods: Levels and activities of plasma MMP-2 and MMP-9 in patients with T1DM were investigated and compared to those of control individuals by enzyme-linked immunosorbent assay and zymography. Results: Circulatory levels and activities of MMP-2 and MMP-9 in patients with T1DM were significantly higher than those in control subjects. Conclusions: MMP expression and activities are significantly increased in patients with T1DM. Our results not only document plasma MMPs levels and activities in the Taiwanese population (with a very low type 1 diabetic incidence), but also suggest that MMP expression and activity are elevated before the onset of complications in diabetic patients. [ABSTRACT FROM AUTHOR]

Background Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. Effective therapies are lacking. We have previously demonstrated that α-melanocyte-stimulating hormone (α-MSH) gene therapy protects against thioacetamide-induced acute liver failure in mice. Recent reports showed that collagen metabolism is a novel target of α-MSH. Therefore, the aim of this study is to investigate whether α-MSH gene therapy possesses anti-hepatic fibrogenic effect in mice. Methods Liver fibrosis was induced in mice by administering carbon tetrachloride (CCl4) continuously for 10 weeks. α-MSH expression plasmid was delivered via electroporation after liver fibrosis had been established. Histopathology, reverse-transcription polymerase chain reaction (RT-PCR), immunoblotting, and gelatin zymography were used to investigate its possible mechanisms of action. Results α-MSH gene therapy reversed established liver fibrosis in CCl4-treated mice. RT-PCR revealed that α-MSH gene therapy attenuated the liver TGF-β1, collagen α1, and cell adhesion molecule mRNA upregulation. Following gene transfer, both the activation of α-smooth muscle actin (α-SMA) and cyclooxygenase-2 (COX-2) was significantly attenuated. Further, α-MSH significantly increased matrix metalloproteinase (MMP) activity with tissue inhibitors of matrix metalloproteinase (TIMP) inactivation. Conclusions We have demonstrated that α-MSH gene therapy reversed established liver fibrosis in mice. It also prevented the upregulated fibrogenic and proinflammatory gene response after CCl4 administration. Its collagenolytic effect may be attributed to MMP and TIMP modulation. In summary, α-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A purple-spore, rhizosphere-inhabiting nematophagous fungus, further identified as Paecilomyces lilacinus, was found to grow on chitosanase-detecting plate. An induced endochitosanase having a molecular mass of 23 kDa was purified from the culture medium by a single cation-exchange column-chromatography step. Its optimum pH, optimum temperature and pI were found to be 6.0, 50 °C and 8.3 respectively. The N-terminal amino acid sequence of the purified enzyme was partially determined. On the basis of the partial sequence XQLPANLXXIYD and the BLAST results, the purified chitosanase was classified as a new member of the family 75 glycohydrolases. Complete hydrolysis of 95% deacetylated chitosan by the isolated chitosanase released chitotriose, chitotetraose and chitopentaose as the major hydrolytic products. Two oligosaccharides, which were further determined to be GlcN–GlcN–GlcNAc and GlcNAc–GlcN–GlcN–GlcNAc by chemical methylation followed by liquid chromatography–tandem MS analysis, were obtained after the denaturation of the purified chito-sanase. This is the first documented finding that chitosanase can be produced in a Paecilomyces strain and that it has binding affinity for specific N-acetylated oligosaccharides. [ABSTRACT FROM AUTHOR]

Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-kappaB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF-kappaB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-kappaB activities. Since Tet itself did not affect NF-kappaB binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF-kappaB upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of IkappaBalpha and inhibit nuclear translocation of p65 by blocking IkappaBalpha kinases alpha and beta activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signal-regulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-kappaB transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-costimulated but not on H(2)O(2)-induced NF-kappaB DNA-binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease-modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

1 Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. 2 We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulaied T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-κB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. 3 We showed that Tel inhibited NF-κB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-κB activities. Since Tet itself did not affect NF-κB binding lo its corresponding DNA sequence, the results suggested that Tet might regulate NF-κB upstream signaling molecules. 4 Further studies demonstrated that Tet could prevent the degradation of IκBα and inhibit nuclear translocation of p65 by blocking IκBα kinases α and β activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signalregulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-κB transcriptional activity by Tet. 5 When four Tel analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-coslimulaled but not on H2O2-induced NF-κB DNA-binding activities. 6 Our results provide the molecular basis of immunomodulation of Tet for being a potential diseasemodifying antirheumalic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

1. Irbesartan is a promising antihypertensive drug with beneficial effects on atherosclerotic processes. In the progression of atherosclerosis, human T-lymphocytes play an important role, but it is not yet known how irbesartan modulates human T-lymphocytes activation. To gain insight into the mechanisms by which irbesartan acts, we investigated its effects on human T-lymphocytes. 2. Primary human T-lymphocytes were isolated from whole blood. Cytokines were determined by ELISA. Activator protein-1 (AP-1) and related protein activities were determined by electrophoretic mobility shift assays, kinase assays. Western blotting and transfection assays. 3. Irbesartan inhibited the production of both tumor necrosis factor-alpha and interferon-gamma by activated T-cells, especially at therapeutic concentrations. Further investigation at the molecular level indicated that the inhibition of activated human T-lymphocytes specifically correlated with the downregulation of AP-1 DNA-binding activity. In the Jurkat T-cell line, irbesartan also inhibited AP-1 transcriptional activity. Finally, we revealed that irbesartan is unique in its ability to inhibit the activation of both c-Jun NH2-terminal protein kinase and p38 MAPK. 4. Our studies show that irbesartan may modulate inflammation-based atherosclerotic diseases through a cell-mediated mechanism involving suppression of human T-lymphocytes activation via downregulation of AP-1 activity. [ABSTRACT FROM AUTHOR]

Abstract Elevated levels of p25 and constitutive activation of CDK5 have been observed in AD brains. This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs. We examined p25 immunoreactivity in brains from sporadic and familial AD cases, as well as other neurologic diseases that exhibit NFT, such as Down's syndrome (DS), Pick's disease (Pick), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD). Neither the p25 immunoreactivity nor the p25/p35 ratio was elevated in the AD brains or in the other tauopathies (n = 34) compared with controls (n = 11). Although Aβ peptides have been suggested to activate calpain-mediated cleavage of p35 to p25 in cultured neurons, p25 levels in brains of TgCRND8 mice, which express high levels of brain Aβ peptides, were similar to those of non-Tg littermates. Our data suggest that high Aβ levels in brain do not activate p35 proteolysis, and p25 is unlikely to be a causative agent for NFT formation in AD or other tauopathies. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH)-induced dopaminergic neurotoxicity is thought to be associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recently, we have reported that copper/zinc(CuZn)-superoxide dismutase transgenic mice are resistant to METH-induced neurotoxicity. In the present study, we examined the role of the neuronal nitric oxide synthase (nNOS), susceptibility of nNOS knockout (KO) mice and sensitization to psychostimulants after neurotoxic doses of METH. Male Swiss Webster mice were treated with or without 7-nitroindazole (7-NI) along with METH (5 mg/kg, ip, q 3 h x 3) and were sacrificed 72 h after the last METH injection. Dopamine (DA) and dopamine transporter (DAT) binding sites were determined in striatum from saline and METH-treated animals. 7-NI completely protected against the depletion of DA, and DAT in striatum. In follow-up experiments nNOS KO mice along with appropriate control (C57BL/6N, SV129 and B6JSV129) mice were treated with METH (5 mg/kg, ip, q 3 h x 3) and were sacrificed 72 h after dosing. This schedule of METH administrations resulted in only 10-20% decrease in tissue content of DA and no apparent change in the number of DAT binding sites in nNOS KO mice. However, this regime of METH resulted in a significant decrease in the content of DA as well as DAT binding sites in the wild-type animals. Pre-exposure to single or multiple doses of METH resulted in a marked locomotion sensitization in response to METH. However, the nNOS KO mice show no sensitization in response to METH after single or multiple injections of METH. Therefore, these studies strongly suggest the role of peroxynitrite, nNOS and DA system in METH-induced neurotoxicity and behavioral sensitization. [ABSTRACT FROM AUTHOR]

The primary goal of a seam tracking robot, based on sensory feedback, is to maintain a prescribed relationship between the end effector and the workpiece throughout the whole motion of the manipulator along the nominal path. The purpose of this article is to present the essential conceptual and theoretical features of a high-speed seam tracking controller for sealant application. The general system configuration is discussed, followed by a brief account of the key aspects involved with the sensing of the seam location and subsequent correction command generation for the guidance of the robot. The theoretical considerations are followed by a detailed account of the physical implementation of the proposed system, with performance evaluation data obtained under actual working conditions. [ABSTRACT FROM AUTHOR]

Background: Autism spectrum disorder (ASD) is defined as a group of genetically and clinically heterogeneous neurodevelopmental disorders. Interplay between de novo and inherited rare variants has been suspected in the development of ASD. Methods: Here, we applied 750K oligonucleotide microarray analysis and whole‐exome sequencing (WES) to five trios from Taiwanese families with ASD. Results: The chromosomal microarray analysis revealed three representative known diagnostic copy number variants that contributed to the clinical presentation: the chromosome locations 2q13, 1q21.1q21.2, and 9q33.1. WES detected 22 rare variants in all trios, including four that were newly discovered, one of which is a de novo variant. Sequencing variants of JMJD1C, TCF12, BIRC6, and NHS have not been previously reported. A novel de novo variant was identified in NHS (p.I7T). Additionally, seven pathogenic variants, including SMPD1, FUT2, BCHE, MYBPC3, DUOX2, EYS, and FLG, were detected in four probands. One of the involved genes, SMPD1, had previously been reported to be mutated in patients with Parkinson's disease. Conclusions: These findings suggest that de novo or inherited rare variants and copy number variants may be double or multiple hits of the probands that lead to ASD. WES could be useful in identifying possible causative ASD variants. [ABSTRACT FROM AUTHOR]