The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global ...perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.
Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ identification and quantification p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative ADNI, N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease EASE-AD). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio HR = 4.430, 95% confidence interval CI = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.
We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mechanical resonators are ubiquitous in modern information technology. With the possibility of coupling them to electromagnetic and plasmonic modes, they hold promise as the key building blocks in ...future quantum information technology. Graphene-based resonators are of interest for technological applications due to their high resonant frequencies, multiple mechanical modes and low mass. The tension-mediated nonlinear coupling between various modes of the resonator can be excited in a controllable manner. Here we engineer a graphene resonator with large frequency tunability at low temperatures, resulting in a large intermodal coupling strength. We observe the emergence of new eigenmodes and amplification of the coupled modes using red and blue parametric excitation, respectively. We demonstrate that the dynamical intermodal coupling is tunable. A cooperativity of 60 between two resonant modes of ∼100 MHz is achieved in the strong coupling regime. The ability to dynamically control the coupling between the high-frequency eigenmodes of a mechanical system opens up the possibility of quantum mechanical experiments at low temperatures.
There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how ...perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.
We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD ASY: n = 13; Control CN: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus ITG and middle frontal gyrus MFG), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione GSH: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.
In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We continuously measure the state of a superconducting quantum bit coupled to a microwave readout cavity by using a fast, ultralow-noise parametric amplifier. This arrangement allows us to observe ...quantum jumps between the qubit states in real time, and should enable quantum error correction and feedback--essential components of quantum information processing.
Rhinitis and rhinosinusitis are multifactorial disease processes in which bacteria may play a role either in infection or stimulation of the inflammatory process. Rhinosinusitis has been historically ...studied with culture-based techniques, which have implicated several common pathogens in disease states. More recently, the NIH Human Microbiome Project has examined the microbiome at a number of accessible body sites, and demonstrated differences among healthy and diseased patients. Recent DNA-based sinus studies have suggested that healthy sinuses are not sterile, as was previously believed, but the normal sinonasal microbiome has yet to be thoroughly examined. Middle meatus swab specimens were collected from 28 consecutive patients presenting with no signs or symptoms of rhinosinusitis. Bacterial colonization was assessed in these specimens using quantitative PCR and 16S rRNA pyrosequencing. All subjects were positive for bacterial colonization of the middle meatus. Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes were the most prevalent and abundant microorganisms detected. Rich and diverse bacterial assemblages are present in the sinonasal cavity in the normal state, including opportunistic pathogens typically found in the nasopharynx. This work helps establish a baseline for understanding how the sinonasal microbiome may impact diseases of the upper airways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study deals with the development of five different brake friction composites to the standard of Indian scenario brake pads by varying the different cashew friction dusts namely furfural ...modified, boron modified, boron-graphite modified, cardanol and CNSL based without varying the other ingredients. The developed brake friction composites were tested for their physical, chemical, mechanical and thermal properties as per industrial standards. The thermal stability was found for varying ingredients and the developed composites using Thermo Gravimetric Analyser. Tribological properties were analysed using full-scale inertia brake dynamometer as per JASO-C-406 Schedule. The ranking of the dyno tested friction composites was done using VIKOR and ELECTRE methods. Scanning Electron Microscopy coupled with elemental mapping was used to elucidate back transfer and surface characteristics of the dyno tested brake pads. The results revealed that boron-graphite modified friction dust-based brake pads were beneficial with good fade, wear resistance and recovery characteristics due to its thermally stable and heat dissipating characteristics.
•Utilisation of various cashew friction dusts as an ingredient in brake pads.•Boron-graphite modified friction dust based brake pads showed lower fade & higher recovery rates.•Boron-graphite modified friction dust based brake pads showed less pad and rotor wear.
Summary Background Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 ...inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. Methods We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov , number NCT00687622. Findings We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. Interpretation The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. Funding GlaxoSmithKline.
Background Chronic rhinosinusitis (CRS) is a prevalent multifactorial disease process in which bacteria are believed to play a role in the propagation of inflammation. Multiple subtypes of CRS have ...been described based on clinical and pathologic features, but a detailed examination of the sinus microbiota in patients with CRS and its clinical subtypes has yet to be performed. Objective We sought to examine the resident microbiota of CRS subtypes and determine whether bacterial diversity is a predictor of disease outcomes. Methods Sinus swabs from patients with CRS and healthy subjects collected during endoscopic sinus surgery were analyzed by means of molecular phylogenetic analysis of 16S rDNA pyrosequences. Results Fifty-six patients with CRS and 26 control subjects were studied. Biodiversity was similar between the CRS and control groups. Among the CRS subtypes examined, only 2 conditions (presence of purulence and comorbid condition of asthma) were associated with significant alterations in microbial community composition. In 27 patients with CRS who were followed postoperatively, those with better outcomes had more diverse bacterial communities present at the time of surgery, along with higher relative abundances of Actinobacteria. Conclusion Analysis of microbiota in a large cohort reveals that particular CRS phenotypes (asthma and purulence) are characterized by distinct compositions of resident bacterial communities. We found that bacterial diversity and composition are predictors of surgical outcome, promoting the concept of community ecology in patients with CRS.
Risk is a significant issue for supply chain managers. Not only must they contend with multiple dimensions of risk in decision‐making, they must reconcile decision‐making with broader organizational ...interests. This study examines the influence of organizational communication regarding supply chain risk on individual decision‐making strategies and the perceptions of risk. A multi‐stage experimental design is applied, in which decision‐makers make decisions across three dimensions of risk and adjust their risk‐taking behavior after being presented with organizational communication regarding supply chain risk levels. The relationship between organizational communication and the perceptions of supply chain risk is then explored after decision‐makers are allowed to adjust their supply chain strategies. The results suggest that decision‐makers adapt sourcing strategies in response to organizational communication regarding supply chain risk. Specifically, they make riskier decisions when the organization communicates improvements in supply chain risk levels. However, when given specific instructions to reduce risk, they do not adjust their supply chain strategies.
The aim of this study is to investigate natural cellulosic fibers extracted from Tridax procumbens plants. The obtained fibers were alkali treated for their effective usage as reinforcement in ...composites. The physical, chemical, crystallinity, thermal, wettability and surface characteristics were analyzed for raw, and alkali treated Tridax procumbens fibers (TPFs). The test results conclude that there was an increase in cellulose content with a reduction in hemicellulose, lignin, and wax upon alkali treatment. This enhanced the thermal stability, tensile strength, crystallinity, and surface roughness characteristics. The contact angle was also lesser for treated TPFs which prove its better wettability with the liquid phase. The Weibull distribution analysis was adopted for the analysis of the fiber diameter and tensile properties. Thus the considerable improvement in the properties of alkali treated TPFs would be worth for developing high-performance polymer composites.
•The aim of this study is to investigate natural cellulosic fibers extracted from Tridax procumbens plants.•The obtained fibers were alkali treated for their effective usage as reinforcement in composites. The physical, chemical, crystallinity, thermal, wettability and surface characteristics were analyzed for raw, and alkali treated.•Tridax procumbens fibers (TPFs). The test results conclude that there was an increase in cellulose content with a reduction in hemicellulose, lignin and wax upon alkali treatment.•The considerable improvement in the properties of alkali treated TPFs would be worth for developing high performance polymer composites.
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