Hasil untuk "physics.atm-clus"

Marie Riddle, Angel I. Pena Dominguez, Benjamin S. Kamerin et al.

In pick-up experiments using nanodroplet and nanocluster beams, the size distribution of hosts carrying a specified number of dopants changes when the vapor density in the pick-up region is altered. This change, analyzed here, has quantitative consequences for the interpretation of data that are sensitive to host size, such as mass spectrometric, spectroscopic, and deflection measurements.

G. Beecham, K. Hamilton, A. Naj et al.

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.

G. Jun, A. Naj, G. Beecham et al.

Yizhen Fu, Qiaoli Du, Tie-Zhong Cui et al.

Clusterin (CLU) is a chaperone-like protein that has been demonstrated to have a direct relationship with cancer occurrence, progression, or metastasis. Clusterin was downregulated in tumor tissues using three datasets of tongue squamous carcinoma from the Gene Expression Omnibus. We further retrieved datasets from The Cancer Genome Atlas and Gene Expression Omnibus to thoroughly investigate the carcinogenic consequences of Clusterin. Our findings revealed that decreased Clusterin expression in malignancies was associated with a worse overall survival prognosis in individuals with multiple tumors; Clusterin gene deep deletions were found in almost all malignancies and were connected to most cancer patient’s prognosis, Clusterin DNA methylation level was dependent on tumor type, Clusterin expression was also linked to the invasion of cancer-associated CD8+ T-cells and fibroblasts in numerous cancer forms. Moreover, pathway enrichment analysis revealed that Clusterin primarily regulates biological processes such as cholesterol metabolism, phospholipid binding, and protein-lipid complex formation. Overall, our pan-cancer research suggests that Clusterin expression levels are linked to tumor carcinogenesis and prognosis, which contributes to understanding the probable mechanism of Clusterin in tumorigenesis as well as its clinical prognostic significance.

Yihan Li, S. Laws, Luke A Miles et al.

L. Pereira, I. Yahyaoui, R. Fiorotti et al.

Partly Funded by Conserjeria de Educacion of Junta de Castilla y Leon and EU-FEDER (CLU-2017-09, VA232P18, UIC 225)

Yefei Zhang, Xiang Lv, Liming Chen et al.

Karolina Rogulska, I. Wojciechowska-Koszko, B. Dołęgowska et al.

Clinical transplantology is a constantly evolving field of medicine. Kidney transplantation has become standard clinical practice, and it has a significant impact on reducing mortality and improving the quality of life of patients. Allogenic transplantation induces an immune response, which may lead to the rejection of the transplanted organ. The gold standard for evaluating rejection of the transplanted kidney by the recipient’s organism is a biopsy of this organ. However, due to the high invasiveness of this procedure, alternative diagnostic methods are being sought. Therefore, the biomarkers may play an essential predictive role in transplant rejection. A review of the most promising biomarkers for early diagnosis and prognosis prediction of allogenic kidney transplant rejection summarizes novel data on neutrophil gelatinase‐associated lipocalin (NGAL), kidney injury molecule‐1 (KIM‐1), C‐X‐C motif chemokine 10 (CXCL‐10), cystatin C (CysC), osteopontin (OPN), and clusterin (CLU) and analyses the dynamics of changes of the biomarkers mentioned above in kidney diseases and the mechanism of rejection of the transplanted kidney.

Jiahong Guo, Zhongqi Yu, Zihao Ma et al.

S. Satapathy, Mark R. Wilson

Clusterin (CLU) was the first reported secreted mammalian chaperone and impacts on serious diseases associated with inappropriate extracellular protein aggregation. Many studies have described intracellular CLU in locations outside the secretory system and recent work has shown that CLU can be released into the cytosol during cell stress. In this article, we critically evaluate evidence relevant to the proposed origins of cellular CLU found outside the secretory system, and advance the hypothesis that the cytosolic release of CLU induced by stress serves to facilitate the trafficking of misfolded proteins to the proteasome and autophagy for degradation. We also propose future research directions that could help establish CLU as a unique chaperone performing critical and synergic roles in both intracellular and extracellular proteostasis.

S. Harris, E. A. Harris

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

S. Rangaraju, E. Dammer, S. Raza et al.

Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometry methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally relevant molecular insights that are not provided by transcriptomics. However, comprehensive proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative mass spectrometry based proteomic analyses of purified CD11b+ acutely-isolated microglia from adult (6 mo) mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]). Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized, suggesting a role for Apoe in phagocytic clearance of Aβ. We report a comprehensive proteomic study of adult mouse microglia derived from acute neuroinflammation and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identify novel roles for microglial proteins in human neurodegeneration.

Sen Wang, Q. Feng, M. Zha et al.

Shobana Sekar, Jacquelyn McDonald, Lori Cuyugan et al.

Alzheimer's disease (AD) is characterized by deficits in cerebral metabolic rates of glucose in the posterior cingulate (PC) and precuneus in AD subjects, and in APOEε4 carriers, decades before the onset of measureable cognitive deficits. However, the cellular and molecular basis of this phenotype remains to be clarified. Given the roles of astrocytes in energy storage and brain immunity, we sought to characterize the transcriptome of AD PC astrocytes. Cells were laser capture microdissected from AD (n = 10) and healthy elderly control (n = 10) subjects for RNA sequencing. We generated >5.22 billion reads and compared sequencing data between controls and AD patients. We identified differentially expressed mitochondria-related genes including TRMT61B, FASTKD2, and NDUFA4L2, and using pathway and weighted gene coexpression analyses, we identified differentially expressed immune response genes. A number of these genes, including CLU, C3, and CD74, have been implicated in beta amyloid generation or clearance. These data provide key insights into astrocyte-specific contributions to AD, and we present this data set as a publicly available resource.

Aleksandra M. Wojtas, Silvia S Kang, Benjamin M Olley et al.

David C. Hondius, Kristel N. Eigenhuis, T. Morrema et al.

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry.Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA.

Mark R. Wilson, A. Zoubeidi

Klavs Hansen, Piero Ferrari

While linear molecules in their vibrational ground state cannot carry angular momentum around their symmetry axis, the presence of vibrational excitations can induce deformations away from linearity and therefore also allow angular momentum along the molecular axis. In this work, a recurrence relation is established for the calculation of the vibrational level densities (densities of states) of linear molecules, specified with respect to both energy and angular momentum. The relation is applied to the carbon clusters of sizes $n=4,6,7$ as a case study.

R. Rosenberg, D. Lambracht-Washington, Gang Yu et al.

Alzheimer's Disease Neuroimaging Initiative