Hasil untuk "physics.atm-clus"

S. Chintala, Jinhong Pan, S. Satapathy et al.

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

Chongze Yuan, Haojie Chen, Shiqi Tu et al.

Lung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression. A high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD. Our study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.

Candace R Fox, G. Parks

Little is known about the role of complement (C’) in infections with highly prevalent circulating human coronaviruses such as OC43, a group of viruses of major public health concern. Treatment of OC43-infected human lung cells with human serum resulted in C3 deposition on their surfaces and generation of C5a, indicating robust C’ activation. Real-time cell viability assays showed that in vitro C’-mediated lysis of OC43 infected cells requires C3, C5 and C6 but not C7, and was substantially delayed as compared to rapid C’-mediated killing of parainfluenza virus type 5 (PIV5)-infected cells. In cells co-infected with OC43 and PIV5, C’-mediated lysis was delayed, similar to OC43 infected cells alone, suggesting that OC43 infection induced dominant inhibitory signals. When OC43-infected cells were treated with human serum, their cell surfaces contained both Vitronectin (VN) and Clusterin (CLU), two host cell C’ inhibitors that can alter membrane attack complex (MAC) formation and C’-mediated killing. VN and CLU were not bound to OC43-infected cells after treatment with antibody-depleted serum. Reconstitution experiments with purified IgG and VN showed that human antibodies are both necessary and sufficient for VN recruitment to OC43-infected lung cells–novel findings with implications for CoV pathogenesis.

P. P. Naik, Subhadip Mukhopadhyay, P. Praharaj et al.

AIMS Secretory clusterin (sCLU) plays an important role in tumor development and cancer progression. However, the molecular mechanisms and physiological functions of sCLU in oral cancer is unclear. We examined the impact of sCLU-mediated autophagy in cell survival and apoptosis inhibition in oral cancer. MAIN METHODS Immunohistochemical analysis was performed to analyze protein expression in patient samples. Autophagy and mitophagy was studied by immunofluorescence microscopy and Western blot. The gain and loss of function was studied by overexpression of plasmid and siRNA approaches. Cellular protection against nutrient starvation and therapeutic stress by sCLU was studied by cell viability assay and caspase assay. KEY FINDINGS The data from oral cancer patients showed that the expression levels of sCLU, ATG14, ULK1, and PARKIN were increase grade wise manners. Interestingly, sCLU overexpression promoted autophagy through AMPK/Akt/mTOR signaling pathway leading to cell survival and protection from long exposure serum starvation induced-apoptosis. Additionally, sCLU was demonstrated to interact with ULK1 and inhibition ULK1 activity by SBI206965 was found to abolish sCLU-induced autophagy indicating critical role of ULK1 in induction of autophagy. Furthermore, sCLU was observed to promote expression of mitophagy-associated proteins in serum starvation conditions to protect OSCC cells from nutrient deprivation. The meta-analysis elucidated that high CLU expression is associated with therapy resistance in cancer and we demonstrated that sCLU-mediated mitophagy was revealed to inhibit OSCC cell death by cisplatin. SIGNIFICANCE The present investigation has highlighted the probable implications of the clusterin-induced autophagy in cell survival and inhibition of apoptosis in oral cancer.

E. Janiszewska, E. Kratz

Male infertility is becoming a rapidly growing problem around the world, mainly in the highly developed countries. Seminal proteome composition seems to be one of the crucial factors of the proper course of fertilization ‐ clusterin (CLU) is among the most important ones. CLU, as one of the crucial seminal plasma glycoproteins, plays a very important role in sperm capacitation and immune tolerance in the female reproductive tract. CLU is also known as a sensitive marker of oxidative stress. It has six n‐glycosylation sites and also exhibits chaperone activity. An analysis of changes in the profile and degree of CLU glycosylation may shed some new light on the molecular mechanisms of the fertilization process and may be used as an additional diagnostic marker of male fertility. This study constitutes a review of the recently available literature concerning human seminal CLU, including changes in its glycosylation, analyzed in the context of human reproduction.

M. Ouyang, Sufeng Cao, Shi-ze Yang et al.

Atomically dispersed Pd/ZnO was synthesized using a facile method. We found that 0.07 wt % Pd was isolated and positively charged on ZnO synthesized using a solvothermal method. By contrast, Pd clu...

Lulu Ren, Fei‐fei Han, Ling-ling Xuan et al.

Clusterin (CLU) is a stress-responding protein associated with cytoprotection in a broad range of pathological processes. However, clusterin's function in diabetes-induced endothelial dysfunction has not been defined. Herein, using two diabetes models, we investigated the role of clusterin in endothelial dysfunction triggered by diabetes and the molecular mechanisms involved. The results revealed that clusterin overexpression inhibited ICAM-1/VCAM-1 expression in aortas and improved endothelium-dependent vasodilatation in db/db diabetic mice and streptozotocin (STZ)-induced diabetes models. Consistently, in vitro, adenoviral clusterin overexpression reduced the expression of a range of pro-inflammatory cytokines and suppressed monocyte adhesion to endothelial cells subjected to high glucose and high palmitate. Further study indicated that clusterin overexpression mitigated mitochondrial excessive fission and reduced mitochondrial ROS production. Conversely, silencing clusterin aggravated mitochondrial fission and endothelial inflammatory activation in high glucose-exposed endothelial cells. Accumulating evidence indicates that impaired mitochondrial dynamics plays a considerable role in promoting endothelial dysfunction in diabetic subjects. Therefore, treatments targeting mitochondrial undue fission may be promising measures to prevent vascular complications of diabetes. Furthermore, AMP-activated protein kinase (AMPK) activation contributed to the modulation of mitochondrial dynamics executed by clusterin. Mechanistically, clusterin promoted the phosphorylation of AMPKα and its downstream target acetyl-CoA carboxylase (ACC), while the inhibition of AMPKα negated the improvement in mitochondrial dynamics provided by clusterin overexpression. Over all, these findings suggest that clusterin exerts beneficial effects in endothelial cells under diabetic conditions via inhibiting mitochondrial fragmentation mediated by AMPK.

Q. Fu, Limei Pan, Delun Huang et al.

A comprehensive identification of the proteins of spermatozoa and seminal plasma enables the full characterization of sperm biology and is essential to understand how seminal plasma influences sperm fertility. In this study, proteomics of buffalo spermatozoa and seminal plasma were analyzed using a bottom-up approach. A total of 2147 and 864 proteins were identified from mature spermatozoa and seminal plasma, respectively. Of these, 371 proteins-42.9% in the seminal plasma set-were common to both spermatozoa and seminal plasma. ODF2, AKAP4, and TUBB were the most highly abundant proteins of spermatozoa whereas the three most highly abundant proteins in seminal plasma were ALB, CLU, and AZGP1. Gene Ontology (GO) analysis indicated that most sperm proteins were involved in transport, phosphorylation and macromolecule localization. More seminal plasma proteins were related to proteolysis, response to stimulus and homeostatic process. Pathways associated with energy metabolism, protein processing and RNA transport were significantly enriched in spermatozoa. In buffalo seminal plasma, three distinguishing GO pathways-proteasome activity, lysosomal activity, complement and coagulation cascades-were found to play important roles in sperm protection. Protein-protein interaction (PPI) network analysis indicated that 531 and 620 proteins participated in buffalo sperm and seminal plasma PPI networks, respectively. Sub-network mining elaborated detailed biological events. This study is the first to provide an in-depth proteomic analysis of buffalo spermatozoa and seminal plasma. The results extend our understanding of male buffalo reproduction and provide clues for determining the relationships between sperm biology and seminal plasma.

Nguyen Phuoc Long, Seongoh Park, N. Anh et al.

Introducing novel biomarkers for accurately detecting and differentiating rheumatoid arthritis (RA) and osteoarthritis (OA) using clinical samples is essential. In the current study, we searched for a novel data-driven gene signature of synovial tissues to differentiate RA from OA patients. Fifty-three RA, 41 OA, and 25 normal microarray-based transcriptome samples were utilized. The area under the curve random forests (RF) variable importance measurement was applied to seek the most influential differential genes between RA and OA. Five algorithms including RF, k-nearest neighbors (kNN), support vector machines (SVM), naïve-Bayes, and a tree-based method were employed for the classification. We found a 16-gene signature that could effectively differentiate RA from OA, including TMOD1, POP7, SGCA, KLRD1, ALOX5, RAB22A, ANK3, PTPN3, GZMK, CLU, GZMB, FBXL7, TNFRSF4, IL32, MXRA7, and CD8A. The externally validated accuracy of the RF model was 0.96 (sensitivity = 1.00, specificity = 0.90). Likewise, the accuracy of kNN, SVM, naïve-Bayes, and decision tree was 0.96, 0.96, 0.96, and 0.91, respectively. Functional meta-analysis exhibited the differential pathological processes of RA and OA; suggested promising targets for further mechanistic and therapeutic studies. In conclusion, the proposed genetic signature combined with sophisticated classification methods may improve the diagnosis and management of RA patients.

R. Obuchowicz, K. Nurzynska, B. Obuchowicz et al.

Dental caries are caused by tooth demineralization due to bacterial plaque formation. However, the resulting lesions are often discrete and thus barely recognizable in intraoral radiography images. Therefore, more advanced detection techniques are in great demand among dentists and radiographers. This study was performed to evaluate the performance of texture feature maps in the recognition of discrete demineralization related to caries plaque formation. Digital intraoral radiology image analysis protocols incorporating first-order features (FOF), co-occurrence matrices, gray tone difference matrices, run-length matrices (RLM), local binary patterns (LBP), and k-means clustering (CLU) were used to transform the digital intraoral radiology images of 10 patients with confirmed caries, which were retrospectively reviewed in a dental clinic. The performance of the resulting texture feature maps was compared with that of radiographic images by radiologists and dental specialists. Significantly improved detection of caries spots was achieved by employing the CLU and FOF texture feature maps. The caries-affected area with sharp margins was well defined using the CLU approach. A pseudo-three-dimensional effect was observed in outlining the demineralization zones inside the cavity with the FOF 5 protocol. In contrast, the LBP and RLM techniques produced less satisfactory results with unsharp edges and less detailed depiction of the lesions. This study illustrated the applicability of texture feature maps to the recognition of demineralized spots on the tooth surface debilitated by caries and identified the best performing techniques.

S. Oh, Min Sun Kim, Su-Jeung Park et al.

While clusterin is reportedly involved in Alzheimer's disease (AD) pathogenesis, how clusterin interacts with amyloid‐β (Aß) to cause Aß neurotoxicity remains unclear in vivo. Using 5×FAD transgenic mice, which develop robust AD pathology and memory deficits when very young, we detected interactions between clusterin and Aß in the mouse brains. The two proteins were concurrently upregulated and bound or colocalized with each other in the same complexes or in amyloid plaques. Neuropathology and cognitive performance were assessed in the progeny of clusterin‐null mice crossed with 5×FAD mice, yielding clu−/−;5×FAD and clu+/+;5×FAD. We found far less of the various pools of Aß proteins, most strikingly soluble Aß oligomers and amyloid plaques in clu−/−;5×FAD mice at 5 months of age. At that age, those mice also had higher levels of neuronal and synaptic proteins and better motor coordination, spatial learning and memory than age‐matched clu+/+;5×FAD mice. However, at 10 months of age, these differences disappeared, with Aß and plaque deposition, neuronal and synaptic proteins and impairment of behavioral and cognitive performance similar in both groups. These findings demonstrate that clusterin is necessarily involved in early stages of AD pathogenesis by enhancing toxic Aß pools to cause Aß‐directed neurodegeneration and behavioral and cognitive impairments, but not in late stage.

D. Cook, M. Kasliwal, A. V. Sistine et al.

We present the Census of the Local Universe (CLU) narrowband survey to search for emission-line (Hα) galaxies. CLU-Hα has imaged ≈3π of the sky (26,470 deg2) with four narrowband filters that probe a distance out to 200 Mpc. We have obtained spectroscopic follow-up for galaxy candidates in 14 preliminary fields (101.6 deg2) to characterize the limits and completeness of the survey. In these preliminary fields, CLU can identify emission lines down to an Hα flux limit of 10−14 erg s−1 cm−2 at 90% completeness, and recovers 83% (67%) of the Hα flux from cataloged galaxies in our search volume at the Σ = 2.5 (Σ = 5) color excess levels. The contamination from galaxies with no emission lines is 61% (12%) for Σ = 2.5 (Σ = 5). Also, in the regions of overlap between our preliminary fields and previous emission-line surveys, we recover the majority of the galaxies found in previous surveys and identify an additional ≈300 galaxies. In total, we find 90 galaxies with no previous distance information, several of which are interesting objects: 7 blue compact dwarfs, 1 green pea, and a Seyfert galaxy; we also identify a known planetary nebula. These objects show that the CLU-Hα survey can be a discovery machine for objects in our own Galaxy and extreme galaxies out to intermediate redshifts. However, the majority of the CLU-Hα galaxies identified in this work show properties consistent with normal star-forming galaxies. CLU-Hα galaxies with new redshifts will be added to existing galaxy catalogs to focus the search for the electromagnetic counterpart to gravitational wave events.

Hee Dong, Jeong-An Gim, Seung Hyeon Yeo et al.

E. Wijsman, N. Pankratz, Yoonha Choi et al.

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10−81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10−8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

J. Pouget, V. Gonçalves, S. Spain et al.

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.

Deng-Feng Zhang, Jin Li, Huan Wu et al.

Theresa M. Harrison, Zanjbeel Mahmood, Edward P. Lau et al.

Abstract Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.

L. Dukić, A. Šimundić, Irena Martinić-Popović et al.

Amy R. Wyatt, J. Yerbury, P. Berghofer et al.

L. Tan, Jin-Tai Yu, Wei Zhang et al.