52 research outputs found
Exosome Release Is Modulated by the Mitochondrial-Lysosomal Crosstalk in Parkinsonâs Disease Stress Conditions
Parkinsonâs disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta region of the brain. The main pathological hallmark involves cytoplasmic inclusions of α-synuclein and mitochondrial dysfunction, which is observed in other part of the central nervous system other than SN suggesting the spread of pathogenesis to bystander neurons. The inter-neuronal communication through exosomes may play an important role in the spread of the disease; however, the mechanisms are not well elucidated. Mitochondria and its role in inter-organellar crosstalk with multivesicular body (MVB) and lysosome and its role in modulation of exosome release in PD is not well understood. In the current study, we investigated the mitochondria-lysosome crosstalk modulating the exosome release in neuronal and glial cells. We observed that PD stress showed enhanced release of exosomes in dopaminergic neurons and glial cells. The PD stress condition in these cells showed fragmented network and mitochondrial dysfunction which further leads to functional deficit of lysosomes and hence inhibition of autophagy flux. Neuronal and glial cells treated with rapamycin showed enhanced autophagy and inhibited the exosomal release. The results here suggest that maintenance of mitochondrial function is important for the lysosomal function and hence exosomal release which is important for the pathogenesis of PD
Expression of expanded FMR1-CGG repeats alters mitochondrial miRNAs and modulates mitochondrial functions and cell death in cellular model of FXTAS
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats located within 5âČUTR of FMR1.These CGG repeats are transcribed into RNAs, which sequester several RNA binding proteins and alter the processing of miRNAs. CGG repeats are also translated into a toxic polyglycine-containing protein, FMRpolyG, that affects mitochondrial and nuclear functions reported in cell and animal models and patient studies. Nuclear-encoded small non-coding RNAs, including miRNAs, are transported to mitochondria; however, the role of mitochondrial miRNAs in FXTAS pathogenesis is not understood. Here, we analyzed mitochondrial miRNAs from HEK293 cells expressing expanded CGG repeats and their implication in the regulation of mitochondrial functions. The analysis of next generation sequencing (NGS) data of small RNAs from HEK293 cells expressing CGG premutation showed decreased level of cellular miRNAs and an altered pattern of association of miRNAs with mitochondria (mito-miRs). Among such mito-miRs, miR-320a was highly enriched in mitoplast and RNA immunoprecipitation of Ago2 (Argonaute-2) followed by Droplet digital PCR (ddPCR)suggested that miR-320a may form a complex with Ago2 and mitotranscripts. Finally, transfection of miR-320a mimic in cells expressing CGG permutation recovers mitochondrial functions and rescues cell death. Overall, this work reveals an altered translocation of miRNAs to mitochondria and the role of miR-320a in FXTAS pathology
TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-ÎșB pathway by promoting turnover of K63 linked ubiquitination of TAK1
Ubiquitin E3-ligases are recruited at different steps of TNF-α-induced NF-ÎșB activation; however, their role in temporal regulation of the pathway remains elusive. The study systematically identified TRIMs as potential feedback regulators of the TNF-α-induced NF-ÎșB pathway. We further observed that TRIM15 is âlateâ response TNF-α-induced gene and inhibits the TNF-α-induced NF-ÎșB pathway in several human cell lines. TRIM15 promotes turnover of K63-linked ubiquitin chains in a PRY/SPRY domain-dependent manner. TRIM15 interacts with TAK1 and inhibits its K63-linked ubiquitination, thus NF-ÎșB activity. Further, TRIM15 interacts with TRIM8 and inhibits cytosolic translocation to antagonize TRIM8 modualted NF-ÎșB. TRIM8 and TRIM15 also show functionally inverse correlation in psoriasis condition. In conclusion, TRIM15 is TNF-α-induced late response gene and inhibits TNF-α induced NF-ÎșB pathway hence a feedback modulator to keep the proinflammatory NF-ÎșB pathway under control
TNF-alpha differentially modulates subunit levels of respiratory electron transport complexes of ER/PR plus ve/-ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential
Background: Tumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the
breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in
ER/PR +ve and ER/PR âve breast cancer cells is not well understood.
Methods: In the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution
mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR
positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in
regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial
complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor
Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial
proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation
between mitochondrial protein expression and survival of breast cancer patients.
Results: The proteome analysis revealed that TNF-α differentially altered the level of critical proteins of
mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential
assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of
TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/
PR âve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the
expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma.
Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of
identified proteins of ETC complexes and survival of the breast cancer patients.
Conclusion: The evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and
proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in
mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of
mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells.
Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF-
7) and ER/PR âve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity
A nonspatial methodology for the analysis of two-way proximity data incorporating the distance-density hypothesis
This paper presents a nonspatial operationalization of the Krumhansl (1978, 1982) distancedensity model of similarity. This model assumes that the similarity between two objects i and j is a function of both the interpoint distance between i and j and the density of other stimulus points in the regions surrounding i and j . We review this conceptual model and associated empirical evidence for such a specification. A nonspatial, tree-fitting methodology is described which is sufficiently flexible to fit a number of competing hypotheses of similarity formation. A sequential, unconstrained minimization algorithm is technically presented together with various program options. Three applications are provided which demonstrate the flexibility of the methodology. Finally, extensions to spatial models, three-way analyses, and hybrid models are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45746/1/11336_2005_Article_BF02295285.pd
Advertising, earnings prediction and market value: An analysis of persistent UK advertisers
YesThis paper examines whether major media advertising expenditures help in predicting future earnings. We consider the role of media advertising in firmsâ marketing efforts and posit that persistent advertisers are more likely to benefit from advertising activities in creating longâlived intangible assets. Employing a sample of persistent UK advertisers over the period 1997â2013, we find that advertising expenditures are significantly positively associated with firmsâ future earnings and market value. We also report size and sectorâbased differences in the association between advertising and firmsâ future earnings. Our additional analysis provides support for the arguments that despite the recent rise in digital advertising budgets, traditional advertising media are still effective in positively influencing firmsâ performance. Overall, the results of this study are consistent with the view that advertising expenditures produce intangible assets, at least for firms in certain sectors. These findings have implications for marketers in providing evidence of the value generated by firmsâ advertising budgets, for investors in validating the relevance of advertising information in influencing future earnings, and for accounting regulators in relation to the provision of useful insights for any future deliberations on financial reporting policies for advertising expenditures
Understanding the Concept of 'Completeness' in Frameworks for Modeling Cardinality Constraints
Temporal XML
Temporal XML is a timestamped instance of an XML data model or, alternatively, an XML document with specially interpreted timestamps which is parsed into a timestamped instance of an XML data model. An XML data model instance is a tree or graph in which each node corresponds to an element, attribute, or value, and each edge represents the lexical nesting of the child in the parent\u2019s content. In temporal XML, a timestamp is added to some nodes or edges in the instance. The timestamp represents the lifetime of the node or edge in one or more temporal dimensions, usually valid time or transaction time
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