MicroRNAs (miRNAs) are small noncoding RNA molecules, which are known to regulate gene expression in physiological and pathological conditions. miRNA profiling was performed using brain tissue from ...patients with HIV encephalitis (HIVE), a neuroinflammatory/degenerative disorder caused by HIV infection of the brain. Microarray analysis showed differential expression of multiple miRNAs in HIVE compared to control brains. Target prediction and gene ontology enrichment analysis disclosed targeting of several gene families/biological processes by differentially expressed miRNAs (DEMs), with cell death-related genes, including caspase-6, showing a bias toward down-regulated DEMs. Consistent with the miRNA data, HIVE brains exhibited higher levels of caspase-6 transcripts compared with control patients. Immunohistochemical analysis showed localization of the cleaved form of caspase-6 in astrocytes in HIVE brain sections. Exposure of cultured human primary astrocytes to HIV viral protein R (Vpr) induced p53 up-regulation, loss of mitochondrial membrane potential, and caspase-6 activation followed by cell injury. Transgenic mice, expressing Vpr in microglial cells, demonstrated astrocyte apoptosis in brain, which was associated with caspase-6 activation and neurobehavioral abnormalities. Overall, these data point to previously unrecognized alterations in miRNA profile in the brain during HIV infection, which contribute to cell death through dysregulation of cell death machinery.--Noorbakhsh, F., Ramachandran, R., Barsby, N., Ellestad, K. K., LeBlanc, A., Dickie, P., Baker, G., Hollenberg, M. D., Cohen, E. A., Power, C. MicroRNA profiling reveals new aspects of HIV neurodegeneration: caspase-6 regulates astrocyte survival.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Finding a cure for HIV is challenged by persisting reservoirs, the mapping of which necessitates invasive procedures. Inviting people with HIV (PWHIV) at the end of life to donate body specimens ...post-mortem through research autopsies is a novel approach, raising ethical concerns.
This case study aims to explore the motivations, barriers, and facilitators of a terminally-ill Canadian PWHIV who requested medical assistance in dying (MAID) and expressed interest in donating his body for HIV cure research.
An in-depth 3-hour and semi-structured interview was conducted with the participant. The interview transcription was thematically coded to identify motivations and perceived barriers and facilitators to participate in end-of-life HIV cure research. Our analysis identified six themes. Two themes expressed motivations: Collaboration in progress in health and science, seeing cure research as collaboration with professionals; and Opportunity to learn more, mostly about science and health. One theme expressed a barrier: Losing interest in or identification with long-term care research matters, especially those related to the management of long-term care. Three themes expressed by facilitators: Receiving information from professionals one trusts and knows, especially clinical and research teams; Perceiving research procedures as simple, useful, and embedded in care, perceiving clinical, educational, and interpersonal benefits that surpass costs of participation; and Perceiving research as one last way to contribute, that is, feeling useful or give back.
Several circumstances facilitated the patient's participation: being a single man, having time to participate, having no strong religious belief, and valuing clear, direct communication. His motivations to participate in HIV cure research were altruistic, and also an experience of working with clinical and research teams. Finally, this perspective highlights HIV cure research participant candidates' need for education about research procedures.
Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope ...protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.
Zika virus (ZIKV) has emerged as an important human pathogen that can cause congenital defects in the fetus and neurological conditions in adults. The interferon (IFN) system has proven crucial in ...restricting ZIKV replication and pathogenesis. The canonical IFN response is triggered by the detection of viral RNA through RIG-I like receptors followed by activation of the adaptor protein MAVS on mitochondrial membranes. Recent studies have shown that a second organelle, peroxisomes, also function as a signaling platforms for the IFN response. Here, we investigated how ZIKV infection affects peroxisome biogenesis and antiviral signaling. We show that ZIKV infection depletes peroxisomes in human fetal astrocytes, a brain cell type that can support persistent infection. The peroxisome biogenesis factor PEX11B was shown to inhibit ZIKV replication, likely by increasing peroxisome numbers and enhancing downstream IFN-dependent antiviral signaling. Given that peroxisomes play critical roles in brain development and nerve function, our studies provide important insights into the roles of peroxisomes in regulating ZIKV infection and potentially neuropathogenesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
At the end of the second section of Lacan's Rome discourse, "Symbol and Language as Structure and Limit of the Psychoanalytic Field", the function of analysis is defined as the recognition in speech ...of the subject's desire. In madness, of whatever nature, we must recognize on the one hand the negative freedom of a kind of speech that has given up trying to gain recognition, which is what we call an obstacle to transference; and, on the other, the singular formation of a delusion which - whether fabular, fantastical, or cosmological, or rather interpretative, demanding, or idealist - objectifies the subject in a language devoid of dialectic.1 It must be noted that in French madness and alienation are synonymous: to be alienated ("aliéné") is also to be mad ("fou"). The comparison of the following two passages underscores this ambivalence: (1): "If psychoanalysis can become a science ... and if it is not to degenerate in its technique ... we must rediscover the meaning of its experience,"8 and (2): Communication can be validly established for the modern subject in science's collective undertaking and in the tasks science ordains in our universal civilization; this communication will be effective within the enormous objectification constituted by this science, and it will allow him to forget his subjectivity.9 Lacan attempts to formalize psychoanalysis as a science by drawing on recent discoveries in various fields, particularly structural linguistics, and yet he claims that the scientific state of civilization has objectified speech. How, indeed, could speech exhaust the meaning of speech ... if not in the act that engenders it? ...Goethe's reversal of its presence at the origin, "In the beginning was the act," is itself reversed in its turn: it was certainly the Word that was in the beginning, and we live in its creation, but it is our mental action that continues this creation by constantly renewing it.10 Psychoanalysis is the practice of renewing the possibility of non-alienated speech.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Inflammasome activation in the central nervous system occurs in both health and disease. Inflammasomes are cytosolic protein complexes that sense specific infectious or host stimuli and initiate ...inflammatory responses through caspase activation. Assembly of inflammasomes results in caspase-1-mediated proteolytic cleavage and release of the pro-inflammatory cytokines, interleukin-1β and interleukin-18, with initiation of pyroptosis, an inflammatory programmed cell death. Recent developments in the inflammasome field have uncovered novel molecular mechanisms that contribute to a broad range of neurological disorders including those associated with specific mutations in inflammasome genes as well as diseases modulated by inflammasome activation. This update focuses on recent developments in the field of inflammasome biology highlighting different inflammasome activators and pathways discovered in the nervous system. We also discuss targeted therapies that regulate inflammasomes and improve neurological outcomes.
Model-driven engineering (MDE) involves the construction and manipulation of many models of different kinds in an engineering process. In principle, models can be used in the product engineering ...lifecycle in an end-to-end manner for representing requirements, designs and implementations, and assisting in deployment and maintenance. The manipulations applied to models may be manual, but they can also be automated—for example, using model transformations, code generation, and validation. To enhance automated analysis, consistency and coherence of models used in an MDE process, it is useful to identify, establish and maintain
trace-links
between models. However, the breadth and scope of trace-links that can be used in MDE is substantial, and managing trace-link information can be very complex. In this paper, we contribute to managing the complexity of traceability information in MDE in two ways: firstly, we demonstrate how to identify the different kinds of trace-links that may appear in an end-to-end MDE process; secondly, we describe a rigorous approach to defining semantically rich trace-links between models, where the models themselves may be constructed using diverse modelling languages. The definition of rich trace-links allows us to use tools to maintain and analyse traceability relationships.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR2 in the pathogenesis of multiple ...sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein-induced EAE caused more severe inflammatory gene expression in the CNS of PAR2 WT animals (P < 0.05), together with enhanced T cell proliferation and interferon gamma production (P < 0.05), compared with KO littermates. Indeed, PAR2 WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR2 KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR2 expression and neuroinflammation with ensuing demyelination and axonal injury.
ABSTRACTActivation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation is thought to mediate anti-inflammatory responses to CNS injury. Several studies have reported an ...increase in phosphorylated STAT3 (pSTAT3) in peripheral T cells and monocytes from patients with multiple sclerosis (MS) during relapses, suggesting that pSTAT3 might represent an inflammatory marker. Here, we examined immunoreactivity for pSTAT3 in brain tissue samples from MS patients and controls. Phosphorylated STAT3 immunoreactivity was sparse within lesions, with no difference between active and inactive lesions. It was, however, significantly greater in white matter (WM) adjacent to active and inactive lesions; moreover, it was significantly greater in WM adjacent to active versus inactive lesions. Phosphorylated STAT3–positive cells were identified as astrocytes and macrophages/microglia. Phosphorylated STAT3 expression was also detected by Western blotting in WM of patients with MS. In comparison, pSTAT3 immunoreactivity was either rare or found focally in brain tissue samples from patients with other neurologic diseases. Our findings show that pSTAT3 does not correlate with inflammatory activity in MS lesions, but that it may play an important role in regulating reactive changes proximal to MS lesions.
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