Project description:Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review article, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.
Project description:Gout is the best-known type of arthritis with a prevalence of 1%-3% in the western world (Therapeutic Advances in Musculoskeletal Disease, 6, 2014 and 131; Journal of Advanced Research, 8, 2017 and 495). Although it is well understood, there is growing evidence of the misdiagnosis of gout from other forms of arthritis. These errors lead to delay in accurate diagnosis (Journal of Advanced Research, 8, 2017 and 495).
Project description:The respiratory mucosa is a major site for pathogen invasion and, hence, a site requiring constant immune surveillance. The type I, semi-invariant natural killer T (NKT) cells are enriched within the lung vasculature. Despite optimal positioning, the role of NKT cells in respiratory infectious diseases remains poorly understood. Hence, we assessed their function in a murine model of pulmonary tularemia--because tularemia is a sepsis-like proinflammatory disease and NKT cells are known to control the cellular and humoral responses underlying sepsis. Here we show for the first time that respiratory infection with Francisella tularensis live vaccine strain resulted in rapid accumulation of NKT cells within the lung interstitium. Activated NKT cells produced interferon-γ and promoted both local and systemic proinflammatory responses. Consistent with these results, NKT cell-deficient mice showed reduced inflammatory cytokine and chemokine response yet they survived the infection better than their wild type counterparts. Strikingly, NKT cell-deficient mice had increased lymphocytic infiltration in the lungs that organized into tertiary lymphoid structures resembling induced bronchus-associated lymphoid tissue (iBALT) at the peak of infection. Thus, NKT cell activation by F. tularensis infection hampers iBALT formation and promotes a systemic proinflammatory response, which exacerbates severe pulmonary tularemia-like disease in mice.
Project description:Microglia are the predominant immune response cells and professional phagocytes of the central nervous system (CNS) that have been shown to be important for brain development and homeostasis. These cells present a broad spectrum of phenotypes across stages of the lifespan and especially in CNS diseases. Their prevalence in all neurological pathologies makes it pertinent to reexamine their distinct roles during steady-state and disease conditions. A major question in the field is determining whether the clustering and phenotypical transformation of microglial cells are leading causes of pathogenesis, or potentially neuroprotective responses to the onset of disease. The recent explosive growth in our understanding of the origin and homeostasis of microglia, uncovering their roles in shaping of the neural circuitry and synaptic plasticity, allows us to discuss their emerging functions in the contexts of cognitive control and psychiatric disorders. The distinct mesodermal origin and genetic signature of microglia in contrast to other neuroglial cells also make them an interesting target for the development of therapeutics. Here, we review the physiological roles of microglia, their contribution to the effects of environmental risk factors (e.g., maternal infection, early-life stress, dietary imbalance), and their impact on psychiatric disorders initiated during development (e.g., Nasu-Hakola disease (NHD), hereditary diffuse leukoencephaly with spheroids, Rett syndrome, autism spectrum disorders (ASDs), and obsessive-compulsive disorder (OCD)) or adulthood (e.g., alcohol and drug abuse, major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, eating disorders and sleep disorders). Furthermore, we discuss the changes in microglial functions in the context of cognitive aging, and review their implication in neurodegenerative diseases of the aged adult (e.g., Alzheimer's and Parkinson's). Taking into account the recent identification of microglia-specific markers, and the availability of compounds that target these cells selectively in vivo, we consider the prospect of disease intervention via the microglial route.
Project description:IntroductionDiffuse large B cell lymphoma (DLBCL) is characterized by genetic, genomic and clinical heterogeneity. Autoimmune diseases (AIDs) have recently been shown to represent significant risk factors for development of DLBCL.Areas coveredStudies that examined the relationships between AIDs and lymphoma in terms of pathogenesis, genetic lesions, and treatment were identified in the MEDLINE database using combinations of medical subject heading (MeSH) terms. Co-authors independently performed study selection for inclusion based on appropriateness of the study question and nature of the study design and sample size. Expert commentary: Identification of AID as a substantial risk factor for DLBCL raises new questions regarding how autoimmunity influences lymphomagenesis and disease behavior. It will be important to identify whether DLBCL cases arising in the setting of AID harbor inferior prognoses, and, if so, whether they also exhibit certain molecular abnormalities that may be targeted to overcome such a gap in clinical outcomes.
Project description:Lead halide perovskites (LHPs) have emerged as perspective materials for light harvesting, due to their tunable band gap and optoelectronic properties. Photocatalytic and photoelectrochemical (PEC) studies, employing LHP/liquid junctions, are evolving, where sacrificial reagents are often used. In this study, we found that a frequently applied electron scavenger (TCNQ) has dual roles: while it leads to rapid electron transfer from the electrode to TCNQ, enhancing the PEC performance, it also accelerates the decomposition of the CsPbBr3 photoelectrode. The instability of the films is caused by the TCNQ-mediated halide exchange between the dichloromethane solvent and the LHP film, during PEC operation. Charge transfer and halide exchange pathways were proposed on the basis of in situ spectroelectrochemical and ex situ surface characterization methods, also providing guidance on planning PEC experiments with such systems.
Project description:BackgroundThe circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pan-cancer evidence supporting this notion has been limited.MethodsIn an integrated approach uniting genomic, transcriptomic and clinical data of 21 cancer types (n?=?18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (ClockLoss) and gain-of-function (ClockGain) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets.ResultsClockLoss and ClockGain were associated with tumour-suppressing and tumour-promoting roles respectively. Downregulation of ClockLoss genes resulted in significantly higher mortality rates in five cancer cohorts (n?=?2914): bladder (P?=?0.027), glioma (P?<?0.0001), pan-kidney (P?=?0.011), clear cell renal cell (P?<?0.0001) and stomach (P?=?0.0007). In contrast, patients with high expression of oncogenic ClockGain genes had poorer survival outcomes (n?=?2784): glioma (P?<?0.0001), pan-kidney (P?=?0.0034), clear cell renal cell (P?=?0.014), lung (P?=?0.046) and pancreas (P?=?0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive ClockLoss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis.ConclusionsLoss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. ClockLoss and ClockGain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with first-line treatments.
Project description:Asymptomatic and symptomatic Alzheimer's disease (AD) subjects may present with equivalent neuropathological burdens but have significantly different antemortem cognitive decline rates. Using the transcriptome as a proxy for functional state, we selected 414 expression profiles of symptomatic AD subjects and age-matched non-demented controls from a community-based neuropathological study. By combining brain tissue-specific protein interactomes with gene networks, we identified functionally distinct composite clusters of genes that reveal extensive changes in expression levels in AD. Global expression for clusters broadly corresponding to synaptic transmission, metabolism, cell cycle, survival, and immune response were downregulated, while the upregulated cluster included largely uncharacterized processes. We propose that loss of EGR3 regulation mediates synaptic deficits by targeting the synaptic vesicle cycle. Our results highlight the utility of integrating protein interactions with gene perturbations to generate a comprehensive framework for characterizing alterations in the molecular network as applied to AD.