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1.  Toward a new STATe: The role of STATs in mitochondrial function 
Seminars in immunology  2014;26(1):20-28.
Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease.
PMCID: PMC4321820  PMID: 24434063
STATs; STAT3; Mitochondria; Review; Cancer; Ischemia/reperfusion; Metabolism
2.  Profound Amnesia after Temporal Lobectomy: An Autoimmune Process Resembling Patient H.M.? 
Case Reports in Neurology  2014;6(3):251-255.
We describe a patient who developed significant cognitive decline with profound amnesia following non-dominant temporal lobectomy for refractory seizures, in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation, neuropsychological evidence of bilateral involvement, and high titres of antibodies directed against glutamic acid decarboxylase (GAD). This case adds to the evidence that the diagnosis of non-paraneoplastic anti-GAD limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline.
PMCID: PMC4249997  PMID: 25473398
Amnesia; Epilepsy; Glutamic acid decarboxylase; Limbic encephalitis; Temporal lobectomy
3.  Effect Size (Cohen's d) of Cognitive Screening Instruments Examined in Pragmatic Diagnostic Accuracy Studies 
Many cognitive screening instruments (CSI) are available to clinicians to assess cognitive function. The optimal method comparing the diagnostic utility of such tests is uncertain. The effect size (Cohen's d), calculated as the difference of the means of two groups divided by the weighted pooled standard deviations of these groups, may permit such comparisons.
Datasets from five pragmatic diagnostic accuracy studies, which examined the Mini-Mental State Examination (MMSE), the Mini-Mental Parkinson (MMP), the Six-Item Cognitive Impairment Test (6CIT), the Montreal Cognitive Assessment (MoCA), the Test Your Memory test (TYM), and the Addenbrooke's Cognitive Examination-Revised (ACE-R), were analysed to calculate the effect size (Cohen's d) for the diagnosis of dementia versus no dementia and for the diagnosis of mild cognitive impairment versus no dementia (subjective memory impairment).
The effect sizes for dementia versus no dementia diagnosis were large for all six CSI examined (range 1.59-1.87). For the diagnosis of mild cognitive impairment versus no dementia, the effect sizes ranged from medium to large (range 0.48-1.45), with MoCA having the largest effect size.
The calculation of the effect size (Cohen's d) in diagnostic accuracy studies is straightforward. The routine incorporation of effect size calculations into diagnostic accuracy studies merits consideration in order to facilitate the comparison of the relative value of CSI.
PMCID: PMC4132220  PMID: 25177332
Diagnostic accuracy; Effect size; Cohen's d; Mini-Mental State Examination; 
Mini-Mental Parkinson; Six-Item Cognitive Impairment Test; Montreal Cognitive Assessment; Test Your Memory test; Addenbrooke's Cognitive Examination-Revised
4.  Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity 
Cell metabolism  2012;16(6):814-824.
Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2−/− brown preadipocytes. Furthermore, Tyk2−/− mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat-lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.
PMCID: PMC3522427  PMID: 23217260
5.  Multi-Tasking: Nuclear Transcription Factors with Novel Roles in the Mitochondria 
Trends in cell biology  2012;22(8):429-437.
Coordinated responses between the nucleus and mitochondria are essential for maintenance of homeostasis. For over 15 years, pools of nuclear transcription factors (TFs), such as p53 and nuclear hormone receptors, have been observed in the mitochondria. The contribution of the mitochondrial pool of these TFs to their well-defined biological actions is in some cases clear and in others not well understood. Recently, a small mitochondrial pool of the TF signal transducer and activator of transcription factor 3 (STAT3) was shown to modulate the activity of the electron transport chain. The mitochondrial function of STAT3 encompasses both its biological actions in the heart as well as its oncogenic effects. This review highlights advances in our understanding of how mitochondrial pools of nuclear TFs may influence the function of this organelle.
PMCID: PMC3516366  PMID: 22705015
nuclear transcription factors; mitochondrial function; apoptosis; STAT3
6.  Cytoprotection by the Modulation of Mitochondrial Electron Transport Chain: The Emerging Role of Mitochondrial STAT3 
Mitochondrion  2011;12(2):180-189.
The down regulation of mitochondrial electron transport is an emerging mechanism of cytoprotective intervention that is effective in pathologic settings such as myocardial ischemia and reperfusion when the continuation of mitochondrial respiration produces reactive oxygen species, mitochondrial calcium overload, and the release of cytochrome c to activate cell death programs. The initial target of deranged electron transport is the mitochondria themselves. In the first part of this review, we describe this concept and summarize different approaches used to regulate mitochondrial respiration by targeting complex I as a proximal site in the electron transport chain (ETC) in order to favor the cytoprotection. The second part of the review highlights the emerging role of signal transducer and activator of transcription 3 (STAT3) in the direct, non-transcriptional regulation of ETC, as an example of a genetic approach to modulate respiration. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain (ETC). The over expression of mitochondrial-targeted STAT3 results in a partial blockade of electron transport at complexes I and II that does not impair mitochondrial membrane potential nor enhance the production of reactive oxygen species (ROS). The targeting of transcriptionally-inactive STAT3 to mitochondria attenuates damage to mitochondria during cell stress, resulting in decreased production of ROS and retention of cytochrome c by mitochondria. The overexpression of STAT3 targeted to mitochondria unveils a novel protective approach mediated by modulation of mitochondrial respiration that is independent of STAT3 transcriptional activity. The limitation of mitochondrial respiration under pathologic circumstances can be approached by activation and over expression of endogenous signaling mechanisms in addition to pharmacologic means. The regulation of mitochondrial respiration comprises a cardioprotective paradigm to decrease cellular injury during ischemia and reperfusion.
PMCID: PMC3278553  PMID: 21930250
7.  The Role of Tyk2 in Regulation of Breast Cancer Growth 
The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2−/− mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2+/+ animals. Accelerated growth of 4T1 cells in Tyk2−/− animals does not appear to be due to decreased function of CD4+, CD8+ T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2−/− mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.
PMCID: PMC3173819  PMID: 21864028
8.  Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca2+ - de novo ceramide - PP2A - ROS dependent signaling pathway 
Cancer research  2010;70(15):6313-6324.
The targeted therapeutics sorafenib and vorinostat interact in a synergistic fashion to kill carcinoma cells by activating CD95, and this drug combination is entering phase I evaluation. In this study we determined how CD95 is activated by treatment with this drug combination. Low doses of sorafenib and vorinostat but not the individual drugs rapidly increased ROS, Ca2+ and ceramide levels in GI tumor cells. The production of ROS was reduced in Rho zero cells. Quenching ROS blocked drug-induced CD95 surface localization and apoptosis. ROS generation, CD95 activation and cell killing was also blocked by quenching of induced Ca2+ levels or by inhibition of PP2A. Inhibition of acidic sphingomyelinase or de novo ceramide generation blocked the induction of ROS however combined inhibition of both acidic sphingomyelinase and de novo ceramide generation was required to block the induction of Ca2+. Quenching of ROS did not impact on drug-induced ceramide/dihydro-ceramide levels whereas quenching of Ca2+ reduced the ceramide increase. Sorafenib and vorinostat treatment radiosensitized liver and pancreatic cancer cells, an effect that was suppressed by quenching ROS or knock down of LASS6. Further, sorafenib and vorinostat treatment suppressed the growth of pancreatic tumors in vivo. Our findings demonstrate that induction of cytosolic Ca2+ by sorafenib and vorinostat is a primary event that elevates dihydroceramide levels, each essential steps in ROS generation that promotes CD95 activation.
PMCID: PMC2918282  PMID: 20631069
9.  Migraine and restless legs syndrome: is there an association? 
The Journal of Headache and Pain  2011;12(4):405-409.
Occasional clinical reports have suggested a link between migraine and restless legs syndrome. We undertook a systematic review of the evidence, which supports this association, and consider possible shared pathogenic mechanisms and the implications for current clinical practice.
PMCID: PMC3139066  PMID: 21660429
Migraine; Restless legs syndrome; Comorbidity; Dopamine; Sleep
10.  Migraine and restless legs syndrome: is there an association? 
The Journal of Headache and Pain  2011;12(4):405-409.
Occasional clinical reports have suggested a link between migraine and restless legs syndrome. We undertook a systematic review of the evidence, which supports this association, and consider possible shared pathogenic mechanisms and the implications for current clinical practice.
PMCID: PMC3139066  PMID: 21660429
Migraine; Restless legs syndrome; Comorbidity; Dopamine; Sleep
11.  Have Quality and Outcomes Framework Depression Indicators changed referrals from primary care to a dedicated memory clinic? 
Mental Health in Family Medicine  2009;6(3):129-132.
The proportion of patients referred from primary care to dedicated dementia clinics who receive a final diagnosis of dementia is low. Many of these non‐demented patients may have depressive disorders, since depression is the most common differential diagnosis of dementia. The UK general practitioner (GP) General Medical Services contract, introduced in April 2006, included a Quality and Outcomes Framework (QOF) with indicators related to depression. We investigated whether introduction of the QOF Depression Indicators changed the pattern of referrals from primary care to a dedicated dementia clinic. The results indicated that the null hypothesis could not be rejected.
PMCID: PMC2838652  PMID: 22477902
dementia; depression; referral patterns
12.  Braille alexia: an apperceptive tactile agnosia? 
PMCID: PMC2117751  PMID: 17635985
13.  Mitochondrial Stat3 Supports Ras-Dependent Oncogenic Transformation 
Science (New York, N.Y.)  2009;324(5935):1713-1716.
STAT3 is a latent cytoplasmic transcription factor responsive to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when tyrosine phosphorylated. We report that malignant transformation by activated Ras is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine phosphorylated, are retained in the cytoplasm, or cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.
PMCID: PMC2840701  PMID: 19556508
14.  Function of Mitochondrial Stat3 in Cellular Respiration 
Science (New York, N.Y.)  2009;323(5915):793-797.
Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3−/− cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.
PMCID: PMC2758306  PMID: 19131594
15.  Concurrence of primary headaches: Lane and Davies (2006) revisited 
PMCID: PMC3451645  PMID: 19238509
16.  A 50-Year-Old Man with Deteriorating Cognitive Function and Impaired Movement 
PLoS Medicine  2009;6(1):e19.
Andrew Larner discusses the diagnosis and management of a man referred to the Cognitive Function Clinic with a 12- to 18-month history of deteriorating memory.
PMCID: PMC2631053  PMID: 19175287
17.  An Acute Evolving Flaccid Quadriparesis in an Elderly Woman 
PLoS Medicine  2008;5(8):e180.
Andrew Larner and colleagues discuss the differential diagnosis, investigation, and management of a 72-year-old woman presenting with progressive lower limb weakness who develops an acute evolving flaccid quadriparesis.
PMCID: PMC2522257  PMID: 18752345
18.  Type I interferons activate apoptosis in a Jurkat cell variant by caspase-dependent and independent mechanisms 
Cellular signalling  2005;18(8):1299-1308.
Although the antiviral actions of interferons (IFNs) are observed in most types of cells, the antiproliferative effects of IFNα/β are variable as are the mechanisms of growth inhibition that may or may not be due to the induction of apoptosis. To understand more about the mechanisms that are responsible for IFNα/β -stimulated apoptosis, we have characterized a new human Jurkat T cell variant named H123 where IFNα activates programmed cell death (PCD). No differences in IFNα -stimulated, Stat-dependent gene expression were detected between H123 cells and the parental Jurkat cells, which are growth inhibited, but do not undergo apoptosis with IFNα. Although IFNα stimulates the activity of both caspase 3 and 9 in H123 cells, the general caspase inhibitor Z-VAD only partially reverses the apoptotic actions of IFNα. Induction of apoptosis by IFNα occurs through a mitochondrial-dependent pathway in H123 cells, as demonstrated by the release of cytochrome C from the mitochondria. Furthermore, IFNα treatment of H123 cells stimulates the release of the serine protease HtrA2/Omi from the mitochondria, suggesting that it plays a role in the apoptotic actions of this cytokine. These results provide evidence for a novel type 1 IFN-mediated pathway that regulates apoptosis of T cells through a mitochondrial-dependent and caspase-dependent and independent pathway.
PMCID: PMC1862448  PMID: 16337360
Type; One; Interferone; Signaling; Jak/Skat; Apoptosis
19.  Migraine with aura and restless legs syndrome 
The Journal of Headache and Pain  2007;8(2):141-142.
PMCID: PMC3476137  PMID: 17497271
20.  Tyk2 Tyrosine Kinase Expression Is Required for the Maintenance of Mitochondrial Respiration in Primary Pro-B Lymphocytes▿  
Molecular and Cellular Biology  2006;26(22):8562-8571.
Tyk2, a member of the Jak family of protein tyrosine kinases, is critical for the biological actions of alpha/beta interferon (IFN-α/β). Although Tyk2−/− mice are phenotypically normal, they exhibit abnormal responses to inflammatory challenges in a variety of cells isolated from Tyk2−/− mice. The reported phenotypic alterations in both Tyk2-null cells and mice are consistent with the possibility that the expression of this tyrosine kinase may regulate mitochondrial function. We report here that Tyk2-null pro-B cells are markedly deficient in basal oxygen consumption and exhibit a significant decrease in steady-state cellular ATP levels compared to wild-type cells. Tyk2-null cells also exhibit impaired complex I, III, and IV function of the mitochondrial electron transport chain. Reconstitution of Tyk2-null pro-B cells with either the wild type or a kinase-inactive mutant of Tyk2 restores basal mitochondrial respiration. By contrast, the kinase activity of Tyk2 is required for maintenance of both complex I-dependent mitochondrial respiration as well as induction of apoptosis in cells incubated with IFN-β. Consistent with the role of Tyk2 in the regulation of tyrosine phosphorylation of Stat3, expression of a constitutively active Stat3 can restore the mitochondrial respiration in Tyk2-null cells treated with IFN-β. Finally, Tyk2−/− mice show decreased exercise tolerance compared to wild-type littermates. Our results implicate a novel role for Tyk2 kinase and Stat3 phosphorylation in mitochondrial respiration.
PMCID: PMC1636766  PMID: 16982690
22.  Control of Lytic Function by Mitogen-activated Protein Kinase/Extracellular Regulatory Kinase 2 (ERK2) in a Human Natural Killer Cell Line: Identification of Perforin and Granzyme B Mobilization by Functional ERK2  
The Journal of Experimental Medicine  1998;187(11):1753-1765.
The signal pathways that control effector function in human natural killer (NK) cells are little known. In this study, we have identified the critical role of the mitogen-activated protein kinase (MAPK) pathway in NK lysis of tumor cells, and this pathway may involve the mobilization of granule components in NK cells upon interaction with sensitive tumor target cells. Evidence was provided by biological, biochemical, and gene transfection methods. NK cell binding to tumor cells for 5 min was sufficient to maximally activate MAPK/extracellular signal–regulatory kinase 2 (ERK2), demonstrated by its tyrosine phosphorylation and by its ability to function as an efficient kinase for myelin basic protein. MAPK activation was achieved in NK cells only after contact with NK-sensitive but not NK-resistant target cells. In immunocytochemical studies, cytoplasmic perforin and granzyme B were both maximally redirected towards the tumor contact zone within 5 min of NK cell contact with tumor cells. A specific MAPK pathway inhibitor, PD098059, could block not only MAPK activation but also redistribution of perforin/granzyme B in NK cells, which occur upon target ligation. PD098059 also interfered with NK lysis of tumor cells in a 5-h 51Cr-release assay, but had no ability to block NK cell proliferation. Transient transfection studies with wild-type and dominant-negative MAPK/ERK2 genes confirmed the importance of MAPK in NK cell lysis. These results document a pivotal role of MAPK in NK effector function, possibly by its control of movement of lytic granules, and clearly define MAPK involvement in a functional pathway unlinked to cell growth or differentiation.
PMCID: PMC2212310  PMID: 9607917
natural killer cell; mitogen-activated protein kinase; perforin; granzyme B; signal transduction

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