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Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients
No full textRab4acontrol over metabolism and mTOR drives disease progression in Systemic Lupus Erythematosus
Full text linkEndosomal trafficking is key to intercellular communication and metabolic regulation of immunological development. Rab4a, an endosomal trafficker, is elevated in lupus T cells and polymorphisms of the Rab4a gene have been linked to disease susceptibility. Here, we report the constitutive activation of Rab4a increases susceptibility and severity to lupus nephritis in the
genetic SLE1.2.3. model of lupus and is corrected by the deletion of Rab4a in T cells. Alternatively, in a pristane model of induced autoimmunity, the deletion of Rab4a in T cells magnifies the pulmonary manifestations of diffuse alveolar hemorrhage that is otherwise protected by the constitutive activation of Rab4a. Rab4a mediates these changes through control over mTOR, mitochondrial function and homeostasis, and immunological development. In particular, inactivation of Rab4a in T cells
reduces expression of activation signals, mitochondrial mass and electrochemical potential. Alterations to Rab4a activity drives the aberrant development and function of anti-inflammatory regulatory T cells and pro-inflammatory double-negative T cells. These data provide new insights into the regulation of metabolism and immunological development through endosomal trafficking. As such, the targeting of Rab4a is a novel therapeutic approach in the treatment of autoimmune diseases such as lupus, which has lacked new targeted therapeutics for more than half a century.NAUpstate Medical UniversityBiochemistry and Molecular BiologyN/
MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS
Full text linkSystemic lupus erythematosus (SLE) is an autoimmune disorder,
characterized by T cell and B cell dysfunction. SLE mitochondria have been
shown to be dysfunctional with increased mass, mitochondrial potential,
decreased ATP, elevated reactive oxygen species (ROS) and reactive nitrogen
species (RNS) concentrations, and altered Ca2+ stores. Drug treatments that
target the mitochondria have shown efficacy in treating SLE. Here we have
investigated electron transport chain (ETC) activity in SLE, to better understand
the causes of mitochondrial dysfunction in SLE.
We have found that mitochondrial complexes I and IV of the ETC have
elevated respiration in SLE compared to healthy controls after both overnight
resting and anti-CD3/CD28 stimulation. We have also shown that SLE complex I
is resistant to NO inhibition of respiration. SLE peripheral blood lymphocytes
(PBL) have increased S-nitrosylation (SNO) while immunoprecipitated complex I
had decreased SNO of proteins compared to healthy controls. The drug Nacetylcysteine (NAC) was able to inhibit complex I activity in SLE, and was found
to reduce the amount of complex I protein NDUFS3 after 15 minutes as
measured by western blotting.
These results have led us to the conclusion that SLE mitochondrial
complex I is in an active form which is resistant to SNO and is driving the
production of ROS and RNS that are associated with SLE. The drug NAC is able
to inhibit complex I respiration which may have therapeutic efficacy by reducing
the ROS and RNS stress in SLE.NAUpstate Medical UniversityMicrobiology and ImmunologyPh
Effects of Rab4A Mutations on Mouse Behavior, mTORC1 Activity,and Surface 8Receptor/TransporterRecycling
Full text linkThrough studying endosomal regulation, I found that a single amino acid 47mutation (Q72L) in the Rab4A gene leads to neurological disorders in two separate 48mouse strains. In the C57Bl/6 (SLE(WT)) background,I found thatknock-in the 49Rab4A gene leads to hyperactivity, which resembles both autism spectrum 50disorders (ASD) and attention-deficit hyperactivity disorder (ADHD). On a lupus-51prone background (SLE(1.2.3)) I found thatthe same mutation led to hypoactivity, 52which indicates a more severe neuropsychiatric systemic lupus erythematosus 53(NPSLE) than SLE(1.2.3)mice with wild type Rab4A.54The same mice were studied in chapter two, where mTORC1 activity was 55confirmed to be elevated in CD4+ T cells when Rab4A was knocked-in (Rab4A(KI))56compared to Rab4A(WT) cells.In young mouse brains prior to disease onset, I found57increases of mTORC1 and oxidative stress in Rab4A(KI) brains relative to 58Rab4A(WT) brains. In the same brains, there was also a depletion of GLUT1 and 59IFNGR1.Many of these changes were absent in the adult mice, after disease had 60developed.61SLE(1.2.3) mice with the three Rab4A alleleswere treated withrapamycin or 62NAC,and brains were collected.In these brains, there wasevidence that the 63hypoactive Rab4A(KI) SLE(1.2.3) had lower mTORC1 activity than Rab4A(WT) and 64Rab4A(KO) mice.This finding indicatesdepression, which is a pattern seen in major 65depressive disorder(MDD). Depression is also a symptoms of NPSLE. Interestingly, 66rapamycin increased mTORC1 activity in theRab4A(KI)brains compared Rab4A(KI) 67mice treated with vehicle, indicating a positive effect from the drug.NAUpstate Medical UniversityBiochemistryN/
Metabolic Control of Autoimmunity in the Liver
Full text linkAutophagy,literally meaning “self-eating,” is an integral part of cellularturnover of damaged organelles and proteins.This process is inextricably linked to mitochondrial function and turnover. Mitochondria can be degraded viaautophagy, known as mitophagy, as well as donate lipid membraneto generate autophagosomes fordigestingother organelles and proteins. On a larger scale, autophagy is essential for organ homeostasis. In the liver, autophagy ensures the turnover of damaged mitochondria that may otherwise increase oxidative stress which modifies DNA, proteins, and lipids resulting in the production of autoantigens or neoplasia. We investigated the role of autophagy and mitochondrial dysfunction prior to disease onset in mouse models of systemic lupus erythematosus (SLE). Patients and mice with SLE exhibit overexpression of transaldolase (TAL) and show predisposition to anti-phospholipid antibody production and associated liver diseases, including hepatocellular carcinoma. Wediscovered deficient mitophagy in the liver of lupus-prone mice prior to disease onset. Furthermore, these mice had increased mitochondrial respirationwith concomitant inner membrane hyperpolarization. These changes were coupled to overexpression of Rab4A, which depletes Drp1and thus inhibitsmitophagy.In addition,activation of complex I of the mechanistic target of rapamycin (mTORC1)was noted along with enhanced production of autoantibodies against mitochondrial phospholipids in lupus-prone mice. These changes were reversed by blockade of mTORC1 by rapamycin treatment in vivo. We then examined the role of TAL, a key enzyme of the pentose phosphate pathway (PPP) in mitochondrial dysfunction and oxidative stress. TAL-deficientmice showedincreased mitochondrial electron transport chain (ETC) activity and mTORC1 activation andreduced autophagy.Since inactivation of TAL caused oxidative stress via depletion of NADPH, we tested the hypothesis that aldose reductase(AR), a NADPH dependent enzymecan correct this metabolic defect without reversing the accumulation of TAL-specific substrates, sedoheptulose 7-phosphate and erythrose 4-phosphate. Moreover, deletion of AR reversed mTORC1 activation without affecting enhanced mitochondrial ETC activity or diminished autophagy. On a more global scale, predisposition to neoplasia and acetaminophen-induced liver failurewere reversed, while anti-phospholipid autoantibody production and liver fibrosis persisted in TAL/AR double-knockout mice indicatingthat the PPPmay act as a metabolic rheostat of organ-specific disease pathogenesis.NAUpstate Medical UniversityBiochemistry and Molecular BiologyPh
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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