1,720,998 research outputs found
Mutant Huntingtin and Elusive Defects in Oxidative Metabolism and Mitochondrial Calcium Handling .
No full textElongation of a polyglutamine (polyQ) stretch in huntingtin protein (Htt) is linked to Huntington's disease (HD) pathogenesis. The mutation in Htt correlates with neuronal dysfunction in the striatum and cerebral cortex and eventually leads to neuronal cell death. The exact mechanisms of the injurious effect of mutant Htt (mHtt) on neurons are not completely understood but might include aberrant gene transcription, defective autophagy, abnormal mitochondrial biogenesis, anomalous mitochondrial dynamics, and trafficking. In addition, deficiency in oxidative metabolism and defects in mitochondrial Ca(2+) handling are considered essential contributing factors to neuronal dysfunction in HD and, consequently, in HD pathogenesis. Since the discovery of the mutation in Htt, the questions whether mHtt affects oxidative metabolism and mitochondrial Ca(2+) handling and, if it does, what mechanisms could be involved were in focus of numerous investigations. However, despite significant research efforts, the detrimental effect of mHtt and the mechanisms by which mHtt might impair oxidative metabolism and mitochondrial Ca(2+) handling remain elusive. In this paper, I will briefly review studies aimed at clarifying the consequences of mHtt interaction with mitochondria and discuss experimental results supporting or arguing against the mHtt effects on oxidative metabolism and mitochondrial Ca(2+) handling
Mitochondrial protein acetylation and left ventricular function in a model of hypertrophic cardiomyopathy and heart failure
No full textIndiana University-Purdue University Indianapolis (IUPUI)Rationale: The childhood heart disease of Friedreich’s Ataxia (FRDA) is characterized by
hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved
in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and
impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of
cardiac metabolism and SIRT3 is protective in heart disease. The underlying pathophysiology of
heart failure in FRDA is unclear. I suspect that increased acetylation in FRDA heart mitochondria
damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart
metabolism.
Objective: My project tested the hypothesis that altered acetylation of mitochondrial proteins
contributes to the cardiomyopathy of FRDA.
Methods: Conditional mouse models of FRDA cardiomyopathy with ablation of FXN (FXN KO)
or FXN and SIRT3 (FXN/SIRT3 DKO) in the heart were compared to healthy controls. Hearts
were evaluated using echocardiography, cardiac catheterization, histology, protein acetylation and expression. FXN KO mice were treated with NAD+ replacement therapy with nicotinamide
riboside (NR), and FXN/SIRT3 DKO mice were treated with FXN protein replacement therapy.
Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the
FXN KO model. High levels of acetylation were associated with cardiac fibrosis, mitochondrial
damage, impaired fat metabolism, and diastolic and systolic dysfunction. Acetylation correlated strongly with worse heart function, and loss of SIRT3 in the FXN KO mouse resulted in
significant decrease in ejection fraction and fractional shortening. Treatment of the FXN/SIRT3
DKO with FXN protein therapy reduced acetylation but was not sufficient to fully rescue heart function. Increasing NAD+ with NR-treatment in the FXN KO lead to increased mitochondrial
protein acetylation and did not improve cardiac outcome.
Conclusion: I found a strong negative correlation between heart function and mitochondrial
protein acetylation. My findings also provide evidence that absence of SIRT3 expression in the
FXN KO heart exacerbates features of heart failure, and that SIRT3 expression is necessary to
rescue the FXN KO heart. These results suggest that SIRT3 inactivation and abnormal acetylation
contribute to the pathophysiology of heart disease in FRDA
The Role of Adenine Nucleotide Translocase in the Mitochondrial Permeability Transition
No full textThe mitochondrial permeability transition, a Ca2+-induced significant increase in permeability of the inner mitochondrial membrane, plays an important role in various pathologies. The mitochondrial permeability transition is caused by induction of the permeability transition pore (PTP). Despite significant effort, the molecular composition of the PTP is not completely clear and remains an area of hot debate. The Ca2+-modified adenine nucleotide translocase (ANT) and F0F1 ATP synthase are the major contenders for the role of pore in the PTP. This paper briefly overviews experimental results focusing on the role of ANT in the mitochondrial permeability transition and proposes that multiple molecular entities might be responsible for the conductance pathway of the PTP. Consequently, the term PTP cannot be applied to a single specific protein such as ANT or a protein complex such as F0F1 ATP synthase, but rather should comprise a variety of potential contributors to increased permeability of the inner mitochondrial membrane
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Paclitaxel alters the function of the small diameter sensory neurons
No full textIndiana University-Purdue University Indianapolis (IUPUI)Although paclitaxel is a commonly used anti-neoplastic agent for
the treatment of solid tumors, therapy often results in a number of side
effects, the most debilitating of which is peripheral neuropathy. Peripheral
neuropathy is defined as a pathology of peripheral nerves, and, depending
on the type of nerves damaged, the neuropathy can be classified as
sensory, motor, or autonomic neuropathy. In the case of peripheral
neuropathy induced by paclitaxel, the symptoms are experienced in the
extremities and are sensory in nature. Patients undergoing chemotherapy
with paclitaxel often report sensory disturbances such as burning, tingling,
numbness, a diminished sensation to pain and temperature, loss of
vibration sense, loss of proprioception, and loss of deep tendon reflexes.
Electrophysiological abnormalities including decreased sensory nerve
action potential amplitude and conduction confirm damage to large
myelinated fibers. However, the involvement of damage to small diameter
sensory neurons in the etiology of paclitaxel – induced peripheral
neuropathy is still controversial. Therefore, experiments were performed to
determine if paclitaxel alters the function of small diameter sensory
neurons and to examine the mechanisms responsible for the change in
function.
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Sensory neuron mediated vasodilatation in paclitaxel – injected
animals was examined as an indirect measure of calcitonin gene related
peptide (CGRP) release and therefore of sensory neuron function. CGRP
release was also directly measured from central terminals in the spinal
cord. To examine mechanisms of paclitaxel – induced sensory neuron
damage, CGRP release and neurite length was examined in paclitaxel –
treated sensory neurons in culture. The results demonstrate that (1)
paclitaxel decreases the ability of small diameter sensory neurons to
produce an increase in blood flow in the skin; (2) paclitaxel alters the
release of CGRP from the small diameter sensory neurons; (3) paclitaxel
causes the neuronal processes of isolated sensory neurons to
degenerate. This dissertation provides novel information showing that
paclitaxel alters the function of small diameter sensory neurons and thus
provides a better understanding of the mechanisms mediating the sensory
disturbances characteristic of peripheral neuropathy resulting from
chemotherapy with paclitaxel
A New Mechanism of Serotonin Transporter Regulation by Simvastatin and the Isoprenylation Pathway
No full textIndiana University-Purdue University Indianapolis (IUPUI)The serotonergic system in the brain is necessary for neurophysiological
processes related to mood, sleep, and cognitive regulation. This system is primarily
regulated through the transport of extracellular serotonin (5-HT) into neuron terminals by
the serotonin transporter (SERT). The activity of SERT is thought to be modulated in part
by cholesterol and lipid rich microdomains within the plasma membrane where SERT
localizes. However, experiments related to the mechanism of membrane cholesterol on
SERT function in the brain has yielded conflicting results and no studies have examined
the contribution of cholesterol biosynthetic intermediates in regulating SERT function.
To address this knowledge gap, this dissertation examined the neuropharmacological
effects of the highly prescribed cholesterol-lowering statin drugs on SERT-dependent 5-
HT uptake into neurons. Unexpectedly, statin treatment increased SERT-dependent 5-HT
uptake in a neuron cell model, and increased in vivo 5-HT content in synaptosomes. The
mechanistic findings demonstrated that (1) statins enhanced activity of SERT rather than
altered distribution at the membrane, (2) statins increased 5-HT uptake in a manner that is
independent of cholesterol per se but is mediated in part by the cholesterol biosynthetic
intermediates of the isoprenylation pathway, namely farnesyl pyrophosphate (FPP) and
geranylgeranyl pyrophosphate (GGPP), (3) direct inhibition of the isoprenylation
pathway through inhibition of GGPP enzyme geranylgeranyl transferase (GGT) also
increased 5-HT uptake in a SERT-dependent manner, and (4) increased 5-HT uptake by
statins or GGT inhibition was dependent on Ca2+/calmodulin-dependent protein kinase
(CAMKII).
Our results provide a novel role for lipid signaling in regulating SERT and a
newly identified function of the isoprenylation pathway in the brain. These results also
provide a possible explanation for the adverse neurological effects associated with the
widely prescribed statin drugs
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
Epilepsy Mutations in Different Regions of the Nav1.2 Channel Cause Distinct Biophysical Effects
Get PDFWhile most cases of epilepsy respond well to common antiepileptic drugs, many genetically-driven epilepsies are refractory to conventional antiepileptic drugs. Over 250 mutations in the Nav1.2 gene (SCN2A) have been implicated in otherwise idiopathic cases of epilepsy, many of which are refractory to traditional antiepileptic drugs. Few of these mutations have been studied in vitro to determine their biophysical effects on the channels, which could reveal why the effects of some are refractory to traditional antiepileptic drugs. The goal of this dissertation was to characterize multiple epilepsy mutations in the SCN2A gene, which I hypothesized would have distinct biophysical effects on the channel’s function. I used patch-clamp electrophysiology to determine the biophysical effects of three SCN2A epilepsy mutations (R1882Q, R853Q, and L835F). Wild-type (WT) or mutant human SCN2A cDNAs were expressed in human embryonic kidney (HEK) cells and subjected to a panel of electrophysiological assays. I predicted that the net effect of each of these mutations was enhancement of channel function; my results regarding the L835F and R1882Q mutations supported this hypothesis. Both mutations enhance persistent current, and R1882Q also impairs fast inactivation. However, examination of the same parameters for the R853Q mutation suggested a decrease of channel function. I hypothesized that the R853Q mutation creates a gating pore in the channel structure through which sodium leaks into the cell when the channel is in its resting conformation. This hypothesis was supported by electrophysiological data from Xenopus oocytes, which showed a significant voltage-dependent leak current at negative potentials when they expressed the R853Q mutant channels. This was absent in oocytes expressing WT channels. Overall, these results suggest that individual mutations in the SCN2A gene generate epilepsy via distinct biophysical effects that may require novel and/or tailored pharmacotherapies for effective management
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