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Mark A Smith

Publications and source records attributed to Mark A Smith.

At least 73 records · Page 4Linked to original sources
PubMed2005

Organic environments on Saturn's moon, Titan: simulating chemical reactions and analyzing products by FT-ICR and ion-trap mass spectrometry.

Laboratory simulations have been carried out to model chemical reactions that possibly take place in the stratosphere of Saturn's moon, Titan. The aerosol products of these reactions (tholin samples) have been systematically analyzed by mass spectrometry using electrospray ionization (ESI) and laser desorption (LD). A wide variety of ions with a general formula C(x)H(y)N(z) detected by ultrahigh resolution and accurate mass measurements in a Fourier transform/ion cyclotron resonance (FT-ICR) cell reflect the complexity of these polymeric products, both in chemical compositions and isomeric distributions. As a common feature, however, tandem mass spectral (MS/MS) data and H/D exchange products in the solution phase support the presence of amino and nitrile functionalities in these (highly unsaturated) "tholin" compounds. The present work demonstrates that ESI-MS coupled with FT-ICR is a suitable and "intact" method to analyze tholin components formed under anaerobic conditions; only species with C(x)H(y)N(z) are detected for freshly prepared and harvested samples. However, when intentionally exposed to water, oxygen-containing compounds are unambiguously detected.

Journal Article↗
PubMed2005

The role of insulin receptor substrate 2 in hypothalamic and beta cell function.

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.

Animals↗
PubMed2005

Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations.

Several recent studies support a link between tau protein phosphorylation and adduction of tau by reactive carbonyls. Indeed, the phosphorylation-dependent adduction of tau by carbonyl products resulting from lipid peroxidation creates the neurofibrillary tangle-related antigen, Alz50. To determine whether epitopes of carbonyl-modified tau are major conformational changes associated with neurofibrillary tangle formation, we examined seven distinct antibodies raised against neurofibrillary tangles that recognize unique epitopes of tau in Alzheimer disease. Consistently, all seven antibodies recognize tau more strongly (4- to 34-fold) after treatment of normal tau with the reactive carbonyl, 4-hydroxy-2-nonenal (HNE), but only when tau is in the phosphorylated state. These findings not only support the idea that oxidative stress is involved in neurofibrillary tangle formation occurring in brains of Alzheimer disease patients, but also show, for the first time, that HNE modifications of tau promote and contribute to the generation of the major conformational properties defining neurofibrillary tangles.

Aged↗
PubMed2005

Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron.

Oxidative modification of cytoplasmic RNA in vulnerable neurons is an important, well documented feature of the pathophysiology of Alzheimer disease. Here we report that RNA-bound iron plays a pivotal role for RNA oxidation in vulnerable neurons in Alzheimer disease brain. The cytoplasm of hippocampal neurons showed significantly higher redox activity and iron(II) staining than age-matched controls. Notably, both were susceptible to RNase, suggesting a physical association of iron(II) with RNA. Ultrastructural analysis further suggested an endoplasmic reticulum association. Both rRNA and mRNA showed twice the iron binding as tRNA. rRNA, extremely abundant in neurons, was considered to provide the greatest number of iron binding sites among cytoplasmic RNA species. Interestingly, the difference of iron binding capacity disappeared after denaturation of RNA, suggesting that the higher order structure may contribute to the greater iron binding of rRNA. Reflecting the difference of iron binding capacity, oxidation of rRNA by the Fenton reaction formed 13 times more 8-hydroxyguanosine than tRNA. Consistent with in situ findings, ribosomes purified from Alzheimer hippocampus contained significantly higher levels of RNase-sensitive iron(II) and redox activity than control. Furthermore, only Alzheimer rRNA contains 8-hydroxyguanosine in reverse transcriptase-PCR. Addressing the biological significance of ribosome oxidation by redox-active iron, in vitro translation with oxidized ribosomes from rabbit reticulocyte showed a significant reduction of protein synthesis. In conclusion these results suggest that rRNA provides a binding site for redox-active iron and serves as a redox center within the cytoplasm of vulnerable neurons in Alzheimer disease in advance of the appearance of morphological change indicating neurodegeneration.

Alzheimer Disease↗
PubMed2005

Low temperature NH(X 3sigma-) radical reactions with NO, saturated, and unsaturated hydrocarbons studied in a pulsed supersonic laval nozzle flow reactor between 53 and 188 K.

The reactions of ground-state imidogen radicals (NH(X 3sigma-)) with NO and select saturated and unsaturated hydrocarbons have been measured in a pulsed supersonic expansion Laval nozzle flow reactor in the temperature range 53-188 K. The rate coefficients for the NH + NO system display negative temperature dependence in the temperature regime currently investigated and a global temperature-dependent fit is best represented in a modified power law functional form, with k1(NH + NO) = (4.11 +/- 0.31) x 10(-11) x (T/300)(-0.30+/-0.17) x exp(77+/-21/T) cm3/s. The reactions of NH with ethylene, acetylene, propene, and diacetylene were measured over the temperature range 53-135 K. In addition, the reactions of NH with methane and ethane were also measured at 53 K, for reasons discussed later. The temperature dependence of the reactions of NH with the unsaturated hydrocarbons are fit using power law expressions, k(T) = A(T/300)(-n), and are as follows: k4 = (2.3 +/- 1.2) x 10(-12) x (T/300)(-1.09+/-0.33) cm3/s, k5 = (4.5 +/- 0.3) x 10(-12) x (T/300)(-1.07+/-0.04) cm3/s, k6 = (5.6 +/- 1.9) x 10(-12) x (T/300)(-1.23+/-0.21) cm3/s, and k7 = (7.4 +/- 1.8) x 10(-12) x (T/300)(-1.23+/-0.15) cm3/s for ethylene, acetylene, propene, and diacetylene, respectively. The rate for NH + ethane at 53 K is measured to be k3 = (6.8 +/- 1.7) x 10(-12) cm3/s, while that for methane at the same temperature represents an upper bound of k2 < or = (1.1 +/- 4.3) x 10(-12) cm3/s, as this is at the limits of measurement with our current technique. The behavior of these systems throughout the temperature range explored indicates that these reactions occur over a potential energy surface without an appreciable barrier through a complex formation mechanism. Implications for chemistry in low temperature environments where these species are found are briefly discussed.

Journal Article↗
PubMed2005

Mitogen- and stress-activated protein kinase 1: convergence of the ERK and p38 pathways in Alzheimer's disease.

Two of the earliest manifestations of the selective neurodegeneration that occurs in Alzheimer's disease (AD) involve the oxidative modification of various biomacromolecules and the reexpression of a multitude of cell cycle-related proteins. Taken together with the proximal and ectopic increases in activated components of the ERK and p38 pathways, involved in mitotic and cellular stress signaling, respectively, there is a clear and important role for mitotic and oxidative insults in the pathogenesis of AD. Despite the mounting evidence, however, for the causal role of mitogenic abnormalities and oxidative stress in AD pathogenesis, the effect of the converging relevant pathways due to chronic stimulation in AD remains largely unknown. To delineate further the mechanism by which mitogenic and stress signaling cascades converge, we focused on one of the downstream effectors of activated ERK and p38, mitogen- and stress-activated kinase 1 (MSK1). Activated MSK1, phosphorylated at residues Ser376 and Thr581, was upregulated in vulnerable neurons in AD when compared to that in age-matched controls, whereas MSK1 phosphorylated at residue Ser360 was not increased in AD. Furthermore, activated MSK1 phosphorylated at Thr581 colocalized strongly with activated p38 but only weakly with activated ERK, whereas MSK1 phosphorylated at Ser376 colocalized strongly with activated ERK but only weakly with activated p38, suggesting potential preferential phosphorylation sites for the two upstream effectors.

Aged↗
PubMed2005

Tau modifiers as therapeutic targets for Alzheimer's disease.

Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Aldehydes↗
PubMed2005

Neurotoxic dopamine quinone facilitates the assembly of tau into fibrillar polymers.

Aberrant aggregation of microtubule associated protein tau is the main characteristic of different disorders known as tauopathies. Different compounds have been described to facilitate tau aberrant aggregation. In this work, we demonstrate that oxidized products of dopamine (neurotoxic dopamine quinone), a neurotransmitter involved in Parkinson's disease, promote tau polymerization. Curiously, neurons expressing dopamine (substantia nigra) show a low content of tau protein and seldom have tau aggregation in tauopathies. In non-dopaminergic neurons, quinone oxidation products may be involved in tau polymerization. These results support a link between oxidative damage and the onset of tauopathies.

Animals↗
PubMed2005

The cell cycle in Alzheimer disease: a unique target for neuropharmacology.

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

Alzheimer Disease↗
PubMed2005

Tau phosphorylation in Alzheimer's disease: pathogen or protector?

During the past decade, hypotheses concerning the pathogenesis of most neurodegenerative diseases have been dominated by the notion that the aggregation of specific proteins and subsequent formation of cytoplasmic and extracellular lesions represent a harbinger of neuronal dysfunction and death. As such, in Alzheimer's disease, phosphorylated tau protein, the major component of neurofibrillary tangles, is considered a central mediator of disease pathogenesis. We challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress and serves a protective function. This novel concept, which can also be applied to protein aggregates in other neurodegenerative diseases, opens a new window of knowledge with broad implications for both the understanding of mechanisms underlying disease pathophysiology and the design of new therapeutic strategies.

Alzheimer Disease↗
PubMed2005

Alzheimer's disease: an intracellular movement disorder?

Axonal transport is essential for maintaining the structure and function of nerve cells. Deficient axonal transport has been implicated in several neurodegenerative diseases, including Alzheimer's disease (AD). In addition to a disturbed cytoskeleton and other abnormalities observed in AD that are suggestive of axonal transport deficits, several AD-related proteins are implicated in the regulation of axonal transport. A recent study has demonstrated that the axonal transport deficit occurs early in the course of AD, preceding amyloid pathology substantially in mouse models of AD; more importantly, the study showed that reduced axonal transport leads to increased amyloid beta production and deposition. These data place axonal transport deficits at a central point in the pathogenesis of AD.

Alzheimer Disease↗
PubMed2005

4-Oxo-2-nonenal is both more neurotoxic and more protein reactive than 4-hydroxy-2-nonenal.

Electrophilic aldehydes, generated from oxidation of polyunsaturated fatty acyl chains under conditions of oxidative stress, bind to proteins and polynucleotides and can lead to cell death. 4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) have been shown here to be toxic to human neuroblastoma cells in culture at low micromolar concentrations. ONE is 4-5 times more neurotoxic at concentrations near the threshold of lethality. The reactions of these two aldehydes with two model proteins, ribonuclease A and beta-lactoglobulin, and their Lys epsilon-dimethylamino derivatives, have been followed spectrophotometrically. On the basis of t(1/2) measurements for the disappearance of the alpha,beta-unsaturated chromophore, ONE is 6-31 times more reactive with these proteins. The fastest reaction of ONE with proteins involves Schiff base formation at Lys epsilon-amino groups, whereas Schiff base formation is not spectroscopically apparent for HNE. Detailed kinetic studies of the initial reactions of HNE and ONE have been carried out with amino acids and amino acid surrogates. Whereas the reactions with imidazole and thiol nucleophiles involve straightforward Michael adduct formation, kinetics analyses reveal the reversibility of both the HNE Michael adduction of amines and the ONE Schiff base adduction of amines. Although ONE is more reactive than HNE toward conjugate addition of imidazole and thiol nucleophiles, it is less reactive than HNE toward Lys/amine Michael adduction. The greater neurotoxicity of ONE could reflect in part the different reactivity characteristics of ONE as compared to HNE.

Aldehydes↗
PubMed2005

Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence.

Senescence is characterized neurologically by a decline in cognitive function, which we propose is the result of degenerative processes initiated by the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis with menopause and andropause. Compelling epidemiologic evidence to support this assertion includes the increased prevalence of Alzheimer disease (AD) in women, the correlation of serum HPG hormones with disease and the decreased incidence, and delay in the onset of AD following hormone replacement therapy. Dysregulation of the axis at this time leads to alterations in the concentrations of all serum HPG hormones (decreased neuronal sex steroid signaling, but increased neuronal gonadotropin releasing hormone, luteinizing hormone, and activin signaling). Hormones of the HPG axis, receptors for which are present in the adult brain, are important regulators of cell proliferation and differentiation during growth and development. Based on this, we propose that dysregulated HPG hormone signaling with menopause/andropause leads to the abortive reentry of differentiated neurons into the cell cycle via a process we term "dyosis." Interestingly, the major biochemical and neuropathologic changes reported for the AD brain also are intimately associated with neuron division: altered AbetaPP metabolism, Abeta deposition, tau phosphorylation, mitochondrial alterations, chromosomal replication, synapse loss, and death of differentiated neurons. Recent evidence supports the premise that AD-related biochemical changes are likely the combined result of increased mitotic signaling by gonadotropins and GnRH, decreased differentiative and neuroprotective signaling via sex steroids, and increased differentiative signaling via activins. This results in a hormonal milieu that is permissive of cell cycle reentry but does not allow completion of metaphase. Partial resetting of the axis following administration of normal endogenous sex steroids delays the onset and decreases the incidence of AD. Ideally, supplementation with HPG hormones should mimic closely the serum concentrations of all HPG hormones in reproductive men and cycling women to prevent dyotic signaling and attempted neuron division.

Adult↗
PubMed2005

Rapid dose escalation with quetiapine: a pilot study.

The original dosing recommendations for quetiapine in the treatment of schizophrenia suggested escalation to 400 mg/d using the following schedule, administered twice daily in divided doses: Day 1, 50 mg; Day 2, 100 mg; Day 3, 200 mg; Day 4, 300 mg; Day 5, 400 mg. In practice, however, clinicians often exceed these recommendations because of the need to obtain a therapeutic response in patients with psychosis as quickly as possible. This study was designed to determine a faster tolerable dosage-escalation schedule for quetiapine in acutely ill, hospitalized patients with schizophrenia. In this multicenter, placebo-controlled, double-blind pilot study, adult patients were randomly assigned to escalation schedules that would achieve a target dosage of 400 mg/d in either 5, 3, or 2 days. Safety and tolerability were assessed by interviews, physical examinations and vital signs, laboratory tests, and electrocardiograms. The enrolled population consisted of 69 patients who were randomized to 1 of the 3 dose-escalation schedules. Treatment-related adverse events were few among the 67 evaluable patients, with most rated as mild in intensity. Among 69 enrolled patients, only 3 withdrew because of an adverse event (agitation). Objective assessments and adverse events were similar between the 3 groups. In this study of patients with acute schizophrenia, quetiapine dosage was increased to 400 mg/d in 5, 3, and 2 days with similar safety and tolerability, suggesting that escalation to therapeutically effective dosages can be accomplished in less than 5 days.

Acute Disease↗
PubMed2005

Comparative genome sequencing of Drosophila pseudoobscura: chromosomal, gene, and cis-element evolution.

We have sequenced the genome of a second Drosophila species, Drosophila pseudoobscura, and compared this to the genome sequence of Drosophila melanogaster, a primary model organism. Throughout evolution the vast majority of Drosophila genes have remained on the same chromosome arm, but within each arm gene order has been extensively reshuffled, leading to a minimum of 921 syntenic blocks shared between the species. A repetitive sequence is found in the D. pseudoobscura genome at many junctions between adjacent syntenic blocks. Analysis of this novel repetitive element family suggests that recombination between offset elements may have given rise to many paracentric inversions, thereby contributing to the shuffling of gene order in the D. pseudoobscura lineage. Based on sequence similarity and synteny, 10,516 putative orthologs have been identified as a core gene set conserved over 25-55 million years (Myr) since the pseudoobscura/melanogaster divergence. Genes expressed in the testes had higher amino acid sequence divergence than the genome-wide average, consistent with the rapid evolution of sex-specific proteins. Cis-regulatory sequences are more conserved than random and nearby sequences between the species--but the difference is slight, suggesting that the evolution of cis-regulatory elements is flexible. Overall, a pattern of repeat-mediated chromosomal rearrangement, and high coadaptation of both male genes and cis-regulatory sequences emerges as important themes of genome divergence between these species of Drosophila.

Animals↗
PubMed2005

Amyloid-beta in Alzheimer's disease: the horse or the cart? Pathogenic or protective?

While the pathogenesis of Alzheimer's disease (AD) is unclear, amyloid-beta plaques remain major lesions in the brain of individuals with AD. Likewise, amyloid-beta is one of the best-studied proteins relating to the pathogenesis of AD. Indeed, the pathological diagnosis of AD tends to be congruous with the quantity of amyloid-beta. However, it is important to recognize that pathological diagnosis merely represents the association of a pattern of pathological changes with a clinical phenotype. Therefore, it should be acknowledged that, although amyloid-beta detection and semiquantification have some diagnostic utility, the simple presence of amyloid plaques, as with proteinaceous accumulations in essentially all neurodegenerative diseases, does not presume aetiology. Thus, in this review, we discuss the role of amyloid-beta in the pathogenesis of AD and provide an alternative view to the widely accepted dogma.

Alzheimer Disease↗