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PubMed2006

Overcoming HIV drug resistance through rational drug design based on molecular, biochemical, and structural profiles of HIV resistance.

There are 20 available drugs for the treatment of human immunodeficiency virus (HIV) infection. With a single exception, all of these drugs inhibit either HIV reverse transcriptase or protease. Reverse transcriptase inhibitors can be further categorized as nucleoside/nucleotide analogs or non-nucleoside reverse transcriptase inhibitors. Resistance that has emerged against all available antiretroviral drugs represents a major challenge in the therapy of HIV infection. Nevertheless, extensive analysis of the molecular and structural mechanisms by which such mutations confer resistance has accumulated over the years. This understanding has driven the development and refinement of novel compounds capable of maintaining antiviral activity against both wild-type and drug-resistant HIV strains. The molecular, biochemical, and structural profiles of reverse transcriptase inhibitor and protease inhibitor resistance are discussed. In addition, how this knowledge has been utilized to generate a new generation of antiviral drugs with activity against drug-resistant HIV is reviewed.

Anti-HIV Agents↗

PubMed2006

Heterodimeric adenosine receptors: a device to regulate neurotransmitter release.

Since 1990 it has been known that dimers are the basic functional form of nearly all G-protein-coupled receptors (GPCRs) and that homo- and heterodimerization may play a key role in correct receptor maturation and trafficking to the plasma membrane. Nevertheless, homo- and heterodimerization of GPCR has become a matter of debate especially in the search for the precise physiological meaning of this phenomenon. This article focuses on how heterodimerization of adenosine A1 and A2A receptors, which are coupled to apparently opposite signalling pathways, allows adenosine to exert a fine-tuning modulation of striatal glutamatergic neurotransmission, providing a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release.

Adenosine↗

PubMed2006

Structural determinants for G-protein activation and specificity in the third intracellular loop of the thyroid-stimulating hormone receptor.

The selectivity of G-protein recognition is determined by the intracellular loops (ICLs) of seven-transmembrane-spanning receptors. In a previous study, we have shown that the N-terminal and central portions of ICL2 from F525 to D530 participate in dual Galphas-/Galphaq-protein activation by the thyroid-stimulating hormone receptor (TSHR). ICL3 is another major determinant for G-protein activation. Therefore, the aim of our study was to identify important amino acids within ICL3 of the TSHR to gain insight in more detail about its specific function for Galphas- and Galphaq-protein activation and selectivity. Single-alanine substitutions of residues in the N-terminal, middle, and C-terminal region of ICL3 were generated. N-terminal residues Y605 and V608 and C-terminal positions K618, K621, and I622 were identified as selectively important for Galphaq activation, whereas mutations in the center of ICL3 had no effect on TSHR signaling. Our findings provide evidence for an amino acid pattern in the N- and C-terminal part of ICL3, which is involved in Galphaq-mediated signaling. Furthermore, molecular modeling of interaction of TSHR ICL2 and 3 with Galphaq suggests three potential contact sites: TSHR C-terminal ICL3 with beta5-6 loop of Galphaq, TSHR ICL2 residues I523-R531 with beta2-3 loop and N-terminal helix of Galphaq, and TSHR ICL2/transmembrane helix (TMH) 3+ICL3/TMH6 with C-terminal tail of Galphaq.

Alanine↗

PubMed2006

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models.

AIMS/HYPOTHESIS: Recently, various transgenic and knock-out mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. MATERIALS AND METHODS: The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, alpha-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD(+)/NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. RESULTS: Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested approximately 26- and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3- to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD(+)/NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. CONCLUSIONS/INTERPRETATION: Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.

Animals↗

PubMed2005

Discriminative stimulus and reinforcing effects of p-fluoro-L-deprenyl in monkeys.

RATIONALE: para-Fluoro-L-deprenyl (Fludepryl), a halogenated derivative of L-deprenyl, shares structural similarities with amphetamine and may have potential as a medication for psychostimulant abuse. OBJECTIVES: p-Fluoro-L-deprenyl was evaluated for psychomotor stimulant, discriminative stimulus, and reinforcing effects in squirrel monkeys. METHODS: One group of monkeys was trained under a ten-response fixed-ratio (FR10) schedule of stimulus termination to discriminate between methamphetamine (0.32 mg/kg, i.m.) and saline. Other monkeys were trained to self-administer i.v. cocaine under either a simple FR10 schedule or a second-order fixed-interval 5-min schedule with FR10 components. RESULTS: Full generalization to the methamphetamine-training stimulus was produced by an i.m. dose of 10.0 mg/kg p-fluoro-L-deprenyl. L-Deprenyl and the metabolites of p-fluoro-L-deprenyl, p-fluoro-L-amphetamine, and p-fluoro-L-methylamphetamine were more potent, producing full generalization at doses of 1.0-3.2 mg/kg. Under the FR10 schedule of drug injection, persistent self-administration behavior was maintained by i.v. cocaine injections but not by injections of vehicle or injection doses of p-fluoro-L-deprenyl up to 1.0 mg/kg. However, p-fluoro-L-deprenyl did maintain moderate levels of i.v. self-administration responding under the second-order schedule of drug injection. Peak response rates maintained by 0.1-mg/kg injections of p-fluoro-L-deprenyl were significantly greater than those associated with saline substitution, yet significantly lower than those maintained by cocaine or D-amphetamine. CONCLUSIONS: p-Fluoro-L-deprenyl has methamphetamine-like discriminative-stimulus properties in squirrel monkeys that appear at higher doses than for its parent compound, L-deprenyl. It also appears to function as a relatively limited reinforcer of intravenous self-administration behavior in monkeys trained to self-administer i.v. cocaine.

Amphetamine-Related Disorders↗

PubMed2005

A comparison of drug-seeking behavior maintained by D-amphetamine, L-deprenyl (selegiline), and D-deprenyl under a second-order schedule in squirrel monkeys.

L-Deprenyl (selegiline) is used in the treatment of Parkinson's disease and has been proposed as an aid for cigarette smoking cessation and a treatment for psychostimulant abuse. L-Deprenyl is metabolized in the body to L-methamphetamine and L-amphetamine, suggesting that it may have abuse potential. The current study assessed whether L-deprenyl or its isomer would maintain drug-seeking behavior on a second-order schedule and whether L-deprenyl would alter drug-seeking behavior maintained by D-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash, and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of D-amphetamine (0.56 mg/kg), administered over a 2-min period at the end of the session. When responding was stable, saline or different i.v. doses of D-amphetamine (0.3-1.0 mg/kg), L-deprenyl (0.1-10.0 mg/kg), and D-deprenyl (0.1-3.0 mg/kg) were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg L-deprenyl intramuscularly 30 min prior to D-amphetamine baseline sessions. D-Amphetamine maintained high rates of drug-seeking behavior on the second-order schedule. D-Deprenyl maintained high rates of drug-seeking behavior similar to D-amphetamine. L-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with L-deprenyl failed to alter drug-seeking behavior maintained by D-amphetamine. These results indicate that D-deprenyl, but not L-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behaviors are actively maintained by D-amphetamine, L-deprenyl, at doses that specifically inhibit type B monoamine oxidase, may not be effective as a treatment.

Animals↗

PubMed2005

Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism.

RATIONALE: When administered chronically to rats, drugs that are effective in bipolar disorder-lithium and the anticonvulsants, valproic acid and carbamazepine-have been shown to downregulate the expression of certain enzymes involved in brain arachidonic acid (AA) release and cyclooxygenase (COX)-mediated metabolism. Phase II clinical trials with the anticonvulsant topiramate [2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate] suggest that this drug may also be effective for bipolar disorder. OBJECTIVES: To see if topiramate has effects similar to those of the other three drugs, we administered topiramate to rats for 14 days at 20 mg/kg, p.o. twice daily. RESULTS: Compared with p.o. vehicle, topiramate treatment did not significantly affect the brain activity or protein level of cytosolic phospholipase A2, secretory PLA2, or Ca2+-independent iPLA2. Additionally, brain protein levels of COX-1, COX-2, 5-lipoxygenase, and cytochrome P450 epoxygenase were unchanged. CONCLUSIONS: These results suggest that topiramate does not modify expression of the enzymes involved in brain AA metabolism that have been shown to be targeted by lithium, valproic acid, or carbamazepine. If topiramate proves effective in bipolar disorder, it may not act by modulating brain AA metabolism. In view of the proven anticonvulsant effect of topiramate, our results also suggest that the AA cascade is not involved in the anti-seizure properties of the drug.

Administration, Oral↗

PubMed2006

A role for corticotropin-releasing factor, but not corticosterone, in acute food-deprivation-induced reinstatement of heroin seeking in rats.

RATIONALE: Acute 1-day food deprivation reinstates heroin seeking in rats via a leptin-dependent mechanism. However, leptin has no effect on footshock- or heroin-priming-induced reinstatement of drug seeking. These data may indicate that the neuronal systems underlying food-deprivation-induced reinstatement are dissociable from those involved in reinstatement induced by footshock stress. OBJECTIVES: We used the reinstatement procedure to examine the roles of the adrenal stress hormone, corticosterone, and brain corticotropin-releasing factor (CRF) in acute food-deprivation-induced reinstatement of extinguished heroin seeking in rats. MATERIALS AND METHODS: The rats were trained to press a lever for heroin (0.05-0.1 mg/kg/infusion, i.v.) for 10 days. Experiment 1: After heroin self-administration training, the rats were divided into two groups, which received either bilateral adrenalectomy surgery or sham surgery. Next, the rats were given 7-10 days of extinction training (during which lever presses were not reinforced with heroin). The rats were subsequently tested for reinstatement after acute (21 h) food deprivation. Experiment 2: After heroin self-administration and extinction training, the rats were tested for reinstatement induced by acute food deprivation. Before the test session, the rats were given intracerebroventricular injections of the CRF receptor antagonist alpha-helical CRF (0, 3, or 10 microg/rat). RESULTS: Adrenalectomy had no effect on the extinction behavior or acute food-deprivation-induced reinstatement of heroin seeking. The CRF receptor antagonist, alpha-helical CRF, dose-dependently blocked food-deprivation-induced reinstatement. CONCLUSIONS: The present data suggest that, as demonstrated for footshock-induced reinstatement of drug seeking, brain CRF, but not corticosterone, plays a critical role in acute food-deprivation-induced reinstatement of heroin seeking.

Adrenalectomy↗

PubMed2006

Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2.

RATIONALE: Atomoxetine is a potent and selective norepinephrine transporter (NET) reuptake inhibitor acting as a nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Previous positron emission tomography (PET) studies had failed to demonstrate the feasibility of measuring a dose-dependent and saturable NET occupancy in human brain using [11C]MeNER. OBJECTIVES: To determine if atomoxetine occupies NET in a dose-dependent fashion using (S,S)-[18F]FMeNER-D2 in nonhuman primate brain. METHODS: A total of eight PET measurements were performed in two cynomolgus monkeys. Each monkey was examined four times with PET: under baseline conditions and after steady-state infusion with 0.03, 0.06, or 0.12 mg/kg/h of atomoxetine. A prolonged intravenous (i.v.) infusion design was developed rather than an i.v. bolus to better mimic an oral absorption profile and to reach plasma steady state. RESULTS: During baseline conditions, (S,S)-[18F]FMeNER-D2 uptake was highest in the locus coeruleus, thalamus, mesencephalon, and the cingulate gyrus, whereas the radioactivity in the caudate was low. Peak equilibrium measurements were achieved using (S,S)-[18F]FMeNER-D2 in contrast to the previously reported data for [11C]MeNER. After administration of atomoxetine, a dose-dependent occupancy from 38 to 82% was observed for various brain regions known to contain high densities of NET. CONCLUSIONS: This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[18F]FMeNER-D2. Furthermore, an asymptotic relationship between N-desmethylatomoxetine plasma concentration and NET occupancy was established. In total, these data encourage further PET studies using (S,S)-[18F]FMeNER-D2 in humans.

Adrenergic Uptake Inhibitors↗

PubMed2006

Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure.

BACKGROUND AND RATIONALE: The reinstatement model is widely used to study relapse to drug addiction. However, the model's validity is open to question. OBJECTIVE: We assess the reinstatement model in terms of criterion and construct validity. RESEARCH HIGHLIGHTS AND CONCLUSIONS: We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model's criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication's effects on reductions in cocaine intake rather than relapse during abstinence. The model's construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.

Alcoholism↗

PubMed2006

Assessment of the aversive and rewarding effects of alcohol in Fischer and Lewis rats.

RATIONALE: Application of the Fischer-Lewis genetic model of drug abuse to the study of alcohol's motivational properties has been limited. OBJECTIVES: To assess the aversive and rewarding effects of ethanol in Fischer and Lewis rats. MATERIALS AND METHODS: Fischer and Lewis rats underwent a four-trial combined conditioned taste aversion/conditioned place preference procedure (CTA/CPP; 0, 1, 1.25, or 1.5 g/kg IP ethanol). Others received 0, 1, or 1.5 g/kg followed by tail blood sampling at 15-, 60- and 180-min post-injection. In additional groups, hypothermia to 0, 1.5, and 3 g/kg was assessed before and 30- and 60-min post-injection. RESULTS: All alcohol-treated groups except low-dose Lewis acquired CTA after one trial. Fischer rats developed stronger CTAs than Lewis at 1.25 and 1.5 g/kg. Ethanol-induced reward in taste or place conditioning was not evident in either strain. Lewis animals showed overall higher peak blood alcohol concentrations, but hypothermia did not vary by strain. CONCLUSION: Compared to Fischer, Lewis rats are less sensitive to alcohol's aversive effects as assessed in the CTA paradigm. The behavioral differences observed are not due to hypothermia, but pharmacokinetic differences may contribute. These data underscore the importance of genetic factors and the aversive effects of initial drug exposures in modeling vulnerability to abuse. In addition to its application with other drugs, the Fischer-Lewis model may be useful for investigating the biobehavioral bases of alcohol abuse.

Alcohol Drinking↗

PubMed2006

Effects of stress modulation on morphine-induced conditioned place preferences and plasma corticosterone levels in Fischer, Lewis, and Sprague-Dawley rat strains.

RATIONALE: There is a direct relationship between hypothalamic-pituitary-adrenal axis (HPA) reactivity and susceptibility to drug use in outbred rats. Specifically, manipulations that increase or decrease HPA activity also increase or decrease drug intake, respectively. Interestingly, this relationship has not been established in the inbred Fischer (F344) and Lewis (LEW) rat strains that are often used as animal models of susceptibility to drug use. OBJECTIVE: The present study investigated the effects of manipulations known to affect HPA activity on morphine-induced conditioned place preference (CPP) in male LEW, F344, and Sprague-Dawley (SD) rats. MATERIALS AND METHODS: In experiment 1, animals were exposed to an injection of methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) and 2-h restraint stress prior to the conditioning of a morphine-induced place preference (1, 4, or 10 mg/kg subcutaneous). In experiment 2, animals were chronically exposed to corticotropin-releasing hormone type 1 receptor antagonist, antalarmin, prior to CPP training. The effects of DMCM/restraint and antalarmin on corticosterone levels were examined in experiments 3 and 4. RESULTS: In outbred rats, DMCM/restraint increased both HPA activity and morphine-induced CPP, while antalarmin decreased CPP and produced a slight, but nonsignificant, decrease in corticosterone levels. In the inbred rats, however, DMCM/restraint increased plasma corticosterone yet decreased place preferences in the LEW strain, and antalarmin treatment decreased plasma corticosterone but increased place preferences in the F344 strain. CONCLUSIONS: These data suggest that the relationship between stress and drug use may be nonmonotonic. The use of these inbred strains in genetic analysis of drug addiction may require reexamination.

Animals↗

PubMed2006

The role of the human ventral premotor cortex in counting successive stimuli.

Adult humans have the ability to count large numbers of successive stimuli exactly. What brain areas underlie this uniquely human process? To identify the candidate brain areas, we first used functional magnetic resonance imaging, and found that the upper part of the left ventral premotor cortex was preferentially activated during counting of successive sensory stimuli presented 10-22 times, while the area was not activated during small number counting up to 4. We then used transcranial magnetic stimulation to assess the necessity of this area, and found that stimulation of this area preferentially disrupted subjects' exact large number enumeration. Stimulation to the area affected neither subjects' number word perception nor their ability to perform a non-numerical sequential letter task. While further investigation is necessary to determine the precise role of the left ventral premotor cortex, the results suggest that the area is indispensably involved for large number counting of successive stimuli, at least for the types of tasks in this study.

Adult↗

PubMed2006

Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture.

Adoptive immunotherapy of cancer patients with cytolytic T lymphocytes (CTL) has been hampered by the inability of the CTL to home into tumors in vivo. Chemokines can attract T lymphocytes to the tumor site, as demonstrated in animal models, but the role of chemokines in T-lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the role of chemokines and their receptors in the migration of a colon carcinoma (CC) patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic CC culture. CTL migration was mediated by chemokine receptor CXCR3 expressed by the CTL and CXCL11 chemokine secreted by the tumor cells. Excess CXCL11 or antibodies to CXCL11 or CXCR3 inhibited migration of CTL to tumor cells. T cell and tumor cell analyses for CXCR3 and CXCL11 expression, respectively, in ten additional CC samples, may suggest their involvement in other CC patients. Our studies, together with previous studies indicating angiostatic activity of CXCL11, suggest that CXCL11 may be useful as an immunotherapeutic agent for cancer patients when transduced into tumor cells or fused to tumor antigen-specific Ab.

Apoptosis↗

PubMed2006

Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group.

BACKGROUND: [corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression. PATIENTS AND METHODS: Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle. RESULTS: Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma. CONCLUSION: The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

Adolescent↗

PubMed2006

Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins.

PURPOSE: We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP). METHODS: Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear-cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP. RESULTS: CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 microM. Tacrolimus enhanced cellular drug uptake at 1 microM, but not at 0.08 microM, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 microM, but was effective at its clinically achievable concentration of 0.25 microM if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 microM. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites. CONCLUSIONS: CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations.

ATP-Binding Cassette Transporters↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2006

Effects of telomere length in Drosophila melanogaster on life span, fecundity, and fertility.

Chromosome length in Drosophila is maintained by targeted transposition of three non-long terminal repeat retrotransposons, HeT-A, TART, and TAHRE, to the chromosome ends. The length and composition of these retrotransposon arrays can vary significantly between chromosome tips and between fly stocks, but the significance and consequences of these length differences are not understood. A dominant genetic factor, Tel, has been described, which causes a severalfold elongation of the retrotransposon arrays at all telomeres. We used this strain to assess possible affects of extended telomeres on the organism. While we found no effect on life span of the adults, we could demonstrate a correlation between long telomeres and reduced fertility and fecundity in individual females, which is also reflected in abnormal oocyte development.

Animals↗