Weyl Double Copy for Gravitational Waves.

We establish the status of the Weyl double copy relation for radiative solutions of the vacuum Einstein equations. We show that all type N vacuum solutions, which describe the radiation region of isolated gravitational systems with appropriate falloff for the matter fields, admit a degenerate Maxwell field that squares to give the Weyl tensor. The converse statement also holds, i.e., if there exists a degenerate Maxwell field on a curved background, then the background is type N. This relation defines a scalar that satisfies the wave equation on the background. We show that for nontwisting radiative solutions, the Maxwell field and the scalar also satisfy the Maxwell equation and the wave equation on Minkowski spacetime. Hence, nontwisting solutions have a straightforward double copy interpretation.

Positive Energy Functional for Massless Scalars in Rotating Black Hole Backgrounds of Maximal Ungauged Supergravity.

We outline a proof of the stability of a massless neutral scalar field ψ in the background of a wide class of four dimensional asymptotically flat rotating and "electrically charged" solutions of supergravity, and the low energy limit of string theory, known as STU metrics. Despite their complexity, we find it possible to circumvent the difficulties presented by the existence of ergo regions and the related phenomenon of superradiance in the original metrics by following a strategy due to Whiting, and passing to an auxiliary metric admitting an everywhere lightlike Killing field and constructing a scalar field ψ (related to a possible unstable mode ψ by a nonlocal transformation) which satisfies the massless wave equation with respect to the auxiliary metric. By contrast with the case for ψ, the associated energy density of ψ is not only conserved but is also non-negative.

A pilot investigation on the effects of combination transcranial direct current stimulation and speed of processing cognitive remediation therapy on simulated driving behavior in older adults with HIV.

Cognitive impairments seen in people living with HIV (PLWH) are associated with difficulties in everyday functioning, specifically driving. This study utilized speed of processing cognitive remediation therapy (SOP-CRT) with transcranial direct current stimulation (tDCS) to gauge the feasibility and impact on simulated driving. Thirty PLWH (M age = 54.53, SD = 3.33) were randomly assigned to either: sham tDCS SOP-CRT or active tDCS SOP-CRT. Seven indicators of simulated driving performance and safety were obtained. Repeated measures ANOVAs controlling for driver's license status (valid and current license or expired/no license) revealed a large training effect on average driving speed. Participants who received active tDCS SOP-CRT showed a slower average driving speed (p = 0.020, d = 0.972) than those who received sham tDCS SOP-CRT. Non-significant small-to-medium effects were seen for driving violations, collisions, variability in lane positioning, and lane deviations. Combination tDCS SOP-CRT was found to increase indices of cautionary simulated driving behavior. Findings reveal a potential avenue of intervention and rehabilitation for improving driving safety among vulnerable at-risk populations, such as those aging with chronic disease.

Black holes in higher derivative gravity.

Extensions of Einstein gravity with higher-order derivative terms arise in string theory and other effective theories, as well as being of interest in their own right. In this Letter we study static black-hole solutions in the example of Einstein gravity with additional quadratic curvature terms. A Lichnerowicz-type theorem simplifies the analysis by establishing that they must have vanishing Ricci scalar curvature. By numerical methods we then demonstrate the existence of further black-hole solutions over and above the Schwarzschild solution. We discuss some of their thermodynamic properties, and show that they obey the first law of thermodynamics.

Critical gravity in four dimensions.

We study four-dimensional gravity theories that are rendered renormalizable by the inclusion of curvature-squared terms to the usual Einstein action with a cosmological constant. By choosing the parameters appropriately, the massive scalar mode can be eliminated and the massive spin-2 mode can become massless. This "critical" theory may be viewed as a four-dimensional analogue of chiral topologically massive gravity, or of critical "new massive gravity" with a cosmological constant, in three dimensions. We find that the on-shell energy for the remaining massless gravitons vanishes. There are also logarithmic spin-2 modes, which have positive energy. The mass and entropy of standard Schwarzschild-type black holes vanish. The critical theory might provide a consistent toy model for quantum gravity in four dimensions.

Universal area product formulas for rotating and charged black holes in four and higher dimensions.

We present explicit results for the product of all horizon areas for general rotating multicharge black holes, both in asymptotically flat and asymptotically anti-de Sitter spacetimes in four and higher dimensions. The expressions are universal, and depend only on the quantized charges, quantized angular momenta and the cosmological constant. If the latter is also quantized these universal results may provide a "looking glass" for probing the microscopics of general black holes.

Chromatographic characterization of neurotoxic esterase.

Neurotoxic esterase (neuropathy target enzyme, NTE) is an enzyme whose irreversible inhibition is the apparent first step in the induction of organophosphorus-induced delayed neuropathy. NTE is an integral membrane protein and thus must be solubilized before isolation can be attempted. This study describes solubilization of active chicken brain NTE with the nondenaturing detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and characterization of the detergent-solubilized enzyme by gel exclusion chromatography. When detergent-solubilized membranes were chromatographed on Sepharose gel exclusion media, NTE activity eluted with an apparent molecular weight of 880-970 kD. When [3H]diisopropylphosphorofluoridate-radiolabeled membranes and unlabeled microsomal membranes were CHAPS-solubilized, combined and chromatographed on Sepharose 4B, NTE activity coeluted with two radiolabeled proteins (Mr = 148 kD and Mr = 112 kD using sodium dodecyl sulfate-polyacrylamide gel electrophoresis with reducing conditions). Another radiolabeled protein (Mr = 92 kD) coeluted exclusively with inhibitor-resistant esterase activity. This study provides strong evidence that the 148 and 112 kD proteins are subunits of a multicomponent NTE complex.

Comparative cholinergic neurotoxicity of oral chlorpyrifos exposures in preweanling and adult rats.

Chlorpyrifos (CPF) is a common organophosphorus (OP) pesticide. Previous studies have demonstrated that neonatal rats are more sensitive than adults to the acute toxicity of high dosages of CPF. The present study examined lethality and age-related differences in neurochemical indicators and functional signs of neurotoxicity following a broad range of acute and repeated oral CPF exposures. There was about a 9-fold difference in sensitivity to the acute-dose lethality of chlorpyrifos among neonatal (7 days-of-age) and adult (90 days-of-age) rats (LD(10): neonates = 15 mg/kg; adults = 136 mg/kg), while juvenile rats (21 days-of-age) exhibited intermediate sensitivity (LD(10) = 47 mg/kg). Neonatal and adult rats (n = 5-7/treatment/age group/time point) were given CPF (0, 0.15, 0.45, 0. 75, 1.5, 4.5, 7.5, or 15 mg/kg/day) for 14 days and sacrificed 4 h after either the first or 14th dose for neurochemical measurements (cholinesterase activity in frontal cortex, plasma and RBC, and muscarinic ([(3)H]QNB) and nicotinic ([(3)H]epibatidine) receptor binding in frontal cortex. No overt signs of functional toxicity (involuntary movements, SLUD signs) were noted in either age group by 4 h after the first dose. With repeated CPF exposures, however, signs of cholinergic toxicity were noted in both age groups at the higher dose levels [no observed effect levels (NOELs): neonate = 4.5 mg/kg/day; adult = 7.5 mg/kg/day]. Similar degrees of ChE inhibition were noted in neonatal brain and blood fractions following acute exposure, but substantial ChE inhibition was only noted in adult plasma and RBC 4 h after the first treatment. Following repeated CPF exposures, similar degrees of ChE inhibition were again noted in tissues from immature animals, but a wide range of sensitivity to inhibition was noted in adult tissues. NOELs based on ChE inhibition for adults were about 1->/=10-fold higher than in neonates with acute exposure but only 0.2-2 times higher with repeated dosing. Moreover, dose-related inhibition of brain ChE was similar between age groups, and similar reductions in both QNB and epibatidine binding were noted between the age groups after repeated dosing, even though by the end of the dosing period young animals (juveniles) were still about 3 times more sensitive than adults, based on acute lethality. We conclude that while immature animals can be markedly more sensitive to lethal effects of high doses of CPF, lesser or no age-related differences are apparent, based on non-lethal endpoints, in particular with repeated exposures.

Common mechanism of toxicity: a case study of organophosphorus pesticides.

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue." This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternative hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.

Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures.

Developing mammals are markedly more sensitive to acute toxicity from exposure to a variety of organophosphorus (OP) pesticides. The present study examined dose-related inhibition of both brain and plasma cholinesterase activity in neonatal and adult rats exposed to sublethal doses of one of three common OP pesticides, methyl parathion, parathion and chlorpyrifos. Effective dose 50 (i.e., ED50 or dose which would inhibit 50% of the cholinesterase activity) values were determined and then correlated with an indicator of acute toxicity, the maximal tolerated dose (MTD). It was found that ED50 estimates for both brain and plasma cholinesterase correlated highly (r = 0.932-0.992) with previously derived MTD values. In no case was there a significant difference between in vivo brain and plasma cholinesterase inhibition across doses in neonatal rats was high (r = 0.962-0.975) but lower in adults (r = 0.700-0.943). The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats. Additionally, under defined experimental conditions, plasma ChE inhibition may be a useful quantitative index for the degree of brain cholinesterase inhibition following OP exposures.

Subacute ethanol consumption reverses p-xylene-induced decreases in axonal transport.

Human exposure to organic solvents is often complicated by ethanol ingestion and the literature is replete with demonstrations of metabolic interactions between ethanol and organic solvents at a pharmacokinetic level. Because of the possible modulation of xylene toxicity by ethanol consumption, the present group of studies characterizes the effect of ethanol on the p-xylene-induced decrease in axonal transport in the rat optic system previously reported by our laboratory. Long-Evans, hooded, male rats were divided randomly into two groups: those receiving 10% ethanol in their drinking water and those receiving water only. These two groups were further subdivided into two groups which were either exposed by inhalation to 1600 ppm p-xylene for 6 h/day, 5 days/week for 8 exposure-days or were treated identically except that they were exposed to air while in the inhalation chambers. The ethanol-drinking rats were given ethanol 6 days prior to and on the days of the inhalation exposure. Immediately after removal from the inhalation chambers on the last exposure day, the animals were injected intraocularly with [35S]methionine and [3H]fucose to measure the synthesis and rapid axonal transport of proteins and glycoproteins, respectively, in the retinal ganglion cells. The animals were sacrificed 20 h later, and the amount of radioactivity in different areas of the retinal ganglion cells was determined by liquid scintillation counting. As in previous experiments, the xylene exposure group showed a significant reduction in axonal transport of proteins and glycoproteins, whereas the ethanol exposure alone produced no significant reductions in the transport of either proteins or glycoproteins. In the animals receiving both ethanol and xylene, however, the ethanol treatment prevented the decreased transport characteristic of the xylene only animals, i.e. in all areas of the optic projections the level of transport were similar to the level present in the control groups. These data suggest that the xylene-induced reduction in rapid axonal transport was reversed (or prevented) by subacute ethanol consumption.

Comparison of in vivo cholinesterase inhibition in neonatal and adult rats by three organophosphorothioate insecticides.

Developing mammals are more sensitive than adults to a variety of organophosphorothioate insecticides (OPs), compounds which act in vivo by inhibition of cholinesterase (ChE). Little is known, however, regarding age-related differences in biochemical responses to these toxicants. The time course of ChE inhibition and recovery in whole brain was compared in neonatal (7 days of age) and adult (80-100 days of age) rats after treatment with maximal tolerated doses (MTDs) of either methyl parathion (MPS), parathion (PS) or chlorpyrifos (CPF). Neonatal rats were more sensitive than adults in all cases (MTDs for MPS, PS and CPF; neonates = 7.8, 2.1 and 45 mg/kg, s.c.; adults = 18, 18, and 279 mg/kg, s.c., respectively). In general, maximal brain ChE inhibition was similar (greater than 78%) in both age groups but ChE activity recovered faster in neonates. Plasma and erythrocyte ChE activities correlated relatively well (r = 0.794-0.943) with brain ChE activity in neonatal rats at all time points between 4 h and 7 days after treatment but similar correlations between circulating and brain ChE activities in adults were more variable (r = 0.211-0.917). The results indicate that neonatal rats are more sensitive to acute lethality from these compounds and that MTD exposures produce extensive brain ChE inhibition in both age groups. Significant inhibitor-related and age-related differences in the duration of ChE inhibition can ensue, however, following such OP exposures.

Phenylmethylsulfonyl fluoride alters sensitivity to organophosphorus-induced delayed neurotoxicity in developing animals.

The serine/cysteine hydrolase inhibitor phenylmethylsulfonyl fluoride (PMSF) markedly intensifies the clinical expression of organophosphorus-induced delayed neurotoxicity (OPIDN) in adult chickens when administered after organophosphate exposure. In this study, we have examined the ability of PMSF post-treatment to affect sensitivity to OPIDN in developing animals at ages normally showing resistance. Chickens (35, 49 or 70 days of age) were treated with diisopropylphosphorofluoridate (DFP, 2 mg/kg, sc) and then treated four hours later with PMSF (90 mg/kg, sc) or vehicle only and examined for clinical signs of ataxia and incoordination. Chickens treated with DFP alone showed a marked age-related increase in the severity of motor deficits. Birds treated with DFP followed by PMSF showed more extensive clinical deficits relative to those treated with DFP only, but relatively similar degrees of motor dysfunction among the age groups. Cervical spinal cord samples processed by the Fink-Heimer degeneration method indicated that PMSF post-treatment induced more extensive axonal degeneration in all age groups relative to treatment with DFP only. As the DFP treatment alone caused greater than or equal to 90% inhibition of neurotoxic esterase activity (NTE, the putative molecular target site for OPIDN), interaction with NTE by PMSF does not appear to be involved in potentiation. We hypothesize that PMSF potentiates OPIDN through impairment of a physiological process which normally imparts resistance to young animals and which regresses during development.

Age-related effects of chlorpyrifos on acetylcholine release in rat brain.

Chlorpyrifos (CPF) is an organophosphorus insecticide that elicits toxicity through inhibition of acetylcholinesterase (AChE). Young animals are markedly more sensitive than adults to the acute toxicity of CPF. We evaluated acetylcholine (ACh) release and its muscarinic receptor-mediated regulation (i.e. muscarinic autoreceptor function, MAF) during maturation as a possible contributing factor to age-related differences in sensitivity. Cortical and striatal slices were prelabeled with [3H]choline chloride, superfused in the presence or absence of the anticholinesterase physostigmine (PHY, 20 microM) and stimulated twice (S1 and S2) with a high concentration of potassium chloride (20 mM). Depolarization-stimulated ACh release (DSAR) was lowest in neonatal, intermediate in juvenile and markedly higher in adult tissues. MAF was not detectable in tissues from neonatal rats but was present in juvenile and adult tissues. ACh release and MAF were studied at 4, 24 and 96 h following oral exposure to CPF (0, 0.5 or 1 x LD10). In general, 40-60% and 80-90% maximal AChE inhibition followed exposure to the respective 0.5 and 1 x LD10 dosages. DSAR was decreased in neonatal cortex 1 day after LD10 exposure but increased in juvenile striatum 1 day after LD10 treatment. In adults, DSAR was reduced at 4 and 24 h after exposure, but increased 96 h after CPF exposure. In juveniles, MAF was reduced in both brain regions at 24 h after 0.5LD10 exposure and at 24 and 96 h after LD10 exposure in cortex. A later reduction in MAF was noted in adult tissues (i.e. only at 96 h after LD10 treatment). Together, the results suggest that ACh release dynamics in brain vary markedly during postnatal maturation and that acute CPF exposure can alter ACh release in an age-related manner. The functional status of presynaptic processes regulating neurotransmitter release may contribute to age-related neurotoxicity elicited by high-dose exposures to chlorpyrifos.

The role of neurotoxic esterase (NTE) in the prevention and potentiation of organophosphorus-induced delayed neurotoxicity (OPIDN).

The first step in the initiation of organophosphorus-induced delayed neuropathy (OPIDN) is proposed to be the phosphorylation of an enzyme found in the nervous system called neurotoxic esterase (neuropathy target esterase, NTE). It has been known for over twenty years that non-neuropathic inhibitors of NTE exist and can actually prevent OPIDN when given before a neuropathic organophosphate (OP). Within the last three years it has become evident that another outcome is possible following in vivo interaction between neuropathic and nonneuropathic NTE inhibitors. When administered after OP exposure, nonneuropathic inhibitors can intensify or potentiate signs of OPIDN in adult chickens. Additionally, whereas developing chickens are typically resistant to the effects of neuropathic OPs, resistant age groups will develop OPIDN when exposure to a neuropathic OP is followed by the non-neuropathic NTE inhibitor phenylmethylsulfonyl fluoride. As in the case of prevention, studies of the potentiation of OPIDN may yield insight into mechanisms involved in the pathogenesis of delayed neurotoxicity. A brief review of current knowledge regarding the role of NTE in both the prevention and potentiation of OPIDN is presented.

Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats.

Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.

Passive avoidance deficits in mice following ethylcholine aziridinium chloride treatment.

High-affinity choline uptake (HACU) appears to be the rate-limiting step in the synthesis of the neurotransmitter acetylcholine. The present experiment was designed to examine the effects of irreversible inhibition of HACU by ethylcholine aziridinium chloride (ECA) on passive avoidance retention in mice. Animals were injected intracerebroventricularly, and one-trial passive avoidance retention evaluated 21 days later. A significant retention deficit was observed in ECA-treated animals upon retest 24 hours after training. ECA-induced changes in retention were accompanied by significant reductions in choline acetyltransferase (CAT) activity in only two of seven brain regions tested, hippocampus (48% of control) and cerebellum (76% of control). The results support the involvement of hippocampal cholinergic activity in mediation of passive avoidance learning.

Neurochemical and behavioral effects of N-ethyl-acetylcholine aziridinium chloride in mice.

N-ethyl-choline aziridinium (ECA) and N-ethyl-acetylcholine aziridinium (EAA) were shown to be inhibitors of high affinity choline uptake in vitro (IC50 = 0.4 microM and 1.5 microM, respectively), and intraventricular administration showed that EAA was more selective in its inhibition of hippocampal choline uptake in vivo. EAA significantly reduced the activity of choline acetyltransferase in the hippocampus 3 to 28 days following intraventricular infusion, but not in the striatum or parahippocampal cortex. Neither muscarinic receptor binding nor glutamic acid decarboxylase activity were affected in any of the three brain regions. EAA (12 or 16 nanomoles, intraventricular) significantly impaired memory performance of mice in a radial arm maze when tested two weeks after treatment. A subgroup analysis implicated long-term reference memory as the mechanism disrupted.

Comparative neurochemical and neurobehavioral effects of repeated chlorpyrifos exposures in young and adult rats.

Neonatal (7 days old) rats are markedly more sensitive than adults (3 months old) to the acute toxic effects of the insecticide, chlorpyrifos (CPF). In the present study, we have compared the effects of subacute CPF exposures in these same age groups. Repeated doses of CPF (40 mg/kg, SC, every 4 days, total of 4 doses) caused extensive inhibition of cortical, hippocampal, and striatal cholinesterase (ChE) activity in adult rats at 4 (90-92%) and 14 (71-78%) days after the last treatment. Rats treated similarly during postnatal maturation (beginning on day 7) showed a much lower degree of ChE inhibition (21-60%) at these time points. Muscarinic ([3H]quinuclidinyl benzilate, QNB) receptor binding in cortex, hippocampus, and striatum was reduced in adult brain at 4 (30-43%) and 14 (22-32%) days after the final treatment, whereas receptor densities were only marginally affected (5-11% reduction) in young rats. Basal motor activity levels were not affected in either young or adult rats as a function of CPF exposure. CPF-treated adult rats exhibited higher activity levels after challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, and 8 weeks after treatment, whereas CPF exposure did not affect the motoric response to scopolamine in rats treated during postnatal maturation. These data suggest that although neonatal rats are more sensitive to acute lethal effects from high doses of CPF, adult rats exhibit more persistent neurochemical and neurobehavioral alterations following repeated, lower-level exposures.