Observing Fearful Faces Leads to Visuo-Spatial Perspective Taking

ERIC Educational Resources Information Center

Zwickel, Jan; Muller, Hermann J.

2010-01-01

A number of recent studies suggested that visuo-spatial perspective taking (VSPT) occurs spontaneously when viewing either a human body or an action by an agent. However, it remains unclear whether VSPT is caused by the observation of an (potential) action or occurs because the observer infers from certain cues that another mind is present…

Botanical modulation of menopausal symptoms: Mechanisms of action?

PubMed Central

Hajirahimkhan, Atieh; Dietz, Birgit M.; Bolton, Judy L.

2013-01-01

Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats which can affect quality of life. Although hormone therapy (HT) has been the treatment of choice for relieving these symptoms, HT has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief, have been controversial and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-HT7 ligands or inhibit serotonin re-uptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for women’s health, could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future. PMID:23408273

Generation of action potentials in a mathematical model of corticotrophs.

PubMed Central

LeBeau, A P; Robson, A B; McKinnon, A E; Donald, R A; Sneyd, J

1997-01-01

Corticotropin-releasing hormone (CRH) is an important regulator of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells. The intracellular signaling system that underlies this process involves modulation of voltage-sensitive Ca2+ channel activity, which leads to the generation of Ca2+ action potentials and influx of Ca2+. However, the mechanisms by which Ca2+ channel activity is modulated in corticotrophs are not currently known. We investigated this process in a Hodgkin-Huxley-type mathematical model of corticotroph plasma membrane electrical responses. We found that an increase in the L-type Ca2+ current was sufficient to generate action potentials from a previously resting state of the model. The increase in the L-type current could be elicited by either a shift in the voltage dependence of the current toward more negative potentials, or by an increase in the conductance of the current. Although either of these mechanisms is potentially responsible for the generation of action potentials, previous experimental evidence favors the former mechanism, with the magnitude of the shift required being consistent with the experimental findings. The model also shows that the T-type Ca2+ current plays a role in setting the excitability of the plasma membrane, but does not appear to contribute in a dynamic manner to action potential generation. Inhibition of a K+ conductance that is active at rest also affects the excitability of the plasma membrane. PMID:9284294

Outcome producing potential influences twelve-month-olds' interpretation of a novel action as goal-directed.

PubMed

Biro, Szilvia; Verschoor, Stephan; Coalter, Esther; Leslie, Alan M

2014-11-01

Learning about a novel, goal-directed action is a complex process. It requires identifying the outcome of the action and linking the action to its outcome for later use in new situations to predict the action or to anticipate its outcome. We investigated the hypothesis that linking a novel action to a salient change in the environment is critical for infants to assign a goal to the novel action. We report a study in which we show that 12-month-old infants, who were provided with prior experience with a novel action accompanied with a salient visible outcome in one context, can interpret the same action as goal-directed even in the absence of the outcome in another context. Our control condition shows that prior experience with the action, but without the salient effect, does not lead to goal-directed interpretation of the novel action. We also found that, for the case of 9-month-olds infants, prior experience with the outcome producing potential of the novel action does not facilitate a goal-directed interpretation of the action. However, this failure was possibly due to difficulties with generalizing the learnt association to another context rather than with linking the action to its outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

Improved actions and asymptotic scaling in lattice Yang-Mills theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Langfeld, Kurt

2007-11-01

Improved actions in SU(2) and SU(3) lattice gauge theories are investigated with an emphasis on asymptotic scaling. A new scheme for tadpole improvement is proposed. The standard but heuristic tadpole improvement emerges from a mean field approximation from the new approach. Scaling is investigated by means of the large distance static quark potential. Both the generic and the new tadpole scheme yield significant improvements on asymptotic scaling when compared with loop improved actions. A study of the rotational symmetry breaking terms, however, reveals that only the new improvement scheme efficiently eliminates the leading irrelevant term from the action.

The marketing potential of corporate social responsibility activities: the case of the alcohol industry in Latin America and the Caribbean.

PubMed

Pantani, Daniela; Peltzer, Raquel; Cremonte, Mariana; Robaina, Katherine; Babor, Thomas; Pinsky, Ilana

2017-01-01

The aims were to: (1) identify, monitor and analyse the Corporate Social Responsibility (CSR) practices of the alcohol industry in Latin America and the Caribbean (LAC) and (2) examine whether the alcohol industry is using these actions to market their products and brands. Nine health experts from Argentina, Brazil and Uruguay conducted a content analysis of 218 CSR activities using a standardized protocol. A content rating procedure was used to evaluate the marketing potential of CSR activities as well as their probable population reach and effectiveness. The LEAD procedure (longitudinal, expert and all data) was applied to verify the accuracy of industry-reported descriptions. A total of 55.8% of the actions were found to have a marketing potential, based on evidence that they are likely to promote brands and products. Actions with marketing potential were more likely to reach a larger audience than actions classified with no marketing potential. Most actions did not fit into any category recommended by the World Health Organization; 50% of the actions involving classroom and college education for young people were found to have marketing potential; 62.3% were classified as meeting the definition of risk management CSR. Alcohol industry Corporate Social Responsibility activities in Latin America and the Caribbean appear to have a strategic marketing role beyond their stated philanthropic and public health purpose. © 2016 Society for the Study of Addiction.

Fluoride’s Effects on the Formation of Teeth and Bones, and the Influence of Genetics

PubMed Central

Everett, E.T.

2011-01-01

Fluorides are present in the environment. Excessive systemic exposure to fluorides can lead to disturbances of bone homeostasis (skeletal fluorosis) and enamel development (dental/enamel fluorosis). The severity of dental fluorosis is also dependent upon fluoride dose and the timing and duration of fluoride exposure. Fluoride’s actions on bone cells predominate as anabolic effects both in vitro and in vivo. More recently, fluoride has been shown to induce osteoclastogenesis in mice. Fluorides appear to mediate their actions through the MAPK signaling pathway and can lead to changes in gene expression, cell stress, and cell death. Different strains of inbred mice demonstrate differential physiological responses to ingested fluoride. Genetic studies in mice are capable of identifying and characterizing fluoride-responsive genetic variations. Ultimately, this can lead to the identification of at-risk human populations who are susceptible to the unwanted or potentially adverse effects of fluoride action and to the elucidation of fundamental mechanisms by which fluoride affects biomineralization. PMID:20929720

Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: comparative in-vitro and in-vivo investigations

NASA Astrophysics Data System (ADS)

Selvaag, Edgar; Anholt, Helle; Moan, Johan; Thune, Per

1997-12-01

Seven oral antidiabetics (chlorpropamide, glibenclamide, glipizide, gliquidone, glymidine, tolazamide, and tolbutamide), and 14 diuretics (bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide, and xipamide) were investigated for potential phototoxicity in vitro using a cell culture model and in vivo in hairless mice. After exposure to broad band UVA, the majority of the substances tested in vitro yielded phototoxic action leading to loss of culture forming ability. In vivo, all tested substances induced edema or ulceration, and lead to a significant increase in skin fold thickness of the mouse skin. In all a number of substances not described to induce clinical photosensitivity nor phototoxicity in vitro or in vivo were detected in our testing. In determining potential photosensitizers, it seems important to utilize different test methods, as not all substances will exhibit action in a given assay.

Clarification of terminology in medication errors: definitions and classification.

PubMed

Ferner, Robin E; Aronson, Jeffrey K

2006-01-01

We have previously described and analysed some terms that are used in drug safety and have proposed definitions. Here we discuss and define terms that are used in the field of medication errors, particularly terms that are sometimes misunderstood or misused. We also discuss the classification of medication errors. A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Errors can be classified according to whether they are mistakes, slips, or lapses. Mistakes are errors in the planning of an action. They can be knowledge based or rule based. Slips and lapses are errors in carrying out an action - a slip through an erroneous performance and a lapse through an erroneous memory. Classification of medication errors is important because the probabilities of errors of different classes are different, as are the potential remedies.

Wrestling with 'doubt-sayers': a first step in leading community-wide climate change action for better health.

PubMed

Ritchie, Jan

2011-12-01

Although the evidence base for climate change is indisputable and the potential human health impact is extremely concerning, to date public health professionals are playing little part in influencing community change to accept and act on the science. In reviewing the techniques used to obstruct action on tobacco control by vested interests through constantly raising doubt about the science in this arena, a similar pattern is seen in obstructing action on climate change. It is clear that the raising of unverified doubt is the primary tool employed by profit-driven corporations to prevent constructive action in both these arenas, with the very high potential for the health of the whole population to suffer as a result. Those promoting the health of Australians have a responsibility to optimise health in this regard and need to think differently through embracing complexity science and then take action, with the first step being to provide constant counter-arguments to the unsubstantiated statements of the 'doubt-sayers'.

The roles of mid-myocardial and epicardial cells in T-wave alternans development: a simulation study.

PubMed

Janusek, D; Svehlikova, J; Zelinka, J; Weigl, W; Zaczek, R; Opolski, G; Tysler, M; Maniewski, R

2018-05-08

The occurrence of T-wave alternans in electrocardiographic signals was recently linked to susceptibility to ventricular arrhythmias and sudden cardiac death. Thus, by detecting and comprehending the origins of T-wave alternans, it might be possible to prevent such events. Here, we simulated T-wave alternans in a computer-generated human heart model by modulating the action potential duration and amplitude during the first part of the repolarization phase. We hypothesized that changes in the intracardiac alternans patterns of action potential properties would differentially influence T-wave alternans measurements at the body surface. Specifically, changes were simulated globally in the whole left and right ventricles to simulate concordant T-wave alternans, and locally in selected regions to simulate discordant and regional discordant, hereinafter referred to as "regional", T-wave alternans. Body surface potential maps and 12-lead electrocardiographic signals were then computed. In depth discrimination, the influence of epicardial layers on T-wave alternans development was significantly higher than that of mid-myocardial cells. Meanwhile, spatial discrimination revealed that discordant and regional action potential property changes had a higher influence on T-wave alternans amplitude than concordant changes. Notably, varying T-wave alternans sources yielded distinct body surface potential map patterns for T-wave alternans amplitude, which can be used for location of regions within hearts exhibiting impaired repolarization. The highest ability for T-wave alternans detection was achieved in lead V1. Ultimately, we proposed new parameters Vector Magnitude Alternans and Vector Angle Alternans, with higher ability for T-wave alternans detection when using multi-lead electrocardiographic signals processing than for single leads. Finally, QT alternans was found to be associated with the process of T-wave alternans generation. The distributions of the body surface T-wave alternans amplitude have been shown to have unique patterns depending on the type of alternans (concordant, discordant or regional) and the location of the disturbance in the heart. The influence of epicardial cells on T-wave alternans development is significantly higher than that of mid-myocardial cells, among which the sub-endocardial layer exerted the highest influence. QT interval alternans is identified as a phenomenon that correlate with T-wave alternans.

Not so secret agents: Event-related potentials to semantic roles in visual event comprehension.

PubMed

Cohn, Neil; Paczynski, Martin; Kutas, Marta

2017-12-01

Research across domains has suggested that agents, the doers of actions, have a processing advantage over patients, the receivers of actions. We hypothesized that agents as "event builders" for discrete actions (e.g., throwing a ball, punching) build on cues embedded in their preparatory postures (e.g., reaching back an arm to throw or punch) that lead to (predictable) culminating actions, and that these cues afford frontloading of event structure processing. To test this hypothesis, we compared event-related brain potentials (ERPs) to averbal comic panels depicting preparatory agents (ex. reaching back an arm to punch) that cued specific actions with those to non-preparatory agents (ex. arm to the side) and patients that did not cue any specific actions. We also compared subsequent completed action panels (ex. agent punching patient) across conditions, where we expected an inverse pattern of ERPs indexing the differential costs of processing completed actions asa function of preparatory cues. Preparatory agents evoked a greater frontal positivity (600-900ms) relative to non-preparatory agents and patients, while subsequent completed actions panels following non-preparatory agents elicited a smaller frontal positivity (600-900ms). These results suggest that preparatory (vs. non-) postures may differentially impact the processing of agents and subsequent actions in real time. Copyright © 2017 Elsevier Inc. All rights reserved.

EVALUATING THE IMPACT OF WATER CHEMISTRY ON CUPROSOLVENCY AND COPPER CORROSION BY-PRODUCT USING A SIMPLE COPPER PIPE RECIRCULATING LOOP SYSTEM

EPA Science Inventory

1991, EPA publicized the Lead and Copper Rule (LCR),which set regulations to minimize the amount of lead copper in drinking water. The LCR set the copper action level at 1.3 mg/L in more then 10% of customer’s first-draw taps sampled. Potential health effects of copper include vo...

EPA and States' Collective Efforts Lead to Regulatory Action on Dicamba

EPA Pesticide Factsheets

Agreement with Monsanto, BASF and DuPont on measures to further minimize the potential for drift to damage neighboring crops from the use of dicamba formulations used to control weeds in genetically modified cotton and soybeans.

Point-particle effective field theory I: classical renormalization and the inverse-square potential

NASA Astrophysics Data System (ADS)

Burgess, C. P.; Hayman, Peter; Williams, M.; Zalavári, László

2017-04-01

Singular potentials (the inverse-square potential, for example) arise in many situations and their quantum treatment leads to well-known ambiguities in choosing boundary conditions for the wave-function at the position of the potential's singularity. These ambiguities are usually resolved by developing a self-adjoint extension of the original prob-lem; a non-unique procedure that leaves undetermined which extension should apply in specific physical systems. We take the guesswork out of this picture by using techniques of effective field theory to derive the required boundary conditions at the origin in terms of the effective point-particle action describing the physics of the source. In this picture ambiguities in boundary conditions boil down to the allowed choices for the source action, but casting them in terms of an action provides a physical criterion for their determination. The resulting extension is self-adjoint if the source action is real (and involves no new degrees of freedom), and not otherwise (as can also happen for reasonable systems). We show how this effective-field picture provides a simple framework for understanding well-known renormalization effects that arise in these systems, including how renormalization-group techniques can resum non-perturbative interactions that often arise, particularly for non-relativistic applications. In particular we argue why the low-energy effective theory tends to produce a universal RG flow of this type and describe how this can lead to the phenomenon of reaction catalysis, in which physical quantities (like scattering cross sections) can sometimes be surprisingly large compared to the underlying scales of the source in question. We comment in passing on the possible relevance of these observations to the phenomenon of the catalysis of baryon-number violation by scattering from magnetic monopoles.

Control of CA3 output by feedforward inhibition despite developmental changes in the excitation-inhibition balance.

PubMed

Torborg, Christine L; Nakashiba, Toshiaki; Tonegawa, Susumu; McBain, Chris J

2010-11-17

In somatosensory cortex, the relative balance of excitation and inhibition determines how effectively feedforward inhibition enforces the temporal fidelity of action potentials. Within the CA3 region of the hippocampus, glutamatergic mossy fiber (MF) synapses onto CA3 pyramidal cells (PCs) provide strong monosynaptic excitation that exhibit prominent facilitation during repetitive activity. We demonstrate in the juvenile CA3 that MF-driven polysynaptic IPSCs facilitate to maintain a fixed EPSC-IPSC ratio during short-term plasticity. In contrast, in young adult mice this MF-driven polysynaptic inhibitory input can facilitate or depress in response to short trains of activity. Transgenic mice lacking the feedback inhibitory loop continue to exhibit both facilitating and depressing polysynaptic IPSCs, indicating that this robust inhibition is not caused by the secondary engagement of feedback inhibition. Surprisingly, eliminating MF-driven inhibition onto CA3 pyramidal cells by blockade of GABA(A) receptors did not lead to a loss of temporal precision of the first action potential observed after a stimulus but triggered in many cases a long excitatory plateau potential capable of triggering repetitive action potential firing. These observations indicate that, unlike other regions of the brain, the temporal precision of single MF-driven action potentials is dictated primarily by the kinetics of MF EPSPs, not feedforward inhibition. Instead, feedforward inhibition provides a robust regulation of CA3 PC excitability across development to prevent excessive depolarization by the monosynaptic EPSP and multiple action potential firings.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yamamura, K.; Maehara, N.; Terayama, K.

Segmental demyelination and axonal degeneration of motor nerves induced by lead exposure is well known in man, and animals. The effect of lead acetate exposure to man may involve the cranial nerves, since vertigo and sensory neuronal deafness have been reported among lead workers. However, there are few reports concerning the dose-effects of lead acetate both to the peripheral nerve and the cranial VII nerve with measurement of blood lead concentration. The authors investigated the effects of lead acetate to the cochlea and the VIII nerve using CM (cochlear microphonics) and AP (action potential) of the guinea pigs. The effectsmore » of lead acetate to the sciatic nerve were measured by MCV of the sciatic nerve with measurement of blood lead concentration.« less

An intracellular analysis of the visual responses of neurones in cat visual cortex.

PubMed Central

Douglas, R J; Martin, K A; Whitteridge, D

1991-01-01

1. Extracellular and intracellular recordings were made from neurones in the visual cortex of the cat in order to compare the subthreshold membrane potentials, reflecting the input to the neurone, with the output from the neurone seen as action potentials. 2. Moving bars and edges, generated under computer control, were used to stimulate the neurones. The membrane potential was digitized and averaged for a number of trials after stripping the action potentials. Comparison of extracellular and intracellular discharge patterns indicated that the intracellular impalement did not alter the neurones' properties. Input resistance of the neurone altered little during stable intracellular recordings (30 min-2 h 50 min). 3. Intracellular recordings showed two distinct patterns of membrane potential changes during optimal visual stimulation. The patterns corresponded closely to the division of S-type (simple) and C-type (complex) receptive fields. Simple cells had a complex pattern of membrane potential fluctuations, involving depolarizations alternating with hyperpolarizations. Complex cells had a simple single sustained plateau of depolarization that was often followed but not preceded by a hyperpolarization. In both simple and complex cells the depolarizations led to action potential discharges. The hyperpolarizations were associated with inhibition of action potential discharge. 4. Stimulating simple cells with non-optimal directions of motion produced little or no hyperpolarization of the membrane in most cases, despite a lack of action potential output. Directional complex cells always produced a single plateau of depolarization leading to action potential discharge in both the optimal and non-optimal directions of motion. The directionality could not be predicted on the basis of the position of the hyperpolarizing inhibitory potentials found in the optimal direction. 5. Stimulation of simple cells with non-optimal orientations occasionally produced slight hyperpolarizations and inhibition of action potential discharge. Complex cells, which had broader orientation tuning than simple cells, could show marked hyperpolarization for non-optimal orientations, but this was not generally the case. 6. The data do not support models of directionality and orientation that rely solely on strong inhibitory mechanisms to produce stimulus selectivity. PMID:1804981

Excitotoxicity in the pathogenesis of autism.

PubMed

Essa, M M; Braidy, N; Vijayan, K R; Subash, S; Guillemin, G J

2013-05-01

Autism is a debilitating neurodevelopment disorder characterised by stereotyped interests and behaviours, and abnormalities in verbal and non-verbal communication. It is a multifactorial disorder resulting from interactions between genetic, environmental and immunological factors. Excitotoxicity and oxidative stress are potential mechanisms, which are likely to serve as a converging point to these risk factors. Substantial evidence suggests that excitotoxicity, oxidative stress and impaired mitochondrial function are the leading cause of neuronal dysfunction in autistic patients. Glutamate is the primary excitatory neurotransmitter produced in the CNS, and overactivity of glutamate and its receptors leads to excitotoxicity. The over excitatory action of glutamate, and the glutamatergic receptors NMDA and AMPA, leads to activation of enzymes that damage cellular structure, membrane permeability and electrochemical gradients. The role of excitotoxicity and the mechanism behind its action in autistic subjects is delineated in this review.

Intermittent blood pressure control: potential consequences for outcome.

PubMed

Leenen, F H

1999-05-01

Although both blood pressure (BP) and left ventricular (LV) mass at initial evaluation predict future cardiovascular risk, the actual BP and LV mass achieved over years of treatment more clearly relate to cardiovascular event rates. Intermittent compliance or noncompliance is the major reason for uncontrolled hypertension and presumably persistent LV hypertrophy. In general, drugs with rapid onset and short duration of action are not desirable because this profile may lead to large variations in BP lowering effect during actual drug intake and rapid disappearance of the antihypertensive effect with missed doses. In addition, intermittent compliance per se introduces the potential for adverse events. For drugs requiring several dose-titrations (e.g., alpha1-blockers), restarting at full doses may lead to excessive drug action and symptomatic hypotension. For other drugs (e.g., short acting beta-blockers or clonidine-like drugs), sudden discontinuation with intermittent compliance may lead to rebound-enhanced sympathetic responsiveness after one to two days, resulting not only in side effects, but also in adverse events, particularly in patients with (silent) coronary artery disease. The rapid onset, short acting dihydropyridines cause intermittent BP control at each dosing, particularly at higher doses. This intermittent control of BP is even more apparent at dosing intervals that are long relative to the duration of action. Thus, sympathetic activation and potential for adverse events can be anticipated at each dosing unless these drugs are being taken frequently at relatively low doses. For diuretics, angiotensin-converting enzyme inhibitors and angiotensin I receptor blockers, no adverse effects have been identified with intermittent compliance. Intermittent BP control is, in general, not an appropriate approach to the management of hypertension and introduces additional risks depending on the type of antihypertensive drug. In contrast, drugs with slow onset and long duration of action provide a more consistent effect during actual drug intake and a more persistent effect during short periods of noncompliance.

Influence of asymmetric attenuation of single and paired dendritic inputs on summation of synaptic potentials and initiation of action potentials.

PubMed

Fortier, Pierre A; Bray, Chelsea

2013-04-16

Previous studies revealed mechanisms of dendritic inputs leading to action potential initiation at the axon initial segment and backpropagation into the dendritic tree. This interest has recently expanded toward the communication between different parts of the dendritic tree which could preprocess information before reaching the soma. This study tested for effects of asymmetric voltage attenuation between different sites in the dendritic tree on summation of synaptic inputs and action potential initiation using the NEURON simulation environment. Passive responses due to the electrical equivalent circuit of the three-dimensional neuron architecture with leak channels were examined first, followed by the responses after adding voltage-gated channels and finally synaptic noise. Asymmetric attenuation of voltage, which is a function of asymmetric input resistance, was seen between all pairs of dendritic sites but the transfer voltages (voltage recorded at the opposite site from stimulation among a pair of dendritic sites) were equal and also summed linearly with local voltage responses during simultaneous stimulation of both sites. In neurons with voltage-gated channels, we reproduced the observations where a brief stimulus to the proximal ascending dendritic branch of a pyramidal cell triggers a local action potential but a long stimulus triggers a somal action potential. Combined stimulation of a pair of sites in this proximal dendrite did not alter this pattern. The attraction of the action potential onset toward the soma with a long stimulus in the absence of noise was due to the higher density of voltage-gated sodium channels at the axon initial segment. This attraction was, however, negligible at the most remote distal dendritic sites and was replaced by an effect due to high input resistance. Action potential onset occurred at the dendritic site of higher input resistance among a pair of remote dendritic sites, irrespective of which of these two sites received the synaptic input. Exploration of the parameter space showed how the gradient of voltage-gated channel densities and input resistances along a dendrite could draw the action potential onset away from the stimulation site. The attraction of action potential onset toward the higher density of voltage-gated channels in the soma during stimulation of the proximal dendrite was, however, reduced after the addition of synaptic noise. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Recent developments in naturally derived antimalarials: cryptolepine analogues.

PubMed

Wright, Colin W

2007-06-01

Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues.

High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chapalamadugu, Kalyan C.; Panguluri, Siva K.; Bennett, Eric S.

2015-01-01

Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72 h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia,more » arrhythmia and significantly prolonged (ms) the, RR (186.2 ± 10.7 vs. 146.4 ± 6.2), PR (46.8 ± 3.1 vs. 39.3 ± 1.6), QRS (10.8 ± 0.6 vs. 8.5 ± 0.2), QTc (57.1 ± 3.5 vs. 40 ± 1.4) and JT (13.4 ± 2.1 vs. 7.0 ± 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD{sub 90}; 73.8 ± 9.5 vs. 50.9 ± 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvβ subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD and NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias. - Highlights: • Hyperoxia treatment leads to arrhythmia with prolonged QTc and action potential duration. • Hyperoxia treatment alters cardiac pyridine nucleotide [NAD(P)H/NAD(P)] levels. • SiRT1 and Kv1.5 are co-regulated in hyperoxic heart injury. • Hyperoxia may lead to cardiotoxicity.« less

A multiscale approach to modelling electrochemical processes occurring across the cell membrane with application to transmission of action potentials.

PubMed

Richardson, G

2009-09-01

By application of matched asymptotic expansions, a simplified partial differential equation (PDE) model for the dynamic electrochemical processes occurring in the vicinity of a membrane, as ions selectively permeate across it, is formally derived from the Poisson-Nernst-Planck equations of electrochemistry. It is demonstrated that this simplified model reduces itself, in the limit of a long thin axon, to the cable equation used by Hodgkin and Huxley to describe the propagation of action potentials in the unmyelinated squid giant axon. The asymptotic reduction from the simplified PDE model to the cable equation leads to insights that are not otherwise apparent; these include an explanation of why the squid giant axon attains a diameter in the region of 1 mm. The simplified PDE model has more general application than the Hodgkin-Huxley cable equation and can, e.g. be used to describe action potential propagation in myelinated axons and neuronal cell bodies.

Colchicine--Update on mechanisms of action and therapeutic uses.

PubMed

Leung, Ying Ying; Yao Hui, Laura Li; Kraus, Virginia B

2015-12-01

To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Lithium attenuates lead induced toxicity on mouse non-adherent bone marrow cells.

PubMed

Banijamali, Mahsan; Rabbani-Chadegani, Azra; Shahhoseini, Maryam

2016-07-01

Lead is a poisonous heavy metal that occurs in all parts of environment and causes serious health problems in humans. The aim of the present study was to investigate the possible protective effect of lithium against lead nitrate induced toxicity in non-adherent bone marrow stem cells. Trypan blue and MTT assays represented that exposure of the cells to different concentrations of lead nitrate decreased viability in a dose dependent manner, whereas, pretreatment of the cells with lithium protected the cells against lead toxicity. Lead reduced the number and differentiation status of bone marrow-derived precursors when cultured in the presence of colony stimulating factor (CSF), while the effect was attenuated by lithium. The cells treated with lead nitrate exhibited cell shrinkage, DNA fragmentation, anion superoxide production, but lithium prevented lead action. Moreover, apoptotic indexes such as PARP cleavage and release of HMGB1 induced by lead, were protected by lithium, suggesting anti-apoptotic effect of lithium. Immunoblot analysis of histone H3K9 acetylation indicated that lithium overcame lead effect on acetylation. In conclusion, lithium efficiently reduces lead toxicity suggesting new insight into lithium action which may contribute to increased cell survival. It also provides a potentially new therapeutic strategy for lithium and a cost-effective approach to minimize destructive effects of lead on bone marrow stem cells. Copyright © 2016 Elsevier GmbH. All rights reserved.

36 CFR 907.16 - Actions where lead Agency designation is necessary.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Actions where lead Agency... DEVELOPMENT CORPORATION ENVIRONMENTAL QUALITY § 907.16 Actions where lead Agency designation is necessary. (a... proximity, the Corporation will seek designation as lead agency for those actions that directly relate to...

36 CFR § 907.16 - Actions where lead Agency designation is necessary.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Actions where lead Agency... DEVELOPMENT CORPORATION ENVIRONMENTAL QUALITY § 907.16 Actions where lead Agency designation is necessary. (a... proximity, the Corporation will seek designation as lead agency for those actions that directly relate to...

36 CFR 907.16 - Actions where lead Agency designation is necessary.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Actions where lead Agency... DEVELOPMENT CORPORATION ENVIRONMENTAL QUALITY § 907.16 Actions where lead Agency designation is necessary. (a... proximity, the Corporation will seek designation as lead agency for those actions that directly relate to...

Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.

PubMed

Fan, Zhuo; Lv, Nanying; Luo, Xiao; Tan, Wen

2017-10-01

Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level. Copyright © 2017. Published by Elsevier B.V.

Cleanups In My Community (CIMC) - Hazardous Waste Corrective Actions, National Layer

EPA Pesticide Factsheets

This data layer provides access to Hazardous Waste Corrective Action sites as part of the CIMC web service. Hazardous waste is waste that is dangerous or potentially harmful to our health or the environment. Hazardous wastes can be liquids, solids, gases, or sludges. They can be discarded commercial products, like cleaning fluids or pesticides, or the by-products of manufacturing processes. The RCRA Corrective Action Program, run by EPA and 43 authorized states and territories, works with facilities that have treated, stored, or disposed of hazardous wastes (TSDs) to protect public health and the environment by investigating and cleaning up hazardous releases to soil, ground water, surface water, and air at their facilities.RCRA Corrective Action sites in all 50 states and four U.S. territories cover 18 million acres of land.EPA estimates that more than 35 million people, roughly 12 percent of the U.S. population, live within one mile of a RCRA Corrective Action site (based on the 2000 U.S. Census).RCRA Corrective Action facilities include many current and former chemical manufacturing plants, oil refineries, lead smelters, wood preservers, steel mills, commercial landfills, and a variety of other types of entities. Due to poor practices prior to environmental regulations, Corrective Action facilities have left large stretches of river sediments laden with PCBs; deposited lead in residential yards and parks beyond site boundaries; polluted drinking water wells

Beyond faithful conduction: short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon

PubMed Central

Bucher, Dirk; Goaillard, Jean-Marc

2011-01-01

Most spiking neurons are divided into functional compartments: a dendritic input region, a soma, a site of action potential initiation, an axon trunk and its collaterals for propagation of action potentials, and distal arborizations and terminals carrying the output synapses. The axon trunk and lower order branches are probably the most neglected and are often assumed to do nothing more than faithfully conducting action potentials. Nevertheless, there are numerous reports of complex membrane properties in non-synaptic axonal regions, owing to the presence of a multitude of different ion channels. Many different types of sodium and potassium channels have been described in axons, as well as calcium transients and hyperpolarization-activated inward currents. The complex time- and voltage-dependence resulting from the properties of ion channels can lead to activity-dependent changes in spike shape and resting potential, affecting the temporal fidelity of spike conduction. Neural coding can be altered by activity-dependent changes in conduction velocity, spike failures, and ectopic spike initiation. This is true under normal physiological conditions, and relevant for a number of neuropathies that lead to abnormal excitability. In addition, a growing number of studies show that the axon trunk can express receptors to glutamate, GABA, acetylcholine or biogenic amines, changing the relative contribution of some channels to axonal excitability and therefore rendering the contribution of this compartment to neural coding conditional on the presence of neuromodulators. Long-term regulatory processes, both during development and in the context of activity-dependent plasticity may also affect axonal properties to an underappreciated extent. PMID:21708220

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

PubMed

Devenyi, Ryan A; Ortega, Francis A; Groenendaal, Willemijn; Krogh-Madsen, Trine; Christini, David J; Sobie, Eric A

2017-04-01

Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K + current and a drastic decrease in the slow delayed rectifier K + current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K + currents influences ventricular arrhythmia susceptibility. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 (SGLT2) inhibitors.

PubMed

Madaan, Tushar; Husain, Ibraheem; Akhtar, Mohamad; Najmi, Abul Kalam

2018-05-11

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti-hyperglycemic drugs with a distinctive mechanism of action focusing on renal absorption ofglucose. Apart from its anti-hyperglycemic effects, a multitude of research studies on this classhave revealed that these drugs have far more versatile and comprehensive pharmacologicaleffects than previously believed. Approximately 30% of FDA approved drugs are repurposedand used for indications other than those they were initially intended for. Repurposing alreadyapproved drugs leads to significant reduction in pre-clinical and clinical R&D costs as well as minimizes the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti-hyperlipidemic, anti-atherosclerotic, anti- obesity, anti-neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre-clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of itspharmacodynamic actions such as natriuresis, hemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti-inflammatory, andanti-oxidative actions. These favorable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The Influence of Glutamate on Axonal Compound Action Potential In Vitro.

PubMed

Abouelela, Ahmed; Wieraszko, Andrzej

2016-01-01

Background  Our previous experiments demonstrated modulation of the amplitude of the axonal compound action potential (CAP) by electrical stimulation. To verify assumption that glutamate released from axons could be involved in this phenomenon, the modification of the axonal CAP induced by glutamate was investigated. Objectives  The major objective of this research is to verify the hypothesis that axonal activity would trigger the release of glutamate, which in turn would interact with specific axonal receptors modifying the amplitude of the action potential. Methods  Segments of the sciatic nerve were exposed to exogenous glutamate in vitro, and CAP was recorded before and after glutamate application. In some experiments, the release of radioactive glutamate analog from the sciatic nerve exposed to exogenous glutamate was also evaluated. Results  The glutamate-induced increase in CAP was blocked by different glutamate receptor antagonists. The effect of glutamate was not observed in Ca-free medium, and was blocked by antagonists of calcium channels. Exogenous glutamate, applied to the segments of sciatic nerve, induced the release of radioactive glutamate analog, demonstrating glutamate-induced glutamate release. Immunohistochemical examination revealed that axolemma contains components necessary for glutamatergic neurotransmission. Conclusion  The proteins of the axonal membrane can under the influence of electrical stimulation or exogenous glutamate change membrane permeability and ionic conductance, leading to a change in the amplitude of CAP. We suggest that increased axonal activity leads to the release of glutamate that results in changes in the amplitude of CAPs.

Closure Report for Corrective Action Unit 539: Areas 25 and 26 Railroad Tracks Nevada National Security Site, Nevada with ROTC-1, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mark Kauss

2011-06-01

This Closure Report (CR) presents information supporting the closure of Corrective Action Unit (CAU) 539: Areas 25 and 26 Railroad Tracks, Nevada National Security Site, Nevada. This CR complies with the requirements of the Federal Facility Agreement and Consent Order (FFACO) that was agreed to by the State of Nevada; U.S. Department of Energy (DOE), Environmental Management; U.S. Department of Defense; and DOE, Legacy Management. The corrective action sites (CASs) within CAU 539 are located within Areas 25 and 26 of the Nevada National Security Site. Corrective Action Unit 539 comprises the following CASs: • 25-99-21, Area 25 Railroad Tracksmore » • 26-99-05, Area 26 Railroad Tracks The purpose of this CR is to provide documentation supporting the completed corrective actions and provide data confirming that the closure objectives for CASs within CAU 539 were met. To achieve this, the following actions were performed: • Reviewed documentation on historical and current site conditions, including the concentration and extent of contamination. • Conducted radiological walkover surveys of railroad tracks in both Areas 25 and 26. • Collected ballast and soil samples and calculated internal dose estimates for radiological releases. • Collected in situ thermoluminescent dosimeter measurements and calculated external dose estimates for radiological releases. • Removed lead bricks as potential source material (PSM) and collected verification samples. • Implemented corrective actions as necessary to protect human health and the environment. • Properly disposed of corrective action and investigation wastes. • Implemented an FFACO use restriction (UR) for radiological contamination at CAS 25-99-21. The approved UR form and map are provided in Appendix F and will be filed in the DOE, National Nuclear Security Administration Nevada Site Office (NNSA/NSO), Facility Information Management System; the FFACO database; and the NNSA/NSO CAU/CAS files. From November 29, 2010, through May 2, 2011, closure activities were performed as set forth in the Streamlined Approach for Environmental Restoration (SAFER) Plan for Corrective Action Unit 539: Areas 25 and 26 Railroad Tracks, Nevada Test Site, Nevada. The purposes of the activities as defined during the data quality objectives process were as follows: • Determine whether contaminants of concern (COCs) are present. • If COCs are present, determine their nature and extent, implement appropriate corrective actions, and properly dispose of wastes. Analytes detected during the closure activities were evaluated against final action levels (FALs) to determine COCs for CAU 539. Assessment of the data generated from closure activities revealed the following: • At CAS 26-99-05, the total effective dose for radiological releases did not exceed the FAL of 25 millirem per Industrial Area year. Potential source material in the form of lead bricks was found at three locations. A corrective action of clean closure was implemented at these locations, and verification samples indicated that no further action is necessary. • At CAS 25-99-21, the total effective dose for radiological releases exceeds the FAL of 25 millirem per Industrial Area year. Potential source material in the form of lead bricks was found at eight locations. A corrective action was implemented by removing the lead bricks and soil above FALs at these locations, and verification samples indicated that no further action is necessary. Pieces of debris with high radioactivity were identified as PSM and remain within the CAS boundary. A corrective action of closure in place with a UR was implemented at this CAS because closure activities showed evidence of remaining soil contamination and radioactive PSM. Future land use will be restricted from surface and intrusive activities. Closure activities generated waste streams consisting of industrial solid waste, recyclable materials, low-level radioactive waste, and mixed low-level radioactive waste. Wastes were disposed of in the appropriate onsite landfills. The NNSA/NSO provides the following recommendations: • Clean closure is required at CAS 26-99-05. • Closure in place is required at CAS 25-99-21. • A UR is required at CAS 25-99-21. • A Notice of Completion to the NNSA/NSO is requested from the Nevada Division of Environmental Protection for closure of CAU 539. • Corrective Action Unit 539 should be moved from Appendix III to Appendix IV of the FFACO.« less

Novel aspects of glucocorticoid actions.

PubMed

Uchoa, E T; Aguilera, G; Herman, J P; Fiedler, J L; Deak, T; de Sousa, M B C

2014-09-01

Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion. © 2014 British Society for Neuroendocrinology.

Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads

USDA-ARS?s Scientific Manuscript database

The ubiquitin/proteasome pathway is the principal system for degradation of proteins in eukaryotes. Ubiquitin is a highly conserved polypeptide that covalently attaches to target proteins through the combined action ofubiquitin-activating enzyme (E1), conjugating enzyme (E2) and a protein ligase (E...

To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents

PubMed Central

2017-01-01

Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia. PMID:28634570

Rapid corticosteroid actions on synaptic plasticity in the mouse basolateral amygdala: relevance of recent stress history and β-adrenergic signaling.

PubMed

Sarabdjitsingh, R A; Joëls, M

2014-07-01

The rodent stress hormone corticosterone rapidly enhances long-term potentiation in the CA1 hippocampal area, but leads to a suppression when acting in a more delayed fashion. Both actions are thought to contribute to stress effects on emotional memory. Emotional memory formation also involves the basolateral amygdala, an important target area for corticosteroid actions. We here (1) investigated the rapid effects of corticosterone on amygdalar synaptic potentiation, (2) determined to what extent these effects depend on the mouse's recent stress history or (3) on prior β-adrenoceptor activation; earlier studies at the single cell level showed that especially a recent history of stress changes the responsiveness of basolateral amygdala neurons to corticosterone. We report that, unlike the hippocampus, stress enhances amygdalar synaptic potentiation in a slow manner. In vitro exposure to 100 nM corticosterone quickly decreases synaptic potentiation, and causes only transient potentiation in tissue from stressed mice. This transient type of potentiation is also seen when β-adrenoceptors are blocked during stress and this is further exacerbated by subsequent in vitro administered corticosterone. We conclude that stress and corticosterone change synaptic potentiation in the basolateral amygdala in a manner opposite to that seen in the hippocampus and that renewed exposure to corticosterone only allows induction of non-persistent forms of synaptic potentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

Quantum corrections to the gravitational potentials of a point source due to conformal fields in de Sitter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fröb, Markus B.; Verdaguer, Enric, E-mail: mfroeb@itp.uni-leipzig.de, E-mail: enric.verdaguer@ub.edu

We derive the leading quantum corrections to the gravitational potentials in a de Sitter background, due to the vacuum polarization from loops of conformal fields. Our results are valid for arbitrary conformal theories, even strongly interacting ones, and are expressed using the coefficients b and b' appearing in the trace anomaly. Apart from the de Sitter generalization of the known flat-space results, we find two additional contributions: one which depends on the finite coefficients of terms quadratic in the curvature appearing in the renormalized effective action, and one which grows logarithmically with physical distance. While the first contribution corresponds tomore » a rescaling of the effective mass, the second contribution leads to a faster fall-off of the Newton potential at large distances, and is potentially measurable.« less

Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria

PubMed Central

Biagini, Giancarlo A.; Fisher, Nicholas; Shone, Alison E.; Mubaraki, Murad A.; Srivastava, Abhishek; Hill, Alisdair; Antoine, Thomas; Warman, Ashley J.; Davies, Jill; Pidathala, Chandrakala; Amewu, Richard K.; Leung, Suet C.; Sharma, Raman; Gibbons, Peter; Hong, David W.; Pacorel, Bénédicte; Lawrenson, Alexandre S.; Charoensutthivarakul, Sitthivut; Taylor, Lee; Berger, Olivier; Mbekeani, Alison; Stocks, Paul A.; Nixon, Gemma L.; Chadwick, James; Hemingway, Janet; Delves, Michael J.; Sinden, Robert E.; Zeeman, Anne-Marie; Kocken, Clemens H. M.; Berry, Neil G.; O’Neill, Paul M.; Ward, Stephen A.

2012-01-01

There is an urgent need for new antimalarial drugs with novel mechanisms of action to deliver effective control and eradication programs. Parasite resistance to all existing antimalarial classes, including the artemisinins, has been reported during their clinical use. A failure to generate new antimalarials with novel mechanisms of action that circumvent the current resistance challenges will contribute to a resurgence in the disease which would represent a global health emergency. Here we present a unique generation of quinolone lead antimalarials with a dual mechanism of action against two respiratory enzymes, NADH:ubiquinone oxidoreductase (Plasmodium falciparum NDH2) and cytochrome bc1. Inhibitor specificity for the two enzymes can be controlled subtly by manipulation of the privileged quinolone core at the 2 or 3 position. Inhibitors display potent (nanomolar) activity against both parasite enzymes and against multidrug-resistant P. falciparum parasites as evidenced by rapid and selective depolarization of the parasite mitochondrial membrane potential, leading to a disruption of pyrimidine metabolism and parasite death. Several analogs also display activity against liver-stage parasites (Plasmodium cynomolgi) as well as transmission-blocking properties. Lead optimized molecules also display potent oral antimalarial activity in the Plasmodium berghei mouse malaria model associated with favorable pharmacokinetic features that are aligned with a single-dose treatment. The ease and low cost of synthesis of these inhibitors fulfill the target product profile for the generation of a potent, safe, and inexpensive drug with the potential for eventual clinical deployment in the control and eradication of falciparum malaria. PMID:22566611

Cannabinoids and glaucoma

PubMed Central

Tomida, I; Pertwee, R G; Azuara-Blanco, A

2004-01-01

Glaucoma is one of the leading causes of blindness in the world. In spite of the diverse therapeutic possibilities, new and better treatments for glaucoma are highly desirable. Cannabinoids effectively lower the intraocular pressure (IOP) and have neuroprotective actions. Thus, they could potentially be useful in the treatment of glaucoma. The purpose of this article is to provide the reader with an overview of the latest achievements in research into the potential use of cannabinoids for glaucoma. PMID:15090428

Trial-Type Dependent Frames of Reference for Value Comparison

PubMed Central

Hunt, Laurence T.; Woolrich, Mark W.; Rushworth, Matthew F. S.; Behrens, Timothy E. J.

2013-01-01

A central question in cognitive neuroscience regards the means by which options are compared and decisions are resolved during value-guided choice. It is clear that several component processes are needed; these include identifying options, a value-based comparison, and implementation of actions to execute the decision. What is less clear is the temporal precedence and functional organisation of these component processes in the brain. Competing models of decision making have proposed that value comparison may occur in the space of alternative actions, or in the space of abstract goods. We hypothesized that the signals observed might in fact depend upon the framing of the decision. We recorded magnetoencephalographic data from humans performing value-guided choices in which two closely related trial types were interleaved. In the first trial type, each option was revealed separately, potentially causing subjects to estimate each action's value as it was revealed and perform comparison in action-space. In the second trial type, both options were presented simultaneously, potentially leading to comparison in abstract goods-space prior to commitment to a specific action. Distinct activity patterns (in distinct brain regions) on the two trial types demonstrated that the observed frame of reference used for decision making indeed differed, despite the information presented being formally identical, between the two trial types. This provides a potential reconciliation of conflicting accounts of value-guided choice. PMID:24068906

40 CFR 141.80 - General requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... and copper action levels measured in samples collected at consumers' taps. (c) Lead and copper action levels. (1) The lead action level is exceeded if the concentration of lead in more than 10 percent of tap... action level is exceeded if the concentration of copper in more than 10 percent of tap water samples...

[Conversion of sound into auditory nerve action potentials].

PubMed

Encke, J; Kreh, J; Völk, F; Hemmert, W

2016-11-01

Outer hair cells play a major role in the hearing process: they amplify the motion of the basilar membrane up to a 1000-fold and at the same time sharpen the excitation patterns. These patterns are converted by inner hair cells into action potentials of the auditory nerve. Outer hair cells are delicate structures and easily damaged, e. g., by overexposure to noise. Hearing aids can amplify the amplitude of the excitation patterns, but they cannot restore their degraded frequency selectivity. Noise overexposure also leads to delayed degeneration of auditory nerve fibers, particularly those with low a spontaneous rate, which are important for the coding of sound in noise. However, this loss cannot be diagnosed by pure-tone audiometry.

Spectral action models of gravity on packed swiss cheese cosmology

NASA Astrophysics Data System (ADS)

Ball, Adam; Marcolli, Matilde

2016-06-01

We present a model of (modified) gravity on spacetimes with fractal structure based on packing of spheres, which are (Euclidean) variants of the packed swiss cheese cosmology models. As the action functional for gravity we consider the spectral action of noncommutative geometry, and we compute its expansion on a space obtained as an Apollonian packing of three-dimensional spheres inside a four-dimensional ball. Using information from the zeta function of the Dirac operator of the spectral triple, we compute the leading terms in the asymptotic expansion of the spectral action. They consist of a zeta regularization of the divergent sum of the leading terms of the spectral actions of the individual spheres in the packing. This accounts for the contribution of points 1 and 3 in the dimension spectrum (as in the case of a 3-sphere). There is an additional term coming from the residue at the additional point in the real dimension spectrum that corresponds to the packing constant, as well as a series of fluctuations coming from log-periodic oscillations, created by the points of the dimension spectrum that are off the real line. These terms detect the fractality of the residue set of the sphere packing. We show that the presence of fractality influences the shape of the slow-roll potential for inflation, obtained from the spectral action. We also discuss the effect of truncating the fractal structure at a certain scale related to the energy scale in the spectral action.

Ultrashort Phenomena in Biochemistry and Biological Signaling

NASA Astrophysics Data System (ADS)

Splinter, Robert

2014-11-01

In biological phenomena there are indications that within the long pulse-length of the action potential on millisecond scale, there is additional ultrashort perturbation encoding that provides the brain with detailed information about the origin (location) and physiological characteristics. The objective is to identify the mechanism-of-action providing the potential for encoding in biological signal propagation. The actual molecular processes involved in the initiation of the action potential have been identified to be in the femtosecond and pico-second scale. The depolarization process of the cellular membrane itself, leading to the onset of the actionpotential that is transmitted to the brain, however is in the millisecond timeframe. One example of the femtosecond chemical interaction is the photoresponse of bacteriorhodopsin. No clear indication for the spatial encoding has so far been verified. Further research will be required on a cellular signal analysis level to confirm or deny the spatial and physiological encoding in the signal wave-trains of intercellular communications and sensory stimuli. The pathological encoding process for cardiac depolarization is however very pronounced and validated, however this electro-chemical process is in the millisecond amplitude and frequency modulation spectrum.

Determination of Nerve Fiber Diameter Distribution From Compound Action Potential: A Continuous Approach.

PubMed

Un, M Kerem; Kaghazchi, Hamed

2018-01-01

When a signal is initiated in the nerve, it is transmitted along each nerve fiber via an action potential (called single fiber action potential (SFAP)) which travels with a velocity that is related with the diameter of the fiber. The additive superposition of SFAPs constitutes the compound action potential (CAP) of the nerve. The fiber diameter distribution (FDD) in the nerve can be computed from the CAP data by solving an inverse problem. This is usually achieved by dividing the fibers into a finite number of diameter groups and solve a corresponding linear system to optimize FDD. However, number of fibers in a nerve can be measured sometimes in thousands and it is possible to assume a continuous distribution for the fiber diameters which leads to a gradient optimization problem. In this paper, we have evaluated this continuous approach to the solution of the inverse problem. We have utilized an analytical function for SFAP and an assumed a polynomial form for FDD. The inverse problem involves the optimization of polynomial coefficients to obtain the best estimate for the FDD. We have observed that an eighth order polynomial for FDD can capture both unimodal and bimodal fiber distributions present in vivo, even in case of noisy CAP data. The assumed FDD distribution regularizes the ill-conditioned inverse problem and produces good results.

Conduction velocity of antigravity muscle action potentials.

PubMed

Christova, L; Kosarov, D; Christova, P

1992-01-01

The conduction velocity of the impulses along the muscle fibers is one of the parameters of the extraterritorial potentials of the motor units allowing for the evaluation of the functional state of the muscles. There are no data about the conduction velocities of antigravity muscleaction potentials. In this paper we offer a method for measuring conduction velocity of potentials of single MUs and the averaged potentials of the interference electromiogram (IEMG) lead-off by surface electrodes from mm. sternocleidomastoideus, trapezius, deltoideus (caput laterale) and vastus medialis. The measured mean values of the conduction velocity of antigravity muscles potentials can be used for testing the functional state of the muscles.

Influence of pre-, post-, and simultaneous perfusion of elevated calcium on the effect of ascending concentrations of lead on digoxin-induced cardiac arrest in isolated frog heart

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krishnamoorthy, M.S.; Muthu, P.; Parthiban, N.

1995-10-01

Cardiotoxicity of lead, a ubiquitous environmental pollutant, has already been documented as a potentially lethal, although rarely recognized, complication of lead intoxication. Further, it has already been reported from this laboratory that lead acetate (LA) preperfusion potentiated cardiotoxicity of digoxin (DGN) in isolated frog heart preparation and that exposure to elevated calcium (elev. Ca{sup 2+}) prior to, and simultaneously with LA at 10{sup {minus}7} M concentration, attenuated this potentiation. As an extension of this work, it was considered of interest to study the effect of perfusion of elev. Ca{sup 2+} (6.5 mM) prior to, after and simultaneously with ascending concentrationsmore » of lead (10{sup {minus}9}, 10{sup {minus}7} and 10{sup {minus}5}M) on DGN induced cardiac arrest (CA) in isolated frog heart, since Pb{sup 2+} and Ca{sup 2+} ions are known to compete with each other for the same target sites at the cellular level, an instance of competitive mass action effect. 15 refs., 1 fig., 1 tab.« less

36 CFR 1010.15 - Actions where lead agency designation is necessary.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Actions where lead agency... ENVIRONMENTAL QUALITY § 1010.15 Actions where lead agency designation is necessary. (a) Consistent with 40 CFR... functional interdependence or geographical proximity, the Trust will seek designation as lead agency for...

36 CFR 907.16 - Actions where lead Agency designation is necessary.

Code of Federal Regulations, 2010 CFR

2010-07-01

... qualifies as one for which the Corporation will seek designation as lead agency, the Corporation will... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Actions where lead Agency... DEVELOPMENT CORPORATION ENVIRONMENTAL QUALITY § 907.16 Actions where lead Agency designation is necessary. (a...

36 CFR 1010.15 - Actions where lead agency designation is necessary.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Actions where lead agency... ENVIRONMENTAL QUALITY § 1010.15 Actions where lead agency designation is necessary. (a) Consistent with 40 CFR... functional interdependence or geographical proximity, the Trust will seek designation as lead agency for...

36 CFR 907.16 - Actions where lead Agency designation is necessary.

Code of Federal Regulations, 2011 CFR

2011-07-01

... qualifies as one for which the Corporation will seek designation as lead agency, the Corporation will... 36 Parks, Forests, and Public Property 3 2011-07-01 2011-07-01 false Actions where lead Agency... DEVELOPMENT CORPORATION ENVIRONMENTAL QUALITY § 907.16 Actions where lead Agency designation is necessary. (a...

36 CFR 1010.15 - Actions where lead agency designation is necessary.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 36 Parks, Forests, and Public Property 3 2012-07-01 2012-07-01 false Actions where lead agency... ENVIRONMENTAL QUALITY § 1010.15 Actions where lead agency designation is necessary. (a) Consistent with 40 CFR... functional interdependence or geographical proximity, the Trust will seek designation as lead agency for...

36 CFR 1010.15 - Actions where lead agency designation is necessary.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 36 Parks, Forests, and Public Property 3 2014-07-01 2014-07-01 false Actions where lead agency... ENVIRONMENTAL QUALITY § 1010.15 Actions where lead agency designation is necessary. (a) Consistent with 40 CFR... functional interdependence or geographical proximity, the Trust will seek designation as lead agency for...

36 CFR § 1010.15 - Actions where lead agency designation is necessary.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 36 Parks, Forests, and Public Property 3 2013-07-01 2012-07-01 true Actions where lead agency... ENVIRONMENTAL QUALITY § 1010.15 Actions where lead agency designation is necessary. (a) Consistent with 40 CFR... functional interdependence or geographical proximity, the Trust will seek designation as lead agency for...

Application of a redox gradostat reactor for assessing rhizosphere microorganism activity on lambda-cyhalothrin

USDA-ARS?s Scientific Manuscript database

The role of bacteria in the degradation of pesticides has been investigated both at the consortial level and the isolate level. Bacterial action on a pesticide can lead to decreased toxicity potential in aquatic systems or decrease its lifetime within the environment. Increasingly there is a need ...

77 FR 7531 - Disapproval and Promulgation of Air Quality Implementation Plans; Montana; Revisions to the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-13

... is also taking final action to disapprove the phrase ``asphalt concrete plants, mineral crushers'' in..., particulate matter, carbon monoxide (CO), sulfur dioxide (SO 2 ), lead, nitrogen oxides (NO X ) or any other... requires asphalt concrete plants, mineral crushers, and mineral screens that have the potential to emit...

Cochlear Processes: A Research Report.

ERIC Educational Resources Information Center

Zwislocki, Jozef J.

This paper summarizes recent research on functions of the cochlea of the inner ear. The cochlea is described as the seat of the first step in the auditory sound analysis and transduction of mechanical vibration into electrochemical processes leading to the generation of neural action potentials. The cochlea is also described as a frequent seat of…

Youth Participatory Action Research: A Pedagogy of Transformational Resistance for Critical Youth Studies

ERIC Educational Resources Information Center

Cammarota, Julio

2017-01-01

This article explains how some youth gain insights into educational processes of social reproduction by participating in a pedagogy of transformational resistance. These insights lead to resistances that have the potential to transform young people's subjectivities while allowing them to envision ways of learning to counteract oppressive and…

78 FR 56589 - Airworthiness Directives; PIAGGIO AERO INDUSTRIES S.p.A Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

... friction in the MLG wheel lever sub-assembly. This condition, if not detected and corrected, could lead to...-off or landing runs. To address this potential unsafe condition, Piaggio Aero Industries (PAI) issued... loss of control during take-off or landing runs. (f) Actions and Compliance Unless already done, do the...

Temporal and spatial characteristics of lead emissions from the lead-acid battery manufacturing industry in China.

PubMed

Liu, Wei; Tian, Jinping; Chen, Lujun; Guo, Yang

2017-01-01

An inventory of lead emissions was established for the lead-acid battery (LAB) manufacturing industry in China from 2000 to 2014. The lead emissions from the LAB manufacturing industry increased from 133 t in 2000 to a peak at 281 t in 2010 with the rapid development of LAB industry. Since 2011, a mandatory national clean action on LAB industry and a series of retrofitting measures have been implemented in China. As a result, more than 80% of small and low-efficient LAB manufacturers were closed, and technical-environmental performance of the industry has been improved significantly. Thus the lead emissions from the industry declined to 113 t in 2014. Geographically, lead emissions were attributed to several provinces with intensive LAB manufacturers, including Zhejiang, Guangdong, Jiangsu, Shandong, and Hebei Province. Spatial transfer of the LAB manufacturing industry from developed areas to developing areas in China was manifest due to strict environmental regulation, posing potential environmental risks to the areas undertaking the industry transfer. In light of the effectiveness of the national clean action, the LAB manufacturing industry will reduce lead emissions further by implementing the entry criteria strictly, adopting policy of total lead emissions control, and establishing a long-term regulatory mechanism for LAB manufacturers. The local authorities in some developing areas should improve abilities of environmental supervision and environmental risk prevention to deal with the spillover of lead emissions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Management concerns about known and potential impacts of lead use in shooting and in fishing activities

USGS Publications Warehouse

Goddard, C.I.; Leonard, N.J.; Stang, D.L.; Wingate, P.J.; Rattner, B.A.; Franson, J.C.; Sheffield, S.R.

2008-01-01

We present a summary of the technical review, jointly requested by the American Fisheries Society and The Wildlife Society, addressing the hazards to wildlife resulting from lead objects or fragments introduced into aquatic and terrestrial environments from the use of ammunition and fishing tackle. Impacts from lead are well documented in humans, as well as in terrestrial and aquatic organisms. Concern about impacts from lead ammunition and fishing tackle has resulted in the development of non-lead alternatives, educational campaigns, and regulations to restrict their use. This article discusses the general biological impacts of lead exposure from fishing and shooting activities to fish, wildlife, and humans; summarizes existing and proposed regulations to reduce lead exposure to biota; reviews alternatives to lead materials that are currently available for fishing; and outlines options for further actions to reduce wildlife and human exposure to lead from fishing activities.

Vulnerabilities to climate change of Massachusetts animal species of greatest conservation need

USGS Publications Warehouse

Galbraith, Hector; Morelli, Toni L.

2017-01-01

Over the last decade, the Commonwealth of Massachusetts has addressed the potential and actual impacts of climate change on state flora and fauna. The state’s involvement began in 2007 when, led by the Division of Fisheries and Wildlife (DFW) and assisted by Manomet Center for Con-servation Research, it carried out one of the first habitat vulnerability assessments in North America (Manomet, 2010). The new methods and processes that resulted were later applied to vulnerability assessments in North America and elsewhere. In 2011, the state assisted the North-eastern Association of Fish and Wildlife Agencies (NEAFWA) in organizing and leading a pio-neering three-year, thirteen-state research effort to evaluate the vulnerabilities of fish and wild-life habitats to climate change in the northeast, from Maine south to West Virginia (NEAFWA, 2012). This focus on climate change vulnerabilities led to three important early realizations: (1) simply categorizing and scoring vulnerabilities might not lead to better conservation outcomes. It was vital to also understand why some resources were more or less vulnerable to climate change in order to identify potential intervention points on which conservation actions and strategies could be based. (2) simply producing research results was not enough; these results had to be cast as specific conservation actions. Moreover (3), these actions needed to be communicated in a useful form to conservation “actors”, such as state agencies, land trusts, land managers, etc. These real-izations led to the next step on the Commonwealth’s journey to effective conservation in an age of climate change - the Massachusetts Wildlife Climate Action Tool (CAT).

Grasping synergies: A motor-control approach to the mirror neuron mechanism

NASA Astrophysics Data System (ADS)

D'Ausilio, Alessandro; Bartoli, Eleonora; Maffongelli, Laura

2015-03-01

The discovery of mirror neurons revived interest in motor theories of perception, fostering a number of new studies as well as controversies. In particular, the degree of motor specificity with which others' actions are simulated is highly debated. Human corticospinal excitability studies support the conjecture that a mirror mechanism encodes object-directed goals or low-level kinematic features of others' reaching and grasping actions. These interpretations lead to different experimental predictions and implications for the functional role of the simulation of others' actions. We propose that the representational granularity of the mirror mechanism cannot be any different from that of the motor system during action execution. Hence, drawing from motor control models, we propose that the building blocks of the mirror mechanism are the relatively few motor synergies explaining the variety of hand functions. The recognition of these synergies, from action observation, can be potentially very robust to visual noise and thus demonstrate a clear advantage of using motor knowledge for classifying others' action.

Ethanol potentiates heat response in the carotid artery via TRPV1.

PubMed

Mustafa, Seham; Ismael, Hishaam N

2017-11-01

Ethanol is one of the most widely used recreational drugs in the world. At high concentrations, it can induce carotid artery vasoconstriction. Hyperthermia potentiates its effects resulting in carotid artery vasoconstriction at any concentration. The aim of this study is to investigate the interaction between ethanol and heating and to understand the underlying mechanisms leading to their synergistic effect. Isometric tension of rabbit carotid artery ring segments suspended in organ baths filled with Krebs solution was recorded. Different concentrations of ethanol were examined at 37°C and during temperature elevation to39-43°C. Capsaicin and capsazepine were used to examine the mechanism of action of ethanol. Ethanol induced contraction at 37°C when the concentration reached 100mM. Contraction was observed at any concentration at higher temperatures. Ethanol potentiated heat-induced contraction. Capsaicin, the vanilloid receptor subtype1 (TRPV1) agonist, potentiated the vasoconstriction due to heating. While capsazepine, TRPV1 antagonist, abolished the effect of ethanol and its potentiation of heating-induced contraction, but it did not abolish the heating effect. Ethanol's mechanism of action and its effect on heating induced-vasoconstriction of the carotid artery is being mediated by TRPV1. The combination of ethanol and hyperthermia can lead to a synergistic effect on carotid vasoconstriction. This effect may induce brain damage and heat stroke. Development of new drugs act as TRPV1 antagonist can be used to prevent these fatal effects. Copyright © 2017 Elsevier Inc. All rights reserved.

The mechanisms associated with the development of hypertension after exposure to lead, mercury species or their mixtures differs with the metal and the mixture ratio.

PubMed

Wildemann, Tanja M; Siciliano, Steven D; Weber, Lynn P

2016-01-02

Hypertension is considered to be the most important risk factor for the development of cardiovascular diseases. Beside life-style risk factors, exposure to lead and mercury species are increasingly discussed as potential risk factors. Although there are a few previous studies, the underlying mechanism by which exposure to lead and mercury disturb blood pressure regulation is not currently understood. Potential mechanisms are oxidative stress production, kidney damage and activation of the renin-angiotensin system (RAS), all of which can interact to cause dysregulation of blood pressure. Male rats (Wistar) were exposed to lead, inorganic mercury, methylmercury or two mixtures of all three metals for four weeks through the drinking water. The two mixture ratios were based on ratios of known reference values or environmental exposure from the literature. To investigate the potential mechanism of actions, blood pressure was measured after four weeks and compared to plasma nitrotyrosine or reduced/oxidized glutathione levels in liver as markers for oxidative stress. Plasma renin and angiotensin II levels were used as markers for RAS activation. Finally, kidney function and injury were assessed via urinary and plasma creatinine levels, creatinine clearance and urinary kidney-injury molecule (KIM-1). While exposure to lead by itself increased oxidative stress and kidney damage along with blood pressure, inorganic mercury did not affect blood pressure or any end-point examined. Conversely, methylmercury instead increased RAS activation along with blood pressure. Surprisingly, when administered as mixtures, lead no longer increased oxidative stress or altered kidney function. Moreover, the mixture based on an environmental ratio no longer had an effect on blood pressure, while the reference value ratio still retained an increase in blood pressure. Based on our results, the prominent mechanism of action associated with the development of hypertension seems to be oxidative stress and kidney damage for lead, while increased RAS activation links methylmercury to hypertension, but these mechanisms along with hypertension disappear when metals are present in some mixtures. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The effective hyper-Kähler potential in the N = 2 supersymmetric QCD

NASA Astrophysics Data System (ADS)

Ketov, Sergei V.

1997-02-01

The effective low-energy hyper-Kähler potential for a massive N = 2 matter in N = 2 super-QCD is investigated. TheN = 2 extended supersymmetry severely restricts the N = 2 matter self-couplings so that their exact form can be fixed by a few parameters, which is apparent in the N = 2 harmonic superspace. In the N = 2 QED with a single matter hypermultiplet, the one-loop perturbative calculations lead to the Taub-NUT hyper-Kähler metric in the massive case, and a free metric in the massless case. It is remarkable that the naive non-renormalization `theorem' does not apply. There exists a manifestly N = 2 supersymmetric duality transformation converting the low-energy effective action for the N = 2 QED hypermultiplet into a sum of the quadratic and the improved (non-polynomial) actions for an N = 2 tensor multiplet. The duality transformation also gives a simple connection between the low-energy effective action in the N = 2 harmonic superspace and the component results.

Decreased electrical excitability of peripheral nerves in demyelinating polyneuropathies.

PubMed Central

Meulstee, J; Darbas, A; van Doorn, P A; van Briemen, L; van der Meché, F G

1997-01-01

Not recognising the presence of decreased excitability may give rise to a seemingly low compound muscle action potential, which may lead erroneously to the conclusion of conduction block. To quantify decreased electrical excitability, stimulation-response curves and the current needed to achieve 90% of the maximal compound muscle action potential amplitude, i90, were obtained in 17 healthy controls, eight patients with Guillain-Barre syndrome, 14 with chronic inflammatory demyelinating polyneuropathy, and 10 with hereditary motor sensory neuropathy type I. Decreased electrical excitability was found in patients with chronic inflammatory demyelinating polyneuropathy and hereditary motor sensory neuropathy type I, by contrast with patients with Guillain-Barré syndrome. Recognising decreased excitability prevents the false assertion of conduction block and has electrodiagnostic importance for the differential diagnosis of demyelinating polyneuropathies. PMID:9120460

Blindsided by the Avatar: White Saviors and Allies out of Hollywood and in Education

ERIC Educational Resources Information Center

Cammarota, Julio

2011-01-01

This article discusses how the white savior syndrome renders the misrepresentation of the potential of people of color to resist and lead the transformation of oppressive conditions within their own social context. Indigenous resistance requires endogenous (internal) leadership such that all social justice actions derive from and continue to flow…

Supporting Teachers as Transformative Intellectuals: Participatory Action Research in Human Rights Education

ERIC Educational Resources Information Center

Hersey, Page Elizabeth

2012-01-01

Human rights education (HRE) holds the potential for educators to begin an honest dialogue with students and to connect local issues with international struggles for human rights. However, HRE and other teaching approaches that build understanding of systems of power and oppression that lead to human rights violations are not widely embraced in…

Effects of intensive forest management practices on insect infestation levels and loblolly pine growth

Treesearch

John T. Nowak; C. Wayne Berisford

2000-01-01

Intensive forest management practices have been shown to increase tree growth and shorten rotation time. However, they may also lead to an increased need for insect pest management because of higher infestation levels and lower action thresholds. To investigate the relationship between intensive management practices arid insect infestation, maximum growth potential...

An Action-Research Project: Community Lead Poisoning Prevention

ERIC Educational Resources Information Center

Rajaram, Shireen S.

2007-01-01

This action-research project focused on gathering data on awareness of lead poisoning, as well as disseminating information on lead poisoning prevention in a metropolitan midwestern city. This project reflects an action-research approach to service learning and was in collaboration with a grass-roots organization. This paper outlines the daunting…

Dorsal–Ventral Gradient for Neuronal Plasticity in the Embryonic Spinal Cord

PubMed Central

Pineda, Ricardo H.; Ribera, Angeles B.

2008-01-01

Within the developing Xenopus spinal cord, voltage-gated potassium (Kv) channel genes display different expression patterns, many of which occur in opposing dorsal–ventral gradients. Regional differences in Kv gene expression would predict different patterns of potassium current (IKv) regulation. However, during the first 24 h of postmitotic differentiation, all primary spinal neurons undergo a temporally coordinated upregulation of IKv density that shortens the duration of the action potential. Here, we tested whether spinal neurons demonstrate regional differences in IKv regulation subsequent to action potential maturation. We show that two types of neurons, I and II, can be identified in culture on the basis of biophysical and pharmacological properties of IKv and different firing patterns. Chronic increases in extracellular potassium, a signature of high neuronal activity, do not alter excitability properties of either neuron type. However, elevating extracellular potassium acutely after the period of action potential maturation leads to different changes in membrane properties of the two types of neurons. IKv of type I neurons gains sensitivity to the blocker XE991, whereas type II neurons increase IKv density and fire fewer action potentials. Moreover, by recording from neurons in vivo, we found that primary spinal neurons can be identified as either type I or type II. Type I neurons predominate in dorsal regions, whereas type II neurons localize to ventral regions. The findings reveal a dorsal–ventral gradient for IKv regulation and a novel form of neuronal plasticity in spinal cord neurons. PMID:18385340

Andrographolide: antibacterial activity against common bacteria of human health concern and possible mechanism of action.

PubMed

Banerjee, Malabika; Parai, Debaprasad; Chattopadhyay, Subrata; Mukherjee, Samir Kumar

2017-05-01

Increasing bacterial resistance to common drugs is a major public health concern for the treatment of infectious diseases. Certain naturally occurring compounds of plant sources have long been reported to possess potential antimicrobial activity. This study was aimed to investigate the antibacterial activity and possible mechanism of action of andrographolide (Andro), a diterpenoid lactone from a traditional medicinal herb Andrographis paniculata. Extent of antibacterial action was assessed by minimal bactericidal concentration method. Radiolabeled N-acetyl glucosamine, leucine, thymidine, and uridine were used to determine the effect of Andro on the biosyntheses of cell wall, protein, DNA, and RNA, respectively. In addition, anti-biofilm potential of this compound was also tested. Andro showed potential antibacterial activity against most of the tested Gram-positive bacteria. Among those, Staphylococcus aureus was found to be most sensitive with a minimal inhibitory concentration value of 100 μg/mL. It was found to be bacteriostatic. Specific inhibition of intracellular DNA biosynthesis was observed in a dose-dependent manner in S. aureus. Andro mediated inhibition of biofilm formation by S. aureus was also found. Considering its antimicrobial potency, Andro might be accounted as a promising lead for new antibacterial drug development.

American Lead Action Memorandum

EPA Pesticide Factsheets

ACTION MEMORANDUM— Request for a Time-Critical Removal Action andExemption from the $2 Million and 12-Month Statutory Limits at the AmericanLead Site, Indianapolis, Marion County, Indiana (Site ID #B56J)

The Potential Impact of Labor Choices on the Efficacy of Marine Conservation Strategies

PubMed Central

Hughes, Zachary D.; Fenichel, Eli P.; Gerber, Leah R.

2011-01-01

Conservation of marine resources is critical to the wellbeing of human communities. Coastal artisanal fishing communities are particularly reliant on marine resources for food and for their livelihoods. Management actions aimed at marine conservation may lead to unanticipated changes in human behavior that influence the ability of conservation programs to achieve their goals. We examine how marine conservation strategies may impact labor decisions that influence both the ecosystem and human livelihoods using simulation modeling. We consider two conservation strategies in the model: direct action through fisheries regulation enforcement, and indirect action through land conservation. Our results indicate that both strategies can increase the abundance of fish, and thus contribute to the maintenance of marine resources. However, our results also show that marine fisheries enforcement may negatively impact the livelihoods of human communities. Land conservation, on the other hand, potentially enhances the livelihood of the human populations. Thus, depending on management objectives, indirect or a combination of direct and indirect conservation strategies may be effective at achieving conservation and sustainability goals. These results highlight the importance of accounting for changes in human behavior resulting from management actions in conservation and management. PMID:21887306

Corrective Action Decision Document/Closure Report for Corrective Action Unit 375: Area 30 Buggy Unit Craters, Nevada National Security Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patrick Matthews

2011-08-01

Corrective Action Unit 375 comprises three corrective action sites (CASs): (1) 25-23-22, Contaminated Soils Site; (2) 25-34-06, Test Cell A Bunker; and (3) 30-45-01, U-30a, b, c, d, e Craters. The purpose of this CADD/CR is to provide justification and documentation supporting the recommendation that no further corrective action is needed for CAU 375 based on the implementation of corrective action of closure in place with administrative controls at CAS 25-23-22, no further action at CAS 25-34-06, and closure in place with administrative controls and removal of potential source material (PSM) at CAS 30-45-01. Corrective action investigation (CAI) activities weremore » performed from July 28, 2010, through April 4, 2011, as set forth in the Corrective Action Investigation Plan for Corrective Action Unit 375: Area 30 Buggy Unit Craters. The approach for the CAI was divided into two facets: investigation of the primary release of radionuclides, and investigation of other releases (migration in washes and chemical releases). The purpose of the CAI was to fulfill data needs as defined during the data quality objective (DQO) process. The CAU 375 dataset of investigation results was evaluated based on the data quality assessment. This assessment demonstrated the dataset is acceptable for use in fulfilling the DQO data needs. Investigation results were evaluated against final action levels (FALs) established in this document. A radiological dose FAL of 25 millirem per year was established based on the Remote Work Area exposure scenario (336 hours of annual exposure). Radiological doses exceeding the FAL were assumed to be present within the default contamination boundaries at CASs 25-23-22 and 30-45-01. No contaminants were identified at CAS 25-34-06, and no corrective action is necessary. Potential source material in the form of lead plate, lead-acid batteries, and oil within an abandoned transformer were identified at CAS 30-45-01, and corrective actions were undertaken that consisted of removing the PSM. Use restrictions and warning signs were implemented for the remaining radiological contamination at CASs 25-23-22 and 30-45-01. These use restrictions were recorded in the FFACO database; the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO) Facility Information Management System; and the NNSA/NSO CAU/CAS files. Therefore, NNSA/NSO provides the following recommendations: (1) No further corrective actions are necessary for CAU 375; (2) A Notice of Completion to NNSA/NSO is requested from the Nevada Division of Environmental Protection for closure of CAU 375; and (3) Move CAU 375 from Appendix III to Appendix IV of the FFACO.« less

A survey of synthetic and natural phytotoxic compounds and phytoalexins as potential antimalarial compounds.

PubMed

Bajsa, Joanna; Singh, Kshipra; Nanayakkara, Dhammika; Duke, Stephen Oscar; Rimando, Agnes Mamaril; Evidente, Antonio; Tekwani, Babu Lal

2007-09-01

The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

Importance of Pipe Deposits to Lead and Copper Rule Compliance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schock, Michael R.; Cantor, Abigail F.; Triantafyllidou, Simoni

When Madison, Wis., exceeded the lead action level in 1992, residential and off-line tests suggested that lead release into the water was more complex than a lead solubility mechanism. Scale analyses (color and texture as well as mineralogical and elemental composition) of five excavated lead service lines (LSLs) revealed that accumulation of manganese (and iron) onto pipe walls had implications for lead corrosion by providing a high-capacity sink for lead. Manganese that accumulated from source well water onto pipe scales (up to 10% by weight of scale composition) served to capture and eventually transport lead to consumer taps. In addition,more » manganese sometimes obstructed the predominance of an insoluble (and thus potentially protective) plattnerite [Pb(IV) solid] scale layer. Full LSL replacement in Madison achieved Lead and Copper Rule compliance and a major reduction in lead contamination and exposure, supplemented by unidirectional flushing of water mains and manganese control in the source well water.« less

Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

PubMed

Xu, Yuanzhong; Tong, Qingchun

2017-07-01

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

Functional role of ambient GABA in refining neuronal circuits early in postnatal development

PubMed Central

Cellot, Giada; Cherubini, Enrico

2013-01-01

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses. PMID:23964205

Real-time Affective Indices of Potential CRM Breakdown: Qualitative Testing of an Operational Hypothesis

NASA Technical Reports Server (NTRS)

Dickerson, Mark

2007-01-01

This viewgraph presentation begins by showing several cases where poor crew resource management (CRM) resulted in aircraft accidents. The presenter reviews the emotional states that are present in a situation that frequently leads to an accident. The operational answer suggested is given as an acronym: PACE, which stand for Probe, Alert, Challenge, Emergency Action.

Synthesis and biological evaluation of platensimycin analogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Hong C.; Ding, Fa-Xiang; Singh, Sheo B.

2009-07-23

Platensimycin (1) displays antibacterial activity due to its inhibition of the elongation condensing enzyme (FabF), a novel mode of action that could potentially lead to a breakthrough in developing a new generation of antibiotics. The medicinal chemistry efforts were focused on the modification of the enone moiety of platensimycin and several analogs showed significant activity against FabF and possess antibacterial activity.

Laser-Induced Modification Of Energy Bands Of Transparent Solids

NASA Astrophysics Data System (ADS)

Gruzdev, Vitaly

2010-10-01

Laser-induced variations of electron energy bands of transparent solids significantly affect the initial stages of laser-induced ablation (LIA) influencing rates of ionization and light absorption by conduction-band electrons. We analyze fast variations with characteristic duration in femto-second time domain that include: 1) switching electron functions from bonding to anti-bonding configuration due to laser-induced ionization; 2) laser-driven oscillations of electrons in quasi-momentum space; and 3) direct distortion of the inter-atomic potential by electric field of laser radiation. Among those effects, the latter two have zero delay and reversibly modify band structure taking place from the beginning of laser action. They are of special interest due to their strong influence on the initial stage and threshold of laser ablation. The oscillations modify the electron-energy bands by adding pondermotive potential. The direct action of radiation's electric field leads to high-frequency Franz-Keldysh effect (FKE) spreading the allowed electron states into the forbidden-energy bands. FKE provides decrease of the effective band gap while the electron oscillations lead either to monotonous increase or oscillatory variations of the gap. We analyze the competition between those two opposite trends and their role in initiating LIA.

Stimulus-dependent deliberation process leading to a specific motor action demonstrated via a multi-channel EEG analysis

PubMed Central

Henz, Sonja; Kutz, Dieter F.; Werner, Jana; Hürster, Walter; Kolb, Florian P.; Nida-Ruemelin, Julian

2015-01-01

The aim of the study was to determine whether a deliberative process, leading to a motor action, is detectable in high density EEG recordings. Subjects were required to press one of two buttons. In a simple motor task the subject knew which button to press, whilst in a color-word Stroop task subjects had to press the right button with the right index finger when meaning and color coincided, or the left button with the left index finger when meaning and color were disparate. EEG recordings obtained during the simple motor task showed a sequence of positive (P) and negative (N) cortical potentials (P1-N1-P2) which are assumed to be related to the processing of the movement. The sequence of cortical potentials was similar in EEG recordings of subjects having to deliberate over how to respond, but the above sequence (P1-N1-P2) was preceded by slowly increasing negativity (N0), with N0 being assumed to represent the end of the deliberation process. Our data suggest the existence of neurophysiological correlates of deliberative processes. PMID:26190987

Using Community-Based Participatory Research to Explore Backyard Gardening Practices and Soil Lead Concentrations in Urban Neighborhoods.

PubMed

Johnson, Sheri; Cardona, Dalila; Davis, Jeremy; Gramling, Benjamin; Hamilton, Chelsea; Hoffmann, Ray; Ruis, Sabrina; Soldat, Doug; Ventura, Steve; Yan, Ke

2016-01-01

Lead exposure is a serious health threat for children. Soil is an important exposure pathway, primarily through ingestion and inhalation. Urban agriculture is increasing. Potential environmental health risks associated with residential gardening may not be well known to community residents. A community-based participatory research (CBPR) approach was implemented to explore the relationship between urban residential vegetable gardening and lead exposure in children. The primary objectives were to characterize local backyard vegetable gardening practices, measure residential and commercial soil lead concentrations and spatial distributions, and identify priorities for individual and collective action. Participants were recruited in two stages. In phase 1, adult gardeners participated in structured interviews. In phase 2, a multistage representative sampling approach was implemented to recruit adult gardeners for interviews and soil testing. Twenty adults participated in gardening practice interviews. Adults perceive many benefits from backyard gardening and initially expressed few concerns about lead exposure risk. Results indicate that children are actively involved in backyard gardening. Total soil lead concentrations from 17 residential properties ranged from 7 to 3,234 mg kg-1(median, 187; mean, 432). Commercial soils had lead concentrations that ranged from 6 to 13 mg kg(-1) (median, 6.5; mean, 7.6). Nonparametric Mann-Whitney comparisons indicated a significant difference in lead concentration between commercial soil and residential soil (p<0.0001). Advocacy for resources needed to eliminate dangerous levels of lead from the environment, especially in communities where divestment has occurred, is enhanced through CBPR. Increasing access to soil testing is an important action step.

TEMPORAL NEUROTRANSMITTER CONDITIONING RESTORES THE FUNCTIONAL ACTIVITY OF ADULT SPINAL-CORD NEURONS IN LONG-TERM CULTURE

PubMed Central

Das, Mainak; Bhargava, Neelima; Bhalkikar, Abhijeet; Kang, Jung Fong; Hickman, James J

2008-01-01

The ability to culture functional adult mammalian spinal-cord neurons represents an important step in the understanding and treatment of a spectrum of neurological disorders including spinal cord injury. Previously, the limited functional recovery of these cells, as characterized by a diminished ability to initiate action potentials and to exhibit repetitive firing patterns, has arisen as a major impediment to their physiological relevance. In this report we demonstrate that single temporal doses of the neurotransmitters serotonin, glutamate (N-acetyl-DL-glutamic acid) and acetylcholine-chloride leads to the full electrophysiological functional recovery of adult mammalian spinal-cord neurons, when they are cultured under defined serum-free conditions. Approximately 60% of the neurons treated regained their electrophysiological signature, often firing single, double and, most importantly, multiple action potentials. PMID:18005959

Qualitative Investigation of the Wellness Recovery Action Plan in a UK NHS Crisis Care Setting.

PubMed

Ashman, Michael; Halliday, Vanessa; Cunnane, Joseph G

2017-07-01

Crisis theory suggests that in addition to presenting a threat to mental well-being, crises are also opportunities where successful interventions can lead to successful outcomes. UK mental health crisis teams aim to reduce hospital admission by treating people at home and by building resilience and supporting learning from crisis, yet data on repeat crisis episodes suggest this could be improved. This qualitative study sought to explore the Wellness Recovery Action Plan (WRAP) as a means of supporting resilience-building and maximising the opportunity potential of crisis. The following themes emerged: The meaning of crisis; Engaging with the WRAP process; WRAP and self-management; and Changes and transformations. This research suggests that WRAP has potential in supporting recovery from crisis, revealing insights into the nature of crisis which can inform the further development of crisis services.

Leading quality improvement in primary care: recommendations for success.

PubMed

Van Hoof, Thomas J; Bisognano, Maureen; Reinertsen, James L; Meehan, Thomas P

2012-09-01

Leadership is increasingly recognized as a potential factor in the success of primary care quality improvement efforts, yet little is definitively known about which specific leadership behaviors are most important. Until more research is available, the authors suggest that primary care clinicians who are committed to developing their leadership skills should commit to a series of actions. These actions include embracing a theory of leadership, modeling the approach for others, focusing on the goal of improving patient outcomes, encouraging teamwork, utilizing available sources of power, and reflecting on one's approach in order to improve it. Primary care clinicians who commit themselves to such actions will be more effective leaders and will be more prepared as new research becomes available on this important factor. Copyright © 2012 Elsevier Inc. All rights reserved.

Selective pressure of antibiotic pollution on bacteria of importance to public health.

PubMed

Tello, Alfredo; Austin, Brian; Telfer, Trevor C

2012-08-01

Many bacteria of clinical importance survive and may grow in different environments. Antibiotic pollution may exert on them a selective pressure leading to an increase in the prevalence of resistance. In this study we sought to determine whether environmental concentrations of antibiotics and concentrations representing action limits used in environmental risk assessment may exert a selective pressure on clinically relevant bacteria in the environment. We used bacterial inhibition as an assessment end point to link antibiotic selective pressures to the prevalence of resistance in bacterial populations. Species sensitivity distributions were derived for three antibiotics by fitting log-logistic models to end points calculated from minimum inhibitory concentration (MIC) distributions based on worldwide data collated by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). To place bacteria represented in these distributions in a broader context, we performed a brief phylogenetic analysis. The potentially affected fraction of bacterial genera at measured environmental concentrations of antibiotics and environmental risk assessment action limits was used as a proxy for antibiotic selective pressure. Measured environmental concentrations and environmental risk assessment action limits were also directly compared to wild-type cut-off values. The potentially affected fraction of bacterial genera estimated based on antibiotic concentrations measured in water environments is ≤ 7%. We estimated that measured environmental concentrations in river sediments, swine feces lagoons, liquid manure, and farmed soil inhibit wild-type populations in up to 60%, 92%, 100%, and 30% of bacterial genera, respectively. At concentrations used as action limits in environmental risk assessment, erythromycin and ciprofloxacin were estimated to inhibit wild-type populations in up to 25% and 76% of bacterial genera. Measured environmental concentrations of antibiotics, as well as concentrations representing environmental risk assessment action limits, are high enough to exert a selective pressure on clinically relevant bacteria that may lead to an increase in the prevalence of resistance.

Postconstruction report of the United Nuclear Corporation Disposal Site at the Oak Ridge Y-12 Plant, Oak Ridge, Tennessee. Environmental Restoration Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oakley, L.B.; Siberell, J.K.; Voskuil, T.L.

1993-06-01

Remedial actions conducted under the auspices of the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) were completed at the Y-12 United Nuclear Corporation (UNC) Disposal Site in August 1992. The purpose of this Postconstruction Report is to summarize numerous technical reports and provide CERCLA documentation for completion of the remedial actions. Other CERCLA reports, such as the Feasibility Study for the UNC Disposal Site, provide documentation leading up to the remedial action decision. The remedial action chosen, placement of a modified RCRA cap, was completed successfully, and performance standards were either met or exceeded. This remedial action provided solutionsmore » to two environmentally contaminated areas and achieved the goal of minimizing the potential for contamination of the shallow groundwater downgradient of the site, thereby providing protection of human health and the environment. Surveillance and maintenance of the cap will be accomplished to ensure cap integrity, and groundwater monitoring downgradient of the site will continue to confirm the acceptability of the remedial action chosen.« less

Online Discussion and the Moral Pathway to Identity Politicization and Collective Action

PubMed Central

Alberici, Augusta Isabella; Milesi, Patrizia

2018-01-01

Research on the mobilizing potential of the Internet has produced some controversy between optimistic vs. skeptical perspectives. Although some attention has been paid to the effects of online discussions on collective participation, very little is known about how people’s experience of online interactions affects the key psychosocial predictors of collective action. The present research investigated whether use of the Internet as a channel for deliberation influenced the moral pathway to collective mobilization by shaping users’ politicized identity, thereby indirectly influencing collective action. Results showed that when people perceived online discussions as a constructive communication context, their politicized identity was imbued with the meaning of responding to a moral obligation, and willingness to participate in collective action was sustained. However, when participants perceived that online discussions were not constructive, their identification with the movement did not refer to moral obligation, and intention to participate in collective action was not sustained. Our discussion focuses on the need to deepen investigation of how people experience the particularities of interacting online, and on how this can affect psychosocial processes leading to collective action.

Neuronal correlates of decisions to speak and act: Spontaneous emergence and dynamic topographies in a computational model of frontal and temporal areas

PubMed Central

Garagnani, Max; Pulvermüller, Friedemann

2013-01-01

The neural mechanisms underlying the spontaneous, stimulus-independent emergence of intentions and decisions to act are poorly understood. Using a neurobiologically realistic model of frontal and temporal areas of the brain, we simulated the learning of perception–action circuits for speech and hand-related actions and subsequently observed their spontaneous behaviour. Noise-driven accumulation of reverberant activity in these circuits leads to their spontaneous ignition and partial-to-full activation, which we interpret, respectively, as model correlates of action intention emergence and action decision-and-execution. Importantly, activity emerged first in higher-association prefrontal and temporal cortices, subsequently spreading to secondary and finally primary sensorimotor model-areas, hence reproducing the dynamics of cortical correlates of voluntary action revealed by readiness-potential and verb-generation experiments. This model for the first time explains the cortical origins and topography of endogenous action decisions, and the natural emergence of functional specialisation in the cortex, as mechanistic consequences of neurobiological principles, anatomical structure and sensorimotor experience. PMID:23489583

40 CFR 6.404 - Lead or cooperating agency.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Lead or cooperating agency. 6.404... ACTIONS Assessing the Environmental Effects Abroad of EPA Actions § 6.404 Lead or cooperating agency. (a) Lead Agency. Section 3-3 of Executive Order 12114 requires the creation of a lead agency whenever an...

40 CFR 6.404 - Lead or cooperating agency.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Lead or cooperating agency. 6.404... ACTIONS Assessing the Environmental Effects Abroad of EPA Actions § 6.404 Lead or cooperating agency. (a) Lead Agency. Section 3-3 of Executive Order 12114 requires the creation of a lead agency whenever an...

40 CFR 6.404 - Lead or cooperating agency.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Lead or cooperating agency. 6.404... ACTIONS Assessing the Environmental Effects Abroad of EPA Actions § 6.404 Lead or cooperating agency. (a) Lead Agency. Section 3-3 of Executive Order 12114 requires the creation of a lead agency whenever an...

40 CFR 6.404 - Lead or cooperating agency.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Lead or cooperating agency. 6.404... ACTIONS Assessing the Environmental Effects Abroad of EPA Actions § 6.404 Lead or cooperating agency. (a) Lead Agency. Section 3-3 of Executive Order 12114 requires the creation of a lead agency whenever an...

40 CFR 6.404 - Lead or cooperating agency.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Lead or cooperating agency. 6.404... ACTIONS Assessing the Environmental Effects Abroad of EPA Actions § 6.404 Lead or cooperating agency. (a) Lead Agency. Section 3-3 of Executive Order 12114 requires the creation of a lead agency whenever an...

Corrective Action Investigation Plan for Corrective Action Unit 204: Storage Bunkers, Nevada Test Site, Nevada (December 2002, Revision No.: 0), Including Record of Technical Change No. 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

NNSA /NSO

The Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 204 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 204 is located on the Nevada Test Site approximately 65 miles northwest of Las Vegas, Nevada. This CAU is comprised of six Corrective Action Sites (CASs) which include: 01-34-01, Underground Instrument House Bunker; 02-34-01, Instrument Bunker; 03-34-01, Underground Bunker; 05-18-02, Chemical Explosives Storage; 05-33-01, Kay Blockhouse; 05-99-02, Explosive Storage Bunker.more » Based on site history, process knowledge, and previous field efforts, contaminants of potential concern for Corrective Action Unit 204 collectively include radionuclides, beryllium, high explosives, lead, polychlorinated biphenyls, total petroleum hydrocarbons, silver, warfarin, and zinc phosphide. The primary question for the investigation is: ''Are existing data sufficient to evaluate appropriate corrective actions?'' To address this question, resolution of two decision statements is required. Decision I is to ''Define the nature of contamination'' by identifying any contamination above preliminary action levels (PALs); Decision II is to ''Determine the extent of contamination identified above PALs. If PALs are not exceeded, the investigation is completed. If PALs are exceeded, then Decision II must be resolved. In addition, data will be obtained to support waste management decisions. Field activities will include radiological land area surveys, geophysical surveys to identify any subsurface metallic and nonmetallic debris, field screening for applicable contaminants of potential concern, collection and analysis of surface and subsurface soil samples from biased locations, and step-out sampling to define the extent of contamination, as necessary. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the corrective action decision document.« less

Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes.

PubMed

Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries

2017-09-01

Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10 -7 to 2.10 -5 M) and verapamil (7 concentrations from 10 -11 to 10 -5 M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC 50 of 2.2·10 -6 M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC 50 of 1.1·10 -6 M; (2) reducing maximum upstroke velocity with IC 50 of 2.6·10 -6 M; and (3) suppressing spontaneous activity with EC 50 of 3.8·10 -6 M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC 50 of 5.3·10 -8 M and prolonged the APD with EC 50 of 2.5·10 -8 M. Verapamil reduced rates of fast depolarization and repolarization with IC 50 s of 1.8 and 2.2·10 -7 M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety. Copyright © 2017 Elsevier Inc. All rights reserved.

Magnetic dynamo action in two-dimensional turbulent magneto-hydrodynamics

NASA Technical Reports Server (NTRS)

Fyfe, D.; Joyce, G.; Montgomery, D.

1977-01-01

Two-dimensional magnetohydrodynamic turbulence is explored by means of numerical simulation. Previous analytical theory, based on non-dissipative constants of the motion in a truncated Fourier representation, is verified by following the evolution of highly non-equilibrium initial conditions numerically. Dynamo action (conversion of a significant fraction of turbulent kinetic energy into long-wavelength magnetic field energy) is observed. It is conjectured that in the presence of dissipation and external forcing, a dual cascade will be observed for zero-helicity situations. Energy will cascade to higher wavenumbers simultaneously with a cascade of mean square vector potential to lower wavenumbers, leading to an omni-directional magnetic energy spectrum.

Structure, synthesis and biological properties of the pentacyclic guanidinium alkaloids.

PubMed

Shi, Yunlong; Moazami, Yasamin; Pierce, Joshua G

2017-06-01

The pentacyclic guanidinium alkaloids (PGAs) are a family of marine natural products that possess a polycyclic guanidine-containing core and a long alkyl chain tethered spermidine-derived tail that is rarely observed in other natural products. These natural products exhibit potent activities on a wide range of organisms and therefore have attracted the attention of many synthetic chemists; however, the structure-activity relationships and mechanisms of action of PGAs remain largely elusive. Herein we summarize the structure, synthesis, toxicity and mechanisms of action of PGAs and highlight their potential as chemical probes and/or therapeutic leads. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lead contamination in Uruguay: the "La Teja" neighborhood case.

PubMed

Mañay, Nelly; Cousillas, Adriana Z; Alvarez, Cristina; Heller, Teresa

2008-01-01

Lead, ubiquitous in the environment as a result of mining and industrialization, is found as a contaminant in humans although it has no known physiological function there. Lead-exposed children are known to be the population with the highest potential health risks. The recommended biomarker to assess environmental lead exposure in animals is lead level in blood. Before 2001, the Department of Toxicology and Environmental Hygiene was the only team to produce human monitoring data on Uruguayan populations (Manay 2001a,b; Mañay et al. 1999). Lead pollution in Uruguay first received official attention during the 2001 La Teja poisoning episode. It was in the La Teja neighbourhood of Montevideo that high BLL were found in children (as high as 20 microg/dL), prompting corrective responses from Health and Environmental authorities. Growing awareness of environmental lead pollution and consequential human health effects from that event, resulted in public debate and demands for solutions from Health and Environmental authorities. Citizens demanded public disclosure of information concerning lead pollution and wanted action to address contaminated Uruguayan sites. In response, the Ministry of Health assembled an interinstitutional multidisciplinary committee, with delegates from health, environmental, labor, educational, and social security authorities, as well as community nongovernmental organizations (NGOs), among others. The University of the Republic was designated to serve as the main responsible entity for technical advice and support. After 2001, new research on lead pollution was undertaken and included multidisciplinary studies with communities in response to health risk alerts. The main emphasis was placed on children exposed to environmental lead. Major sources of Uruguayan lead contamination, similar to those in other developing countries, result from metallurgical industries, lead-acid battery processing, lead wire and pipe factories, metal foundries, metal recyclers, leaded gasoline (before December 2003), lead water pipes in old houses, and scrap and smelter solid wastes, among others. Nonoccupational lead exposure usually results from living in or near current or former manufacturing areas or improper handling of lead-containing materials or solid wastes (a particularly important health risk for children). In this chapter, we reviewed available studies published or reported after the pollution events first announced in 2001. These studies include data on exposure, health, and actions taken to mitigate or prevent lead exposure from pollution events in Uruguay. Uruguay adopted CDC's 10 microg/dL as the reference BLL for children (CDC 1991) and a BLL of 30 microg/dL for workers (from the ACGIH standard). Environmental authorities adopted the Canadian reference concentrations for soil: residential and playgrounds (> 140 mg/kg) or industrial areas (> 600 mg/kg) (CCME 2006). Most studies reviewed addressed soil pollution as the main source of lead exposure. Results of thousands of analyses indicated that most children had BLL above reference intervention limits. A significant decrease in BLL was also found over time in the study results, demonstrating the importance of medical intervention, nutrition, and environmental education. The severity of lead pollution discovered required official governmental actions, both to reduce sources of lead contamination and to address the health implications for children who had been exposed to environmental or industrial lead pollution. Dogs were discovered to be useful sentinels for environmental lead pollution; they had higher BLL than children when exposed to the same polluted environment and developed symptoms of lead intoxication earlier and at lower BLL than did children. This same pattern was also observed in families with children and pet dogs living in the La Teja neighborhood. This discovery renders dogs prospectively useful in lead pollution monitoring and diagnosis, particularly in developing countries. BLL results from similar human lead exposure studies conducted 10 yr apart showed significant BLL reductions, after 10 yr, for nonoccupationally exposed Uruguayans. The phase-out of leaded gasoline is thought to have contributed to this improvement. New laws to address occupational and environmental exposures were passed to prevent new cases of lead contamination, and new research studies are underway to monitor lead pollution. Moreover, a systematic surveillance screening program for lead workers and children is planned, although it is not yet underway. The sensitization of the public to the lead pollution problem has been a key driver of governmental action to mitigate and prevent further lead pollution in Uruguay. The changes made since 2001 appear to have yielded positive results. BLL from different populations studied more recently show decreased lead levels, suggesting a lower contribution of environmental lead to exposure of children and nonoccupationally exposed adults. The diverse analytical data collected on lead pollution in Uruguay between 2001 and 2004 were the main ingredient that allowed effective identification of lead pollution in Uruguay and paved the way for official intervention to prevent new pollution events. Nevertheless, full research studies must still be done, including both spot analysis of environmental soil, air, and water samples, and extensive screening of BLL. Future health and environmental actions are needed, not only to remediate known areas of lead pollution, but also to investigate other sources of potential health risks.

The Nucleosome Remodeling and Deacetylase (NuRD) Complex in Development and Disease

PubMed Central

Basta, Jeannine; Rauchman, Michael

2014-01-01

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis and accelerated ageing. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer. PMID:24880148

Linking Science of Flood Forecasts to Humanitarian Actions for Improved Preparedness and Effective Response

NASA Astrophysics Data System (ADS)

Uprety, M.; Dugar, S.; Gautam, D.; Kanel, D.; Kshetri, M.; Kharbuja, R. G.; Acharya, S. H.

2017-12-01

Advances in flood forecasting have provided opportunities for humanitarian responders to employ a range of preparedness activities at different forecast time horizons. Yet, the science of prediction is less understood and realized across the humanitarian landscape, and often preparedness plans are based upon average level of flood risk. Working under the remit of Forecast Based Financing (FbF), we present a pilot from Nepal on how available flood and weather forecast products are informing specific pre-emptive actions in the local preparedness and response plans, thereby supporting government stakeholders and humanitarian agencies to take early actions before an impending flood event. In Nepal, forecasting capabilities are limited but in a state of positive flux. Whilst local flood forecasts based upon rainfall-runoff models are yet to be operationalized, streamflow predictions from Global Flood Awareness System (GLoFAS) can be utilized to plan and implement preparedness activities several days in advance. Likewise, 3-day rainfall forecasts from Nepal Department of Hydrology and Meteorology (DHM) can further inform specific set of early actions for potential flash floods due to heavy precipitation. Existing community based early warning systems in the major river basins of Nepal are utilizing real time monitoring of water levels and rainfall together with localised probabilistic flood forecasts which has increased warning lead time from 2-3 hours to 7-8 hours. Based on these available forecast products, thresholds and trigger levels have been determined for different flood scenarios. Matching these trigger levels and assigning responsibilities to relevant actors for early actions, a set of standard operating procedures (SOPs) are being developed, broadly covering general preparedness activities and science informed anticipatory actions for different forecast lead times followed by the immediate response activities. These SOPs are currently being rolled out and tested by the Ministry of Home Affairs (MoHA) through its district emergency operation centres in West Nepal. Potential scale up and successful implementation of this science based approach would be instrumental to take forward global commitments on disaster risk reduction, climate change adaptation and sustainable goals in Nepal.

Corrective Action Decision Document/Closure Report for Corrective Action Unit 372: Area 20 Cabriolet/Palanquin Unit Craters, Nevada National Security Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, Patrick and Sloop, Christy

2011-04-01

This Corrective Action Decision Document (CADD)/Closure Report (CR) has been prepared for Corrective Action Unit (CAU) 372, Area 20 Cabriolet/Palanquin Unit Craters, located within Areas 18 and 20 at the Nevada National Security Site, Nevada, in accordance with the Federal Facility Agreement and Consent Order (FFACO). Corrective Action Unit 372 comprises four corrective action sites (CASs): • 18-45-02, Little Feller I Surface Crater • 18-45-03, Little Feller II Surface Crater • 20-23-01, U-20k Contamination Area • 20-45-01, U-20L Crater (Cabriolet) The purpose of this CADD/CR is to provide justification and documentation supporting the recommendation that no further corrective action ismore » needed for CAU 372 based on the implementation of the corrective action of closure in place with administrative controls at all CASs. Corrective action investigation (CAI) activities were performed from November 9, 2009, through December 10, 2010, as set forth in the Corrective Action Investigation Plan for Corrective Action Unit 372: Area 20 Cabriolet/Palanquin Unit Craters. The approach for the CAI was divided into two facets: investigation of the primary release of radionuclides and investigation of other releases (migration in washes and chemical releases). The purpose of the CAI was to fulfill data needs as defined during the data quality objective (DQO) process. The CAU 372 dataset of investigation results was evaluated based on a data quality assessment. This assessment demonstrated the dataset is acceptable for use in fulfilling the DQO data needs. Investigation results were evaluated against final action levels (FALs) established in this document. A radiological dose FAL was established of 25 millirem per year based on the Remote Work Area exposure scenario (336 hours of annual exposure). Radiological doses exceeding the FAL were found to be present at all four CASs. It is assumed that radionuclide levels present within the Little Feller I and Cabriolet high contamination areas and within the craters at Palanquin and Cabriolet exceed the FAL. It is also assumed that potential source material in the form of lead bricks at Little Feller I and lead-acid batteries at Palanquin and Cabriolet exceed the FAL. Therefore, corrective actions were undertaken that consist of removing potential source material, where present, and implementing a use restriction and posting warning signs at each CAS. These use restrictions were recorded in the FFACO database; the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO) Facility Information Management System; and the NNSA/NSO CAU/CAS files. Therefore, NNSA/NSO provides the following recommendations: • No further corrective actions are necessary for CAU 372. • A Notice of Completion to NNSA/NSO is requested from the Nevada Division of Environmental Protection for closure of CAU 372. • Corrective Action Unit 372 should be moved from Appendix III to Appendix IV of the FFACO.« less

Reducing abrupt climate change risk using the Montreal Protocol and other regulatory actions to complement cuts in CO2 emissions.

PubMed

Molina, Mario; Zaelke, Durwood; Sarma, K Madhava; Andersen, Stephen O; Ramanathan, Veerabhadran; Kaniaru, Donald

2009-12-08

Current emissions of anthropogenic greenhouse gases (GHGs) have already committed the planet to an increase in average surface temperature by the end of the century that may be above the critical threshold for tipping elements of the climate system into abrupt change with potentially irreversible and unmanageable consequences. This would mean that the climate system is close to entering if not already within the zone of "dangerous anthropogenic interference" (DAI). Scientific and policy literature refers to the need for "early," "urgent," "rapid," and "fast-action" mitigation to help avoid DAI and abrupt climate changes. We define "fast-action" to include regulatory measures that can begin within 2-3 years, be substantially implemented in 5-10 years, and produce a climate response within decades. We discuss strategies for short-lived non-CO(2) GHGs and particles, where existing agreements can be used to accomplish mitigation objectives. Policy makers can amend the Montreal Protocol to phase down the production and consumption of hydrofluorocarbons (HFCs) with high global warming potential. Other fast-action strategies can reduce emissions of black carbon particles and precursor gases that lead to ozone formation in the lower atmosphere, and increase biosequestration, including through biochar. These and other fast-action strategies may reduce the risk of abrupt climate change in the next few decades by complementing cuts in CO(2) emissions.

From pregnancy to cardiovascular disease: lessons from relaxin-deficient animals to understanding relaxin actions in the vascular system.

PubMed

Jelinic, Maria; Marshall, Sarah A; Leo, Chen Huei; Parry, Laura J; Tare, Marianne

2018-06-07

Early maternal vascular adaptations to pregnancy are predominantly driven by changes in vascular tone, reactivity and remodelling. Failure of the maternal systemic vasculature to adapt sufficiently can lead to serious complications of pregnancy. The hormone relaxin is widely recognised for its contribution to the essential renal and systemic haemodynamic adaptations in early pregnancy through direct actions on the maternal vasculature. Studies in relaxin gene knockout mice revealed that endogenous relaxin is not only a 'pregnancy hormone' but has pleiotropic actions in various tissues in males and non-pregnant females. There is strong interest in relaxin's actions in the vasculature and its utility in the treatment of vascular diseases. Relaxin treatment in rodents for 2-5 days or acute intravenous injection enhances endothelium-dependent relaxation and decreases myogenic tone in resistance arteries. These vascular actions are prolonged, even in the absence of circulating relaxin, and are underpinned by the production of endothelium-derived relaxing factors including nitric oxide, endothelium-derived hyperpolarization and prostacyclin. Relaxin is also capable of remodelling the vascular wall in a variety of blood vessels in disease conditions. Lessons learned in pregnancy research have aided studies investigating the potential therapeutic potential of relaxin in cardiovascular disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

2008 Lead (Pb) National Ambient Air Quality Standards (NAAQS) Implementation Actions

EPA Pesticide Factsheets

Read about the EPA's infrastructure actions for the 2008 lead NAAQS. These actions are regarding states' failure to submit SIPs addressing various parts of the standards. Here you can read the federal register notices, fact sheets, and the docket folder.

Conducting processes in simulated chronic inflammatory demyelinating polyneuropathy at 20°C-42°C.

PubMed

Stephanova, D I; Daskalova, M; Mladenov, M

2015-03-01

Decreased conducting processes leading usually to conduction block and increased weakness of limbs during cold (cold paresis) or warmth (heat paresis) have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To explore the mechanisms of these symptoms, the effects of temperature (from 20°C to 42°C) on nodal action potentials and their current kinetics in previously simulated case of 70% CIDP are investigated, using our temperature dependent multi-layered model of the myelinated human motor nerve fiber. The results show that potential amplitudes have a bifid form at 20°C. As in the normal case, for the CIDP case, the nodal action potentials are determined mainly by the nodal sodium currents (I Na ) for the temperature range of 20-39°C, as the contribution of nodal fast and slow potassium currents (I Kf and I Ks ) to the total ionic current (Ii) is negligible. Also, the contribution of I Kf and I Ks to the membrane repolarization is enhanced at temperatures higher than 39°C. However, in the temperature range of 20-42°C, all potential parameters in the CIDP case, except for the conduction block during hyperthermia (≥ 40°C) which is again at 45°C, worsen: (i) conduction velocities and potential amplitudes are decreased; (ii) afterpotentials and threshold stimulus currents for the potential generation are increased; (iii) the current kinetics of action potentials is slowed and (iv) the conduction block during hypothermia (≤ 25°C) is at temperatures lower than 20°C. These potential parameters are more altered during hyperthermia and are most altered during hypothermia. The present results suggest that the conducting processes in patients with CIDP are in higher risk during hypothermia than hyperthermia.

Superfund Record of Decision (EPA Region 4): USMC Camp Lejeune Military Reservation, NC. (First remedial action), September 1992. Interim report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1992-09-23

The 500-acre Camp Lejeune Military Reservation is located 15 miles southeast of Jacksonville, in Onslow County, North Carolina. Within the site lies the Hadnot Point Industrial Area (HPIA), which was constructed in the late 1930's. It is composed of 75 buildings and facilities, which include gas stations, offices, storage yards, maintenance shops, and a dry cleaning plant. Several areas of the HPIA have been investigated for potential contamination attributed to Marine Corps activities and operations that resulted in a generation of potentially hazardous wastes. The ROD addresses an interim remedial action for the shallow aquifer at the HPIA to protectmore » human health from exposure to VOCs and metals. The primary contaminants of concern affecting the shallow ground water aquifer are VOCs, including benzene and TCE; and metals, including arsenic, chromium, and lead.« less

Antifungal effect and action mechanism of antimicrobial peptide polybia-CP.

PubMed

Wang, Kairong; Jia, Fengjing; Dang, Wen; Zhao, Yanyan; Zhu, Ranran; Sun, Mengyang; Qiu, Shuai; An, Xiaoping; Ma, Zelin; Zhu, Yuanyuan; Yan, Jiexi; Kong, Ziqing; Yan, Wenjin; Wang, Rui

2016-01-01

The incidence of life-threatening invasive fungal infections increased significantly in recent years. However, the antifungal therapeutic options are very limited. Antimicrobial peptides are a class of potential lead chemical for the development of novel antifungal agents. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and determined its antifungal effects against a series of Candidian species. Our results showed that polybia-CP has potent antifungal activity and fungicidal activity against the tested fungal cells with a proposed membrane-active action mode. In addition, polybia-CP could induce the increase of cellular reactive oxygen species production, which would attribute to its antifungal activity. In conclusion, the present study suggests that polybia-CP has potential as an antifungal agent or may offer a new strategy for antifungal therapeutic option. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Chloride conducting light activated channel GtACR2 can produce both cessation of firing and generation of action potentials in cortical neurons in response to light.

PubMed

Malyshev, A Y; Roshchin, M V; Smirnova, G R; Dolgikh, D A; Balaban, P M; Ostrovsky, M A

2017-02-15

Optogenetics is a powerful technique in neuroscience that provided a great success in studying the brain functions during the last decade. Progress of optogenetics crucially depends on development of new molecular tools. Light-activated cation-conducting channelrhodopsin2 was widely used for excitation of cells since the emergence of optogenetics. In 2015 a family of natural light activated chloride channels GtACR was identified which appeared to be a very promising tool for using in optogenetics experiments as a cell silencer. Here we examined properties of GtACR2 channel expressed in the rat layer 2/3 pyramidal neurons by means of in utero electroporation. We have found that despite strong inhibition the light stimulation of GtACR2-positive neurons can surprisingly lead to generation of action potentials, presumably initiated in the axonal terminals. Thus, when using the GtACR2 in optogenetics experiments, its ability to induce action potentials should be taken into account. Our results also open an interesting possibility of using the GtACR2 both as cell silencer and cell activator in the same experiment varying the pattern of light stimulation. Copyright © 2017 Elsevier B.V. All rights reserved.

The current state of drug discovery and a potential role for NMR metabolomics.

PubMed

Powers, Robert

2014-07-24

The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on high-throughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics.

FURTHER STUDY OF SOMA, DENDRITE, AND AXON EXCITATION IN SINGLE NEURONS

PubMed Central

Eyzaguirre, Carlos; Kuffler, Stephen W.

1955-01-01

The present investigation continues a previous study in which the soma-dendrite system of sensory neurons was excited by stretch deformation of the peripheral dendrite portions. Recording was done with intracellular leads which were inserted into the cell soma while the neuron was activated orthodromically or antidromically. The analysis was also extended to axon conduction. Crayfish, Procambarus alleni (Faxon) and Orconectes virilis (Hagen), were used. 1. The size and time course of action potentials recorded from the soma-dendrite complex vary greatly with the level of the cell's membrane potential. The latter can be changed over a wide range by stretch deformation which sets up a "generator potential" in the distal portions of the dendrites. If a cell is at its resting unstretched equilibrium potential, antidromic stimulation through the axon causes an impulse which normally overshoots the resting potential and decays into an afternegativity of 15 to 20 msec. duration. The postspike negativity is not followed by an appreciable hyperpolarization (positive) phase. If the membrane potential is reduced to a new steady level a postspike positivity appears and increases linearly over a depolarization range of 12 to 20 mv. in various cells. At those levels the firing threshold of the cell for orthodromic discharges is generally reached. 2. The safety factor for conduction between axon and cell soma is reduced under three unrelated conditions, (a) During the recovery period (2 to 3 msec.) immediately following an impulse which has conducted fully over the cell soma, a second impulse may be delayed, may invade the soma partially, or may be blocked completely. (b) If progressive depolarization is produced by stretch, it leads to a reduction of impulse height and eventually to complete block of antidromic soma invasion, resembling cathodal block, (c) In some cells, when the normal membrane potential is within several millivolts of the relaxed resting state, an antidromic impulse may be blocked and may set up within the soma a local potential only. The local potential can sum with a second one or it may sum with potential changes set up in the dendrites, leading to complete invasion of the soma. Such antidromic invasion block can always be relieved by appropriate stretch which shifts the membrane potential out of the "blocking range" nearer to the soma firing level. During the afterpositivity of an impulse in a stretched cell the membrane potential may fall below or near the blocking range. During that period another impulse may be delayed or blocked. 3. Information regarding activity and conduction in dendrites has been obtained indirectly, mainly by analyzing the generator action under various conditions of stretch. The following conclusions have been reached: The large dendrite branches have similar properties to the cell body from which they arise and carry the same kind of impulses. In the finer distal filaments of even lightly depolarized dendrites, however, no axon type all-or-none conduction occurs since the generator potential persists to a varying degree during antidromic invasion of the cell. With the membrane potential at its resting level the dendrite terminals contribute to the prolonged impulse afternegativity of the soma. 4. Action potentials in impaled axons and in cell bodies have been compared. It is thought that normally the over-all duration of axon impulses is shorter. Local activity during reduction of the safety margin for conduction was studied. 5. An analysis was made of high frequency grouped discharges which occasionally arise in cells. They differ in many essential aspects from the regular discharges set up by the generator action. It is proposed that grouped discharges occur only when invasion of dendrites is not synchronous, due to a delay in excitation spread between soma and dendrites. Each impulse in a group is assumed to be caused by an impulse in at least one of the large dendrite branches. Depolarization of dendrites abolishes the grouped activity by facilitating invasion of the large dendrite branches. PMID:13252238

Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic β cells: a simulation study

PubMed Central

Cha, Chae Young; Nakamura, Yasuhiko; Himeno, Yukiko; Wang, JianWu; Fujimoto, Shinpei; Inagaki, Nobuya; Earm, Yung E

2011-01-01

To clarify the mechanisms underlying the pancreatic β-cell response to varying glucose concentrations ([G]), electrophysiological findings were integrated into a mathematical cell model. The Ca2+ dynamics of the endoplasmic reticulum (ER) were also improved. The model was validated by demonstrating quiescent potential, burst–interburst electrical events accompanied by Ca2+ transients, and continuous firing of action potentials over [G] ranges of 0–6, 7–18, and >19 mM, respectively. These responses to glucose were completely reversible. The action potential, input impedance, and Ca2+ transients were in good agreement with experimental measurements. The ionic mechanisms underlying the burst–interburst rhythm were investigated by lead potential analysis, which quantified the contributions of individual current components. This analysis demonstrated that slow potential changes during the interburst period were attributable to modifications of ion channels or transporters by intracellular ions and/or metabolites to different degrees depending on [G]. The predominant role of adenosine triphosphate–sensitive K+ current in switching on and off the repetitive firing of action potentials at 8 mM [G] was taken over at a higher [G] by Ca2+- or Na+-dependent currents, which were generated by the plasma membrane Ca2+ pump, Na+/K+ pump, Na+/Ca2+ exchanger, and TRPM channel. Accumulation and release of Ca2+ by the ER also had a strong influence on the slow electrical rhythm. We conclude that the present mathematical model is useful for quantifying the role of individual functional components in the whole cell responses based on experimental findings. PMID:21708953

Path integrals with higher order actions: Application to realistic chemical systems

NASA Astrophysics Data System (ADS)

Lindoy, Lachlan P.; Huang, Gavin S.; Jordan, Meredith J. T.

2018-02-01

Quantum thermodynamic parameters can be determined using path integral Monte Carlo (PIMC) simulations. These simulations, however, become computationally demanding as the quantum nature of the system increases, although their efficiency can be improved by using higher order approximations to the thermal density matrix, specifically the action. Here we compare the standard, primitive approximation to the action (PA) and three higher order approximations, the Takahashi-Imada action (TIA), the Suzuki-Chin action (SCA) and the Chin action (CA). The resulting PIMC methods are applied to two realistic potential energy surfaces, for H2O and HCN-HNC, both of which are spectroscopically accurate and contain three-body interactions. We further numerically optimise, for each potential, the SCA parameter and the two free parameters in the CA, obtaining more significant improvements in efficiency than seen previously in the literature. For both H2O and HCN-HNC, accounting for all required potential and force evaluations, the optimised CA formalism is approximately twice as efficient as the TIA formalism and approximately an order of magnitude more efficient than the PA. The optimised SCA formalism shows similar efficiency gains to the CA for HCN-HNC but has similar efficiency to the TIA for H2O at low temperature. In H2O and HCN-HNC systems, the optimal value of the a1 CA parameter is approximately 1/3 , corresponding to an equal weighting of all force terms in the thermal density matrix, and similar to previous studies, the optimal α parameter in the SCA was ˜0.31. Importantly, poor choice of parameter significantly degrades the performance of the SCA and CA methods. In particular, for the CA, setting a1 = 0 is not efficient: the reduction in convergence efficiency is not offset by the lower number of force evaluations. We also find that the harmonic approximation to the CA parameters, whilst providing a fourth order approximation to the action, is not optimal for these realistic potentials: numerical optimisation leads to better approximate cancellation of the fifth order terms, with deviation between the harmonic and numerically optimised parameters more marked in the more quantum H2O system. This suggests that numerically optimising the CA or SCA parameters, which can be done at high temperature, will be important in fully realising the efficiency gains of these formalisms for realistic potentials.

2008 Lead (Pb) National Ambient Air Quality Standards (NAAQS) Implementation Actions Fact Sheets

EPA Pesticide Factsheets

This page contains the fact sheets for the 2008 Lead (Pb) NAAQS. These actions deal with the finding of failure to submit various portions of the State Implementation Plans (SIPs) for the 2008 Lead NAAQS.

Electrostatic generator/motor having rotors of varying thickness and a central stator electrically connected together into two groups

DOEpatents

Post, Richard F.

2010-11-16

A sub-module consists of a set of two outer sets of stationary fan-blade-shaped sectors. These outer sectors include conductive material and are maintained at ground potential in several examples. Located midway between them is a set of stationary sector plates with each plate being electrically insulated from the others. An example provides that the inner sector plates are connected together alternately, forming two groups of parallel-connected condensers that are then separately connected, through high charging circuit resistances, to a source of DC potential with respect to ground, with an additional connecting lead being provided for each group to connect their output as an AC output to a load. These same leads can he used, when connected to a driver circuit, to produce motor action.

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

PubMed Central

Chan, John D.; Agbedanu, Prince N.; Grab, Thomas; Zamanian, Mostafa; Dosa, Peter I.; Day, Timothy A.; Marchant, Jonathan S.

2015-01-01

Abstract Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors. PMID:26367744

Beyond self-serving bias: diffusion of responsibility reduces sense of agency and outcome monitoring

PubMed Central

Sidarus, Nura; Bonicalzi, Sofia; Haggard, Patrick

2017-01-01

Abstract Diffusion of responsibility across agents has been proposed to underlie decreased helping and increased aggression in group behaviour. However, few studies have directly investigated effects of the presence of other people on how we experience the consequences of our actions. This EEG study investigated whether diffusion of responsibility simply reflects a post-hoc self-serving bias, or rather has direct effects on how we process the outcomes of our actions, and our experience of agency over them. Participants made voluntary actions whose outcomes were more or less negative. Presence of another potential agent reduced participants’ sense of agency over those outcomes, even though it was always obvious who caused each outcome. Further, presence of another agent reduced the amplitude of feedback-related negativity evoked by outcome stimuli, suggesting reduced outcome monitoring. The presence of other agents may lead to diffusion of responsibility by weakening the neural linkage between one’s actions and their outcomes. PMID:27803288

Beyond self-serving bias: diffusion of responsibility reduces sense of agency and outcome monitoring.

PubMed

Beyer, Frederike; Sidarus, Nura; Bonicalzi, Sofia; Haggard, Patrick

2017-01-01

Diffusion of responsibility across agents has been proposed to underlie decreased helping and increased aggression in group behaviour. However, few studies have directly investigated effects of the presence of other people on how we experience the consequences of our actions. This EEG study investigated whether diffusion of responsibility simply reflects a post-hoc self-serving bias, or rather has direct effects on how we process the outcomes of our actions, and our experience of agency over them. Participants made voluntary actions whose outcomes were more or less negative. Presence of another potential agent reduced participants' sense of agency over those outcomes, even though it was always obvious who caused each outcome. Further, presence of another agent reduced the amplitude of feedback-related negativity evoked by outcome stimuli, suggesting reduced outcome monitoring. The presence of other agents may lead to diffusion of responsibility by weakening the neural linkage between one's actions and their outcomes. © The Author (2016). Published by Oxford University Press.

Helical Antimicrobial Sulfono- {gamma} -AApeptides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yaqiong; Wu, Haifan; Teng, Peng

Host-defense peptides (HDPs) such as magainin 2 have emerged as potential therapeutic agents combating antibiotic resistance. Inspired by their structures and mechanism of action, herein we report the fi rst example of antimicrobial helical sulfono- γ - AApeptide foldamers. The lead molecule displays broad-spectrum and potent antimicrobial activity against multi-drug-resistant Gram- positive and Gram-negative bacterial pathogens. Time-kill studies and fl uorescence microscopy suggest that sulfono- γ -AApeptides eradicate bacteria by taking a mode of action analogous to that of HDPs. Clear structure - function relationships exist in the studied sequences. Longer sequences, presumably adopting more-de fi ned helical structures, aremore » more potent than shorter ones. Interestingly, the sequence with less helical propensity in solution could be more selective than the stronger helix-forming sequences. Moreover, this class of antimicrobial agents are resistant to proteolytic degradation. These results may lead to the development of a new class of antimicrobial foldamers combating emerging antibiotic-resistant pathogens.« less

An Approach to Forward Presence in a Resource-Constrained Environment

DTIC Science & Technology

2013-03-01

working quietly to coordinate cooperation between Indonesia, Malaysia , and Singapore , who were historically distrustful of each other. Through...freedom of action. Non-state actors will likely seek to capitalize on these weakening and corrupt failing states as potential safe havens. The low...11 Figure 1. 2011 Defense Spending: United States vs . 16 Next Leading Spenders44 Department of Defense can feel like it is hard pressed for

Logistics for the implementation of lead-free solders on electronic assemblies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vianco, P.T.; Artaki, I.

1993-12-31

The prospects of legislative and regulatory action aimed at taxing, restricting or banning lead-bearing materials from manufactured products has prompted the electronics community to examine the implementation of lead-free solders to replace currently used lead-containing alloys in the manufacture of electronic devices and assemblies. The logistics for changing the well established ``tin-lead solder technology`` require not only the selection of new compositions but also the qualification of different surface finishes and manufacturing processes. The meniscometer/wetting balance technique was used to evaluate the wettability of several candidate lead-free solders as well as to establish windows on processing parameters so as tomore » facilitate prototype manufacturing. Electroplated and electroless 100Sn coatings, as well as organic preservatives, were also examined as potential alternative finishes for device leads and terminations as well as circuit board conductor surfaces to replace traditional tin-lead layers. Sandia National Laboratories and AT&T have implemented a program to qualify the manufacturing feasibility of surface mount prototype circuit boards using several commercial lead-free solders by infrared reflow technology.« less

Participatory Evaluation with Youth Leads to Community Action Project

ERIC Educational Resources Information Center

Ashton, Carolyn; Arnold, Mary E.; Wells, Elissa E.

2010-01-01

4-H has long emphasized the importance of civic engagement and community service for positive youth development. One pathway to this ideal is youth action research and evaluation. This article demonstrates how participatory youth research and evaluation can lead to the successful implementation of community action projects. It describes the…

Local Equity Action Development (LEAD). Education Policy Brief. Volume 4, Number 9, Fall 2006

ERIC Educational Resources Information Center

Ritter, Shana; Skiba, Russell J.

2006-01-01

Local Equity Action Development (LEAD) is a local change process grounded in cultural competence that addresses disproportionality in special education and other equity issues facing schools. This brief describes LEAD, outlines the concept of cultural competence, and offers examples of how LEAD is being implemented in a number of Indiana school…

Boolean function applied to Mimosa pudica movements.

PubMed

De Luccia, Thiago Paes de Barros; Friedman, Pedro

2011-09-01

Seismonastic or thigmonastic movements of Mimosa pudica L. is mostly because of the fast loss of water from swollen motor cells, resulting in temporary collapse of cells and quick curvature in the parts where these cells are located. Because of this, the plant has been much studied since the 18th century, leading us to think about the classical binomial stimulus-response (action-reaction) when compared to animals. Mechanic and electrical stimuli were used to investigate the analogy of mimosa branch with an artificial neuron model and to observe the action potential propagation through the mimosa branch. Boolean function applied to the mimosa branch in analogy with an artificial neuron model is one of the peculiarities of our hypothesis.

Action potential propagation recorded from single axonal arbors using multi-electrode arrays.

PubMed

Tovar, Kenneth R; Bridges, Daniel C; Wu, Bian; Randall, Connor; Audouard, Morgane; Jang, Jiwon; Hansma, Paul K; Kosik, Kenneth S

2018-04-11

We report the presence of co-occurring extracellular action potentials (eAPs) from cultured mouse hippocampal neurons among groups of planar electrodes on multi-electrode arrays (MEAs). The invariant sequences of eAPs among co-active electrode groups, repeated co-occurrences and short inter-electrode latencies are consistent with action potential propagation in unmyelinated axons. Repeated eAP co-detection by multiple electrodes was widespread in all our data records. Co-detection of eAPs confirms they result from the same neuron and allows these eAPs to be isolated from all other spikes independently of spike sorting algorithms. We averaged co-occurring events and revealed additional electrodes with eAPs that would otherwise be below detection threshold. We used these eAP cohorts to explore the temperature sensitivity of action potential propagation and the relationship between voltage-gated sodium channel density and propagation velocity. The sequence of eAPs among co-active electrodes 'fingerprints' neurons giving rise to these events and identifies them within neuronal ensembles. We used this property and the non-invasive nature of extracellular recording to monitor changes in excitability at multiple points in single axonal arbors simultaneously over several hours, demonstrating independence of axonal segments. Over several weeks, we recorded changes in inter-electrode propagation latencies and ongoing changes in excitability in different regions of single axonal arbors. Our work illustrates how repeated eAP co-occurrences can be used to extract physiological data from single axons with low electrode density MEAs. However, repeated eAP co-occurrences leads to over-sampling spikes from single neurons and thus can confound traditional spike-train analysis.

Auxiliary field loop expansion of the effective action for a class of stochastic partial differential equations

NASA Astrophysics Data System (ADS)

Cooper, Fred; Dawson, John F.

2016-02-01

We present an alternative to the perturbative (in coupling constant) diagrammatic approach for studying stochastic dynamics of a class of reaction diffusion systems. Our approach is based on an auxiliary field loop expansion for the path integral representation for the generating functional of the noise induced correlation functions of the fields describing these systems. The systems we consider include Langevin systems describable by the set of self interacting classical fields ϕi(x , t) in the presence of external noise ηi(x , t) , namely (∂t - ν∇2) ϕ - F [ ϕ ] = η, as well as chemical reaction annihilation processes obtained by applying the many-body approach of Doi-Peliti to the Master Equation formulation of these problems. We consider two different effective actions, one based on the Onsager-Machlup (OM) approach, and the other due to Janssen-deGenneris based on the Martin-Siggia-Rose (MSR) response function approach. For the simple models we consider, we determine an analytic expression for the Energy landscape (effective potential) in both formalisms and show how to obtain the more physical effective potential of the Onsager-Machlup approach from the MSR effective potential in leading order in the auxiliary field loop expansion. For the KPZ equation we find that our approximation, which is non-perturbative and obeys broken symmetry Ward identities, does not lead to the appearance of a fluctuation induced symmetry breakdown. This contradicts the results of earlier studies.

Regulation of gap junction conductance by calcineurin through Cx43 phosphorylation: implications for action potential conduction.

PubMed

Jabr, Rita I; Hatch, Fiona S; Salvage, Samantha C; Orlowski, Alejandro; Lampe, Paul D; Fry, Christopher H

2016-11-01

Cardiac arrhythmias are associated with raised intracellular [Ca 2+ ] and slowed action potential conduction caused by reduced gap junction (GJ) electrical conductance (Gj). Ventricular GJs are composed of connexin proteins (Cx43), with Gj determined by Cx43 phosphorylation status. Connexin phosphorylation is an interplay between protein kinases and phosphatases but the precise pathways are unknown. We aimed to identify key Ca 2+ -dependent phosphorylation sites on Cx43 that regulate cardiac gap junction conductance and action potential conduction velocity. We investigated the role of the Ca 2+ -dependent phosphatase, calcineurin. Intracellular [Ca 2+ ] was raised in guinea-pig myocardium by a low-Na solution or increased stimulation. Conduction velocity and Gj were measured in multicellular strips. Phosphorylation of Cx43 serine residues (S365 and S368) and of the intermediary regulator I1 at threonine35 was measured by Western blot. Measurements were made in the presence and absence of inhibitors to calcineurin, I1 or protein phosphatase-1 and phosphatase-2.Raised [Ca 2 + ] i decreased Gj, reduced Cx43 phosphorylation at S365 and increased it at S368; these changes were reversed by calcineurin inhibitors. Cx43-S368 phosphorylation was reversed by the protein kinase C inhibitor chelerythrine. Raised [Ca 2+ ] i also decreased I1 phosphorylation, also prevented by calcineurin inhibitors, to increase activity of the Ca 2+ -independent phosphatase, PPI. The PP1 inhibitor, tautomycin, prevented Cx43-365 dephosphorylation, Cx43-S368 phosphorylation and Gj reduction in raised [Ca 2+ ] i . PP2A had no role. Conduction velocity was reduced by raised [Ca 2+ ] i and reversed by calcineurin inhibitors. Reduced action potential conduction and Gj in raised [Ca 2+ ] are regulated by calcineurin-dependent Cx43-S365 phosphorylation, leading to Cx43-S368 dephosphorylation. The calcineurin action is indirect, via I1 dephosphorylation and subsequent activation of PP1.

Miscellaneous Lasing Actions in Organo-Lead Halide Perovskite Films.

PubMed

Duan, Zonghui; Wang, Shuai; Yi, Ningbo; Gu, Zhiyuan; Gao, Yisheng; Song, Qinghai; Xiao, Shumin

2017-06-21

Lasing actions in organo-lead halide perovskite films have been heavily studied in the past few years. However, due to the disordered nature of synthesized perovskite films, the lasing actions are usually understood as random lasers that are formed by multiple scattering. Herein, we demonstrate the miscellaneous lasing actions in organo-lead halide perovskite films. In addition to the random lasers, we show that a single or a few perovskite microparticles can generate laser emissions with their internal resonances instead of multiple scattering among them. We experimentally observed and numerically confirmed whispering gallery (WG)-like microlasers in polygon shaped and other deformed microparticles. Meanwhile, owing to the nature of total internal reflection and the novel shape of the nanoparticle, the size of the perovskite WG laser can be significantly decreased to a few hundred nanometers. Thus, wavelength-scale lead halide perovskite lasers were realized for the first time. All of these laser behaviors are complementary to typical random lasers in perovskite film and will help the understanding of lasing actions in complex lead halide perovskite systems.

40 CFR 141.80 - General requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

...) NATIONAL PRIMARY DRINKING WATER REGULATIONS Control of Lead and Copper § 141.80 General requirements. (a... drinking water regulations for lead and copper. Unless otherwise indicated, each of the provisions of this... and copper action levels measured in samples collected at consumers' taps. (c) Lead and copper action...

Mechanisms defining the electrotonic potential abnormalities in simulated amyotrophic lateral sclerosis.

PubMed

Stephanova, D I; Krustev, S M; Negrev, N

2012-06-01

Electrotonic potentials allow the accommodative processes to polarizing stimuli to be assessed. Electrotonic potential transients in response to applied polarizing stimuli are caused by the kinetics of underlying axonal conductances. Here, we study these transients using our multi-layered model of the human motor nerve, in three simulated cases of the motor neuron disease amyotrophic lateral sclerosis (ALS): ALS1, ALS2 and ALS3 are three consecutively greater degrees of uniform axonal dysfunctions along the human motor nerve fibre. The results show that the responses in the ALS1 case are quite similar to the normal case. In contrast, in the ALS2 and ALS3 cases, long-lasting (100 ms) subthreshold depolarizing stimuli activate the classical "transient" Na(+) channels in the nodal and in the internodal axolemma beneath the myelin sheath; this leads to action potential generation during the early parts of the electrotonic responses in all compartments along the fibre length. The results also show that the electrotonic potentials in response to long-lasting (100 ms) subthreshold hyperpolarizing stimuli in the ALS1 and ALS2 cases are quiet similar to those of the normal case. However, the current kinetics in the ALS3 case differs from the normal case after the termination of the long-lasting hyperpolarizing stimuli. In the most abnormal ALS3 case, the activation of the Na(+) channels in the nodal and in the internodal axolemma leads to repetitive action potential generation in the late parts (100-200 ms) of the hyperpolarizing electrotonic responses. The results show that the repetitive firing, due to the progressively increased nodal and internodal ion channel dysfunction, are consistent with the loss of functional potassium channels involving both the fast and the slow potassium channel types. The results confirm that the electrotonic potentials in the three simulated ALS cases are specific indicators for the motor neuron disease ALS. The mechanisms underlying the simulated ALS are also discussed.

40 CFR 300.820 - Administrative record file for a removal action.

Code of Federal Regulations, 2010 CFR

2010-07-01

... SUBSTANCES POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.820 Administrative record file for a removal action. (a) If, based on the site evaluation, the lead agency determines... public comment. At such time, the lead agency shall publish in a major local newspaper of general...

Action potentials reliably invade axonal arbors of rat neocortical neurons

PubMed Central

Cox, Charles L.; Denk, Winfried; Tank, David W.; Svoboda, Karel

2000-01-01

Neocortical pyramidal neurons have extensive axonal arborizations that make thousands of synapses. Action potentials can invade these arbors and cause calcium influx that is required for neurotransmitter release and excitation of postsynaptic targets. Thus, the regulation of action potential invasion in axonal branches might shape the spread of excitation in cortical neural networks. To measure the reliability and extent of action potential invasion into axonal arbors, we have used two-photon excitation laser scanning microscopy to directly image action-potential-mediated calcium influx in single varicosities of layer 2/3 pyramidal neurons in acute brain slices. Our data show that single action potentials or bursts of action potentials reliably invade axonal arbors over a range of developmental ages (postnatal 10–24 days) and temperatures (24°C-30°C). Hyperpolarizing current steps preceding action potential initiation, protocols that had previously been observed to produce failures of action potential propagation in cultured preparations, were ineffective in modulating the spread of action potentials in acute slices. Our data show that action potentials reliably invade the axonal arbors of neocortical pyramidal neurons. Failures in synaptic transmission must therefore originate downstream of action potential invasion. We also explored the function of modulators that inhibit presynaptic calcium influx. Consistent with previous studies, we find that adenosine reduces action-potential-mediated calcium influx in presynaptic terminals. This reduction was observed in all terminals tested, suggesting that some modulatory systems are expressed homogeneously in most terminals of the same neuron. PMID:10931955

A novel natural product inspired scaffold with robust neurotrophic, neurogenic and neuroprotective action

PubMed Central

Chakravarty, Sumana; Maitra, Swati; Reddy, R Gajendra; Das, Tapatee; Jhelum, Priya; Kootar, Scherazad; Rajan, Wenson D.; Samanta, Anumita; Samineni, Ramesh; Pabbaraja, Srihari; Kernie, Steven G.; Mehta, Goverdhan; Kumar, Arvind

2015-01-01

In search for drugs to treat neuropsychiatric disorders wherein neurotrophic and neurogenic properties are affected, two neurotrophically active small molecules specially crafted following natural product leads based on 2-oxa-spiro[5.5]-undecane scaffold, have been thoroughly evaluated for their neurotrophic, neurogenic and neuroprotective potential in ex vivo primary culture and in vivo zebrafish and mouse models. The outcome of in vivo investigations suggest that one of these molecules is more neurotrophic than neurogenic while the other one is more neurogenic than neurotrophic and the former exhibits remarkable neuroprotection in a mouse acute ischemic stroke model. The molecular mechanisms of action of these compounds appear to be through the TrkB-MEK-ERK-CREB-BDNF pathway as pre-treatment with neurotrophin receptor TrkB inhibitor ANA-12 and MEK inhibitor PD98059 attenuates the neurotrophic action of compounds. PMID:26388493

Stiff self-interacting strings at high temperature QCD

NASA Astrophysics Data System (ADS)

S Bakry, A.; Chen, X.; Deliyergiyev, M.; Galal, A.; Khalaf, A.; M Pengming, P.

2018-03-01

We investigate the implications of Nambu-Goto (NG), Lüscher Weisz (LW) and Polyakov-Kleinert (PK) effective string actions for the Casimir energy and the width of the quantum delocalization of the string in 4-dim pure SU(3) Yang-Mills lattice gauge theory. At a temperature closer to the critical point T/Tc=0.9, we found that the next to leading-order (NLO) contributions from the expansion of the NG string in addition to the boundary terms in LW action to decrease the deviations from the lattice data in the intermediate distance scales for both the quark-antiquark QQ̅ potential and broadening of the color tube compared to the free string approximation. We conjecture possible stiffness of the QCD string through studying the effects of extrinsic curvature term in PK action and find a good fitting behavior for the lattice Monte-Carlo data at both long and intermediate quark separations regions.

Proline-rich antimicrobial peptides: potential therapeutics against antibiotic-resistant bacteria.

PubMed

Li, Wenyi; Tailhades, Julien; O'Brien-Simpson, Neil M; Separovic, Frances; Otvos, Laszlo; Hossain, M Akhter; Wade, John D

2014-10-01

The increasing resistance of pathogens to antibiotics causes a huge clinical burden that places great demands on academic researchers and the pharmaceutical industry for resolution. Antimicrobial peptides, part of native host defense, have emerged as novel potential antibiotic alternatives. Among the different classes of antimicrobial peptides, proline-rich antimicrobial peptides, predominantly sourced from insects, have been extensively investigated to study their specific modes of action. In this review, we focus on recent developments in these peptides. They show a variety of modes of actions, including mechanism shift at high concentration, non-lytic mechanisms, as well as possessing different intracellular targets and lipopolysaccharide binding activity. Furthermore, proline-rich antimicrobial peptides display the ability to not only modulate the immune system via cytokine activity or angiogenesis but also possess properties of penetrating cell membranes and crossing the blood brain barrier suggesting a role as potential novel carriers. Ongoing studies of these peptides will likely lead to the development of more potent antimicrobial peptides that may serve as important additions to the armoury of agents against bacterial infection and drug delivery.

Planar Diamond-Based Multiarrays to Monitor Neurotransmitter Release and Action Potential Firing: New Perspectives in Cellular Neuroscience.

PubMed

Carabelli, Valentina; Marcantoni, Andrea; Picollo, Federico; Battiato, Alfio; Bernardi, Ettore; Pasquarelli, Alberto; Olivero, Paolo; Carbone, Emilio

2017-02-15

High biocompatibility, outstanding electrochemical responsiveness, inertness, and transparency make diamond-based multiarrays (DBMs) first-rate biosensors for in vitro detection of electrochemical and electrical signals from excitable cells together, with potential for in vivo applications as neural interfaces and prostheses. Here, we will review the electrochemical and physical properties of various DBMs and how these devices have been employed for recording released neurotransmitter molecules and all-or-none action potentials from living cells. Specifically, we will overview how DBMs can resolve localized exocytotic events from subcellular compartments using high-density microelectrode arrays (MEAs), or monitoring oxidizable neurotransmitter release from populations of cells in culture and tissue slices using low-density MEAs. Interfacing DBMs with excitable cells is currently leading to the promising opportunity of recording electrical signals as well as creating neuronal interfaces through the same device. Given the recent increasingly growing development of newly available DBMs of various geometries to monitor electrical activity and neurotransmitter release in a variety of excitable and neuronal tissues, the discussion will be limited to planar DBMs.

Implications of movement-related cortical potential for understanding neural adaptations in muscle strength tasks

PubMed Central

2014-01-01

This systematic review aims to provide information about the implications of the movement-related cortical potential (MRCP) in acute and chronic responses to the counter resistance training. The structuring of the methods of this study followed the proposals of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). It was performed an electronically search in Pubmed/Medline and ISI Web of Knowledge data bases, from 1987 to 2013, besides the manual search in the selected references. The following terms were used: Bereitschaftspotential, MRCP, strength and force. The logical operator “AND” was used to combine descriptors and terms used to search publications. At the end, 11 studies attended all the eligibility criteria and the results demonstrated that the behavior of MRCP is altered because of different factors such as: force level, rate of force development, fatigue induced by exercise, and the specific phase of muscular action, leading to an increase in the amplitude in eccentric actions compared to concentric actions, in acute effects. The long-term adaptations demonstrated that the counter resistance training provokes an attenuation in the amplitude in areas related to the movement, which may be caused by neural adaptation occurred in the motor cortex. PMID:24602228

Outbreak column 17: Situational Awareness for healthcare outbreaks

PubMed Central

2015-01-01

Outbreak column 17 introduces the utility of Situation Awareness (SA) for outbreak management. For any given time period, an individual or team’s SA involves a perception of what is going on, meaning derived from the perception and a prediction of what is likely to happen next. The individual or team’s SA informs, but is separate to, both the decisions and actions that follow. The accuracy and completeness of an individual or team’s SA will therefore impact on the effectiveness of decisions and actions taken. SA was developed by the aviation industry and is utilised in situations which, like outbreaks, have dynamic, i.e. continuously changing problem spaces, and wherein a loss of SA is likely to lead to both poor decision-making and actions with potentially fatal consequences. The potential benefits of using SA for outbreaks are discussed and include: (1) retrospectively to identify if poor decision-making was a result of a poor SA; (2) prospectively to identify where the system is weakest; and (3) as a teaching tool to improve the skills of individuals and teams in developing a shared understanding of the here and now. PMID:28989433

Risks to children from exposure to lead in air during remedial or removal activities at Superfund sites: a case study of the RSR lead smelter Superfund site.

PubMed

Khoury, Ghassan A; Diamond, Gary L

2003-01-01

Superfund sites that are contaminated with lead and undergoing remedial action generate lead-enriched dust that can be released into the air. Activities that can emit lead-enriched dust include demolition of lead smelter buildings, stacks, and baghouses; on-site traffic of heavy construction vehicles; and excavation of soil. Typically, air monitoring stations are placed around the perimeter of a site of an ongoing remediation to monitor air lead concentrations that might result from site emissions. The National Ambient Air Quality (NAAQ) standard, established in 1978 to be a quarterly average of 1.5 microg/m(3), is often used as a trigger level for corrective action to reduce emissions. This study explored modeling approaches for assessing potential risks to children from air lead emissions from the RSR Superfund site in West Dallas, TX, during demolition and removal of a smelter facility. The EPA Integrated Exposure Uptake Biokinetic (IEUBK) model and the International Commission of Radiologic Protection (ICRP) lead model were used to simulate blood lead concentrations in children, based on monitored air lead concentrations. Although air lead concentrations at monitoring stations located in the downwind community intermittently exceeded the NAAQ standard, both models indicated that exposures to children in the community areas did not pose a significant long-term or acute risk. Long-term risk was defined as greater than 5% probability of a child having a long-term blood lead concentration that exceeded 10 microg/dl, which is the CDC and the EPA blood lead concern level. Short-term or acute risk was defined as greater than 5% probability of a child having a blood lead concentration on any given day that exceeded 20 microg/dl, which is the CDC trigger level for medical evaluation (this is not intended to imply that 20 microg/dl is a threshold for health effects in children exposed acutely to airborne lead). The estimated potential long-term and short-term exposures at the downwind West Dallas community did not result in more than 5% of children exceeding the target blood lead levels. The models were also used to estimate air lead levels for short-term and long-term exposures that would not exceed specified levels of risk (risk-based concentrations, RBCs). RBCs were derived for various daily exposure durations (3 or 8 h/day) and frequencies (1-7 days/week). RBCs based on the ICRP model ranged from 0.3 (7 days/week, 8 h/day) to 4.4 microg/m(3) (1 day/week, 3 h/day) for long-term exposures and were lower than those based on the IEUBK model. For short-term exposures, the RBCs ranged from 3.5 to 29.0 microg/m(3). Recontamination of remediated residential yards from deposition of air lead emitted during remedial activities at the RSR Superfund site was also examined. The predicted increase in soil concentration due to lead deposition at the monitoring station, which represented the community at large, was 3.0 mg/kg. This potential increase in soil lead concentration was insignificant, less than 1% increase, when compared to the clean-up level of 500 mg/kg developed for residential yards at the site.

A Compartmentalized Mathematical Model of the β1-Adrenergic Signaling System in Mouse Ventricular Myocytes

PubMed Central

Bondarenko, Vladimir E.

2014-01-01

The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca2+]i transients; changes in intracellular and transmembrane Ca2+ fluxes; and [Na+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca2+]i transients. In particular, the model includes two subpopulations of the L-type Ca2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions. PMID:24586529

Action-based Dynamical Modeling for the Milky Way Disk: The Influence of Spiral Arms

NASA Astrophysics Data System (ADS)

Trick, Wilma H.; Bovy, Jo; D'Onghia, Elena; Rix, Hans-Walter

2017-04-01

RoadMapping is a dynamical modeling machinery developed to constrain the Milky Way’s (MW) gravitational potential by simultaneously fitting an axisymmetric parametrized potential and an action-based orbit distribution function (DF) to discrete 6D phase-space measurements of stars in the Galactic disk. In this work, we demonstrate RoadMapping's robustness in the presence of spiral arms by modeling data drawn from an N-body simulation snapshot of a disk-dominated galaxy of MW mass with strong spiral arms (but no bar), exploring survey volumes with radii 500 {pc}≤slant {r}\\max ≤slant 5 {kpc}. The potential constraints are very robust, even though we use a simple action-based DF, the quasi-isothermal DF. The best-fit RoadMapping model always recovers the correct gravitational forces where most of the stars that entered the analysis are located, even for small volumes. For data from large survey volumes, RoadMapping finds axisymmetric models that average well over the spiral arms. Unsurprisingly, the models are slightly biased by the excess of stars in the spiral arms. Gravitational potential models derived from survey volumes with at least {r}\\max =3 {kpc} can be reliably extrapolated to larger volumes. However, a large radial survey extent, {r}\\max ˜ 5 {kpc}, is needed to correctly recover the halo scale length. In general, the recovery and extrapolability of potentials inferred from data sets that were drawn from inter-arm regions appear to be better than those of data sets drawn from spiral arms. Our analysis implies that building axisymmetric models for the Galaxy with upcoming Gaia data will lead to sensible and robust approximations of the MW’s potential.

Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase, a Potent Drug Target for Diabetes and Its Complications

PubMed Central

Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh

2013-01-01

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects. PMID:23613832

Prospecting for novel plant-derived molecules of Rauvolfia serpentina as inhibitors of Aldose Reductase, a potent drug target for diabetes and its complications.

PubMed

Pathania, Shivalika; Randhawa, Vinay; Bagler, Ganesh

2013-01-01

Aldose Reductase (AR) is implicated in the development of secondary complications of diabetes, providing an interesting target for therapeutic intervention. Extracts of Rauvolfia serpentina, a medicinal plant endemic to the Himalayan mountain range, have been known to be effective in alleviating diabetes and its complications. In this study, we aim to prospect for novel plant-derived inhibitors from R. serpentina and to understand structural basis of their interactions. An extensive library of R. serpentina molecules was compiled and computationally screened for inhibitory action against AR. The stability of complexes, with docked leads, was verified using molecular dynamics simulations. Two structurally distinct plant-derived leads were identified as inhibitors: indobine and indobinine. Further, using these two leads as templates, 16 more leads were identified through ligand-based screening of their structural analogs, from a small molecules database. Thus, we obtained plant-derived indole alkaloids, and their structural analogs, as potential AR inhibitors from a manually curated dataset of R. serpentina molecules. Indole alkaloids reported herein, as a novel structural class unreported hitherto, may provide better insights for designing potential AR inhibitors with improved efficacy and fewer side effects.

How and why do infants imitate? An ideomotor approach to social and imitative learning in infancy (and beyond).

PubMed

Paulus, Markus

2014-10-01

It has been proposed that already in infancy, imitative learning plays a pivotal role in the acquisition of knowledge and abilities. Yet the cognitive mechanisms underlying the acquisition of novel action knowledge through social learning have remained unclear. The present contribution presents an ideomotor approach to imitative learning (IMAIL) in infancy (and beyond) that draws on the ideomotor theory of action control and on recent findings of perception-action matching. According to IMAIL, the central mechanism of imitative and social learning is the acquisition of cascading bidirectional action-effect associations through observation of own and others' actions. First, the observation of the visual effect of own actions leads to the acquisition of first-order action-effect associations, linking motor codes to the action's typical visual effects. Second, observing another person's action leads to motor activation (i.e., motor resonance) due to the first-order associations. This activated motor code then becomes linked to the other salient effects produced by the observed action, leading to the acquisition of (second-order) action-effect associations. These novel action-effect associations enable later imitation of the observed actions. The article reviews recent behavioral and neurophysiological studies with infants and adults that provide empirical support for the model. Furthermore, it is discussed how the model relates to other approaches on social-cognitive development and how developmental changes in imitative abilities can be conceptualized.

Leading Change in Tissue Viability Best Practice: An Action Learning Programme for Link Nurse Practitioners

ERIC Educational Resources Information Center

Kellie, Jean; Henderson, Eileen; Milsom, Brian; Crawley, Hayley

2010-01-01

This account of practice reports on an action learning initiative designed and implemented in partnership between a regional NHS Acute Trust and a UK Business School. The central initiative was the implementation of an action learning programme entitled "Leading change in tissue viability best practice: a development programme for Link Nurse…

32 CFR 536.32 - Transfer of claims among armed services branches.

Code of Federal Regulations, 2010 CFR

2010-07-01

... take all actions on the claim. Where the DA is the lead agency, any final action will include other agencies. Similarly, where another agency is the lead agency, that agency will be requested to include DA... another agency has taken denial action on a claim that involves the DA, without informing the DA, and in...

The effects of an action video game on visual and affective information processing.

PubMed

Bailey, Kira; West, Robert

2013-04-04

Playing action video games can have beneficial effects on visuospatial cognition and negative effects on social information processing. However, these two effects have not been demonstrated in the same individuals in a single study. The current study used event-related brain potentials (ERPs) to examine the effects of playing an action or non-action video game on the processing of emotion in facial expression. The data revealed that 10h of playing an action or non-action video game had differential effects on the ERPs relative to a no-contact control group. Playing an action game resulted in two effects: one that reflected an increase in the amplitude of the ERPs following training over the right frontal and posterior regions that was similar for angry, happy, and neutral faces; and one that reflected a reduction in the allocation of attention to happy faces. In contrast, playing a non-action game resulted in changes in slow wave activity over the central-parietal and frontal regions that were greater for targets (i.e., angry and happy faces) than for non-targets (i.e., neutral faces). These data demonstrate that the contrasting effects of action video games on visuospatial and emotion processing occur in the same individuals following the same level of gaming experience. This observation leads to the suggestion that caution should be exercised when using action video games to modify visual processing, as this experience could also have unintended effects on emotion processing. Published by Elsevier B.V.

The interaction between felt touch and tactile consequences of observed actions: an action-based somatosensory congruency paradigm.

PubMed

Deschrijver, Eliane; Wiersema, Jan R; Brass, Marcel

2016-07-01

Action observation leads to a representation of both the motor aspect of an observed action (motor simulation) and its somatosensory consequences (action-based somatosensory simulation) in the observer's brain. In the current electroencephalography-study, we investigated the neuronal interplay of action-based somatosensory simulation and felt touch. We presented index or middle finger tapping movements of a human or a wooden hand, while simultaneously presenting 'tap-like' tactile sensations to either the corresponding or non-corresponding fingertip of the participant. We focused on an early stage of somatosensory processing [P50, N100 and N140 sensory evoked potentials (SEPs)] and on a later stage of higher-order processing (P3-complex). The results revealed an interaction effect of animacy and congruency in the early P50 SEP and an animacy effect in the N100/N140 SEPs. In the P3-complex, we found an interaction effect indicating that the influence of congruency was larger in the human than in the wooden hand. We argue that the P3-complex may reflect higher-order self-other distinction by signaling simulated action-based touch that does not match own tactile information. As such, the action-based somatosensory congruency paradigm might help understand higher-order social processes from a somatosensory point of view. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

[Patterns of action potential firing in cortical neurons of neonatal mice and their electrophysiological property].

PubMed

Furong, Liu; Shengtian, L I

2016-05-25

To investigate patterns of action potential firing in cortical heurons of neonatal mice and their electrophysiological properties. The passive and active membrane properties of cortical neurons from 3-d neonatal mice were observed by whole-cell patch clamp with different voltage and current mode. Three patterns of action potential firing were identified in response to depolarized current injection. The effects of action potential firing patterns on voltage-dependent inward and outward current were found. Neurons with three different firing patterns had different thresholds of depolarized current. In the morphology analysis of action potential, the three type neurons were different in rise time, duration, amplitude and threshold of the first action potential evoked by 80 pA current injection. The passive properties were similar in three patterns of action potential firing. These results indicate that newborn cortical neurons exhibit different patterns of action potential firing with different action potential parameters such as shape and threshold.

Role of action potential configuration and the contribution of Ca2+ and K+ currents to isoprenaline-induced changes in canine ventricular cells

PubMed Central

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, PP

2012-01-01

BACKGROUND AND PURPOSE Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca2+ current (ICa), slow delayed rectifier K+ current (IKs) and fast delayed rectifier K+ current (IKr) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. EXPERIMENTAL APPROACH Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. KEY RESULTS In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the IKr blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the IKs blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the ICa blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating ICa followed by a rise in IKs, both currents increased with increasing the cycle length. CONCLUSIONS AND IMPLICATIONS The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of IKs– but not IKr– may be responsible for the observed shortening of action potentials. PMID:22563726

Role of action potential configuration and the contribution of C²⁺a and K⁺ currents to isoprenaline-induced changes in canine ventricular cells.

PubMed

Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, P P

2012-10-01

Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca²⁺ current (I(Ca)), slow delayed rectifier K⁺ current (I(Ks)) and fast delayed rectifier K⁺ current (I(Kr)) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the I(Kr) blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the I(Ks) blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the I(Ca) blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating I(Ca) followed by a rise in I(Ks) , both currents increased with increasing the cycle length. The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of I(Ks) - but not I(Kr) - may be responsible for the observed shortening of action potentials. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Boolean function applied to Mimosa pudica movements

PubMed Central

Friedman, Pedro

2011-01-01

Seismonastic or thigmonastic movements of Mimosa pudica L. is mostly because of the fast loss of water from swollen motor cells, resulting in temporary collapse of cells and quick curvature in the parts where these cells are located. Because of this, the plant has been much studied since the 18th century, leading us to think about the classical binomial stimulus-response (action-reaction) when compared to animals. Mechanic and electrical stimuli were used to investigate the analogy of mimosa branch with an artificial neuron model and to observe the action potential propagation through the mimosa branch. Boolean function applied to the mimosa branch in analogy with an artificial neuron model is one of the peculiarities of our hypothesis. PMID:21847029

Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives

PubMed Central

Feijóo-Bandín, Sandra; Aragón-Herrera, Alana; Rodríguez-Penas, Diego; Portolés, Manuel; Roselló-Lletí, Esther; Rivera, Miguel; González-Juanatey, José R.; Lago, Francisca

2017-01-01

Despite the great effort of the medical community during the last decades, cardiovascular diseases remain the leading cause of death worldwide, increasing their prevalence every year mainly due to our new way of life. In the last years, the study of new hormones implicated in the regulation of energy metabolism and inflammation has raised a great interest among the scientific community regarding their implications in the development of cardiometabolic diseases. In this review, we will summarize the main actions of relaxin, a pleiotropic hormone that was previously suggested to improve acute heart failure and that participates in both metabolism and inflammation regulation at cardiovascular level, and will discuss its potential as future therapeutic target to prevent/reduce cardiovascular diseases. PMID:28868039

Simple potential model for interaction of dark particles with massive bodies

NASA Astrophysics Data System (ADS)

Takibayev, Nurgali

2018-01-01

A simple model for interaction of dark particles with matter based on resonance behavior in a three-body system is proposed. The model describes resonant amplification of effective interaction between two massive bodies at large distances between them. The phenomenon is explained by catalytic action of dark particles rescattering at a system of two heavy bodies which are understood here as the big stellar objects. Resonant amplification of the effective interaction between the two heavy bodies imitates the increase in their mass while their true gravitational mass remains unchanged. Such increased interaction leads to more pronounced gravitational lensing of bypassing light. It is shown that effective interaction between the heavy bodies is changed at larger distances and can transform into repulsive action.

LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

PubMed Central

Brachet, Anna; Norwood, Stephanie; Brouwers, Jos F.; Palomer, Ernest; Helms, J. Bernd

2015-01-01

Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate–type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid–type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP. PMID:25753037

The Current State of Drug Discovery and a Potential Role for NMR Metabolomics

PubMed Central

2015-01-01

The pharmaceutical industry has significantly contributed to improving human health. Drugs have been attributed to both increasing life expectancy and decreasing health care costs. Unfortunately, there has been a recent decline in the creativity and productivity of the pharmaceutical industry. This is a complex issue with many contributing factors resulting from the numerous mergers, increase in out-sourcing, and the heavy dependency on high-throughput screening (HTS). While a simple solution to such a complex problem is unrealistic and highly unlikely, the inclusion of metabolomics as a routine component of the drug discovery process may provide some solutions to these problems. Specifically, as the binding affinity of a chemical lead is evolved during the iterative structure-based drug design process, metabolomics can provide feedback on the selectivity and the in vivo mechanism of action. Similarly, metabolomics can be used to evaluate and validate HTS leads. In effect, metabolomics can be used to eliminate compounds with potential efficacy and side effect problems while prioritizing well-behaved leads with druglike characteristics. PMID:24588729

Non-thermal mechanism of weak microwave fields influence on neurons

NASA Astrophysics Data System (ADS)

Shneider, M. N.; Pekker, M.

2013-09-01

A non-thermal mechanism of weak microwave field impact on a nerve fiber is proposed. It is shown that in the range of about 30-300 GHz, there are strongly pronounced resonances associated with the excitation of ultrasonic vibrations in the membrane as a result of interaction with electromagnetic radiation. The viscous dissipation limits the resonances and results in their broadening. These forced vibrations create acoustic pressure, which may lead to the redistribution of the protein transmembrane channels, and thus changing the threshold of the action potential excitation in the axons of the neural network. The influence of the electromagnetic microwave radiation on various specific areas of myelin nerve fibers was analyzed: the nodes of Ranvier, and the initial segment—the area between the neuron hillock and the first part of the axon covered with the myelin layer. It was shown that the initial segment is the most sensitive area of the myelined neurons from which the action potential normally starts.

Social identity threat motivates science-discrediting online comments.

PubMed

Nauroth, Peter; Gollwitzer, Mario; Bender, Jens; Rothmund, Tobias

2015-01-01

Experiencing social identity threat from scientific findings can lead people to cognitively devalue the respective findings. Three studies examined whether potentially threatening scientific findings motivate group members to take action against the respective findings by publicly discrediting them on the Web. Results show that strongly (vs. weakly) identified group members (i.e., people who identified as "gamers") were particularly likely to discredit social identity threatening findings publicly (i.e., studies that found an effect of playing violent video games on aggression). A content analytical evaluation of online comments revealed that social identification specifically predicted critiques of the methodology employed in potentially threatening, but not in non-threatening research (Study 2). Furthermore, when participants were collectively (vs. self-) affirmed, identification did no longer predict discrediting posting behavior (Study 3). These findings contribute to the understanding of the formation of online collective action and add to the burgeoning literature on the question why certain scientific findings sometimes face a broad public opposition.

Two-Term Asymptotic Approximation of a Cardiac Restitution Curve*

PubMed Central

Cain, John W.; Schaeffer, David G.

2007-01-01

If spatial extent is neglected, ionic models of cardiac cells consist of systems of ordinary differential equations (ODEs) which have the property of excitability, i.e., a brief stimulus produces a prolonged evolution (called an action potential in the cardiac context) before the eventual return to equilibrium. Under repeated stimulation, or pacing, cardiac tissue exhibits electrical restitution: the steady-state action potential duration (APD) at a given pacing period B shortens as B is decreased. Independent of ionic models, restitution is often modeled phenomenologically by a one-dimensional mapping of the form APDnext = f(B – APDprevious). Under some circumstances, a restitution function f can be derived as an asymptotic approximation to the behavior of an ionic model. In this paper, extending previous work, we derive the next term in such an asymptotic approximation for a particular ionic model consisting of two ODEs. The two-term approximation exhibits excellent quantitative agreement with the actual restitution curve, whereas the leading-order approximation significantly underestimates actual APD values. PMID:18080006

Action potential broadening in a presynaptic channelopathy

NASA Astrophysics Data System (ADS)

Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

2016-07-01

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

Scroll wave dynamics in a three-dimensional cardiac tissue model: roles of restitution, thickness, and fiber rotation.

PubMed Central

Qu, Z; Kil, J; Xie, F; Garfinkel, A; Weiss, J N

2000-01-01

Scroll wave (vortex) breakup is hypothesized to underlie ventricular fibrillation, the leading cause of sudden cardiac death. We simulated scroll wave behaviors in a three-dimensional cardiac tissue model, using phase I of the Luo-Rudy (LR1) action potential model. The effects of action potential duration (APD) restitution, tissue thickness, filament twist, and fiber rotation were studied. We found that APD restitution is the major determinant of scroll wave behavior and that instabilities arising from APD restitution are the main determinants of scroll wave breakup in this cardiac model. We did not see a "thickness-induced instability" in the LR1 model, but a minimum thickness is required for scroll breakup in the presence of fiber rotation. The major effect of fiber rotation is to maintain twist in a scroll wave, promoting filament bending and thus scroll breakup. In addition, fiber rotation induces curvature in the scroll wave, which weakens conduction and further facilitates wave break. PMID:10827961

Social Identity Threat Motivates Science-Discrediting Online Comments

PubMed Central

Nauroth, Peter; Gollwitzer, Mario; Bender, Jens; Rothmund, Tobias

2015-01-01

Experiencing social identity threat from scientific findings can lead people to cognitively devalue the respective findings. Three studies examined whether potentially threatening scientific findings motivate group members to take action against the respective findings by publicly discrediting them on the Web. Results show that strongly (vs. weakly) identified group members (i.e., people who identified as “gamers”) were particularly likely to discredit social identity threatening findings publicly (i.e., studies that found an effect of playing violent video games on aggression). A content analytical evaluation of online comments revealed that social identification specifically predicted critiques of the methodology employed in potentially threatening, but not in non-threatening research (Study 2). Furthermore, when participants were collectively (vs. self-) affirmed, identification did no longer predict discrediting posting behavior (Study 3). These findings contribute to the understanding of the formation of online collective action and add to the burgeoning literature on the question why certain scientific findings sometimes face a broad public opposition. PMID:25646725

Characteristics of action potentials and their underlying outward currents in rat taste receptor cells.

PubMed

Chen, Y; Sun, X D; Herness, S

1996-02-01

1. Taste receptor cells produce action potentials as a result of transduction mechanisms that occur when these cells are stimulated with tastants. These action potentials are thought to be key signaling events in relaying information to the central nervous system. We explored the ionic basis of action potentials from dissociated posterior rat taste cells using the patch-clamp recording technique in both voltage-clamp and current-clamp modes. 2. Action potentials were evoked by intracellular injection of depolarizing current pulses from a holding potential of -80 mV. The threshold potential for firing of action potentials was approximately -35 mV; the input resistance of these cells averaged 6.9 G omega. With long depolarizing pulses, two or three action potentials could be elicited with successive attenuation of the spike height. Afterhyperpolarizations were observed often. 3. Both sodium and calcium currents contribute to depolarizing phases of the action potential. Action potentials were blocked completely in the presence of the sodium channel blocker tetrodotoxin. Calcium contributions could be visualized as prolonged calcium plateaus when repolarizing potassium currents were blocked and barium was used as a charge carrier. 4. Outward currents were composed of sustained delayed rectifier current, transient potassium current, and calcium-activated potassium current. Transient and sustained potassium currents activated close to -30 mV and increased monotonically with further depolarization. Up to half the outward current inactivated with decay constants on the order of seconds. Sustained and transient currents displayed steep voltage dependence in conductance and inactivation curves. Half inactivation occurred at -20 +/- 3.1 mV (mean +/- SE) with a decrease of 11.2 +/- 0.5 mV per e-fold. Half maximal conductance occurred at 3.6 +/- 1.8 mV and increased 12.2 +/- 0.6 mV per e-fold. Calcium-activated potassium current was evidenced by application of apamin and the use of calcium-free bathing solution. It was most obvious at more depolarized holding potentials that inactivated much of the transient and sustained outward currents. 5. Potassium currents contribute to both the repolarization and afterhyperpolarization phases of the action potential. These currents were blocked by bath application of tetraethylammonium, which also substantially broadened the action potential. Application of 4-aminopyridine was able to selectively block transient potassium currents without affecting sustained currents. This also broadened the action potential as well as eliminated the afterhyperpolarization. 6. A second type of action potential was observed that differed in duration. These slow action potentials had t1/2 durations of 9.6 ms compared with 1.4 ms for fast action potentials. Input resistances of the two groups were indistinguishable. Approximately one-fourth of the cells eliciting action potentials were of the slow type. 7. Cells eliciting fast action potentials had large outward currents capable of producing a quick repolarization, whereas cells with slow action potentials had small outward currents by comparison. The average values of fast cells were 2,563 pA and 1.4 ms compared with 373 pA and 9.6 ms for slow cells. Current and duration values were related exponentially. No significant difference was noted for inward currents. 8. These results suggest that many taste receptor cells conduct action potentials, which may be classified broadly into two groups on the basis of action potential duration and potassium current magnitude. These groups may be related to cell turnover. The physiological role of action potentials remains to be elucidated but may be important for communication within the taste bud as well as to the afferent nerve.

40 CFR 141.88 - Monitoring requirements for lead and copper in source water.

Code of Federal Regulations, 2010 CFR

2010-07-01

... the basis of tap samples collected in accordance with § 141.86 shall collect lead and copper source... value or be considered one-half the PQL. (b) Monitoring frequency after system exceeds tap water action level. Any system which exceeds the lead or copper action level at the tap shall collect one source...

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

PubMed Central

Kimm, Tilia; Khaliq, Zayd M.

2015-01-01

Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency–current (f–I) relationship, whereas BK channel inhibition had little effect on the f–I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f–I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. SIGNIFICANCE STATEMENT This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both channel types participate in action potential repolarization about equally, they have contrasting and partially opposite effects in regulating neuronal firing at frequencies typical of bursting. Our analysis shows that this results from their different kinetic properties, with fast-activating BK channels serving to short-circuit activation of Kv2 channels, which tend to slow firing by producing a deep afterhyperpolarization. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. PMID:26674866

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.

PubMed

Kimm, Tilia; Khaliq, Zayd M; Bean, Bruce P

2015-12-16

Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both channel types participate in action potential repolarization about equally, they have contrasting and partially opposite effects in regulating neuronal firing at frequencies typical of bursting. Our analysis shows that this results from their different kinetic properties, with fast-activating BK channels serving to short-circuit activation of Kv2 channels, which tend to slow firing by producing a deep afterhyperpolarization. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. Copyright © 2015 the authors 0270-6474/15/3516404-14$15.00/0.

Next-to-next-to-leading order gravitational spin-squared potential via the effective field theory for spinning objects in the post-Newtonian scheme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Levi, Michele; Steinhoff, Jan, E-mail: michele.levi@upmc.fr, E-mail: jan.steinhoff@aei.mpg.de

2016-01-01

The next-to-next-to-leading order spin-squared interaction potential for generic compact binaries is derived for the first time via the effective field theory for gravitating spinning objects in the post-Newtonian scheme. The spin-squared sector is an intricate one, as it requires the consideration of the point particle action beyond minimal coupling, and mainly involves the spin-squared worldline couplings, which are quite complex, compared to the worldline couplings from the minimal coupling part of the action. This sector also involves the linear in spin couplings, as we go up in the nonlinearity of the interaction, and in the loop order. Hence, there ismore » an excessive increase in the number of Feynman diagrams, of which more are higher loop ones. We provide all the Feynman diagrams and their values. The beneficial ''nonrelativistic gravitational'' fields are employed in the computation. This spin-squared correction, which enters at the fourth post-Newtonian order for rapidly rotating compact objects, completes the conservative sector up to the fourth post-Newtonian accuracy. The robustness of the effective field theory for gravitating spinning objects is shown here once again, as demonstrated in a recent series of papers by the authors, which obtained all spin dependent sectors, required up to the fourth post-Newtonian accuracy. The effective field theory of spinning objects allows to directly obtain the equations of motion, and the Hamiltonians, and these will be derived for the potential obtained here in a forthcoming paper.« less

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

State and location dependence of action potential metabolic cost in cortical pyramidal neurons.

PubMed

Hallermann, Stefan; de Kock, Christiaan P J; Stuart, Greg J; Kole, Maarten H P

2012-06-03

Action potential generation and conduction requires large quantities of energy to restore Na(+) and K(+) ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na(+)/K(+) charge overlap as a measure of action potential energy efficiency, we found that action potential initiation in the axon initial segment (AIS) and forward propagation into the axon were energetically inefficient, depending on the resting membrane potential. In contrast, action potential backpropagation into dendrites was efficient. Computer simulations predicted that, although the AIS and nodes of Ranvier had the highest metabolic cost per membrane area, action potential backpropagation into the dendrites and forward propagation into axon collaterals dominated energy consumption in cortical pyramidal neurons. Finally, we found that the high metabolic cost of action potential initiation and propagation down the axon is a trade-off between energy minimization and maximization of the conduction reliability of high-frequency action potentials.

Distribution functions for resonantly trapped orbits in the Galactic disc

NASA Astrophysics Data System (ADS)

Monari, Giacomo; Famaey, Benoit; Fouvry, Jean-Baptiste; Binney, James

2017-11-01

The present-day response of a Galactic disc stellar population to a non-axisymmetric perturbation of the potential has previously been computed through perturbation theory within the phase-space coordinates of the unperturbed axisymmetric system. Such an Eulerian linearized treatment, however, leads to singularities at resonances, which prevent quantitative comparisons with data. Here, we manage to capture the behaviour of the distribution function (DF) at a resonance in a Lagrangian approach, by averaging the Hamiltonian over fast angle variables and re-expressing the DF in terms of a new set of canonical actions and angles variables valid in the resonant region. We then follow the prescription of Binney, assigning to the resonant DF the time average along the orbits of the axisymmetric DF expressed in the new set of actions and angles. This boils down to phase-mixing the DF in terms of the new angles, such that the DF for trapped orbits depends only on the new set of actions. This opens the way to quantitatively fitting the effects of the bar and spirals to Gaia data in terms of DFs in action space.

Managing Hyperkalemia: Stepping Into a New Frontier.

PubMed

Pham, Antony Q; Sexton, Jessica; Wimer, Dexter; Rana, Isha; Nguyen, Timothy

2017-10-01

Maintaining potassium balance in the body is essential for cellular function. Even a slight increase in normal serum potassium levels (3.5-5.0 mEq/L) can interfere with metabolism, electrical action potentials, and cellular processes. Hyperkalemia is commonly seen in patients with chronic kidney disease (CKD) and in patients on renin-angiotensin-aldosterone system (RAAS) inhibitors. Sodium polystyrene sulfonate (SPS), diuretics, and hemodialysis are currently available methods for removing potassium from the body; however, these options have their limitations. Patiromer (Veltassa) and sodium zirconium cyclosilicate are 2 new therapeutic options that can potentially lead a new frontier in the management of hyperkalemia. This article will review these novel treatments.

Breaking the silence about sexual abuse of deaf youth.

PubMed

Mertens, D M

1996-12-01

Sexual abuse of deaf youth is a serious problem that needs to have attention given to it in a way that will lead to real changes in the lives of the boys and girls affected. Through the use of an emancipatory approach to research, this study investigated the various theories that people hold as to why sexual abuse occurs in this population and what can be done to prevent it. Data were collected at one residential school through document review, observation, interviews, and a survey of staff. The results revealed that some participants held theories that blame the victim or the culture and that such theories would not lead to positive, meaningful change. Other theories that recognize the power inequities inherent in a sexual abuse situation are discussed as leading to potentially fruitful political and social actions.

Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells.

PubMed

Liu, Jinxu; Tu, Huiyin; Zhang, Dongze; Zheng, Hong; Li, Yu-Long

2012-10-25

The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells. Whole-cell patch-clamp results showed that differentiation (9 days) didn't change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential. Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation.

Tackle mechanisms and match characteristics in women's elite football tournaments.

PubMed

Tscholl, P; O'Riordan, D; Fuller, C W; Dvorak, J; Junge, A

2007-08-01

Several tools have been used for assessing risk situations and for gathering tackle information from international football matches for men but not for women. To analyse activities in women's football and to identify the characteristics and risk potentials of tackles. Retrospective video analysis. Video recordings of 24 representative matches from six women's top-level tournaments were analysed for tackle parameters and their risk potential. 3531 tackles were recorded. Tackles in which the tackling player came from the side and stayed on her feet accounted for nearly half of all challenges for the ball in which body contact occurred. 2.7% of all tackles were classified as risk situations, with sliding-in tackles from behind and the side having the highest risk potential. Match referees sanctioned sliding-in tackles more often than other tackles (20% v 17%, respectively). Tackle parameters did not change in the duration of a match; however, there was an increase in the number of injury risk situations and foul plays towards the end of each half. Match properties provide valuable information for a better understanding of injury situations in football. Staying on feet and jumping vertically tackle actions leading to injury were sanctioned significantly more times by the referee than those not leading to injury (p<0.001), but no such difference was seen for sliding-in tackles (previously reported to have the highest injury potential in women's football). Therefore, either the laws of the game are not adequate or match referees in women's football are not able to distinguish between sliding-in tackles leading to and those not leading to injury.

Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System.

PubMed

Wang, Wang; McKinnie, Shaun M K; Farhan, Maikel; Paul, Manish; McDonald, Tyler; McLean, Brent; Llorens-Cortes, Catherine; Hazra, Saugata; Murray, Allan G; Vederas, John C; Oudit, Gavin Y

2016-08-01

Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia-reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart. © 2016 American Heart Association, Inc.

Corrective Action Decision Document/Closure Report for Corrective Action Unit 561: Waste Disposal Areas, Nevada National Security Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mark Krauss

2011-08-01

CAU 561 comprises 10 CASs: (1) 01-19-01, Waste Dump; (2) 02-08-02, Waste Dump and Burn Area; (3) 03-19-02, Debris Pile; (4) 05-62-01, Radioactive Gravel Pile; (5) 12-23-09, Radioactive Waste Dump; (6) 22-19-06, Buried Waste Disposal Site; (7) 23-21-04, Waste Disposal Trenches ; (8) 25-08-02, Waste Dump; (9) 25-23-21, Radioactive Waste Dump; and (10) 25-25-19, Hydrocarbon Stains and Trench. The purpose of this CADD/CR is to provide justification and documentation supporting the recommendation for closure of CAU 561 with no further corrective action. The purpose of the CAI was to fulfill the following data needs as defined during the DQO process:more » (1) Determine whether COCs are present; (2) If COCs are present, determine their nature and extent; and (3) Provide sufficient information and data to complete appropriate corrective actions. The following contaminants were determined to be present at concentrations exceeding their corresponding FALs: (1) No contamination exceeding FALs was identified at CASs 01-19-01, 03-19-02, 05-62-01, 12-23-09, and 22-19-06. (2) The surface and subsurface soil within the burn area at CAS 02-08-02 contains arsenic and lead above the FALs of 23 milligrams per kilogram (mg/kg) and 800 mg/kg, respectively. The surface and subsurface soil within the burn area also contains melted lead slag (potential source material [PSM]). The soil within the waste piles contains polyaromatic hydrocarbons (PAHs) above the FALs. The contamination within the burn area is spread throughout the area, as it was not feasible to remove all the PSM (melted lead), while at the waste piles, the contamination is confined to the piles. (3) The surface and subsurface soils within Trenches 3 and 5 at CAS 23-21-04 contain arsenic and polychlorinated biphenyls (PCBs) above the FALs of 23 mg/kg and 0.74 mg/kg, respectively. The soil was removed from both trenches, and the soil that remains at this CAS does not contain contamination exceeding the FALs. Lead bricks and counterweights were also removed, and the soil below these items does not contain contamination that exceeds the FAL for lead. (4) The concrete-like material at CAS 25-08-02 contains arsenic above the FAL of 23 mg/kg. This concrete-like material was removed, and the soil that remains at this CAS does not contain contamination exceeding the FALs. Lead-acid batteries were also removed, and the soil below the batteries does not contain contamination that exceeds the FAL for lead. (5) The surface soils within the main waste dump at the posted southern radioactive material area (RMA) at CAS 25-23-21 contain cesium (Cs)-137 and PCBs above the FALs of 72.9 picocuries per gram (pCi/g) and 0.74 mg/kg, respectively. The soil was removed from the RMA, and the soil that remains at this CAS does not contain contamination exceeding the FALs. (6) The surface and subsurface soils at CAS 25-25-19 do not contain contamination exceeding the FALs. In addition, lead bricks were removed, and the soil below these items does not contain contamination that exceeds the FAL for lead. The following best management practices were implemented: (1) Housekeeping debris at CASs 02-08-02, 23-21-04, 25-08-02, 25-23-21, and 25-25-19 was removed and disposed of; (2) The open trenches at CAS 23-21-04 were backfilled; (3) The waste piles at CAS 25-08-02 were removed and the area leveled to ground surface; and (4) The remaining waste piles at the main waste dump at CAS 25-23-21 were leveled to ground surface. Therefore, NNSA/NSO provides the following recommendations: (1) No further action for CASs 01-19-01, 03-19-02, 05-62-01, 12-23-09, and 22-19-06; (2) Closure in place with an FFACO use restriction (UR) at CAS 02-08-02 for the remaining PAH-, arsenic-, and lead-contaminated soil, and the melted lead PSM. The UR form and map have been filed in the NNSA/NSO Facility Information Management System, the FFACO database, and the NNSA/NSO CAU/CAS files; (3) No further corrective action at CAS 23-21-04, as the lead bricks and counterweights (PSM) have been removed, and the COCs of arsenic and PCBs in soil have been removed; (4) No further corrective action at CAS 25-08-02, as the COC of arsenic in soil has been removed, and the lead-acid batteries have been removed; (5) No further corrective action at CAS 25-23-21, as the COCs of Cs-137 and PCBs in soil have been removed, and the cast-iron pipes have been removed and disposed of; (6) No further corrective action at CAS 25-25-19, as the lead bricks (PSM) been removed; (7) A Notice of Completion to the NNSA/NSO is requested from the Nevada Division of Environmental Protection for closure of CAU 561; and (8) Corrective Action Unit 561 should be moved from Appendix III to Appendix IV of the FFACO.« less

Crossed motor innervation of the base of human tongue

PubMed Central

Jordan, Amy S.; Nicholas, Christian L.; Cori, Jennifer M.; Semmler, John G.; Trinder, John

2015-01-01

Muscle fibers of the genioglossus (GG) form the bulk of the muscle mass at the base of the tongue. The motor control of the tongue is critical for vocalization, feeding, and breathing. Our goal was to assess the patterns of motor innervation of GG single motor units (SMUs) in humans. Simultaneous monopolar recordings were obtained from four sites in the base of the tongue bilaterally at two antero-posterior levels from 16 resting, awake, healthy adult males, who wore a face mask with airway pressure and airflow sensors. We analyzed 69 data segments in which at least one lead contained large action potentials generated by an SMU. Such potentials served as triggers for spike-triggered averaging (STA) of signals recorded from the other three sites. Spontaneous activity of the SMUs was classified as inspiratory modulated, expiratory modulated, or tonic. Consistent with the antero-posterior orientation of GG fibers, 44 STAs (77%) recorded ipsilateral to the trigger yielded sharp action potentials with a median amplitude of 52 μV [interquartile range (IQR): 25–190] that were time shifted relative to the trigger by about 1 ms. Notably, 48% of recordings on the side opposite to the trigger also yielded sharp action potentials. Of those, 17 (29%) had a median amplitude of 63 μV (IQR: 39–96), and most were generated by tonic SMUs. Thus a considerable proportion of GG muscle fibers receive a crossed motor innervation. Crossed innervation may help ensure symmetry and stability of tongue position and movements under normal conditions and following injury or degenerative changes affecting the tongue. PMID:25855691

Occupational lead poisoning: can it be eliminated?

PubMed

Kaufman, J D; Burt, J; Silverstein, B

1994-11-01

The continued occurrence of occupational lead poisoning and overexposure in the United States represents a serious challenge to the occupational health community. We outline a proposed action strategy which integrates case-based surveillance, hazard surveillance, increased requirements for biological monitoring, and targeted educational activities, with a goal of eliminating occupational lead poisoning. The system provides a simple mechanism for monitoring compliance in lead-using employers, in order to identify employers for enforcement action. Lead poisoning should be viewed as an eradicable condition; successfully solving the persistent lead overexposure problem can serve as a model for approaching other occupational diseases.

Effects of premature stimulation on HERG K+ channels

PubMed Central

Lu, Yu; Mahaut-Smith, Martyn P; Varghese, Anthony; Huang, Christopher L-H; Kemp, Paul R; Vandenberg, Jamie I

2001-01-01

The unusual kinetics of human ether-à-go-go-related gene (HERG) K+ channels are consistent with a role in the suppression of arrhythmias initiated by premature beats. Action potential clamp protocols were used to investigate the effect of premature stimulation on HERG K+ channels, transfected in Chinese hamster ovary cells, at 37 °C. HERG K+ channel currents peaked during the terminal repolarization phase of normally paced action potential waveforms. However, the magnitude of the current and the time point at which conductance was maximal depended on the type of action potential waveform used (epicardial, endocardial, Purkinje fibre or atrial). HERG K+ channel currents recorded during premature action potentials consisted of an early transient outward current followed by a sustained outward current. The magnitude of the transient current component showed a biphasic dependence on the coupling interval between the normally paced and premature action potentials and was maximal at a coupling interval equivalent to 90% repolarization (APD90) for ventricular action potentials. The largest transient current response occurred at shorter coupling intervals for Purkinje fibre (APD90– 20 ms) and atrial (APD90– 30 ms) action potentials. The magnitude of the sustained current response following premature stimulation was similar to that recorded during the first action potential for ventricular action potential waveforms. However, for Purkinje and atrial action potentials the sustained current response was significantly larger during the premature action potential than during the normally paced action potential. A Markov model that included three closed states, one open and one inactivated state with transitions permitted between the pre-open closed state and the inactivated state, successfully reproduced our results for the effects of premature stimuli, both during square pulse and action potential clamp waveforms. These properties of HERG K+ channels may help to suppress arrhythmias initiated by early afterdepolarizations and premature beats in the ventricles, Purkinje fibres or atria. PMID:11744759

Somatostatin type-2 receptor activation inhibits glutamate release and prevents status epilepticus

PubMed Central

Kozhemyakin, Maxim; Rajasekaran, Karthik; Todorovic, Marko S.; Kowalski, Samuel L.; Balint, Corinne; Kapur, Jaideep

2013-01-01

Summary Newer therapies are needed for the treatment of status epilepticus (SE) refractory to benzodiazepines. Enhanced glutamatergic neurotransmission leads to SE, and AMPA receptors are modified during SE. Reducing glutamate release during SE is a potential approach to terminate SE. The neuropeptide somatostatin (SST) is proposed to diminish presynaptic glutamate release by activating SST type-2 receptors (SST2R). SST exerts an anticonvulsant action in some experimental models of seizures. Here, we investigated the mechanism of action of SST on excitatory synaptic transmission at the Schaffer collateral-CA1 synapses and the ability of SST to treat SE in rats using patch-clamp electrophysiology and video-EEG monitoring of seizures. SST reduced action potential-dependent EPSCs (sEPSCs) at Schaffer collateral-CA1 synapses at concentrations up to 1 μM; higher concentrations had no effect or increased the sEPSC frequency. SST also prevented paired-pulse facilitation of evoked EPSCs and did not alter action-potential-independent miniature EPSCs (mEPSCs). The effect of SST on EPSCs was inhibited by the SST2R antagonist cyanamid-154806 and was mimicked by the SST2R agonists, octreotide and lanreotide. Both SST and octreotide reduced the firing rate of CA1 pyramidal neurons. Intraventricular administration of SST, within a range of doses, either prevented or attenuated pilocarpine-induced SE or delayed the median time to the first grade 5 seizure by 11 min. Similarly, octreotide or lanreotide prevented or attenuated SE in more than 65% of animals. Compared to the pilocarpine model, octreotide was highly potent in preventing or attenuating continuous hippocampal stimulation-induced SE in all animals within 60 min of SE onset. Our results demonstrate that SST, through the activation of SST2Rs, diminishes presynaptic glutamate release and attenuates SE. PMID:23473742

Reconciling tensor and scalar observables in G-inflation

NASA Astrophysics Data System (ADS)

Ramírez, Héctor; Passaglia, Samuel; Motohashi, Hayato; Hu, Wayne; Mena, Olga

2018-04-01

The simple m2phi2 potential as an inflationary model is coming under increasing tension with limits on the tensor-to-scalar ratio r and measurements of the scalar spectral index ns. Cubic Galileon interactions in the context of the Horndeski action can potentially reconcile the observables. However, we show that this cannot be achieved with only a constant Galileon mass scale because the interactions turn off too slowly, leading also to gradient instabilities after inflation ends. Allowing for a more rapid transition can reconcile the observables but moderately breaks the slow-roll approximation leading to a relatively large and negative running of the tilt αs that can be of order ns‑1. We show that the observables on CMB and large scale structure scales can be predicted accurately using the optimized slow-roll approach instead of the traditional slow-roll expansion. Upper limits on |αs| place a lower bound of rgtrsim 0.005 and, conversely, a given r places a lower bound on |αs|, both of which are potentially observable with next generation CMB and large scale structure surveys.

Advanced Technologies for Robotic Exploration Leading to Human Exploration: Results from the SpaceOps 2015 Workshop

NASA Technical Reports Server (NTRS)

Lupisella, Mark L.; Mueller, Thomas

2016-01-01

This paper will provide a summary and analysis of the SpaceOps 2015 Workshop all-day session on "Advanced Technologies for Robotic Exploration, Leading to Human Exploration", held at Fucino Space Center, Italy on June 12th, 2015. The session was primarily intended to explore how robotic missions and robotics technologies more generally can help lead to human exploration missions. The session included a wide range of presentations that were roughly grouped into (1) broader background, conceptual, and high-level operations concepts presentations such as the International Space Exploration Coordination Group Roadmap, followed by (2) more detailed narrower presentations such as rover autonomy and communications. The broader presentations helped to provide context and specific technical hooks, and helped lay a foundation for the narrower presentations on more specific challenges and technologies, as well as for the discussion that followed. The discussion that followed the presentations touched on key questions, themes, actions and potential international collaboration opportunities. Some of the themes that were touched on were (1) multi-agent systems, (2) decentralized command and control, (3) autonomy, (4) low-latency teleoperations, (5) science operations, (6) communications, (7) technology pull vs. technology push, and (8) the roles and challenges of operations in early human architecture and mission concept formulation. A number of potential action items resulted from the workshop session, including: (1) using CCSDS as a further collaboration mechanism for human mission operations, (2) making further contact with subject matter experts, (3) initiating informal collaborative efforts to allow for rapid and efficient implementation, and (4) exploring how SpaceOps can support collaboration and information exchange with human exploration efforts. This paper will summarize the session and provide an overview of the above subjects as they emerged from the SpaceOps 2015 Workshop session.

Covert Action Lead -- Central Intelligence Agency or Special Forces

DTIC Science & Technology

2007-05-01

to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data...place as an elevated threat to the U.S., combined with the decline in the CIA’s ability to perform Covert Action, is it now time for Special Forces to... time for Special Forces to assume the lead role in Covert Action? iii TABLE OF CONTENTS INTRODUCTION

Electrophysiology of neurones of the inferior mesenteric ganglion of the cat.

PubMed Central

Julé, Y; Szurszewski, J H

1983-01-01

Intracellular recordings were obtained from cells in vitro in the inferior mesenteric ganglia of the cat. Neurones could be classified into three types: non-spontaneous, irregular discharging and regular discharging neurones. Non-spontaneous neurones had a stable resting membrane potential and responded with action potentials to indirect preganglionic nerve stimulation and to intracellular injection of depolarizing current. Irregular discharging neurones were characterized by a discharge of excitatory post-synaptic potentials (e.p.s.p.s.) which sometimes gave rise to action potentials. This activity was abolished by hexamethonium bromide, chlorisondamine and d-tubocurarine chloride. Tetrodotoxin and a low Ca2+ -high Mg2+ solution also blocked on-going activity in irregular discharging neurones. Regular discharging neurones were characterized by a rhythmic discharge of action potentials. Each action potential was preceded by a gradual depolarization of the intracellularly recorded membrane potential. Intracellular injection of hyperpolarizing current abolished the regular discharge of action potential. No synaptic potentials were observed during hyperpolarization of the membrane potential. Nicotinic, muscarinic and adrenergic receptor blocking drugs did not modify the discharge of action potentials in regular discharging neurones. A low Ca2+ -high Mg2+ solution also had no effect on the regular discharge of action potentials. Interpolation of an action potential between spontaneous action potentials in regular discharging neurones reset the rhythm of discharge. It is suggested that regular discharging neurones were endogenously active and that these neurones provided synaptic input to irregular discharging neurones. PMID:6140310

Electrophysiology of neurones of the inferior mesenteric ganglion of the cat.

PubMed

Julé, Y; Szurszewski, J H

1983-11-01

Intracellular recordings were obtained from cells in vitro in the inferior mesenteric ganglia of the cat. Neurones could be classified into three types: non-spontaneous, irregular discharging and regular discharging neurones. Non-spontaneous neurones had a stable resting membrane potential and responded with action potentials to indirect preganglionic nerve stimulation and to intracellular injection of depolarizing current. Irregular discharging neurones were characterized by a discharge of excitatory post-synaptic potentials (e.p.s.p.s.) which sometimes gave rise to action potentials. This activity was abolished by hexamethonium bromide, chlorisondamine and d-tubocurarine chloride. Tetrodotoxin and a low Ca2+ -high Mg2+ solution also blocked on-going activity in irregular discharging neurones. Regular discharging neurones were characterized by a rhythmic discharge of action potentials. Each action potential was preceded by a gradual depolarization of the intracellularly recorded membrane potential. Intracellular injection of hyperpolarizing current abolished the regular discharge of action potential. No synaptic potentials were observed during hyperpolarization of the membrane potential. Nicotinic, muscarinic and adrenergic receptor blocking drugs did not modify the discharge of action potentials in regular discharging neurones. A low Ca2+ -high Mg2+ solution also had no effect on the regular discharge of action potentials. Interpolation of an action potential between spontaneous action potentials in regular discharging neurones reset the rhythm of discharge. It is suggested that regular discharging neurones were endogenously active and that these neurones provided synaptic input to irregular discharging neurones.

Corrective Action Investigation Plan for Corrective Action Unit 562: Waste Systems Nevada Test Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alfred Wickline

2009-04-01

Corrective Action Unit 562 is located in Areas 2, 23, and 25 of the Nevada Test Site, which is approximately 65 miles northwest of Las Vegas, Nevada. Corrective Action Unit 562 is comprised of the 13 corrective action sites (CASs) listed below: • 02-26-11, Lead Shot • 02-44-02, Paint Spills and French Drain • 02-59-01, Septic System • 02-60-01, Concrete Drain • 02-60-02, French Drain • 02-60-03, Steam Cleaning Drain • 02-60-04, French Drain • 02-60-05, French Drain • 02-60-06, French Drain • 02-60-07, French Drain • 23-60-01, Mud Trap Drain and Outfall • 23-99-06, Grease Trap • 25-60-04, Buildingmore » 3123 Outfalls These sites are being investigated because existing information on the nature and extent of potential contamination is insufficient to evaluate and recommend corrective action alternatives. Additional information will be obtained by conducting a corrective action investigation before evaluating corrective action alternatives and selecting the appropriate corrective action for each CAS. The results of the field investigation will support a defensible evaluation of viable corrective action alternatives that will be presented in the Corrective Action Decision Document. The sites will be investigated based on the data quality objectives (DQOs) developed on December 11, 2008, by representatives of the Nevada Division of Environmental Protection; U.S. Department of Energy (DOE), National Nuclear Security Administration Nevada Site Office; Stoller-Navarro Joint Venture; and National Security Technologies, LLC. The DQO process was used to identify and define the type, amount, and quality of data needed to develop and evaluate appropriate corrective actions for CAU 562. Appendix A provides a detailed discussion of the DQO methodology and the DQOs specific to each CAS. The scope of the corrective action investigation for CAU 562 includes the following activities: • Move surface debris and/or materials, as needed, to facilitate sampling. • Conduct radiological surveys. • Perform field screening. • Collect and submit environmental samples for laboratory analysis to determine the nature and extent of any contamination released by each CAS. • Collect samples of source material to determine the potential for a release. • Collect samples of potential remediation wastes. • Collect quality control samples. This Corrective Action Investigation Plan has been developed in accordance with the Federal Facility Agreement and Consent Order that was agreed to by the State of Nevada; DOE, Environmental Management; U.S. Department of Defense; and DOE, Legacy Management (FFACO, 1996; as amended February 2008). Under the Federal Facility Agreement and Consent Order, this Corrective Action Investigation Plan will be submitted to the Nevada Division of Environmental Protection for approval. Fieldwork will be conducted following approval of the plan.« less

Dynamics of action potential initiation in the GABAergic thalamic reticular nucleus in vivo.

PubMed

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold.

Corrective Action Decision Document for Corrective Action Unit 562: Waste Systems Nevada Test Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mark Krause

2010-08-01

This Corrective Action Decision Document (CADD) presents information supporting the selection of corrective action alternatives (CAAs) leading to the closure of Corrective Action Unit (CAU) 562, Waste Systems, in Areas 2, 23, and 25 of the Nevada Test Site, Nevada. This complies with the requirements of the Federal Facility Agreement and Consent Order (FFACO) that was agreed to by the State of Nevada; U.S. Department of Energy (DOE), Environmental Management; U.S. Department of Defense; and DOE, Legacy Management. Corrective Action Unit 562 comprises the following corrective action sites (CASs): • 02-26-11, Lead Shot • 02-44-02, Paint Spills and French Drainmore » • 02-59-01, Septic System • 02-60-01, Concrete Drain • 02-60-02, French Drain • 02-60-03, Steam Cleaning Drain • 02-60-04, French Drain • 02-60-05, French Drain • 02-60-06, French Drain • 02-60-07, French Drain • 23-60-01, Mud Trap Drain and Outfall • 23-99-06, Grease Trap • 25-60-04, Building 3123 Outfalls The purpose of this CADD is to identify and provide the rationale for the recommendation of CAAs for the 13 CASs within CAU 562. Corrective action investigation (CAI) activities were performed from July 27, 2009, through May 12, 2010, as set forth in the CAU 562 Corrective Action Investigation Plan. The purpose of the CAI was to fulfill the following data needs as defined during the data quality objective (DQO) process: • Determine whether COCs are present. • If COCs are present, determine their nature and extent. • Provide sufficient information and data to complete appropriate corrective actions. A data quality assessment (DQA) performed on the CAU 562 data demonstrated the quality and acceptability of the data for use in fulfilling the DQO data needs. Analytes detected during the CAI were evaluated against appropriate final action levels (FALs) to identify the COCs for each CAS. The results of the CAI identified COCs at 10 of the 13 CASs in CAU 562, and thus corrective action is required. Assessment of the data generated from investigation activities conducted at CAU 562 is shown in Table ES-1. Based on the evaluation of analytical data from the CAI, review of future and current operations at the 13 CASs, and the detailed and comparative analysis of the potential CAAs, the following corrective actions are recommended for CAU 562. • No further action is the preferred corrective action for CASs 02-60-01, 02-60-06, and 02-60-07. • Clean closure is the preferred corrective action for CASs 02-26-11, 02-44-02, 02-59-01, 02-60-02, 02-60-03, 02-60-04, 02-60-05, 23-60-01, 23-99-06, and 25-60-04. The preferred CAAs were evaluated on technical merit focusing on performance, reliability, feasibility, safety, and cost. The alternatives were judged to meet all requirements for the technical components evaluated. The alternatives meet all applicable federal and state regulations for closure of the site and will reduce potential exposures to contaminated media to acceptable levels. The DOE, National Nuclear Security Administration Nevada Site Office provides the following recommendations: • No further corrective action is required at CASs 02-60-01, 02-60-06, and 02-60-07. • Clean closure is recommended for the remaining 10 CASs in CAU 562. • A Corrective Action Plan will be submitted to the Nevada Division of Environmental Protection that contains a detailed description of the proposed actions that will be taken to implement the selected corrective actions.« less

Taking action against ocean acidification: a review of management and policy options.

PubMed

Billé, Raphaël; Kelly, Ryan; Biastoch, Arne; Harrould-Kolieb, Ellycia; Herr, Dorothée; Joos, Fortunat; Kroeker, Kristy; Laffoley, Dan; Oschlies, Andreas; Gattuso, Jean-Pierre

2013-10-01

Ocean acidification has emerged over the last two decades as one of the largest threats to marine organisms and ecosystems. However, most research efforts on ocean acidification have so far neglected management and related policy issues to focus instead on understanding its ecological and biogeochemical implications. This shortfall is addressed here with a systematic, international and critical review of management and policy options. In particular, we investigate the assumption that fighting acidification is mainly, but not only, about reducing CO2 emissions, and explore the leeway that this emerging problem may open in old environmental issues. We review nine types of management responses, initially grouped under four categories: preventing ocean acidification; strengthening ecosystem resilience; adapting human activities; and repairing damages. Connecting and comparing options leads to classifying them, in a qualitative way, according to their potential and feasibility. While reducing CO2 emissions is confirmed as the key action that must be taken against acidification, some of the other options appear to have the potential to buy time, e.g. by relieving the pressure of other stressors, and help marine life face unavoidable acidification. Although the existing legal basis to take action shows few gaps, policy challenges are significant: tackling them will mean succeeding in various areas of environmental management where we failed to a large extent so far.

Taking Action Against Ocean Acidification: A Review of Management and Policy Options

NASA Astrophysics Data System (ADS)

Billé, Raphaël; Kelly, Ryan; Biastoch, Arne; Harrould-Kolieb, Ellycia; Herr, Dorothée; Joos, Fortunat; Kroeker, Kristy; Laffoley, Dan; Oschlies, Andreas; Gattuso, Jean-Pierre

2013-10-01

Ocean acidification has emerged over the last two decades as one of the largest threats to marine organisms and ecosystems. However, most research efforts on ocean acidification have so far neglected management and related policy issues to focus instead on understanding its ecological and biogeochemical implications. This shortfall is addressed here with a systematic, international and critical review of management and policy options. In particular, we investigate the assumption that fighting acidification is mainly, but not only, about reducing CO2 emissions, and explore the leeway that this emerging problem may open in old environmental issues. We review nine types of management responses, initially grouped under four categories: preventing ocean acidification; strengthening ecosystem resilience; adapting human activities; and repairing damages. Connecting and comparing options leads to classifying them, in a qualitative way, according to their potential and feasibility. While reducing CO2 emissions is confirmed as the key action that must be taken against acidification, some of the other options appear to have the potential to buy time, e.g. by relieving the pressure of other stressors, and help marine life face unavoidable acidification. Although the existing legal basis to take action shows few gaps, policy challenges are significant: tackling them will mean succeeding in various areas of environmental management where we failed to a large extent so far.

Antimalarial Pyrido[1,2-a]benzimidazoles: Lead Optimization, Parasite Life Cycle Stage Profile, Mechanistic Evaluation, Killing Kinetics, and in Vivo Oral Efficacy in a Mouse Model.

PubMed

Singh, Kawaljit; Okombo, John; Brunschwig, Christel; Ndubi, Ferdinand; Barnard, Linley; Wilkinson, Chad; Njogu, Peter M; Njoroge, Mathew; Laing, Lizahn; Machado, Marta; Prudêncio, Miguel; Reader, Janette; Botha, Mariette; Nondaba, Sindisiwe; Birkholtz, Lyn-Marie; Lauterbach, Sonja; Churchyard, Alisje; Coetzer, Theresa L; Burrows, Jeremy N; Yeates, Clive; Denti, Paolo; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Chibale, Kelly

2017-02-23

Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

Stroke rehabilitation

PubMed Central

Bindawas, Saad M.; Vennu, Vishal S.

2016-01-01

Stroke is a major cause of death and other complications worldwide. In Saudi Arabia, stroke has become an emerging health issue leading to disability and death. However, stroke care including rehabilitation services, in Saudi Arabia lags behind developed countries. Stroke rehabilitation is an essential recovery option after stroke and should start as early as possible to avoid potential complications. The growing evidence on stroke rehabilitation effectiveness in different health care settings and outcome measures used widely are reviewed in this call to action paper. PMID:27744457

Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine.

PubMed

He, Dao-Yao; Ron, Dorit

2006-11-01

We recently showed that the up-regulation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the midbrain, is the molecular mechanism by which the putative anti-addiction drug Ibogaine mediates its desirable action of reducing alcohol consumption. Human reports and studies in rodents have shown that a single administration of Ibogaine results in a long-lasting reduction of drug craving (humans) and drug and alcohol intake (rodents). Here we determine whether, and how, Ibogaine exerts its long-lasting actions on GDNF expression and signaling. Using the dopaminergic-like SHSY5Y cell line as a culture model, we observed that short-term Ibogaine exposure results in a sustained increase in GDNF expression that is mediated via the induction of a long-lasting autoregulatory cycle by which GDNF positively regulates its own expression. We show that the initial exposure of cells to Ibogaine or GDNF results in an increase in GDNF mRNA, leading to protein expression and to the corresponding activation of the GDNF signaling pathway. This, in turn, leads to a further increase in the mRNA level of the growth factor. The identification of a GDNF-mediated, autoregulatory long-lasting feedback loop could have important implications for GDNF's potential value as a treatment for addiction and neurodegenerative diseases.

Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons

PubMed Central

Williams, Stephen R; Stuart, Greg J

1999-01-01

Electrophysiological recordings and pharmacological manipulations were used to investigate the mechanisms underlying the generation of action potential burst firing and its postsynaptic consequences in visually identified rat layer 5 pyramidal neurons in vitro.Based upon repetitive firing properties and subthreshold membrane characteristics, layer 5 pyramidal neurons were separated into three classes: regular firing and weak and strong intrinsically burst firing.High frequency (330 ± 10 Hz) action potential burst firing was abolished or greatly weakened by the removal of Ca2+ (n = 5) from, or by the addition of the Ca2+ channel antagonist Ni2+ (250–500 μm; n = 8) to, the perfusion medium.The blockade of apical dendritic sodium channels by the local dendritic application of TTX (100 nm; n = 5) abolished or greatly weakened action potential burst firing, as did the local apical dendritic application of Ni2+ (1 mm; n = 5).Apical dendritic depolarisation resulted in low frequency (157 ± 26 Hz; n = 6) action potential burst firing in regular firing neurons, as classified by somatic current injection. The intensity of action potential burst discharges in intrinsically burst firing neurons was facilitated by dendritic depolarisation (n = 11).Action potential amplitude decreased throughout a burst when recorded somatically, suggesting that later action potentials may fail to propagate axonally. Axonal recordings demonstrated that each action potential in a burst is axonally initiated and that no decrement in action potential amplitude is apparent in the axon > 30 μm from the soma.Paired recordings (n = 16) from synaptically coupled neurons indicated that each action potential in a burst could cause transmitter release. EPSPs or EPSCs evoked by a presynaptic burst of action potentials showed use-dependent synaptic depression.A postsynaptic, TTX-sensitive voltage-dependent amplification process ensured that later EPSPs in a burst were amplified when generated from membrane potentials positive to -60 mV, providing a postsynaptic mechanism that counteracts use-dependent depression at synapses between layer 5 pyramidal neurons. PMID:10581316

High prevalence of elevated blood lead levels in both rural and urban Iowa newborns: Spatial patterns and area-level covariates

PubMed Central

Zahrieh, David; Young, Sean G.; Oleson, Jacob; Ryckman, Kelli K.; Wels, Brian; Simmons, Donald L.; Saftlas, Audrey

2017-01-01

Lead in maternal blood can cross the placenta and result in elevated blood lead levels in newborns, potentially producing negative effects on neurocognitive function, particularly if combined with childhood lead exposure. Little research exists, however, into the burden of elevated blood lead levels in newborns, or the places and populations in which elevated lead levels are observed in newborns, particularly in rural settings. Using ~2300 dried bloods spots collected within 1–3 days of birth among Iowa newborns, linked with the area of mother’s residence at the time of birth, we examine the spatial patterns of elevated (>5 μg/dL) blood lead levels and the ecological-level predictors of elevated blood lead levels. We find that one in five newborns exceed the 5 μg/dL action level set by the US Centers for Disease Control & Prevention (CDC). Bayesian spatial zero inflated regression indicates that elevated blood lead in newborns is associated with areas of increased pre-1940s housing and childbearing-age women with low educational status in both rural and urban settings. No differences in blood lead levels or the proportion of children exceeding 5 μg/dL are observed between urban and rural maternal residence, though a spatial cluster of elevated blood lead is observed in rural counties. These characteristics can guide the recommendation for testing of infants at well-baby appointments in places where risk factors are present, potentially leading to earlier initiation of case management. The findings also suggest that rural populations are at as great of risk of elevated blood lead levels as are urban populations. Analysis of newborn dried blood spots is an important tool for lead poisoning surveillance in newborns and can direct public health efforts towards specific places and populations where lead testing and case management will have the greatest impact. PMID:28520816

pigk Mutation underlies macho behavior and affects Rohon-Beard cell excitability

PubMed Central

Carmean, V.; Yonkers, M. A.; Tellez, M. B.; Willer, J. R.; Willer, G. B.; Gregg, R. G.; Geisler, R.; Neuhauss, S. C.

2015-01-01

The study of touch-evoked behavior allows investigation of both the cells and circuits that generate a response to tactile stimulation. We investigate a touch-insensitive zebrafish mutant, macho (maco), previously shown to have reduced sodium current amplitude and lack of action potential firing in sensory neurons. In the genomes of mutant but not wild-type embryos, we identify a mutation in the pigk gene. The encoded protein, PigK, functions in attachment of glycophosphatidylinositol anchors to precursor proteins. In wild-type embryos, pigk mRNA is present at times when mutant embryos display behavioral phenotypes. Consistent with the predicted loss of function induced by the mutation, knock-down of PigK phenocopies maco touch insensitivity and leads to reduced sodium current (INa) amplitudes in sensory neurons. We further test whether the genetic defect in pigk underlies the maco phenotype by overexpressing wild-type pigk in mutant embryos. We find that ubiquitous expression of wild-type pigk rescues the touch response in maco mutants. In addition, for maco mutants, expression of wild-type pigk restricted to sensory neurons rescues sodium current amplitudes and action potential firing in sensory neurons. However, expression of wild-type pigk limited to sensory cells of mutant embryos does not allow rescue of the behavioral touch response. Our results demonstrate an essential role for pigk in generation of the touch response beyond that required for maintenance of proper INa density and action potential firing in sensory neurons. PMID:26133798

A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes.

PubMed Central

Pandit, S V; Clark, R B; Giles, W R; Demir, S S

2001-01-01

Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca(2+)-independent transient outward K(+) current (I(t)) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na(+) current (I(Na)) in the endocardial myocytes results in a faster upstroke (dV/dt(max)). This, in addition to the smaller magnitude of I(t), is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K(+) current (I(ss)), and a larger influx of Ca(2+) ions via the L-type Ca(2+) current (I(CaL)). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca(2+) transient [Ca(2+)](i), and the resultant increase in the Na(+)-Ca(2+) exchanger (I(NaCa)) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle. PMID:11720973

Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea.

PubMed

Pimentel, M

2016-01-01

The role of gut microbiota in the pathophysiology of irritable bowel syndrome (IBS) is supported by various lines of evidence, including differences in mucosal and faecal microbiota between patients with IBS and healthy individuals, development of post-infectious IBS, and the efficacy of some probiotics and nonsystemic antibiotics (e.g. rifaximin). To review the literature regarding the role of rifaximin in IBS and its potential mechanism(s) of action. A literature search was conducted using the terms 'rifaximin', 'irritable bowel syndrome' and 'mechanism of action'. Rifaximin was approved in 2015 for the treatment of IBS with diarrhoea. In contrast to other currently available IBS therapies that require daily administration to maintain efficacy, 2-week rifaximin treatment achieved symptom improvement that persisted ≥12 weeks post-treatment. The mechanisms of action of rifaximin, therefore, may extend beyond direct bactericidal effects. Data suggest that rifaximin may decrease host proinflammatory responses to bacterial products in patients with IBS. In some cases, small intestinal bacterial overgrowth (SIBO) may play a role in the clinical symptoms of IBS. Because of the high level of solubility of rifaximin in the small intestine, rifaximin may reset microbial diversity in this environment. Consistent with this hypothesis, rifaximin has antibiotic efficacy against isolates derived from patients with SIBO. Resetting microbial diversity via rifaximin use may lead to a decrease in bacterial fermentation and a reduction in the clinical symptoms of IBS. © 2015 John Wiley & Sons Ltd.

WE-G-BRA-07: Analyzing the Safety Implications of a Brachytherapy Process Improvement Project Utilizing a Novel System-Theory-Based Hazard-Analysis Technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, A; Samost, A; Viswanathan, A

Purpose: To investigate the hazards in cervical-cancer HDR brachytherapy using a novel hazard-analysis technique, System Theoretic Process Analysis (STPA). The applicability and benefit of STPA to the field of radiation oncology is demonstrated. Methods: We analyzed the tandem and ring HDR procedure through observations, discussions with physicists and physicians, and the use of a previously developed process map. Controllers and their respective control actions were identified and arranged into a hierarchical control model of the system, modeling the workflow from applicator insertion through initiating treatment delivery. We then used the STPA process to identify potentially unsafe control actions. Scenarios weremore » then generated from the identified unsafe control actions and used to develop recommendations for system safety constraints. Results: 10 controllers were identified and included in the final model. From these controllers 32 potentially unsafe control actions were identified, leading to more than 120 potential accident scenarios, including both clinical errors (e.g., using outdated imaging studies for planning), and managerial-based incidents (e.g., unsafe equipment, budget, or staffing decisions). Constraints identified from those scenarios include common themes, such as the need for appropriate feedback to give the controllers an adequate mental model to maintain safe boundaries of operations. As an example, one finding was that the likelihood of the potential accident scenario of the applicator breaking during insertion might be reduced by establishing a feedback loop of equipment-usage metrics and equipment-failure reports to the management controller. Conclusion: The utility of STPA in analyzing system hazards in a clinical brachytherapy system was demonstrated. This technique, rooted in system theory, identified scenarios both technical/clinical and managerial in nature. These results suggest that STPA can be successfully used to analyze safety in brachytherapy and may prove to be an alternative to other hazard analysis techniques.« less

Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine.

PubMed

Harraz, Maged M; Snyder, Solomon H

2015-01-01

Psychotropic actions of cocaine are generally thought to involve its blockade of monoamine transporters leading to increased synaptic levels of monoamines, especially dopamine. Subsequent intracellular events have been less well characterized. We describe a signaling system wherein lower behavioral stimulant doses of cocaine, as well as higher neurotoxic doses, activate a cascade wherein nitric oxide nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to generate a complex with the ubiquitin-E3-ligase Siah1 which translocates to the nucleus. With lower cocaine doses, nuclear GAPDH augments CREB signaling, while at higher doses p53 signaling is enhanced. The drug CGP3466B very potently blocks GAPDH nitrosylation, hindering both signaling cascades and inhibits both behavioral activating and neurotoxic effects of cocaine. This system affords potentially novel approaches to the therapy of cocaine abuse.

Association between social capital and health in women of reproductive age: a population-based study.

PubMed

Baheiraei, Azam; Bakouei, Fatemeh; Mohammadi, Eesa; Majdzadeh, Reza; Hosseni, Mostafa

2016-12-01

Women's health is a public health priority. The origins of health inequalities are very complex. The present study was conducted to determine the association between social capital and health status in reproductive-age women in Tehran, Iran. In this population-based, cross-sectional study, the Social Capital Integrated Questionnaire, the SF-36 and socio-demographic questionnaires were used. Analysis of data by one-way ANOVA test and stepwise multiple linear regression showed that the manifestation dimensions of social capital (groups and networks, trust and solidarity, collective action and cooperation) can potentially lead to the outcome dimensions of social capital (social cohesion and inclusion, and empowerment and political action), which in turn affect health inequities after controlling for socio-demographic differences. © The Author(s) 2015.

The "politics of the queue": the politicization of people living with HIV/AIDS in Tanzania.

PubMed

Beckmann, Nadine; Bujra, Janet

2010-01-01

Starting from a body of literature on movements around "biological citizenship," this article analyses the political significance of HIV-positive people's collective action in Tanzania. We explore reasons for the limited impact of Tanzanian AIDS activism on the wider political scene, concluding that the formation of a "movement" is still in its infancy and faces many constraints, though some breakthroughs have been made. Participation in PLHA groups in Tanzania encourages politicizing struggles over representation, democratic forms and gender that can lead to a process of political socialization in which members learn to recognize and confront abuses of power. It is in such low-level, less visible social transformations that the greatest potential of participation in collective action around HIV/AIDS in Tanzania lies.

Fruits for Prevention and Treatment of Cardiovascular Diseases

PubMed Central

Zhao, Cai-Ning; Meng, Xiao; Li, Ya; Li, Sha; Liu, Qing; Tang, Guo-Yi; Li, Hua-Bin

2017-01-01

Cardiovascular diseases (CVDs) are leading global health problems. Accumulating epidemiological studies have indicated that consuming fruits was inversely related to the risk of CVDs. Moreover, substantial experimental studies have supported the protective role of fruits against CVDs, and several fruits (grape, blueberry, pomegranate, apple, hawthorn, and avocado) have been widely studied and have shown potent cardiovascular protective action. Fruits can prevent CVDs or facilitate the restoration of morphology and functions of heart and vessels after injury. The involved mechanisms included protecting vascular endothelial function, regulating lipids metabolism, modulating blood pressure, inhibiting platelets function, alleviating ischemia/reperfusion injury, suppressing thrombosis, reducing oxidative stress, and attenuating inflammation. The present review summarizes recent discoveries about the effects of fruits on CVDs and discusses potential mechanisms of actions based on evidence from epidemiological, experimental, and clinical studies. PMID:28608832

Poverty and child health in the UK: using evidence for action

PubMed Central

Wickham, Sophie; Anwar, Elspeth; Barr, Ben; Law, Catherine; Taylor-Robinson, David

2016-01-01

There are currently high levels of child poverty in the UK, and for the first time in almost two decades child poverty has started to rise in absolute terms. Child poverty is associated with a wide range of health-damaging impacts, negative educational outcomes and adverse long-term social and psychological outcomes. The poor health associated with child poverty limits children's potential and development, leading to poor health and life chances in adulthood. This article outlines some key definitions with regard to child poverty, reviews the links between child poverty and a range of health, developmental, behavioural and social outcomes for children, describes gaps in the evidence base and provides an overview of current policies relevant to child poverty in the UK. Finally, the article outlines how child health professionals can take action by (1) supporting policies to reduce child poverty, (2) providing services that reduce the health consequences of child poverty and (3) measuring and understanding the problem and assessing the impact of action. PMID:26857824

Application of systems and control theory-based hazard analysis to radiation oncology.

PubMed

Pawlicki, Todd; Samost, Aubrey; Brown, Derek W; Manger, Ryan P; Kim, Gwe-Ya; Leveson, Nancy G

2016-03-01

Both humans and software are notoriously challenging to account for in traditional hazard analysis models. The purpose of this work is to investigate and demonstrate the application of a new, extended accident causality model, called systems theoretic accident model and processes (STAMP), to radiation oncology. Specifically, a hazard analysis technique based on STAMP, system-theoretic process analysis (STPA), is used to perform a hazard analysis. The STPA procedure starts with the definition of high-level accidents for radiation oncology at the medical center and the hazards leading to those accidents. From there, the hierarchical safety control structure of the radiation oncology clinic is modeled, i.e., the controls that are used to prevent accidents and provide effective treatment. Using STPA, unsafe control actions (behaviors) are identified that can lead to the hazards as well as causal scenarios that can lead to the identified unsafe control. This information can be used to eliminate or mitigate potential hazards. The STPA procedure is demonstrated on a new online adaptive cranial radiosurgery procedure that omits the CT simulation step and uses CBCT for localization, planning, and surface imaging system during treatment. The STPA procedure generated a comprehensive set of causal scenarios that are traced back to system hazards and accidents. Ten control loops were created for the new SRS procedure, which covered the areas of hospital and department management, treatment design and delivery, and vendor service. Eighty three unsafe control actions were identified as well as 472 causal scenarios that could lead to those unsafe control actions. STPA provides a method for understanding the role of management decisions and hospital operations on system safety and generating process design requirements to prevent hazards and accidents. The interaction of people, hardware, and software is highlighted. The method of STPA produces results that can be used to improve safety and prevent accidents and warrants further investigation.

The human ether-a-go-go-related gene (hERG) current inhibition selectively prolongs action potential of midmyocardial cells to augment transmural dispersion.

PubMed

Yasuda, C; Yasuda, S; Yamashita, H; Okada, J; Hisada, T; Sugiura, S

2015-08-01

The majority of drug induced arrhythmias are related to the prolongation of action potential duration following inhibition of rapidly activating delayed rectifier potassium current (I(Kr)) mediated by the hERG channel. However, for arrhythmias to develop and be sustained, not only the prolongation of action potential duration but also its transmural dispersion are required. Herein, we evaluated the effect of hERG inhibition on transmural dispersion of action potential duration using the action potential clamp technique that combined an in silico myocyte model with the actual I(Kr) measurement. Whole cell I(Kr) current was measured in Chinese hamster ovary cells stably expressing the hERG channel. The measured current was coupled with models of ventricular endocardial, M-, and epicardial cells to calculate the action potentials. Action potentials were evaluated under control condition and in the presence of 1, 10, or 100 μM disopyramide, an hERG inhibitor. Disopyramide dose-dependently increased the action potential durations of the three cell types. However, action potential duration of M-cells increased disproportionately at higher doses, and was significantly different from that of epicardial and endocardial cells (dispersion of repolarization). By contrast, the effects of disopyramide on peak I(Kr) and instantaneous current-voltage relation were similar in all cell types. Simulation study suggested that the reduced repolarization reserve of M-cell with smaller amount of slowly activating delayed rectifier potassium current levels off at longer action potential duration to make such differences. The action potential clamp technique is useful for studying the mechanism of arrhythmogenesis by hERG inhibition through the transmural dispersion of repolarization.

Use of twitter among local health departments: an analysis of information sharing, engagement, and action.

PubMed

Neiger, Brad L; Thackeray, Rosemary; Burton, Scott H; Thackeray, Callie R; Reese, Jennifer H

2013-08-19

Social media offers unprecedented opportunities for public health to engage audiences in conversations and collaboration that could potentially lead to improved health conditions. While there is some evidence that local health departments (LHDs) are using social media and Twitter in particular, little is known about how Twitter is used by LHDs and how they use it to engage followers versus disseminating one-way information. To examine how LHDs use Twitter to share information, engage with followers, and promote action, as well as to discover differences in Twitter use among LHDs by size of population served. The Twitter accounts for 210 LHDs were stratified into three groups based on size of population served (n=69 for less than 100,000; n=89 for 100,000-499,999; n=52 for 500,000 or greater). A sample of 1000 tweets was obtained for each stratum and coded as being either about the organization or about personal-health topics. Subcategories for organization included information, engagement, and action. Subcategories for personal health included information and action. Of all LHD tweets (n=3000), 56.1% (1682/3000) related to personal health compared with 39.5% (1186/3000) that were about the organization. Of the personal-health tweets, 58.5% (984/1682) involved factual information and 41.4% (697/1682) encouraged action. Of the organization-related tweets, 51.9% (615/1186) represented one-way communication about the organization and its events and services, 35.0% (416/1186) tried to engage followers in conversation, and 13.3% (158/1186) encouraged action to benefit the organization (eg, attend events). Compared with large LHDs, small LHDs were more likely to post tweets about their organization (Cramer's V=0.06) but were less likely to acknowledge events and accomplishments of other organizations (χ²=12.83, P=.02, Cramer's V=0.18). Small LHDs were also less likely to post personal health-related tweets (Cramer's V=0.08) and were less likely to post tweets containing suggestions to take action to modify their lifestyle. While large LHDs were more likely to post engagement-related tweets about the organization (Cramer's V=0.12), they were less likely to ask followers to take action that would benefit the organization (χ²=7.59, P=.02. Cramer's V=0.08). While certain associations were statistically significant, the Cramer's V statistic revealed weak associations. Twitter is being adopted by LHDs, but its primary use involves one-way communication on personal-health topics as well as organization-related information. There is also evidence that LHDs are starting to use Twitter to engage their audiences in conversations. As public health transitions to more dialogic conversation and engagement, Twitter's potential to help form partnerships with audiences and involve them as program participants may lead to action for improved health.

Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection

PubMed Central

Cherian, Philip T.; Wu, Xiaoqian; Yang, Lei; Scarborough, Jerrod S.; Singh, Aman P.; Alam, Zahidul A.; Lee, Richard E.; Hurdle, Julian G.

2015-01-01

Objectives Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. Methods A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. Results Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole. Conclusions This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases. PMID:26286574

Dynamics of Action Potential Initiation in the GABAergic Thalamic Reticular Nucleus In Vivo

PubMed Central

Muñoz, Fabián; Fuentealba, Pablo

2012-01-01

Understanding the neural mechanisms of action potential generation is critical to establish the way neural circuits generate and coordinate activity. Accordingly, we investigated the dynamics of action potential initiation in the GABAergic thalamic reticular nucleus (TRN) using in vivo intracellular recordings in cats in order to preserve anatomically-intact axo-dendritic distributions and naturally-occurring spatiotemporal patterns of synaptic activity in this structure that regulates the thalamic relay to neocortex. We found a wide operational range of voltage thresholds for action potentials, mostly due to intrinsic voltage-gated conductances and not synaptic activity driven by network oscillations. Varying levels of synchronous synaptic inputs produced fast rates of membrane potential depolarization preceding the action potential onset that were associated with lower thresholds and increased excitability, consistent with TRN neurons performing as coincidence detectors. On the other hand the presence of action potentials preceding any given spike was associated with more depolarized thresholds. The phase-plane trajectory of the action potential showed somato-dendritic propagation, but no obvious axon initial segment component, prominent in other neuronal classes and allegedly responsible for the high onset speed. Overall, our results suggest that TRN neurons could flexibly integrate synaptic inputs to discharge action potentials over wide voltage ranges, and perform as coincidence detectors and temporal integrators, supported by a dynamic action potential threshold. PMID:22279567

Decision making and action implementation: evidence for an early visually triggered motor activation specific to potential actions.

PubMed

Tandonnet, Christophe; Garry, Michael I; Summers, Jeffery J

2013-07-01

To make a decision may rely on accumulating evidence in favor of one alternative until a threshold is reached. Sequential-sampling models differ by the way of accumulating evidence and the link with action implementation. Here, we tested a model's prediction of an early action implementation specific to potential actions. We assessed the dynamics of action implementation in go/no-go and between-hand choice tasks by transcranial magnetic stimulation of the motor cortex (single- or paired-pulse TMS; 3-ms interstimulus interval). Prior to implementation of the selected action, the amplitude of the motor evoked potential first increased whatever the visual stimulus but only for the hand potentially involved in the to-be-produced action. These findings suggest that visual stimuli can trigger an early motor activation specific to potential actions, consistent with race-like models with continuous transmission between decision making and action implementation. Copyright © 2013 Society for Psychophysiological Research.

SOLVING A COPPER CORROSION PROBLEM WITH ORTHOPHOSPHATE: INDIAN HILL, OHIO CASE STUDY

EPA Science Inventory

Many small and medium-sized water systems have troublt complying with the copper Action Level (of the Lead and Copper Rule), sometimes concurrently with meeting the lead Action level. The problem is especially troubling and widespread with ground water supplies having high alkali...

The effects of saxitoxin and tetrodotoxin on nerve conduction in the presence of lithium ions and of magnesium ions

PubMed Central

Evans, M. H.

1969-01-01

1. It has been shown that nerve fibres from rat cauda equina will conduct action potentials after immersion in saline in which lithium chloride is substituted for sodium chloride. 2. Both saxitoxin and tetrodotoxin inhibit lithium-generated action potentials. The concentration of toxin needed to inhibit the lithium-generated action potentials is similar to that needed to inhibit sodium-generated action potentials. 3. If magnesium chloride is added to the saline to give a concentration of 10-15 mM there is usually a slight fall in amplitude of the compound action potential. Saxitoxin and tetrodotoxin now inhibit the action potential to a greater degree than in the absence of magnesium ions. PMID:5789802

The unifying role of dissipative action in the dynamic failure of solids

DOE PAGES

Grady, Dennis

2015-05-19

Dissipative action, the product of dissipation energy and transport time, is fundamental to the dynamic failure of solids. Invariance of the dissipative action underlies the fourth-power nature of structured shock waves observed in selected solid metals and compounds. Dynamic failure through shock compaction, tensile spall and adiabatic shear are also governed by a constancy of the dissipative action. This commonality underlying the various modes of dynamic failure is described and leads to deeper insights into failure of solids in the intense shock wave event. These insights are in turn leading to a better understanding of the shock deformation processes underlyingmore » the fourth-power law. Experimental result and material models encompassing the dynamic failure of solids are explored for the purpose of demonstrating commonalities leading to invariance of the dissipation action. As a result, calculations are extended to aluminum and uranium metals with the intent of predicting micro-scale energetics and spatial scales in the structured shock wave.« less

Leading Causes of Death in Nonmetropolitan and Metropolitan Areas— United States, 1999–2014

PubMed Central

Garcia, Macarena C.; Bastian, Brigham; Rossen, Lauren M.; Ingram, Deborah D.; Faul, Mark; Massetti, Greta M.; Thomas, Cheryll C.; Hong, Yuling; Yoon, Paula W.; Iademarco, Michael F.

2017-01-01

Problem/Condition Higher rates of death in nonmetropolitan areas (often referred to as rural areas) compared with metropolitan areas have been described but not systematically assessed. Period Covered 1999–2014 Description of System Mortality data for U.S. residents from the National Vital Statistics System were used to calculate age-adjusted death rates and potentially excess deaths for nonmetropolitan and metropolitan areas for the five leading causes of death. Age-adjusted death rates included all ages and were adjusted to the 2000 U.S. standard population by the direct method. Potentially excess deaths are defined as deaths among persons aged <80 years that exceed the numbers that would be expected if the death rates of states with the lowest rates (i.e., benchmark states) occurred across all states. (Benchmark states were the three states with the lowest rates for each cause during 2008–2010.) Potentially excess deaths were calculated separately for nonmetropolitan and metropolitan areas. Data are presented for the United States and the 10 U.S. Department of Health and Human Services public health regions. Results Across the United States, nonmetropolitan areas experienced higher age-adjusted death rates than metropolitan areas. The percentages of potentially excess deaths among persons aged <80 years from the five leading causes were higher in nonmetropolitan areas than in metropolitan areas. For example, approximately half of deaths from unintentional injury and chronic lower respiratory disease in nonmetropolitan areas were potentially excess deaths, compared with 39.2% and 30.9%, respectively, in metropolitan areas. Potentially excess deaths also differed among and within public health regions; within regions, nonmetropolitan areas tended to have higher percentages of potentially excess deaths than metropolitan areas. Interpretation Compared with metropolitan areas, nonmetropolitan areas have higher age-adjusted death rates and greater percentages of potentially excess deaths from the five leading causes of death, nationally and across public health regions. Public Health Action Routine tracking of potentially excess deaths in nonmetropolitan areas might help public health departments identify emerging health problems, monitor known problems, and focus interventions to reduce preventable deaths in these areas. PMID:28081058

MO-G-BRE-08: Taxonomy of Corrective Actions in Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sutlief, S; Brown, D

2014-06-15

Purpose: Various causal taxonomies have been developed for healthcare incidents and for radiation therapy in particular. The causal analysis of incidents leads to corrective actions which can also be organized into a taxonomy. Such a corrective action classification system would provide information about the situational context, the action type, and the leverage of the action in order to detect patterns in the corrective actions frequently employed in radiation therapy. It would also provide practical guidance to the radiation therapy community for determining the appropriateness and potential effectiveness of proposed corrective actions. Materials: A review of causal analysis reports and correctivemore » action plans was conducted using the following sources: US NRC medical event reports, IAEA reports, ROSIS submissions, US Veterans Health Administration reports, and singleincident report sources. The corrective actions presented in the published sources were then mapped onto four corrective action taxonomy prototypes: role-based, safety-context-based, responsibility-based, and hierarchy of hazard control. The resulting corrective action taxonomy was then validated through use of the published sources. Results: The responsibility-based taxonomy and hierarchy of hazard taxonomy provided more intuitive and sensible categories than the role-based taxonomy or the safety-context taxonomy. The most frequent corrective actions were added safety barriers, training, process standardization, and development of a quality improvement program where one was lacking. Conclusion: Published corrective action statements in radiation therapy emphasize what to do more so than whom the recipient is or which process step is affected. The hierarchy of hazard taxonomy provides a suitable framework for radiation therapy and has the advantage of providing insight into the likelihood that a particular corrective action will mitigate the recurrence of the error it was meant to correct. This information would be useful to medical center administration, safety personnel, and regulators who must assess the projected efficacy of corrective actions. Derek Brown is a director of TreatSafely, LLC.« less

What is a food and what is a medicinal product in the European Union? Use of the benchmark dose (BMD) methodology to define a threshold for "pharmacological action".

PubMed

Lachenmeier, Dirk W; Steffen, Christian; el-Atma, Oliver; Maixner, Sibylle; Löbell-Behrends, Sigrid; Kohl-Himmelseher, Matthias

2012-11-01

The decision criterion for the demarcation between foods and medicinal products in the EU is the significant "pharmacological action". Based on six examples of substances with ambivalent status, the benchmark dose (BMD) method is evaluated to provide a threshold for pharmacological action. Using significant dose-response models from literature clinical trial data or epidemiology, the BMD values were 63mg/day for caffeine, 5g/day for alcohol, 6mg/day for lovastatin, 769mg/day for glucosamine sulfate, 151mg/day for Ginkgo biloba extract, and 0.4mg/day for melatonin. The examples for caffeine and alcohol validate the approach because intake above BMD clearly exhibits pharmacological action. Nevertheless, due to uncertainties in dose-response modelling as well as the need for additional uncertainty factors to consider differences in sensitivity within the human population, a "borderline range" on the dose-response curve remains. "Pharmacological action" has proven to be not very well suited as binary decision criterion between foods and medicinal product. The European legislator should rethink the definition of medicinal products, as the current situation based on complicated case-by-case decisions on pharmacological action leads to an unregulated market flooded with potentially illegal food supplements. Copyright © 2012 Elsevier Inc. All rights reserved.

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

PubMed Central

Connors, S. P.; Gill, E. W.; Terrar, D. A.

1992-01-01

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1393293

Self-Regulation and Mechanisms of Action in Psychotherapy: A Theory-Based Translational Perspective

PubMed Central

Strauman, Timothy J.; Goetz, Elena L.; Detloff, Allison M.; MacDuffie, Katherine E.; Zaunmüller, Luisa; Lutz, Wolfgang

2012-01-01

Psychotherapy is a complex, multi-layered process with the potential to bring about changes at multiple levels of functioning, from the neurobiology of the brain to the individual’s role in the social world. Although studies of the mechanisms by which psychotherapy leads to change continue to appear, there remains much to be learned about how psychological interventions work. To guide explorations of how and for whom particular treatment approaches lead to change, researchers can rely on theory to identify potential loci for change and on translational research methods to integrate basic behavioral science and neuroscience with clinical science. In this article, we describe research linking individual differences in the self-regulation of personal goal pursuit with the etiology and treatment of mood disorders. The research draws upon regulatory focus theory as a model of self-regulation and on microintervention designs – controlled laboratory investigations of a specific therapeutic technique – to generate and test hypotheses about how psychological interventions can help to reverse maladaptive self-regulatory processes. PMID:23072383

Reduction of radiation-induced cell cycle blocks by caffeine does not necessarily lead to increased cell killing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Musk, S.R.

1991-03-01

The effect of caffeine upon the radiosensitivities of three human tumor lines was examined and correlated with its action upon the radiation-induced S-phase and G2-phase blocks. Caffeine was found to reduce at least partially the S-phase and G2-phase blocks in all the cell lines examined but potentiated cytotoxicity in only one of the three tumor lines. That reductions have been demonstrated to occur in the absence of increased cell killing provides supporting evidence for the hypothesis that reductions may not be causal in those cases when potentiation of radiation-induced cytotoxicity is observed in the presence of caffeine.

The integration and interpretation of pharmacogenomics - a comparative study between the United States of America and Europe: towards better health care.

PubMed

Bartlett, Mark J; Shephard, Elizabeth A

2016-06-01

The study of pharmacogenomics has, by harnessing sequence information from human genomes, the potential to lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. For this potential to be realized results need to be interpreted to the prescriber into a format which dictates an action. This mini review briefly describes the history, the regulatory environment, opinions towards, and implementation, integration and interpretation of pharmacogenomics in the United States of America and Europe. The article discusses also how interpretation of pharmacogenomics could move forward to better implementation in health care.

NASA's Planetary Defense Coordination Office at NASA HQ

NASA Astrophysics Data System (ADS)

Daou, D.; Johnson, L.; Fast, K. E.; Landis, R.; Friedensen, V. P.; Kelley, M.

2017-09-01

NASA and its partners maintain a watch for near-Earth objects (NEOs), asteroids and comets that pass close to the Earth, as part of an ongoing effort to discover, catalog, and characterize these bodies. The PDCO is responsible for: • Ensuring the early detection of potentially hazardous objects (PHOs) - asteroids and comets whose orbit are predicted to bring them within 0.05 Astronomical Units of Earth; and of a size large enough to reach Earth's surface - that is, greater than perhaps 30 to 50 meters; • Tracking and characterizing PHOs and issuing warnings about potential impacts; • Providing timely and accurate communications about PHOs; and • Performing as a lead coordination node in U.S. Government planning for response to an actual impact threat. The PDCO collaborates with other U.S. Government agencies, other national and international agencies, and professional and amateur astronomers around the world. The PDCO also is responsible for facilitating communications between the science community and the public should any potentially hazardous NEO be discovered. In addition, the PDCO works closely with the United Nations Office of Outer Space Affairs, its Committee on the Peaceful Uses of Outer Space, and its Action Team on Near Earth Objects (also known as Action Team 14). The PDCO is a leading member of the International Asteroid Warning Network (IAWN) and the Space Missions Planning Advisory Group (SMPAG), multinational endeavors recommended by the United Nations for an international response to the NEO impact hazard and established and operated by the spacecapable nations. The PDCO also communicates with the scientific community through channels such as NASA's Small Bodies Assessment Group (SBAG). In this talk, we will provide an update to the office's various efforts and new opportunities for partnerships in the continuous international effort for Planetary Defense.

NASA's Planetary Defense Coordination Office at NASA HQ

NASA Astrophysics Data System (ADS)

Daou, D.; Johnson, L.; Fast, K. E.; Landis, R.; Friedensen, V. P.; Kelley, M.

2017-12-01

NASA and its partners maintain a watch for near-Earth objects (NEOs), asteroids and comets that pass close to the Earth, as part of an ongoing effort to discover, catalog, and characterize these bodies. The PDCO is responsible for: Ensuring the early detection of potentially hazardous objects (PHOs) - asteroids and comets whose orbit are predicted to bring them within 0.05 Astronomical Units of Earth; and of a size large enough to reach Earth's surface - that is, greater than perhaps 30 to 50 meters; Tracking and characterizing PHOs and issuing warnings about potential impacts; Providing timely and accurate communications about PHOs; and Performing as a lead coordination node in U.S. Government planning for response to an actual impact threat. The PDCO collaborates with other U.S. Government agencies, other national and international agencies, and professional and amateur astronomers around the world. The PDCO also is responsible for facilitating communications between the science community and the public should any potentially hazardous NEO be discovered. In addition, the PDCO works closely with the United Nations Office of Outer Space Affairs, its Committee on the Peaceful Uses of Outer Space, and its Action Team on Near Earth Objects (also known as Action Team 14). The PDCO is a leading member of the International Asteroid Warning Network (IAWN) and the Space Missions Planning Advisory Group (SMPAG), multinational endeavors recommended by the United Nations for an international response to the NEO impact hazard and established and operated by the space-capable nations. The PDCO also communicates with the scientific community through channels such as NASA's Small Bodies Assessment Group (SBAG). In this talk, we will provide an update to the office's various efforts and new opportunities for partnerships in the continuous international effort for Planetary Defense.

40 CFR 300.815 - Administrative record file for a remedial action.

Code of Federal Regulations, 2010 CFR

2010-07-01

... SUBSTANCES POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.815... investigation phase. At such time, the lead agency shall publish in a major local newspaper of general circulation a notice of the availability of the administrative record file. (b) The lead agency shall provide...

Teaching physiology and the World Wide Web: electrochemistry and electrophysiology on the Internet.

PubMed

Dwyer, T M; Fleming, J; Randall, J E; Coleman, T G

1997-12-01

Students seek active learning experiences that can rapidly impart relevant information in the most convenient way possible. Computer-assisted education can now use the resources of the World Wide Web to convey the important characteristics of events as elemental as the physical properties of osmotically active particles in the cell and as complex as the nerve action potential or the integrative behavior of the intact organism. We have designed laboratory exercises that introduce first-year medical students to membrane and action potentials, as well as the more complex example of integrative physiology, using the dynamic properties of computer simulations. Two specific examples are presented. The first presents the physical laws that apply to osmotic, chemical, and electrical gradients, leading to the development of the concept of membrane potentials; this module concludes with the simulation of the ability of the sodium-potassium pump to establish chemical gradients and maintain cell volume. The second module simulates the action potential according to the Hodgkin-Huxley model, illustrating the concepts of threshold, inactivation, refractory period, and accommodation. Students can access these resources during the scheduled laboratories or on their own time via our Web site on the Internet (http./(/)phys-main.umsmed.edu) by using the World Wide Web protocol. Accurate version control is possible because one valid, but easily edited, copy of the labs exists at the Web site. A common graphical interface is possible through the use of the Hypertext mark-up language. Platform independence is possible through the logical and arithmetic calculations inherent to graphical browsers and the Javascript computer language. The initial success of this program indicates that medical education can be very effective both by the use of accurate simulations and by the existence of a universally accessible Internet resource.

A mathematical model of the electrophysiological alterations in rat ventricular myocytes in type-I diabetes.

PubMed

Pandit, Sandeep V; Giles, Wayne R; Demir, Semahat S

2003-02-01

Our mathematical model of the rat ventricular myocyte (Pandit et al., 2001) was utilized to explore the ionic mechanism(s) that underlie the altered electrophysiological characteristics associated with the short-term model of streptozotocin-induced, type-I diabetes. The simulations show that the observed reductions in the Ca(2+)-independent transient outward K(+) current (I(t)) and the steady-state outward K(+) current (I(ss)), along with slowed inactivation of the L-type Ca(2+) current (I(CaL)), can result in the prolongation of the action potential duration, a well-known experimental finding. In addition, the model demonstrates that the slowed reactivation kinetics of I(t) in diabetic myocytes can account for the more pronounced rate-dependent action potential duration prolongation in diabetes, and that a decrease in the electrogenic Na(+)-K(+) pump current (I(NaK)) results in a small depolarization in the resting membrane potential (V(rest)). This depolarization reduces the availability of the Na(+) channels (I(Na)), thereby resulting in a slower upstroke (dV/dt(max)) of the diabetic action potential. Additional simulations suggest that a reduction in the magnitude of I(CaL), in combination with impaired sarcoplasmic reticulum uptake can lead to a decreased sarcoplasmic reticulum Ca(2+) load. These factors contribute to characteristic abnormal [Ca(2+)](i) homeostasis (reduced peak systolic value and rate of decay) in myocytes from diabetic animals. In combination, these simulation results provide novel information and integrative insights concerning plausible ionic mechanisms for the observed changes in cardiac repolarization and excitation-contraction coupling in rat ventricular myocytes in the setting of streptozotocin-induced, type-I diabetes.

Alcohol modulation of BK channel gating depends on β subunit composition

PubMed Central

Kuntamallappanavar, Guruprasad

2016-01-01

In most mammalian tissues, Ca2+i/voltage-gated, large conductance K+ (BK) channels consist of channel-forming slo1 and auxiliary (β1–β4) subunits. When Ca2+i (3–20 µM) reaches the vicinity of BK channels and increases their activity at physiological voltages, β1- and β4-containing BK channels are, respectively, inhibited and potentiated by intoxicating levels of ethanol (50 mM). Previous studies using different slo1s, lipid environments, and Ca2+i concentrations—all determinants of the BK response to ethanol—made it impossible to determine the specific contribution of β subunits to ethanol action on BK activity. Furthermore, these studies measured ethanol action on ionic current under a limited range of stimuli, rendering no information on the gating processes targeted by alcohol and their regulation by βs. Here, we used identical experimental conditions to obtain single-channel and macroscopic currents of the same slo1 channel (“cbv1” from rat cerebral artery myocytes) in the presence and absence of 50 mM ethanol. First, we assessed the role five different β subunits (1,2,2-IR, 3-variant d, and 4) in ethanol action on channel function. Thus, two phenotypes were identified: (1) ethanol potentiated cbv1-, cbv1+β3-, and cbv1+β4-mediated currents at low Ca2+i while inhibiting current at high Ca2+i, the potentiation–inhibition crossover occurring at 20 µM Ca2+i; (2) for cbv1+β1, cbv1+wt β2, and cbv1+β2-IR, this crossover was shifted to ∼3 µM Ca2+i. Second, applying Horrigan–Aldrich gating analysis on both phenotypes, we show that ethanol fails to modify intrinsic gating and the voltage-dependent parameters under examination. For cbv1, however, ethanol (a) drastically increases the channel’s apparent Ca2+ affinity (nine-times decrease in Kd) and (b) very mildly decreases allosteric coupling between Ca2+ binding and channel opening (C). The decreased Kd leads to increased channel activity. For cbv1+β1, ethanol (a) also decreases Kd, yet this decrease (two times) is much smaller than that of cbv1; (b) reduces C; and (c) decreases coupling between Ca2+ binding and voltage sensing (parameter E). Decreased allosteric coupling leads to diminished BK activity. Thus, we have identified critical gating modifications that lead to the differential actions of ethanol on slo1 with and without different β subunits. PMID:27799321

Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location.

PubMed

Crago, Patrick E; Makowski, Nathaniel S

2014-10-01

Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic interventions involving motor or sensory stimulation.

Simulation of action potential propagation in plants.

PubMed

Sukhov, Vladimir; Nerush, Vladimir; Orlova, Lyubov; Vodeneev, Vladimir

2011-12-21

Action potential is considered to be one of the primary responses of a plant to action of various environmental factors. Understanding plant action potential propagation mechanisms requires experimental investigation and simulation; however, a detailed mathematical model of plant electrical signal transmission is absent. Here, the mathematical model of action potential propagation in plants has been worked out. The model is a two-dimensional system of excitable cells; each of them is electrically coupled with four neighboring ones. Ion diffusion between excitable cell apoplast areas is also taken into account. The action potential generation in a single cell has been described on the basis of our previous model. The model simulates active and passive signal transmission well enough. It has been used to analyze theoretically the influence of cell to cell electrical conductivity and H(+)-ATPase activity on the signal transmission in plants. An increase in cell to cell electrical conductivity has been shown to stimulate an increase in the length constant, the action potential propagation velocity and the temperature threshold, while the membrane potential threshold being weakly changed. The growth of H(+)-ATPase activity has been found to induce the increase of temperature and membrane potential thresholds and the reduction of the length constant and the action potential propagation velocity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Action-projection in Japanese conversation: topic particles wa, mo, and tte for triggering categorization activities

PubMed Central

Tanaka, Hiroko

2015-01-01

Conversation analytic work has revealed how anticipatory completions and preemptive actions can offer invaluable glimpses into the cognitive, contextual, grammatical, and temporal bases of projectability in turn-taking, by virtue of their potential not only as a display of participants' online prediction of roughly what it might take to complete a turn-in-progress but also to plan the next move. While the predicate-final word order and the incremental transformability of turns in Japanese generally lead to delayed projectability of turn-endings, this may be partially offset by the capacity of certain postpositional particles to trigger and propel prospective action trajectories. This article engages in a case study of the topic particle wa (and related particles mo and tte), by demonstrating how its grammatical affordances, the categorization activities, and cognitive processing it can set in motion, coupled with the immediate contextual, and temporal-productional features may coalesce to a point of critical mass, thereby enhancing the projectability of the not-yet-produced trajectory of the current turn. The discussion attempts to contribute to recent debates on ways language-specific lexicogrammatical resources are deeply interlinked with the types of opportunities that are provided for social action. PMID:26379565

'This is ordinary behaviour': categorization and culpability in Hamas leaders' accounts of the Palestinian/Israeli conflict.

PubMed

McKinlay, Andy; McVittie, Chris; Sambaraju, Rahul

2012-12-01

The present paper examines the talk of three senior figures from the Palestinian Hamas political movement. Data are drawn from a series of journalistic interviews that were conducted in the months leading up to the invasion of Gaza by Israel in December 2007. Using membership categorization analysis, we explore the membership categories and category-bound attributes that interviewers use in questions about responsibility for potentially culpable actions and the ways that these are taken up, challenged, or reworked by interviewees in presenting their own versions. The analytic findings show that interviewers deploy categories bound up with terrorism while interviewees develop alternative categorizations of resistance. Interviewers construct Palestinians as victims of Hamas' actions while interviewees construct them as victims of Israeli aggression and international indifference. In warranting these alternative constructions, the interviewees contrast current behaviours of the international community with those of the past and align current Palestinian actions with those previously taken by Western nations in resisting illegitimate occupations. Through these descriptions of categories and actions, the interviewees attribute to the wider international community responsibility for addressing the events of the ongoing conflict. ©2011 The British Psychological Society.

Distribution functions for orbits trapped at the resonances in the Galactic disc

NASA Astrophysics Data System (ADS)

Monari, G.

2017-12-01

The present-day response of a Galactic disc stellar population to a non-axisymmetric perturbation of the potential has previously been computed through perturbation theory within the phase-space coordinates of the unperturbed axisymmetric system. Such an Eulerian linearized treatment however leads to singularities at resonances, which prevent quantitative comparisons with data. Monari et al. manage to capture the behaviour of the distribution function (DF) at a resonance in a Lagrangian approach, by averaging the Hamiltonian over fast angle variables and re-expressing the DF in terms of a new set of canonical actions and angles variables valid in the resonant region. They then follow the prescription of Binney (2016), assigning to the resonant DF the time average along the orbits of the axisymmetric DF expressed in the new set of actions and angles. This boils down to phase-mixing the DF in terms of the new angles, such that the DF for trapped orbits only depends on the new set of actions. This opens the way to quantitatively fitting the effects of the bar and spirals to Gaia data in terms of distribution functions in action space.

Cortical pyramidal cells as non-linear oscillators: experiment and spike-generation theory.

PubMed

Brumberg, Joshua C; Gutkin, Boris S

2007-09-26

Cortical neurons are capable of generating trains of action potentials in response to current injections. These discharges can take different forms, e.g., repetitive firing that adapts during the period of current injection or bursting behaviors. We have used a combined experimental and computational approach to characterize the dynamics leading to action potential responses in single neurons. Specifically we investigated the origin of complex firing patterns in response to sinusoidal current injections. Using a reduced model, the theta-neuron, alongside recordings from cortical pyramidal cells we show that both real and simulated neurons show phase-locking to sine wave stimuli up to a critical frequency, above which period skipping and 1-to-x phase-locking occurs. The locking behavior follows a complex "devil's staircase" phenomena, where locked modes are interleaved with irregular firing. We further show that the critical frequency depends on the time scale of spike generation and on the level of spike frequency adaptation. These results suggest that phase-locking of neuronal responses to complex input patterns can be explained by basic properties of the spike-generating machinery.

Anterior Cingulate Cortex Instigates Adaptive Switches in Choice by Integrating Immediate and Delayed Components of Value in Ventromedial Prefrontal Cortex

PubMed Central

Guitart-Masip, Marc; Kurth-Nelson, Zeb; Dolan, Raymond J.

2014-01-01

Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action. PMID:24573291

The therapeutic potential of iron-targeting gallium compounds in human disease: From basic research to clinical application.

PubMed

Chitambar, Christopher R

2017-01-01

Gallium, group IIIa metal, shares certain chemical characteristics with iron which enable it to function as an iron mimetic that can disrupt iron-dependent tumor cell growth. Gallium may also display antimicrobial activity by disrupting iron homeostasis in certain bacteria and fungi. Gallium's action on iron homeostasis leads to inhibition of ribonucleotide reductase, mitochondrial function, and changes in proteins of iron transport and storage. In addition, gallium induces an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Early clinical trials evaluated the efficacy of the simple gallium salts, gallium nitrate and gallium chloride. However, newer gallium-ligands such as Tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate have been developed and are undergoing clinical evaluation. Additional gallium-ligands that demonstrate antitumor activity in preclinical studies have emerged. Their mechanisms of action and their spectrum of antitumor activity may extend beyond the earlier generations of gallium compounds and warrant further investigation. This review will focus on the evolution and potential of gallium-based therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Secondary metabolites from three Florida sponges with antidepressant activity.

PubMed

Kochanowska, Anna J; Rao, Karumanchi V; Childress, Suzanne; El-Alfy, Abir; Matsumoto, Rae R; Kelly, Michelle; Stewart, Gina S; Sufka, Kenneth J; Hamann, Mark T

2008-02-01

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.

Ergodic properties of spiking neuronal networks with delayed interactions

NASA Astrophysics Data System (ADS)

Palmigiano, Agostina; Wolf, Fred

The dynamical stability of neuronal networks, and the possibility of chaotic dynamics in the brain pose profound questions to the mechanisms underlying perception. Here we advance on the tractability of large neuronal networks of exactly solvable neuronal models with delayed pulse-coupled interactions. Pulse coupled delayed systems with an infinite dimensional phase space can be studied in equivalent systems of fixed and finite degrees of freedom by introducing a delayer variable for each neuron. A Jacobian of the equivalent system can be analytically obtained, and numerically evaluated. We find that depending on the action potential onset rapidness and the level of heterogeneities, the asynchronous irregular regime characteristic of balanced state networks loses stability with increasing delays to either a slow synchronous irregular or a fast synchronous irregular state. In networks of neurons with slow action potential onset, the transition to collective oscillations leads to an increase of the exponential rate of divergence of nearby trajectories and of the entropy production rate of the chaotic dynamics. The attractor dimension, instead of increasing linearly with increasing delay as reported in many other studies, decreases until eventually the network reaches full synchrony

Nonlinear physics of electrical wave propagation in the heart: a review

NASA Astrophysics Data System (ADS)

Alonso, Sergio; Bär, Markus; Echebarria, Blas

2016-09-01

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that is triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media with applications to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact for cardiac arrhythmias.

Anterior cingulate cortex instigates adaptive switches in choice by integrating immediate and delayed components of value in ventromedial prefrontal cortex.

PubMed

Economides, Marcos; Guitart-Masip, Marc; Kurth-Nelson, Zeb; Dolan, Raymond J

2014-02-26

Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action.

[Loudness optimized registration of compound action potential in cochlear implant recipients].

PubMed

Berger, Klaus; Hocke, Thomas; Hessel, Horst

2017-11-01

Background Postoperative measurements of compound action potentials are not always possible due to the insufficient acceptance of the CI-recipients. This study investigated the impact of different parameters on the acceptance of the measurements. Methods Compound action potentials of 16 CI recipients were measured with different pulse-widths. Recipients performed a loudness rating at the potential thresholds with the different sequences. Results Compound action potentials obtained with higher pulse-widths were rated softer than those obtained with smaller pulse-widths. Conclusions Compound action potentials measured with higher pulse-widths generate a gap between loudest acceptable presentation level and potential threshold. This gap contributes to a higher acceptance of postoperative measurements. Georg Thieme Verlag KG Stuttgart · New York.

Inducing repetitive action potential firing in neurons via synthesized photoresponsive nanoscale cellular prostheses.

PubMed

Lu, Siyuan; Madhukar, Anupam

2013-02-01

Recently we reported an analysis that examined the potential of synthesized photovoltaic functional abiotic nanosystems (PVFANs) to modulate membrane potential and activate action potential firing in neurons. Here we extend the analysis to delineate the requirements on the electronic energy levels and the attendant photophysical properties of the PVFANs to induce repetitive action potential under continuous light, a capability essential for the proposed potential application of PVFANs as retinal cellular prostheses to compensate for loss of photoreceptors. We find that repetitive action potential firing demands two basic characteristics in the electronic response of the PVFANs: an exponential dependence of the PVFAN excited state decay rate on the membrane potential and a three-state system such that, following photon absorption, the electron decay from the excited state to the ground state is via intermediate state(s) whose lifetime is comparable to the refractory time following an action potential. In this study, the potential of synthetic photovoltaic functional abiotic nanosystems (PVFANs) is examined under continuous light to modulate membrane potential and activate action potential firing in neurons with the proposed potential application of PVFANs as retinal cellular prostheses. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of K(+) channel openers on spontaneous action potentials in detrusor smooth muscle of the guinea-pig urinary bladder.

PubMed

Takagi, Hiroaki; Hashitani, Hikaru

2016-10-15

The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM). A higher concentration of NS1619 (30μM) hyperpolarized the membrane and abolished action potential firing. NS309 (10μM) and SKA31 (100μM), small conductance Ca(2+)-activated K(+) (SK) channel openers, dramatically increased the duration of the after-hyperpolarization and then abolished action potential firing in an apamin (100nM)-sensitive manner. Flupirtine (10μM), a Kv7 channel opener, inhibited action potential firing without hyperpolarizing the membrane in a manner sensitive to XE991 (10μM), a Kv7 channel blocker. BRL37344 (10μM), a β3-adrenceptor agonist, or rolipram (10nM), a phosphodiesterase 4 inhibitor, also inhibited action potential firing. A higher concentration of rolipram (100nM) hyperpolarized the DSM and abolished the action potentials. IbTX (100nM) prevented the rolipram-induced blockade of action potentials but not the hyperpolarization. BK and Kv7 channels appear to predominantly contribute to the stabilization of DSM excitability. Spare SK channels could be pharmacologically activated to suppress DSM excitability. BK channels appear to be involved in the cyclic AMP-induced inhibition of action potentials but not the membrane hyperpolarization. Copyright © 2016 Elsevier B.V. All rights reserved.

Dissemination and implementation sciences in pharmacy: A call to action for professional organizations.

PubMed

Seaton, Terry L

There is a substantial gap between the generation of new knowledge and its widespread incorporation into routine clinical practice, including the medication use process. Principles of dissemination and implementation sciences, if fully embraced by clinicians and researchers, have the potential of improving healthcare effectiveness, efficiency, quality, and safety. This commentary is a call to action for member-driven professional organizations in pharmacy to serve their members and the profession by proactively and strategically leading efforts to develop pharmacist's abilities to incorporate principles of dissemination and implementation sciences into their practice. Additionally, these organizations should provide meaningful support for dissemination and implementation research that hastens the adoption, promotes intervention fidelity, and demonstrates the scaling and sustaining of evidence-based practices to optimize patient care delivery and medication therapy outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

Insulin-Like Growth Factor System in Cancer: Novel Targeted Therapies

PubMed Central

Brahmkhatri, Varsha P.; Prasanna, Chinmayi; Atreya, Hanudatta S.

2015-01-01

Insulin-like growth factors (IGFs) are essential for growth and survival that suppress apoptosis and promote cell cycle progression, angiogenesis, and metastatic activities in various cancers. The IGFs actions are mediated through the IGF-1 receptor that is involved in cell transformation induced by tumour. These effects depend on the bioavailability of IGFs, which is regulated by IGF binding proteins (IGFBPs). We describe here the role of the IGF system in cancer, proposing new strategies targeting this system. We have attempted to expand the general viewpoint on IGF-1R, its inhibitors, potential limitations of IGF-1R, antibodies and tyrosine kinase inhibitors, and IGFBP actions. This review discusses the emerging view that blocking IGF via IGFBP is a better option than blocking IGF receptors. This can lead to the development of novel cancer therapies. PMID:25866791

Proline-rich antimicrobial peptides: converging to a non-lytic mechanism of action.

PubMed

Scocchi, Marco; Tossi, Alessandro; Gennaro, Renato

2011-07-01

Proline-rich antimicrobial peptides are a group of cationic host defense peptides of vertebrates and invertebrates characterized by a high content of proline residues, often associated with arginine residues in repeated motifs. Those isolated from some mammalian and insect species, although not evolutionarily related, use a similar mechanism to selectively kill Gram-negative bacteria, with a low toxicity to animals. Unlike other types of antimicrobial peptides, their mode of action does not involve the lysis of bacterial membranes but entails penetration into susceptible cells, where they then act intracellularly. Some aspects of the transport system and cytoplasmic targets have been elucidated. These features make them attractive both as anti-infective lead compounds and as a new class of potential cell-penetrating peptides capable of internalising membrane-impermeant drugs into both bacterial and eukaryotic cells.

Hazard and Risk of Glacial Lake Outburst Floods in the Nepal Himalayas

NASA Astrophysics Data System (ADS)

Rounce, David; McKinney, Daene

2016-04-01

As the climate changes and glaciers continue to melt, the number of glacial lakes and the size of these lakes is rapidly increasing. These glacial lakes are contained by terminal moraines composed of debris, soil, and sometimes ice, which are susceptible to fail catastrophically and cause a glacial lake outburst flood (GLOF). Understanding the hazard and risk associated with these lakes is important for downstream communities and other stakeholders, e.g., hydroelectric companies. Unfortunately, existing methods that are used to assess GLOF hazards yield conflicting classifications, which leads to confusion amongst the stakeholders who these studies are meant to assist. This study assesses existing methods on potentially dangerous glacial lakes in Nepal and uses these methods to develop an objective and holistic risk & action framework that may be used to assist and prioritize risk-mitigation actions.

Imaging Action Potential in Single Mammalian Neurons by Tracking the Accompanying Sub-Nanometer Mechanical Motion.

PubMed

Yang, Yunze; Liu, Xian-Wei; Wang, Hui; Yu, Hui; Guan, Yan; Wang, Shaopeng; Tao, Nongjian

2018-03-28

Action potentials in neurons have been studied traditionally by intracellular electrophysiological recordings and more recently by the fluorescence detection methods. Here we describe a label-free optical imaging method that can measure mechanical motion in single cells with a sub-nanometer detection limit. Using the method, we have observed sub-nanometer mechanical motion accompanying the action potential in single mammalian neurons by averaging the repeated action potential spikes. The shape and width of the transient displacement are similar to those of the electrically recorded action potential, but the amplitude varies from neuron to neuron, and from one region of a neuron to another, ranging from 0.2-0.4 nm. The work indicates that action potentials may be studied noninvasively in single mammalian neurons by label-free imaging of the accompanying sub-nanometer mechanical motion.

Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

PubMed

Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

2017-11-01

Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Novel nicotine analogues with potential anti-mycobacterial activity.

PubMed

Gandhi, Paresh T; Athmaram, Thimmasandra Narayanappa; Arunkumar, Gundaiah Ramesh

2016-04-15

Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Latent Toxoplasma gondii infection leads to improved action control.

PubMed

Stock, Ann-Kathrin; Heintschel von Heinegg, Evelyn; Köhling, Hedda-Luise; Beste, Christian

2014-03-01

The parasite Toxoplasma gondii has been found to manipulate the behavior of its secondary hosts to increase its own dissemination which is commonly believed to be to the detriment of the host (manipulation hypothesis). The manipulation correlates with an up-regulation of dopaminergic neurotransmission. In humans, different pathologies have been associated with T. gondii infections but most latently infected humans do not seem to display overt impairments. Since a dopamine plus does not necessarily bear exclusively negative consequences in humans, we investigated potential positive consequences of latent toxoplasmosis (and the presumed boosting of dopaminergic neurotransmission) on human cognition and behavior. For this purpose, we focused on action cascading which has been shown to be modulated by dopamine. Based on behavioral and neurophysiological (EEG) data obtained by means of a stop-change paradigm, we were able to demonstrate that healthy young humans can actually benefit from latent T. gondii infection as regards their performance in this task (as indicated by faster response times and a smaller P3 component). The data shows that a latent infection which is assumed to affect the dopaminergic system can lead to paradoxical improvements of cognitive control processes in humans. Copyright © 2013 Elsevier Inc. All rights reserved.

[Can overestimating one's own capacities of action lead to fall? A study on the perception of affordance in the elderly].

PubMed

Luyat, Marion; Domino, Delphine; Noël, Myriam

2008-12-01

Falls are frequent in the elderly and account for medical complications and loss of autonomy. Affordance, a concept proposed by Gibson, can help to understand a possible cause of falls. An affordance is defined as a potentiality of action offered by the environment in relation with both the properties of this environment and the properties of the organism. Most of our daily activities reflect a perfect adjustment between the perception of these potentialities of action and our actual action abilities. In other words, we correctly perceive affordances. However, in the elderly, postural abilities are reduced and equilibration is more unstable. Thus, some falls could result from a misperception of the affordances of posturability. The aim of our study was to test the hypothesis that cognitive overestimation of real postural abilities in the elderly may cause falls. There would be a gap between what the old subjects believe to be able to do and what they actually can do. Fifteen young adults (mean age = 24 years) and fifteen older adults (mean age = 72 years) had to judge if they were able to stand upright on an inclined surface. The exploration of the inclined surface was made in two conditions: visually and also by haptics (without vision with a cane). In a second part, we measured their real postural stance on the inclined surface. The results show that the perceptual judgments were not different among old and young people. However, as expected, the old subjects had lower postural boundaries than the younger. They could stand on lower inclinations of the surface. These results show an involution of the perception of the affordances in aging. They support the hypothesis of a cognitive overestimation of action abilities in the elderly, possibly due to a difficulty to actualize the new limits for action.

Synaptic depolarization is more effective than back-propagating action potentials during induction of associative long-term potentiation in hippocampal pyramidal neurons.

PubMed

Hardie, Jason; Spruston, Nelson

2009-03-11

Long-term potentiation (LTP) requires postsynaptic depolarization that can result from EPSPs paired with action potentials or larger EPSPs that trigger dendritic spikes. We explored the relative contribution of these sources of depolarization to LTP induction during synaptically driven action potential firing in hippocampal CA1 pyramidal neurons. Pairing of a weak test input with a strong input resulted in large LTP (approximately 75% increase) when the weak and strong inputs were both located in the apical dendrites. This form of LTP did not require somatic action potentials. When the strong input was located in the basal dendrites, the resulting LTP was smaller (< or =25% increase). Pairing the test input with somatically evoked action potentials mimicked this form of LTP. Thus, back-propagating action potentials may contribute to modest LTP, but local synaptic depolarization and/or dendritic spikes mediate a stronger form of LTP that requires spatial proximity of the associated synaptic inputs.

Cardiac action potential imaging

NASA Astrophysics Data System (ADS)

Tian, Qinghai; Lipp, Peter; Kaestner, Lars

2013-06-01

Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

[Mechanism of action and effects of corticoids in asthma].

PubMed

Lacronique, J; Russo-Marie, F; Marsac, J

1989-01-01

The value of oral or inhaled glucocorticoids (GCS) in asthma is well recognized. Their use has remained empirical for a long time. However, some progress has been achieved recently in the understanding of their general mode of action and of their bronchial effects suggesting that in the near future ther may be some new therapeutic perspectives. The fundamental action of GCS involves a close intracellular interaction between the specific glucocorticoid hormone receptor and the cellular genome which results in the activation of the genes coding the proteins responsible for the phenotypic response of the cell and thus for their biological action. The place of the extra-genomic mechanisms remains ill understood. The immunomodulating action of GCS is difficult to dissociate from their anti-inflammatory and anti-allergic effects which seem to predominate in asthma. They inhibit all stages of the inflammatory reaction in acting on the key mediators of the inflammatory response, the pharmacologically active lipids (LPA: prostaglandins, leukotrienes, PAF-acether) which are a result of the catabolism of arachidonic acid which occurs during the course of membrane activation. The phospholipid A2 (PLA2), a membrane enzyme responsible for the splitting of the phospholipids in the presence of calcium and leading to the liberation of LPA is the driving force of the reaction in such a way that the products of the nuclear activation subsequently reactivated. GCS is considered as a natural modulator of inflammation, inducing the synthesis of lipocortin, an inhibitory protein of PLA2, which explains the blockage in the generation of LPA and thus the inflammatory reaction. The regulation of the activity of these or of the lipocortin seems to lead to the intervention of the phosphorylation. But numerous questions remain concerning the precise action of PLO2, the existence of endogenous lipocortin, their secretion and their extra-cellular action. In spite of these unknown facts it is not impossible to envisage a clinical potential for lipocortin, once sequenced and produced, when the pharmacological and immunological problems have been surmounted. In asthma the effect of GCS essentially involve: the inhibition of all the bronchial components of inflammation: the synthesis, liberation and peripheral action of the mediators; the oedema and mucous congestion.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessing anesthetic activity through modulation of the membrane dipole potential.

PubMed

Davis, Benjamin Michael; Brenton, Jonathan; Davis, Sterenn; Shamsher, Ehtesham; Sisa, Claudia; Grgic, Ljuban; Cordeiro, M Francesca

2017-10-01

There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient's response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F 3 ), but not the structurally similar noninducer, 1,2-dichlorohexafluorocyclobutane (F 6 ), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

A simple model for the generation of the vestibular evoked myogenic potential (VEMP).

PubMed

Wit, Hero P; Kingma, Charlotte M

2006-06-01

To describe the mechanism by which the vestibular evoked myogenic potential is generated. Vestibular evoked myogenic potential generation is modeled by adding a large number of muscle motor unit action potentials. These action potentials occur randomly in time along a 100 ms long time axis. But because between approximately 15 and 20 ms after a loud short sound stimulus (almost) no action potentials are generated during VEMP measurements in human subjects, no action potentials are present in the model during this time. The evoked potential is the result of the lack of amplitude cancellation in the averaged surface electromyogram at the edges of this 5 ms long time interval. The relatively simple model describes generation and some properties of the vestibular evoked myogenic potential very well. It is shown that, in contrast with other evoked potentials (BAEPs, VERs), the vestibular evoked myogenic potential is the result of an interruption of activity and not that of summed synchronized neural action potentials.

Developmental excitatory-to-inhibitory GABA polarity switch is delayed in Ts65Dn mice, a genetic model of Down syndrome.

PubMed

Lysenko, Larisa V; Kim, Jeesun; Madamba, Francisco; Tyrtyshnaia, Anna A; Ruparelia, Aarti; Kleschevnikov, Alexander M

2018-07-01

Down syndrome (DS) is the most frequent genetic cause of developmental abnormalities leading to intellectual disability. One notable phenomenon affecting the formation of nascent neural circuits during late developmental periods is developmental switch of GABA action from depolarizing to hyperpolarizing mode. We examined properties of this switch in DS using primary cultures and acute hippocampal slices from Ts65Dn mice, a genetic model of DS. Cultures of DIV3-DIV13 Ts65Dn and control normosomic (2 N) neurons were loaded with FURA-2 AM, and GABA action was assessed using local applications. In 2 N cultures, the number of GABA-activated cells dropped from ~100% to 20% between postnatal days 3-13 (P3-P13) reflecting the switch in GABA action polarity. In Ts65Dn cultures, the timing of this switch was delayed by 2-3 days. Next, microelectrode recordings of multi-unit activity (MUA) were performed in CA3 slices during bath application of the GABA A agonist isoguvacine. MUA frequency was increased in P8-P12 and reduced in P14-P22 slices reflecting the switch of GABA action from excitatory to inhibitory mode. The timing of this switch was delayed in Ts65Dn by approximately 2 days. Finally, frequency of giant depolarizing potentials (GDPs), a form of primordial neural activity, was significantly increased in slices from Ts65Dn pups at P12 and P14. These experimental evidences show that GABA action polarity switch is delayed in Ts65Dn model of DS, and that these changes lead to a delay in maturation of nascent neural circuits. These alterations may affect properties of neural circuits in adult animals and, therefore, represent a prospective target for pharmacotherapy of cognitive impairment in DS. Copyright © 2018 Elsevier Inc. All rights reserved.

Structural pierce into molecular mechanism underlying Clostridium perfringens Epsilon toxin function.

PubMed

Khalili, Saeed; Jahangiri, Abolfazl; Hashemi, Zahra Sadat; Khalesi, Bahman; Mard-Soltani, Maysam; Amani, Jafar

2017-03-01

Epsilon toxin of the Clostridium perfringens garnered a lot of attention due to its potential for toxicity in humans, extreme potency for cytotoxicity in mice and lack of any approved therapeutics prescribed for human. However, the intricacies of the Epsilon toxin action mechanism are yet to be understood. In this regard, various in silico tools have been exploited to model and refine the 3D structure of the toxin and its two receptors. The receptor proteins were embedded into designed lipid membranes within an aqueous and ionized environment. Thereafter, the modeled structures subjected to series of consecutive molecular dynamics runs to achieve the most natural like coordination for each model. Ultimately, protein-protein interaction analyses were performed to understand the probable action mechanism. The obtained results successfully confirmed the accuracy of employed methods to achieve high quality models for the toxin and its receptors within their lipid bilayers. Molecular dynamics analyses lead the structures to a more native like coordination. Moreover, the results of previous empirical studies were confirmed, while new insights for action mechanisms including the detailed roles of Hepatitis A virus cellular receptor 1 (HAVCR1) and Myelin and lymphocyte protein (MAL) proteins were achieved. In light of previous and our observations, we suggested novel models which elucidated the existing interplay between potential players of Epsilon toxin action mechanism with detailed structural evidences. These models would pave the way to have more robust understanding of the Epsilon toxin biology, more precise vaccine construction and more successful drug (inhibitor) design. Copyright © 2017 Elsevier Ltd. All rights reserved.

A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates.

PubMed

Mahajan, Aman; Shiferaw, Yohannes; Sato, Daisuke; Baher, Ali; Olcese, Riccardo; Xie, Lai-Hua; Yang, Ming-Jim; Chen, Peng-Sheng; Restrepo, Juan G; Karma, Alain; Garfinkel, Alan; Qu, Zhilin; Weiss, James N

2008-01-15

Mathematical modeling of the cardiac action potential has proven to be a powerful tool for illuminating various aspects of cardiac function, including cardiac arrhythmias. However, no currently available detailed action potential model accurately reproduces the dynamics of the cardiac action potential and intracellular calcium (Ca(i)) cycling at rapid heart rates relevant to ventricular tachycardia and fibrillation. The aim of this study was to develop such a model. Using an existing rabbit ventricular action potential model, we modified the L-type calcium (Ca) current (I(Ca,L)) and Ca(i) cycling formulations based on new experimental patch-clamp data obtained in isolated rabbit ventricular myocytes, using the perforated patch configuration at 35-37 degrees C. Incorporating a minimal seven-state Markovian model of I(Ca,L) that reproduced Ca- and voltage-dependent kinetics in combination with our previously published dynamic Ca(i) cycling model, the new model replicates experimentally observed action potential duration and Ca(i) transient alternans at rapid heart rates, and accurately reproduces experimental action potential duration restitution curves obtained by either dynamic or S1S2 pacing.

Typical gray matter axons in mammalian brain fail to conduct action potentials faithfully at fever-like temperatures.

PubMed

Pekala, Dobromila; Szkudlarek, Hanna; Raastad, Morten

2016-10-01

We studied the ability of typical unmyelinated cortical axons to conduct action potentials at fever-like temperatures because fever often gives CNS symptoms. We investigated such axons in cerebellar and hippocampal slices from 10 to 25 days old rats at temperatures between 30 and 43°C. By recording with two electrodes along axonal pathways, we confirmed that the axons were able to initiate action potentials, but at temperatures >39°C, the propagation of the action potentials to a more distal recording site was reduced. This temperature-sensitive conduction may be specific for the very thin unmyelinated axons because similar recordings from myelinated CNS axons did not show conduction failures. We found that the conduction fidelity improved with 1 mmol/L TEA in the bath, probably due to block of voltage-sensitive potassium channels responsible for the fast repolarization of action potentials. Furthermore, by recording electrically activated antidromic action potentials from the soma of cerebellar granule cells, we showed that the axons failed less if they were triggered 10-30 msec after another action potential. This was because individual action potentials were followed by a depolarizing after-potential, of constant amplitude and shape, which facilitated conduction of the following action potentials. The temperature-sensitive conduction failures above, but not below, normal body temperature, and the failure-reducing effect of the spike's depolarizing after-potential, are two intrinsic mechanisms in normal gray matter axons that may help us understand how the hyperthermic brain functions. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Silver enhances antibiotic activity against gram-negative bacteria.

PubMed

Morones-Ramirez, J Ruben; Winkler, Jonathan A; Spina, Catherine S; Collins, James J

2013-06-19

A declining pipeline of clinically useful antibiotics has made it imperative to develop more effective antimicrobial therapies, particularly against difficult-to-treat Gram-negative pathogens. Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. We show that silver disrupts multiple bacterial cellular processes, including disulfide bond formation, metabolism, and iron homeostasis. These changes lead to increased production of reactive oxygen species and increased membrane permeability of Gram-negative bacteria that can potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different metabolic states, as well as restore antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of urinary tract infection that the ability of silver to induce oxidative stress can be harnessed to potentiate antibiotic activity. Additionally, we demonstrate in vitro and in two different mouse models of peritonitis that silver sensitizes Gram-negative bacteria to the Gram-positive-specific antibiotic vancomycin, thereby expanding the antibacterial spectrum of this drug. Finally, we used silver and antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro and in a mouse biofilm infection model that silver can enhance antibacterial action against bacteria that produce biofilms. This work shows that silver can be used to enhance the action of existing antibiotics against Gram-negative bacteria, thus strengthening the antibiotic arsenal for fighting bacterial infections.

Potential Alleviation of Chlorella vulgaris and Zingiber officinale on Lead-Induced Testicular Toxicity: an Ultrastructural Study.

PubMed

Mustafa, Hesham Noaman

2015-01-01

Natural, products were studied to combat reproductive alterations of lead. The current work aimed to disclose the efficacy of Chlorella vulgaris and Zingiber officinale to alleviate lead acetate induced toxicity. Sixty adult male Wistar rats were distributed into four groups. Group 1 was considered control, group 2 received 200 mg/l PbAc water, group 3 received 50 mg/kg/rat of C. vulgaris extract and 200 mg/l PbAc water, and group 4 received 100 mg/kg/rat of Z. officinale and 200 mg/l PbAc water for 90 days. Testis samples were subjected to ultrastructural examination. It was observed that PbAc caused degenerative alterations in the spermatogenic series in many tubules, with a loss of germ cells and vacuoles inside the cytoplasm and between the germ cells. Mitochondria exhibited ballooning, with lost cristae and widening of the interstitial tissue, while nuclear envelopes of primary spermatocytes were broken up, and axonemes of the mid-pieces of the sperms were distorted. With the treatment with C. vulgaris or Z. officinale, there were noticeable improvements in these modifications. It was concluded that both C. vulgaris and Z. officinale represent convincing medicinal components that may be used to ameliorate testicular toxicity in those exposed to lead in daily life with superior potentials revealed by C. vulgaris due to its chelating action.

Real-time detection of antibiotic activity by measuring nanometer-scale bacterial deformation

NASA Astrophysics Data System (ADS)

Iriya, Rafael; Syal, Karan; Jing, Wenwen; Mo, Manni; Yu, Hui; Haydel, Shelley E.; Wang, Shaopeng; Tao, Nongjian

2017-12-01

Diagnosing antibiotic-resistant bacteria currently requires sensitive detection of phenotypic changes associated with antibiotic action on bacteria. Here, we present an optical imaging-based approach to quantify bacterial membrane deformation as a phenotypic feature in real-time with a nanometer scale (˜9 nm) detection limit. Using this approach, we found two types of antibiotic-induced membrane deformations in different bacterial strains: polymyxin B induced relatively uniform spatial deformation of Escherichia coli O157:H7 cells leading to change in cellular volume and ampicillin-induced localized spatial deformation leading to the formation of bulges or protrusions on uropathogenic E. coli CFT073 cells. We anticipate that the approach will contribute to understanding of antibiotic phenotypic effects on bacteria with a potential for applications in rapid antibiotic susceptibility testing.

40 CFR 300.415 - Removal action.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 28 2011-07-01 2011-07-01 false Removal action. 300.415 Section 300... PLAN Hazardous Substance Response § 300.415 Removal action. (a)(1) In determining the appropriate extent of action to be taken in response to a given release, the lead agency shall first review the...

Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

PubMed Central

Vivekananda, Umesh; Novak, Pavel; Bello, Oscar D.; Korchev, Yuri E.; Krishnakumar, Shyam S.; Volynski, Kirill E.; Kullmann, Dimitri M.

2017-01-01

Although action potentials propagate along axons in an all-or-none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog–digital modulation is depolarization-mediated inactivation of presynaptic Kv1-family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization. We recorded instead from small boutons supplied by intact axons identified with scanning ion conductance microscopy in primary hippocampal cultures and asked how distinct potassium channels interact in determining the basal spike width and its modulation by subthreshold somatic depolarization. Pharmacological or genetic deletion of Kv1.1 broadened presynaptic spikes without preventing further prolongation by brief depolarizing somatic prepulses. A heterozygous mouse model of episodic ataxia type 1 harboring a dominant Kv1.1 mutation had a similar broadening effect on basal spike shape as deletion of Kv1.1; however, spike modulation by somatic prepulses was abolished. These results argue that the Kv1.1 subunit is not necessary for subthreshold modulation of spike width. However, a disease-associated mutant subunit prevents the interplay of analog and digital transmission, possibly by disrupting the normal stoichiometry of presynaptic potassium channels. PMID:28193892

Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing

PubMed Central

Mizani, Tuba; Hamblin, Angela; Parton, Marina; Orosz, Zsolt; Athanasou, Nick; Hassan, Bass; Flanagan, Adrienne M.; Ahmed, Ahmed; Winter, Stuart; Harris, Adrian; Popitsch, Niko; Church, David; Taylor, Jenny C.

2018-01-01

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer. PMID:29610388

Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location

PubMed Central

Crago, Patrick E; Makowski, Nathan S

2014-01-01

Objective Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. Approach We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Main Results Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases.. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. Significance This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic interventions involving motor or sensory stimulation. PMID:25161163

Alteration of neural action potential patterns by axonal stimulation: the importance of stimulus location

NASA Astrophysics Data System (ADS)

Crago, Patrick E.; Makowski, Nathaniel S.

2014-10-01

Objective. Stimulation of peripheral nerves is often superimposed on ongoing motor and sensory activity in the same axons, without a quantitative model of the net action potential train at the axon endpoint. Approach. We develop a model of action potential patterns elicited by superimposing constant frequency axonal stimulation on the action potentials arriving from a physiologically activated neural source. The model includes interactions due to collision block, resetting of the neural impulse generator, and the refractory period of the axon at the point of stimulation. Main results. Both the mean endpoint firing rate and the probability distribution of the action potential firing periods depend strongly on the relative firing rates of the two sources and the intersite conduction time between them. When the stimulus rate exceeds the neural rate, neural action potentials do not reach the endpoint and the rate of endpoint action potentials is the same as the stimulus rate, regardless of the intersite conduction time. However, when the stimulus rate is less than the neural rate, and the intersite conduction time is short, the two rates partially sum. Increases in stimulus rate produce non-monotonic increases in endpoint rate and continuously increasing block of neurally generated action potentials. Rate summation is reduced and more neural action potentials are blocked as the intersite conduction time increases. At long intersite conduction times, the endpoint rate simplifies to being the maximum of either the neural or the stimulus rate. Significance. This study highlights the potential of increasing the endpoint action potential rate and preserving neural information transmission by low rate stimulation with short intersite conduction times. Intersite conduction times can be decreased with proximal stimulation sites for muscles and distal stimulation sites for sensory endings. The model provides a basis for optimizing experiments and designing neuroprosthetic interventions involving motor or sensory stimulation.

Effect of an educational game on university students' learning about action potentials.

PubMed

Luchi, Kelly Cristina Gaviao; Montrezor, Luís Henrique; Marcondes, Fernanda K

2017-06-01

The aim of this study was to evaluate the effect of an educational game that is used for teaching the mechanisms of the action potentials in cell membranes. The game was composed of pieces representing the intracellular and extracellular environments, ions, ion channels, and the Na + -K + -ATPase pump. During the game activity, the students arranged the pieces to demonstrate how the ions move through the membrane in a resting state and during an action potential, linking the ion movement with a graph of the action potential. To test the effect of the game activity on student understanding, first-year dental students were given the game to play at different times in a series of classes teaching resting membrane potential and action potentials. In all experiments, students who played the game performed better in assessments. According to 98% of the students, the game supported the learning process. The data confirm the students' perception, indicating that the educational game improved their understanding about action potentials. Copyright © 2017 the American Physiological Society.

Understanding the electrical behavior of the action potential in terms of elementary electrical sources.

PubMed

Rodriguez-Falces, Javier

2015-03-01

A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However, this model is unsuitably complex for teaching purposes. In addition, the Hodgkin and Huxley approach describes the shape of the action potential only in terms of ionic currents, i.e., it is unable to explain the electrical significance of the action potential or describe the electrical field arising from this source using basic concepts of electromagnetic theory. The goal of the present report was to propose a new model to describe the electrical behaviour of the action potential in terms of elementary electrical sources (in particular, dipoles). The efficacy of this model was tested through a closed-book written exam. The proposed model increased the ability of students to appreciate the distributed character of the action potential and also to recognize that this source spreads out along the fiber as function of space. In addition, the new approach allowed students to realize that the amplitude and sign of the extracellular electrical potential arising from the action potential are determined by the spatial derivative of this intracellular source. The proposed model, which incorporates intuitive graphical representations, has improved students' understanding of the electrical potentials generated by bioelectrical sources and has heightened their interest in bioelectricity. Copyright © 2015 The American Physiological Society.

Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

PubMed

Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

2015-05-01

Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Urocortin2 prolongs action potential duration and modulates potassium currents in guinea pig myocytes and HEK293 cells.

PubMed

Yang, Li-Zhen; Zhu, Yi-Chun

2015-07-05

We previously reported that activation of corticotropin releasing factor receptor type 2 by urocortin2 up-regulates both L-type Ca(2+) channels and intracellular Ca(2+) concentration in ventricular myocytes and plays an important role in cardiac contractility and arrhythmogenesis. This study goal was to further test the hypothesis that urocortin2 may modulate action potentials as well as rapidly and slowly activating delayed rectifier potassium currents. With whole cell patch-clamp techniques, action potentials and slowly activating delayed rectifier potassium currents were recorded in isolated guinea pig ventricular myocytes, respectively. And rapidly activating delayed rectifier potassium currents were tested in hERG-HEK293 cells. Urocortin2 produced a time- and concentration-dependent prolongation of action potential duration. The EC50 values of action potential duration and action potential duration at 90% of repolarization were 14.73 and 24.3nM respectively. The prolongation of action potential duration of urocortin2 was almost completely or partly abolished by H-89 (protein kinase A inhibitor) or KB-R7943 (Na(+)/Ca(2+) exchange inhibitor) pretreatment respectively. And urocortin2 caused reduction of rapidly activating delayed rectifier potassium currents in hERG-HEK293 cells. In addition, urocortin2 slowed the rate of slowly activating delayed rectifier potassium channel activation, and rightward shifted the threshold of slowly activating delayed rectifier potassium currents to more positive potentials. Urocortin2 prolonged action potential duration via activation of protein kinase A and Na(+)/ Ca(2+) exchange in isolated guinea pig ventricular myocytes in a time- and concentration- dependent manner. In hERG-HEK293 cells, urocortin2 reduced rapidly activating delayed rectifier potassium current density which may contribute to action potential duration prolongation. Copyright © 2015 Elsevier B.V. All rights reserved.

Population of computational rabbit-specific ventricular action potential models for investigating sources of variability in cellular repolarisation.

PubMed

Gemmell, Philip; Burrage, Kevin; Rodriguez, Blanca; Quinn, T Alexander

2014-01-01

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K(+), inward rectifying K(+), L-type Ca(2+), and Na(+)/K(+) pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation.

Population of Computational Rabbit-Specific Ventricular Action Potential Models for Investigating Sources of Variability in Cellular Repolarisation

PubMed Central

Gemmell, Philip; Burrage, Kevin; Rodriguez, Blanca; Quinn, T. Alexander

2014-01-01

Variability is observed at all levels of cardiac electrophysiology. Yet, the underlying causes and importance of this variability are generally unknown, and difficult to investigate with current experimental techniques. The aim of the present study was to generate populations of computational ventricular action potential models that reproduce experimentally observed intercellular variability of repolarisation (represented by action potential duration) and to identify its potential causes. A systematic exploration of the effects of simultaneously varying the magnitude of six transmembrane current conductances (transient outward, rapid and slow delayed rectifier K+, inward rectifying K+, L-type Ca2+, and Na+/K+ pump currents) in two rabbit-specific ventricular action potential models (Shannon et al. and Mahajan et al.) at multiple cycle lengths (400, 600, 1,000 ms) was performed. This was accomplished with distributed computing software specialised for multi-dimensional parameter sweeps and grid execution. An initial population of 15,625 parameter sets was generated for both models at each cycle length. Action potential durations of these populations were compared to experimentally derived ranges for rabbit ventricular myocytes. 1,352 parameter sets for the Shannon model and 779 parameter sets for the Mahajan model yielded action potential duration within the experimental range, demonstrating that a wide array of ionic conductance values can be used to simulate a physiological rabbit ventricular action potential. Furthermore, by using clutter-based dimension reordering, a technique that allows visualisation of multi-dimensional spaces in two dimensions, the interaction of current conductances and their relative importance to the ventricular action potential at different cycle lengths were revealed. Overall, this work represents an important step towards a better understanding of the role that variability in current conductances may play in experimentally observed intercellular variability of rabbit ventricular action potential repolarisation. PMID:24587229

Action potential propagation: ion current or intramembrane electric field?

PubMed

Martí, Albert; Pérez, Juan J; Madrenas, Jordi

2018-01-01

The established action potential propagation mechanisms do not satisfactorily explain propagation on myelinated axons given the current knowledge of biological channels and membranes. The flow across ion channels presents two possible effects: the electric potential variations across the lipid bilayers (action potential) and the propagation of an electric field through the membrane inner part. The proposed mechanism is based on intra-membrane electric field propagation, this propagation can explain the action potential saltatory propagation and its constant delay independent of distance between Ranvier nodes in myelinated axons.

Lead (II) detection and contamination routes in environmental sources, cookware and home-prepared foods from Zimatlán, Oaxaca, Mexico.

PubMed

Villalobos, M; Merino-Sánchez, C; Hall, C; Grieshop, J; Gutiérrez-Ruiz, M E; Handley, M A

2009-04-01

An interdisciplinary investigation, involving environmental geochemists, epidemiologists, nurses, and anthropologists, was undertaken to determine the contamination source and pathway of an on-going outbreak of lead poisoning among migrants originating from Zimatlán, Oaxaca, Mexico and living in Seaside, California, and among their US-born children. An initial investigation in Seaside identified grasshopper foodstuff ("chapulines") imported from Mexico and consumed as snacks, as containing alarmingly high lead concentrations (up to 2300 mg/kg). The focus in the present work concentrates on the Oaxacan area of origin of the problem in Mexico, and two potential sources of contamination were investigated: wind-borne dusts from existing mine residues as potential contaminants of soil, plant, and fauna; and food preparation practices using lead-glazed ceramic cookware. Over a three year period, sampling was conducted in Oaxaca using community-level sampling and also targeted sampling with families of cases with lead poisoning in California. In addition to fresh field chapulines, we analyzed for total lead: soil, water, mine residues, and plant materials, both from areas adjacent to or at an abandoned waste site containing mine tailings, and from fields where chapulines are collected; foodstuffs gathered in community markets or in a food transport business; and foodstuffs and cookware gathered from relatives of case families in California. Also, selected new and used lead-glazed clay cookware was extracted for lead, using 0.02 M citric acid and with 4% acetic acid. The results indicated significant presence of lead in mine wastes, in specific foodstuffs, and in glazed cookware, but no extensive soil contamination was identified. In-situ experiments demonstrated that lead incorporation in food is made very efficient through grinding of spices in glazed cookware, with the combination of a harsh mechanical action and the frequent presence of acidic lime juice, but without heating, resulting in high but variable levels of contamination.

5-(Halomethyl)uridine derivatives as potential antitumor radiosensitizers: A DFT study

NASA Astrophysics Data System (ADS)

Wang, Shoushan; Zhang, Min; Liu, Peng; Xie, Shilei; Cheng, Faliang; Wang, Lishi

2018-01-01

Considering the fact that the efficiency of the uridine-5-methyl radical in producing cytotoxic DNA intrastrand cross-link lesions is greatly higher than that of the uridine-5-yl radical, the radiosensitizing action of 5-(halomethyl)uridines (5-XCH2U, X = F, Cl, or Br) is studied in the present work. It is found that 5-XCH2U has sufficient electron affinity to capture a pre-hydrated or a hydrated electron, and electron attachment leads to significantly facile X- elimination forming the uridine-5-methyl radical. All these three halogenated uridine derivatives are shown to be potential radiosensitizers, with their radiosensitizing abilities increased in an order 5-FCH2U < 5-ClCH2U ≈ 5-BrCH2U.

Can observations look back to the beginning of inflation?

NASA Astrophysics Data System (ADS)

Wetterich, C.

2016-03-01

The cosmic microwave background can measure the inflaton potential only if inflation lasts sufficiently long before the time of horizon crossing of observable fluctuations, such that non-linear effects in the time evolution of Green's functions lead to a loss of memory of initial conditions for the ultraviolet tail of the spectrum. Within a derivative expansion of the quantum effective action for an interacting scalar field we discuss the most general solution for the correlation function, including arbitrary pure and mixed quantum states. In this approximation no loss of memory occurs - cosmic microwave observations see the initial spectrum at the beginning of inflation, processed only mildly by the scale-violating effects at horizon crossing induced by the inflaton potential.

A multi-target caffeine derived rhodium(i) N-heterocyclic carbene complex: evaluation of the mechanism of action.

PubMed

Zhang, Jing-Jing; Muenzner, Julienne K; Abu El Maaty, Mohamed A; Karge, Bianka; Schobert, Rainer; Wölfl, Stefan; Ott, Ingo

2016-08-16

A rhodium(i) and a ruthenium(ii) complex with a caffeine derived N-heterocyclic carbene (NHC) ligand were biologically investigated as organometallic conjugates consisting of a metal center and a naturally occurring moiety. While the ruthenium(ii) complex was largely inactive, the rhodium(i) NHC complex displayed selective cytotoxicity and significant anti-metastatic and in vivo anti-vascular activities and acted as both a mammalian and an E. coli thioredoxin reductase inhibitor. In HCT-116 cells it increased the reactive oxygen species level, leading to DNA damage, and it induced cell cycle arrest, decreased the mitochondrial membrane potential, and triggered apoptosis. This rhodium(i) NHC derivative thus represents a multi-target compound with promising anti-cancer potential.

Minocycline inhibits D-amphetamine-elicited action potential bursts in a central snail neuron.

PubMed

Chen, Y-H; Lin, P-L; Wong, R-W; Wu, Y-T; Hsu, H-Y; Tsai, M-C; Lin, M-J; Hsu, Y-C; Lin, C-H

2012-10-25

Minocycline is a second-generation tetracycline that has been reported to have powerful neuroprotective properties. In our previous studies, we found that d-amphetamine (AMPH) elicited action potential bursts in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. This study sought to determine the effects of minocycline on the AMPH-elicited action potential pattern changes in the central snail neuron, using the two-electrode voltage clamping method. Extracellular application of AMPH at 300 μM elicited action potential bursts in the RP4 neuron. Minocycline dose-dependently (300-900 μM) inhibited the action potential bursts elicited by AMPH. The inhibitory effects of minocycline on AMPH-elicited action potential bursts were restored by forskolin (50 μM), an adenylate cyclase activator, and by dibutyryl cAMP (N(6),2'-O-Dibutyryladenosine 3',5'-cyclic monophosphate; 1mM), a membrane-permeable cAMP analog. Co-administration of forskolin (50 μM) plus tetraethylammonium chloride (TEA; 5mM) or co-administration of TEA (5mM) plus dibutyryl cAMP (1mM) also elicited action potential bursts, which were prevented and inhibited by minocycline. In addition, minocycline prevented and inhibited forskolin (100 μM)-elicited action potential bursts. Notably, TEA (50mM)-elicited action potential bursts in the RP4 neuron were not affected by minocycline. Minocycline did not affect steady-state outward currents of the RP4 neuron. However, minocycline did decrease the AMPH-elicited steady-state current changes. Similarly, minocycline decreased the effects of forskolin-elicited steady-state current changes. Pretreatment with H89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; 10 μM), a protein kinase A inhibitor, inhibited AMPH-elicited action potential bursts and decreased AMPH-elicited steady-state current changes. These results suggest that the cAMP-protein kinase A signaling pathway and the steady-state current are involved in the inhibitory effects of minocycline upon AMPH-elicited action potential bursts. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Corrective Action Investigation Plan for Corrective Action Unit 405: Area 3 Septic Systems, Tonopah Test Range, Nevada(April 2001, Rev. 0) with Record of Technical Change No. 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

DOE /NV

2001-04-26

This Corrective Action Investigation Plan contains the U.S. Department of Energy, Nevada Operations Office's (DOE/NV's) approach to collect the data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit (CAU) 405, Area 3 Septic Systems, Tonopah Test Range (TTR), under the Federal Facility Agreement and Consent Order. Corrective Action Unit 405 consists of Corrective Action Sites 03-05-002-SW03, 03-05-002-SW04, and 03-05-002-SW07 (also collectively known as: Septic Waste Systems [SWSs] 3, 4, and 7). Located in Area 3 in the northwest section of the TTR, approximately 140 miles northwest of Las Vegas, this location was historically (betweenmore » 1960 and 1990) used as a research facility with the mission to perform defense-related projects, and whose operations generated sanitary and industrial wastewaters potentially contaminated with COPCs and disposed of in septic tanks and leachfields. Though Septic Waste Systems 3, 4, and 7 were origin ally constructed to receive sanitary sewage, they may have inadvertently received effluent containing potentially hazardous and radiological constituents containing acetone, benzene, ethylbenzene, 4-methyl-2-pentanone, toluene, xylenes, volatile organic compound constituents, phenols, arsenic, barium, lead, mercury, hydrocarbons of oil and grease, and uranium-234, -235, and -238. The Area 3 septic systems were documented in a DOE/NV 1996 report as being included in the septic tank abandonment program conducted by Sandia National Laboratories in 1993; however, this program was not completed and the possibility exists that some of the Area 3 septic tanks may not have been abandoned. Even though all of the SWSs addressed in this CAIP are inactive, geophysical surveys conducted in 1993 were generally inconclusive and did not provide useful data for the purposes of this investigation. The scope of this current investigation, therefore, will be to determine the existence of the identified CO PCs and excavation will be the primary investigation method employed for these leachfield systems, but this effort may be limited by existing facilities and utilities. The results of this field investigation will support a defensible evaluation of corrective action alternatives in the subsequent corrective action decision document.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Heidi, E-mail: heidi.mwalker@yahoo.ca; Sinclair, A. John, E-mail: john.sinclair@ad.umanitoba.ca; Spaling, Harry, E-mail: harry.spaling@kingsu.ca

Meaningful public engagement is a challenging, but promising, feature of strategic environmental assessment (SEA) due to its potential for integrating sustainability principles into policies, plans and programs in developing countries such as Kenya. This research examined two selected SEA case studies to identify the extent of participation, learning outcomes attributable to participation, and if any learning outcomes led to social action for sustainability at the community level. Strengths across the two cases were the inclusion of marginalized populations and consideration of socio-economic concerns. Consistent weaknesses included inadequate notice, document inaccessibility, lack of feedback and communication, and late analysis of alternatives.more » Despite some learning conditions being unfulfilled, examples of instrumental, communicative, and transformative learning were identified through a focus group and semi-structured interviews with community participants and public officials. Some of these learning outcomes led to individual and social actions that contribute to sustainability. -- Highlights: • The strengths and weaknesses of Kenyan SEA public participation processes were identified. • Multiple deficiencies in the SEA process likely frustrate meaningful public engagement. • Participant learning was observed despite process weaknesses. • Participant learning can lead to action for sustainability at the community level.« less

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

PubMed Central

Choi, Miyeon; Lee, Seung Hoon; Wang, Sung Eun; Ko, Seung Yeon; Song, Mihee; Choi, June-Seek; Duman, Ronald S.; Son, Hyeon

2015-01-01

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine. PMID:26647181

Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology.

PubMed

Darbre, Philippa D; Mannello, Ferdinando; Exley, Christopher

2013-11-01

This review examines recent evidence linking exposure to aluminium with the aetiology of breast cancer. The human population is exposed to aluminium throughout daily life including through diet, application of antiperspirants, use of antacids and vaccination. Aluminium has now been measured in a range of human breast structures at higher levels than in blood serum and experimental evidence suggests that the tissue concentrations measured have the potential to adversely influence breast epithelial cells including generation of genomic instability, induction of anchorage-independent proliferation and interference in oestrogen action. The presence of aluminium in the human breast may also alter the breast microenvironment causing disruption to iron metabolism, oxidative damage to cellular components, inflammatory responses and alterations to the motility of cells. The main research need is now to investigate whether the concentrations of aluminium measured in the human breast can lead in vivo to any of the effects observed in cells in vitro and this would be aided by the identification of biomarkers specific for aluminium action. © 2013.

Superfund Record of Decision (EPA Region 8): Anaconda Smelter site, (Operable Unit 11 - Flue Dust), Deer Lodge County, Anaconda, MT. (Second remedial action), September 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1991-09-23

The 6,000-acre Anaconda Smelter site is a former copper and ore processing facility in Deer Lodge County, Montana. Land use in the area is predominantly residential. The site is bounded on the north and east, respectively, by the Warm Springs Creek and Mill Creek, both of which are potential sources of drinking water. From 1884 until 1980 when activities ceased, the site was used for ore processing and smelting operations. In 1988, EPA conducted an investigation to determine the nature and extent of the flue dust contamination. A 1988 ROD addressed the Mill Creek Operable Unit (OU15) and documented themore » relocation of residents from the community surrounding the smelter site as the selected remedial action. The Record of Decision (ROD) addresses the Flue Dust Operable Unit (OU11). The primary contaminants of concern affecting this site from the flue dust materials are metals including arsenic, cadmium, and lead. The selected remedial action for the site is included.« less

Integrating big data and actionable health coaching to optimize wellness.

PubMed

Hood, Leroy; Lovejoy, Jennifer C; Price, Nathan D

2015-01-09

The Hundred Person Wellness Project (HPWP) is a 10-month pilot study of 100 'well' individuals where integrated data from whole-genome sequencing, gut microbiome, clinical laboratory tests and quantified self measures from each individual are used to provide actionable results for health coaching with the goal of optimizing wellness and minimizing disease. In a commentary in BMC Medicine, Diamandis argues that HPWP and similar projects will likely result in 'unnecessary and potential harmful over-testing'. We argue that this new approach will ultimately lead to lower costs, better healthcare, innovation and economic growth. The central points of the HPWP are: 1) it is focused on optimizing wellness through longitudinal data collection, integration and mining of individual data clouds, enabling development of predictive models of wellness and disease that will reveal actionable possibilities; and 2) by extending this study to 100,000 well people, we will establish multiparameter, quantifiable wellness metrics and identify markers for wellness to early disease transitions for most common diseases, which will ultimately allow earlier disease intervention, eventually transitioning the individual early on from a disease back to a wellness trajectory.

[Factors related to the blood lead level in children 6 to 30 months old in the Prospective Lead Study in Mexico City].

PubMed

Rothenberg, S J; Schnaas-Arrieta, L; Pérez-Guerrero, I A; Hernández-Cervantes, R; Martínez-Medina, S; Perroni-Hernández, E

1993-01-01

A majority of the sample of children (N = 160-121, ages 6-30 months) from the Mexico City Prospective Lead Study exceeds the lowest limit action level (10 micrograms/dl) of the Centers for Disease Control standards for childhood lead exposure. Over one-third of the sample at 18 months and 24 months exceeds the action level (15 micrograms/dl) for aggressive intervention. Diet plays an important role in regulating early childhood blood lead levels. Fresh milk and breast feeding are associated with lower lead levels, but extended breast feeding is related to elevated lead levels. Low income and poor maternal education are associated with higher lead concentration in children. Child consumption of canned milk and juice, up to this date, is associated with elevated child lead levels. Canned products sealed with lead are disappearing from Mexican markets. Efforts to improve childhood nutrition and poverty may be expected to have the additional benefit of lowering lead levels of Mexican children.

Selective effects of an octopus toxin on action potentials

PubMed Central

Dulhunty, Angela; Gage, Peter W.

1971-01-01

1. A lethal, water soluble toxin (Maculotoxin, MTX) with a molecular weight less than 540, can be extracted from the salivary glands of an octopus (Hapalochlaena maculosa). 2. MTX blocks action potentials in sartorius muscle fibres of toads without affecting the membrane potential. Delayed rectification is not inhibited by the toxin. 3. At low concentrations (10-6-10-5 g/ml.) MTX blocks action potentials only after a certain number have been elicited. The number of action potentials, which can be defined accurately, depends on the concentration of MTX and the concentration of sodium ions in the extracellular solution. 4. The toxin has no post-synaptic effect at the neuromuscular junction and it is concluded that it blocks neuromuscular transmission by inhibiting action potentials in motor nerve terminals. PMID:4330930

Relationship between size and latency of action potentials in human muscle sympathetic nerve activity.

PubMed

Salmanpour, Aryan; Brown, Lyndon J; Steinback, Craig D; Usselman, Charlotte W; Goswami, Ruma; Shoemaker, J Kevin

2011-06-01

We employed a novel action potential detection and classification technique to study the relationship between the recruitment of sympathetic action potentials (i.e., neurons) and the size of integrated sympathetic bursts in human muscle sympathetic nerve activity (MSNA). Multifiber postganglionic sympathetic nerve activity from the common fibular nerve was collected using microneurography in 10 healthy subjects at rest and during activation of sympathetic outflow using lower body negative pressure (LBNP). Burst occurrence increased with LBNP. Integrated burst strength (size) varied from 0.22 ± 0.07 V at rest to 0.28 ± 0.09 V during LBNP. Sympathetic burst size (i.e., peak height) was directly related to the number of action potentials within a sympathetic burst both at baseline (r = 0.75 ± 0.13; P < 0.001) and LBNP (r = 0.75 ± 0.12; P < 0.001). Also, the amplitude of detected action potentials within sympathetic bursts was directly related to the increased burst size at both baseline (r = 0.59 ± 0.16; P < 0.001) and LBNP (r = 0.61 ± 0.12; P < 0.001). In addition, the number of detected action potentials and the number of distinct action potential clusters within a given sympathetic burst were correlated at baseline (r = 0.7 ± 0.1; P < 0.001) and during LBNP (r = 0.74 ± 0.03; P < 0.001). Furthermore, action potential latency (i.e., an inverse index of neural conduction velocity) was decreased as a function of action potential size at baseline and LBNP. LBNP did not change the number of action potentials and unique clusters per sympathetic burst. It was concluded that there exists a hierarchical pattern of recruitment of additional faster conducting neurons of larger amplitude as the sympathetic bursts become stronger (i.e., larger amplitude bursts). This fundamental pattern was evident at rest and was not altered by the level of baroreceptor unloading applied in this study.

Action Research: A Methodology for Change and Development

ERIC Educational Resources Information Center

Somekh, Bridget

2005-01-01

This book presents a fresh view of action research as a methodology uniquely suited to researching the processes of innovation and change. Drawing on twenty-five years' experience of leading or facilitating action research projects, Bridget Somekh argues that action research can be a powerful systematic intervention, which goes beyond describing,…

All optical experimental design for neuron excitation, inhibition, and action potential detection

NASA Astrophysics Data System (ADS)

Walsh, Alex J.; Tolstykh, Gleb; Martens, Stacey; Sedelnikova, Anna; Ibey, Bennett L.; Beier, Hope T.

2016-03-01

Recently, infrared light has been shown to both stimulate and inhibit excitatory cells. However, studies of infrared light for excitatory cell inhibition have been constrained by the use of invasive and cumbersome electrodes for cell excitation and action potential recording. Here, we present an all optical experimental design for neuronal excitation, inhibition, and action potential detection. Primary rat neurons were transfected with plasmids containing the light sensitive ion channel CheRiff. CheRiff has a peak excitation around 450 nm, allowing excitation of transfected neurons with pulsed blue light. Additionally, primary neurons were transfected with QuasAr2, a fast and sensitive fluorescent voltage indicator. QuasAr2 is excited with yellow or red light and therefore does not spectrally overlap CheRiff, enabling imaging and action potential activation, simultaneously. Using an optic fiber, neurons were exposed to blue light sequentially to generate controlled action potentials. A second optic fiber delivered a single pulse of 1869nm light to the neuron causing inhibition of the evoked action potentials (by the blue light). When used in concert, these optical techniques enable electrode free neuron excitation, inhibition, and action potential recording, allowing research into neuronal behaviors with high spatial fidelity.

Inhibitors of ubiquitin E3 ligase as potential new antimalarial drug leads.

PubMed

Jain, Jagrati; Jain, Surendra K; Walker, Larry A; Tekwani, Babu L

2017-06-02

Protein ubiquitylation is an important post-translational regulation, which has been shown to be necessary for life cycle progression and survival of Plasmodium falciparum. Ubiquitin is a highly conserved 76 amino acid polypeptide, which attaches covalently to target proteins through combined action of three classes of enzymes namely, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin-protein ligase (E3). Ubiquitin E1 and E2 are highly conserved within eukaryotes. However, the P. falciparum E3 ligase is substantially variable and divergent compared to the homologs from other eukaryotes, which make the E3 ligase a parasite-specific target. A set of selected E3 ubiquitin ligase inhibitors was tested in vitro against a chloroquine-sensitive P. falciparum D6 strain (PfD6) and a chloroquine-resistant P. falciparum W2 strain (PfW2). The inhibitors were also tested against Vero and transformed THP1 cells for cytotoxicity. The lead antimalarial E3 ubiquitin ligase inhibitors were further evaluated for the stage-specific antimalarial action and effects on cellular development of P. falciparum in vitro. Statistics analysis was done by two-way ANOVA followed by Tukey and Sidak multiple comparison test using GraphPad Prism 6. E3 ligase inhibitors namely, JNJ 26854165, HLI 373 and Nutlin 3 showed prominent antimalarial activity against PfD6 and PfW2. These inhibitors were considerably less cytotoxic to mammalian Vero cells. JNJ 26854165, HLI 373 and Nutlin 3 blocked the development of P. falciparum parasite at the trophozoite and schizont stages, resulting in accumulation of distorted trophozoites and immature schizonts. Interruption of trophozoites and schizont maturation by the antimalarial E3 ligase inhibitors suggest the role of ubiquitin/proteasome functions in the intraerythrocytic development of malaria parasite. The ubiquitin/proteasome functions may be critical for schizont maturation. Further investigations on the lead E3 ligase inhibitors shall provide better understanding regarding the importance of E3 ligase functions in the malaria parasite as a potential new antimalarial drug target and a new class of antimalarial drug leads.

Increasing chloride in rivers of the conterminous U.S. and linkages to potential corrosivity and lead action level exceedances in drinking water.

PubMed

Stets, E G; Lee, C J; Lytle, D A; Schock, M R

2018-02-01

Corrosion in water-distribution systems is a costly problem and controlling corrosion is a primary focus of efforts to reduce lead (Pb) and copper (Cu) in tap water. High chloride concentrations can increase the tendency of water to cause corrosion in distribution systems. The effects of chloride are also expressed in several indices commonly used to describe the potential corrosivity of water, the chloride-sulfate mass ratio (CSMR) and the Larson Ratio (LR). Elevated CSMR has been linked to the galvanic corrosion of Pb whereas LR is indicative of the corrosivity of water to iron and steel. Despite the known importance of chloride, CSMR, and LR to the potential corrosivity of water, monitoring of seasonal and interannual changes in these parameters is not common among water purveyors. We analyzed long-term trends (1992-2012) and the current status (2010-2015) of chloride, CSMR, and LR in order to investigate the short and long-term temporal variability in potential corrosivity of US streams and rivers. Among all sites in the trend analyses, chloride, CSMR, and LR increased slightly, with median changes of 0.9mgL -1 , 0.08, and 0.01, respectively. However, urban-dominated sites had much larger increases, 46.9mgL -1 , 2.50, and 0.53, respectively. Median CSMR and LR in urban streams (4.01 and 1.34, respectively) greatly exceeded thresholds found to cause corrosion in water distribution systems (0.5 and 0.3, respectively). Urbanization was strongly correlated with elevated chloride, CSMR, and LR, especially in the most snow-affected areas in the study, which are most likely to use road salt. The probability of Pb action-level exceedances (ALEs) in drinking water facilities increased along with raw surface water CSMR, indicating a statistical connection between surface water chemistry and corrosion in drinking water facilities. Optimal corrosion control will require monitoring of critical constituents reflecting the potential corrosivity in surface waters. Published by Elsevier B.V.

75 FR 13131 - Notice of Intent To Prepare an Environmental Impact Statement (EIS) for the Sale of Plum Island, NY

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-18

..., GSA, as the operational Joint Lead Agency, announces its Notice of Intent (NOI) to prepare an EIS for... York. The US Department of Homeland Security (DHS) will act as a Joint Lead Agency in ongoing...-Action Alternative''). The Action Alternative will be further refined into a series of reasonably...

Cross-Species Coherence in Effects and Modes of Action in Support of Causality Determinations in the U.S. Environmental Protection Agency’s Integrated Science Assessment for Lead

EPA Science Inventory

The peer-reviewed literature on the health and ecological effects of lead (Pb) indicates common effects and underlying modes of action across multiple organisms for several endpoints. Based on such observations, the United States Environmental Protection Agency (EPA) applied a cr...

A Public Health Approach to Addressing Lead

EPA Pesticide Factsheets

Describes EPA’s achievements in reducing childhood lead exposures and emphasizes the need to continue actions to further reduce lead exposures, especially in those communities where exposures remain high.

Cortical Action Potential Backpropagation Explains Spike Threshold Variability and Rapid-Onset Kinetics

PubMed Central

Yu, Yuguo; Shu, Yousheng; McCormick, David A.

2008-01-01

Neocortical action potential responses in vivo are characterized by considerable threshold variability, and thus timing and rate variability, even under seemingly identical conditions. This finding suggests that cortical ensembles are required for accurate sensorimotor integration and processing. Intracellularly, trial-to-trial variability results not only from variation in synaptic activities, but also in the transformation of these into patterns of action potentials. Through simultaneous axonal and somatic recordings and computational simulations, we demonstrate that the initiation of action potentials in the axon initial segment followed by backpropagation of these spikes throughout the neuron results in a distortion of the relationship between the timing of synaptic and action potential events. In addition, this backpropagation also results in an unusually high rate of rise of membrane potential at the foot of the action potential. The distortion of the relationship between the amplitude time course of synaptic inputs and action potential output caused by spike back-propagation results in the appearance of high spike threshold variability at the level of the soma. At the point of spike initiation, the axon initial segment, threshold variability is considerably less. Our results indicate that spike generation in cortical neurons is largely as expected by Hodgkin—Huxley theory and is more precise than previously thought. PMID:18632930

Androgenic signaling systems and their role in behavioral evolution.

PubMed

Fuxjager, Matthew J; Schuppe, Eric R

2018-06-05

Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Modeling the Development of Goal-Specificity in Mirror Neurons.

PubMed

Thill, Serge; Svensson, Henrik; Ziemke, Tom

2011-12-01

Neurophysiological studies have shown that parietal mirror neurons encode not only actions but also the goal of these actions. Although some mirror neurons will fire whenever a certain action is perceived (goal-independently), most will only fire if the motion is perceived as part of an action with a specific goal. This result is important for the action-understanding hypothesis as it provides a potential neurological basis for such a cognitive ability. It is also relevant for the design of artificial cognitive systems, in particular robotic systems that rely on computational models of the mirror system in their interaction with other agents. Yet, to date, no computational model has explicitly addressed the mechanisms that give rise to both goal-specific and goal-independent parietal mirror neurons. In the present paper, we present a computational model based on a self-organizing map, which receives artificial inputs representing information about both the observed or executed actions and the context in which they were executed. We show that the map develops a biologically plausible organization in which goal-specific mirror neurons emerge. We further show that the fundamental cause for both the appearance and the number of goal-specific neurons can be found in geometric relationships between the different inputs to the map. The results are important to the action-understanding hypothesis as they provide a mechanism for the emergence of goal-specific parietal mirror neurons and lead to a number of predictions: (1) Learning of new goals may mostly reassign existing goal-specific neurons rather than recruit new ones; (2) input differences between executed and observed actions can explain observed corresponding differences in the number of goal-specific neurons; and (3) the percentage of goal-specific neurons may differ between motion primitives.

77 FR 15638 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-16

...We are revising an earlier proposed airworthiness directive (AD) for certain The Boeing Company Model 737-600, -700, -700C, -800, - 900 and -900ER series airplanes. That NPRM proposed to require modifying the fluid drain path in the wing leading edge area, forward of the wing front spar, and doing all applicable related investigative and corrective actions. That NPRM was prompted by a report of leaking fuel from the wing leading edge area at the inboard end of the number 5 leading edge slat. This action revises that NPRM by including installing new seal disks on the latches in the fuel shutoff valve access door as part of the modification and by specifying that certain inspections are detailed inspections. This action also revises the applicability to include additional airplanes. We are proposing this AD to prevent flammable fluids from accumulating in the wing leading edge, and draining inboard and onto the engine exhaust nozzle, which could result in a fire. Since these actions impose an additional burden over that proposed in the NPRM, we are reopening the comment period to allow the public the chance to comment on these proposed changes.

Ethical Issues in Using Children's Blood Lead Levels as a Remedial Action Objective

PubMed Central

Evans, Emily Lorraine

2011-01-01

The Environmental Protection Agency measures the success or failure of Superfund site remediation efforts against remedial action objectives (RAOs). RAOs are frequently based on environmental contaminant concentrations, but with lead exposure, blood lead levels from the population at risk are often used. Although childhood lead screening is an important public health tool, an RAO based on child blood lead levels raises ethical concerns: public health efforts that are more reactive than preventive, a blood lead standard (10 μg/dL) that may not be fully protective, the use of a measure whose validity and reliability may be easily compromised, and exacerbation of environmental injustice and systematic disadvantages. The example of Bunker Hill mine, Kellogg, Idaho, allowed an examination of these ethical concerns. PMID:21836120

Median and ulnar muscle and sensory evoked potentials.

PubMed

Felsenthal, G

1978-08-01

The medical literature was reviewed to find suggested clinical applications of the study of the amplitude of evoked muscle action potentials (MAP) and sensory action potentials (SAP). In addition, the literature was reviewed to ascertain the normal amplitude and duration of the evoked MAP and SAP as well as the factors affecting the amplitude: age, sex, temperature, ischemia. The present study determined the normal amplitude and duration of the median and ulnar MAP and SAP in fifty normal subjects. The amplitude of evoked muscle or sensory action potentials depends on multiple factors. Increased skin resistance, capacitance, and impedance at the surface of the recording electrode diminishes the amplitude. Similarly, increased distance from the source of the action potential diminishes its amplitude. Increased interelectrode distance increases the amplitude of the bipolarly recorded sensory action potential until a certain interelectrode distance is exceeded and the diphasic response becomes tri- or tetraphasic. Artifact or poor technique may reduce the potential difference between the recording electrodes or obscure the late positive phase of the action potential and thus diminish the peak to peak amplitude measurement. Intraindividual comparison indicated a marked difference of amplitude in opposite hands. The range of the MAP of the abductor pollicis brevis in one hand was 40.0--100% of the response in the opposite hand. For the abductor digiti minimi, the MAP was 58.5--100% of the response of the opposite hand. The median and ulnar SAP was between 50--100% of the opposite SAP. Consequent to these findings the effect of hand dominance on the amplitude of median and ulnar evoked muscle and sensory action potentials was studied in 41 right handed volunteers. The amplitudes of the median muscle action potential (p less than 0.02) and the median and ulnar sensory action potentials (p less than 0.001) were significantly less in the dominant hand. There was no significant difference between the ulnar muscle action potentials or for the median and ulnar distal motor and sensory latencies in the right and left hands of this group of volunteers.

Transport of BMAA into Neurons and Astrocytes by System xc.

PubMed

Albano, Rebecca; Lobner, Doug

2018-01-01

The study of the mechanism of β-N-methylamino-L-alanine (BMAA) neurotoxicity originally focused on its effects at the N-methyl-D-aspartate (NMDA) receptor. In recent years, it has become clear that its mechanism of action is more complicated. First, there are certain cell types, such as motor neurons and cholinergic neurons, where the dominate mechanism of toxicity is through action at AMPA receptors. Second, even in cortical neurons where the primary mechanism of toxicity appears to be activation of NMDA receptors, there are other mechanisms involved. We found that along with NMDA receptors, activation of mGLuR5 receptors and effects on the cystine/glutamate antiporter (system x c -) were involved in the toxicity. The effects on system x c - are of particular interest. System x c - mediates the transport of cystine into the cell in exchange for releasing glutamate into the extracellular fluid. By releasing glutamate, system x c - can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and in this way may protect cells against oxidative stress. We have previously published that BMAA inhibits cystine uptake leading to GSH depletion and had indirect evidence that BMAA is transported into the cells by system x c -. We now present direct evidence that BMAA is transported into both astrocytes and neurons through system x c -. The fact that BMAA is transported by system x c - also provides a mechanism for BMAA to enter brain cells potentially leading to misincorporation into proteins and protein misfolding.

[CNC proteins in physiology and pathology].

PubMed

Gęgotek, Agnieszka; Skrzydlewska, Elżbieta

2015-07-06

CNC proteins consist of Bach1, Bach2 and 4 homologous transcription factors: Nrf1, Nrf2, Nrf3 and p45NF-E2. Transcription factors belonging to this group of proteins play a crucial role in protection of cells against oxidative stress. Under physiological conditions, they remain in the cytoplasm in the inactive form or are degraded. However, in oxidative stress conditions, they are translocated to the nucleus, and bind to DNA in the ARE sequence. Consequently, there is transcription of genes encoding cytoprotective proteins, such as phase II enzymes, or low molecular weight antioxidant proteins (i.e., thioredoxin, ferritin, metallothionein) responsible for protecting cells from reactive oxygen species (ROS) action. The activity of transcriptional proteins depends directly on the redox state of the cell. ROS as second messenger signals, control inhibitors of cytoplasmic CNC proteins or potentiate the activity of kinases (MAPK, PKC, PI3K, PERK), leading to phosphorylation of transcription factors. This is conducive to translocation of these molecules into the nucleus and to formation of complexes that initiate the gene expression. Disorders of regulation of the activity of transcription factors belonging to the CNC proteins caused by gene mutations, epigenetic modifications or increased activity of p62, p21, or k-Ras, B-Raf and c-Myc oncogenes, induce changes in the level of ARE-dependent gene expression, which can lead even to the development of carcinogenesis. On the other hand, Nrf transcription factors, inducing the expression of antioxidants and enzymes responsible for the detoxification of xenobiotics, can be considered as a potential target of the action of chemopreventive factors in anticancer therapy.

Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.

PubMed

van Ginkel, Paul R; Darjatmoko, Soesiawati R; Sareen, Dhruv; Subramanian, Lalita; Bhattacharya, Saswati; Lindstrom, Mary J; Albert, Daniel M; Polans, Arthur S

2008-04-01

To test the efficacy of resveratrol, a nontoxic plant product, in the treatment of uveal melanoma. The effect of oral administration and peritumor injection of resveratrol was tested on tumor growth in two animal models of uveal melanoma. The mechanism of resveratrol action on uveal melanoma cells was studied in vitro in a cell-viability assay: with JC-1 dye, to measure mitochondrial membrane potential; by Western blot analysis, to analyze the cellular redistribution of cytochrome c and Smac/diablo; and in a fluorescence assay with specific substrates, to measure activation of different caspases. Resveratrol treatment inhibited tumor growth in animal models of uveal melanoma. Since oral administration resulted in relatively low bioavailability of resveratrol, the effect of increased local levels was tested by peritumor injection of the drug. This method resulted in tumor cell death and tumor regression. In vitro experiments with multiple uveal melanoma cell lines demonstrate that resveratrol causes a decrease in cell viability, resulting at least in part from an increase in apoptosis through a mitochondrial pathway. An early event in drug action is the direct targeting of mitochondria by resveratrol, which leads to a decrease in mitochondrial membrane potential and the eventual activation of caspase-3. These data suggest that resveratrol can inhibit tumor growth and can induce apoptosis via the intrinsic mitochondrial pathway and that by further increasing bioavailability of resveratrol the potency of the drug can be increased, leading to tumor regression. The nontoxic nature of the drug at levels needed for therapy make resveratrol an attractive candidate for the treatment of uveal melanoma.

Reduction of atrial fibrillation by Tanshinone IIA in chronic heart failure.

PubMed

He, Zhifeng; Sun, Changzheng; Xu, Yi; Cheng, Dezhi

2016-12-01

The aim of the present study was to confirm the effect of Tanshinone IIA (TAN) on the prevention of AF in chronic heart failure (CHF), and to elucidate the underlying electrophysiological mechanisms for the antiarrhythmic effects of TAN at the level of the atrium in an experimental model of CHF. In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1μm) and isoproterenol (1μm) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of TAN (10μm) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. TAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, TAN application moderately increased interatrial conduction time. TAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to prolongations of atrial post-repolarization refractoriness and a moderate increase in interatrial conduction time. Copyright © 2016. Published by Elsevier Masson SAS.

Tyrosine Phosphorylation Determines Afterdischarge Initiation by Regulating an Ionotropic Cholinergic Receptor.

PubMed

White, Sean H; Sturgeon, Raymond M; Gu, Yueling; Nensi, Alysha; Magoski, Neil S

2018-02-21

Changes to neuronal activity often involve a rapid and precise transition from low to high excitability. In the marine snail, Aplysia, the bag cell neurons control reproduction by undergoing an afterdischarge, which begins with synaptic input releasing acetylcholine to open an ionotropic cholinergic receptor. Gating of this receptor causes depolarization and a shift from silence to continuous action potential firing, leading to the neuroendocrine secretion of egg-laying hormone and ovulation. At the onset of the afterdischarge, there is a rise in intracellular Ca 2+ , followed by both protein kinase C (PKC) activation and tyrosine dephosphorylation. To determine whether these signals influence the acetylcholine ionotropic receptor, we examined the bag cell neuron cholinergic response both in culture and isolated clusters using whole-cell and/or sharp-electrode electrophysiology. The acetylcholine-induced current was not altered by increasing intracellular Ca 2+ via voltage-gated Ca 2+ channels, clamping intracellular Ca 2+ with exogenous Ca 2+ buffers, or activating PKC with phorbol esters. However, lowering phosphotyrosine levels by inhibiting tyrosine kinases both reduced the cholinergic current and prevented acetylcholine from triggering action potentials or afterdischarge-like bursts. In other systems, acetylcholine receptors are often modulated by multiple signals, but bag cell neurons appear to be more restrictive in this regard. Prior work finds that, as the afterdischarge proceeds, tyrosine dephosphorylation leads to biophysical alterations that promote persistent firing. Because this firing is subsequent to the cholinergic input, inhibiting the acetylcholine receptor may represent a means of properly orchestrating synaptically induced changes in excitability. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Ionotropic glutamate receptor GluA4 and T-type calcium channel Cav 3.1 subunits control key aspects of synaptic transmission at the mouse L5B-POm giant synapse.

PubMed

Seol, Min; Kuner, Thomas

2015-12-01

The properties and molecular determinants of synaptic transmission at giant synapses connecting layer 5B (L5B) neurons of the somatosensory cortex (S1) with relay neurons of the posteriomedial nucleus (POm) of the thalamus have not been investigated in mice. We addressed this by using direct electrical stimulation of fluorescently labelled single corticothalamic terminals combined with molecular perturbations and whole-cell recordings from POm relay neurons. Consistent with their function as drivers, we found large-amplitude excitatory postsynaptic currents (EPSCs) and multiple postsynaptic action potentials triggered by a single presynaptic action potential. To study the molecular basis of these two features, ionotropic glutamate receptors and low voltage-gated T-type calcium channels were probed by virus-mediated genetic perturbation. Loss of GluA4 almost abolished the EPSC amplitude, strongly delaying the onset of action potential generation, but maintaining the number of action potentials generated per presynaptic action potential. In contrast, knockdown of the Cav 3.1 subunit abrogated the driver function of the synapse at a typical resting membrane potential of -70 mV. However, when depolarizing the membrane potential to -60 mV, the synapse relayed single action potentials. Hence, GluA4 subunits are required to produce an EPSC sufficiently large to trigger postsynaptic action potentials within a defined time window after the presynaptic action potential, while Cav 3.1 expression is essential to establish the driver function of L5B-POm synapses at hyperpolarized membrane potentials. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Metal concentrations in cosmetics commonly used in Nigeria.

PubMed

Orisakwe, Orish Ebere; Otaraku, Jonathan Oye

2013-01-01

Trace amounts of potentially toxic metals can be either intentionally added to cosmetics or present as impurities in the raw materials. In the present study, the levels of lead, cadmium, nickel, chromium, and mercury have been assessed in 28 body creams and lotions, 10 powders, 3 soaps, 5 eye make-ups, and 4 lipsticks widely available on Nigerian markets. The increases over suggested or mandated levels of lead in these creams and lotions ranged from 6.1 to 45.9 and from 1.2 to 9.2 mg kg⁻¹ when compared with Cosmetic Ingredients Review Expert Panel 2007 and German safe maximum permissible limit of lead in cosmetics, respectively. About 61% of the body cosmetics, the lotions, and the creams contained detectable levels of nickel ranging from 1.1 to 6.4-9.2 mg kg⁻¹. Chromium and mercury were undetected in 100% of the cosmetic product. Taken together, lead and cadmium were high in creams and lotions. Most of the imported creams and creamy white coloured cosmetics contained higher levels of metal contaminants than the other colours. Regulatory Agencies in developing nations should take appropriate action for cosmetics that contain lead and cadmium beyond the reference limits.

Metal Concentrations in Cosmetics Commonly Used in Nigeria

PubMed Central

Orisakwe, Orish Ebere; Otaraku, Jonathan Oye

2013-01-01

Trace amounts of potentially toxic metals can be either intentionally added to cosmetics or present as impurities in the raw materials. In the present study, the levels of lead, cadmium, nickel, chromium, and mercury have been assessed in 28 body creams and lotions, 10 powders, 3 soaps, 5 eye make-ups, and 4 lipsticks widely available on Nigerian markets. The increases over suggested or mandated levels of lead in these creams and lotions ranged from 6.1 to 45.9 and from 1.2 to 9.2 mg kg−1 when compared with Cosmetic Ingredients Review Expert Panel 2007 and German safe maximum permissible limit of lead in cosmetics, respectively. About 61% of the body cosmetics, the lotions, and the creams contained detectable levels of nickel ranging from 1.1 to 6.4–9.2 mg kg−1. Chromium and mercury were undetected in 100% of the cosmetic product. Taken together, lead and cadmium were high in creams and lotions. Most of the imported creams and creamy white coloured cosmetics contained higher levels of metal contaminants than the other colours. Regulatory Agencies in developing nations should take appropriate action for cosmetics that contain lead and cadmium beyond the reference limits. PMID:24385889

Low concentrations of procaine and diethylaminoethanol reduce the excitability but not the action potential amplitude of hippocampal pyramidal cells.

PubMed

Butterworth, J F; Cole, L R

1990-10-01

To determine whether concentrations of diethylaminoethanol (DEAE) and procaine below those that reduce the amplitude of action potentials might alter the excitability of brain cells, a single microelectrode intracellular recording technique was used to measure firing threshold and action potential amplitude of pyramidal cells in rat hippocampal slices. At low concentrations of both DEAE (less than or equal to 5 mM) and procaine (less than or equal to 0.5 mM), firing threshold was significantly increased (P less than 0.01), whereas action potential spike amplitude was minimally altered. At higher concentrations, both drugs significantly decreased action potential spike amplitude (P less than 0.025) as well as increased firing threshold (P less than 0.001). Diethylaminoethanol tended to increase threshold relatively more than procaine, when drug concentrations that similarly reduced action potential amplitude were compared. All actions of DEAE and procaine were reversible. Inhibition of action potentials by DEAE and procaine was clearly concentration-dependent (P less than or equal to 0.015). Diethylaminoethanol effects on threshold were marginally concentration-dependent (P = 0.08); procaine did not demonstrate clear concentration-dependent effects (P = 0.33) over the concentrations tested in this study. These similar actions of procaine and DEAE on brain cells suggest a mechanism by which intravenous local anesthetics may contribute to the general anesthetic state. Moreover, it appears possible that procaine metabolism and DEAE accumulation may underlie the prolonged effects sometimes seen after intravenous procaine administration.

Minimal supergravity models of inflation

NASA Astrophysics Data System (ADS)

Ferrara, Sergio; Kallosh, Renata; Linde, Andrei; Porrati, Massimo

2013-10-01

We present a superconformal master action for a class of supergravity models with one arbitrary function defining the Jordan frame. It leads to a gauge-invariant action for a real vector multiplet, which upon gauge fixing describes a massive vector multiplet, or to a dual formulation with a linear multiplet and a massive tensor field. In both cases the models have one real scalar, the inflaton, naturally suited for single-field inflation. Vectors and tensors required by supersymmetry to complement a single real scalar do not acquire vacuum expectation values during inflation, so there is no need to stabilize the extra scalars that are always present in the theories with chiral matter multiplets. The new class of models can describe any inflaton potential that vanishes at its minimum and grows monotonically away from the minimum. In this class of supergravity models, one can fit any desirable choice of inflationary parameters ns and r.

Health consumer groups in the UK: a new social movement?

PubMed

Allsop, Judith; Jones, Kathryn; Baggott, Rob

2004-09-01

This paper argues that a health consumer movement has developed in the United Kingdom over the last decade. Drawing on two empirical studies of groups that promote and/or represent the interests of patients, users and carers, it argues that groups formed by people with personal experience of a condition are now more widespread. Feelings of pain and loss can lead to the identification of others in a similar position, and to the formation of groups and action in the political sphere. Research shows that groups share a common discourse and follow similar participative practices, and there is extensive networking. Informal and formal alliances have formed to pursue joint action and indicate a wider health consumer movement. As governments have also increased the opportunities for participation, this has the potential for patients and carers to shape services in ways more responsive to their needs.

Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets

PubMed Central

Pratheeshkumar, Poyil; Sreekala, Chakkenchath; Zhang, Zhuo; Budhraja, Amit; Ding, Songze; Son, Young-Ok; Wang, Xin; Hitron, Andrew; Hyun-Jung, Kim; Wang, Lei; Lee, Jeong-Chae; Shi, Xianglin

2016-01-01

Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions. PMID:22583402

How Canada can help global adolescent health mature.

PubMed

Vandermorris, Ashley; Bhutta, Zulfiqar A

2017-08-10

There is an emerging focus on adolescent health within the global health community as we come to recognize that the adolescent years are formative in determining health and health-related behaviours across the life-course. Such attention is not only relevant on the global scale but is imperative in Canada as well. This commentary provides a brief review of recent investments targeting global adolescent health and presents five potential avenues for action which emerged out of the recent Canadian Partnership for Women and Children's Health (CanWaCH) Global Adolescent Health conference. These avenues are: (1) Demand data; (2) Embrace complexity; (3) Be holistic; (4) Engage adolescents; and (5) Commit to Canada. As international agencies signal their commitment to global adolescent health, Canada is well-positioned to lead this call to action by espousing the fundamental adolescent health tenets of advocacy, equity, justice, and collaboration in order to move this critical agenda forward.

EVIDENCE FOR BASE EXCISION REPAIR PROCESSING OF DNA INTERSTRAND CROSSLINKS

PubMed Central

Kothandapani, Anbarasi; Patrick, Steve M

2013-01-01

Many bifunctional alkylating agents and anticancer drugs exert their cytotoxicity by producing cross links between the two complementary strands of DNA, termed interstrand crosslinks (ICLs). This blocks the strand separating processes during DNA replication and transcription, which can lead to cell cycle arrest and apoptosis. Cells use multiple DNA repair systems to eliminate the ICLs. Concerted action of repair proteins involved in Nucleotide Excision Repair and Homologous Recombination pathways are suggested to play a key role in the ICL repair. However, recent studies indicate a possible role for Base Excision Repair (BER) in mediating the cytotoxicity of ICL inducing agents in mammalian cells. Elucidating the mechanism of BER mediated modulation of ICL repair would help in understanding the recognition and removal of ICLs and aid in the development of potential therapeutic agents. In this review, the influence of BER proteins on ICL DNA repair and the possible mechanisms of action are discussed. PMID:23219605

Presynaptic ionotropic receptors controlling and modulating the rules for spike timing-dependent plasticity.

PubMed

Verhoog, Matthijs B; Mansvelder, Huibert D

2011-01-01

Throughout life, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. In line with predictions made by Hebb, synapse strength can be modified depending on the millisecond timing of action potential firing (STDP). The sign of synaptic plasticity depends on the spike order of presynaptic and postsynaptic neurons. Ionotropic neurotransmitter receptors, such as NMDA receptors and nicotinic acetylcholine receptors, are intimately involved in setting the rules for synaptic strengthening and weakening. In addition, timing rules for STDP within synapses are not fixed. They can be altered by activation of ionotropic receptors located at, or close to, synapses. Here, we will highlight studies that uncovered how network actions control and modulate timing rules for STDP by activating presynaptic ionotropic receptors. Furthermore, we will discuss how interaction between different types of ionotropic receptors may create "timing" windows during which particular timing rules lead to synaptic changes.

Australian recommendations for the integration of emergency care for older people: Consensus Statement.

PubMed

Lowthian, Judy A; Arendts, Glenn; Strivens, Edward

2018-05-07

Management of older patients during acute illness or injury does not occur in isolation in emergency departments. We aimed to develop a collaborative Consensus Statement to enunciate principles of integrated emergency care. Briefing notes, informed by research and evidence reviews, were developed and evaluated by a Consensus Working Party comprising cross-specialty representation from clinical experts, service providers, consumers and policymakers. The Consensus Working Party then convened to discuss and develop the statement's content. A subcommittee produced a draft, which was reviewed and edited by the Consensus Working Party. Consensus was reached after three rounds of discussion, with 12 principles and six recommendations for how to follow these principles, including an integrated care framework for action. Dissemination will encourage stakeholders and associated policy bodies to embrace the principles and priorities for action, potentially leading to collaborative work practices and improvement of care during and after acute illness or injury. © 2018 AJA Inc.

Magnetic dynamo action in two-dimensional turbulent magneto-hydrodynamics

NASA Technical Reports Server (NTRS)

Fyfe, D.; Joyce, G.; Montgomery, D.

1976-01-01

Two-dimensional magnetohydrodynamic turbulence is explored by means of numerical simulation. Previous analytical theory, based on non-dissipative constants of the motion in a truncated Fourier representation, is verified by following the evolution of highly non-equilibrium initial conditions numerically. Dynamo action (conversion of a significant fraction of turbulent kinetic energy into long-wavelength magnetic field energy) is observed. It is conjectured that in the presence of dissipation and external forcing, a dual cascade will be observed for zero-helicity situations. Energy will cascade to higher wave numbers simultaneously with a cascade of mean square vector potential to lower wave numbers, leading to an omni-directional magnetic energy spectrum which varies as 1/k 3 at lower wave numbers, simultaneously with a buildup of magnetic excitation at the lowest wave number of the system. Equipartition of kinetic and magnetic energies is expected at the highest wave numbers in the system.

Dissipative, forced turbulence in two-dimensional magnetohydrodynamics

NASA Technical Reports Server (NTRS)

Fyfe, D.; Montgomery, D.; Joyce, G.

1976-01-01

The equations of motion for turbulent two-dimensional magnetohydrodynamic flows are solved in the presence of finite viscosity and resistivity, for the case in which external forces (mechanical and/or magnetic) act on the fluid. The goal is to verify the existence of a magnetohydrodynamic dynamo effect which is represented mathematically by a substantial back-transfer of mean square vector potential to the longest allowed Fourier wavelengths. External forces consisting of a random part plus a fraction of the value at the previous time step are employed, after the manner of Lilly for the Navier-Stokes case. The regime explored is that for which the mechanical and magnetic Reynolds numbers are in the region of 100 to 1000. The conclusions are that mechanical forcing terms alone cannot lead to dynamo action, but that dynamo action can result from either magnetic forcing terms or from both mechanical and magnetic forcing terms simultaneously.

Testing the Motor Simulation Account of Source Errors for Actions in Recall

PubMed Central

Lange, Nicholas; Hollins, Timothy J.; Bach, Patric

2017-01-01

Observing someone else perform an action can lead to false memories of self-performance – the observation inflation effect. One explanation is that action simulation via mirror neuron activation during action observation is responsible for observation inflation by enriching memories of observed actions with motor representations. In three experiments we investigated this account of source memory failures, using a novel paradigm that minimized influences of verbalization and prior object knowledge. Participants worked in pairs to take turns acting out geometric shapes and letters. The next day, participants recalled either actions they had performed or those they had observed. Experiment 1 showed that participants falsely retrieved observed actions as self-performed, but also retrieved self-performed actions as observed. Experiment 2 showed that preventing participants from encoding observed actions motorically by taxing their motor system with a concurrent motor task did not lead to the predicted decrease in false claims of self-performance. Indeed, Experiment 3 showed that this was the case even if participants were asked to carefully monitor their recall. Because our data provide no evidence for a motor activation account, we also discussed our results in light of a source monitoring account. PMID:29033874

78 FR 34031 - Burned Area Emergency Response, Forest Service

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-06

...) Evaluate potential threats to critical values; (2) determine the risk level for each threat; (3) identify... actions that meet the objectives; (6) evaluate potential response actions on likelihood for timely... stabilization actions. Improved the descriptive guidelines for employing response actions involving...

Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ⋆

PubMed Central

Ojima, Iwao; Awasthi, Divya; Wei, Longfei; Haranahalli, Krupanandan

2016-01-01

This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed. PMID:28555087

Lead Phytochemicals for Anticancer Drug Development

PubMed Central

Singh, Sukhdev; Sharma, Bhupender; Kanwar, Shamsher S.; Kumar, Ashok

2016-01-01

Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed. PMID:27877185

Conduction velocity of action potentials measured from unidimensional latency-topography in human and frog skeletal muscle fibers.

PubMed

Homma, S; Nakajima, Y; Hayashi, K; Toma, S

1986-01-01

Conduction of an action potential along skeletal muscle fibers was graphically displayed by unidimensional latency-topography, UDLT. Since the slopes of the equipotential line were linear and the width of the line was constant, it was possible to calculate conduction velocity from the slope. To determine conduction direction of the muscle action potential elicited by electric stimulation applied directly to the muscle, surface recording electrodes were placed on a two-dimensional plane over a human muscle. Thus a bi-dimensional topography was obtained. Then, twelve or sixteen surface electrodes were placed linearly along the longitudinal direction of the action potential conduction which was disclosed by the bi-dimensional topography. Thus conduction velocity of muscle action potential in man, calculated from the slope, was for m. brachioradialis, 3.9 +/- 0.4 m/s; for m. biceps brachii, 3.6 +/- 0.2 m/s; for m. sternocleidomastoideus, 3.6 +/- 0.4 m/s. By using a tungsten microelectrode to stimulate the motor axons, a convex-like equipotential line of an action potential in UDLT was obtained from human muscle fibers. Since a similar pattern of UDLT was obtained from experiments on isolated frog muscles, in which the muscle action potential was elicited by stimulating the motor axon, it was assumed that the maximum of the curve corresponds to the end-plate region, and that the slopes on both sides indicate bi-directional conduction of the action potential.

Active action potential propagation but not initiation in thalamic interneuron dendrites

PubMed Central

Casale, Amanda E.; McCormick, David A.

2012-01-01

Inhibitory interneurons of the dorsal lateral geniculate nucleus of the thalamus modulate the activity of thalamocortical cells in response to excitatory input through the release of inhibitory neurotransmitter from both axons and dendrites. The exact mechanisms by which release can occur from dendrites are, however, not well understood. Recent experiments using calcium imaging have suggested that Na/K based action potentials can evoke calcium transients in dendrites via local active conductances, making the back-propagating action potential a candidate for dendritic neurotransmitter release. In this study, we employed high temporal and spatial resolution voltage-sensitive dye imaging to assess the characteristics of dendritic voltage deflections in response to Na/K action potentials in interneurons of the mouse dorsal lateral geniculate nucleus. We found that trains or single action potentials elicited by somatic current injection or local synaptic stimulation led to action potentials that rapidly and actively back-propagated throughout the entire dendritic arbor and into the fine filiform dendritic appendages known to release GABAergic vesicles. Action potentials always appeared first in the soma or proximal dendrite in response to somatic current injection or local synaptic stimulation, and the rapid back-propagation into the dendritic arbor depended upon voltage-gated sodium and TEA-sensitive potassium channels. Our results indicate that thalamic interneuron dendrites integrate synaptic inputs that initiate action potentials, most likely in the axon initial segment, that then back-propagate with high-fidelity into the dendrites, resulting in a nearly synchronous release of GABA from both axonal and dendritic compartments. PMID:22171033

Event-Related Potentials Discriminate Familiar and Unusual Goal Outcomes in 5-Month-Olds and Adults

ERIC Educational Resources Information Center

Michel, Christine; Kaduk, Katharina; Ní Choisdealbha, Áine; Reid, Vincent M.

2017-01-01

Previous event-related potential (ERP) work has indicated that the neural processing of action sequences develops with age. Although adults and 9-month-olds use a semantic processing system, perceiving actions activates attentional processes in 7-month-olds. However, presenting a sequence of action context, action execution and action conclusion…

Cognitive strategies take advantage of the cooperative potential of heterogeneous networks

NASA Astrophysics Data System (ADS)

Vukov, Jeromos; Santos, Francisco C.; Pacheco, Jorge M.

2012-06-01

Understanding the emergence and maintenance of cooperation is one of the most challenging topics of our time. Evolutionary game theory offers a very flexible framework within which to address this challenge. Here we use the prisoner's dilemma game to investigate the performance of individuals who are capable of adopting reactive strategies in communities structurally organized by means of Barabási-Albert scale-free networks. We find that basic cognitive abilities, such as the capability to distinguish their partners and act according to their previous actions, enable cooperation to thrive. This result is particularly significant whenever fear is the leading social tension, as this fosters retaliation, thus enforcing and sustaining cooperation. Being able to simultaneously reward fellow cooperators and punish defectors proves instrumental in achieving cooperation and the welfare of the community. As a result, central individuals can successfully lead the community and turn defective players into cooperative ones. Finally, even when participation costs—known to be detrimental to cooperation in scale-free networks—are explicitly included, we find that basic cognitive abilities have enough potential to help cooperation to prevail.

Eliminating mirror responses by instructions.

PubMed

Bardi, Lara; Bundt, Carsten; Notebaert, Wim; Brass, Marcel

2015-09-01

The observation of an action leads to the activation of the corresponding motor plan in the observer. This phenomenon of motor resonance has an important role in social interaction, promoting imitation, learning and action understanding. However, mirror responses not always have a positive impact on our behavior. An automatic tendency to imitate others can introduce interference in action execution and non-imitative or opposite responses have an advantage in some contexts. Previous studies suggest that mirror tendencies can be suppressed after extensive practice or in complementary joint action situations revealing that mirror responses are more flexible than previously thought. The aim of the present study was to gain insight into the mechanisms that allow response flexibility of motor mirroring. Here we show that the mere instruction of a counter-imitative mapping changes mirror responses as indexed by motor evoked potentials (MEPs) enhancement induced by transcranial magnetic stimulation (TMS). Importantly, mirror activation was measured while participants were passively watching finger movements, without having the opportunity to execute the task. This result suggests that the implementation of task instructions activates stimulus-response association that can overwrite the mirror representations. Our outcome reveals one of the crucial mechanisms that might allow flexible adjustments of mirror responses in different contexts. The implications of this outcome are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Systematic Evaluation of Dissolved Lead Sorption Losses to Particulate Syringe Filter Materials

EPA Science Inventory

Distinguishing between soluble and particulate lead in drinking water is useful in understanding the mechanism of lead release and identifying remedial action. Typically, particulate lead is defined as the amount of lead removed by a 0.45 µm filter. Unfortunately, there is little...

Understanding the Electrical Behavior of the Action Potential in Terms of Elementary Electrical Sources

ERIC Educational Resources Information Center

Rodriguez-Falces, Javier

2015-01-01

A concept of major importance in human electrophysiology studies is the process by which activation of an excitable cell results in a rapid rise and fall of the electrical membrane potential, the so-called action potential. Hodgkin and Huxley proposed a model to explain the ionic mechanisms underlying the formation of action potentials. However,…

Detachable glass microelectrodes for recording action potentials in active moving organs.

PubMed

Barbic, Mladen; Moreno, Angel; Harris, Tim D; Kay, Matthew W

2017-06-01

Here, we describe new detachable floating glass micropipette electrode devices that provide targeted action potential recordings in active moving organs without requiring constant mechanical constraint or pharmacological inhibition of tissue motion. The technology is based on the concept of a glass micropipette electrode that is held firmly during cell targeting and intracellular insertion, after which a 100-µg glass microelectrode, a "microdevice," is gently released to remain within the moving organ. The microdevices provide long-term recordings of action potentials, even during millimeter-scale movement of tissue in which the device is embedded. We demonstrate two different glass micropipette electrode holding and detachment designs appropriate for the heart (sharp glass microdevices for cardiac myocytes in rats, guinea pigs, and humans) and the brain (patch glass microdevices for neurons in rats). We explain how microdevices enable measurements of multiple cells within a moving organ that are typically difficult with other technologies. Using sharp microdevices, action potential duration was monitored continuously for 15 min in unconstrained perfused hearts during global ischemia-reperfusion, providing beat-to-beat measurements of changes in action potential duration. Action potentials from neurons in the hippocampus of anesthetized rats were measured with patch microdevices, which provided stable base potentials during long-term recordings. Our results demonstrate that detachable microdevices are an elegant and robust tool to record electrical activity with high temporal resolution and cellular level localization without disturbing the physiological working conditions of the organ. NEW & NOTEWORTHY Cellular action potential measurements within tissue using glass micropipette electrodes usually require tissue immobilization, potentially influencing the physiological relevance of the measurement. Here, we addressed this limitation with novel 100-µg detachable glass microelectrodes that can be precisely positioned to provide long-term measurements of action potential duration during unconstrained tissue movement. Copyright © 2017 the American Physiological Society.

Parkin Deficiency Reduces Hippocampal Glutamatergic Neurotransmission by Impairing AMPA Receptor Endocytosis.

PubMed

Cortese, Giuseppe P; Zhu, Mei; Williams, Damian; Heath, Sarah; Waites, Clarissa L

2016-11-30

Mutations in the gene encoding Parkin, an E3 ubiquitin ligase, lead to juvenile-onset Parkinson's disease by inducing the selective death of midbrain dopaminergic neurons. Accumulating evidence indicates that Parkin also has an important role in excitatory glutamatergic neurotransmission, although its precise mechanism of action remains unclear. Here, we investigate Parkin's role at glutamatergic synapses of rat hippocampal neurons. We find that Parkin-deficient neurons exhibit significantly reduced AMPA receptor (AMPAR)-mediated currents and cell-surface expression, and that these phenotypes result from decreased postsynaptic expression of the adaptor protein Homer1, which is necessary for coupling AMPAR endocytic zones with the postsynaptic density. Accordingly, Parkin loss of function leads to the reduced density of postsynaptic endocytic zones and to impaired AMPAR internalization. These findings demonstrate a novel and essential role for Parkin in glutamatergic neurotransmission, as a stabilizer of postsynaptic Homer1 and the Homer1-linked endocytic machinery necessary for maintaining normal cell-surface AMPAR levels. Mutations in Parkin, a ubiquitinating enzyme, lead to the selective loss of midbrain dopaminergic neurons and juvenile-onset Parkinson's disease (PD). Parkin loss of function has also been shown to alter hippocampal glutamatergic neurotransmission, providing a potential explanation for PD-associated cognitive impairment. However, very little is known about Parkin's specific sites or mechanisms of action at glutamatergic synapses. Here, we show that Parkin deficiency leads to decreased AMPA receptor-mediated activity due to disruption of the postsynaptic endocytic zones required for maintaining proper cell-surface AMPA receptor levels. These findings demonstrate a novel role for Parkin in synaptic AMPA receptor internalization and suggest a Parkin-dependent mechanism for hippocampal dysfunction that may explain cognitive deficits associated with some forms of PD. Copyright © 2016 the authors 0270-6474/16/3612243-16$15.00/0.

Searching for a potential antibacterial lead structure against bacterial biofilms among new naphthoquinone compounds.

PubMed

Moreira, C S; Silva, A C J A; Novais, J S; Sá Figueiredo, A M; Ferreira, V F; da Rocha, D R; Castro, H C

2017-03-01

The aims of this study were to design, synthesize and to evaluate 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against Gram-negative and Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, to probe for potential lead structures. Thirty-six new analogues were prepared with good yields using a simple, fast, operational three-procedure reaction and a thiol addition to an ο-quinone methide using microwave irradiation. All compounds were tested against Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Proteus mirabilis ATCC 15290, Serratia marcescens ATCC 14756, Klebsiella pneumoniae ATCC 4352, Enterobacter cloacae ATCC 23355, Enterococcus faecalis ATCC 29212, S. aureus ATCC 25923, Staphylococcus simulans ATCC 27851, Staphylococcus epidermidis ATCC 12228 and a hospital strain of MRSA. Their antibacterial activity was determined using the disc diffusion method, revealing the activity of 19 compounds, mainly against Gram-positive strains. Interestingly, the minimal inhibitory concentration ranges detected for the hit molecules (32-128 μg ml -1 ) were within Clinical and Laboratory Standards Institute levels. Promisingly, compound 15 affected the MRSA strain, with a reduction of up to 50% in biofilm formation, which is better than vancomycin as biofilm forms a barrier against the antibiotic that avoids its action. After probing 36 naphthoquinones for a potential antibacterial lead structure against the bacterial biofilm, we found that compound 15 should be explored further and also should be structurally modified in the near future to test against Gram-negative strains. Since vancomycin is one of the last treatment options currently available, and it is unable to inhibit biofilm, the research of new antimicrobials is urgent. In this context, 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones proved to be a promising lead structure against MRSA and bacterial biofilm. © 2016 The Society for Applied Microbiology.

Developing novel anti-fibrotic therapeutics to modulate post-surgical wound healing in glaucoma: big potential for small molecules

PubMed Central

Yu-Wai-Man, Cynthia; Khaw, Peng Tee

2015-01-01

Ocular fibrosis leads to significant visual impairment and blindness in millions of people worldwide, and is one of the largest areas of unmet need in clinical ophthalmology. The antimetabolites, mitomycin C and 5-fluorouracil, are the current gold standards used primarily to prevent fibrosis after glaucoma surgery, but have potentially blinding complications like tissue damage, breakdown and infection. This review thus focuses on the development of new classes of small molecule therapeutics to prevent post-surgical fibrosis in the eye, especially in the context of glaucoma filtration surgery. We discuss recent advances and innovations in ophthalmic wound healing research, including antibodies, RNAi, gene therapy, nanoparticles, liposomes, dendrimers, proteoglycans and small molecule inhibitors. We also review the challenges involved in terms of drug delivery, duration of action and potential toxicity of new anti-fibrotic agents in the eye. PMID:25983855

Electro-mechanical response of a 3D nerve bundle model to mechanical loads leading to axonal injury.

PubMed

Cinelli, I; Destrade, M; Duffy, M; McHugh, P

2017-07-01

Axonal damage is one of the most common pathological features of traumatic brain injury, leading to abnormalities in signal propagation for nervous systems. We present a 3D fully coupled electro-mechanical model of a nerve bundle, made with the finite element software Abaqus 6.13-3. The model includes a real-time coupling, modulated threshold for spiking activation and independent alteration of the electrical properties for each 3-layer fibre within the bundle. Compression and tension are simulated to induce damage at the nerve membrane. Changes in strain, stress distribution and neural activity are investigated for myelinated and unmyelinated nerve fibres, by considering the cases of an intact and of a traumatized nerve membrane. Results show greater changes in transmitting action potential in the myelinated fibre.

Translating novel findings of perceptual-motor codes into the neuro-rehabilitation of movement disorders.

PubMed

Pazzaglia, Mariella; Galli, Giulia

2015-01-01

The bidirectional flow of perceptual and motor information has recently proven useful as rehabilitative tool for re-building motor memories. We analyzed how the visual-motor approach has been successfully applied in neurorehabilitation, leading to surprisingly rapid and effective improvements in action execution. We proposed that the contribution of multiple sensory channels during treatment enables individuals to predict and optimize motor behavior, having a greater effect than visual input alone. We explored how the state-of-the-art neuroscience techniques show direct evidence that employment of visual-motor approach leads to increased motor cortex excitability and synaptic and cortical map plasticity. This super-additive response to multimodal stimulation may maximize neural plasticity, potentiating the effect of conventional treatment, and will be a valuable approach when it comes to advances in innovative methodologies.

Cytokines in Sepsis: Potent Immunoregulators and Potential Therapeutic Targets—An Updated View

PubMed Central

Bernhagen, Jürgen; Bucala, Richard

2013-01-01

Sepsis and septic shock are among the leading causes of death in intensive care units worldwide. Numerous studies on their pathophysiology have revealed an imbalance in the inflammatory network leading to tissue damage, organ failure, and ultimately, death. Cytokines are important pleiotropic regulators of the immune response, which have a crucial role in the complex pathophysiology underlying sepsis. They have both pro- and anti-inflammatory functions and are capable of coordinating effective defense mechanisms against invading pathogens. On the other hand, cytokines may dysregulate the immune response and promote tissue-damaging inflammation. In this review, we address the current knowledge of the actions of pro- and anti-inflammatory cytokines in sepsis pathophysiology as well as how these cytokines and other important immunomodulating agents may be therapeutically targeted to improve the clinical outcome of sepsis. PMID:23853427

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes.

PubMed

Stoney, Patrick N; Helfer, Gisela; Rodrigues, Diana; Morgan, Peter J; McCaffery, Peter

2016-03-01

Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. © 2015 Wiley Periodicals, Inc.

Quadratic adaptive algorithm for solving cardiac action potential models.

PubMed

Chen, Min-Hung; Chen, Po-Yuan; Luo, Ching-Hsing

2016-10-01

An adaptive integration method is proposed for computing cardiac action potential models accurately and efficiently. Time steps are adaptively chosen by solving a quadratic formula involving the first and second derivatives of the membrane action potential. To improve the numerical accuracy, we devise an extremum-locator (el) function to predict the local extremum when approaching the peak amplitude of the action potential. In addition, the time step restriction (tsr) technique is designed to limit the increase in time steps, and thus prevent the membrane potential from changing abruptly. The performance of the proposed method is tested using the Luo-Rudy phase 1 (LR1), dynamic (LR2), and human O'Hara-Rudy dynamic (ORd) ventricular action potential models, and the Courtemanche atrial model incorporating a Markov sodium channel model. Numerical experiments demonstrate that the action potential generated using the proposed method is more accurate than that using the traditional Hybrid method, especially near the peak region. The traditional Hybrid method may choose large time steps near to the peak region, and sometimes causes the action potential to become distorted. In contrast, the proposed new method chooses very fine time steps in the peak region, but large time steps in the smooth region, and the profiles are smoother and closer to the reference solution. In the test on the stiff Markov ionic channel model, the Hybrid blows up if the allowable time step is set to be greater than 0.1ms. In contrast, our method can adjust the time step size automatically, and is stable. Overall, the proposed method is more accurate than and as efficient as the traditional Hybrid method, especially for the human ORd model. The proposed method shows improvement for action potentials with a non-smooth morphology, and it needs further investigation to determine whether the method is helpful during propagation of the action potential. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses

PubMed Central

2017-01-01

Introduction Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. Aim The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. Methods A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. Results The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Conclusion Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors. PMID:29077727

One nuclear calcium transient induced by a single burst of action potentials represents the minimum signal strength in activity-dependent transcription in hippocampal neurons.

PubMed

Yu, Yan; Oberlaender, Kristin; Bengtson, C Peter; Bading, Hilmar

2017-07-01

Neurons undergo dramatic changes in their gene expression profiles in response to synaptic stimulation. The coupling of neuronal excitation to gene transcription is well studied and is mediated by signaling pathways activated by cytoplasmic and nuclear calcium transients. Despite this, the minimum synaptic activity required to induce gene expression remains unknown. To address this, we used cultured hippocampal neurons and cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH) that allows detection of nascent transcripts in the cell nucleus. We found that a single burst of action potentials, consisting of 24.4±5.1 action potentials during a 6.7±1.9s depolarization of 19.5±2.0mV causing a 9.3±0.9s somatic calcium transient, is sufficient to activate transcription of the immediate early gene arc (also known as Arg3.1). The total arc mRNA yield produced after a single burst-induced nuclear calcium transient was very small and, compared to unstimulated control neurons, did not lead to a significant increase in arc mRNA levels measured using quantitative reverse transcriptase PCR (qRT-PCR) of cell lysates. Significantly increased arc mRNA levels became detectable in hippocampal neurons that had undergone 5-8 consecutive burst-induced nuclear calcium transients at 0.05-0.15Hz. These results indicate that a single burst-induced nuclear calcium transient can activate gene expression and that transcription is rapidly shut off after synaptic stimulation has ceased. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fitting membrane resistance along with action potential shape in cardiac myocytes improves convergence: application of a multi-objective parallel genetic algorithm.

PubMed

Kaur, Jaspreet; Nygren, Anders; Vigmond, Edward J

2014-01-01

Fitting parameter sets of non-linear equations in cardiac single cell ionic models to reproduce experimental behavior is a time consuming process. The standard procedure is to adjust maximum channel conductances in ionic models to reproduce action potentials (APs) recorded in isolated cells. However, vastly different sets of parameters can produce similar APs. Furthermore, even with an excellent AP match in case of single cell, tissue behaviour may be very different. We hypothesize that this uncertainty can be reduced by additionally fitting membrane resistance (Rm). To investigate the importance of Rm, we developed a genetic algorithm approach which incorporated Rm data calculated at a few points in the cycle, in addition to AP morphology. Performance was compared to a genetic algorithm using only AP morphology data. The optimal parameter sets and goodness of fit as computed by the different methods were compared. First, we fit an ionic model to itself, starting from a random parameter set. Next, we fit the AP of one ionic model to that of another. Finally, we fit an ionic model to experimentally recorded rabbit action potentials. Adding the extra objective (Rm, at a few voltages) to the AP fit, lead to much better convergence. Typically, a smaller MSE (mean square error, defined as the average of the squared error between the target AP and AP that is to be fitted) was achieved in one fifth of the number of generations compared to using only AP data. Importantly, the variability in fit parameters was also greatly reduced, with many parameters showing an order of magnitude decrease in variability. Adding Rm to the objective function improves the robustness of fitting, better preserving tissue level behavior, and should be incorporated.

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses.

PubMed

Sultana, Janet; Calabró, Marco; Garcia-Serna, Ricard; Ferrajolo, Carmen; Crisafulli, Concetta; Mestres, Jordi; Trifirò', Gianluca

2017-01-01

Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors.

M3 cholinoreceptors alter electrical activity of rat left atrium via suppression of L-type Ca2+ current without affecting K+ conductance.

PubMed

Filatova, Tatiana S; Naumenko, Nikolay; Galenko-Yaroshevsky, Pavel A; Abramochkin, Denis V

2017-05-01

Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10 -5  M) in the presence of selective M2 antagonist methoctramine (10 -7  M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10 -8  M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K + currents I to , I Kur , and I Kir . In the absence of M2 blocker methoctramine, pilocarpine (10 -5  M) produced stronger attenuation of I CaL and induced an increase in I Kir . This additive inward rectifier current could be abolished by highly selective blocker of K ir 3.1/3.4 channels tertiapin-Q (10 -6  M) and therefore was identified as I KACh . Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of I CaL , but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of I KACh.

Corrective Action Decision Document/Closure Report for Corrective Action Unit 367: Area 10 Sedan, Ess and Uncle Unit Craters Nevada National Security Site, Nevada, Revision 0

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patrick Matthews

2011-06-01

Corrective Action Unit 367 comprises four corrective action sites (CASs): • 10-09-03, Mud Pit • 10-45-01, U-10h Crater (Sedan) • 10-45-02, Ess Crater Site • 10-45-03, Uncle Crater Site The purpose of this Corrective Action Decision Document/Closure Report is to provide justification and documentation of the corrective actions and site closure activities implemented at CAU 367. A corrective action of closure in place with use restrictions was completed at each of the three crater CASs (10-45-01, 10-45-02, and 10-45-03); corrective actions were not required at CAS 10-09-03. In addition, a limited soil removal corrective action was conducted at the locationmore » of a potential source material release. Based on completion of these correction actions, no additional corrective action is required at CAU 367, and site closure is considered complete. Corrective action investigation (CAI) activities were performed from February 2010 through March 2011, as set forth in the Corrective Action Investigation Plan for Corrective Action Unit 367: Area 10 Sedan, Ess and Uncle Unit Craters, Nevada Test Site, Nevada. The approach for the CAI was divided into two facets: investigation of the primary release of radionuclides, and investigation of non-test or other releases (e.g., migration in washes and potential source material). Based on the proximity of the Uncle, Ess, and Sedan craters, the impact of the Sedan test on the fallout deposited from the two earlier tests, and aerial radiological surveys, the CAU 367 investigation was designed to study the releases from the three crater CASs as one combined release (primary release). Corrective Action Site 10-09-03, Mud Pit, consists of two mud pits identified at CAU 367. The mud pits are considered non-test releases or other releases and were investigated independent of the three crater CASs. The purpose of the CAI was to fulfill data needs as defined during the data quality objective (DQO) process. The CAU 367 dataset of investigation results was evaluated based on a data quality assessment. This assessment demonstrated the dataset is complete and acceptable for use in fulfilling the DQO data needs. Analytes detected during the CAI were evaluated against final action levels (FALs) established in this document. For the primary release, radiological doses exceeding the FAL of 25 millirem per year were not found to be present in the surface or shallow subsurface soil outside the default contamination boundary. However, it was assumed that radionuclides are present in subsurface media within each of the three craters (Sedan, Ess, and Uncle) due to prompt injection of radionuclides from the tests. Based on the assumption of radiological dose exceeding the FAL, corrective actions were undertaken that consisted of implementing a use restriction and posting warning signs at each crater CAS. These use restrictions were recorded in the FFACO database; the U.S. Department of Energy, National Nuclear Security Administration Nevada Site Office (NNSA/NSO) Facility Information Management System; and the NNSA/NSO CAU/CAS files. With regard to other releases, no contaminants of concern were identified at the mud pits or any of the other release locations, with one exception. Potential source material in the form of lead was found at one location. A corrective action of clean closure was implemented at this location, and verification samples indicated that no further action is necessary. Therefore, NNSA/NSO provides the following recommendations: • A Notice of Completion to NNSA/NSO is requested from the Nevada Division of Environmental Protection for closure of CAU 367. • Corrective Action Unit 367 should be promoted from Appendix III to Appendix IV of the FFACO.« less

Lead exposure in Latin America and the Caribbean. Lead Research Group of the Pan-American Health Organization.

PubMed Central

Romieu, I; Lacasana, M; McConnell, R

1997-01-01

As a result of the rapid industrialization of Latin America and the Caribbean during the second half of this century, exposure to lead has become an increasingly important problem. To obtain an estimate of the magnitude of lead exposure in the region, we carried out a survey and a literature search on potential sources of lead exposure and on blood lead concentrations. Sixteen out of 18 Latin American and 2 out of 10 Caribbean countries responded to the survey. Lead in gasoline remains a major problem, although the lead content has decreased in many countries in the last few years. The impact of leaded fuel is more important in urban settings, given their high vehicular density. Seventy-five percent of the population of the region lives in urban areas, and children younger than 15 years of age, the most susceptible group, comprise 30% of the population. Other sources of lead exposure identified in the region included industrial emissions, battery recycling, paint and varnishes, and contaminated food and water. Lead is recognized as a priority problem by national authorities in 72% of the countries that responded to the survey, and in 50% of the countries some legislation exists to regulate the lead content in certain products. However, compliance is low. There is an urgent need for a broad-based coalition between policy makers, industry, workers, unions, health care providers, and the community to take actions to reduce environmental and occupational lead exposures in all the Latin American and Caribbean countries. Images Figure 1. Figure 2. PMID:9189704

A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy.

PubMed

Thomas, Merlin

2012-08-01

The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment. A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes. The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of individuals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.

Statins: Do they have potential in the treatment of polycystic ovary syndrome?

PubMed Central

Kodaman, Pinar H.; Duleba, Antoni J.

2010-01-01

Many women of reproductive age are affected by polycystic ovary syndrome (PCOS), a heterogeneous endocrinopathy characterized by androgen excess, chronic oligo-anovulation and/or polycystic ovarian morphology. In addition, PCOS is often associated with insulin resistance, systemic inflammation and oxidative stress which, on one hand, lead to endothelial dysfunction and dyslipidemia with subsequent cardiovascular sequelae and, on the other hand, to hyperplasia of the ovarian theca compartment with resultant hyperandrogenism and anovulation. While traditionally statins have been used to treat dyslipidemia by blocking HMG-CoA reductase, the rate limiting step in cholesterol biosynthesis; in fact, they possess pleiotropic actions, resulting in antioxidant, anti-inflammatory and anti-proliferative effects. Statins offer a novel therapeutic approach to PCOS in that they address the dyslipidemia associated with the syndrome, as well as hyperandrogenism/hyperandrogenemia. These actions may be due to an inhibition of the effects of systemic inflammation and insulin resistance/hyperinsulinemia. Evidence to date, both in vitro and in vivo, suggests that statins have potential in the treatment of PCOS; however, further clinical trials are needed before they can be considered a standard of care in the medical management of this common endocrinopathy. PMID:18181091

Secondary Metabolites from Three Florida Sponges with Antidepressant Activity

PubMed Central

Kochanowska, Anna J.; Rao, Karumanchi V.; Childress, Suzanne; El-Alfy, Abir; Matsumoto, Rae R.; Kelly, Michelle; Stewart, Gina S.; Sufka, Kenneth J.; Hamann, Mark T.

2016-01-01

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety–depression continuum model. Among the isolated compounds, 5,6-dibromo-N,N-dimethyltryptamine (1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo-N,N-dimethyltryptamine (2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs. PMID:18217716

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials.

PubMed

Pérez, Bianca C; Teixeira, Cátia; Figueiras, Marta; Gut, Jiri; Rosenthal, Philip J; Gomes, José R B; Gomes, Paula

2012-08-01

A series of cinnamic acid/4-aminoquinoline conjugates conceived to link, through a proper retro-enantio dipeptide, a heterocyclic core known to prevent hemozoin formation, to a trans-cinnamic acid motif capable of inhibiting enzyme catalytic Cys residues, were synthesized as potential dual-action antimalarials. The effect of amino acid configuration and the absence of the dipeptide spacer were also assessed. The replacement of the D-amino acids by their natural L counterparts led to a decrease in both anti-plasmodial and falcipain-inhibitory activity, suggesting that the former are preferable. Molecules with such spacer were active against blood-stage Plasmodium falciparum, in vitro, and hemozoin formation, implying that the dipeptide has a key role in mediating these two activities. In turn, compounds without spacer were better falcipain-2 inhibitors, likely because these compounds are smaller and have their vinyl bonds in closer vicinity to the catalytic Cys, as suggested by molecular modeling calculations. These novel conjugates constitute promising leads for the development of new antiplasmodials targeted at blood-stage malaria parasites. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Difficult decisions: Migration from Small Island Developing States under climate change

NASA Astrophysics Data System (ADS)

Kelman, Ilan

2015-04-01

The impacts of climate change on Small Island Developing States (SIDS) are leading to discussions regarding decision-making about the potential need to migrate. Despite the situation being well-documented, with many SIDS aiming to raise the topic to prominence and to take action for themselves, limited support and interest has been forthcoming from external sources. This paper presents, analyzes, and critiques a decision-making flowchart to support actions for SIDS dealing with climate change-linked migration. The flowchart contributes to identifying the pertinent topics to consider and the potential support needed to implement decision-making. The flowchart has significant limitations and there are topics which it cannot resolve. On-the-ground considerations include who decides, finances, implements, monitors, and enforces each decision. Additionally, views within communities differ, hence mechanisms are needed for dealing with differences, while issues to address include moral and legal blame for any climate change-linked migration, the ultimate goal of the decision-making process, the wider role of migration in SIDS communities and the right to judge decision-making and decisions. The conclusions summarize the paper, emphasizing the importance of considering contexts beyond climate change and multiple SIDS voices.

A novel framework for feature extraction in multi-sensor action potential sorting.

PubMed

Wu, Shun-Chi; Swindlehurst, A Lee; Nenadic, Zoran

2015-09-30

Extracellular recordings of multi-unit neural activity have become indispensable in neuroscience research. The analysis of the recordings begins with the detection of the action potentials (APs), followed by a classification step where each AP is associated with a given neural source. A feature extraction step is required prior to classification in order to reduce the dimensionality of the data and the impact of noise, allowing source clustering algorithms to work more efficiently. In this paper, we propose a novel framework for multi-sensor AP feature extraction based on the so-called Matched Subspace Detector (MSD), which is shown to be a natural generalization of standard single-sensor algorithms. Clustering using both simulated data and real AP recordings taken in the locust antennal lobe demonstrates that the proposed approach yields features that are discriminatory and lead to promising results. Unlike existing methods, the proposed algorithm finds joint spatio-temporal feature vectors that match the dominant subspace observed in the two-dimensional data without needs for a forward propagation model and AP templates. The proposed MSD approach provides more discriminatory features for unsupervised AP sorting applications. Copyright © 2015 Elsevier B.V. All rights reserved.

40 CFR 141.84 - Lead service line replacement requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 24 2013-07-01 2013-07-01 false Lead service line replacement... PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Control of Lead and Copper § 141.84 Lead service line replacement requirements. (a) Systems that fail to meet the lead action level in tap samples...

40 CFR 141.84 - Lead service line replacement requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 24 2012-07-01 2012-07-01 false Lead service line replacement... PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Control of Lead and Copper § 141.84 Lead service line replacement requirements. (a) Systems that fail to meet the lead action level in tap samples...

40 CFR 141.84 - Lead service line replacement requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 23 2014-07-01 2014-07-01 false Lead service line replacement... PROGRAMS (CONTINUED) NATIONAL PRIMARY DRINKING WATER REGULATIONS Control of Lead and Copper § 141.84 Lead service line replacement requirements. (a) Systems that fail to meet the lead action level in tap samples...

Evaluation of an Early-Warning System for Heat Wave-Related Mortality in Europe: Implications for Sub-seasonal to Seasonal Forecasting and Climate Services

PubMed Central

Lowe, Rachel; García-Díez, Markel; Ballester, Joan; Creswick, James; Robine, Jean-Marie; Herrmann, François R.; Rodó, Xavier

2016-01-01

Heat waves have been responsible for more fatalities in Europe over the past decades than any other extreme weather event. However, temperature-related illnesses and deaths are largely preventable. Reliable sub-seasonal-to-seasonal (S2S) climate forecasts of extreme temperatures could allow for better short-to-medium-term resource management within heat-health action plans, to protect vulnerable populations and ensure access to preventive measures well in advance. The objective of this study is to assess the extent to which S2S climate forecasts could be incorporated into heat-health action plans, to support timely public health decision-making ahead of imminent heat wave events in Europe. Forecasts of apparent temperature at different lead times (e.g., 1 day, 4 days, 8 days, up to 3 months) were used in a mortality model to produce probabilistic mortality forecasts up to several months ahead of the 2003 heat wave event in Europe. Results were compared to mortality predictions, inferred using observed apparent temperature data in the mortality model. In general, we found a decreasing transition in skill between excellent predictions when using observed temperature, to predictions with no skill when using forecast temperature with lead times greater than one week. However, even at lead-times up to three months, there were some regions in Spain and the United Kingdom where excess mortality was detected with some certainty. This suggests that in some areas of Europe, there is potential for S2S climate forecasts to be incorporated in localised heat–health action plans. In general, these results show that the performance of this climate service framework is not limited by the mortality model itself, but rather by the predictability of the climate variables, at S2S time scales, over Europe. PMID:26861369

Evaluation of an Early-Warning System for Heat Wave-Related Mortality in Europe: Implications for Sub-seasonal to Seasonal Forecasting and Climate Services.

PubMed

Lowe, Rachel; García-Díez, Markel; Ballester, Joan; Creswick, James; Robine, Jean-Marie; Herrmann, François R; Rodó, Xavier

2016-02-06

Heat waves have been responsible for more fatalities in Europe over the past decades than any other extreme weather event. However, temperature-related illnesses and deaths are largely preventable. Reliable sub-seasonal-to-seasonal (S2S) climate forecasts of extreme temperatures could allow for better short-to-medium-term resource management within heat-health action plans, to protect vulnerable populations and ensure access to preventive measures well in advance. The objective of this study is to assess the extent to which S2S climate forecasts could be incorporated into heat-health action plans, to support timely public health decision-making ahead of imminent heat wave events in Europe. Forecasts of apparent temperature at different lead times (e.g., 1 day, 4 days, 8 days, up to 3 months) were used in a mortality model to produce probabilistic mortality forecasts up to several months ahead of the 2003 heat wave event in Europe. Results were compared to mortality predictions, inferred using observed apparent temperature data in the mortality model. In general, we found a decreasing transition in skill between excellent predictions when using observed temperature, to predictions with no skill when using forecast temperature with lead times greater than one week. However, even at lead-times up to three months, there were some regions in Spain and the United Kingdom where excess mortality was detected with some certainty. This suggests that in some areas of Europe, there is potential for S2S climate forecasts to be incorporated in localised heat-health action plans. In general, these results show that the performance of this climate service framework is not limited by the mortality model itself, but rather by the predictability of the climate variables, at S2S time scales, over Europe.

Disciplinary careers of drug-impaired physicians.

PubMed

Holtman, Matthew C

2007-02-01

Alcohol and drug abuse are among the leading reasons for disciplinary action against physicians by state licensing authorities in the United States. I use event history models to describe the longitudinal patterns in disciplinary actions taken against physicians' licenses by state medical boards in the United States, 1990-2000. Adverse licensure action episodes that included discipline for drug or alcohol abuse were more likely to be followed by license restoration than episodes that did not. However, those restorations were also more likely to be followed by subsequent disciplinary action than episodes that did not include discipline for drug abuse. Furthermore, disciplinary licensure actions for drug abuse were the category most likely to be followed by a subsequent action for the same reason over the longer term (4-11 years). The increased risk of repeat disciplinary action associated with drug abuse may result in part from intensive surveillance of physicians who complete impaired physician programs, through mechanisms that include urine screening. However, it is also likely that the chronic nature of addiction leads to continued risk of relapse even among physicians receiving appropriate treatment.

Supersymmetric Dirac Born Infeld action with self-dual mass term

NASA Astrophysics Data System (ADS)

Nishino, Hitoshi; Rajpoot, Subhash; Reed, Kevin

2005-05-01

We introduce a Dirac Born Infeld action to a self-dual N = 1 supersymmetric vector multiplet in three dimensions. This action is based on the supersymmetric generalized self-duality in odd dimensions developed originally by Townsend, Pilch and van Nieuwenhuizen. Even though such a self-duality had been supposed to be very difficult to generalize to a supersymmetrically interacting system, we show that the Dirac Born Infeld action is actually compatible with supersymmetry and self-duality in three dimensions, even though the original self-duality receives corrections by the Dirac Born Infeld action. The interactions can be further generalized to arbitrary (non)polynomial interactions. As a by-product, we also show that a third-rank field strength leads to a more natural formulation of self-duality in 3D. We also show an interesting role played by the third-rank field strength leading to supersymmetry breaking, in addition to accommodating a Chern Simons form.

Effects of tacrolimus on action potential configuration and transmembrane ion currents in canine ventricular cells.

PubMed

Szabó, László; Szentandrássy, Norbert; Kistamás, Kornél; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Horváth, Balázs; Magyar, János; Bányász, Tamás; Pál, Balázs; Nánási, Péter P

2013-03-01

Tacrolimus is a commonly used immunosuppressive agent which causes cardiovascular complications, e.g., hypertension and hypertrophic cardiomyopathy. In spite of it, there is little information on the cellular cardiac effects of the immunosuppressive agent tacrolimus in larger mammals. In the present study, therefore, the concentration-dependent effects of tacrolimus on action potential morphology and the underlying ion currents were studied in canine ventricular cardiomyocytes. Standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques were applied in myocytes enzymatically dispersed from canine ventricular myocardium. Tacrolimus (3-30 μM) caused a concentration-dependent reduction of maximum velocity of depolarization and repolarization, action potential amplitude, phase-1 repolarization, action potential duration, and plateau potential, while no significant change in the resting membrane potential was observed. Conventional voltage clamp experiments revealed that tacrolimus concentrations ≥3 μM blocked a variety of ion currents, including I(Ca), I(to), I(K1), I(Kr), and I(Ks). Similar results were obtained under action potential voltage clamp conditions. These effects of tacrolimus developed rapidly and were fully reversible upon washout. The blockade of inward currents with the concomitant shortening of action potential duration in canine myocytes is the opposite of those observed previously with tacrolimus in small rodents. It is concluded that although tacrolimus blocks several ion channels at higher concentrations, there is no risk of direct interaction with cardiac ion channels when applying tacrolimus in therapeutic concentrations.

Antiviral interactions of combinations of highly potent 2,4(1H,3H)-pyrimidinedione congeners and other anti-HIV agents.

PubMed

Hartman, Tracy L; Yang, Lu; Buckheit, Robert W

2011-12-01

Structure-activity relationship evaluation of seventy-four 2,4(1H,3H)-pyrimidinedione derivatives identified seven lead compounds based on anti-HIV-1 potency, extended range of action to include HIV-2, virus entry inhibition, reverse transcriptase inhibition, and lack of cytotoxicity to human cells. The selected pyrimidinedione congeners are highly active inhibitors of HIV-1 with EC(50) values ranging from 0.6 to 2 nM in CEM-SS cells infected with laboratory derived viruses, 11-20 nM in fresh human PBMCs infected with subtype B (HT/92/599) virus, and 2-7 nM in PBMCs infected with the clinical subtype C (ZA/97/003) virus. Combination antiviral assays were performed using the laboratory adapted RF strain of HIV-1 in CEM-SS cells and with a clade B and C low passage clinical isolate in fresh human peripheral mononuclear cells and the compound interactions were analyzed using MacSynergy II. The seven pyrimidinedione compounds resulted in additive to synergistic interactions in combination with entry and fusion inhibitors, nonnucleoside and nucleoside reverse transcriptase inhibitors, and the protease inhibitors. No evidence of antagonistic antiviral activity or synergistic cytotoxicity was detected with the combinations of compounds tested. The dual mechanism of action of the pyrimidinediones resulting in inhibition of both virus entry and reverse transcription suggests excellent potential of these lead pyrimidinediones as candidates for combination therapy with other approved HIV inhibitors of varying mechanism of action. Copyright © 2011. Published by Elsevier B.V.

WCDRR and the CEOS activities on disaters

NASA Astrophysics Data System (ADS)

Petiteville, I.; Ishida, C.; Danzeglocke, J.; Eddy, A.; Gaetani, F.; Frye, S.; Kuligowski, B.; Zoffoli, S.; Poland, M.; Jones, B.

2015-04-01

Agencies from CEOS (Committee on Earth Observation Satellites) have traditionally focused their efforts on the response phase. Rapid urbanization and increased severity of weather events has led to growing economic and human losses from disasters, requiring international organisations to act now in all disaster risk management (DRM) phases, especially through improved disaster risk reduction policies and programmes. As part of this effort, CEOS agencies have initiated a series of actions aimed at fostering the use of Earth observation (EO) data to support disaster risk reduction and at raising the awareness of policy and decision-makers and major stakeholders of the benefits of using satellite EO in all phases of DRM. CEOS is developing a long-term vision for sustainable application of satellite EO to all phases of DRM. CEOS is collaborating with regional representatives of the DRM user community, on a multi-hazard project involving three thematic pilots (floods, seismic hazards and volcanoes) and a Recovery Observatory that supports resilient recovery from one major disaster. These pilot activities are meant as trail blazers that demonstrate the potential offered by satellite EO for comprehensive DRM. In the framework of the 2015 3rd World Conference on Disaster Risk Reduction (WCDRR), the CEOS space agencies intend to partner with major stakeholders, including UN organizations, the Group on Earth Observations (GEO), international relief agencies, leading development banks, and leading regional DRM organisations, to define and implement a 15-year plan of actions (2015- 2030) that responds to high-level Post-2015 Framework for Disaster Risk Reduction priorities. This plan of action will take into account lessons learned from the CEOS pilot activities.

What you find is not always what you fix--how other aspects than causes of accidents decide recommendations for remedial actions.

PubMed

Lundberg, Jonas; Rollenhagen, Carl; Hollnagel, Erik

2010-11-01

In accident investigation, the ideal is often to follow the principle "what-you-find-is-what-you-fix", an ideal reflecting that the investigation should be a rational process of first identifying causes, and then implement remedial actions to fix them. Previous research has however identified cognitive and political biases leading away from this ideal. Somewhat surprisingly, however, the same factors that often are highlighted in modern accident models are not perceived in a recursive manner to reflect how they influence the process of accident investigation in itself. Those factors are more extensive than the cognitive and political biases that are often highlighted in theory. Our purpose in this study was to reveal constraints affecting accident investigation practices that lead the investigation towards or away from the ideal of "what-you-find-is-what-you-fix". We conducted a qualitative interview study with 22 accident investigators from different domains in Sweden. We found a wide range of factors that led investigations away from the ideal, most which more resembled factors involved in organizational accidents, rather than reflecting flawed thinking. One particular limitation of investigation was that many investigations stop the analysis at the level of "preventable causes", the level where remedies that were currently practical to implement could be found. This could potentially limit the usefulness of using investigations to get a view on the "big picture" of causes of accidents as a basis for further remedial actions. 2010 Elsevier Ltd. All rights reserved.

Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

PubMed

Sarfstein, Rive; Friedman, Yael; Attias-Geva, Zohar; Fishman, Ami; Bruchim, Ilan; Werner, Haim

2013-01-01

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres.

PubMed

Hof, Thomas; Sallé, Laurent; Coulbault, Laurent; Richer, Romain; Alexandre, Joachim; Rouet, René; Manrique, Alain; Guinamard, Romain

2016-01-15

The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle. TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells. The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells. Transient receptor potential melastatin 4 (TRPM4) Ca(2+)-activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC50 of 32.8 and 36.1×10(-6) mol l(-1), respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na(+) and K(+); sensitivity to voltage, Ca(2+) and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = -0.65 ± 0.15 pA pF(-1); n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate cardiac conduction and be involved in triggering arrhythmias. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

14 CFR 1216.306 - Actions normally requiring an EIS.

Code of Federal Regulations, 2013 CFR

2013-01-01

... normally requiring an EIS. (a) NASA will prepare an EIS for actions with the potential to significantly... action or mitigation of its potentially significant impacts. (b) Typical NASA actions normally requiring... material greater than the quantity for which the NASA Nuclear Flight Safety Assurance Manager may grant...

Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects.

PubMed

Yuan, Chun-Su

2007-06-01

To review the mechanisms of action of methylnaltrexone and its effects on opioid bowel dysfunction, as well as its effects on other opioid-induced adverse effects (ADEs), and its potential roles in clinical practice. A literature search using the MEDLINE and Cochrane Collaboration databases for articles published between 1966 and March 2007 was performed. Additional data sources were obtained from manual searches of recent journal articles, book chapters, and monographs. An updated literature search showed no additional publications. Abstracts and original preclinical and clinical research reports published in the English language were identified for review. Review articles, commentaries, and news reports of this compound were excluded. Literature related to opioids, opioid receptors, opioid antagonists, methylnaltrexone, opioid-induced bowel dysfunction, constipation, nausea, and vomiting was evaluated and selected based on consideration of the support shown for the proof of concept, mechanistic findings, and timeliness. Fifty-eight original articles from preclinical studies and clinical trials using methylnaltrexone were identified. Pharmacologic action, benefits, and ADEs of methylnaltrexone were reviewed, with a focus on its effects on bowel dysfunction after opioids. Emphases were placed on its receptor binding activities and therapeutically relevant sites of action (peripheral vs central), in which peripheral opioid receptors in the body contribute to physiological and drug-induced effects. Morphine and related opioids are associated with a number of limiting ADEs, including opioid-induced bowel dysfunction. Methylnaltrexone, a quaternary derivative of naltrexone, blocks peripheral effects of opioids while sparing central analgesic effects. It is currently under late-stage clinical investigation for the treatment of opioid-induced constipation in patients with advanced illness. Reported results showed the drug to be generally well-tolerated. The rapid reversal of constipation is very encouraging. Hastening postoperative discharge may also be possible. Methylnaltrexone has the potential to prevent or treat opioid-induced peripherally mediated ADEs on bowel dysfunction without interfering with central analgesia. The study of methylnaltrexone leads to a greater understanding of the mechanisms of action of opioid pharmacology.

Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J

PubMed Central

Vitolo, Ottavio; Gong, Bing; Cao, Zixuan; Ishii, Hideki; Jaracz, Stanislav; Nakanishi, Koji; Arancio, Ottavio; Dzyuba, Sergei V.; Lefort, Roger; Shelanski, Michael

2009-01-01

A new Ginkgo biloba extract P8A (TTL), 70% enriched with terpene trilactones, prevents Aβ1-42 induced inhibition of long-term potentiation in the CA1 region of mouse hippocampal slices. This neuroprotective effect is attributed in large part to ginkgolide J that completely replicates the effect of the extract. Ginkgolide J is also capable of inhibiting cell death of rodent hippocampal neurons caused by Aβ1-42. This beneficial and multi-faceted mode of action of the ginkgolide makes it a new and promising lead in designing therapies against Alzheimer’s disease. PMID:17640772

Drug-micronutrient interactions: food for thought and thought for action.

PubMed

Karadima, Vasiliki; Kraniotou, Christina; Bellos, George; Tsangaris, George Th

2016-01-01

Micronutrients are indispensable for a variety of vital functions. Micronutrient deficiencies are a global problem concerning two billion people. In most cases, deficiencies are treatable with supplementation of the elements in lack. Drug-nutrient interactions can also lead to micronutrient reduce or depletion by various pathways. Supplementation of the elements and long-term fortification programs for populations at risk can prevent and restore the related deficiencies. Within the context of Predictive, Preventive, and Personalized Medicine, a multi-professional network should be developed in order to identify, manage, and prevent drug-micronutrient interactions that can potentially result to micronutrient deficiencies.

Insights into the disparate action of osmolytes and macromolecular crowders on amyloid formation

PubMed Central

Sukenik, Shahar

2012-01-01

It is widely recognized that amyloid formation sensitively responds to conditions set by myriad cellular solutes. These cosolutes include two important classes: macromolecular crowders and compatible osmolytes. We have recently found that addition of macromolecular PEG only slightly affects fibril formation of a model peptide in vitro. Polyol osmolytes, in contrast, lengthen the lag time for aggregation, and lead to larger fibril mass at equilibrium. To further hypothesize on the molecular underpinnings of the disparate effect of the two cosolute classes, we have further analyzed the experiments using an available kinetic mechanism describing fibril aggregation. Model calculations suggest that all cosolutes similarly lengthen the time required for nucleation, possibly due to their excluded volume effect. However, PEGs may in addition promote fibril fragmentation, leading to lag times that are overall almost unvaried. Moreover, polyols effectively slow the monomer-fibril detachment rates, thereby favoring additional fibril formation. Our analysis provides first hints that cosolutes act not only by changing association or dissociation rates, but potentially also by directing the formation of fibrils of varied morphologies with different mechanical properties. Although additional experiments are needed to unambiguously resolve the action of excluded cosolutes on amyloid formation, it is becoming clear that these compounds are important to consider in the search for ways to modulate fibril formation. PMID:22453174

Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target.

PubMed

Azad, Gajendra Kumar; Singh, Vikash; Mandal, Papita; Singh, Prabhat; Golla, Upendarrao; Baranwal, Shivani; Chauhan, Sakshi; Tomar, Raghuvir S

2014-01-01

Ebselen is a synthetic, lipid-soluble seleno-organic compound. The high electrophilicity of ebselen enables it to react with multiple cysteine residues of various proteins. Despite extensive research on ebselen, its target molecules and mechanism of action remains less understood. We performed biochemical as well as in vivo experiments employing budding yeast as a model organism to understand the mode of action of ebselen. The growth curve analysis and FACS (florescence activated cell sorting) assays revealed that ebselen exerts growth inhibitory effects on yeast cells by causing a delay in cell cycle progression. We observed that ebselen exposure causes an increase in intracellular ROS levels and mitochondrial membrane potential, and that these effects were reversed by addition of antioxidants such as reduced glutathione (GSH) or N-acetyl-l-cysteine (NAC). Interestingly, a significant increase in ROS levels was noticed in gdh3-deleted cells compared to wild-type cells. Furthermore, we showed that ebselen inhibits GDH function by interacting with its cysteine residues, leading to the formation of inactive hexameric GDH. Two-dimensional gel electrophoresis revealed protein targets of ebselen including CPR1, the yeast homolog of Cyclophilin A. Additionally, ebselen treatment leads to the inhibition of yeast sporulation. These results indicate a novel direct connection between ebselen and redox homeostasis.

Cell-type-dependent action potentials and voltage-gated currents in mouse fungiform taste buds.

PubMed

Kimura, Kenji; Ohtubo, Yoshitaka; Tateno, Katsumi; Takeuchi, Keita; Kumazawa, Takashi; Yoshii, Kiyonori

2014-01-01

Taste receptor cells fire action potentials in response to taste substances to trigger non-exocytotic neurotransmitter release in type II cells and exocytotic release in type III cells. We investigated possible differences between these action potentials fired by mouse taste receptor cells using in situ whole-cell recordings, and subsequently we identified their cell types immunologically with cell-type markers, an IP3 receptor (IP3 R3) for type II cells and a SNARE protein (SNAP-25) for type III cells. Cells not immunoreactive to these antibodies were examined as non-IRCs. Here, we show that type II cells and type III cells fire action potentials using different ionic mechanisms, and that non-IRCs also fire action potentials with either of the ionic mechanisms. The width of action potentials was significantly narrower and their afterhyperpolarization was deeper in type III cells than in type II cells. Na(+) current density was similar in type II cells and type III cells, but it was significantly smaller in non-IRCs than in the others. Although outwardly rectifying current density was similar between type II cells and type III cells, tetraethylammonium (TEA) preferentially suppressed the density in type III cells and the majority of non-IRCs. Our mathematical model revealed that the shape of action potentials depended on the ratio of TEA-sensitive current density and TEA-insensitive current one. The action potentials of type II cells and type III cells under physiological conditions are discussed. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The optimal distance between two electrode tips during recording of compound nerve action potentials in the rat median nerve

PubMed Central

Li, Yongping; Lao, Jie; Zhao, Xin; Tian, Dong; Zhu, Yi; Wei, Xiaochun

2014-01-01

The distance between the two electrode tips can greatly influence the parameters used for recording compound nerve action potentials. To investigate the optimal parameters for these recordings in the rat median nerve, we dissociated the nerve using different methods and compound nerve action potentials were orthodromically or antidromically recorded with different electrode spacings. Compound nerve action potentials could be consistently recorded using a method in which the middle part of the median nerve was intact, with both ends dissociated from the surrounding fascia and a ground wire inserted into the muscle close to the intact part. When the distance between two stimulating electrode tips was increased, the threshold and supramaximal stimulating intensity of compound nerve action potentials were gradually decreased, but the amplitude was not changed significantly. When the distance between two recording electrode tips was increased, the amplitude was gradually increased, but the threshold and supramaximal stimulating intensity exhibited no significant change. Different distances between recording and stimulating sites did not produce significant effects on the aforementioned parameters. A distance of 5 mm between recording and stimulating electrodes and a distance of 10 mm between recording and stimulating sites were found to be optimal for compound nerve action potential recording in the rat median nerve. In addition, the orthodromic compound action potential, with a biphasic waveform that was more stable and displayed less interference (however also required a higher threshold and higher supramaximal stimulus), was found to be superior to the antidromic compound action potential. PMID:25206798

Short infrared laser pulses block action potentials in neurons

NASA Astrophysics Data System (ADS)

Walsh, Alex J.; Tolstykh, Gleb P.; Martens, Stacey L.; Ibey, Bennett L.; Beier, Hope T.

2017-02-01

Short infrared laser pulses have many physiological effects on cells including the ability to stimulate action potentials in neurons. Here we show that short infrared laser pulses can also reversibly block action potentials. Primary rat hippocampal neurons were transfected with the Optopatch2 plasmid, which contains both a blue-light activated channel rhodopsin (CheRiff) and a red-light fluorescent membrane voltage reporter (QuasAr2). This optogenetic platform allows robust stimulation and recording of action potential activity in neurons in a non-contact, low noise manner. For all experiments, QuasAr2 was imaged continuously on a wide-field fluorescent microscope using a Krypton laser (647 nm) as the excitation source and an EMCCD camera operating at 1000 Hz to collect emitted fluorescence. A co-aligned Argon laser (488 nm, 5 ms at 10Hz) provided activation light for CheRiff. A 200 mm fiber delivered infrared light locally to the target neuron. Reversible action potential block in neurons was observed following a short infrared laser pulse (0.26-0.96 J/cm2; 1.37-5.01 ms; 1869 nm), with the block persisting for more than 1 s with exposures greater than 0.69 J/cm2. Action potential block was sustained for 30 s with the short infrared laser pulsed at 1-7 Hz. Full recovery of neuronal activity was observed 5-30s post-infrared exposure. These results indicate that optogenetics provides a robust platform for the study of action potential block and that short infrared laser pulses can be used for non-contact, reversible action potential block.

Medication errors: definitions and classification

PubMed Central

Aronson, Jeffrey K

2009-01-01

To understand medication errors and to identify preventive strategies, we need to classify them and define the terms that describe them. The four main approaches to defining technical terms consider etymology, usage, previous definitions, and the Ramsey–Lewis method (based on an understanding of theory and practice). A medication error is ‘a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient’. Prescribing faults, a subset of medication errors, should be distinguished from prescription errors. A prescribing fault is ‘a failure in the prescribing [decision-making] process that leads to, or has the potential to lead to, harm to the patient’. The converse of this, ‘balanced prescribing’ is ‘the use of a medicine that is appropriate to the patient's condition and, within the limits created by the uncertainty that attends therapeutic decisions, in a dosage regimen that optimizes the balance of benefit to harm’. This excludes all forms of prescribing faults, such as irrational, inappropriate, and ineffective prescribing, underprescribing and overprescribing. A prescription error is ‘a failure in the prescription writing process that results in a wrong instruction about one or more of the normal features of a prescription’. The ‘normal features’ include the identity of the recipient, the identity of the drug, the formulation, dose, route, timing, frequency, and duration of administration. Medication errors can be classified, invoking psychological theory, as knowledge-based mistakes, rule-based mistakes, action-based slips, and memory-based lapses. This classification informs preventive strategies. PMID:19594526

Action potentials and ion conductances in wild-type and CALHM1-knockout type II taste cells

PubMed Central

Saung, Wint Thu; Foskett, J. Kevin

2017-01-01

Taste bud type II cells fire action potentials in response to tastants, triggering nonvesicular ATP release to gustatory neurons via voltage-gated CALHM1-associated ion channels. Whereas CALHM1 regulates mouse cortical neuron excitability, its roles in regulating type II cell excitability are unknown. In this study, we compared membrane conductances and action potentials in single identified TRPM5-GFP-expressing circumvallate papillae type II cells acutely isolated from wild-type (WT) and Calhm1 knockout (KO) mice. The activation kinetics of large voltage-gated outward currents were accelerated in cells from Calhm1 KO mice, and their associated nonselective tail currents, previously shown to be highly correlated with ATP release, were completely absent in Calhm1 KO cells, suggesting that CALHM1 contributes to all of these currents. Calhm1 deletion did not significantly alter resting membrane potential or input resistance, the amplitudes and kinetics of Na+ currents either estimated from action potentials or recorded from steady-state voltage pulses, or action potential threshold, overshoot peak, afterhyperpolarization, and firing frequency. However, Calhm1 deletion reduced the half-widths of action potentials and accelerated the deactivation kinetics of transient outward currents, suggesting that the CALHM1-associated conductance becomes activated during the repolarization phase of action potentials. NEW & NOTEWORTHY CALHM1 is an essential ion channel component of the ATP neurotransmitter release mechanism in type II taste bud cells. Its contribution to type II cell resting membrane properties and excitability is unknown. Nonselective voltage-gated currents, previously associated with ATP release, were absent in cells lacking CALHM1. Calhm1 deletion was without effects on resting membrane properties or voltage-gated Na+ and K+ channels but contributed modestly to the kinetics of action potentials. PMID:28202574

Somatic spikes regulate dendritic signaling in small neurons in the absence of backpropagating action potentials.

PubMed

Myoga, Michael H; Beierlein, Michael; Regehr, Wade G

2009-06-17

Somatic spiking is known to regulate dendritic signaling and associative synaptic plasticity in many types of large neurons, but it is unclear whether somatic action potentials play similar roles in small neurons. Here we ask whether somatic action potentials can also influence dendritic signaling in an electrically compact neuron, the cerebellar stellate cell (SC). Experiments were conducted in rat brain slices using a combination of imaging and electrophysiology. We find that somatic action potentials elevate dendritic calcium levels in SCs. There was little attenuation of calcium signals with distance from the soma in SCs from postnatal day 17 (P17)-P19 rats, which had dendrites that averaged 60 microm in length, and in short SC dendrites from P30-P33 rats. Somatic action potentials evoke dendritic calcium increases that are not affected by blocking dendritic sodium channels. This indicates that dendritic signals in SCs do not rely on dendritic sodium channels, which differs from many types of large neurons, in which dendritic sodium channels and backpropagating action potentials allow somatic spikes to control dendritic calcium signaling. Despite the lack of active backpropagating action potentials, we find that trains of somatic action potentials elevate dendritic calcium sufficiently to release endocannabinoids and retrogradely suppress parallel fiber to SC synapses in P17-P19 rats. Prolonged SC firing at physiologically realistic frequencies produces retrograde suppression when combined with low-level group I metabotropic glutamate receptor activation. Somatic spiking also interacts with synaptic stimulation to promote associative plasticity. These findings indicate that in small neurons the passive spread of potential within dendrites can allow somatic spiking to regulate dendritic calcium signaling and synaptic plasticity.

Action potentials and ion conductances in wild-type and CALHM1-knockout type II taste cells.

PubMed

Ma, Zhongming; Saung, Wint Thu; Foskett, J Kevin

2017-05-01

Taste bud type II cells fire action potentials in response to tastants, triggering nonvesicular ATP release to gustatory neurons via voltage-gated CALHM1-associated ion channels. Whereas CALHM1 regulates mouse cortical neuron excitability, its roles in regulating type II cell excitability are unknown. In this study, we compared membrane conductances and action potentials in single identified TRPM5-GFP-expressing circumvallate papillae type II cells acutely isolated from wild-type (WT) and Calhm1 knockout (KO) mice. The activation kinetics of large voltage-gated outward currents were accelerated in cells from Calhm1 KO mice, and their associated nonselective tail currents, previously shown to be highly correlated with ATP release, were completely absent in Calhm1 KO cells, suggesting that CALHM1 contributes to all of these currents. Calhm1 deletion did not significantly alter resting membrane potential or input resistance, the amplitudes and kinetics of Na + currents either estimated from action potentials or recorded from steady-state voltage pulses, or action potential threshold, overshoot peak, afterhyperpolarization, and firing frequency. However, Calhm1 deletion reduced the half-widths of action potentials and accelerated the deactivation kinetics of transient outward currents, suggesting that the CALHM1-associated conductance becomes activated during the repolarization phase of action potentials. NEW & NOTEWORTHY CALHM1 is an essential ion channel component of the ATP neurotransmitter release mechanism in type II taste bud cells. Its contribution to type II cell resting membrane properties and excitability is unknown. Nonselective voltage-gated currents, previously associated with ATP release, were absent in cells lacking CALHM1. Calhm1 deletion was without effects on resting membrane properties or voltage-gated Na + and K + channels but contributed modestly to the kinetics of action potentials. Copyright © 2017 the American Physiological Society.

The El Paso smelter 20 years later: residual impact on Mexican children.

PubMed

Díaz-Barriga, F; Batres, L; Calderón, J; Lugo, A; Galvao, L; Lara, I; Rizo, P; Arroyave, M E; McConnell, R

1997-01-01

Although there has been considerable concern regarding cross-border industrial contamination between Mexico and the United States, there are remarkably few data. One notable case study is the smelter in El Paso, Texas. In 1974 blood lead levels higher than 40 micrograms/dl were detected in 52% of children studied near the smelter, in the adjacent Mexican community of Anapra in Ciudad Juarez, Chihuahua. Lead smelting at this plant was halted in 1985, and as a result, lead levels in air decreased sharply; consequently, children's exposure to lead and other metals should have diminished accordingly. In order to assess the effect of removal of lead emissions from the area, three geographical locations in Anapra, varying in distance from the smelter source, were evaluated for lead, arsenic, and cadmium levels in soil and for lead in blood of children. It was found that lead levels in soil were inversely correlated with distance from the smelter. Arsenic and cadmium levels in soil were constant among the three sectors. However, at residential sites closer to the smelter, a higher percentage of children was found with blood lead levels exceeding the Centers for Disease Control's action level of 10.0 micrograms/dl. In the sector closest to the border 43% of children had blood lead levels greater than 10.0 micrograms/dl. Although blood lead levels in children living in Anapra have dropped approximately fourfold in 20 years, our results indicate a moderate continued risk of lead exposure. This study demonstrates the persistent impact that may result from cross-border contamination and raises provocative questions regarding appropriate action and the responsibility for financing such action.

Reducing abrupt climate change risk using the Montreal Protocol and other regulatory actions to complement cuts in CO2 emissions

PubMed Central

Molina, Mario; Zaelke, Durwood; Sarma, K. Madhava; Andersen, Stephen O.; Ramanathan, Veerabhadran; Kaniaru, Donald

2009-01-01

Current emissions of anthropogenic greenhouse gases (GHGs) have already committed the planet to an increase in average surface temperature by the end of the century that may be above the critical threshold for tipping elements of the climate system into abrupt change with potentially irreversible and unmanageable consequences. This would mean that the climate system is close to entering if not already within the zone of “dangerous anthropogenic interference” (DAI). Scientific and policy literature refers to the need for “early,” “urgent,” “rapid,” and “fast-action” mitigation to help avoid DAI and abrupt climate changes. We define “fast-action” to include regulatory measures that can begin within 2–3 years, be substantially implemented in 5–10 years, and produce a climate response within decades. We discuss strategies for short-lived non-CO2 GHGs and particles, where existing agreements can be used to accomplish mitigation objectives. Policy makers can amend the Montreal Protocol to phase down the production and consumption of hydrofluorocarbons (HFCs) with high global warming potential. Other fast-action strategies can reduce emissions of black carbon particles and precursor gases that lead to ozone formation in the lower atmosphere, and increase biosequestration, including through biochar. These and other fast-action strategies may reduce the risk of abrupt climate change in the next few decades by complementing cuts in CO2 emissions. PMID:19822751

Rat electropharmacograms of the flavonoids rutin and quercetin in comparison to those of moclobemide and clinically used reference drugs suggest antidepressive and/or neuroprotective action.

PubMed

Dimpfel, Wilfried

2009-04-01

In order to be able to test single constituents of herbal plant extracts with respect to possible clinical usefulness, the model of local field potential analysis leading to the so-called electropharmacogram has been successfully used in rats to classify the effects of theanine and theogallin in the past. The present investigation aims at the prediction of efficacy and possible mechanisms of action of rutin and quercetin. Adult rats (day-night converted) were instrumented with four bipolar concentric electrodes into the frontal cortex, hippocampus, striatum and reticular formation. Field potentials were recorded during a pre-drug reference period of 45 min followed by oral administration of the particular test compound and 4h recording thereafter. Data were transmitted wirelessly to the computer for spectral frequency analysis. Rutin (5-80 mg/kg) as well as quercetin (5-40 mg/kg orally) produced similar electropharmacograms with dose dependent decreases of spectral alpha2 and beta1 frequencies within all brain areas. Peak effects were reached 4h after administration. The pattern of changes approached that obtained after 2.5mg/kg of moclobemide during the first hour as revealed by discriminant analysis in comparison to a large matrix of other drugs with known clinical indications. Data suggest antidepressant capabilities for rutin and quercetin with inhibition of monoamino oxidase at least as part of the mechanism of action. Both compounds should be tested clinically in patients with symptoms of depression.

Biological indicators in response to radiofrequency/microwave exposure.

PubMed

Marjanović, Ana Marija; Pavičić, Ivan; Trošić, Ivančica

2012-09-01

Over the years, due to rapid technological progress, radiation from man-made sources exceeded that of natural origin. There is a general concern regarding a growing number of appliances that use radiofrequency/ microwave (RF/MW) radiation with particular emphasis on mobile communication systems. Since nonthermal biological effects and mechanisms of RF/MW radiation are still uncertain, laboratory studies on animal models, tissues, cells, and cell free system are of extraordinary importance in bioelectromagnetic research. We believe that such investigations play a supporting role in public risk assessment. Cellular systems with the potential for a clear response to RF/MW exposures should be used in those studies. It is known that organism is a complex electrochemical system where processes of oxidation and reduction regularly occur. One of the plausible mechanisms is connected with generation of reactive oxygen species (ROS). Depending on concentration, ROS can have both beneficial and deleterious effects. Positive effects are connected with cell signalling, defence against infectious agents, and proliferative cell ability. On the other hand, excessive production, which overloads antioxidant defence mechanism, leads to cellular damage with serious potential for disease development. ROS concentration increase within the cell caused by RF/MW radiation seems to be a biologically relevant hypothesis to give clear insight into the RF/MW action at non-thermal level of radiation. In order to better understand the exact mechanism of action and its consequences, further research is needed in the field. We would like to present current knowledge on possible biological mechanisms of RF/MW actions.

Supporting clinical leadership through action: The nurse consultant role.

PubMed

Rosser, Elizabeth; Grey, Rachael; Neal, Deborah; Reeve, Julie; Smith, Caroline; Valentine, Janine

2017-12-01

To evaluate the effectiveness of an action learning set to enhance clinical leadership and extend their scope and confidence more strategically. As the most senior clinical role in most healthcare systems, the consultant nurse role is a solitary one. They are required to develop personal resilience, commitment and a belief in their ability to lead, with new consultants needing a strong support network to succeed. Following a 2-year action learning set, four nurse consultants, one therapy consultant, and a university educationalist engaged in a cooperative inquiry approach using four cycles of discussion, reflection, analysis and action over an 18-month period from March 2015-July 2016, to learn how to change and enhance their working practices. Data were analysed thematically. Four themes emerged where the action learning set (i) offered structure and support, (ii) enabled a wider influence and (iii) empowered them to lead. The cooperative inquiry helped them realise how much they had gained from their collective learning and they felt empowered to lead. Their motivation to "make a difference" remains palpable. The outcomes of the cooperative inquiry included an enhanced understanding of the importance of openness and trust and a willingness to share and learn from each other in a respectful and confidential environment with a receptiveness to change. Self-leadership has clearly been accepted and embraced, and their collaboration has improved communication across the organisation, enhanced their strategic leadership capability and given confidence to disseminate externally. The action learning set offered structure to support these clinical leaders to keep them focused across the breadth of their role. Additionally, peer review with external facilitation has enabled these clinical leaders to gain a wider influence and empowered them to lead. © 2017 John Wiley & Sons Ltd.

MITOCHONDRIAL DISEASES PART III: THERAPEUTIC INTERVENTIONS IN MOUSE MODELS OF OXPHOS DEFICIENCIES

PubMed Central

Peralta, Susana; Torraco, Alessandra; Iommarini, Luisa; Diaz, Francisca

2015-01-01

Mitochondrial defects are the cause of numerous disorders affecting the oxidative phosphorylation system (OXPHOS) in humans leading predominantly to neurological and muscular degeneration. The molecular origin, manifestations, and progression of mitochondrial diseases have a broad spectrum, which makes very challenging to find a globally effective therapy. The study of the molecular mechanisms underlying the mitochondrial dysfunction indicates that there is a wide range of pathways, enzymes and molecules that could be potentially targeted for therapeutic purpose. Therefore, focusing on the pathology of the disease is essential to design new treatments. In this review, we will summarize and discuss the different therapeutic interventions tested in some mouse models of mitochondrial diseases laying emphasis on the molecular mechanisms of action and their potential applications. PMID:25638392

Interaction of injectable neurotropic drugs with the red cell membrane.

PubMed

Reinhart, Walter H; Lubszky, Szabina; Thöny, Sandra; Schulzki, Thomas

2014-10-01

The normal red blood cell (RBC) shape is a biconcave discocyte. An intercalation of a drug in the outer half of the membrane lipid bilayer leads to echinocytosis, an intercalation in the inner half to stomatocytosis. We have used the shape transforming capacity of RBCs as a model to analyse the membrane interaction potential of various neurotropic drugs. Chlorpromazine, clomipramine, citalopram, clonazepam, and diazepam induced a reversible stomatocytosis, phenytoin induced echinocytosis, while the anticonvulsants levetiracetam, valproic acid and phenobarbital had no effect. This diversity of RBC shape transformations suggests that the pharmacological action is not linked to the membrane interaction. We conclude that this simple RBC shape transformation assay could be a useful tool to screen for potential drug interactions with cell membranes. Copyright © 2014. Published by Elsevier Ltd.

Forecasting in the presence of expectations

NASA Astrophysics Data System (ADS)

Allen, R.; Zivin, J. G.; Shrader, J.

2016-05-01

Physical processes routinely influence economic outcomes, and actions by economic agents can, in turn, influence physical processes. This feedback creates challenges for forecasting and inference, creating the potential for complementarity between models from different academic disciplines. Using the example of prediction of water availability during a drought, we illustrate the potential biases in forecasts that only take part of a coupled system into account. In particular, we show that forecasts can alter the feedbacks between supply and demand, leading to inaccurate prediction about future states of the system. Although the example is specific to drought, the problem of feedback between expectations and forecast quality is not isolated to the particular model-it is relevant to areas as diverse as population assessments for conservation, balancing the electrical grid, and setting macroeconomic policy.

Politically informed advice for climate action

NASA Astrophysics Data System (ADS)

Geden, Oliver

2018-06-01

Upward estimates for carbon budgets are unlikely to lead to action-focused climate policy. Climate researchers need to understand processes and incentives in policymaking and politics to communicate effectively.

Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications

PubMed Central

Ch’ng, Jun-Hong; Moll, Kirsten; Quintana, Maria del Pilar; Chan, Sherwin Chun Leung; Masters, Ellen; Moles, Ernest; Liu, Jianping; Eriksson, Anders B.; Wahlgren, Mats

2016-01-01

The spread of artemisinin-resistant parasites could lead to higher incidence of patients with malaria complications. However, there are no current treatments that directly dislodge sequestered parasites from the microvasculature. We show that four common antiplasmodial drugs do not disperse rosettes (erythrocyte clusters formed by malaria parasites) and therefore develop a cell-based high-throughput assay to identify potential rosette-disrupting compounds. A pilot screen of 2693 compounds identified Malaria Box compound MMV006764 as a potential candidate. Although it reduced rosetting by a modest 20%, MMV006764 was validated to be similarly effective against both blood group O and A rosettes of three laboratory parasite lines. Coupled with its antiplasmodial activity and drug-likeness, MMV006764 represents the first small-molecule compound that disrupts rosetting and could potentially be used in a resource-limited setting to treat patients deteriorating rapidly from malaria complications. Such dual-action drugs that simultaneously restore microcirculation and reduce parasite load could significantly reduce malaria morbidity and mortality. PMID:27403804

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers

PubMed Central

Hirshfield, Kim M.; Tolkunov, Denis; Zhong, Hua; Ali, Siraj M.; Stein, Mark N.; Murphy, Susan; Vig, Hetal; Vazquez, Alexei; Glod, John; Moss, Rebecca A.; Belyi, Vladimir; Chan, Chang S.; Chen, Suzie; Goodell, Lauri; Foran, David; Yelensky, Roman; Palma, Norma A.; Sun, James X.; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.; Kaufman, Howard; Poplin, Elizabeth; Mehnert, Janice; Tan, Antoinette R.; Bertino, Joseph R.; Aisner, Joseph; DiPaola, Robert S.

2016-01-01

Background. The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important. Methods. A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Results. Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0–10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing. Conclusion. Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability. Implications for Practice: Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents. PMID:27566247

A self-management approach using self-initiated action plans for symptoms with ongoing nurse support in patients with Chronic Obstructive Pulmonary Disease (COPD) and comorbidities: the COPE-III study protocol.

PubMed

Lenferink, Anke; Frith, Peter; van der Valk, Paul; Buckman, Julie; Sladek, Ruth; Cafarella, Paul; van der Palen, Job; Effing, Tanja

2013-09-01

Chronic Obstructive Pulmonary Disease (COPD) frequently coexists with other diseases. Whereas COPD action plans are currently part of usual care, they are less suitable and potentially unsafe for use in the presence of comorbidities. This study evaluates whether an innovative treatment approach directed towards COPD and frequently existing comorbidities can reduce COPD exacerbation days. We hypothesise that this approach, which combines self-initiated action plans and nurse support, will accelerate proper treatment actions and lead to better control of deteriorating symptoms. In this multicenter randomised controlled trial we aim to include 300 patients with COPD (GOLD II-IV), and with at least one comorbidity (cardiovascular disease, diabetes, anxiety and/or depression). Patients will be recruited from hospitals in the Netherlands (n = 150) and Australia (n = 150) and will be assigned to an intervention or control group. All patients will learn to complete daily symptom diaries for 12-months. Intervention group patients will participate in self-management training sessions to learn the use of individualised action plans for COPD and comorbidities, linked to the diary. The primary outcome is the number of COPD exacerbation days. Secondary outcomes include hospitalisations, quality of life, self-efficacy, adherence, patient's satisfaction and confidence, health care use and cost data. Intention-to-treat analyses (random effect negative binomial regression and random effect mixed models) and cost-effectiveness analyses will be performed. Prudence should be employed before extrapolating the use of COPD specific action plans in patients with comorbidities. This study evaluates the efficacy of tailored action plans for both COPD and common comorbidities. Copyright © 2013 Elsevier Inc. All rights reserved.

HYGIENE-AND FOOD-RELATED BEHAVIORS ASSOCIATED WITH BLOOD LEAD LEVELS OF YOUNG CHILDREN FROM LEAD-CONTAMINATED HOMES

EPA Science Inventory

Exposures associated with blood lead levels greater than 40 ug/dl in young children who live in lead-contaminated homes have been well documented. As the action level for lead is reduced, activities that contribute to lower levels of lead exposure must be identified. A child's ea...

New Sides of Aldosterone Action in Cardiovascular System as Potential Targets for Therapeutic Intervention.

PubMed

Kolodziejczyk, Patrycjusz; Gromotowicz-Poplawska, Anna; Aleksiejczuk, Michal; Chabielska, Ewa; Tutka, Piotr; Miltyk, Wojciech

2018-03-26

Aldosterone, the main mineralocorticoid hormone, plays a crucial role in the regulation of electrolyte homeostasis and blood pressure. Although, this role is undoubtedly important, it is not a hormonal action that attracts the most attention. Aldosterone seems to be very important important as a local messenger in the pathology of cardiovascular diseases (CVD). In the last few years, the attention was focused on the correlation between raised aldosterone level and increased risk of cardiovascular events. It has been demonstrated that aldosterone contributes to fibrosis, inflammation, endothelial dysfunction, fibrinolytic disordes, and oxidative stress leading to CVD development and progression. It used to be thought that the effects of aldosterone are mediated via classic nuclear receptors - mineralocorticoid receptors (MR). Now we know that the mechanism of aldosterone action in cardiovascular system is much more complex, since experimental and clinical studies indicate that MR blockade may be not sufficient to abolish aldosterone-incuced harmful effects in the cardiovascular system. Therefore, the involvement of some other than MR, receptors and factors is suggested. Moreover, in addition to the generally known genomic action of aldosterone, which involves MR activation, the nongenomic pathways are postulated in the mode of hormone action. More and more attention is focused on the membrane-coupled receptors, which mediate the rapid effects of aldosterone and have been already confirmed in different cells and tissues of a cardiovascular system. The confirmation of multiple mechanisms of aldosterone action opens a new perspective for more effective therapeutic intervention in aldosterone-related CVD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combinatorial mutagenesis of the voltage-sensing domain enables the optical resolution of action potentials firing at 60 Hz by a genetically encoded fluorescent sensor of membrane potential.

PubMed

Piao, Hong Hua; Rajakumar, Dhanarajan; Kang, Bok Eum; Kim, Eun Ha; Baker, Bradley J

2015-01-07

ArcLight is a genetically encoded fluorescent voltage sensor using the voltage-sensing domain of the voltage-sensing phosphatase from Ciona intestinalis that gives a large but slow-responding optical signal in response to changes in membrane potential (Jin et al., 2012). Fluorescent voltage sensors using the voltage-sensing domain from other species give faster yet weaker optical signals (Baker et al., 2012; Han et al., 2013). Sequence alignment of voltage-sensing phosphatases from different species revealed conserved polar and charged residues at 7 aa intervals in the S1-S3 transmembrane segments of the voltage-sensing domain, suggesting potential coil-coil interactions. The contribution of these residues to the voltage-induced optical signal was tested using a cassette mutagenesis screen by flanking each transmembrane segment with unique restriction sites to allow for the testing of individual mutations in each transmembrane segment, as well as combinations in all four transmembrane segments. Addition of a counter charge in S2 improved the kinetics of the optical response. A double mutation in the S4 domain dramatically reduced the slow component of the optical signal seen in ArcLight. Combining that double S4 mutant with the mutation in the S2 domain yielded a probe with kinetics <10 ms. Optimization of the linker sequence between S4 and the fluorescent protein resulted in a new ArcLight-derived probe, Bongwoori, capable of resolving action potentials in a hippocampal neuron firing at 60 Hz. Additional manipulation of the voltage-sensing domain could potentially lead to fluorescent sensors capable of optically resolving neuronal inhibition and subthreshold synaptic activity. Copyright © 2015 the authors 0270-6474/15/350372-15$15.00/0.

Optical cell stimulation for neuronal excitation (Conference Presentation)

NASA Astrophysics Data System (ADS)

Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

2017-02-01

Optical manipulation of cellular functions represents a growing field in biomedical sciences. The possibility to modulate specific targets with high spatial and temporal precision in a contactless manner allows a broad range of applications. Here, we present a study on stimulation of neuronal cells by optical means. As a long-term objective, we seek to improve the performance of current electric neurostimulation, especially in the context of cochlear implants. Firstly, we tested a gold nanoparticle mediated approach to modulate transmembrane conductivity by irradiation using a picosecond pulsed Nd:YAG laser at 532 nm for 40 ms in a neuroblastoma cell line (N2A) and primary murine neurons. The light absorption leads to a rapid temperature increase of the gold nanoparticles, which can induce an increased permeabilisation of the cellular membrane. Calcium transients were recorded as an indicator of neuronal activity. Although calcium signals were reliably detected upon laser irradiation, the temporal behavior did not resemble action potentials. The origin of these signals was investigated by an inhibitor study. These results indicate calcium induced calcium release (CICR) as the major source of the calcium transients. Consecutively, we tested alternative approaches for cell stimulation, such as glutamate release and optogenetics, and evaluated the potential of these methods for the application in a cochlear implant. Compared to the gold nanoparticle approach, both techniques induce less cellular stress and reliably produce action potentials.

A miniature mimic of host defense peptides with systemic antibacterial efficacy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sarig, Hadar; Livne, Liran; Held-Kuznetsov, Victoria

Oligomers of acylated lysines (OAKs) are synthetic mimics of host defense peptides (HDPs) with promising antimicrobial properties. Here we challenged the OAK concept for its ability to generate both systemically efficient and economically viable lead compounds for fighting multidrug-resistant bacteria. We describe the design and characterization of a miniature OAK composed of only 3 lysyls and 2 acyls (designated C{sub 12({omega}7)}K-{beta}{sub 12}) that preferentially targets gram-positive species by a bacteriostatic mode of action. To gain insight into the mechanism of action, we examined the interaction of OAK with various potential targets, including phospholipid bilayers, using surface plasmon resonance, and Langmuirmore » monolayers, using insertion assays, epifluorescence microscopy, and grazing incidence X-ray diffraction, in a complementary manner. Collectively, the data support the notion that C{sub 12({omega}7)}K-{beta}{sub 12} damages the plasma-membrane architecture similarly to HDPs, that is, following a near-classic 2-step interaction including high-affinity electrostatic adhesion and a subsequent shallow insertion that was limited to the phospholipid head group region. Notably, preliminary acute toxicity and efficacy studies performed with mouse models of infection have consolidated the potential of OAK for treating bacterial infections, including systemic treatments of methicillin-resistant Staphylococcus aureus. Such simple yet robust chemicals might be useful for various antibacterial applications while circumventing potential adverse effects associated with cytolytic compounds.« less

The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+)-dependence of a transient K+ current.

PubMed

Levic, Snezana; Lv, Ping; Yamoah, Ebenezer N

2011-01-01

Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+) current that regulates patterning of action potentials is I(A). This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A) are not normally classified as Ca(2+)-dependent, we demonstrate that throughout the development of chicken hair cells, I(A) is greatly reduced by acute alterations of intracellular Ca(2+). As determinants of spike timing and firing frequency, intracellular Ca(2+) buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A) are tightly regulated by intracellular Ca(2+). Such feedback mechanism between the functional expression of I(A) and intracellular Ca(2+) may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea. © 2011 Levic et al.

78 FR 23740 - Notice of Availability of a Swine Brucellosis and Pseudorabies Proposed Action Plan

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-22

...] Notice of Availability of a Swine Brucellosis and Pseudorabies Proposed Action Plan AGENCY: Animal and... proposed action plan describing a potential new approach to managing swine brucellosis and pseudorabies...-0086) a notice that made a proposed action plan describing a potential new approach to managing swine...

Comprehending Sentences with the Body: Action Compatibility in British Sign Language?

ERIC Educational Resources Information Center

Vinson, David; Perniss, Pamela; Fox, Neil; Vigliocco, Gabriella

2017-01-01

Previous studies show that reading sentences about actions leads to specific motor activity associated with actually performing those actions. We investigate how sign language input may modulate motor activation, using British Sign Language (BSL) sentences, some of which explicitly encode direction of motion, versus written English, where motion…

The SU(2) action-angle variables

NASA Technical Reports Server (NTRS)

Ellinas, Demosthenes

1993-01-01

Operator angle-action variables are studied in the frame of the SU(2) algebra, and their eigenstates and coherent states are discussed. The quantum mechanical addition of action-angle variables is shown to lead to a noncommutative Hopf algebra. The group contraction is used to make the connection with the harmonic oscillator.

Importance of Fe and Mn Pipe Deposits to Lead and Copper Rule Compliance - abstract

EPA Science Inventory

When Madison, WI exceeded the lead Action Level in 1992, residential and off-line tests suggested that lead release into the water was more complex than a lead solubility mechanism. The water utility chose to address the Lead and Copper Rule (LCR) exceedance by implementing full ...

Modulating anosognosia for hemiplegia: The role of dangerous actions in emergent awareness.

PubMed

D'Imperio, Daniela; Bulgarelli, Cristina; Bertagnoli, Sara; Avesani, Renato; Moro, Valentina

2017-07-01

Anosognosia for hemiplegia is a lack of awareness of motor deficits following a right hemisphere lesion. Residual forms of awareness co-occur with an explicit denial of hemiplegia. The term emergent awareness refers to a condition in which awareness of motor deficits is reported verbally during the actual performance of an action involving the affected body part. In this study, two tasks were used to explore the potential effects of i) attempting actions which are impossible for sufferers of hemiplegia and ii) attempting actions which are potentially dangerous. Sixteen hemiplegic patients (8 anosognosic, and 8 non-anosognosic) were asked to perform both potentially dangerous and neutral actions. Our results confirm an increase in emergent awareness in anosognosic patients during the execution of both of these types of action. Moreover, actions that are potentially dangerous improved the degree of awareness. However, lesions in the fronto-temporal areas appear to be associated with a reduced effect of action execution (emergent awareness) while lesions in the basal ganglia and amygdale and the white matter underlying the insula and fronto-temporal areas are associated with a lesser degree of improvement resulting from attempting to perform dangerous actions. Copyright © 2017 Elsevier Ltd. All rights reserved.

A rationale for lowering the blood lead action level from 10 to 2 μg/dL☆

PubMed Central

Gilbert, Steven G.; Weiss, Bernard

2008-01-01

Fifteen years ago, in 1991, the U.S. Centers for Disease Control and Prevention (CDC) established 10 μg/dL as the lowest level of concern for children’s blood lead levels. This value is extremely important because, historically, policy makers and public health officials generally have acted to remove sources of lead exposure only after the CDC’s level of concern had been exceeded. A growing body of evidence, however, reveals that blood lead levels below 10 μg/dL may impair neurobehavioral development. There is now sufficient and compelling scientific evidence for the CDC to lower the blood lead action level in children. This review argues that a level of 2 μg/dL is a useful and feasible replacement. Although it can be argued, in turn, that no threshold for the health effects of lead is demonstrable, analytically a blood level of 2 μg/dL is readily and accurately measured and provides a benchmark for successful prevention. Lowering the level of concern would encourage and accelerate the investments needed to ensure that children are protected from lead exposure in their homes, schools, and play settings. Such a program would also offer economic advantages because of the coupling between lead, educational attainment, earnings and anti-social conduct. By lowering the blood action level, CDC will promote policies and initiatives designed to further reduce children’s exposure to this potent developmental neurotoxicant. PMID:16889836

[Effect of pulse magnetic field on distribution of neuronal action potential].

PubMed

Zheng, Yu; Cai, Di; Wang, Jin-Hai; Li, Gang; Lin, Ling

2014-08-25

The biological effect on the organism generated by magnetic field is widely studied. The present study was aimed to observe the change of sodium channel under magnetic field in neurons. Cortical neurons of Kunming mice were isolated, subjected to 15 Hz, 1 mT pulse magnetic stimulation, and then the currents of neurons were recorded by whole-cell patch clamp. The results showed that, under magnetic stimulation, the activation process of Na(+) channel was delayed, and the inactivation process was accelerated. Given the classic three-layer model, the polarization diagram of cell membrane potential distribution under pulse magnetic field was simulated, and it was found that the membrane potential induced was associated with the frequency and intensity of magnetic field. Also the effect of magnetic field-induced current on action potential was simulated by Hodgkin-Huxley (H-H) model. The result showed that the generation of action potential was delayed, and frequency and the amplitudes were decreased when working current was between -1.32 μA and 0 μA. When the working current was higher than 0 μA, the generation frequency of action potential was increased, and the change of amplitudes was not obvious, and when the working current was lower than -1.32 μA, the time of rising edge and amplitudes of action potential were decreased drastically, and the action potential was unable to generate. These results suggest that the magnetic field simulation can affect the distribution frequency and amplitude of action potential of neuron via sodium channel mediation.

Importance of Pipe Deposits to Lead and Copper Rule Compliance

EPA Science Inventory

When Madison, WI exceeded the lead Action Level in 1992, residential and off-line tests suggested that lead release into the water was more complex than a simple lead solubility mechanism. In-depth scale analyses (color/texture, mineralogical and elemental composition) of 5 excav...

Intracellular recording of action potentials by nanopillar electroporation.

PubMed

Xie, Chong; Lin, Ziliang; Hanson, Lindsey; Cui, Yi; Cui, Bianxiao

2012-02-12

Action potentials have a central role in the nervous system and in many cellular processes, notably those involving ion channels. The accurate measurement of action potentials requires efficient coupling between the cell membrane and the measuring electrodes. Intracellular recording methods such as patch clamping involve measuring the voltage or current across the cell membrane by accessing the cell interior with an electrode, allowing both the amplitude and shape of the action potentials to be recorded faithfully with high signal-to-noise ratios. However, the invasive nature of intracellular methods usually limits the recording time to a few hours, and their complexity makes it difficult to simultaneously record more than a few cells. Extracellular recording methods, such as multielectrode arrays and multitransistor arrays, are non-invasive and allow long-term and multiplexed measurements. However, extracellular recording sacrifices the one-to-one correspondence between the cells and electrodes, and also suffers from significantly reduced signal strength and quality. Extracellular techniques are not, therefore, able to record action potentials with the accuracy needed to explore the properties of ion channels. As a result, the pharmacological screening of ion-channel drugs is usually performed by low-throughput intracellular recording methods. The use of nanowire transistors, nanotube-coupled transistors and micro gold-spine and related electrodes can significantly improve the signal strength of recorded action potentials. Here, we show that vertical nanopillar electrodes can record both the extracellular and intracellular action potentials of cultured cardiomyocytes over a long period of time with excellent signal strength and quality. Moreover, it is possible to repeatedly switch between extracellular and intracellular recording by nanoscale electroporation and resealing processes. Furthermore, vertical nanopillar electrodes can detect subtle changes in action potentials induced by drugs that target ion channels.

Intracellular recording of action potentials by nanopillar electroporation

NASA Astrophysics Data System (ADS)

Xie, Chong; Lin, Ziliang; Hanson, Lindsey; Cui, Yi; Cui, Bianxiao

2012-03-01

Action potentials have a central role in the nervous system and in many cellular processes, notably those involving ion channels. The accurate measurement of action potentials requires efficient coupling between the cell membrane and the measuring electrodes. Intracellular recording methods such as patch clamping involve measuring the voltage or current across the cell membrane by accessing the cell interior with an electrode, allowing both the amplitude and shape of the action potentials to be recorded faithfully with high signal-to-noise ratios. However, the invasive nature of intracellular methods usually limits the recording time to a few hours, and their complexity makes it difficult to simultaneously record more than a few cells. Extracellular recording methods, such as multielectrode arrays and multitransistor arrays, are non-invasive and allow long-term and multiplexed measurements. However, extracellular recording sacrifices the one-to-one correspondence between the cells and electrodes, and also suffers from significantly reduced signal strength and quality. Extracellular techniques are not, therefore, able to record action potentials with the accuracy needed to explore the properties of ion channels. As a result, the pharmacological screening of ion-channel drugs is usually performed by low-throughput intracellular recording methods. The use of nanowire transistors, nanotube-coupled transistors and micro gold-spine and related electrodes can significantly improve the signal strength of recorded action potentials. Here, we show that vertical nanopillar electrodes can record both the extracellular and intracellular action potentials of cultured cardiomyocytes over a long period of time with excellent signal strength and quality. Moreover, it is possible to repeatedly switch between extracellular and intracellular recording by nanoscale electroporation and resealing processes. Furthermore, vertical nanopillar electrodes can detect subtle changes in action potentials induced by drugs that target ion channels.

Action potential bursts in central snail neurons elicited by paeonol: roles of ionic currents

PubMed Central

Chen, Yi-hung; Lin, Pei-lin; Hsu, Hui-yu; Wu, Ya-ting; Yang, Han-yin; Lu, Dah-yuu; Huang, Shiang-suo; Hsieh, Ching-liang; Lin, Jaung-geng

2010-01-01

Aim: To investigate the effects of 2′-hydroxy-4′-methoxyacetophenone (paeonol) on the electrophysiological behavior of a central neuron (right parietal 4; RP4) of the giant African snail (Achatina fulica Ferussac). Methods: Intracellular recordings and the two-electrode voltage clamp method were used to study the effects of paeonol on the RP4 neuron. Results: The RP4 neuron generated spontaneous action potentials. Bath application of paeonol at a concentration of ≥500 μmol/L reversibly elicited action potential bursts in a concentration-dependent manner. Immersing the neurons in Co2+-substituted Ca2+-free solution did not block paeonol-elicited bursting. Pretreatment with the protein kinase A (PKA) inhibitor KT-5720 or the protein kinase C (PKC) inhibitor Ro 31-8220 did not affect the action potential bursts. Voltage-clamp studies revealed that paeonol at a concentration of 500 μmol/L had no remarkable effects on the total inward currents, whereas paeonol decreased the delayed rectifying K+ current (IKD) and the fast-inactivating K+ current (IA). Application of 4-aminopyridine (4-AP 5 mmol/L), an inhibitor of IA, or charybdotoxin 250 nmol/L, an inhibitor of the Ca2+-activated K+ current (IK(Ca)), failed to elicit action potential bursts, whereas tetraethylammonium chloride (TEA 50 mmol/L), an IKD blocker, successfully elicited action potential bursts. At a lower concentration of 5 mmol/L, TEA facilitated the induction of action potential bursts elicited by paeonol. Conclusion: Paeonol elicited a bursting firing pattern of action potentials in the RP4 neuron and this activity relates closely to the inhibitory effects of paeonol on the IKD. PMID:21042287

Consequences of converting graded to action potentials upon neural information coding and energy efficiency.

PubMed

Sengupta, Biswa; Laughlin, Simon Barry; Niven, Jeremy Edward

2014-01-01

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na(+) and K(+) channels, with generator potential and graded potential models lacking voltage-gated Na(+) channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na(+) channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a 'footprint' in the generator potential that obscures incoming signals. These three processes reduce information rates by ∼50% in generator potentials, to ∼3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation.

Consequences of Converting Graded to Action Potentials upon Neural Information Coding and Energy Efficiency

PubMed Central

Sengupta, Biswa; Laughlin, Simon Barry; Niven, Jeremy Edward

2014-01-01

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ∼50% in generator potentials, to ∼3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation. PMID:24465197

Synchronization of action potentials during low-magnesium-induced bursting

PubMed Central

Johnson, Sarah E.; Hudson, John L.

2015-01-01

The relationship between mono- and polysynaptic strength and action potential synchronization was explored using a reduced external Mg2+ model. Single and dual whole cell patch-clamp recordings were performed in hippocampal cultures in three concentrations of external Mg2+. In decreased Mg2+ medium, the individual cells transitioned to spontaneous bursting behavior. In lowered Mg2+ media the larger excitatory synaptic events were observed more frequently and fewer transmission failures occurred, suggesting strengthened synaptic transmission. The event synchronization was calculated for the neural action potentials of the cell pairs, and it increased in media where Mg2+ concentration was lowered. Analysis of surrogate data where bursting was present, but no direct or indirect connections existed between the neurons, showed minimal action potential synchronization. This suggests the synchronization of action potentials is a product of the strengthening synaptic connections within neuronal networks. PMID:25609103

Synchronization of action potentials during low-magnesium-induced bursting.

PubMed

Johnson, Sarah E; Hudson, John L; Kapur, Jaideep

2015-04-01

The relationship between mono- and polysynaptic strength and action potential synchronization was explored using a reduced external Mg(2+) model. Single and dual whole cell patch-clamp recordings were performed in hippocampal cultures in three concentrations of external Mg(2+). In decreased Mg(2+) medium, the individual cells transitioned to spontaneous bursting behavior. In lowered Mg(2+) media the larger excitatory synaptic events were observed more frequently and fewer transmission failures occurred, suggesting strengthened synaptic transmission. The event synchronization was calculated for the neural action potentials of the cell pairs, and it increased in media where Mg(2+) concentration was lowered. Analysis of surrogate data where bursting was present, but no direct or indirect connections existed between the neurons, showed minimal action potential synchronization. This suggests the synchronization of action potentials is a product of the strengthening synaptic connections within neuronal networks. Copyright © 2015 the American Physiological Society.

Millisecond infrared laser pulses depolarize and elicit action potentials on in-vitro dorsal root ganglion neurons

PubMed Central

Paris, Lambert; Marc, Isabelle; Charlot, Benoit; Dumas, Michel; Valmier, Jean; Bardin, Fabrice

2017-01-01

This work focuses on the optical stimulation of dorsal root ganglion (DRG) neurons through infrared laser light stimulation. We show that a few millisecond laser pulse at 1875 nm induces a membrane depolarization, which was observed by the patch-clamp technique. This stimulation led to action potentials firing on a minority of neurons beyond an energy threshold. A depolarization without action potential was observed for the majority of DRG neurons, even beyond the action potential energy threshold. The use of ruthenium red, a thermal channel blocker, stops the action potential generation, but has no effects on membrane depolarization. Local temperature measurements reveal that the depolarization amplitude is sensitive to the amplitude of the temperature rise as well as to the time rate of change of temperature, but in a way which may not fully follow a photothermal capacitive mechanism, suggesting that more complex mechanisms are involved. PMID:29082085

[Effects of dauricine on action potentials and slow inward currents of guinea pig ventricular papillary muscles].

PubMed

Li, S N; Zhang, K Y

1992-11-01

Effects of dauricine (Dau) on the action potentials (AP), the slow action potentials (SAP), and the slow inward currents (Isi) of guinea pig ventricular papillary muscles were observed by means of intracellular microelectrode and single sucrose gap voltage clamp technique. In the early stage, Dau shortened action potential duration 100 (APD100) and effective refractory period (ERP) (ERP/APD < 1; P < 0.01), but did not affect APD20 and other parameters. In the late stage, Dau prolonged APD100, ERP, and APD20, significantly decreased action potential amplitude (APA), maximum velocity (Vmax), and overshot (OS) (ERP/APD > 1; P < 0.01), greatly diminished APA and OS of SAP induced by isoprenaline (P < 0.01), and remarkably inhibited Isi (P < 0.01). The results suggested that Dau exerted an inhibitory effect on Na+, Ca2+, and K+ channels.

Simulation of axonal excitability using a Spreadsheet template created in Microsoft Excel.

PubMed

Brown, A M

2000-08-01

The objective of this present study was to implement an established simulation protocol (A.M. Brown, A methodology for simulating biological systems using Microsoft Excel, Comp. Methods Prog. Biomed. 58 (1999) 181-90) to model axonal excitability. The simulation protocol involves the use of in-cell formulas directly typed into a spreadsheet and does not require any programming skills or use of the macro language. Once the initial spreadsheet template has been set up the simulations described in this paper can be executed with a few simple keystrokes. The model axon contained voltage-gated ion channels that were modeled using Hodgkin Huxley style kinetics. The basic properties of axonal excitability modeled were: (1) threshold of action potential firing, demonstrating that not only are the stimulus amplitude and duration critical in the generation of an action potential, but also the resting membrane potential; (2) refractoriness, the phenomenon of reduced excitability immediately following an action potential. The difference between the absolute refractory period, when no amount of stimulus will elicit an action potential, and relative refractory period, when an action potential may be generated by applying increased stimulus, was demonstrated with regard to the underlying state of the Na(+) and K(+) channels; (3) temporal summation, a process by which two sub-threshold stimuli can unite to elicit an action potential was shown to be due to conductance changes outlasting the first stimulus and summing with the second stimulus-induced conductance changes to drive the membrane potential past threshold; (4) anode break excitation, where membrane hyperpolarization was shown to produce an action potential by removing Na(+) channel inactivation that is present at resting membrane potential. The simulations described in this paper provide insights into mechanisms of axonal excitation that can be carried out by following an easily understood protocol.

Optical mapping of optogenetically shaped cardiac action potentials.

PubMed

Park, Sarah A; Lee, Shin-Rong; Tung, Leslie; Yue, David T

2014-08-19

Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation.

Optical mapping of optogenetically shaped cardiac action potentials

PubMed Central

Park, Sarah A.; Lee, Shin-Rong; Tung, Leslie; Yue, David T.

2014-01-01

Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation. PMID:25135113

Marine Corps Energy: Instilling an Ethos of Energy Efficiency

DTIC Science & Technology

2012-03-20

promulgate this vision and strategy. Of course, as Kotter warns, the vision is never really in threat of being over-communicated. The Marine Corps always...the stages of creating major change John Kotter recommends in Leading Change to determine whether those actions are sufficient to bring about the...Corps against the stages of creating major change John Kotter recommends in Leading Change to determine whether those actions are sufficient to bring

Injury risk associated with playing actions during competitive soccer

PubMed Central

Rahnama, N; Reilly, T; Lees, A

2002-01-01

Objective: To assess the exposure of players to injury risk during English Premier League soccer matches in relation to selected factors. Methods: Injury risk was assessed by rating the injury potential of playing actions during competition with respect to (a) type of playing action, (b) period of the game, (c) zone of the pitch, and (d) playing either at home or away. In all, 10 games from the English Premier League 1999–2000 were chosen for analysis. A notation system was used whereby 16 soccer specific playing actions were classified into three categories: those inducing actual injury, those with a potential for injury (graded as mild, moderate, or high), and those deemed to have no potential for injury. The pitch was divided into 18 zones, and the position of each event was recorded along with time elapsed in the game, enabling six 15 minute periods to be defined. Results: Close to 18 000 actions were notated. On average (mean (SD)), 1788 (73) events (one every three seconds), 767 (99) events with injury potential (one every six seconds), and 2 (1) injuries (one every 45 minutes) per game were recorded. An overall injury incidence of 53 per 1000 playing hours was calculated. Receiving a tackle, receiving a "charge", and making a tackle were categorised as having a substantial injury risk, and goal catch, goal punch, kicking the ball, shot on goal, set kick, and heading the ball were all categorised as having a significant injury risk. All other actions were deemed low in risk. The first 15 minutes of each half contained the highest number of actions with mild injury potential, the last 15 minutes having the highest number of actions with moderate injury potential (p<0.01). The first and last 15 minutes of the game had the highest number of actions with high injury potential, although not significant. More actions with mild injury potential occurred in the goal area, and more actions with moderate and high injury potential occurred in the zone adjacent to the goal area (p<0.001). There was no significant difference between home and away with regard to injury potential. Conclusions: Playing actions with high injury risk were linked to contesting possession. Injury risk was highest in the first and last 15 minutes of the game, reflecting the intense engagements in the opening period and the possible effect of fatigue in the closing period. Injury risk was concentrated in the areas of the pitch where possession of the ball is most vigorously contested, which were specific attacking and defending zones close to the goal. Injury potential was no greater in away matches than at home. PMID:12351333

Chronic social isolation suppresses proplastic response and promotes proapoptotic signalling in prefrontal cortex of Wistar rats.

PubMed

Djordjevic, Ana; Adzic, Miroslav; Djordjevic, Jelena; Radojcic, Marija B

2010-08-15

Successful adaptation to stress involves synergized actions of glucocorticoids and catecholamines at several levels of the CNS, including the prefrontal cortex (PFC). Inside the PFC, hormonal signals trigger concerted actions of transcriptional factors, such as glucocorticoid receptor (GR) and nuclear factor kappa B (NFkappaB), culminating in a balanced, proadaptive expression of their common genes, such as proplastic NCAM and/or apoptotic Bax and Bcl-2. In the present study, we hypothesized that chronic stress may compromise the balance between GR and NFkappaB signals and lead to an altered/maladaptive expression of their cognate genes in the PFC. Our results obtained with Wistar rats exposed to chronic social isolation indicated alterations of the GR relative to the NFkappaB, in favor of the GR, in both the cytoplasmic and the nuclear compartments of the PFC. Although these alterations did not affect the induction of proplastic NCAM gene, they decreased the NCAM sialylation necessary for plastic response and caused marked relocation of the mitochondrial membrane antiapoptotic Bcl-2 protein to its cytoplasmic form. Moreover, the compromised PSA-NCAM plastic response found under chronic stress was sustained after exposure of animals to the subsequent acute stress, whereas the proapoptotic signals were further emphasized. It is concluded that chronic social isolation of Wistar animals leads to a maladaptive response of the PFC, considering the diminishment of its plastic potential and potentiating of apoptosis. Such conditions in the PFC are likely to compromise its ability to interact with other CNS structures, such as the hippocampus, which is necessary for successful adaptation to stress. (c) 2010 Wiley-Liss, Inc.

Elevated heart rate triggers action potential alternans and sudden death. translational study of a homozygous KCNH2 mutation.

PubMed

Schweigmann, Ulrich; Biliczki, Peter; Ramirez, Rafael J; Marschall, Christoph; Takac, Ina; Brandes, Ralf P; Kotzot, Dieter; Girmatsion, Zenawit; Hohnloser, Stefan H; Ehrlich, Joachim R

2014-01-01

Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.

Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model.

PubMed

Toib, Amir; Zhang, Chen; Borghetti, Giulia; Zhang, Xiaoxiao; Wallner, Markus; Yang, Yijun; Troupes, Constantine D; Kubo, Hajime; Sharp, Thomas E; Feldsott, Eric; Berretta, Remus M; Zalavadia, Neil; Trappanese, Danielle M; Harper, Shavonn; Gross, Polina; Chen, Xiongwen; Mohsin, Sadia; Houser, Steven R

2017-09-01

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na + and Ca 2+ in the development of HCM, but the role of repolarizing K + currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K + currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K + currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K + channel subunits. In conclusion, decrease in repolarizing K + currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility. NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K + currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. Copyright © 2017 the American Physiological Society.

Detecting extinction risk from climate change by IUCN Red List criteria.

PubMed

Keith, David A; Mahony, Michael; Hines, Harry; Elith, Jane; Regan, Tracey J; Baumgartner, John B; Hunter, David; Heard, Geoffrey W; Mitchell, Nicola J; Parris, Kirsten M; Penman, Trent; Scheele, Ben; Simpson, Christopher C; Tingley, Reid; Tracy, Christopher R; West, Matt; Akçakaya, H Resit

2014-06-01

Anthropogenic climate change is a key threat to global biodiversity. To inform strategic actions aimed at conserving biodiversity as climate changes, conservation planners need early warning of the risks faced by different species. The IUCN Red List criteria for threatened species are widely acknowledged as useful risk assessment tools for informing conservation under constraints imposed by limited data. However, doubts have been expressed about the ability of the criteria to detect risks imposed by potentially slow-acting threats such as climate change, particularly because criteria addressing rates of population decline are assessed over time scales as short as 10 years. We used spatially explicit stochastic population models and dynamic species distribution models projected to future climates to determine how long before extinction a species would become eligible for listing as threatened based on the IUCN Red List criteria. We focused on a short-lived frog species (Assa darlingtoni) chosen specifically to represent potential weaknesses in the criteria to allow detailed consideration of the analytical issues and to develop an approach for wider application. The criteria were more sensitive to climate change than previously anticipated; lead times between initial listing in a threatened category and predicted extinction varied from 40 to 80 years, depending on data availability. We attributed this sensitivity primarily to the ensemble properties of the criteria that assess contrasting symptoms of extinction risk. Nevertheless, we recommend the robustness of the criteria warrants further investigation across species with contrasting life histories and patterns of decline. The adequacy of these lead times for early warning depends on practicalities of environmental policy and management, bureaucratic or political inertia, and the anticipated species response times to management actions. © 2014 Society for Conservation Biology.

Assessing the skill of seasonal meteorological forecast products for predicting droughts and water scarcity in highly regulated basins

NASA Astrophysics Data System (ADS)

Squeri, Marika; Giuliani, Matteo; Castelletti, Andrea; Pulido-Velazquez, Manuel; Marcos-Garcia, Patricia; Macian-Sorribes, Hector

2017-04-01

Drought and water scarcity are important issues in Southern Europe and many predictions suggest that their frequency and severity will increase over the next years, potentially leading to negative environmental and socio-economic impacts. This work focuses on the Jucar river basin, located in the hinterland of Valencia (Eastern Spain), which is historically affected by long and severe dry periods that negatively impact several economic sectors, with irrigated agriculture representing the main consumptive demand in the basin (79%). Monitoring drought and water scarcity is crucial to activate timely drought management strategies in the basin. However, most traditional drought indexes fail in detecting critical events due to the large presence of human regulation supporting the irrigated agriculture. Over the last 20 years, a sophisticated drought monitoring system has been set up to properly capture the status of the catchment by means of the state index, a weighted linear combination of twelve indicators that depends on observations of precipitation, streamflow, reservoirs' storages and groundwater levels in representative locations at the basin. In this work, we explore the possibility of predicting the state index, which is currently used only as a monitoring tool, in order to prompt anticipatory actions before the drought/water scarcity event starts. In particular, we test the forecasting skill of retrospective seasonal meteorological predictions from the European Centre for Medium-range Weather Forecasts (ECMWF) System 4. The 7-months lead time of these products allows predicting in February the values of the state index until September, thus covering the entire agricultural season. Preliminary results suggest that the Sys4-ECMWF products are skillful in predicting the state index, potentially supporting the design of anticipatory drought management actions.

Putting the public (back) into public health: leadership, evidence and action.

PubMed

South, J; Connolly, A M; Stansfield, J A; Johnstone, P; Henderson, G; Fenton, K A

2018-03-13

There is a strong evidence-based rationale for community capacity building and community empowerment as part of a strategic response to reduce health inequalities. Within the current UK policy context, there are calls for increased public engagement in prevention and local decision-making in order to give people greater control over the conditions that determine health. With reference to the challenges and opportunities within the English public health system, this essay seeks to open debate about what is required to mainstream community-centred approaches and ensure that the public is central to public health. The essay sets out the case for a reorientation of public health practice in order to build impactful action with communities at scale leading to a reduction in the health gap. National frameworks that support local practice are described. Four areas of challenge that could potentially drive an implementation gap are discussed: (i) achieving integration and scale, (ii) effective community mobilization, (iii) evidencing impact and (iv) achieving a shift in power. The essay concludes with a call to action for developing a contemporary public health practice that is rooted in communities and offers local leadership to strengthen local assets, increase community control and reduce health inequalities.

Poverty and child health in the UK: using evidence for action.

PubMed

Wickham, Sophie; Anwar, Elspeth; Barr, Ben; Law, Catherine; Taylor-Robinson, David

2016-08-01

There are currently high levels of child poverty in the UK, and for the first time in almost two decades child poverty has started to rise in absolute terms. Child poverty is associated with a wide range of health-damaging impacts, negative educational outcomes and adverse long-term social and psychological outcomes. The poor health associated with child poverty limits children's potential and development, leading to poor health and life chances in adulthood. This article outlines some key definitions with regard to child poverty, reviews the links between child poverty and a range of health, developmental, behavioural and social outcomes for children, describes gaps in the evidence base and provides an overview of current policies relevant to child poverty in the UK. Finally, the article outlines how child health professionals can take action by (1) supporting policies to reduce child poverty, (2) providing services that reduce the health consequences of child poverty and (3) measuring and understanding the problem and assessing the impact of action. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Preventive and Prophylactic Mechanisms of Action of Pomegranate Bioactive Constituents

PubMed Central

Viladomiu, Monica; Hontecillas, Raquel; Lu, Pinyi; Bassaganya-Riera, Josep

2013-01-01

Pomegranate fruit presents strong anti-inflammatory, antioxidant, antiobesity, and antitumoral properties, thus leading to an increased popularity as a functional food and nutraceutical source since ancient times. It can be divided into three parts: seeds, peel, and juice, all of which seem to have medicinal benefits. Several studies investigate its bioactive components as a means to associate them with a specific beneficial effect and develop future products and therapeutic applications. Many beneficial effects are related to the presence of ellagic acid, ellagitannins (including punicalagins), punicic acid and other fatty acids, flavonoids, anthocyanidins, anthocyanins, estrogenic flavonols, and flavones, which seem to be its most therapeutically beneficial components. However, the synergistic action of the pomegranate constituents appears to be superior when compared to individual constituents. Promising results have been obtained for the treatment of certain diseases including obesity, insulin resistance, intestinal inflammation, and cancer. Although moderate consumption of pomegranate does not result in adverse effects, future studies are needed to assess safety and potential interactions with drugs that may alter the bioavailability of bioactive constituents of pomegranate as well as drugs. The aim of this review is to summarize the health effects and mechanisms of action of pomegranate extracts in chronic inflammatory diseases. PMID:23737845

76 FR 70975 - Petition Requesting Exception From Lead Content Limits

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-16

... Exception From Lead Content Limits AGENCY: Consumer Product Safety Commission. ACTION: Notice. SUMMARY: The... requesting an exception from the 100 ppm lead content limit under section 101(b) of the Consumer Product... younger that contain lead content in excess of 100 ppm are considered to be banned hazardous substances...

PREDICTING LEAD DISSOLUTION IN DRINKING WATER DISTRIBUTION SYSTEMS: EFFECT OF FLUORIDE ADDITIVES ON LEAD SOLUBILITY AND CORROSION

EPA Science Inventory

Many water systems have encountered difficulties in meeting the action levels established by the Lead and Copper Rule. Several chemical parameters contribute to the corrosion of lead plumbing and may influence the nature of the passivating films formed on distribution materials....

40 CFR 35.6115 - Political subdivision-lead remedial Cooperative Agreements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Political subdivision-lead remedial... subdivision-lead remedial Cooperative Agreements. (a) General. If the State concurs, EPA may allow a political.... If it is designated the lead for remedial action, the political subdivision must provide the...

24 CFR 570.461 - Post-preliminary approval requirements; lead-based paint.

Code of Federal Regulations, 2011 CFR

2011-04-01

... requirements; lead-based paint. 570.461 Section 570.461 Housing and Urban Development Regulations Relating to... GRANTS Urban Development Action Grants § 570.461 Post-preliminary approval requirements; lead-based paint. The recipient may receive preliminary approval prior to the accomplishment of lead-based paint...

24 CFR 570.461 - Post-preliminary approval requirements; lead-based paint.

Code of Federal Regulations, 2013 CFR

2013-04-01

... requirements; lead-based paint. 570.461 Section 570.461 Housing and Urban Development Regulations Relating to... GRANTS Urban Development Action Grants § 570.461 Post-preliminary approval requirements; lead-based paint. The recipient may receive preliminary approval prior to the accomplishment of lead-based paint...

24 CFR 570.461 - Post-preliminary approval requirements; lead-based paint.

Code of Federal Regulations, 2012 CFR

2012-04-01

... requirements; lead-based paint. 570.461 Section 570.461 Housing and Urban Development Regulations Relating to... GRANTS Urban Development Action Grants § 570.461 Post-preliminary approval requirements; lead-based paint. The recipient may receive preliminary approval prior to the accomplishment of lead-based paint...

40 CFR 35.6055 - State-lead pre-remedial Cooperative Agreements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 1 2013-07-01 2013-07-01 false State-lead pre-remedial Cooperative... for Superfund Response Actions Pre-Remedial Response Cooperative Agreements § 35.6055 State-lead pre-remedial Cooperative Agreements. (a) To receive a State-lead pre-remedial Cooperative Agreement, the...

24 CFR 570.461 - Post-preliminary approval requirements; lead-based paint.

Code of Federal Regulations, 2014 CFR

2014-04-01

... requirements; lead-based paint. 570.461 Section 570.461 Housing and Urban Development Regulations Relating to... GRANTS Urban Development Action Grants § 570.461 Post-preliminary approval requirements; lead-based paint. The recipient may receive preliminary approval prior to the accomplishment of lead-based paint...

40 CFR 35.6115 - Political subdivision-lead remedial Cooperative Agreements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Political subdivision-lead remedial... subdivision-lead remedial Cooperative Agreements. (a) General. If the State concurs, EPA may allow a political.... If it is designated the lead for remedial action, the political subdivision must provide the...

40 CFR 35.6115 - Political subdivision-lead remedial Cooperative Agreements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Political subdivision-lead remedial... subdivision-lead remedial Cooperative Agreements. (a) General. If the State concurs, EPA may allow a political.... If it is designated the lead for remedial action, the political subdivision must provide the...

40 CFR 35.6115 - Political subdivision-lead remedial Cooperative Agreements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Political subdivision-lead remedial... subdivision-lead remedial Cooperative Agreements. (a) General. If the State concurs, EPA may allow a political.... If it is designated the lead for remedial action, the political subdivision must provide the...

Impact of DIC, Sulfate and Chloride on Pb(II) Solubility

EPA Science Inventory

Corrosion of lead and the subsequent release of lead into drinking water distribution systems pose a concern to public health. Consequently, the U.S. Environmental Protection Agency’s (U.S. EPA) Lead and Copper rule established an action level for lead at the consumer’s tap of 0....

40 CFR 35.6115 - Political subdivision-lead remedial Cooperative Agreements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Political subdivision-lead remedial... subdivision-lead remedial Cooperative Agreements. (a) General. If the State concurs, EPA may allow a political.... If it is designated the lead for remedial action, the political subdivision must provide the...

76 FR 38650 - Draft Integrated Science Assessment for Lead

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

... Science Assessment for Lead AGENCY: Environmental Protection Agency. ACTION: Notice of extension of public... Lead'' (EPA/600/R-10/075A). The original Federal Register notice announcing the public comment period... review of the National Ambient Air Quality Standards (NAAQS) for Lead. DATES: The public comment period...

24 CFR 570.461 - Post-preliminary approval requirements; lead-based paint.

Code of Federal Regulations, 2010 CFR

2010-04-01

... requirements; lead-based paint. 570.461 Section 570.461 Housing and Urban Development Regulations Relating to... GRANTS Urban Development Action Grants § 570.461 Post-preliminary approval requirements; lead-based paint. The recipient may receive preliminary approval prior to the accomplishment of lead-based paint...

Spontaneous action potentials and neural coding in unmyelinated axons.

PubMed

O'Donnell, Cian; van Rossum, Mark C W

2015-04-01

The voltage-gated Na and K channels in neurons are responsible for action potential generation. Because ion channels open and close in a stochastic fashion, spontaneous (ectopic) action potentials can result even in the absence of stimulation. While spontaneous action potentials have been studied in detail in single-compartment models, studies on spatially extended processes have been limited. The simulations and analysis presented here show that spontaneous rate in unmyelinated axon depends nonmonotonically on the length of the axon, that the spontaneous activity has sub-Poisson statistics, and that neural coding can be hampered by the spontaneous spikes by reducing the probability of transmitting the first spike in a train.

Improving Cardiac Action Potential Measurements: 2D and 3D Cell Culture.

PubMed

Daily, Neil J; Yin, Yue; Kemanli, Pinar; Ip, Brian; Wakatsuki, Tetsuro

2015-11-01

Progress in the development of assays for measuring cardiac action potential is crucial for the discovery of drugs for treating cardiac disease and assessing cardiotoxicity. Recently, high-throughput methods for assessing action potential using induced pluripotent stem cell (iPSC) derived cardiomyocytes in both two-dimensional monolayer cultures and three-dimensional tissues have been developed. We describe an improved method for assessing cardiac action potential using an ultra-fast cost-effective plate reader with commercially available dyes. Our methods improve dramatically the detection of the fluorescence signal from these dyes and make way for the development of more high-throughput methods for cardiac drug discovery and cardiotoxicity.

Action potentials contribute to epileptic high-frequency oscillations recorded with electrodes remote from neurons.

PubMed

Kobayashi, Katsuhiro; Akiyama, Tomoyuki; Ohmori, Iori; Yoshinaga, Harumi; Gotman, Jean

2015-05-01

The importance of epileptic high-frequency oscillations (HFOs) in electroencephalogram (EEG) is growing. Action potentials generating some HFOs are observed in the vicinity of neurons in experimental animals. However electrodes that are remote from neurons, as in case of clinical situations, should not record action potentials. We propose to resolve this question by a realistic simulation of epileptic neuronal network. The rat dentate gyrus with sclerosis was simulated in silico. We computed the current dipole moment generated by each granule cell and the field potentials in a measurement area far from neurons. The dentate gyrus was stimulated through synaptic input to evoke discharges resembling interictal epileptiform discharges, which had superimposed HFOs⩽295Hz that were recordable with remote electrodes and represented bursts of action potentials of granule cells. The increase in power of HFOs was associated with the progression of sclerosis, the reduction of GABAergic inhibition, and the increase in cell connectivity. Spectral frequency of HFOs had similar tendencies. HFOs recorded with electrodes remote from neurons could actually be generated by clusters of action potentials. The phenomenon of action potentials recorded with remote electrodes can possibly extend the clinical meaning of EEG. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

A physical action potential generator: design, implementation and evaluation.

PubMed

Latorre, Malcolm A; Chan, Adrian D C; Wårdell, Karin

2015-01-01

The objective was to develop a physical action potential generator (Paxon) with the ability to generate a stable, repeatable, programmable, and physiological-like action potential. The Paxon has an equivalent of 40 nodes of Ranvier that were mimicked using resin embedded gold wires (Ø = 20 μm). These nodes were software controlled and the action potentials were initiated by a start trigger. Clinically used Ag-AgCl electrodes were coupled to the Paxon for functional testing. The Paxon's action potential parameters were tunable using a second order mathematical equation to generate physiologically relevant output, which was accomplished by varying the number of nodes involved (1-40 in incremental steps of 1) and the node drive potential (0-2.8 V in 0.7 mV steps), while keeping a fixed inter-nodal timing and test electrode configuration. A system noise floor of 0.07 ± 0.01 μV was calculated over 50 runs. A differential test electrode recorded a peak positive amplitude of 1.5 ± 0.05 mV (gain of 40x) at time 196.4 ± 0.06 ms, including a post trigger delay. The Paxon's programmable action potential like signal has the possibility to be used as a validation test platform for medical surface electrodes and their attached systems.

Organisational Factors of Occupational Accidents with Movement Disturbance (OAMD) and Prevention

PubMed Central

LECLERCQ, Sylvie

2014-01-01

Workplace design and upkeep, or human factors, are frequently advanced for explaining so-called Occupational Slip, Trip and Fall Accidents (OSTFAs). Despite scientific progress, these accidents, and more broadly Occupational Accidents with Movement Disturbance (OAMDs), are also commonly considered to be “simple”. This paper aims to stimulate changes in such perceptions by focusing on organisational factors that often combine with other accident factors to cause movement disturbance and injury in work situations. These factors frequently lead to arbitration between production and safety, which involves implementation of controls by workers. These controls can lead to greater worker exposure to OAMD risk. We propose a model that focuses on such controls to account specifically for the need to confront production and safety logics within a company and to enhance the potential for appropriate prevention action. These are then integrated into the set of controls highlighted by work organisation model developed by the NIOSH. PMID:25345425

Conservation and restoration of mangroves: Global status, perspectives, and prognosis

USGS Publications Warehouse

Romañach, Stephanie; DeAngelis, Donald L.; Koh, Hock Lye; Li, Yuhong; Teh, Su Yean; Barizan, Raja Sulaiman Raja; Zhai, Lu

2018-01-01

Mangrove forests provide critical services around the globe to both human populations and the ecosystems they occupy. However, losses of mangrove habitat of more than 50% have been recorded in some parts of the world, and these losses are largely attributable to human activities. The importance of mangroves and the threats to their persistence have long been recognized, leading to actions taken locally, by national governments, and through international agreements for their protection. In this review, we explore the status of mangrove forests as well as efforts to protect them. We examine threats to the persistence of mangroves, consequences, and potential solutions for effective conservation. We present case studies from disparate regions of the world, showing that the integration of human livelihood needs in a manner that balances conservation goals can present solutions that could lead to long-term sustainability of mangrove forests throughout the world.

Metal tissue levels in Steller sea lion (Eumetopias jubatus) pups.

PubMed

Holmes, Amie L; Wise, Sandra S; Goertz, Caroline E C; Dunn, J Lawrence; Gulland, Frances M D; Gelatt, Tom; Beckmen, Kimberlee B; Burek, Kathy; Atkinson, Shannon; Bozza, Mary; Taylor, Robert; Zheng, Tongzhang; Zhang, Yawei; Aboueissa, Abouel-Makarim; Wise, John Pierce

2008-08-01

The endangered Western population of the Steller sea lion declined for three decades for uncertain reasons. We present baseline data of metal concentrations in pups as a first step towards investigating the potential threat of developmental exposures to contaminants. Seven metals were investigated: arsenic, cadmium, silver, aluminum, mercury, lead and vanadium. Vanadium was detected in only a single blubber sample. Mercury appears to be the most toxicologically significant metal with concentrations in the liver well above the current action level for mercury in fish. The concentrations of aluminum, arsenic, silver, cadmium and lead were present in one-fourth to two-thirds of all samples and were at either comparable or below concentrations previously reported. Neither gender nor region had a significant effect on metal burdens. Future work should consider metal concentrations in juveniles and adults and toxicological studies need to be performed to begin to assess the toxicity of these metals.

Real-time detection of antibiotic activity by measuring nanometer-scale bacterial deformation.

PubMed

Iriya, Rafael; Syal, Karan; Jing, Wenwen; Mo, Manni; Yu, Hui; Haydel, Shelley E; Wang, Shaopeng; Tao, Nongjian

2017-12-01

Diagnosing antibiotic-resistant bacteria currently requires sensitive detection of phenotypic changes associated with antibiotic action on bacteria. Here, we present an optical imaging-based approach to quantify bacterial membrane deformation as a phenotypic feature in real-time with a nanometer scale (∼9  nm) detection limit. Using this approach, we found two types of antibiotic-induced membrane deformations in different bacterial strains: polymyxin B induced relatively uniform spatial deformation of Escherichia coli O157:H7 cells leading to change in cellular volume and ampicillin-induced localized spatial deformation leading to the formation of bulges or protrusions on uropathogenic E. coli CFT073 cells. We anticipate that the approach will contribute to understanding of antibiotic phenotypic effects on bacteria with a potential for applications in rapid antibiotic susceptibility testing. (2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

PubMed Central

2017-01-01

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs. PMID:28968083

Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy

PubMed Central

de Freitas, Lucas Freitas; Hamblin, Michael R

2016-01-01

Photobiomodulation (PBM) also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action. However, in recent years, much knowledge has been gained in this area, which will be summarized in this review. One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infra-red region. The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production. Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium to enter the cell. After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO and Ca2+, leading to activation of transcription factors. These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes. Stem cells and progenitor cells appear to be particularly susceptible to LLLT. PMID:28070154

Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy.

PubMed

de Freitas, Lucas Freitas; Hamblin, Michael R

2016-01-01

Photobiomodulation (PBM) also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action. However, in recent years, much knowledge has been gained in this area, which will be summarized in this review. One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infra-red region. The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production. Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium to enter the cell. After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO and Ca2+, leading to activation of transcription factors. These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes. Stem cells and progenitor cells appear to be particularly susceptible to LLLT.

The One that Does, Leads: Action Relations Influence the Perceived Temporal Order of Graspable Objects

ERIC Educational Resources Information Center

Roberts, Katherine L.; Humphreys, Glyn W.

2010-01-01

Perception and action are influenced by the "possibilities for action" in the environment. Neuropsychological studies (e.g., Riddoch, Humphreys, Edwards, Baker, & Willson, 2003) have demonstrated that objects that are perceived to be interacting (e.g., a corkscrew going toward the top of a wine bottle) are perceptually integrated…

First Time Facilitator's Experience: Designing and Facilitating an Action Learning Programme in China

ERIC Educational Resources Information Center

Wang, Jinshuai; Bloodworth, Mike

2016-01-01

This paper describes an action learning programme with China Unicom Broadband Limited (CUBO) to support its vision of transforming to become a world-leading broadband communications and information service provider. 64 Department directors and supervisors were invited to take part in the "China Unicom Broadband Online Phoenix Action Learning…

Middle School Responses to Cyberbullying: An Action Research Study

ERIC Educational Resources Information Center

Zidack, Astri Marie

2013-01-01

This action research study engaged a small public middle school in the northwest United States in a collaborative process to address cyberbullying issues that often lead to academic and behavior problems in schools (Hinduja, 2010; Olweus, 2010). The specific purpose of this action research study was to address the middle school's cyberbullying…

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Dose Dependent Dopaminergic Modulation of Reward-Based Learning in Parkinson's Disease

ERIC Educational Resources Information Center

van Wouwe, N. C.; Ridderinkhof, K. R.; Band, G. P. H.; van den Wildenberg, W. P. M.; Wylie, S. A.

2012-01-01

Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement-based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward…

The Meaning and Organization of Physical Education Teachers' Actions during Conflict with Students.

ERIC Educational Resources Information Center

Flavier, Eric; Bertone, Stefano; Hauw, Denis; Durand, Marc

2002-01-01

Used course-of-action theory to identify typical organization of teachers' actions when in conflict with students. Middle school physical educators were interviewed and filmed during lessons. Overall, teacher-student conflicts were infrequent. When conflict occurred, teacher attempts at resolution were under strong time pressure, leading to risk…

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2011 CFR

2011-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2010 CFR

2010-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2014 CFR

2014-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2012 CFR

2012-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

40 CFR 300.800 - Establishment of an administrative record.

Code of Federal Regulations, 2013 CFR

2013-07-01

... POLLUTION CONTINGENCY PLAN Administrative Record for Selection of Response Action § 300.800 Establishment of... agency for a federal facility. (3) If EPA is involved in the selection of the response action at a... record that contains the documents that form the basis for the selection of a response action. The lead...

Exploring the Connections between Action Research and Teacher Leadership: A Reflection on Teacher-Leader Research for Confronting New Challenges

ERIC Educational Resources Information Center

Wolkenhauer, Rachel; Hill, Ashley Pennypacker; Dana, Nancy Fichtman; Stukey, Marisa

2017-01-01

This reflective article examines the relationship between teachers' engagement in action research and their ability to lead within their schools. As part of "The New Educator's" special issue, "Developing an Inquiry Stance toward Instructional Improvement: Teacher-Leader Action Research," this article demonstrates the…

Children Perseverate to a Human's Actions but Not to a Robot's Actions

ERIC Educational Resources Information Center

Moriguchi, Yusuke; Kanda, Takayuki; Ishiguro, Hiroshi; Itakura, Shoji

2010-01-01

Previous research has shown that young children commit perseverative errors from their observation of another person's actions. The present study examined how social observation would lead children to perseverative tendencies, using a robot. In Experiment 1, preschoolers watched either a human model or a robot sorting cards according to one…

Regulation of fear extinction by long-term depression: The roles of endocannabinoids and brain derived neurotrophic factor.

PubMed

Bennett, Maxwell R; Arnold, Jonathon; Hatton, Sean N; Lagopoulos, Jim

2017-02-15

The extinction of a conditioned fear response is of great interest in the search for a means of ameliorating adverse neurobiological changes resulting from stress. The discovery that endocannibinoid (EC) levels are inversely related to the extent of such stress, and that the amygdala is a primary site mediating stress, suggests that ECs in this brain region might play a major role in extinction. Supporting this are the observations that the basolateral complex of the amygdala shows an increase in ECs only during extinction and that early clinical trials indicate that cannabinoid-like agents, when taken orally by patients suffering from post traumatic stress disorder (PTSD), reduce insomnia and nightmares. In order to optimize the potential of these agents to ameliorate symptoms of PTSD four important questions need to be answered: first, what is the identity of the cells that release ECs in the amygdala during extinction; second, what are their sites of action; third, what roles do the ECs play in the alleviation of long- depression (LTD), a process central to extinction; and finally, to what extent does brain derived neurotrophic factor (BDNF) facilitate the release of ECs? A review of the relevant literature is presented in an attempt to answer these questions. It is suggested that the principal cell involved in EC synthesis and release during extinction is the so-called excitatory extinction neuron in the basal nucleus of the amygdala. Furthermore that the main site of action of the ECs is the adjacent calcitonin gene-related peptide inhibitory interneurons, whose normal role of blocking the excitatory neurons is greatly diminished. The molecular pathways leading (during extinction trials) to the synthesis and release of ECs from synaptic spines of extinction neurons, that is potentiated by BDNF, are also delineated in this review. Finally, consideration is given to how the autocrine action of BDNF, linked to the release of ECs, can lead to the sustained release of these, so maintaining extinction over long times. Copyright © 2016 Elsevier B.V. All rights reserved.

A long-term study of ecological impacts of river channelization on the population of an endangered fish: Lessons learned for assessment and restoration

USGS Publications Warehouse

Roberts, James H.; Anderson, Gregory B.; Angermeier, Paul

2016-01-01

Projects to assess environmental impact or restoration success in rivers focus on project-specific questions but can also provide valuable insights for future projects. Both restoration actions and impact assessments can become “adaptive” by using the knowledge gained from long-term monitoring and analysis to revise the actions, monitoring, conceptual model, or interpretation of findings so that subsequent actions or assessments are better informed. Assessments of impact or restoration success are especially challenging when the indicators of interest are imperiled species and/or the impacts being addressed are complex. From 1997 to 2015, we worked closely with two federal agencies to monitor habitat availability for and population density of Roanoke logperch (Percina rex), an endangered fish, in a 24-km-long segment of the upper Roanoke River, VA. We primarily used a Before-After-Control-Impact analytical framework to assess potential impacts of a river channelization project on the P. rex population. In this paper, we summarize how our extensive monitoring facilitated the evolution of our (a) conceptual understanding of the ecosystem and fish population dynamics; (b) choices of ecological indicators and analytical tools; and (c) conclusions regarding the magnitude, mechanisms, and significance of observed impacts. Our experience with this case study taught us important lessons about how to adaptively develop and conduct a monitoring program, which we believe are broadly applicable to assessments of environmental impact and restoration success in other rivers. In particular, we learned that (a) pre-treatment planning can enhance monitoring effectiveness, help avoid unforeseen pitfalls, and lead to more robust conclusions; (b) developing adaptable conceptual and analytical models early was crucial to organizing our knowledge, guiding our study design, and analyzing our data; (c) catchment-wide processes that we did not monitor, or initially consider, had profound implications for interpreting our findings; and (d) using multiple analytical frameworks, with varying assumptions, led to clearer interpretation of findings than the use of a single framework alone. Broader integration of these guiding principles into monitoring studies, though potentially challenging, could lead to more scientifically defensible assessments of project effects.

Direct detection of a single evoked action potential with MRS in Lumbricus terrestris.

PubMed

Poplawsky, Alexander J; Dingledine, Raymond; Hu, Xiaoping P

2012-01-01

Functional MRI (fMRI) measures neural activity indirectly by detecting the signal change associated with the hemodynamic response following brain activation. In order to alleviate the temporal and spatial specificity problems associated with fMRI, a number of attempts have been made to detect neural magnetic fields (NMFs) with MRI directly, but have thus far provided conflicting results. In this study, we used MR to detect axonal NMFs in the median giant fiber of the earthworm, Lumbricus terrestris, by examining the free induction decay (FID) with a sampling interval of 0.32 ms. The earthworm nerve cords were isolated from the vasculature and stimulated at the threshold of action potential generation. FIDs were acquired shortly after the stimulation, and simultaneous field potential recordings identified the presence or absence of single evoked action potentials. FIDs acquired when the stimulus did not evoke an action potential were summed as background. The phase of the background-subtracted FID exhibited a systematic change, with a peak phase difference of (-1.2 ± 0.3) × 10(-5) radians occurring at a time corresponding to the timing of the action potential. In addition, we calculated the possible changes in the FID magnitude and phase caused by a simulated action potential using a volume conductor model. The measured phase difference matched the theoretical prediction well in both amplitude and temporal characteristics. This study provides the first evidence for the direct detection of a magnetic field from an evoked action potential using MR. Copyright © 2011 John Wiley & Sons, Ltd.

The Direct Detection of a Single Evoked Action Potential with Magnetic Resonance Spectroscopy in Lumbricus Terrestris

PubMed Central

Poplawsky, Alexander J.; Dingledine, Raymond

2011-01-01

Functional MRI (fMRI) indirectly measures neural activity by detecting the signal change associated with the hemodynamic response following brain activation. In order to alleviate the temporal and spatial specificity problems associated with fMRI, a number of attempts have been made to detect neural magnetic fields (NMFs) with MRI directly, but have thus far provided conflicting results. In the present study, we used magnetic resonance to detect axonal NMFs in the median giant fiber of the earthworm, Lumbricus terrestris, by examining the free-induction decay (FID) with a sampling interval of 0.32 ms. The earthworm nerve cords were isolated from the vasculature and stimulated at the threshold of action potential generation. FIDs were acquired shortly after the stimulation and simultaneous field potential recordings identified the presence or absence of single evoked action potentials. FIDs acquired when the stimulus did not evoke an action potential were summed as background. The phase of the background-subtracted FID exhibited a systematic change, with a peak phase difference of [-1.2 ± 0.3] ×10-5 radians occurring at a time corresponding to the timing of the action potential. In addition, we calculated the possible changes in the FID magnitude and phase due to a simulated action potential using a volume conductor model. The measured phase difference matched the theoretical prediction well in both amplitude and temporal characteristics. This study provides the first evidence for the direct detection of a magnetic field from an evoked action potential using magnetic resonance. PMID:21728204

Sodium and calcium currents shape action potentials in immature mouse inner hair cells

PubMed Central

Marcotti, Walter; Johnson, Stuart L; Rüsch, Alfons; Kros, Corné J

2003-01-01

Before the onset of hearing at postnatal day 12, mouse inner hair cells (IHCs) produce spontaneous and evoked action potentials. These spikes are likely to induce neurotransmitter release onto auditory nerve fibres. Since immature IHCs express both α1D (Cav1.3) Ca2+ and Na+ currents that activate near the resting potential, we examined whether these two conductances are involved in shaping the action potentials. Both had extremely rapid activation kinetics, followed by fast and complete voltage-dependent inactivation for the Na+ current, and slower, partially Ca2+-dependent inactivation for the Ca2+ current. Only the Ca2+ current is necessary for spontaneous and induced action potentials, and 29 % of cells lacked a Na+ current. The Na+ current does, however, shorten the time to reach the action-potential threshold, whereas the Ca2+ current is mainly involved, together with the K+ currents, in determining the speed and size of the spikes. Both currents increased in size up to the end of the first postnatal week. After this, the Ca2+ current reduced to about 30 % of its maximum size and persisted in mature IHCs. The Na+ current was downregulated around the onset of hearing, when the spiking is also known to disappear. Although the Na+ current was observed as early as embryonic day 16.5, its role in action-potential generation was only evident from just after birth, when the resting membrane potential became sufficiently negative to remove a sizeable fraction of the inactivation (half inactivation was at −71 mV). The size of both currents was positively correlated with the developmental change in action-potential frequency. PMID:12937295

Renormalization group scale-setting from the action—a road to modified gravity theories

NASA Astrophysics Data System (ADS)

Domazet, Silvije; Štefančić, Hrvoje

2012-12-01

The renormalization group (RG) corrected gravitational action in Einstein-Hilbert and other truncations is considered. The running scale of the RG is treated as a scalar field at the level of the action and determined in a scale-setting procedure recently introduced by Koch and Ramirez for the Einstein-Hilbert truncation. The scale-setting procedure is elaborated for other truncations of the gravitational action and applied to several phenomenologically interesting cases. It is shown how the logarithmic dependence of the Newton's coupling on the RG scale leads to exponentially suppressed effective cosmological constant and how the scale-setting in particular RG-corrected gravitational theories yields the effective f(R) modified gravity theories with negative powers of the Ricci scalar R. The scale-setting at the level of the action at the non-Gaussian fixed point in Einstein-Hilbert and more general truncations is shown to lead to universal effective action quadratic in the Ricci tensor.

The dependence of the action potential of the frog's heart on the external and intracellular sodium concentration

PubMed Central

Niedergerke, R.; Orkand, R. K.

1966-01-01

1. The overshoot of the action potential of the frog's heart was reduced when external sodium chloride was replaced by sucrose. However, the potential decrement was only 17·3 mV for a 10-fold reduction of sodium as compared with 58 mV expected on the basis of the sodium hypothesis of excitation. 2. Replacement of up to 75% of the external sodium by choline did not reduce the overshoot, provided atropine was present in sufficient concentrations to suppress any parasympathomimetic action. 3. The maximum rate of rise of the action potential markedly declined in low sodium fluids whether sucrose or choline chloride was used to replace sodium chloride. 4. The maximum rate of rise was reduced to only a small extent when external sodium was replaced by lithium. 5. Increasing the intracellular sodium concentration in exchange for lost potassium caused overshoots to decline. The effects resembled those obtained in similar experiments with skeletal muscle fibres (Desmedt, 1953). 6. Action potentials occurring under certain conditions even in the presence of very low external sodium concentrations (≤ 5% normal) also declined in height when the intracellular sodium concentration was increased. 7. The behaviour of the action potential in low external sodium concentrations may be explained by an action of calcium on the excitable membrane. PMID:5921833