bluuebunny/crossref_metadata_2025_split huggingface dataset:
Henipavirus Encephalitis: Recent Developments and Advances
Authors: Ong Kien Chai , Wong Kum Thong 
Published: August 2015

AbstractThe genusHenipaviruswithin the familyParamyxoviridae includes the Hendra virus (HeV) andNipah virus (NiV) which were discovered in the 1990s inAustralia andMalaysia, respectively, after emerging to cause severe and often fatal outbreaks in humans and animals. WhileHeVis confined toAustralia, more recentNiVoutbreaks have been reported inBangladesh,India and thePhilippines. The clinical manifestations of both henipaviruses in humans appear similar, with a predominance of an acute encephalitic syndrome. Likewise, the pathological features are similar and characterized by disseminated, multi‐organ vasculopathy comprising endothelial infection/ulceration, vasculitis, vasculitis‐induced thrombosis/occlusion, parenchymal ischemia/microinfarction, and parenchymal cell infection in the central nervous system (CNS), lung, kidney and other major organs. This unique dual pathogenetic mechanism of vasculitis‐induced microinfarction and neuronal infection causes severe tissue damage in theCNS. Both viruses can also cause relapsing encephalitis months and years after the acute infection. Many animal models studied to date have largely confirmed the pathology of henipavirus infection, and provided the means to test new therapeutic agents and vaccines. As the bat is the natural host of henipaviruses and has worldwide distribution, spillover events into human populations are expected to occur in the future.
Understanding Enterovirus 71 Neuropathogenesis and Its Impact on Other Neurotropic Enteroviruses
Authors: Ong Kien Chai , Wong Kum Thong 
Published: August 2015

AbstractEnterovirus A71 (EV‐A71) belongs to the species group A in the Enterovirus genus within the Picornaviridae family. EV‐A71 usually causes self‐limiting hand, foot and mouth disease or herpangina but rarely causes severe neurological complications such as acute flaccid paralysis and encephalomyelitis. The pathology and neuropathogenesis of these neurological syndromes is beginning to be understood. EV‐A71 neurotropism for motor neurons in the spinal cord and brainstem, and other neurons, is mainly responsible for central nervous system damage. This review on the general aspects, recent developments and advances of EV‐A71 infection will focus on neuropathogenesis and its implications on other neurotropic enteroviruses, such as poliovirus and the newly emergent Enterovirus D68. With the imminent eradication of poliovirus, EV‐A71 is likely to replace it as an important neurotropic enterovirus of worldwide importance.
West Nile Virus Encephalitis 16 Years Later
Authors: Kleinschmidt‐DeMasters Bette K. , Beckham J. David 
Published: August 2015

AbstractArboviruses (Arthropod‐borne viruses) include several families of viruses (Flaviviridae, Togaviradae, Bunyaviradae, Reoviradae) that are spread by arthropod vectors, most commonly mosquitoes, ticks and sandflies. The RNA genome allows these viruses to rapidly adapt to ever‐changing host and environmental conditions. Thus, these virus families are largely responsible for the recent expansion in geographic range of emerging viruses including West Nile virus (WNV), dengue virus and Chikungunya virus. This review will focus on WNV, especially as it has progressively spread westward in North America since its introduction in New York in 1999. By 2003, WNV infections in humans had reached almost all lower 48 contiguous United States (US) and since that time, fluctuations in outbreaks have occurred. Cases decreased between 2008 and 2011, followed by a dramatic flair in 2012, with the epicenter in the Dallas‐Fort Worth region of Texas. The 2012 outbreak was associated with an increase in reported neuroinvasive cases. Neuroinvasive disease continues to be a problem particularly in the elderly and immunocompromised populations, although WNV infections also represented the second most frequent cause of pediatric encephalitis in these same years. Neuropathological features in cases from the 2012 epidemic highlight the extent of viral damage that can occur in the CNS.
Emerging Infections of CNS: Avian Influenza A Virus, Rift Valley Fever Virus and Human Parechovirus
Authors: Wiley Clayton A. , Bhardwaj Nitin , Ross Ted M. , Bissel Stephanie J. 
Published: August 2015

AbstractHistory is replete with emergent pandemic infections that have decimated the human population. Given the shear mass of humans that now crowd the earth, there is every reason to suspect history will repeat itself. We describe three RNA viruses that have recently emerged in the human population to mediate severe neurological disease. These new diseases are results of new mutations in the infectious agents or new exposure pathways to the agents or both. To appreciate their pathogenesis, we summarize the essential virology and immune response to each agent. Infection is described in the context of known host defenses. Once the viruses evade immune defenses and enter central nervous system (CNS) cells, they rapidly co‐opt host RNA processing to a cataclysmic extent. It is not clear why the brain is particularly susceptible to RNA viruses; but perhaps because of its tremendous dependence on RNA processing for physiological functioning, classical mechanisms of host defense (eg, interferon disruption of viral replication) are diminished or not available. Effectiveness of immunity, immunization and pharmacological therapies is reviewed to contextualize the scope of the public health challenge. Unfortunately, vaccines that confer protection from systemic disease do not necessarily confer protection for the brain after exposure through unconventional routes.
Actions of KMUP‐1, a xanthine and piperazine derivative, on voltage‐gated Na+ and Ca2+‐activated K+ currents in GH3 pituitary tumour cells
Authors: Lo Yi‐Ching , Tseng Yu‐Ting , Liu Chi‐Ming , Wu Bin‐Nan , Wu Sheng‐Nan 
Published: August 2015

Background and Purpose7‐[2‐[4‐(2‐Chlorophenyl)piperazinyl]ethyl]‐1,3‐dimethylxanthine (KMUP‐1) is a xanthine‐based derivative. It has soluble GC activation and K+‐channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study.Experimental ApproachThe aim of this study was to evaluate effects of KMUP‐1 on the amplitude and gating of voltage‐gated Na+ current (INa) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca2+‐activated K+ current and the activity of large‐conductance Ca2+‐activated K+ (BKCa) channels were also studied.Key ResultsKMUP‐1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP‐1 (3 μM) shifted the steady‐state inactivation of INa to a hyperpolarized potential by −10 mV, despite inability to alter the recovery of INa from inactivation. In cell‐attached configuration, KMUP‐1 applied to bath increased BKCa‐channel activity; however, in inside‐out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP‐1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A.Conclusions and ImplicationsApart from activating BKCa channels, KMUP‐1 preferentially suppresses late INa. The effects of KUMP‐1 on ion currents presented here constitute an underlying ionic mechanism of its actions.
Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor
Authors: Potasiewicz A. , Kos T. , Ravazzini F. , Puia G. , Arias H. R. , Popik P , Nikiforuk A. 
Published: August 2015

Background and Purposeα7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).Experimental ApproachThe attentional set‐shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro‐cognitive activity of each ligand [i.e., PAM‐2 (0.5, 1.0, and 2.0 mg·kg−1), DMXBA and A‐582941 (0.3 and 1.0 mg·kg−1)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM‐2 (0.5 mg·kg−1) was co‐injected with inactive doses of either agonist ‐ DMXBA: 0.1 (NORT); 0.3 mg·kg−1 (ASST) or A‐582941: 0.1 mg·kg−1.Key ResultsPAM‐2, DMXBA, and A‐582941 improved cognition in a MLA‐dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co‐injection of inactive doses of PAM‐2 and DMXBA or A‐582941 also improved cognition, suggesting drug interactions. Moreover, PAM‐2 reversed the scopolamine‐induced NORT deficit. The electrophysiological results also support the view that PAM‐2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC50 = 34 ± 3 μM and Emax = 225 ± 5 %.Conclusions and ImplicationsOur results support the view that α7 nAChRs are involved in cognition processes and that PAM‐2 is a novel promising candidate for the treatment of cognitive disorders.
Superagonism at G protein‐coupled receptors and beyond
Authors: Schrage R , De Min A , Hochheiser K , Kostenis E , Mohr K 
Published: August 2015

Ligands targeting GPCRs can be categorized according to their intrinsic efficacy to trigger a specific, receptor‐mediated response. A ligand endowed with the same level of efficacy as the endogenous agonist can be classified as a full agonist, whereas a compound that displays greater efficacy, that is, higher receptor signalling output than the endogenous agonist, can be called a superagonist. Subsequent to GPCR activation, an intracellular signalling cascade is set in motion, which may generate substantial amplification of the signal. This may obscure superagonism in pharmacological assays and, therefore, the definition of superagonism necessitates a combination of operational approaches, reduction of spare receptors or estimation of receptor activation close to the receptor level to quantify relative agonist efficacies in a particular system.The first part of this review will compare GPCR superagonism with superagonism in the field of immunology, where this term is well established. In the second part, known GPCR superagonists will be reviewed. Then, the experimental and analytical challenges in the deconvolution of GPCR superagonism will be addressed. Finally, the potential benefit of superagonism is discussed.The molecular mechanisms behind GPCR superagonism are not completely understood. However, crystallography shows that agonist binding alone is not sufficient for a fully active receptor state and that binding of the G protein is at least equally important. Accordingly, the emerging number of reported superagonists implies that ligand‐induced receptor conformations more active than the ones stabilized by the endogenous agonist are indeed feasible. Superagonists may have therapeutic potential when receptor function is impaired or to induce negative feedback mechanisms.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc
High glucose‐induced changes in hyaloid‐retinal vessels during early ocular development of zebrafish: a short‐term animal model of diabetic retinopathy
Authors: Jung Seung‐Hyun , Kim Young Sook , Lee Yu‐Ri , Kim Jin Sook 
Published: August 2015

Background and PurposeAlthough a variety of animal models have been used to test drug candidates and examine the pathogenesis of diabetic retinopathy, time‐saving and inexpensive models are still needed to evaluate the increasing number of therapeutic approaches.Experimental ApproachWe developed a model for diabetic retinopathy using the early stage of transgenic zebrafish (flk:EGFP) by treating embryos with 130 mM glucose, from 3‐6 days post fertilisation (high‐glucose model). On day 6, lenses from zebrafish larvae were isolated and treated with 3% trypsin, and changes in hyaloid‐retinal vessels were analysed using fluorescent stereomicroscopy. In addition, expression of tight junction proteins (such as zonula occludens‐1), effects of hyperosmolar solutions and of hypoxia, andVegfexpression were assessed by RT –PCR. NO production was assessed with a fluorescent substrate. Effects of inhibitors of the VEGF receptor, NO synthesis and a VEGF antibody (ranibizumab) were also measured.Key ResultsIn this high‐glucose model, dilation of hyaloid‐retinal vessels, on day 6, was accompanied by morphological lesions with disruption of tight junction proteins, overproduction ofVegfmRNA and increased NO production. Treatment of this high‐glucose model with an inhibitor of VEGF receptor tyrosine kinase or an inhibitor of NO synthase or ranibizumab decreased dilation of hyaloid‐retinal vessels.Conclusions and ImplicationsThese findings suggest that short‐term exposure of zebrafish larvae to high‐glucose conditions could be used for screening and drug discovery for diabetic retinopathy and particularly for disorders of retinal vessels related to disruption of tight junction proteins and excessive VEGF and NO production.
Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats
Authors: Ayanwuyi Lydia O , Stopponi Serena , Ubaldi Massimo , Cippitelli Andrea , Nasuti Cinzia , Damadzic Ruslan , Heilig Markus , Schank Jesse , Cheng Kejun , Rice Kenner C , Ciccocioppo Roberto 
Published: August 2015

Background and PurposeSubstance P and its preferred neurokinin receptor NK1 have been implicated in stress and anxiety and have been proposed as possible therapeutic targets for the treatment of anxiety/depression. Attention is also being focused on the role this neuropeptide system may play in drug addiction, because stress‐related mechanisms promote drug abuse.Experimental ApproachThe effects of the rat‐specific NK1 receptor antagonist, L822429, on alcohol intake and seeking behaviour was investigated in genetically selected Marchigian Sardinian alcohol preferring rats. These rats demonstrate an anxious phenotype and are highly sensitive to stress and stress‐induced drinking.Key ResultsSystemic administration of L822429 significantly reduced operant alcohol self‐administration in Marchigian Sardinian alcohol preferring rats, but did not reduce alcohol self‐administration in stock Wistar rats. NK1 receptor antagonism also attenuated yohimbine‐induced reinstatement of alcohol seeking at all doses tested but had no effect on cue‐induced reinstatement of alcohol seeking. L822429 reduced operant alcohol self‐administration when injected into the lateral cerebroventricles or the medial amygdala. L822429 injected into the medial amygdala also significantly reduced anxiety‐like behaviour in the elevated plus maze test. No effects on alcohol intake were observed following injection of L822429 into the dorsal or the ventral hippocampus.Conclusions and ImplicationsOur results suggest that NK1 receptor antagonists may be useful for the treatment of alcohol addiction associated with stress or comorbid anxiety disorders. The medial amygdala appears to be an important brain site of action of NK1 receptor antagonism.
Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias
Authors: Sengmany K , Gregory K J 
Published: August 2015

The metabotropic glutamate receptor subtype 5 (mGlu5) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR‐based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine‐tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus‐bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc
Human induced pluripotent stem cell‐derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block
Authors: Paci M , Hyttinen J , Rodriguez B , Severi S 
Published: August 2015

Background and PurposeTwo new technologies are likely to revolutionize cardiac safety and drug development: in vitro experiments on human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) and in silico human adult ventricular cardiomyocyte (hAdultV‐CM) models. Their combination was recently proposed as a potential replacement for the present hERG‐based QT study for pharmacological safety assessments. Here, we systematically compared in silico the effects of selective ionic current block on hiPSC‐CM and hAdultV‐CM action potentials (APs), to identify similarities/differences and to illustrate the potential of computational models as supportive tools for evaluating new in vitro technologies.Experimental ApproachIn silico AP models of ventricular‐like and atrial‐like hiPSC‐CMs and hAdultV‐CM were used to simulate the main effects of four degrees of block of the main cardiac transmembrane currents.Key ResultsQualitatively, hiPSC‐CM and hAdultV‐CM APs showed similar responses to current block, consistent with results from experiments. However, quantitatively, hiPSC‐CMs were more sensitive to block of (i) L‐type Ca2+ currents due to the overexpression of the Na+/Ca2+ exchanger (leading to shorter APs) and (ii) the inward rectifier K+ current due to reduced repolarization reserve (inducing diastolic potential depolarization and repolarization failure).Conclusions and ImplicationsIn silico hiPSC‐CMs and hAdultV‐CMs exhibit a similar response to selective current blocks. However, overall hiPSC‐CMs show greater sensitivity to block, which may facilitate in vitro identification of drug‐induced effects. Extrapolation of drug effects from hiPSC‐CM to hAdultV‐CM and pro‐arrhythmic risk assessment can be facilitated by in silico predictions using biophysically‐based computational models.
State‐dependent blocking mechanism of Kv1.3 channels by the antimycobacterial drug clofazimine
Authors: Faouzi Malika , Starkus John , Penner Reinhold 
Published: August 2015

Background and PurposeKv1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca2+ signalling in T cells by regulating the membrane potential and with it the driving force for Ca2+ influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen‐induced Ca2+ oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv1.3 channels with high potency and selectivity.Experimental ApproachWe used patch‐clamp methodology to investigate clofazimine's mechanism of action in Kv1.3 channels expressed in HEK293 cells.Key ResultsClofazimine blocked Kv1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use‐dependent open‐channel block during long depolarizations, resulting in accelerated K+ current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use‐dependent and state‐dependent in that they clearly required prior channel opening. The clofazimine‐sensitive closed‐deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C‐type inactivated state significantly affected. Kv1.3 channels carrying the H399T mutation and lacking C‐type inactivation were insensitive to clofazimine block of the closed‐deactivated state, but retained their susceptibility to open‐channel block.Conclusions and ImplicationsGiven the prominent role of Kv1.3 in shaping Ca2+ oscillations, the use‐dependent and state‐dependent block of Kv1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which Kv1.3‐expressing T cells play a significant role.
Priming and memory of stress responses in organisms lacking a nervous system
Authors: Hilker Monika , Schwachtje Jens , Baier Margarete , Balazadeh Salma , Bäurle Isabel , Geiselhardt Sven , Hincha Dirk K. , Kunze Reinhard , Mueller‐Roeber Bernd , Rillig Matthias C. , Rolff Jens , Romeis Tina , Schmülling Thomas , Steppuhn Anke , van Dongen Joost , Whitcomb Sarah J. , Wurst Susanne , Zuther Ellen , Kopka Joachim 
Published: August 2015

ABSTRACTExperience and memory of environmental stimuli that indicate future stress can prepare (prime) organismic stress responses even in species lacking a nervous system. The process through which such organisms prepare their phenotype for an improved response to future stress has been termed ‘priming’. However, other terms are also used for this phenomenon, especially when considering priming in different types of organisms and when referring to different stressors. Here we propose a conceptual framework for priming of stress responses in bacteria, fungi and plants which allows comparison of priming with other terms, e.g. adaptation, acclimation, induction, acquired resistance and cross protection. We address spatial and temporal aspects of priming and highlight current knowledge about the mechanisms necessary for information storage which range from epigenetic marks to the accumulation of (dormant) signalling molecules. Furthermore, we outline possible patterns of primed stress responses. Finally, we link the ability of organisms to become primed for stress responses (their ‘primability’) with evolutionary ecology aspects and discuss which properties of an organism and its environment may favour the evolution of priming of stress responses.