bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of adenosine A2A receptor reduces osteoclast formation via PKA‐ and ERK1/2‐mediated suppression of NFκB nuclear translocation
Authors: Mediero Aránzazu , Perez‐Aso Miguel , Cronstein Bruce N 
Published: May 2013

Background and PurposeWe previously reported that adenosine, acting at adenosine A2A receptors (A2AR), inhibits osteoclast (OC) differentiation in vitro (A2AR activation OC formation reduces by half) and in vivo. For a better understanding how adenosine A2AR stimulation regulates OC differentiation, we dissected the signalling pathways involved in A2AR signalling.Experimental ApproachOC differentiation was studied as TRAP+ multinucleated cells following M‐CSF/RANKL stimulation of either primary murine bone marrow cells or the murine macrophage line, RAW264.7, in presence/absence of the A2AR agonist CGS21680, the A2AR antagonist ZM241385, PKA activators (8‐Cl‐cAMP 100 nM, 6‐Bnz‐cAMP) and the PKA inhibitor (PKI). cAMP was quantitated by EIA and PKA activity assays were carried out. Signalling events were studied in PKA knockdown (lentiviral shRNA for PKA) RAW264.7 cells (scrambled shRNA as control). OC marker expression was studied by RT‐PCR.Key ResultsA2AR stimulation increased cAMP and PKA activity which and were reversed by addition of ZM241385. The direct PKA stimuli 8‐Cl‐cAMP and 6‐Bnz‐cAMP inhibited OC maturation whereas PKI increased OC differentiation. A2AR stimulation inhibited p50/p105 NFκB nuclear translocation in control but not in PKA KO cells. A2AR stimulation activated ERK1/2 by a PKA‐dependent mechanism, an effect reversed by ZM241385, but not p38 and JNK activation. A2AR stimulation inhibited OC expression of differentiation markers by a PKA‐mechanism.Conclusions and ImplicationsA2AR activation inhibits OC differentiation and regulates bone turnover via PKA‐dependent inhibition of NFκB nuclear translocation, suggesting a mechanism by which adenosine could target bone destruction in inflammatory diseases like Rheumatoid Arthritis.
Molecular modelling, synthesis, cytotoxicity and anti‐tumour mechanisms of 2‐aryl‐6‐substituted quinazolinones as dual‐targeted anti‐cancer agents
Authors: Hour M J , Lee K H , Chen T L , Lee K T , Zhao Yu , Lee H Z 
Published: May 2013

Background and PurposeOur previous study demonstrated that 6‐(pyrrolidin‐1‐yl)‐2‐(3‐methoxyphenyl)quinazolin‐4‐one (HMJ38) was a potent anti‐tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti‐cancer agents and to examine the anti‐cancer mechanisms.Experimental ApproachUsing computer‐aided drug design, 2‐aryl‐6‐substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C‐2 and C‐6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTrackerTM Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis.Key ResultsCompounds MJ65–70 exhibited strong anti‐proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non‐small carcinoma H460, hepatoma Hep3B and oral cancer HSC‐3 cells, with one compund MJ66 (6‐(pyrrolidin‐1‐yl)‐2‐(naphthalen‐1‐yl)quinazolin‐4‐one) highly active against M21 cells (IC50 about 0.033 μM). Treatment of CH27 or HSC‐3 cells with MJ65–70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65–70‐induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl‐2 phosphorylation were also observed, after treatment with MJ65–70.Conclusions and ImplicationMJ65–70 are dual‐targeted, tubulin‐ and JNK‐binding, anti‐cancer agents and induce cancer cell death through up‐regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual‐targeted anti‐cancer drugs, contributing to clinical anti‐cancer drug discovery and application.
Functional and morphological characterization of glutamate transporters in the rat locus coeruleus
Authors: Medrano M C , Gerrikagoitia I , Martínez‐Millán L , Mendiguren A , Pineda J 
Published: May 2013

Background and PurposeExcitatory amino acid transporters (EAATs) in the CNS contribute to the clearance of glutamate released during neurotransmission. The aim of this study was to explore the role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate.Experimental ApproachWe measured the effect of different EAAT subtype inhibitors/enhancers on glutamate‐ and KCl‐induced activation of LC neurons in rat slices. EAAT2–3 expression in the LC was also characterized by immunohistochemistry.Key ResultsThe EAAT2–5 inhibitor DL‐threo‐β‐benzyloxaspartic acid (100 μM), but not the EAAT2, 4, 5 inhibitor L‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (100 μM) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 μM), enhanced the glutamate‐ and KCl‐induced activation of the firing rate of LC neurons. These effects were blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 μM) was the only EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone (200 mg·kg−1 i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate and DHK, suggesting a functional impact of EAAT2 up‐regulation on the glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC.Conclusions and ImplicationsThese results remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas glial EAAT2 would regulate tonic glutamate concentrations in this nucleus.
Learning From Their Own Actions: The Unique Effect of Producing Actions on Infants' Action Understanding
Authors: Gerson Sarah A. , Woodward Amanda L. 
Published: May 2013

Prior research suggests that infants' action production affects their action understanding, but little is known about the aspects of motor experience that render these effects. In Study 1, the relative contributions of self‐produced (n = 30) and observational (n = 30) action experience on 3‐month‐old infants' action understanding was assessed using a visual habituation paradigm. In Study 2, generalization of training to a new context was examined (n = 30). Results revealed a unique effect of active over observational experience. Furthermore, findings suggest that benefits of trained actions do not generalize broadly, at least following brief training.
Conservation management and sustainable harvest quotas are sensitive to choice of climate modelling approach for two marine gastropods
Authors: Fordham D. A. , Brook B. W. , Caley M. J. , Bradshaw C. J. A. , Mellin C. 
Published: May 2013

AbstractAimTo establish the robustness of two alternative methods for predicting the future ranges and abundances for two wild‐harvested abalone species (Haliotis rubra Donovan 1808 and H. laevigata Leach 1814): single atmosphere–ocean general circulation model (GCM) or ensemble‐averaged GCM forecasts.LocationSouth Australia.MethodsWe assessed the ability of 20 GCMs to simulate observed seasonal sea surface temperature (SST) between 1980–1999, globally, and regionally for the Indian and Pacific Oceans south of the Equator. We used model rankings to characterize a set of representative climate futures, using three different‐sized GCM ensembles and two individual GCMs (the Parallel Climate Model and the Community Climate System Model, version 3.0). Ecological niche models were then coupled to physiological information to compare forecast changes in area of occupancy, population size and harvest area based on forecasts using the various GCM selection methods, as well as different greenhouse gas emission scenarios and climate sensitivities.ResultsWe show that: (1) the skill with which climate models reproduce recent SST records varies considerably amongst GCMs, with multimodel ensemble averages showing closer agreement to observations than single models; (2) choice of GCM, and the decision on whether or not to use ensemble‐averaged climate forecasts, can strongly influence spatiotemporal predictions of range, abundance and fishing potential; and (3) comparable hindcasting skill does not necessarily guarantee that GCM forecasts and ecological and evolutionary responses to these forecast changes, will be similar amongst closely ranked models.ConclusionBy averaging across an ensemble of seven highly ranked skilful GCMs, inherent uncertainties stemming from GCM differences are incorporated into forecasts of change in species range, abundance and sustainable fishing area. Our results highlight the need to make informed and explicit decisions on GCM choice, model sensitivity and emission scenarios when exploring conservation options for marine species and the sustainability of future harvests using ecological niche models.
Molecular identification of a phytoplasma associated with Sophora Root yellows
Authors: Chen X. F. , Liang Y. C. , Chen N. , Su W. M. , Xiao H. , Wang X. , Zhu X. P. 
Published: May 2013

SummaryA phytoplasma infecting Sophora Root (Sophora alopecuroides) was detected and identified in Alar, Xinjiang Uygur Autonomous Region of China. Typical phytoplasma bodies were observed in sieve tubes of the diseased plants by transmission electron microscopy. A partial 16S rRNA gene and ribosomal protein (rp) genes containing rpl22 (rplV) and rps3 (rpsC) were amplified by direct and nested PCR. Based on the sequence similarity of the 16S rRNA and rp genes with accompanying phylogenetic analyses, the phytoplasma associated with Sophora Root yellows belongs to the 16SrI group (aster yellows group). Virtual RFLP analysis of these 16S rRNA and rp gene sequences showed distinct differences from those of reference phytoplasma strains representing previously described subgroups of the 16SrI group. Moreover, the similarity coefficient (0.92) of the RFLP profile of this phytoplasma was less than the threshold similarity coefficient (0.97) required for subgroup classification. Thus, the phytoplasma isolate of Sophora Root plants, designated as ‘SoRY’, represents a new subgroup. Furthermore, this is the first report of phytoplasma disease associated with Sophora Root plants.
The Fragility of Consensus: Public Reason, Diversity and Stability
Authors: Thrasher John , Vallier Kevin 
Published: May 2013

AbstractJohn Rawls's transition from A Theory of Justice to Political Liberalism was driven by his rejection of Theory's account of stability. The key to his later account of stability is the idea of public reason. We see Rawls's account of stability as an attempt to solve a mutual assurance problem. We maintain that Rawls's solution fails because his primary assurance mechanism, in the form of public reason, is fragile. His conception of public reason relies on a condition of consensus that we argue is unrealistic in modern, pluralistic democracies. After rejecting Rawls's conception of public reason, we offer an ‘indirect alternative’ that we believe is much more robust. We cite experimental evidence to back up this claim.
Prevention of sudden unexpected death in epilepsy: A realistic goal?
Authors: Ryvlin Philippe , Nashef Lina , Tomson Torbjörn 
Published: May 2013

SummarySudden unexpected death in epilepsy (SUDEP) represents one of the most severe consequences of drug‐resistant epilepsy, for which no evidence‐based prevention is available. Development of effective prevention will depend on the following: (1) better understanding of the pathophysiology of SUDEP to define the most appropriate targets of intervention, and (2) identification of risk factors for SUDEP that would allow for the design of feasible clinical trials to test targeted interventions in high‐risk populations. The most important known risk factor is the occurrence and frequency of generalized tonic–clonic seizure (GTCS), a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to minimize the risk of GTCS with optimal medical management and patient education. However, whether one might prevent SUDEP in patients with refractory epilepsy by using more frequent review of antiepileptic treatment and earlier referral for presurgical evaluation, remains to be seen. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS‐induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate‐ or adenosine‐induced postictal brainstem depression. Promising interventions can be tested first on surrogate markers, such as postictal hypoxia in epilepsy monitoring units (EMUs), before SUDEP trials can be implemented. EMU safety should also be improved to avoid SUDEP occurrence in that setting. Finally, the development of ambulatory SUDEP prevention devices should be encouraged but raises a number of unsolved issues.
Animal and human data: Where are our concepts for drug‐resistant epilepsy going?
Authors: Potschka Heidrun 
Published: May 2013

SummaryDrug‐resistant epilepsy remains a challenge in the therapeutic management of patients with epilepsy. Identification of factors contributing to drug resistance might render a basis for the development of novel therapeutic approaches, for the reorganization of screening programs in drug development, and for the design of personalized treatment concepts. Therefore, experimental and clinical studies need to link efforts and collaborate in order to elucidate drug‐resistance mechanisms, to define the relative clinical relevance of selected mechanisms, and to develop and validate novel therapeutic concepts in overcoming resistance.
EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy
Authors: Holmes Gregory L. 
Published: May 2013

SummaryCognitive impairment is a common and often devastating comorbidity of pharmacoresistent epilepsy. The cognitive comorbidity can be both chronic, primarily due to the underlying etiology of the epilepsy, and dynamic or evolving because of recurrent seizures or interictal spikes. There is now considerable evidence that interictal spikes can contribute to cognitive impairment. Interictal spikes in both rodents and humans result in transient impairment of memory retrieval, whereas in immature animals, interictal spikes can result in long‐term adverse effects on brain development. Interictal spikes therefore contribute to the cognitive impairment in the pharmacoresistant epilepsies. Effective treatment of pharmacoresistant epilepsy needs to target not only the overt seizures but interictal electroencephalography (EEG) abnormalities as well.
Multimodal neuroimaging: Potential biomarkers for response to antiepileptic drugs?
Authors: Coan Ana C. , Cendes Fernando 
Published: May 2013

SummaryNeuroimaging techniques in epilepsy are used widely for definition of the epileptogenic lesion and surgical decision. However, its applications extend to the knowledge of epileptic mechanisms and include the identification of prognostic features that can help our decisions on the appropriate type of treatment on an individual basis. Structural neuroimaging may be able to identify patients more likely to respond to antiepileptic drug (AED) treatment and also patients who are better candidates for earlier surgical treatment. In the past decades, quantitative analyses have also improved our knowledge about epileptogenic lesions and networks as well as the following prognoses: seizure control, cognitive outcome, and comorbidities. New advanced neuroimaging techniques such as functional magnetic resonance imaging (MRI) and the development biotracers that could be associated with inflammation and specific genetic patterns will add further knowledge to the development of epilepsy treatments.
Exome sequencing reveals new causal mutations in children with epileptic encephalopathies
Authors: Veeramah Krishna R. , Johnstone Laurel , Karafet Tatiana M. , Wolf Daniel , Sprissler Ryan , Salogiannis John , Barth‐Maron Asa , Greenberg Michael E. , Stuhlmann Till , Weinert Stefanie , Jentsch Thomas J. , Pazzi Marjorie , Restifo Linda L. , Talwar Dinesh , Erickson Robert P. , Hammer Michael F. 
Published: May 2013

SummaryPurposeThe management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses.MethodsWe performed WES (mean coverage approximately 40×) on 10 trios comprised of unaffected parents and a child with sporadic epilepsy characterized by difficult‐to‐control seizures and some combination of developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, or motor deficits. Sequence processing and variant calling were performed using standard bioinformatics tools. A custom filtering system was used to prioritize de novo variants of possible functional significance for validation by Sanger sequencing.Key FindingsIn 9 of 10 probands, we identified one or more de novo variants predicted to alter protein function, for a total of 15. Four probands had de novo mutations in genes previously shown to harbor heterozygous mutations in patients with severe, early onset epilepsies (two in SCN1A, and one each in CDKL5 and EEF1A2). In three children, the de novo variants were in genes with functional roles that are plausibly relevant to epilepsy (KCNH5, CLCN4, and ARHGEF15). The variant in KCNH5 alters one of the highly conserved arginine residues of the voltage sensor of the encoded voltage‐gated potassium channel. In vitro analyses using cell‐based assays revealed that the CLCN4 mutation greatly impaired ion transport by the ClC‐4 2Cl−/H+‐exchanger and that the mutation in ARHGEF15 reduced GEF exchange activity of the gene product, Ephexin5, by about 50%. Of interest, these seven probands all presented with seizures within the first 6 months of life, and six of these have intractable seizures.SignificanceThe finding that 7 of 10 children carried de novo mutations in genes of known or plausible clinical significance to neuronal excitability suggests that WES will be of use for the molecular genetic diagnosis of sporadic epilepsies in children, especially when seizures are of early onset and difficult to control.
Identification of a biomanipulation‐driven regime shift in Lake Vesijärvi: implications for lake management
Authors: Anttila Saku , Ketola Mirva , Kuoppamäki Kirsi , Kairesalo Timo 
Published: May 2013

Summary

The biomanipulation of Lake Vesijärvi in southern Finland putatively changed the lake ecosystem resulting in a clear‐water state, but the dynamics behind the observed change remained unverified.

We used a general analytical approach to identify abrupt transitions in the long‐term monitoring data of Lake Vesijärvi. Methods included the identification of breakpoints in chlorophyll a (response variable), in total phosphorus (TP; key driver) and in large‐bodied cladocerans (feedback mechanism of biomanipulation). In addition, we characterised the frequency distribution and temporal variance of the response variable, as well as the interaction between TP and chlorophyll a.

According to long‐term records, biomanipulation resulted in two distinct states: (i) a eutrophic state, where chlorophyll a and TP were linearly correlated and (ii) a mesotrophic state, where the key driver and response variables were not significantly correlated. The changed relationship between the key driver and response variables, together with the increase in the body size of cladocerans, suggested a hysteresis‐type transition phase. However, the frequency distribution and the temporal variance of chlorophyll a agreed also with a threshold‐type of transition.

Zooplankton seemed to be more important in maintaining the clear‐water state than previously reported. Our results highlight the role of long‐term monitoring data and the characterisation of abrupt transitions in ecosystem interactions as tools for sustainable management of lake ecosystems.
Evolutionary history of alpine and subalpine Daphnia in western North America
Authors: Miner Brooks E. , Knapp Roland A. , Colbourne John K. , Pfrender Michael E. 
Published: May 2013

Summary

Studying adaptation within a multispecies complex can be challenging due to uncertainty about the evolutionary relationships among populations. An accurate phylogenetic context is especially important for drawing conclusions about phenotypic evolution for species used as model organisms in ecological and evolutionary research.

Within the zooplankton genus Daphnia, carapace melanin pigmentation has often been suggested as an adaptation to ultraviolet radiation exposure in clear‐water habitats. However, the evolutionary history of melanism has been obscured because of phylogenetic uncertainty.
We inferred a molecular phylogeny based on the mitochondrial ND5 and COI loci and used it to explore the evolutionary history of populations belonging to the Daphnia pulex species complex that inhabit alpine and subalpine lakes and ponds in western North America.

Our analysis confirms the existence of a distinct mitochondrial clade for Daphnia melanica within the D. pulex species complex and shows it to be more geographically widespread than previously thought and includes populations from several disjunct sites.

We show that melanism, once used as a diagnostic character for identifying Daphnia species, is polymorphic within the D. melanica clade. This polymorphism suggests the possibility of independent parallel evolutionary losses and gains of melanism in this species complex.
Fracture Resistance Behavior of High‐Thermal‐Conductivity Silicon Nitride Ceramics
Authors: Zhou You , Ohji Tatsuki , Hyuga Hideki , Yoshizawa Yu‐ichi , Murayama Norimitsu , Hirao Kiyoshi 
Published: May 2013

Silicon nitride ceramics were prepared from a high‐purity silicon powder doped with 2 mol% Y2O3 and 5 mol% MgO as sintering additives via a route of sintering of reaction‐bonded silicon nitride (SRBSN). The materials sintered at 1900°C for 3, 6, 12, and 24 h had thermal conductivities of 109, 125, 146, and 154 W/m/K, and four‐point bending strengths of 786, 676, 608, and 505 MPa, respectively. The fracture toughness values, determined by the single‐edge‐precracked‐beam (SEPB) method, were 8.4, 8.6, 9.7, and 10.7 MPa m1/2 for the materials sintered for 3, 6, 12, and 24 h, respectively, which were similar to the results measured by the chevron‐notched‐beam (CNB) test method. The materials sintered for longer times (12 and 24 h) showed stronger R‐curve behaviors over longer range of crack extension, in comparison with the materials sintered for shorter times (3 and 6 h).