102 research outputs found
Effects of Antiepileptic Drugs on GABA Responses and on Reduction of GABA Responses by PTZ and DMCM on Mouse Neurons in Cell Culture
The mechanisms of action of antiepileptic drugs effective against generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against seizures induced in experimental animals by pentylenĂtĂtrazol (PTZ) and methyl-6,7-dimethoxy-4-ethyl-Î-carboline-3-carboxylate (DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included: ethosuximide (ESM), dimethadione (DMO), sodium valproate (VPA), and diazepam (DZP). Two experimental AEDs, CGS 9896 and ZK 91296, with anticonvulsant action against PTZ- or DMCM-induced seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ- and DMCM-induced inhibition of GABA responses were also evaluated. PTZ and DMCM revers-ibly reduced GABA responses in a concentration-dependent manner. PTZ complĂtĂly inhibited GABA responses at 10 mM (IC 50 of 1.1 mM), whereas DMCM-induced inhibition of GABA responses reached a plateau level of 39% of control values at 1 p.M (IC 50 of 33 nM). ESM (1,200 ÎM), DMO (6 mM), VPA (200 u.M), CGS 9896 (2 ÎM), and ZK 98% (2 Î M ) did not alter GABA responses. DZP enhanced GABA responses in a concentration-dependent manner. The inhibition of GABA responses produced by PTZ 1 mM was unaltered by ESM (600 Î M ), DMO (6 mM), CGS 9896 (1 Î M), or ZK 9896 (1 ÎM)- Coapplication of VPA (200 ÎM) and PTZ (1 mM) slightly enhanced the PTZ effect. DZP (> 10 nM), however, reversed the PTZ-induced reduction of GABA responses. The DMCM (250 nM) inhibition of GABA-responses was unaltered by ESM (600 Î.M), DMO (2 mM), or VPA (200 ÎM). CGS 9896 (2 Î M ) and ZK 91296 (2 ÎM), however, antagonized the DMCM effect. DZP (> 10 nM) significantly reversed the DMCM-induced inhibition of GABA responses. The lack of effect of VPA, ESM, and DMO on postsynaptic GABA responses suggests that direct enhancement of postsynaptic GABA action is not a common mechanism of action of antiabsence AEDs. The AEDs DZP, CGS 98%, and ZK 912% all reversed DMCM, but not PTZ, reduction of GABA responses, suggesting that these AEDs blocked DMCM seizures by acting at benzodiazepine receptors. However, since only DZP enhanced GABA responses, it is unclear how CGS 98% and ZK 912% blocked PTZ seizures. Key Words: AnticonvulsantsâGABAâNeuron cultureâCell cultureâSpinal cord neuronsâConvulsants. RESUMEN Los mecanismos de accidn de las medicaciones antiepilĂpticas eficaces contra los ataques generalizados de ausencia (AEDs antiausencia) permanecen inciertos. Los AEDs antiausencia son, generalmente, eficaces contra ataques experimentales inducidos por el pentilentetrazol (PTZ) y el metil-6,7-dimetoxy-4-etil-Pcarbolina-3-carboxilato (DMCM) en animates, medicaciones que reducen la inhibiciĂn GABAĂrgica. Hemos estudiado los efectos de varios AEDs sobre respuestas-GABA registradas en las neuronas de la mĂdula espinal de ratones que habian crecido en cultivos de cĂlulas primarieas disociadas. Cuatro AEDs antiausencia fueron incluidos: etoxusimida (ESM), dimetadiona (DMO), valproato sĂdico (VPA) y diazepan (DZP). TambtĂn se incluyeron dos AEDs experimentales, CGS 9896 y ZK 912%, con acciĂn anticonvulsiva contra los ataques inducidos por PTZ o DMCM. TambiĂn se valoraron los posibles efectos de los AEDs antiausencia y experimentales sobre el PTZ y la inhibiciĂn de las respuestas-GABA inducidas por el DMCM. El PTZ y el DMCM redujeron las respuestas-GABA de modo reversible y dependiendo de sus concentraciones. El PTZ inhibiĂ cmpleta-mente las respuestas-GABA a 10 mM (IC 50 de 1.1 mM) mientras que la inhibitiĂn de las respuestas GABA inducida por el DMCM alcanzĂ un nivel estable del 39% de los valores control con 1 Î. M (IC 50 de 33 mM). La ESM (1200 Î.M), la DMO (6 mM), el VPA (200 Î M ), el CGS 98% (2 Î M) y el ZK 98% (2 Î M) no alteraron las respuestas-GABA. El DZP aumentĂ las respuestas GABA de una manera concentraciĂn-dependiente. La inhibition de las respuestas-GABA producidas por el PTZ (1 mM), no se altero con las ESM (600 Î M), la DMO (6 mM), el CGS 98% (1 Î M) o el ZK 98% (1 Î .M). La co-aplicacion de VPA (200 Î M) y el PTZ (1 mM) aument6 ligeramente los efectos del PTZ. Sin embargo el DZP (10 nM) revirtiĂ significativamente la inhibition de las respuestas GABA inducidas por el DMCM. La falta de efectos de CPA, ESM y DMO sobre las respuestas GABA post-sinĂpticas sugiere que el incremento de la acciĂn GABA post-sinĂptica no es un mecanismo comĂn de actuatiĂn de las AEDs antiausencia. Todas las AEDs DZP, CGS 98% y ZK 912% revirtieron la reduction de las respuestas GABA producidas por el DMCM pero no las inducidas por el PTZ lo que sugiere que estos AEDs bloquean los ataques DMCM actuando sobre los receptores de la benzodiazepina. Sin embargo, puesto que el incremento de las respuestas GABA sĂlĂ se produce por el DZP, permanece todavia sin aclarar el por quĂ el CGS 98% y el ZK 912% bloquean los ataques producidos por el PTZ. ZUSAMMENFASSUNG Der Wirkmechansimus von Antiepileptika gegen generalisierte Absencen ist unklar. Antiabsencemittel sind generell wirkungs-voll gegen PTZ- und Methyl-6,7-Dimethoxy-4-Ăthyl-P-Carbolin-Î-Carboxylat (DMCM) induzierte tierexperimentelle AnfĂlle, also von Medikamenten, die die GABA-erge Inhibition reduzieren. Es wurde vermutet, daĂ Antiabsencemittel die GABA-erge Inhibition verstĂrken. Wir untersuchten die Wirkung von verschiedenen Antiepileptika auf GABA-Antworten in spinalen MĂuseneuronen, die in Zellkulturen gew-achsen waren. Es wurden 4 Absencemittel untersucht: Ethosux-imid (ESM), Dimethadion (DMD), Sodium Valproat (VPA) und Diazepam (DZP). ZusĂtzlich wurden 2 experimentelle Antiepileptika, CGS 98% und ZK 912%, die gegen PTZ0 oder DMCM-induzierte AnfĂlle wirkungsvoll sind, eingeschlossen. Mogliche Wirkungen der Antiabsence- und experimentellen Antiepileptika auf PTZ- und DMCM-induzierte Hemmung der GABA-Antworten wurden ebenfalls ausgewertet. PTZ und DMCM zeigten eine konzentrationsabhĂngige reversible Reduktion der GABA-Antworten. PTZ zeigte eine komplette Hemmung der GABA-Antworten bei 10 mM (IC 50 1,1 mM), DMCM-Hemmung der GABA-Antworten zeigte ein Plateau von 39% der Kontroll-werte bei 1 uJtf (ICJO von 33 mAfl. ESM (1200 uJtf), DMD (6 mM), VPA (200 Î M), CGS 98% (2 Î M) und ZK 98% (2 Î M) anderten nicht die GABA-Antworten. DZP verstarkte die GABA-Antworten konzentrationsabhangig. Die durch PTZ (1 mM) hervorgerufene Hemmung der GABA-Antworten war bei ESM (600 Î M), DMD (6 mM), CGS 98% (1 mAO und ZK 3836 (1 mM) unverĂndert. ZusĂtliche Anwendung von VPA (200 mM) und PTZ (1 mM) verstĂrkten geringfĂgig den PTZ-Effekt. DZP (10 nM) kehrte die durch PTZ hervorgerufene Reduktion der GABA-Antworten um. Die durch DMCM (250 nM) hervorgerufene Hemmung der GABA-Antworten war durch ESM (600 Î .M), DMD (2 mM) und VPA (200 Î M ) unbeeinflusst. CGS 98% (2 Î M) und ZK 912% (2 Î M ) antagonisierten die DMCM-Wirkung. DZP (>10 nM) kehrte die durch DMCM-induzierte Hemmung der GABA-Antworten um. Das Fehlen einer Wirkung von VPA. ESM und DMD auf die postsynaptischen GABA-Antworten legen nahe, daĂ eine direkte VerstĂrkung der postsynaptischen GABA-Aktion kein gemeinsamer Mechanis-mus der Antiabsencemittel darstellt. Die Antiepileptika DZP, CGS 98% und ZK 912% kehrten die DMCM-Wirkung auf die GABA-Antworten um, jedoch nicht die von PTZ, was vermuten lapt, daĂ diese Antiepileptika die DMCM-AnfĂlle Ăber die Wirkung an den Benzodiazipin-Rezeptoren verhinderte. Da jedoch nur DZP GABA-Antworten verstarkte, ist unklar, in welcher Weise CGS 98% und ZK 912% die PTZ-AnfaUe ver-hinderten.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65188/1/j.1528-1157.1989.tb05275.x.pd
Latent provisions for building information modeling (BIM) contracts: a social network analysis approach
The effective adoption and use of Building Information Modeling (BIM) require appropriate contract design to fairly allocate the contracting partiesâ rights and responsibilities. Several standards for BIM protocols and contracts have been developed for the industry. However, the awareness and the use of these are rather limited, leading to unclear provisions in BIM contracts. Therefore, the research aims to identify the influential legal aspects that serve as the latent contract provisions in BIM contracts. A questionnaire survey was conducted to survey experts and active BIM users in construction projects. The data were analyzed using social network analysis (SNA) by assuming interdependent relationships among various the legal aspects in BIM contacts. The key legal aspects associated with BIM contracts pertain to the roles and responsibilities of the project participants. The results also reveal that data security is the center of all latent legal aspects in the contracts. The study provides significant new insights into clarifying the required contract provisions in BIM contracts
The variable influence of dispersant on degradation of oil hydrocarbons in subarctic deep-sea sediments at low temperatures (0-5 °C)
The microbial degradation of petroleum hydrocarbons at low temperatures was investigated in subarctic deep-sea sediments in th e Faroe Shetland Channel (FSC). The effect of the marine oil dispersant, Superdispersant 25 on hydrocarbon degradation was also examined. Sediments collected at 500 and 1000 m depth were spiked with a model oil containing 20 hydrocarbons and incubated at ambient temperature (5 and 0 °C, respectively) with and without marine dispersant. Treatment of sediments with hydrocarbons resulted in the enrichment of Gammaproteobacteria, and specifically the genera Pseudoalteromonas, Pseudomonas, Halomonas, and Cobetia. Hydrocarbon degradation was faster at 5 °C (500 m) with 65-89% of each component degraded after 50 days compared to 0-47% degradation at 0 °C (1000 m), where the aromatic hydrocarbons fluoranthene, anthracene, and Dibenzothiophene showed no degradation. Dispersant significantly increased the rate of degradation at 1000 m, but had no effect at 500 m. There was no statistically significant effect of Superdispersant 25 on the bacterial community structure at either station. These results show that the indigenous bacterial community in the FSC has the capacity to mitigate some of the effects of a potential oil spill, however, the effect of dispersant is ambiguous and further research is needed to understand the implications of its use
Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the Clavicipitaceae reveals dynamics of alkaloid Loci
The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (EpichloĂ« and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and someâincluding the infamous ergot alkaloidsâhave potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses
Shedding Light on the Galaxy Luminosity Function
From as early as the 1930s, astronomers have tried to quantify the
statistical nature of the evolution and large-scale structure of galaxies by
studying their luminosity distribution as a function of redshift - known as the
galaxy luminosity function (LF). Accurately constructing the LF remains a
popular and yet tricky pursuit in modern observational cosmology where the
presence of observational selection effects due to e.g. detection thresholds in
apparent magnitude, colour, surface brightness or some combination thereof can
render any given galaxy survey incomplete and thus introduce bias into the LF.
Over the last seventy years there have been numerous sophisticated
statistical approaches devised to tackle these issues; all have advantages --
but not one is perfect. This review takes a broad historical look at the key
statistical tools that have been developed over this period, discussing their
relative merits and highlighting any significant extensions and modifications.
In addition, the more generalised methods that have emerged within the last few
years are examined. These methods propose a more rigorous statistical framework
within which to determine the LF compared to some of the more traditional
methods. I also look at how photometric redshift estimations are being
incorporated into the LF methodology as well as considering the construction of
bivariate LFs. Finally, I review the ongoing development of completeness
estimators which test some of the fundamental assumptions going into LF
estimators and can be powerful probes of any residual systematic effects
inherent magnitude-redshift data.Comment: 95 pages, 23 figures, 3 tables. Now published in The Astronomy &
Astrophysics Review. This version: bring in line with A&AR format
requirements, also minor typo corrections made, additional citations and
higher rez images adde
BIM competencies for delivering waste-efficient building projects in a circular economy
Competency measures are increasingly becoming effective ways for construction organizations to measure their ability to deliver waste-efficient projects. Despite the ongoing efforts in achieving the goals of the circular economy through BIM adoption, there is still a paucity of studies on building information modeling (BIM) competencies for delivering waste-efficient building projects. This paper, therefore, aims to identify and investigate critical BIM competencies for delivering waste-efficient building projects in a circular economy. The study adopts a pluralistic approach, using a combination of the review of extant literature, focus group discussions and questionnaire survey. Analysis of the focus group discussion along with the result of the literature review revealed forty-three preliminary BIM competencies, which were subjected to rigorous statistical analyses. Four broad categories of BIM competencies for delivering waste-efficient building projects emerged from the analyses. These are project management-related, construction-related, procurement-related, and design-related BIM competencies. Construction firms could use the BIM competencies identified in this study to enhance the delivery of waste-efficient building projects as well as assess their BIM competency requirements at an individual and organizational level
The interstitium in cardiac repair: role of the immune-stromal cell interplay
Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases
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