Structure of a novel InsP3 receptor Südhof, T.C.; Newton, C.L.; Archer, B.T. ...
EMBO journal,
November 1991, Letnik:
10, Številka:
11
Journal Article
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Inositol 1,4,5‐trisphosphate (InsP3) constitutes a major intracellular second messenger that transduces many growth factor and neurotransmitter signals. InsP3 causes the release of Ca2+ from ...intracellular stores by binding to specific receptors that are coupled to Ca2+ channels. One such receptor from cerebellum has previously been extensively characterized. We have now determined the full structure of a second, novel InsP3 receptor which we refer to as type 2 InsP3 receptor as opposed to the cerebellar type 1 InsP3 receptor. The type 2 InsP3 receptor has the same general structural design as the cerebellar type 1 InsP3 receptor with which it shares 69% sequence identity. Expression of the amino‐terminal 1078 amino acids of the type 2 receptor demonstrates high affinity binding of InsP3 to the type 2 receptor with a similar specificity but higher affinity than observed for the type 1 receptor. These results demonstrate the presence of several types of InsP3 receptor in brain and raise the possibility that intracellular Ca2+ signaling may involve multiple pathways with different regulatory properties dependent on different InsP3 receptors.
Application of metapopulation models is becoming increasingly widespread in the conservation of species in fragmented landscapes. We provide one of the first detailed comparisons of two of the most ...common modeling techniques, incidence function models and stage-based matrix models, and test their accuracy in predicting patch occupancy for a real metapopulation. We measured patch occupancies and demographic rates for regional populations of the Florida scrub lizard (Sceloporus woodi) and compared the observed occupancies with those predicted by each model. Both modeling strategies predicted patch occupancies with good accuracy (77-80%) and gave similar results when we compared hypothetical management scenarios involving removal of key habitat patches and degradation of habitat quality. To compare the two modeling approaches over a broader set of conditions, we simulated metapopulation dynamics for 150 artificial landscapes composed of equal-sized patches (2-1024 ha) spaced at equal distances (50-750 m). Differences in predicted patch occupancy were small to moderate (<20%) for about 74% of all simulations, but 22% of the landscapes had differences of >50%. Incidence function models and stage-based matrix models differ in their approaches, assumptions, and requirements for empirical data, and our findings provide evidence that the two models can produce different results. We encourage researchers to use both techniques and further examine potential differences in model output. The feasibility of obtaining data for population modeling varies widely among species and limits the modeling approaches appropriate for each species. Understanding different modeling approaches will become increasingly important as conservation programs undertake the challenge of managing for multiple species in a landscape context.
Progress in gravitational-wave astronomy depends upon having sensitive detectors with good data quality. Since the end of the LIGO-Virgo-KAGRA third Observing run in March 2020, ...detector-characterization efforts have lead to increased sensitivity of the detectors, swifter validation of gravitational-wave candidates and improved tools used for data-quality products. In this article, we discuss these efforts in detail and their impact on our ability to detect and study gravitational-waves. These include the multiple instrumental investigations that led to reduction in transient noise, along with the work to improve software tools used to examine the detectors data-quality. We end with a brief discussion on the role and requirements of detector characterization as the sensitivity of our detectors further improves in the future Observing runs.
Dry, sandy scrub habitats of the Floridapeninsula represent naturally fragmentedremnants of xeric ecosystems that werewidespread during the Pliocene and earlyPleistocene. This habitat is ...characterized byhigh endemism, and distribution of genetic andevolutionary diversity among scrub ``islands'' isof compelling interest because Florida scrub israpidly disappearing under human development. We compare range-wide diversity inmitochondrial cytochrome b sequences forthree scrub-associated lizards with contrastinglevels of habitat specificity. All speciesshow strong geographic partitioning of geneticdiversity, supporting the hypothesis that scrubfauna is highly restricted by vicariantseparations. The mole skink (Eumecesegregius), the least habitat specific, has thelowest phylogeographic structure among thelizards (Φ^sub st^ = 0.631). The mtDNAgeneology for E. egregius is not entirelyconcordant with the five recognized subspeciesand supports a link between populations incentral Florida (E. e. lividus) and theFlorida Keys (E.e. egregius) rather thana previously proposed affiliation betweennorthern and southern populations. The Floridascrub lizard (Sceloporus woodi) is themost habitat specific of the lizards and hasthe strongest phylogeographic structure (Φ^sub st^ = 0.876). The sand skink (Neosepsreynoldsi) falls between the moleskink and scrub lizard in terms of habitatspecificity and phylogeographic structure (Φ^sub st^ = 0.667). For all three species,networks of mtDNA haplotypes coalesce on twocentral ridges that contain the oldest scrub. The geographic structure and deep evolutionarylineages observed in these species have strongimplications for conservation, includingstrategies for translocation, reserve design,and management of landscape connectivity.PUBLICATION ABSTRACT
Background and purpose:
M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and ...schizophrenia. However, the discovery of subtype‐selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh‐binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC‐42 (4‐n‐butyl‐1‐4‐(2‐methylphenyl)‐4‐oxo‐1‐butyl‐piperidine), which bind to an allosteric site and selectively activate the M1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs.
Experimental approach:
In this study, we have compared the pharmacological profile of AC‐42 and a close structural analogue, 77‐LH‐28‐1 (1‐3‐(4‐butyl‐1‐piperidinyl)propyl‐3,4‐dihydro‐2(1H)‐quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology.
Key results:
Calcium mobilization and inositol phosphate accumulation assays revealed that both AC‐42 and 77‐LH‐28‐1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77‐LH‐28‐1, but not AC‐42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77‐LH‐28‐1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration.
Conclusions and implications:
These data suggest that 77‐LH‐28‐1 is a potent, selective, bioavailable and brain‐penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC‐42, with which to study the pharmacology of the M1 mAChR.
British Journal of Pharmacology (2008) 154, 1104–1115; doi:10.1038/bjp.2008.152; published online 5 May 2008
We examined the dietary response of pumas (Puma concolor) to a population decline of the plains vizcacha (Lagostomus maximus), and compared the diet of pumas in semi-arid scrub of Argentina to ...predicted patterns based on a biogeographic analysis of the diet of this species throughout the Americas. Feces of pumas were collected in Lihue Calel National Park in 1985-1988 and in 1994, and populations of vizcachas were monitored during the same period by direct observation of marked animals and burrow surveys. Vizcachas were the most abundant prey in feces of pumas during all years and composed 51.6-84.9% of the diet. During 1986-1994, the population of vizcachas declined >90% in Lihue Calel National Park, and ≥14% on surrounding ranches. The proportion of vizcachas in feces of pumas declined by 33%, and consumption of ungulates increased. Weight of prey and breadth of diet of pumas were lower in our study site than in almost all other areas in North and South America. We hypothesize that pumas are selectively foraging on vizcachas because this species provides a clumped resource that is spatially predictable, easy to handle, and, at times, abundant.
This paper describes a novel combined approach to targeting GBM with multiple RNA-based therapeutics. Overall, the results demonstrate the good potential of a smart safe and clinically applicable ...combined regimen for the treatment of glioblastoma, opening up a new avenue in the treatment of this aggressive disease
Since the establishment of the alien mussel Mytilus galloprovincialis in South Africa, several authors have studied its interactions with individual indigenous species. However, the broader ...implications of this invasion on the intertidal zone remain undocumented. This paper analyses the impacts of this mussel on the rocky-shore invertebrate community structure at Marcus Island on the west coast of South Africa. The effects of the invasion were linked to 3 key elements and were not consistently spread across the intertidal zone, but were focused within the mid-to-low shore. Firstly, physical stress in the mid-intertidal zones was ameliorated by the presence of M. galloprovincialis beds. Secondly, habitat complexity was increased where M. galloprovincialis replaced bare rock or less complex secondary habitat. Thirdly, habitat became less patchy as mussel beds blanketed the shore. Consequently, invertebrate density and species richness increased substantially, and community composition changed significantly in the mid- shore. Lower on the shore, significant changes in invertebrate community structure were driven by a switch from mono-layered beds of the small indigenous mussel Aulacomya ater to multilayered beds of M. galloprovincialis, despite no change in total species richness.
Inflammatory processes may be important in the initiation and propagation of uterine contractions and preterm labor in human pregnancies. Recently, a murine model of preterm labor has been described. ...The purpose of our study was to determine whether murine decidua responds to inflammatory mediators, such as lipopolysaccharide (LPS) and the inflammatory cytokines interleukin (IL)-1 beta and tumor necrosis factor (TNF). Allogeneic pregnant mice (C3H/Hen females mated with C57/B6 males) were killed at 12-14 days of pregnancy, decidual tissue was isolated, and explants were placed on the polycarbonate membrane of Costar Transwell inserts. Initial validation studies of this explant system, including biochemical and histologic evaluations, indicated that the decidual tissue remained intact, viable, and responsive to IL-1 beta for at least 5 days in explant culture. Treatment of murine decidual explants with LPS, IL-1 beta, and TNF resulted in significant increases in the production of prostaglandin E2 (PGE2) and IL-6. Thus the regulation of PGE2 and IL-6 production from murine decidua by LPS and inflammatory cytokines is similar to findings previously reported for human decidua. Our findings are consistent with the view that the pathophysiology of infection-induced preterm labor in the mouse may be similar to that in human pregnancy and supports the continued development of murine models of preterm labor.
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