809 research outputs found
The atypical ubiquitin E2 conjugase UBE2L3 is an indirect caspase-1 target and controls IL-1beta secretion by inflammasomes
Caspase-1 activation by inflammasome signalling scaffolds initiates inflammation and antimicrobial responses. Caspase-1 proteolytically converts newly induced pro-IL-1ι into its mature form and directs its secretion, triggers pyroptosis and the release of non-substrate alarmins such as IL-1ι and HMGB1. While some caspase-1 substrates involved in these events are known, the identities and roles of non-proteolytic targets remain unknown. Here we report using unbiased proteomics that the UBE2L3 ubiquitin conjugase is an indirect target of caspase-1. Caspase-1, but not caspase-4, control led pyroptosis-and ubiquitin-independent proteasomal degradation of UBE2L3 upon canonical and non-canonical inflammasome activation by sterile danger signals and bacterial infection. Mechanistically, UBE2L3 acted post-translationally to promote K48-ubiquitylation and turnover of pro-IL-1β and dampen mature-IL-1β production. UBE2L3 depletion increased pro-IL-1β levels and mature-IL-1β secretion by inflammasomes. These findings on UBE2L3 as a molecular rheostat have implications for IL-1-driven pathology in hereditary fever syndromes, and autoinflammatory conditions associated with UBE2L3 polymorphisms
Regulation of G protein-coupled receptors by palmitoylation and cholesterol
Due to their membrane location, G protein-coupled receptors (GPCRs) are subject to regulation by soluble and integral membrane proteins as well as membrane components, including lipids and sterols. GPCRs also undergo a variety of post-translational modifications, including palmitoylation. A recent article by Zheng et al. in BMC Cell Biology demonstrates cooperative roles for receptor palmitoylation and cholesterol binding in GPCR dimerization and G protein coupling, underlining the complex regulation of these receptors
Spatially anisotropic S=1 square-lattice antiferromagnet with single-ion anisotropy realized in a Ni(II) pyrazine-n, n'-dioxide coordination polymer
Spatially anisotropic S=1 square-lattice antiferromagnet with single-ion anisotropy realized in a Ni(II) pyrazine- n,nⲠ-dioxide coordination polymer
The Ni(NCS)2(pyzdo)2 coordination polymer is found to be an S=1 spatially anisotropic square lattice with easy-axis single-ion anisotropy. This conclusion is based upon considering in concert the experimental probes x-ray diffraction, magnetic susceptibility, magnetic-field-dependent heat capacity, muon-spin relaxation, neutron diffraction, neutron spectroscopy, and pulsed-field magnetization. Long-range antiferromagnetic (AFM) order develops at TN=18.5K. Although the samples are polycrystalline, there is an observable spin-flop transition and saturation of the magnetization at â80T. Linear spin-wave theory yields spatially anisotropic exchanges within an AFM square lattice, Jx=0.235meV, Jy=2.014meV, and an easy-axis single-ion anisotropy D=-1.622meV (after renormalization). The anisotropy of the exchanges is supported by density functional theory
A two-domain elevator mechanism for sodium/proton antiport
Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pHâ6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3âĂ
resolution, solved from crystals grown at pHâ7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500âionsâper second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general
Gendered Representations of Male and Female Social Actors in Iranian Educational Materials
This research investigates the representations of gendered social actors within the subversionary discourse of equal educational opportunities for males and females in Iranian English as a Foreign Language (EFL) books. Using critical discourse analysis (CDA) as the theoretical framework, the authors blend van Leeuwenâs (Texts and practices: Readings in critical discourse analysis, Routledge, London, 2003) âSocial Actor Network Modelâ and Sunderlandâs (Gendered discourses, Palgrave Macmillan, Hampshire, 2004) âGendered Discourses Modelâ in order to examine the depictions of male and female social actors within this gendered discourse. The gendered discourse of equal opportunities was buttressed by such representations within a tight perspective in proportion to gender ideologies prevailing in Iran. Resorting to CDA, we can claim that resistance against such gendered discourse in Iranian EFL textbooks militates against such gender norms. These representations of male and female social actors in school books are indicative of an all-encompassing education, reinforcing that the discourse of equal opportunities is yet to be realized in the education system of Iran
Amygdaloid Kindling and the GABA System
The effect of increased brain GABA levels on fully kindled amygdala seizures was investigated in Long-Evans rats. The newly synthesized GABA-transaminase inhibitor, -Î-acetylenic GABA (GAG) administered on four consecutive days (100 mg/kg, followed by 50 mg/kg, i.p.) was found to either significantly reduce, or eliminate entirely, the behavioral seizures normally produced by amygdala stimulation. The effect is seen after the first injection of GAG although its magnitude was greater on subsequent days. Behavioral seizures reappeared 2 to 3 days after termination of GAG treatment. The duration of electrographic seizures (self-sustained amygdala after-discharge) was either unchanged or greater on the first day of GAG treatment, but was briefer on subsequent days. The duration of afterdischarges returned to normal levels 1 to 2 days earlier than the behavioral seizures after the termination of GAG. Picrotoxin (1.5-2 mg/kg, i.p.) did not antagonize either electrographic or behavioral effects of inhibition produced with GAG. Electrical stimulation of amygdala delivered during the initial sedation stage induced by picrotoxin resulted in further regression of kindled seizures in the majority of animals. Although in doses employed, GAG alleviates amygdaloid-kindled seizures its use requires caution in view of its ability to reduce arousal level. RĂSUMĂ L'effet de l'ĂlĂvation des taux cĂrĂbraux de GABA sur les crises amygdaliennes par effet d'embrasement complet a ĂtĂĂtudiĂ chez des rats Long-Evans. l'injection pendant 4 jours consĂcutifs de 100 mg/kg suivis de 50 mg/kg i.p. d'un inhibiteur de la GABA. Transaminase nouvellement synthĂtisĂ (Î-acetylenic GABA ou GAG) a significativement rĂduit ou mĂme supprimĂ les crises normalement provoquĂes par la stimulation amygdalienne. l'effet est observĂ aprĂs la premiere injection de GAG, mais son importance s'accroit les jours suivants. Les crises rĂapparaissent 2 ou 3 jours aprĂs la fin du traitement au GAG. Du point de vue Ălectrographique, la durĂe de la postdĂcharge amygdalienne autoentretenue est inchingĂe ou accrue le premier jour du traitement, mais elle diminue les jours suivants pour retourner Ă la normale un ou deux jours avant que les crises ne rĂapparaissent aprĂs la fin de ('administration du GAG. l'injection de picrotoxine (1.5-2 mg/kg i.p.) ne s'oppose pas aux effets inhibiteurs du GAG sur les crises ou leur accompagnement EEG. La stimulation Ălectrique de l'amygdala pendant l'Ătape sĂdative initiate induite par la picrotoxine provoque une rĂgression supplĂmentaire des crises d'embrasement chez la majoritĂ des animaux. Bien que, aux doses utilisĂes, le GAG attĂnue les crises amyg-daliennes d'embrasement, son utilisation nĂcessite des prĂcautions compte tenu de sa tendance Ă rĂduire le niveau d'Ăveil. RESUMEN En ratas Long-Evans se ha investigado el efecto del aumento de los niveles cerebrales de GABA, sobre los ataques originados en la amĂgdala totalmente condicionada, (Kindling). El recientemente sintetizado in-hibidor de la GABA transaminasa, Î-acetilĂnico GABA (GAG), redujo significativamente o eliminĂ totalmente las crisis de comportamiento que habitualmente se producen con la estimulaciĂn de la amĂgdala. El efecto se observa despuĂs de la primera in-yecciĂn de GAG pero su magnitud aumentĂ en dias subsiguientes. Las crisis de comportamiento reaparecieron a los 2â3 dĂas de la interrupciĂn del tratamiento con GAG. La duraciĂn de los ataques electrogrĂficos (perservaciĂn de la post-descarga de la amigdala) no se modificĂ, o incluso aumentĂ, en el primer dia de la administraciĂn de GAG pero se redujo en los dias siguientes. La duraciĂn de las post-descargas volviĂ a sus niveles normales 1 o 2 dias antes que la reapariciĂn de las crisis de comportamiento una vez terminado el tratamiento con GAG. La picrotoxina (1.5-2 mg/kg, i.p.) no antagonizĂ los efectos inhibitorios producidos por el GAG sobre el electroencefalograma o las crisis de comportamiento. La estimulaciĂn elĂctrica sobre la amĂgdala, aplicada durante la fase de sedaciĂn inicial inducida por la picrotoxina, condujo a una regresiĂn aĂn mĂs intensa de las crisis condicionadas, en la mayorĂa de los animales. A pesar de que, con las dosis utilizadas, el GAG alivia las crisis de la amĂgdala previamente condicionada, se requiere gran precauciĂn en su utilizaciĂn en vista de su propiedad de reducir el nivel del despertar. ZUSAMMENFASSUNG Die Wirkung erhĂhter GABA-Spiegel des Gehirns auf AmygdalonkrĂmpfe nach Kindling wurden bei Long-Evans-Ratten untersucht. Der neuerdings synthetisierte GABA-TYansaminasen-Inhibitor, Gamma-Acetylen-GABA (GAG) wurde an 4 aufeinander-folgenden Tagen in einer Dosis von 100 mg/kg und anschlieliend 50 mg/kg i.p. verabfolgt. Er reduzierte entweder signifikant oder eliminierte vĂllig die anfalls-weisen VerhaltensĂnderungen, die normalerweise durch Stimulation des Amygdalon produziert wurden. Die Wirkung ist nach der Erstinjektion des GAG zu beobachten, obgleich ihr AusmaĂ an folgenden Tagen grĂĂer war. Die VerhaltensanfĂlle kamen 2 bis 3 Tagen nach Beendigung der GAG-Behandlung wieder. Die Dauer der elektrographischen AnfĂlle (sich selbst un-terhaltende Amydalonnachentladungen) blieben entweder gleich oder sie wurden grĂĂer am 1. Tag der GAG-Behandlung, wurden aber kĂrzer an folgenden Tagen. Die Dauer der Nachentladungen nor-malisierte sich 1 bis 2 Tage frĂher als die VerhaltensanfĂlle nach Beendigung des GAG verschwanden. Picrotoxin (1.5 bis 2 mg/kg i.p.) wirken nicht als Antagonist gegenĂber der durch GAG produzierten Hemmung der elektrographischen-oder Verhalten-seffekte. Die elektrische Stimulierung des Amygdalon wĂhrend der initialen Sedierung nach Picrotoxin ver-ursachte bei der Mehrzahl der Tiere einen weiteren RĂckgang der durch Kindling entstandenen AnfĂlle. Obgleich das GAG in den verwandten Dosen, die durch Kindling des Amygdalon erzeugten KrĂmpfe leichter ablaufen lUĂt, erfordert seine Anwendung Vorsicht hinsichtlich seiner FĂhigkeit, das Erreg-barkeitsniveau zu senken.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66112/1/j.1528-1157.1980.tb04058.x.pd
Western Indian Ocean marine and terrestrial records of climate variability: a review and new concepts on land-ocean interactions since AD 1660
We examine the relationship between three tropical and two subtropical western Indian Ocean coral oxygen isotope time series to surface air temperatures (SAT) and rainfall over India, tropical East Africa and southeast Africa. We review established relationships, provide new concepts with regard to distinct rainfall seasons, and mean annual temperatures. Tropical corals are coherent with SAT over western India and East Africa at interannual and multidecadal periodicities. The subtropical corals correlate with Southeast African SAT at periodicities of 16â30 years. The relationship between the coral records and land rainfall is more complex. Running correlations suggest varying strength of interannual teleconnections between the tropical coral oxygen isotope records and rainfall over equatorial East Africa. The relationship with rainfall over India changed in the 1970s. The subtropical oxygen isotope records are coherent with South African rainfall at interdecadal periodicities. Paleoclimatological reconstructions of land rainfall and SAT reveal that the inferred relationships generally hold during the last 350 years. Thus, the Indian Ocean corals prove invaluable for investigating landâocean interactions during past centuries
Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells
Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens Îą-galactosylceramide (ÎąGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of ÎąGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-ÎąGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins
Meredys, a multi-compartment reaction-diffusion simulator using multistate realistic molecular complexes
<p>Abstract</p> <p>Background</p> <p>Most cellular signal transduction mechanisms depend on a few molecular partners whose roles depend on their position and movement in relation to the input signal. This movement can follow various rules and take place in different compartments. Additionally, the molecules can form transient complexes. Complexation and signal transduction depend on the specific states partners and complexes adopt. Several spatial simulator have been developed to date, but none are able to model reaction-diffusion of realistic multi-state transient complexes.</p> <p>Results</p> <p><it>Meredys </it>allows for the simulation of multi-component, multi-feature state molecular species in two and three dimensions. Several compartments can be defined with different diffusion and boundary properties. The software employs a Brownian dynamics engine to simulate reaction-diffusion systems at the reactive particle level, based on compartment properties, complex structure, and hydro-dynamic radii. Zeroth-, first-, and second order reactions are supported. The molecular complexes have realistic geometries. Reactive species can contain user-defined feature states which can modify reaction rates and outcome. Models are defined in a versatile NeuroML input file. The simulation volume can be split in subvolumes to speed up run-time.</p> <p>Conclusions</p> <p><it>Meredys </it>provides a powerful and versatile way to run accurate simulations of molecular and sub-cellular systems, that complement existing multi-agent simulation systems. <it>Meredys </it>is a Free Software and the source code is available at <url>http://meredys.sourceforge.net/</url>.</p
- âŚ