The oxidation state of basaltic martian meteorites is determined from the partitioning of europium (Eu) in their pyroxenes. The estimated redox conditions for these samples correlate with their ...initial neodymium and strontium isotopic compositions. This is interpreted to imply varying degrees of interaction between the basaltic parent melts, derived from a source in the martian mantle, and a crustal component. Thus, the mantle source of these martian basalts may have a redox state close to that of the iron-wüstite buffer, whereas the martian crust may be more oxidized (with a redox state higher than or equal to that of the quartz-fayalite- magnetite buffer). A difference in redox state of more than 3 log units between mantle and crustal reservoirs on Mars could result from oxidation of the crust by a process such as aqueous alteration, together with a subsequent lack of recycling of this oxidized crust through the reduced upper mantle.
BACKGROUND AND PURPOSE In 2006, a life‐threatening ‘cytokine storm’, not predicted by pre‐clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of ...the CD28 superagonist monoclonal antibody (mAb) TGN1412. To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre‐clinical safety testing has been established. Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology.
EXPERIMENTAL APPROACH Polychromatic flow cytometry and intracellular cytokine staining were employed to dissect the in vitro immunopharmacology of TGN1412 and other therapeutic mAbs at the cellular level to identify differences between humans and species used for pre‐clinical safety testing.
KEY RESULTS In vitro IL‐2 and IFN‐γ release from CD4+ effector memory T‐cells were key indicators of a TGN1412‐type response. This mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells. In contrast to humans, CD28 is not expressed on the CD4+ effector memory T‐cells of all species used for pre‐clinical safety testing, so cannot be stimulated by TGN1412.
CONCLUSIONS AND IMPLICATIONS It is likely that activation of CD4+ effector memory T‐cells by TGN1412 was responsible for the cytokine storm. Lack of CD28 expression on the CD4+ effector memory T‐cells of species used for pre‐clinical safety testing of TGN1412 offers an explanation for the failure to predict a ‘cytokine storm’ in humans.
We present here analyses of mass-independent effects in the Ti isotope ratios of 17 coarse-grained (compact Type A and Type B) calcium–aluminum-rich inclusions (CAIs) from the Allende CV3 chondrite ...utilizing a method developed for rapid measurement of Ti isotopes by laser ablation multi-collector inductively coupled plasma mass spectrometry (LA-MC-ICPMS). Based on the analyses of the synthetic CMAS glasses doped with varying amounts of Ca, Cr and V, an empirical scheme for correction of potential isobaric interferences and matrix effects was developed. Using this scheme, mass-independent variations of the Ti isotope ratios 46Ti/47Ti, 48Ti/47Ti and 50Ti/47Ti were measured with external reproducibilities (2SD) of ±0.4, ±0.5, and ±1.8 for ε46Ti, ε48Ti, and ε50Ti, respectively, based on repeat measurements of standard glasses. The Ti isotope compositions of the 17 Allende refractory inclusions analyzed here show that most of these CAIs are “normal” with limited variation in their mass-independent Ti isotope composition. One CAI (designated as CMS-1) has a significantly larger mass-independent ε50Ti anomaly and is identified as having Fractionation and Unidentified Nuclear (FUN) effects. The limited range in the Ti isotope compositions of normal CAIs (ε50Ti excesses ranging from 2.9 to 11.4) suggests that they originated from a nebular reservoir that was relatively well-mixed, although not completely homogenized (at the level of precision of the analyses reported here), in its isotopic composition. The distinctive isotopic composition of the FUN CAI CMS-1 indicates that it formed from a reservoir in the protoplanetary disk that was spatially or temporally distinct from that from which the normal CAIs were formed.
We aimed to evaluate the effect of caffeine/modafinil on sleep deprivation (SD) induced alterations in recognition memory and synaptic proteins. The data revealed a beneficial effect of ...caffeine/modafinil against deficit in the familiar object retrieval performance and object exploration ratio after 48 h SD. Caffeine treatment prevented the SD induced down-regulation of synaptophysin and synapsin I proteins with no change in PSD-95 protein in hippocampus. However, modafinil administration improved the down-regulation of synaptophysin, synapsin I and PSD-95 proteins in hippocampus. Hence, caffeine/modafinil can serve as counter measures in amelioration of SD induced consequences at behavioural and protein levels.
Short-lived radionuclides (SLRs) once present in the solar nebula can be used as probes of the formation environment of our Solar System within the Milky Way Galaxy. The first-formed solids in the ...Solar System, calcium-, aluminum-rich inclusions (CAIs) in meteorites, record the one-time existence of SLRs such as 10Be and 26Al in the solar nebula. We measured the 10Be–10B isotope systematics in 29 CAIs from several CV3, CO3, CR2, and CH/CB chondrites and show that all except for a FUN CAI record a homogeneous initial 10Be/9Be with a single probability density peak at 10Be/9Be = 7.4 × 10–4. Integrating these data with those of previous studies, we find that most CAIs (81%) for which 10Be–10B isotope systematics have been determined, record a homogeneous initial 10Be/9Be ratio in the early Solar System with a weighted mean 10Be/9Be = (7.1 ± 0.2) × 10–4. This uniform distribution provides evidence that 10Be was predominantly formed in the parent molecular cloud and inherited by the solar nebula. Possible explanations for why unusual CAIs (FUNs, PLACs, those from CH/CBs, and those irradiated on the parent body) recorded a 10Be/9Be ratio outside of 7.1 × 10−4 include the following: 1) They incorporated a component of 10Be that was produced in the nebula by irradiation; 2) they formed after normal CAIs; and 3) they were processed (post-formation) in a way that affected their original 10Be signatures. Given the rarity of these examples, the overall uniformity of initial 10Be/9Be suggests that Solar System 10Be was predominantly inherited from the molecular cloud.
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