The cause of changes in atmospheric carbon dioxide (CO2) during the recent ice ages is yet to be fully explained. Most mechanisms for glacial-interglacial CO2 change have centred on carbon exchange ...with the deep ocean, owing to its large size and relatively rapid exchange with the atmosphere. The Southern Ocean is thought to have a key role in this exchange, as much of the deep ocean is ventilated to the atmosphere in this region. However, it is difficult to reconstruct changes in deep Southern Ocean carbon storage, so few direct tests of this hypothesis have been carried out. Here we present deep-sea coral boron isotope data that track the pH-and thus the CO2 chemistry-of the deep Southern Ocean over the past forty thousand years. At sites closest to the Antarctic continental margin, and most influenced by the deep southern waters that form the ocean's lower overturning cell, we find a close relationship between ocean pH and atmospheric CO2: during intervals of low CO2, ocean pH is low, reflecting enhanced ocean carbon storage; and during intervals of rising CO2, ocean pH rises, reflecting loss of carbon from the ocean to the atmosphere. Correspondingly, at shallower sites we find rapid (millennial- to centennial-scale) decreases in pH during abrupt increases in CO2, reflecting the rapid transfer of carbon from the deep ocean to the upper ocean and atmosphere. Our findings confirm the importance of the deep Southern Ocean in ice-age CO2 change, and show that deep-ocean CO2 release can occur as a dynamic feedback to rapid climate change on centennial timescales.
The Lunar Reconnaissance Orbiter Camera (LROC) Wide Angle Camera (WAC) and Narrow Angle Cameras (NACs) are on the NASA Lunar Reconnaissance Orbiter (LRO). The WAC is a 7-color push-frame camera (100 ...and 400 m/pixel visible and UV, respectively), while the two NACs are monochrome narrow-angle linescan imagers (0.5 m/pixel). The primary mission of LRO is to obtain measurements of the Moon that will enable future lunar human exploration. The overarching goals of the LROC investigation include landing site identification and certification, mapping of permanently polar shadowed and sunlit regions, meter-scale mapping of polar regions, global multispectral imaging, a global morphology base map, characterization of regolith properties, and determination of current impact hazards.
Medullary thyroid cancer often develops in patients with somatic or germline mutations in
RET
. Selpercatinib is a novel RET inhibitor. In a phase 1–2 trial, a response to selpercatinib occurred in ...38 of 55 previously treated patients (69%) and in 64 of 88 previously untreated patients (73%). Toxic effects were mainly low grade.
Gaps in our understanding of genetic susceptibility to malignant hyperthermia (MH) limit the application and interpretation of genetic diagnosis of the condition. Our aim was to define the prevalence ...and role of variants in the three genes implicated in MH susceptibility in the largest comprehensively phenotyped MH cohort worldwide.
We initially included one individual from each positive family tested in the UK MH Unit since 1971 to detect variants in RYR1, CACNA1S, or STAC3. Screening for genetic variants has been ongoing since 1991 and has involved a range of techniques, most recently next generation sequencing. We assessed the pathogenicity of variants using standard guidelines, including family segregation studies. The prevalence of recurrent variants of unknown significance was compared with the prevalence reported in a large database of sequence variants in low-risk populations.
We have confirmed MH susceptibility in 795 independent families, for 722 of which we have a DNA sample. Potentially pathogenic variants were found in 555 families, with 25 RYR1 and one CACNA1S variants previously unclassified recurrent variants significantly over-represented (P<1×10−7) in our cohort compared with the Exome Aggregation Consortium database. There was genotype–phenotype discordance in 86 of 328 families suitable for segregation analysis. We estimate non-RYR1/CACNA1S/STAC3 susceptibility occurs in 14–23% of MH families.
Our data provide current estimates of the role of variants in RYR1, CACNA1S, and STAC3 in susceptibility to MH in a predominantly white European population.
We developed a high-throughput HTRF (homogeneous time-resolved fluorescence) assay for Akt kinase activity and screened approx. 270000 compounds for their ability to inhibit the three isoforms of ...Akt. Two Akt inhibitors were identified that exhibited isoenzyme specificity. The first compound (Akt-I-1) inhibited only Akt1 (IC50 4.6 microM) while the second compound (Akt-I-1,2) inhibited both Akt1 and Akt2 with IC50 values of 2.7 and 21 microM respectively. Neither compound inhibited Akt3 nor mutants lacking the PH (pleckstrin homology) domain at concentrations up to 250 microM. These compounds were reversible inhibitors, and exhibited a linear mixed-type inhibition against ATP and peptide substrate. In addition to inhibiting kinase activity of individual Akt isoforms, both inhibitors blocked the phosphorylation and activation of the corresponding Akt isoforms by PDK1 (phosphoinositide-dependent kinase 1). A model is proposed in which these inhibitors bind to a site formed only in the presence of the PH domain. Binding of the inhibitor is postulated to promote the formation of an inactive conformation. In support of this model, antibodies to the Akt PH domain or hinge region blocked the inhibition of Akt by Akt-I-1 and Akt-I-1,2. These inhibitors were found to be cell-active and to block phosphorylation of Akt at Thr308 and Ser473, reduce the levels of active Akt in cells, block the phosphorylation of known Akt substrates and promote TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in LNCap prostate cancer cells.
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards ...can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control.
Electrospinning is a popular technique to fabricate tissue engineering scaffolds due to the exceptional tunability of the fiber morphology, which can be used to control the scaffold mechanical ...properties, degradation rate, and cell behavior. Recent work has focused on electrospinning natural polymers such as gelatin to improve the regeneration potential of these grafts. Gelatin scaffolds must be crosslinked to avoid rapid dissolution upon implantation with current crosslinking strategies requiring additional post-processing steps. Despite the strong dependence of scaffold properties on fiber morphology, there has been minimal emphasis on retaining the original fiber morphology of electrospun gelatin scaffolds after implantation. This work describes a method for
in situ
crosslinking of gelatin to produce electrospun fibers with improved fiber morphology retention after implantation. A double barrel syringe with an attached mixing head and a diisocyanate crosslinker were utilized to generate electrospun scaffolds that crosslink during the electrospinning process. These
in situ
crosslinked fiber meshes retained morphology after 1 week incubation in water at 37 °C; whereas, uncrosslinked meshes lost the fibrous morphology within 24 hours. Degree of crosslinking was quantified and relationships between the crosslinker ratio and enzymatic degradation rate were evaluated. The degradation rate decreased with increased crosslinker ratio, resulting in a highly tunable system. Additionally, tensile testing under simulated physiological conditions indicated that increased crosslinker ratios resulted in increases in initial modulus and tensile strength. Overall, this
in situ
crosslinking technique provides a method to crosslink gelatin during electrospinning and can be used to tune the degradation rate of resulting scaffolds while enabling improved fiber morphology retention after implantation.
In situ
crosslinking provides a method to crosslink gelatin during electrospinning enabling tunable degradation rates and displaying improved fiber morphology retention after implantation.
Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The ...two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to approach the cue, whereas bred low-responder rats (bLRs) learned to approach the location of food delivery, suggesting that bHRs but not bLRs attributed incentive value to the cue. Moreover, although less impulsive on a measure of 'impulsive choice', bHRs were more impulsive on a measure of 'impulsive action'- ie, they had difficulty withholding an action to receive a reward, indicative of 'behavioral disinhibition'. The dopamine agonist quinpirole caused greater psychomotor activation in bHRs relative to bLRs, suggesting dopamine supersensitivity. Indeed, relative to bLRs, bHRs also had a greater proportion of dopamine D2(high) receptors, the functionally active form of the receptor, in the striatum, in spite of lower D2 mRNA levels and comparable total D2 binding. In addition, fast-scan cyclic voltammetry revealed that bHRs had more spontaneous dopamine 'release events' in the core of the nucleus accumbens than bLRs. Thus, bHRs exhibit parallels to 'externalizing disorders' in humans, representing a genetic animal model of addiction vulnerability associated with a propensity to attribute incentive salience to reward-related cues, behavioral disinhibition, and increased dopaminergic 'tone.'
During Martian solar days 57–100, the Mars Science Laboratory Curiosity rover acquired and processed a solid (sediment) sample and analyzed its mineralogy and geochemistry with the Chemistry and ...Mineralogy and Sample Analysis at Mars instruments. An aeolian deposit—herein referred to as the Rocknest sand shadow—was inferred to represent a global average soil composition and selected for study to facilitate integration of analytical results with observations from earlier missions. During first‐time activities, the Mars Hand Lens Imager (MAHLI) was used to support both science and engineering activities related to sample assessment, collection, and delivery. Here we report on MAHLI activities that directly supported sample analysis and provide MAHLI observations regarding the grain‐scale characteristics of the Rocknest sand shadow. MAHLI imaging confirms that the Rocknest sand shadow is one of a family of bimodal aeolian accumulations on Mars—similar to the coarse‐grained ripples interrogated by the Mars Exploration Rovers Spirit and Opportunity—in which a surface veneer of coarse‐grained sediment stabilizes predominantly fine‐grained sediment of the deposit interior. The similarity in grain size distribution of these geographically disparate deposits support the widespread occurrence of bimodal aeolian transport on Mars. We suggest that preservation of bimodal aeolian deposits may be characteristic of regions of active deflation, where winnowing of the fine‐sediment fraction results in a relatively low sediment load and a preferential increase in the coarse‐grained fraction of the sediment load. The compositional similarity of Martian aeolian deposits supports the potential for global redistribution of fine‐grained components, combined with potential local contributions.
Key Points
Curiosity acquired and examined its first solid sample at the Rocknest sand shadow
MAHLI images were critical in the science investigation of Rocknest materials
MAHLI images played a critical role supporting first‐time engineering activities
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