Evidence for ammonium-bearing minerals in Ceres

Evidence for ammonium-bearing minerals was found on the surface of the largest asteroid Ceres. The presence of ammonium-bearing clays suggests that Ceres has experienced a period of alteration by substantial amounts of an ammonium-bearing fluid. The presence of the ammonium-bearing clays does not preclude Ceres maintaining a volatile inventory in the core or in a volatile-rich zone at some distance below the surface. Telescopic observations of Ceres, using the 3.0 meter NASA Infrared telescope facility prompted this reevaluation of its surface mineralogy

Columbus crater and other possible groundwater-fed paleolakes of Terra Sirenum, Mars

Columbus crater in the Terra Sirenum region of the Martian southern highlands contains light-toned layered deposits with interbedded sulfate and phyllosilicate minerals, a rare occurrence on Mars. Here we investigate in detail the morphology, thermophysical properties, mineralogy, and stratigraphy of these deposits; explore their regional context; and interpret the crater's aqueous history. Hydrated mineral-bearing deposits occupy a discrete ring around the walls of Columbus crater and are also exposed beneath younger materials, possibly lava flows, on its floor. Widespread minerals identified in the crater include gypsum, polyhydrated and monohydrated Mg/Fe-sulfates, and kaolinite; localized deposits consistent with montmorillonite, Fe/Mg-phyllosilicates, jarosite, alunite, and crystalline ferric oxide or hydroxide are also detected. Thermal emission spectra suggest abundances of these minerals in the tens of percent range. Other craters in northwest Terra Sirenum also contain layered deposits and Al/Fe/Mg-phyllosilicates, but sulfates have so far been found only in Columbus and Cross craters. The region's intercrater plains contain scattered exposures of Al-phyllosilicates and one isolated mound with opaline silica, in addition to more common Fe/Mg-phyllosilicates with chlorides. A Late Noachian age is estimated for the aqueous deposits in Columbus, coinciding with a period of inferred groundwater upwelling and evaporation, which (according to model results reported here) could have formed evaporites in Columbus and other craters in Terra Sirenum. Hypotheses for the origin of these deposits include groundwater cementation of crater-filling sediments and/or direct precipitation from subaerial springs or in a deep (∼900 m) paleolake. Especially under the deep lake scenario, which we prefer, chemical gradients in Columbus crater may have created a habitable environment at this location on early Mars

Clay Bearing Units in the Region around Mawrth Vallis: Stratigraphy, Extent, and Possible Alteration Fronts

The largest exposure of phyllosilicates on Mars occurs on the highland plains around Mawrth Vallis. This exposure extends for about 300 km southward from the edge of the dichotomy boundary, covering an area greater than 200 x 300 kilometers over an elevation range of approximately 2000 meters. At least two different types of hydrated phyllosilicates (Fe/Mg-rich and Al-rich phyllosilicates) have been identified in OMEGA data based on absorption bands near 2.3 and 2.2 micrometers, respectively. These clay-bearing units are associated with layered, indurated light-toned units with complex spatial and stratigraphic relationships, and are unconfomably overlain by a darker, indurated, more heavily cratered unit. Ongoing analysis of OMEGA (approximately 1 kilometer/pixel) and CRISM multi-spectral (MSP, 200 meters/pixel) data reveal hydrated minerals with absorptions at approximately 2.2 or 2.3 micrometers in locations up to 300 kilometers away from the borders of the previously identified extent of clay-bearing units. We seek to: 1) further constrain the mineralogy of the hydrated species identified in [5], and 2) understand spatial and stratigraphic relationships between the different hydrated minerals and the cratered plains units in which they are found. In this work we perform mineralogical and stratigraphic comparisons between units to test whether these extended units may be related, in order to establish a broad zone of alteration

Competition for RISC binding predicts in vitro potency of siRNA

Short interfering RNAs (siRNA) guide degradation of target RNA by the RNA-induced silencing complex (RISC). The use of siRNA in animals is limited partially due to the short half-life of siRNAs in tissues. Chemically modified siRNAs are necessary that maintain mRNA degradation activity, but are more stable to nucleases. In this study, we utilized alternating 2′-O-methyl and 2′-deoxy-2′-fluoro (OMe/F) chemically modified siRNA targeting PTEN and Eg5. OMe/F-modified siRNA consistently reduced mRNA and protein levels with equal or greater potency and efficacy than unmodified siRNA. We showed that modified siRNAs use the RISC mechanism and lead to cleavage of target mRNA at the same position as unmodified siRNA. We further demonstrated that siRNAs can compete with each other, where highly potent siRNAs can compete with less potent siRNAs, thus limiting the ability of siRNAs with lower potency to mediate mRNA degradation. In contrast, a siRNA with low potency cannot compete with a highly efficient siRNA. We established a correlation between siRNA potency and ability to compete with other siRNAs. Thus, siRNAs that are more potent inhibitors for mRNA destruction have the potential to out-compete less potent siRNAs indicating that the amount of a cellular component, perhaps RISC, limits siRNA activity

Restraint of appetite and reduced regional brain volumes in anorexia nervosa: a voxel-based morphometric study

<p>Abstract</p> <p>Background</p> <p>Previous Magnetic Resonance Imaging (MRI) studies of people with anorexia nervosa (AN) have shown differences in brain structure. This study aimed to provide preliminary extensions of this data by examining how different levels of appetitive restraint impact on brain volume.</p> <p>Methods</p> <p>Voxel based morphometry (VBM), corrected for total intracranial volume, age, BMI, years of education in 14 women with AN (8 RAN and 6 BPAN) and 21 women (HC) was performed. Correlations between brain volume and dietary restraint were done using Statistical Package for the Social Sciences (SPSS).</p> <p>Results</p> <p>Increased right dorsolateral prefrontal cortex (DLPFC) and reduced right anterior insular cortex, bilateral parahippocampal gyrus, left fusiform gyrus, left cerebellum and right posterior cingulate volumes in AN compared to HC. RAN compared to BPAN had reduced left orbitofrontal cortex, right anterior insular cortex, bilateral parahippocampal gyrus and left cerebellum. Age negatively correlated with right DLPFC volume in HC but not in AN; dietary restraint and BMI predicted 57% of variance in right DLPFC volume in AN.</p> <p>Conclusions</p> <p>In AN, brain volume differences were found in appetitive, somatosensory and top-down control brain regions. Differences in regional GMV may be linked to levels of appetitive restraint, but whether they are state or trait is unclear. Nevertheless, these discrete brain volume differences provide candidate brain regions for further structural and functional study in people with eating disorders.</p

Targeting Huntingtin expression in patients with Huntington's disease

Background Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. Methods We conducted a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial involving adults with early Huntington’s disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. Results Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and −20%, −25%, −28%, −42%, and −38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). Conclusions Intrathecal administration of HTTRx to patients with early Huntington’s disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT02519036.

Platform Randomised trial of INterventions against COVID-19 in older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk

Introduction: There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications. Methods and analysis: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50–64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 ‘hot hubs’ and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes

Rumination in bipolar disorder: evidence for an unquiet mind

Depression in bipolar disorder has long been thought to be a state characterized by mental inactivity. However, recent research demonstrates that patients with bipolar disorder engage in rumination, a form of self-focused repetitive cognitive activity, in depressed as well as in manic states. While rumination has long been associated with depressed states in major depressive disorder, the finding that patients with bipolar disorder ruminate in manic states is unique to bipolar disorder and challenges explanations put forward for why people ruminate. We review the research on rumination in bipolar disorder and propose that rumination in bipolar disorder, in both manic and depressed states, reflects executive dysfunction. We also review the neurobiology of bipolar disorder and recent neuroimaging studies of rumination, which is consistent with our hypothesis that the tendency to ruminate reflects executive dysfunction in bipolar disorder. Finally, we relate the neurobiology of rumination to the neurobiology of emotion regulation, which is disrupted in bipolar disorder

Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity