Identification of p38 MAPK as a novel therapeutic target for Friedreich\u27s ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA

Geochemistry of Carbonates on Mars: Implications for Climate History and Nature of Aqueous Environments

Ongoing research on martian meteorites and a new set of observations of carbonate minerals provided by an unprecedented series of robotic missions to Mars in the past 15 years help define new constraints on the history of martian climate with important crosscutting themes including: the CO_2 budget of Mars, the role of Mg-, Fe-rich fluids on Mars, and the interplay between carbonate formation and acidity. Carbonate minerals have now been identified in a wide range of localities on Mars as well as in several martian meteorites. The martian meteorites contain carbonates in low abundances (<1 vol.%) and with a wide range of chemistries. Carbonates have also been identified by remote sensing instruments on orbiting spacecraft in several surface locations as well as in low concentrations (2–5 wt.%) in the martian dust. The Spirit rover also identified an outcrop with 16 to 34 wt.% carbonate material in the Columbia Hills of Gusev Crater that strongly resembled the composition of carbonate found in martian meteorite ALH 84001. Finally, the Phoenix lander identified concentrations of 3–6 wt.% carbonate in the soils of the northern plains. The carbonates discovered to date do not clearly indicate the past presence of a dense Noachian atmosphere, but instead suggest localized hydrothermal aqueous environments with limited water availability that existed primarily in the early to mid-Noachian followed by low levels of carbonate formation from thin films of transient water from the late Noachian to the present. The prevalence of carbonate along with evidence for active carbonate precipitation suggests that a global acidic chemistry is unlikely and a more complex relationship between acidity and carbonate formation is present

Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing. The antiallodynic action of β2 adrenergic agonists is known to require activation of the delta-opioid (DOP) receptor but better knowledge of the molecular mechanisms involved is necessary. Using a mouse line in which DOP receptors were selectively ablated in neurons expressing Nav1.8 sodium channels (DOP cKO), we showed that these DOP peripheral receptors were necessary for the antiallodynic action of the β2 adrenergic agonist formoterol in the cuff model. Using a knock-in mouse line expressing a fluorescent version of the DOP receptor fused with the enhanced green fluorescent protein (DOPeGFP), we established in a previous study, that mechanical allodynia is associated with a smaller percentage of DOPeGFP positive small peptidergic sensory neurons in dorsal root ganglia (DRG), with a reduced density of DOPeGFP positive free nerve endings in the skin and with increased DOPeGFP expression at the cell surface. Here, we showed that the density of DOPeGFP positive free nerve endings in the skin is partially restored and no increase in DOPeGFP translocation to the plasma membrane is observed in mice in which mechanical pain is alleviated upon chronic oral administration of formoterol. This study, therefore, extends our previous results by confirming that changes in the mechanical threshold are associated with changes in peripheral DOP profile. It also highlights the common impact on DOP receptors between serotonin noradrenaline reuptake inhibitors such as duloxetine and the β2 mimetic formoterol.journal article20192020 02 14importe

YbV3_3Sb4_4 and EuV3_3Sb4_4, vanadium-based kagome metals with Yb2+^{2+} and Eu2+^{2+} zig-zag chains

Here we present YbV$_3$Sb$_4$ and EuV$_3$Sb$_4$, two new compounds exhibiting slightly distorted vanadium-based kagome nets interleaved with zig-zag chains of divalent Yb$^{2+}$ and Eu$^{2+}$ ions. Single crystal growth methods are reported alongside magnetic, electronic, and thermodynamic measurements. YbV$_3$Sb$_4$ is a nonmagnetic metal with no collective phase transitions observed between 60mK and 300K. Conversely, EuV$_3$Sb$_4$ is a magnetic kagome metal exhibiting easy-plane ferromagnetic-like order below $T_\text{C}$=32K with signatures of noncollinearity under low field. Our discovery of YbV$_3$Sb$_4$ and EuV$_3$Sb$_4$ demonstrate another direction for the discovery and development of vanadium-based kagome metals while incorporating the chemical and magnetic degrees of freedom offered by a rare-earth sublattice

Atomic Resonance and Scattering

Contains reports on six research projects.National Science Foundation (PHY83-06273)Joint Services Electronics Program (DAAL03-86-K-0002)National Science Foundation (PHY84-11483)U.S. Navy-Office of Naval Research (Grant N00014-79-C-0183)Joint Services Electronics Program (Contract DAAG29-83-K-0003)National Science Foundation (Grant PHY83-07172-A01)U.S. Navy - Office of Naval Research (Grant N00014-83-K-0695)National Science Foundation (Grant CHE84-21392

Partial rupture of a locked patch of the Sumatra megathrust during the 2007 earthquake sequence

The great Sumatra–Andaman earthquake and tsunami of 2004 was a dramatic reminder of the importance of understanding the seismic and tsunami hazards of subduction zones [1,2,3,4]. In March 2005, the Sunda megathrust ruptured again, producing an event [5] of moment magnitude (Mw) 8.6 south of the 2004 rupture area, which was the site of a similar event in 1861 (ref. 6). Concern was then focused on the Mentawai area, where large earthquakes had occurred in 1797 (Mw = 8.8) and 1833 (Mw = 9.0) [6,7]. Two earthquakes, one of Mw = 8.4 and, twelve hours later, one of Mw = 7.9, indeed occurred there on 12 September 2007. Here we show that these earthquakes ruptured only a fraction of the area ruptured in 1833 and consist of distinct asperities within a patch of the megathrust that had remained locked in the interseismic period. This indicates that the same portion of a megathrust can rupture in different patterns depending on whether asperities break as isolated seismic events or cooperate to produce a larger rupture. This variability probably arises from the influence of non-permanent barriers, zones with locally lower pre-stress due to the past earthquakes. The stress state of the portion of the Sunda megathrust that had ruptured in 1833 and 1797 was probably not adequate for the development of a single large rupture in 2007. The moment released in 2007 amounts to only a fraction both of that released in 1833 and of the deficit of moment that had accumulated as a result of interseismic strain since 1833. The potential for a large megathrust event in the Mentawai area thus remains large

Reducing the risks of nuclear war - the role of health professionals

Any use of nuclear weapons would be catastrophic for humanity. Even a “limited” nuclear war involving only 250 of the 13 000 nuclear weapons in the world could kill 120 million people outright and cause global climate disruption leading to a nuclear famine, putting 2 billion people at risk. We now call on health professional associations to inform their members worldwide about the threat to human survival and to join with the IPPNW to support efforts to reduce the near-term risks of nuclear war