Oral Treatment with Cu[superscript II](atsm) Increases Mutant SOD1 In Vivo but Protects Motor Neurons and Improves the Phenotype of a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper[superscript II] [Cu[superscript II](atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu[superscript II](atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched ⁶⁵Cu[superscript II](atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu[superscript II](atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu[superscript II](atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu[superscript II](atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by the Society for Neuroscience. The published article can be found at: http://www.jneurosci.org/

Phase A Science Case for MAVIS -- The Multi-conjugate Adaptive-optics Visible Imager-Spectrograph for the VLT Adaptive Optics Facility

We present the Phase A Science Case for the Multi-conjugate Adaptive-optics Visible Imager-Spectrograph (MAVIS), planned for the Adaptive Optics Facility (AOF) of the Very Large Telescope (VLT). MAVIS is a general-purpose instrument for exploiting the highest possible angular resolution of any single optical telescope available in the next decade, either on Earth or in space, and with sensitivity comparable to (or better than) larger aperture facilities. MAVIS uses two deformable mirrors in addition to the deformable secondary mirror of the AOF, providing a mean V-band Strehl ratio of >10% (goal >15%) across a relatively large (30 arc second) science field. This equates to a resolution of <20mas at 550nm - comparable to the K-band diffraction limit of the next generation of extremely large telescopes, making MAVIS a genuine optical counterpart to future IR-optimised facilities like JWST and the ELT. Moreover, MAVIS will have unprecedented sky coverage for a high-order AO system, accessing at least 50% of the sky at the Galactic Pole, making MAVIS a truly general purpose facility instrument. As such, MAVIS will have both a Nyquist-sampled imager (30x30 arcsec field), and a powerful integral field spectrograph with multiple spatial and spectral modes spanning 370-1000nm. This science case presents a distilled set of thematically linked science cases drawn from the MAVIS White Papers (www.mavis-ao.org/whitepapers), selected to illustrate the driving requirements of the instrument resulting from the recent MAVIS Phase A study

Phase A Science Case for MAVIS -- The Multi-conjugate Adaptive-optics Visible Imager-Spectrograph for the VLT Adaptive Optics Facility

141 pages, 79 figures, 10Mb. Modified version of the Phase A Science Case submitted to ESO in April 2020 as part of the MAVIS Phase A design study. Full resolution version available upon requestWe present the Phase A Science Case for the Multi-conjugate Adaptive-optics Visible Imager-Spectrograph (MAVIS), planned for the Adaptive Optics Facility (AOF) of the Very Large Telescope (VLT). MAVIS is a general-purpose instrument for exploiting the highest possible angular resolution of any single optical telescope available in the next decade, either on Earth or in space, and with sensitivity comparable to (or better than) larger aperture facilities. MAVIS uses two deformable mirrors in addition to the deformable secondary mirror of the AOF, providing a mean V-band Strehl ratio of >10% (goal >15%) across a relatively large (30 arc second) science field. This equates to a resolution of <20mas at 550nm - comparable to the K-band diffraction limit of the next generation of extremely large telescopes, making MAVIS a genuine optical counterpart to future IR-optimised facilities like JWST and the ELT. Moreover, MAVIS will have unprecedented sky coverage for a high-order AO system, accessing at least 50% of the sky at the Galactic Pole, making MAVIS a truly general purpose facility instrument. As such, MAVIS will have both a Nyquist-sampled imager (30x30 arcsec field), and a powerful integral field spectrograph with multiple spatial and spectral modes spanning 370-1000nm. This science case presents a distilled set of thematically linked science cases drawn from the MAVIS White Papers (www.mavis-ao.org/whitepapers), selected to illustrate the driving requirements of the instrument resulting from the recent MAVIS Phase A study

TRY plant trait database - enhanced coverage and open access

10.1111/gcb.14904GLOBAL CHANGE BIOLOGY261119-18

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially