Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.OBJECTIVE Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. RESEARCH DESIGN AND METHODS Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). RESULTS Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. CONCLUSIONS Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.This work was supported by grants from the Juvenile Diabetes Research Foundation (#1-2008-280) and the National Institutes of Health to R.T.D. (grants NS-054847 and DK-073594). E.A. was supported by a grant from the National Science and Engineering Research Council (#3311686-06) to P.F. and subsequently by a postgraduate scholarship from the Manitoba Health Research Council. S.K.R.C. and E.Z. were supported by grants to P.F. from the Canadian Institutes for Health Research (#MOP-84214) and the Juvenile Diabetes Research Foundation (#1-2008-193). D.R.S. was supported by a grant to P.F. from the Manitoba Health Research Council. This work was also funded by the St. Boniface General Hospital and Research Foundation

Mysterious Dust-emitting Object Orbiting TIC 400799224

We report the discovery of a unique object of uncertain nature - but quite possibly a disintegrating asteroid or minor planet - orbiting one star of the widely separated binary TIC 400799224. We initially identified the system in data from TESS Sector 10 via an abnormally shaped fading event in the light curve (hereafter "dips"). Follow-up speckle imaging determined that TIC 400799224 is actually two stars of similar brightness at 0.″62 separation, forming a likely bound binary with projected separation of ∼300 au. We cannot yet determine which star in the binary is host to the dips in flux. ASAS-SN and Evryscope archival data show that there is a strong periodicity of the dips at ∼19.77 days, leading us to believe that an occulting object is orbiting the host star, though the duration, depth, and shape of the dips vary substantially. Statistical analysis of the ASAS-SN data shows that the dips only occur sporadically at a detectable threshold in approximately one out of every three to five transits, lending credence to the possibility that the occulter is a sporadically emitted dust cloud. The cloud is also fairly optically thick, blocking up to 37% or 75% of the light from the host star, depending on the true host. Further observations may allow for greater detail to be gleaned as to the origin and composition of the occulter, as well as to a determination of which of the two stars comprising TIC 400799224 is the true host star of the dips

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene &lt;sup&gt;1-5&lt;/sup&gt; . Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations

TESS discovery of a super-earth and three sub-neptunes hosted by the bright, sunlike star HD 108236

We report the discovery and validation of four extrasolar planets hosted by the nearby, bright, Sun-like (G3V) star HD 108236 using data from the Transiting Exoplanet Survey Satellite (TESS). We present transit photometry, reconnaissance, and precise Doppler spectroscopy, as well as high-resolution imaging, to validate the planetary nature of the objects transiting HD 108236, also known as the TESS Object of Interest (TOI) 1233. The innermost planet is a possibly rocky super-Earth with a period of 3.79523+0.00047-0.00044 days and has a radius of 1.586 ± 0.098 R⊗.The outer planets are sub-Neptunes, with potential gaseous envelopes, having radii of 2.068+0.10-0.091 R⊗, 2.72 ± 0.11 R⊗, and 3.12+0.13-0.12 R⊗ and periods of 6.20370+0.00064-0.00052 days, 14.17555+0.00099-0.0011 days, and 19.5917+0.0022-0.0020 days, respectively. With V and Ks magnitudes of 9.2 and 7.6, respectively, the bright host star makes the transiting planets favorable targets for mass measurements and, potentially, for atmospheric characterization via transmission spectroscopy. HD 108236 is the brightest Sun-like star in the visual (V ) band known to host four or more transiting exoplanets. The discovered planets span a broad range of planetary radii and equilibrium temperatures and share a common history of insolation from a Sun-like star (R∗ = 0.888 ± 0.017 R⊙, Teff = 5730 ± 50 K), making HD 108236 an exciting, opportune cosmic laboratory for testing models of planet formation and evolution

Effects of eight neuropsychiatric copy number variants on human brain structure

peer reviewedMany copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions. © 2021, The Author(s)