The SKX 1084 hominin patella from Swartkrans Member 2, South Africa: An integrated analysis of its outer morphology and inner structure

SKX 1084 is an isolated partial patella from Swartkrans Member 2, South Africa, attributed to a small-bodied Paranthropus robustus. This study provides complementary information on its outer conformation and, for the first time for a fossil hominin patella, documents its inner structure in the perspective of adding biomechanically-related evidence to clarify its identity. We used X-ray micro-tomography to investigate SKX 1084 and to extract homologous information from a sample of 12 recent human, one Neanderthal, and two adult Pan, patellae. We used geometric morphometrics to compare the outer equatorial contours. In SKX 1084, we identified two cancellous bony spots suitable for textural assessment (trabecular bone volume fraction, trabecular thickness, degree of anisotropy), and two related virtual slices for measuring the maximum cortico-trabecular thickness (CTT) of the articular surface. SKX 1084 shows a more complex articular shape than that for Pan, but still simpler than typical in Homo sapiens. At all sites, its CTT is thinner compared to Pan and approaches the condition in humans. This is also true for the expanded volume of the cancellous network. However, at both investigated spots, SKX 1084 is systematically intermediate between Homo and Pan for trabecular bone volume fraction and trabecular thickness, a pattern already shown in previous analyses on other Paranthropus postcranial remains. In the absence of any structural signal from patellae unambiguously sampling Paranthropus, as well as of comparable evidence extracted from specimens representing early Homo, our results do not allow rejection of the original taxonomic attribution of SKX 1084

Stellar Velocity Dispersion of a Massive Quenching Galaxy at z = 4.01

We present the first stellar velocity dispersion measurement of a massive quenching galaxy at z = 4. The galaxy is first identified as a massive z ≥ 4 galaxy with suppressed star formation from photometric redshifts based on deep multiband data. A follow-up spectroscopic observation with MOSFIRE on Keck revealed strong multiple absorption features, which are identified as Balmer lines, giving a secure redshift of z = 4.01. This is the most distant quiescent galaxy known to date. Thanks to the high S/N of the spectrum, we are able to estimate the stellar velocity dispersion, σ=268±59 km s⁻¹, making a significant leap from the previous highest redshift measurement at z = 2.8. Interestingly, we find that the velocity dispersion is consistent with that of massive galaxies today, implying no significant evolution in velocity dispersion over the last 12 Gyr. Based on a stringent upper limit on its physical size from deep optical images (r_(eff) < 1.3 kpc), we find that its dynamical mass is consistent with the stellar mass inferred from photometry. Furthermore, the galaxy is located on the mass fundamental plane extrapolated from lower redshift galaxies. The observed no strong evolution in σ suggests that the mass in the core of massive galaxies does not evolve significantly, while most of the mass growth occurs in the outskirts of the galaxies, which also increases the size. This picture is consistent with a two-phase formation scenario in which mass and size growth is due to accretion in the outskirts of galaxies via mergers. Our results imply that the first phase may be completed as early as z ~ 4

DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

The SARS-CoV-2 spike protein binds and modulates estrogen receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor alpha (ER alpha). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 sub-unit. In cultured cells, S DNA transfection increased ER alpha cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ER alpha lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ER alpha and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ER alpha interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology

Stellar Velocity Dispersion of a Massive Quenching Galaxy at z = 4.01

We present the first stellar velocity dispersion measurement of a massive quenching galaxy at z = 4. The galaxy is first identified as a massive z ≥ 4 galaxy with suppressed star formation from photometric redshifts based on deep multiband data. A follow-up spectroscopic observation with MOSFIRE on Keck revealed strong multiple absorption features, which are identified as Balmer lines, giving a secure redshift of z = 4.01. This is the most distant quiescent galaxy known to date. Thanks to the high S/N of the spectrum, we are able to estimate the stellar velocity dispersion, σ=268±59 km s⁻¹, making a significant leap from the previous highest redshift measurement at z = 2.8. Interestingly, we find that the velocity dispersion is consistent with that of massive galaxies today, implying no significant evolution in velocity dispersion over the last 12 Gyr. Based on a stringent upper limit on its physical size from deep optical images (r_(eff) < 1.3 kpc), we find that its dynamical mass is consistent with the stellar mass inferred from photometry. Furthermore, the galaxy is located on the mass fundamental plane extrapolated from lower redshift galaxies. The observed no strong evolution in σ suggests that the mass in the core of massive galaxies does not evolve significantly, while most of the mass growth occurs in the outskirts of the galaxies, which also increases the size. This picture is consistent with a two-phase formation scenario in which mass and size growth is due to accretion in the outskirts of galaxies via mergers. Our results imply that the first phase may be completed as early as z ~ 4

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

Funder: Government Department of BusinessFunder: Energy and Industrial Strategy (BEIS)Funder: Vice-Chancellor Fellowship from the University of BristolFunder: Shanghai Thousand Talents ProgramFunder: Academy of Medical Sciences (AMS) Springboard AwardFunder: BBSRC Innovation fellowshipFunder: NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of BristolBACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of 25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.This research has been conducted using the UK Biobank resource under Application Numbers ‘40135’ and ‘15825’. J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit [MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/7]. J.Z. is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK [SBF006\1117]. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (G.D.S., T.R.G. and R.E.W.). This study received funding from the UK Medical Research Council [MR/R013942/1]. J.Z., Y.M.Z. and T.R.G are funded by a BBSRC Innovation fellowship. J.Z. is supported by the Shanghai Thousand Talents Program. Y.M.Z. is supported by the National Natural Science Foundation of China [81800636]. H.Z. is supported by the Training Program of the Major Research Plan of the National Natural Science Foundation of China [91642120], a grant from the Science and Technology Project of Beijing, China [D18110700010000] and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research [BMU2017JI007]. N.F. is supported by the National Institutes of Health awards R01-MD012765, R01-DK117445 and R21-HL140385. R.C. is funded by a Wellcome Trust GW4 Clinical Academic Training Fellowship [WT 212557/Z/18/Z]. The Trøndelag Health Study (the HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. M.C.B. is supported by the UK Medical Research Council (MRC) Skills Development Fellowship [MR/P014054/1]. S.F. is supported by a Wellcome Trust PhD studentship [WT108902/Z/15/Z]. Q.Y. is funded by a China Scholarship Council PhD scholarship [CSC201808060273]. Y.C. was supported by the National Key R&D Program of China [2016YFC0900500, 2016YFC0900501 and 2016YFC0900504]. The China Kadoorie Biobank baseline survey and the first resurvey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust [202922/Z/16/Z, 088158/Z/09/Z and 104085/Z/14/Z]. Japan-Kidney-Biobank was supported by AMED under Grant Number 20km0405210. P.C.H. is supported by Cancer Research UK [grant number: C18281/A19169]. A.K. was supported by DFG KO 3598/5–1. N.F. is supported by NIH awards R01-DK117445, R01-MD012765 and R21-HL140385. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health

The MUSE Atlas of Disks (MAD): resolving star formation rates and gas metallicities on <100 pc scales†

We study the physical properties of the ionized gas in local discs using the sample of 38 nearby ∼108.5–11.2 M⊙ Star-Forming Main-Sequence (SFMS) galaxies observed so far as part of the MUSE Atlas of Disks (MAD). Specifically, we use all strong emission lines in the MUSE wavelength range 4650–9300 Å to investigate the resolved ionized gas properties on ∼100 pc scales. This spatial resolution enables us to disentangle H ii regions from the diffuse ionized gas (DIG) in the computation of gas metallicities and star formation rates (SFRs) of star-forming regions. The gas metallicities generally decrease with radius. The metallicity of the H ii regions is on average ∼0.1 dex higher than that of the DIG, but the metallicity radial gradient in both components is similar. The mean metallicities within the inner galaxy cores correlate with the total stellar mass of the galaxies. On our < 100 pc scales, we find two correlations previously reported at kpc scales: a spatially resolved mass–metallicity relation (RMZR) and a spatially resolved SFMS (RSFMS). We find no secondary dependence of the RMZR with the SFR density. We find that both resolved relations have a local origin, as they do not depend on the total stellar mass. The observational results of this paper are consistent with the inside-out scenario for the growth of galactic disks

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk