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Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson's disease
No full textPathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. Although LRRK2 kinase inhibitors are advancing clinically, non-invasive readouts of LRRK2-linked pathway modulation remain limited. Profiling urinary proteomes from 1,215 individuals across three cohorts and integrating whole-genome sequencing from >500 participants to map genotype-proteome associations, we identified 177 urinary proteins associated with pathogenic LRRK2, enriched for lysosomal/glycosphingolipid, immune, and membrane-trafficking pathways. Machine learning narrowed the features to a cohort-agnostic 30-protein panel that classified G2019S carriers with a mean ROC AUC of 0.91 across independent tests. To evaluate translation, we performed multi-organ and urinary proteomics in rat gain- and loss-of-function models (BAC-LRRK2(G2019S) and Lrrk2(KO)) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses-strongest in kidney-and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted LRRK2 mutation status in patients (AUC 0.75) and reversed with Lrrk2 inhibition, supporting their pharmacodynamic utility. Together, our findings establish urine as a scalable, non-invasive matrix that captures systemic and brain-relevant consequences of LRRK2 dysfunction and nominate candidate pharmacodynamic markers set to support LRRK2-directed trials
Status of the Southern Wide-field Gamma-ray Observatory
No full textThe Southern Wide-field Gamma-Ray Observatory (SWGO) will be a next-generation gamma-ray observatory located in the Southern Hemisphere. Building upon the experience of previous and current ground-based particle array observatories, SWGO will feature a large detection area, a high-altitude site, and a southern location to explore the gamma-ray sky up to PeV energies. Following the recent site selection at Pampa la Bola in Chile, located at an altitude of 4770 meters above sea level, the collaboration is now focusing on developing an on-site pathfinder. In this contribution, we present the current status of SWGO, highlight recent progress in R&D activities, and outline the future plans for the observatory
COSMOS Spectroscopic Redshift Compilation (First Data Release): 488,000 Redshifts Encompassing Two Decades of Spectroscopy
No full textWe present the COSMOS Spectroscopic Redshift Compilation encompassing similar to 20 yr of spectroscopic redshifts within a 10 deg(2) area centered on the 2 deg(2) COSMOS legacy field. This compilation contains 487,666 redshifts of 266,284 unique objects from 138 individual programs up to z similar to 8 with median stellar mass similar to 10(8.4)-10(10) M-circle dot (redshift dependent). Rest-frame NUVrJ colors and star formation rate-stellar mass correlations show that the compilation primarily contains low-to-intermediate-mass star-forming and massive, quiescent galaxies at z 2. Sources in the compilation cover a diverse range of environments, including protoclusters such as "Hyperion." The full compilation is 50% spectroscopically complete by i similar to 23.4 mag and Ks similar to 21.6 mag; however, this is redshift dependent. Spatially, the compilation is >50% (>30%) complete within the central (outer) region limited to i 3 massive star-forming galaxies. This highlights how combining self-organizing maps with our compilation can provide guidance for future spectroscopic observations to get a complete spectroscopic view of galaxy populations. Lastly, the compilation will undergo periodic data releases incorporating new spectroscopic redshifts and providing a lasting legacy resource for the community
Planetary nebulae as tracers of stellar population properties: a pilot study with MUSE
No full textPlanetary nebulae (PNe) are the only single stars in galaxies outside the Local Group that can be used as kinematic tracers of the diffuse light in the extended halo. Analysing their luminosity-specific number density across galaxies of different morphologies has also shown hints that they may be used as tracers of the age and metallicity of stellar populations. A proper understanding of this relation has been hindered by the fact that simultaneously detecting PNe and accurately measuring stellar properties is extremely difficult using classical narrow-band imaging methods, which cannot detect PNe in the bright centres of galaxies. In this work, we use integral-field spectroscopy to overcome this challenge, analysing the inner regions of a sample of 10 early-type galaxies from the Extended Planetary Nebulae Survey (ePN.S) for which archival MUSE data were available. With the Diffuse Emission-Line Filter (DELF) technique, we automate the detection of PNe, and perform spectral fitting on the diffuse light to infer kinematics and stellar population parameters. We compare the PN number density profile and its associated alpha-parameter with multiple properties of the host galaxies. We find that our sample follows the previously observationally constrained correlation with the metallicity of the host galaxy. We find a weak anticorrelation between the alpha-parameter and the far-ultraviolet excess, highlighting the possible relation between the visibility lifetime of PNe on the spectral energy distribution of their host galaxies, with fewer PNe detected in association with stellar populations characterized by an ultraviolet excess
3D imaging of neuronal inclusions and protein aggregates in human neurodegeneration by multiscale x-ray phase-contrast tomography
No full textThis study leverages x-ray phase-contrast tomography (XPCT) for detailed analysis of neurodegenerative diseases, focusing on the three-dimensional (3D) visualization and quantification of neuropathological features within fixed human postmortem tissue. XPCT with synchrotron radiation offers micrometer and even sub-micron resolution, enabling us to examine intra- and extraneuronal aggregates and inclusions such as Lewy bodies (LBs), granulovacuolar degeneration (GvD), Hirano bodies (HBs), neurofibrillary tangles (NFTs), β-amyloid plaques, and vascular amyloid deposits in three dimensions. In the reconstructions, we identified the highest electron densities in Hirano and LBs, while NFTs exhibited no significant increase in XPCT contrast. Using cutting-edge high-resolution x-ray synchrotron beamlines, we were now able to detect even detect subcellular differences in electron densities found in GvD. Small-scale inhomogeneities of the electron density were also detected in LBs, potentially relating to inclusions of organelles. Additionally, we reveal here a peculiar 3D geometry of HBs and demonstrate the co-occurrence with GvD in the same neuron. These findings underscore the potential of XPCT as a powerful, label-free tool for spatially resolved neuropathological investigations, opening new avenues for the systematic 3D characterization of inclusions and aggregates in neurodegeneration
VAPA at the inner nuclear membrane affects nuclear lamins and nuclear morphology
No full textVesicle-associated membrane protein-associated protein A (VAPA) is a protein of the endoplasmic reticulum (ER) and a component of several membrane contact sites (MCSs). We show here that VAPA also localizes to the inner nuclear membrane (INM), in close proximity to nuclear lamins, INM proteins and nucleoporins. Using our proteomics approach ‘rapamycin- and APEX-dependent identification of proteins by SILAC’ (RAPIDS), we identified several nuclear proximity partners of VAPA, including emerin, different LAP2 isoforms, lamin A/C and Nup153. Depletion of VAPA in various cellular systems resulted in reduced nuclear lamin levels and aberrant nuclear morphology, including the formation of membrane invaginations and tunnels. Furthermore, histone acetylation levels were altered. Our data suggest that VAPA has distinct nuclear functions, in addition to its established role as an ER organizer
Bayesian MINFLUX Localization Microscopy
No full textMINFLUX microscopy allows for localization of fluorophores with nanometer precision by using targeted scanning with an illumination profile with a minimum. However, current scanning patterns and the overall procedure are based on heuristics and may therefore be suboptimal. Here, we present a rigorous Bayesian approach that offers maximal resolution from either a minimal number of detected photons or a minimal number of exposures. We estimate using simulated localization runs that this approach should reduce the number of photons required for 1 nm resolution by a factor of about four
Die Natur ist kein Parteimitglied: Mit den Gesetzen der Physik gegen politische Ignoranz
No full textThe nuclear envelope protein TMEM209 is an integral component of the nuclear pore complex and interacts with Nup210
No full textA highly curved membrane region connecting the inner and the outer nuclear membrane serves as a platform where nucleoporins with one or more transmembrane domains promote anchoring of the nuclear pore complex to the nuclear envelope. In mammalian cells, three transmembrane nucleoporins, Nup210, POM121 and NDC1, are inserted at this site. Here, we characterize TMEM209, which had initially been identified as a protein concentrated at the nuclear envelope, as a fourth transmembrane nucleoporin. Proximity labeling revealed that TMEM209 occurs close to proteins of the inner nuclear membrane and to other nucleoporins. TMEM209 localized to the nuclear pore complex in immunofluorescence microscopy and biochemically interacted with Nup210 via a region containing its two transmembrane domains. TMEM209 depletion impaired cell growth and delayed entry into S, G2 and M phases of the cell cycle. Conversely, its overexpression specifically dissociated Nup210 from the nuclear envelope. Together, these findings establish TMEM209 as a novel transmembrane nucleoporin that cooperates with Nup210 in cell cycle progression and cell proliferation