Metrics for measuring distances in configuration spaces

In order to characterize molecular structures we introduce configurational fingerprint vectors which are counterparts of quantities used experimentally to identify structures. The Euclidean distance between the configurational fingerprint vectors satisfies the properties of a metric and can therefore safely be used to measure dissimilarities between configurations in the high dimensional configuration space. We show that these metrics correlate well with the RMSD between two configurations if this RMSD is obtained from a global minimization over all translations, rotations and permutations of atomic indices. We introduce a Monte Carlo approach to obtain this global minimum of the RMSD between configurations

Tycho Brahe's 1572 supernova as a standard type Ia explosion revealed from its light echo spectrum

Type Ia supernovae (SNe Ia) are thermonuclear explosions of white dwarf stars in close binary systems. They play an important role as cosmological distance indicators and have led to the discovery of the accelerated expansion of the Universe. Among the most important unsolved questions are how the explosion actually proceeds and whether accretion occurs from a companion or via the merging of two white dwarfs. Tycho Brahe's supernova of 1572 (SN 1572) is thought to be one of the best candidates for a SN Ia in the Milky Way. The proximity of the SN 1572 remnant has allowed detailed studies, such as the possible identification of the binary companion, and provides a unique opportunity to test theories of the explosion mechanism and the nature of the progenitor. The determination of the yet unknown exact spectroscopic type of SN 1572 is crucial to relate these results to the diverse population of SNe Ia. Here we report an optical spectrum of Tycho Brahe's supernova near maximum brightness, obtained from a scattered-light echo more than four centuries after the direct light of the explosion swept past Earth. We find that SN 1572 belongs to the majority class of normal SNe Ia. The presence of a strong Ca II IR feature at velocities exceeding 20,000 km/s, which is similar to the previously observed polarized features in other SNe Ia, suggests asphericity in SN 1572.Comment: 15 pages, 3 figures - accepted for publication in Natur

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

© 2018, American Society for Clinical Investigation. This article has been published in final form at https://doi.org/10.1172/JCI120612First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.Peer reviewe

A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP

Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity

Credit Rating Agency Announcements and the Eurozone Sovereign Debt Crisis

This paper studies the impact of credit rating agency (CRA) announcements on the value of the Euro and the yields of French, Italian, German and Spanish long-term sovereign bonds during the culmination of the Eurozone debt crisis in 2011-2012. The employed GARCH models show that CRA downgrade announcements negatively affected the value of the Euro currency and also increased its volatility. Downgrading increased the yields of French, Italian and Spanish bonds but lowered the German bond's yields, although Germany's rating status was never touched by CRA. There is no evidence for Granger causality from bond yields to rating announcements. We infer from these findings that CRA announcements significantly influenced crisis-time capital allocation in the Eurozone. Their downgradings caused investors to rebalance their portfolios across member countries, out of ailing states' debt into more stable borrowers' securities

Making Sense of Complex Carbon and Metal/Carbon Systems by Secondary Electron Hyperspectral Imaging

Carbon and carbon/metal systems with a multitude of functionalities are ubiquitous in new technologies but understanding on the nanoscale remains elusive due to their affinity for interaction with their environment and limitations in available characterization techniques. This paper introduces a spectroscopic technique and demonstrates its capacity to reveal chemical variations of carbon. The effectiveness of this approach is validated experimentally through spatially averaging spectroscopic techniques and using Monte Carlo modeling. Characteristic spectra shapes and peak positions for varying contributions of sp2-like or sp3-like bond types and amorphous hydrogenated carbon are reported under circumstances which might be observed on highly oriented pyrolytic graphite (HOPG) surfaces as a result of air or electron beam exposure. The spectral features identified above are then used to identify the different forms of carbon present within the metallic films deposited from reactive organometallic inks. While spectra for metals is obtained in dedicated surface science instrumentation, the complex relations between carbon and metal species is only revealed by secondary electron (SE) spectroscopy and SE hyperspectral imaging obtained in a state-of-the-art scanning electron microscope (SEM). This work reveals the inhomogeneous incorporation of carbon on the nanoscale but also uncovers a link between local orientation of metallic components and carbon form

BigStitcher: reconstructing high-resolution image datasets of cleared and expanded samples.

Light-sheet imaging of cleared and expanded samples creates terabyte-sized datasets that consist of many unaligned three-dimensional image tiles, which must be reconstructed before analysis. We developed the BigStitcher software to address this challenge. BigStitcher enables interactive visualization, fast and precise alignment, spatially resolved quality estimation, real-time fusion and deconvolution of dual-illumination, multitile, multiview datasets. The software also compensates for optical effects, thereby improving accuracy and enabling subsequent biological analysis

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis

An Integrated Micro- and Macroarchitectural Analysis of the Drosophila Brain by Computer-Assisted Serial Section Electron Microscopy

A new software package allows for dense electron microscopy reconstructions of neuronal networks in the fruit fly brain, and reveals specific differences in microcircuits between insects and vertebrates