Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein (α-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable β-amyloid-sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that β-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small β-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although the β-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of β-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders

The Fast, Luminous Ultraviolet Transient AT2018cow: Extreme Supernova, or Disruption of a Star by an Intermediate-Mass Black Hole?

Wide-field optical surveys have begun to uncover large samples of fast (t_(rise) ≲ 5 d), luminous (M_(peak) 10 days. The spectrum remains extremely hot throughout its evolution, and the photospheric radius contracts with time (receding below R < 10^(14) cm after 1 month). This behaviour does not match that of any known supernova, although a relativistic jet within a fallback supernova could explain some of the observed features. Alternatively, the transient could originate from the disruption of a star by an intermediate-mass black hole, although this would require long-lasting emission of highly super-Eddington thermal radiation. In either case, AT 2018cow suggests that the population of fast luminous transients represents a new class of astrophysical event. Intensive follow-up of this event in its late phases, and of any future events found at comparable distance, will be essential to better constrain their origins

Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses

Correlates of immune-mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of 40 volunteers followed for up to 1 yr after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity, including complement, the inflammasome, and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (modular immune in vitro construct [MIMIC] system), by the coordinated up-regulation of transcripts for specific transcription factors, including STAT1, IRF7, and ETS2, which are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional, and persistent immune response that integrates all effector cells of the immune system

RV Kronprins Håkon (cruise no. 2019708) Longyearbyen – Longyearbyen 19.09. – 16.10.2019

The HACON cruise is a major component of the FRINATEK HACON project, which aims at investigating the role of the Gakkel Ridge and Arctic Ocean in biological connectivity amongst ocean basins and global biogeography of chemosynthetic ecosystems. The HACON study area is centered in the Aurora seamount and Aurora vent field

Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice

15 pags, 7 figs, 2 tabsParkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein (α-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable β-amyloid-sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. Wefound that β-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small β-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. Weconclude that although the β-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of β-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders.This work was supported in part by the Michael J. Fox Foundation (to L.V.-D. and N.C.) and Grant P50NS108675 (Alabama Udall Center). The authors declare that they have no conflicts of interest with the contents of this article.Peer reviewe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Single-cell RNA sequencing of liver fine-needle aspirates captures immune diversity in the blood and liver in chronic hepatitis B patients

Background and Aims: HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing. Approach and Results: We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S3 picowell-based and the 10× Chromium reverse-emulsion droplet–based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences. Conclusions: The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.</p

A Large Fraction of Hydrogen-rich Supernova Progenitors Experience Elevated Mass Loss Shortly Prior to Explosion

Spectroscopic detection of narrow emission lines traces the presence of circumstellar mass distributions around massive stars exploding as core-collapse supernovae. Transient emission lines disappearing shortly after the supernova explosion suggest that the material spatial extent is compact and implies an increased mass loss shortly prior to explosion. Here, we present a systematic survey for such transient emission lines (Flash Spectroscopy) among Type II supernovae detected in the first year of the Zwicky Transient Facility survey. We find that at least six out of ten events for which a spectrum was obtained within two days of the estimated explosion time show evidence for such transient flash lines. Our measured flash event fraction (&gt;30% at 95% confidence level) indicates that elevated mass loss is a common process occurring in massive stars that are about to explode as supernovae

The prevalence and influence of circumstellar material around hydrogen-rich supernova progenitors

Narrow transient emission lines (flash-ionization features) in early supernova (SN) spectra trace the presence of circumstellar material (CSM) around the massive progenitor stars of core-collapse SNe. The lines disappear within days after the SN explosion, suggesting that this material is spatially confined, and originates from enhanced mass loss shortly (months to a few years) prior to explosion. We performed a systematic survey of H-rich (Type II) SNe discovered within less than two days from explosion during the first phase of the Zwicky Transient Facility (ZTF) survey (2018-2020), finding thirty events for which a first spectrum was obtained within $< 2$ days from explosion. The measured fraction of events showing flash ionisation features ($>36\%$ at $95\%$ confidence level) confirms that elevated mass loss in massive stars prior to SN explosion is common. We find that SNe II showing flash ionisation features are not significantly brighter, nor bluer, nor more slowly rising than those without. This implies that CSM interaction does not contribute significantly to their early continuum emission, and that the CSM is likely optically thin. We measured the persistence duration of flash ionisation emission and find that most SNe show flash features for $\approx 5$ days. Rarer events, with persistence timescales $>10$ days, are brighter and rise longer, suggesting these may be intermediate between regular SNe II and strongly-interacting SNe IIn

The Fast, Luminous Ultraviolet Transient AT2018cow: Extreme Supernova, or Disruption of a Star by an Intermediate-Mass Black Hole?

Wide-field optical surveys have begun to uncover large samples of fast (t_(rise) ≲ 5 d), luminous (M_(peak) 10 days. The spectrum remains extremely hot throughout its evolution, and the photospheric radius contracts with time (receding below R < 10^(14) cm after 1 month). This behaviour does not match that of any known supernova, although a relativistic jet within a fallback supernova could explain some of the observed features. Alternatively, the transient could originate from the disruption of a star by an intermediate-mass black hole, although this would require long-lasting emission of highly super-Eddington thermal radiation. In either case, AT 2018cow suggests that the population of fast luminous transients represents a new class of astrophysical event. Intensive follow-up of this event in its late phases, and of any future events found at comparable distance, will be essential to better constrain their origins