| 1. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Sakornsakolpat, Phuwanat, et al.
(author)
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Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
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Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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| 6. |
- Abdalla, H., et al.
(author)
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Gamma-ray blazar spectra with HESS II mono analysis : The case of PKS2155-304 and PG1553+113
- 2017
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 600
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Journal article (peer-reviewed)abstract
- Context. The addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV for small zenith angle observations. Such an extension of the instrument's energy range is particularly beneficial for studies of active galactic nuclei with soft spectra, as expected for those at a redshift >= 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553 + 113 (0.43 < z < 0.58) are among the brightest objects in the gamma-ray sky, both showing clear signatures of gamma-ray absorption at E > 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Aims. The aims of this work are twofold: to demonstrate the monoscopic analysis of CT5 data with a low energy threshold, and to obtain accurate measurements of the spectral energy distributions (SED) of PKS 2155-304 and PG 1553 + 113 near their SED peaks at energies approximate to 100 GeV. Methods. Multiple observational campaigns of PKS 2155 304 and PG 1553 + 113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument (CT1-5). A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters which are derived from this analysis. Results. Using the data from CT5, the energy spectra of PKS 2155 304 and PG 1553 + 113 were reconstructed down to conservative threshold energies of 80 GeV for PKS 2155 304, which transits near zenith, and 110 GeV for the more northern PG 1553 + 113. The measured spectra, well fitted in both cases by a log-parabola spectral model ( with a 5.0 similar to statistical preference for non-zero curvature for PKS 2155 304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E approximate to 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155 304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties.
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| 7. |
- Galván, Ignacio Fdez., et al.
(author)
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OpenMolcas : From Source Code to Insight
- 2019
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In: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 15:11, s. 5925-5964
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Journal article (peer-reviewed)abstract
- In this Article we describe the OpenMolcas environment and invite the computational chemistry community to collaborate. The open-source project already includes a large number of new developments realized during the transition from the commercial MOLCAS product to the open-source platform. The paper initially describes the technical details of the new software development platform. This is followed by brief presentations of many new methods, implementations, and features of the OpenMolcas program suite. These developments include novel wave function methods such as stochastic complete active space self-consistent field, density matrix renormalization group (DMRG) methods, and hybrid multiconfigurational wave function and density functional theory models. Some of these implementations include an array of additional options and functionalities. The paper proceeds and describes developments related to explorations of potential energy surfaces. Here we present methods for the optimization of conical intersections, the simulation of adiabatic and nonadiabatic molecular dynamics, and interfaces to tools for semiclassical and quantum mechanical nuclear dynamics. Furthermore, the Article describes features unique to simulations of spectroscopic and magnetic phenomena such as the exact semiclassical description of the interaction between light and matter, various X-ray processes, magnetic circular dichroism, and properties. Finally, the paper describes a number of built-in and add-on features to support the OpenMolcas platform with postcalculation analysis and visualization, a multiscale simulation option using frozen-density embedding theory, and new electronic and muonic basis sets.
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| 8. |
- Gardner, Alex S., et al.
(author)
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A Reconciled Estimate of Glacier Contributions to Sea Level Rise : 2003 to 2009
- 2013
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 340:6134, s. 852-857
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Journal article (peer-reviewed)abstract
- Glaciers distinct from the Greenland and Antarctic Ice Sheets are losing large amounts of water to the world's oceans. However, estimates of their contribution to sea level rise disagree. We provide a consensus estimate by standardizing existing, and creating new, mass-budget estimates from satellite gravimetry and altimetry and from local glaciological records. In many regions, local measurements are more negative than satellite-based estimates. All regions lost mass during 2003-2009, with the largest losses from Arctic Canada, Alaska, coastal Greenland, the southern Andes, and high-mountain Asia, but there was little loss from glaciers in Antarctica. Over this period, the global mass budget was -259 +/- 28 gigatons per year, equivalent to the combined loss from both ice sheets and accounting for 29 +/- 13% of the observed sea level rise.
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| 9. |
- Hofer, M., et al.
(author)
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International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients
- 2014
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In: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 53:6, s. 1125-1129
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Journal article (peer-reviewed)abstract
- Objectives. The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. Methods. We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. Results. Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. Conclusion. We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.
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| 10. |
- Månberg, Anna, 1985-, et al.
(author)
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Altered perivascular fibroblast activity precedes ALS disease onset
- 2021
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In: Nature Medicine. - : Nature Publishing Group. - 1078-8956 .- 1546-170X. ; 27:4, s. 640-646
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Journal article (peer-reviewed)abstract
- Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
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| 11. |
- van Kempen, Leon C. L., et al.
(author)
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The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene
- 2016
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:369
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Journal article (peer-reviewed)abstract
- Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesized that gene expression from gonosomes (sex chromosomes) might play an important role. We demonstrate that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit from two X chromosomes. The gonosomal protein phosphatase 2 regulatory subunit B, beta (PPP2R3B) gene is located on the pseudoautosomal region (PAR) of the X chromosome in females and the Y chromosome in males. We observed that, despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression was lower in males than in females and was independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate-recognizing subunit of protein phosphatase 2A. PR70 decreased melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing the cell division cycle 6 (CDC6)-chromatin licensing and DNA replication factor 1 (CDT1) interaction, which delays the firing of origins of DNA replication. Hence, PR70 functionally behaves as an X-linked tumor suppressor gene.
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