Model Convolution: A Computational Approach to Digital Image Interpretation

Digital fluorescence microscopy is commonly used to track individual proteins and their dynamics in living cells. However, extracting molecule-specific information from fluorescence images is often limited by the noise and blur intrinsic to the cell and the imaging system. Here we discuss a method called “model-convolution,” which uses experimentally measured noise and blur to simulate the process of imaging fluorescent proteins whose spatial distribution cannot be resolved. We then compare model-convolution to the more standard approach of experimental deconvolution. In some circumstances, standard experimental deconvolution approaches fail to yield the correct underlying fluorophore distribution. In these situations, model-convolution removes the uncertainty associated with deconvolution and therefore allows direct statistical comparison of experimental and theoretical data. Thus, if there are structural constraints on molecular organization, the model-convolution method better utilizes information gathered via fluorescence microscopy, and naturally integrates experiment and theory

Diverse Hematological Malignancies Including Hodgkin-Like Lymphomas Develop in Chimeric MHC Class II Transgenic Mice

A chimeric HLA-DR4-H2-E (DR4) homozygous transgenic mouse line spontaneously develops diverse hematological malignancies with high frequency (70%). The majority of malignancies were distributed equally between T and B cell neoplasms and included lymphoblastic T cell lymphoma (LTCL), lymphoblastic B cell lymphoma (LBCL), diffuse large B cell lymphoma (DLBCL), the histiocyte/T cell rich variant of DLBCL (DLBCL-HA/T cell rich DLBCL), splenic marginal zone lymphoma (SMZL), follicular B cell lymphoma (FBL) and plasmacytoma (PCT). Most of these neoplasms were highly similar to human diseases. Also, some non-lymphoid malignancies such as acute myeloid leukemia (AML) and histiocytic sarcoma were found. Interestingly, composite lymphomas, including Hodgkin-like lymphomas, were also detected that had CD30+ Hodgkin/Reed-Sternberg (H/RS)-like cells, representing a tumor type not previously described in mice. Analysis of microdissected H/RS-like cells revealed their origin as germinal center B cells bearing somatic hypermutations and, in some instances, crippled mutations, as described for human Hodgkin lymphoma (HL). Transgene integration in an oncogene was excluded as an exclusive driving force of tumorigenesis and age-related lymphoma development suggests a multi-step process. Thus, this DR4 line is a useful model to investigate common molecular mechanisms that may contribute to important neoplastic diseases in man

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was 1252.4 ml per year in the nintedanib group and 1293.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of 120.21 (95% CI, 120.94 to 0.53; P=0.58) and 1.69 (95% CI, 120.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

The seismicity of Mars

The InSight (Interior Exploration using Seismic Investigations, Geodesy and Heat Transport) mission landed in Elysium Planitia on Mars on 26 November 2018 and fully deployed its seismometer by the end of February 2019. The mission aims to detect, characterize and locate seismic activity on Mars, and to further constrain the internal structure, composition and dynamics of the planet. Here, we present seismometer data recorded until 30 September 2019, which reveal that Mars is seismically active. We identify 174 marsquakes, comprising two distinct populations: 150 small-magnitude, high-frequency events with waves propagating at crustal depths and 24 low-frequency, subcrustal events of magnitude Mw 3–4 with waves propagating at various depths in the mantle. These marsquakes have spectral characteristics similar to the seismicity observed on the Earth and Moon. We determine that two of the largest detected marsquakes were located near the Cerberus Fossae fracture system. From the recorded seismicity, we constrain attenuation in the crust and mantle, and find indications of a potential low-S-wave-velocity layer in the upper mantle. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.We acknowledge NASA, CNES and its partner agencies and institutions (UKSA, SSO, DLR, JPL, IPGP-CNRS, ETHZ, IC and MPS-MPG) and the flight operations team at JPL, SISMOC, MSDS, IRIS-DMC and PDS for providing SEIS data. The Swiss co-authors were jointly funded by (1) the Swiss National Science Foundation and French Agence Nationale de la Recherche (SNF-ANR project 157133 ‘Seismology on Mars’), (2) the Swiss National Science Foundation (SNF project 172508 ‘Mapping the internal structure of Mars’), (3) the Swiss State Secretariat for Education, Research and Innovation (SEFRI project ‘MarsQuake Service-Preparatory Phase’) and (4) ETH Research grant no. ETH-06 17-02. Additional support came from the Swiss National Supercomputing Centre (CSCS) under project ID s922. The Swiss contribution in the implementation of the SEIS electronics was made possible by funding from the federal Swiss Space Office (SSO) and contractual and technical support from the ESA-PRODEX office. The French Team acknowledge the French Space Agency CNES, which has supported and funded all SEIS-related contracts and CNES employees, as well as CNRS and the French team universities for personal and infrastructure support. Additional support was provided by ANR (ANR-14-CE36-0012-02 and ANR-19-CE31-0008-08) and, for the IPGP team, by the UnivEarthS Labex programme (ANR-10-LABX-0023), IDEX Sorbonne Paris Cité (ANR-11-IDEX-0005-0). SEIS-SP development and delivery were funded by the UK Space Agency. A portion of the work was carried out at the InSight Project at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. The MPS SEIS team acknowledges funding for development of the SEIS leveling system by the DLR German Space Agency. We thank gempa GmbH for software development related to the MQS tools. This paper is InSight contribution number 102.Peer reviewe