Noncytotoxic Roles of Granzymes in Health and Disease

Granzymes are serine proteases previously believed to play exclusive and somewhat redundant roles in lymphocyte-mediated target cell death. However, recent studies have challenged this paradigm. Distinct substrate profiles and functions have since emerged for each granzyme while their dysregulated proteolytic activities have been linked to diverse pathologies

Granzyme K mediates IL-23-dependent inflammation and keratinocyte proliferation in psoriasis

Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization in vitro revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity

TROPOMI/S5P total ozone column data: global ground-based validation and consistency with other satellite missions

In this work, the TROPOMI near real time (NRTI) and offline (OFFL) total ozone column (TOC) products are presented and compared to daily ground-based quality-assured Brewer and Dobson TOC measurements deposited in the World Ozone and Ultraviolet Radiation Data Centre (WOUDC). Additional comparisons to individual Brewer measurements from the Canadian Brewer Network and the European Brewer Network (Eubrewnet) are performed. Furthermore, twilight zenith-sky measurements obtained with ZSL-DOAS (Zenith Scattered Light Differential Optical Absorption Spectroscopy) instruments, which form part of the SAOZ network (Système d'Analyse par Observation Zénitale), are used for the validation. The quality of the TROPOMI TOC data is evaluated in terms of the influence of location, solar zenith angle, viewing angle, season, effective temperature, surface albedo and clouds. For this purpose, globally distributed ground-based measurements have been utilized as the background truth. The overall statistical analysis of the global comparison shows that the mean bias and the mean standard deviation of the percentage difference between TROPOMI and ground-based TOC is within 0 –1.5 % and 2.5 %–4.5 %, respectively. The mean bias that results from the comparisons is well within the S5P product requirements, while the mean standard deviation is very close to those limits, especially considering that the statistics shown here originate both from the satellite and the ground-based measurements.This research has been supported by the European Space Agency “Preparation and Operations of the Mission Performance Centre (MPC) for the Copernicus Sentinel-5 Precursor Satellite” (contract no. 4000117151/16/1-LG)

PET-BIDS, an extension to the brain imaging data structure for positron emission tomography

The Brain Imaging Data Structure (BIDS) is a standard for organizing and describing neuroimaging datasets, serving not only to facilitate the process of data sharing and aggregation, but also to simplify the application and development of new methods and software for working with neuroimaging data. Here, we present an extension of BIDS to include positron emission tomography (PET) data, also known as PET-BIDS, and share several open-access datasets curated following PET-BIDS along with tools for conversion, validation and analysis of PET-BIDS datasets

SPARC Overexpression Inhibits Cell Proliferation in Neuroblastoma and Is Partly Mediated by Tumor Suppressor Protein PTEN and AKT

Secreted protein acidic and rich in cysteine (SPARC) is also known as BM-40 or Osteonectin, a multi-functional protein modulating cell–cell and cell–matrix interactions. In cancer, SPARC is not only linked with a highly aggressive phenotype, but it also acts as a tumor suppressor. In the present study, we sought to characterize the function of SPARC and its role in sensitizing neuroblastoma cells to radio-therapy. SPARC overexpression in neuroblastoma cells inhibited cell proliferation in vitro. Additionally, SPARC overexpression significantly suppressed the activity of AKT and this suppression was accompanied by an increase in the tumor suppressor protein PTEN both in vitro and in vivo. Restoration of neuroblastoma cell radio-sensitivity was achieved by overexpression of SPARC in neuroblastoma cells in vitro and in vivo. To confirm the role of the AKT in proliferation inhibited by SPARC overexpression, we transfected neuroblastoma cells with a plasmid vector carrying myr-AKT. Myr-AKT overexpression reversed SPARC-mediated PTEN and increased proliferation of neuroblastoma cells in vitro. PTEN overexpression in parallel with SPARC siRNA resulted in decreased AKT phosphorylation and proliferation in vitro. Taken together, these results establish SPARC as an effector of AKT-PTEN-mediated inhibition of proliferation in neuroblastoma in vitro and in vivo

Validation of ozone measurements from the Atmospheric Chemistry Experiment (ACE)

This paper presents extensive bias determination analyses of ozone observations from the Atmospheric Chemistry Experiment (ACE) satellite instruments: the ACE Fourier Transform Spectrometer (ACE-FTS) and the Measurement of Aerosol Extinction in the Stratosphere and Troposphere Retrieved by Occultation (ACE-MAESTRO) instrument. Here we compare the latest ozone data products from ACE-FTS and ACE-MAESTRO with coincident observations from nearly 20 satellite-borne, airborne, balloon-borne and ground-based instruments, by analysing volume mixing ratio profiles and partial column densities. The ACE-FTS version 2.2 Ozone Update product reports more ozone than most correlative measurements from the upper troposphere to the lower mesosphere. At altitude levels from 16 to 44 km, the average values of the mean relative differences are nearly all within +1 to +8%. At higher altitudes (45 60 km), the ACE-FTS ozone amounts are significantly larger than those of the comparison instruments, with mean relative differences of up to +40% (about + 20% on average). For the ACE-MAESTRO version 1.2 ozone data product, mean relative differences are within +/- 10% (average values within +/- 6%) between 18 and 40 km for both the sunrise and sunset measurements. At higher altitudes (similar to 35-55 km), systematic biases of opposite sign are found between the ACE-MAESTRO sunrise and sunset observations. While ozone amounts derived from the ACE-MAESTRO sunrise occultation data are often smaller than the coincident observations (with mean relative differences down to -10%), the sunset occultation profiles for ACE-MAESTRO show results that are qualitatively similar to ACE-FTS, indicating a large positive bias (mean relative differences within +10 to +30%) in the 45-55 km altitude range. In contrast, there is no significant systematic difference in bias found for the ACE-FTS sunrise and sunset measurements

PET-BIDS, an extension to the brain imaging data structure for positron emission tomography

The Brain Imaging Data Structure (BIDS) is a standard for organizing and describing neuroimaging datasets. It serves not only to facilitate the process of data sharing and aggregation, but also to simplify the application and development of new methods and software for working with neuroimaging data. Here, we present an extension of BIDS to include positron emission tomography (PET) data (PET-BIDS). We describe the PET-BIDS standard in detail and share several open-access datasets curated following PET-BIDS. Additionally, we highlight several tools which are already available for converting, validating and analyzing PET-BIDS datasets.Competing Interest StatementThe authors have declared no competing interest

How Certain are We of the Uncertainties in Recent Ozone Profile Trend Assessments of Merged Limbo Ccultation Records? Challenges and Possible Ways Forward

Most recent assessments of long-term changes in the vertical distribution of ozone (by e.g. WMO and SI2N) rely on data sets that integrate observations by multiple instruments. Several merged satellite ozone profile records have been developed over the past few years; each considers a particular set of instruments and adopts a particular merging strategy. Their intercomparison by Tummon et al. revealed that the current merging schemes are not sufficiently refined to correct for all major differences between the limb/occultation records. This shortcoming introduces uncertainties that need to be known to obtain a sound interpretation of the different satellite-based trend studies. In practice however, producing realistic uncertainty estimates is an intricate task which depends on a sufficiently detailed understanding of the characteristics of each contributing data record and on the subsequent interplay and propagation of these through the merging scheme. Our presentation discusses these challenges in the context of limb/occultation ozone profile records, but they are equally relevant for other instruments and atmospheric measurements. We start by showing how the NDACC and GAW-affiliated ground-based networks of ozonesonde and lidar instruments allowed us to characterize fourteen limb/occultation ozone profile records, together providing a global view over the last three decades. Our prime focus will be on techniques to estimate long-term drift since our results suggest this is the main driver of the major trend differences between the merged data sets. The single-instrument drift estimates are then used for a tentative estimate of the systematic uncertainty in the profile trends from merged data records. We conclude by reflecting on possible further steps needed to improve the merging algorithms and to obtain a better characterization of the uncertainties involved

An evaluation of the potential application of Lean Thinking in shipbuilding: multiple-case study.

A indústria de construção naval é competitiva a nível mundial e os principais estaleiros procuram reduzir os seus custos de modo a oferecerem preços atraentes aos clientes, em geral armadores. Redução de custos pode ser alcançada através da constante eliminação de desperdícios aplicando uma filosofia gerencial que é a Mentalidade Enxuta (Lean Thinking). Esta filosofia iniciou em uma indústria automotiva (Toyota Motor Corporation) e hoje é aplicada em diversas áreas tais como construção civil, mecânica, aeronáutica, química, elétrica, alimentícia, farmacêutica, médica e serviços. No caso do Brasil, há várias indústrias procurando adotar a filosofia enxuta nos seus processos produtivos. Nesta dissertação procura-se explorar o potencial de aplicação desta filosofia em estaleiros. Para a avaliação, foi realizado um estudo de casos múltiplos em estaleiros brasileiros, inclusive de diferentes tamanhos e segmentos, aço e fibra. As análises tiveram como base um modelo proposto da filosofia Lean para a indústria naval, onde os casos são avaliados segundo determinados elementos. O objetivo é orientar os estaleiros em relação às oportunidades de redução de custos e tempo de fabricação, com aumento da qualidade e consequente maior satisfação do cliente.The shipbuilding industry is very competitive at a global level and the major shipyards are searching ways to reduce their costs in order to offer attractive prices to the shipowners. Cost reduction can be achieved through the constant reduction of waste applying a managerial philosophy that is known as Lean Thinking. This philosophy was initiated by an automotive industry (Toyota Motor Corporation) and today is applied in many industries such as civil construction, mechanics, aeronautics, chemical, electric, food, pharmaceutical, medical and services. In Brazil many industries are implementing the Lean Thinking philosophy in their productive processes. In this thesis the potential of the application of this philosophy is explored in shipyards. For the evaluation a multiple-case study was carried out in Brazilian shipyards, of different sizes and segments, steel and fiber. The analyses had as a base a proposed model for Lean in shipbuilding, where the cases are evaluated under determined elements. The objective is to guide shipbuilders in relation to the opportunities to reduce cost and construction time, with greater quality and consequently greater customer satisfaction