The Proteolytic Activation of Vascular Endothelial Growth Factor-C

The enzymatic cleavage of the protein backbone (proteolysis) is integral to many biological processes, such as for the breakdown of proteins in the digestive system. Specific proteolytic cleavages are also used to turn on or off the activity of proteins. For example, lymph­angiogenic vascular endothelial growth factor C (VEGF-C) is synthesized as a precursor molecule that must be converted to a mature form by the enzymatic removal of C- and N-terminal propeptides before it can bind and activate its receptors. The constitutive C-terminal cleavage is mediated by proprotein convertases such as furin. The subsequent activating cleavage can be mediated by at least 4 different proteinases: by plasmin, ADAMTS3, prostate-specific antigen (PSA) and cathepsin D. Processing by different proteinases results in distinct forms of "mature" VEGF-C that differ in their affinity and their receptor activation potential. The CCBE1 protein regulates the activating cleavage of VEGF-C by ADAMTS3 and PSA, but not by plasmin. During embryonic development of the lymphatic system, VEGF-C is activated primarily by the ADAMTS3 proteinase. In contrast, it is believed that plasmin is responsible for wound-healing lymphangiogenesis and PSA for tumor-associated pathological lymphangio­genesis. Cathepsin D has also been implicated in tumor lymphangiogenesis. In addition, cathepsin D contained in saliva might activate latent VEGF-C upon wound licking, thereby accelerating wound healing. The molecular details of proteolytic activation of VEGF-C have only recently been extensively explored, and it is likely that not all activating proteinases are known as yet. It appears that the activity of VEGF-C is regulated for different specific functions by different proteinases. Although VEGF-C clearly plays a pivotal role for tumor progression and metastasis in experimental animal studies, the relevance of most correlative studies on the role of VEGF-C in human cancers has been quite limited until now, also due to the lack of methods for differentiating between inactive and active forms of VEGF-CPeer reviewe

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

The ALICE experiment at the CERN LHC

ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008

Untargeted stable isotope-resolved metabolomics to assess the effect of PI3Kβ inhibition on metabolic pathway activities in a PTEN null breast cancer cell line

The combination of high-resolution LC-MS untargeted metabolomics with stable isotope-resolved tracing is a promising approach for the global exploration of metabolic pathway activities. In our established workflow we combine targeted isotopologue feature extraction with the non-targeted X(13)CMS routine. Metabolites, detected by X(13)CMS as differentially labeled between two biological conditions are subsequently integrated into the original targeted library. This strategy enables monitoring of changes in known pathways as well as the discovery of hitherto unknown metabolic alterations. Here, we demonstrate this workflow in a PTEN (phosphatase and tensin homolog) null breast cancer cell line (MDA-MB-468) exploring metabolic pathway activities in the absence and presence of the selective PI3Kβ inhibitor AZD8186. Cells were fed with [U-(13)C] glucose and treated for 1, 3, 6, and 24 h with 0.5 µM AZD8186 or vehicle, extracted by an optimized sample preparation protocol and analyzed by LC-QTOF-MS. Untargeted differential tracing of labels revealed 286 isotope-enriched features that were significantly altered between control and treatment conditions, of which 19 features could be attributed to known compounds from targeted pathways. Other 11 features were unambiguously identified based on data-dependent MS/MS spectra and reference substances. Notably, only a minority of the significantly altered features (11 and 16, respectively) were identified when preprocessing of the same data set (treatment vs. control in 24 h unlabeled samples) was performed with tools commonly used for label-free (i.e. w/o isotopic tracer) non-targeted metabolomics experiments (Profinder´s batch recursive feature extraction and XCMS). The structurally identified metabolites were integrated into the existing targeted isotopologue feature extraction workflow to enable natural abundance correction, evaluation of assay performance and assessment of drug-induced changes in pathway activities. Label incorporation was highly reproducible for the majority of isotopologues in technical replicates with a RSD below 10%. Furthermore, inter-day repeatability of a second label experiment showed strong correlation (Pearson R (2) > 0.99) between tracer incorporation on different days. Finally, we could identify prominent pathway activity alterations upon PI3Kβ inhibition. Besides pathways in central metabolism, known to be changed our workflow revealed additional pathways, like pyrimidine metabolism or hexosamine pathway. All pathways identified represent key metabolic processes associated with cancer metabolism and therapy

The HyMethShip Project: Innovative Emission Free Propulsion for Ships

The HyMethShip project (Hydrogen-Methanol Ship Propulsion Using On-board Pre-combustion Carbon Capture) is a cooperative R&D project funded by the European Union’s Horizon 2020 research and innovation programme.The project aims to drastically reduce emissions while improving the efficiency of waterborne transport. The HyMethShip system will achieve a reduction in CO2 of more than 97% and practically eliminate SOx and PM emissions. NOx emissions will fall by over 80%. below the IMO Tier III limit. The energy efficiency of the HyMethShip system is expected to be more than 45% greater than the best available technology (renewable methanol as the fuel coupled with conventional post-combustion carbon capturing).The HyMethShip system innovatively combines a membrane reactor, a CO2 capture system, a storage system for CO2 and methanol as well as a hydrogen-fueled combustion engine into one system. Methanol is reformed to hydrogen, which is then burned in a conventional reciprocating engine that has been upgraded to burn multiple fuel types and specially optimized for hydrogen use. The basic engine type is the same as the one currently used on the majority of ships. This project will develop this system further and integrate it into shipboard installations. The system will be developed, validated, and demonstrated on-shore on an engine in the range of 1 to 2 MW.The project started in 2018 and will run for 3 years. The work is structured into 11 work packages that deal with the pre-combustion carbon capture system and the internal combustion engine as well as assess safety, economic and environmental factors and system integration. The consortium consists of 13 partners including a globally operating shipping company, a major shipyard, a ship classification society, research institutes and universities and equipment manufacturers.The publication will present the structure of the work and preliminary results of the project

The HyMethShip Project. Innovative Emission Free Propulsion for Ships

The HyMethShip project (Hydrogen-Methanol Ship Propulsion Using On-board Pre-combustion Carbon Capture) is a cooperative R&D project funded by the European Union’s Horizon 2020 research and innovation programme.The project aims to drastically reduce emissions while improving the efficiency of waterborne transport. The HyMethShip system will achieve a reduction in CO2 of more than 97% and practically eliminate SOx and PM emissions. NOx emissions will fall by over 80%. below the IMO Tier III limit. The energy efficiency of the HyMethShip system is expected to be more than 45% greater than the best available technology (renewable methanol as the fuel coupled with conventional post-combustion carbon capturing).The HyMethShip system innovatively combines a membrane reactor, a CO2 capture system, a storage system for CO2 and methanol as well as a hydrogen-fueled combustion engine into one system. Methanol is reformed to hydrogen, which is then burned in a conventional reciprocating engine that has been upgraded to burn multiple fuel types and specially optimized for hydrogen use. The basic engine type is the same as the one currently used on the majority of ships. This project will develop this system further and integrate it into shipboard installations. The system will be developed, validated, and demonstrated on-shore on an engine in the range of 1 to 2 MW.The project started in 2018 and will run for 3 years. The work is structured into 11 work packages that deal with the pre-combustion carbon capture system and the internal combustion engine as well as assess safety, economic and environmental factors and system integration. The consortium consists of 13 partners including a globally operating shipping company, a major shipyard, a ship classification society, research institutes and universities and equipment manufacturers.The publication will present the structure of the work and preliminary results of the project