Urinary exosome-like vesicles (ELVs) are a heterogenous mixture (diameter 40–200nm) containing vesicles shed from all segments of the nephron including glomerular podocytes. Contamination with ...Tamm–Horsfall protein (THP) oligomers has hampered their isolation and proteomic analysis. Here we improved ELV isolation protocols employing density centrifugation to remove THP and albumin, and isolated a glomerular membranous vesicle (GMV)–enriched subfraction from 7 individuals identifying 1830 proteins and in 3 patients with glomerular disease identifying 5657 unique proteins. The GMV fraction was composed of podocin/podocalyxin-positive irregularly shaped membranous vesicles and podocin/podocalyxin-negative classical exosomes. Ingenuity pathway analysis identified integrin, actin cytoskeleton, and Rho GDI signaling in the top three canonical represented signaling pathways and 19 other proteins associated with inherited glomerular diseases. The GMVs are of podocyte origin and the density gradient technique allowed isolation in a reproducible manner. We show many nephrotic syndrome proteins, proteases, and complement proteins involved in glomerular disease are in GMVs and some were only shed in the disease state (nephrin, TRPC6, INF2 and phospholipase A2 receptor). We calculated sample sizes required to identify new glomerular disease biomarkers, expand the ELV proteome, and provide a reference proteome in a database that may prove useful in the search for biomarkers of glomerular disease.
Background:
In the United Kingdom, around 184,000 adults are admitted to an intensive care unit (ICU) each year with over 30% receiving mechanical ventilation. Oxygen is the commonest therapeutic ...intervention provided to these patients but it is unclear how much oxygen should be administered for the best clinical outcomes.
Methods:
The UK-ROX trial will evaluate the clinical and cost-effectiveness of conservative oxygen therapy (the minimum oxygen concentration required to maintain an oxygen saturation of 90% ± 2%) versus usual oxygen therapy in critically ill adults receiving supplemental oxygen when invasively mechanically ventilated in ICUs in England, Wales and Northern Ireland. The trial will recruit 16,500 patients from approximately 100 UK adult ICUs. Using a deferred consent model, enrolled participants will be randomly allocated (1:1) to conservative or usual oxygen therapy until ICU discharge or 90 days after randomisation.
Objectives:
The primary clinical outcome is all cause mortality at 90 days following randomisation.
Discussion:
The UK-ROX trial has received ethical approval from the South Central – Oxford C Research Ethics Committee (Reference: 20/SC/0423) and the Confidentiality Advisory Group (Reference: 22/CAG/0154). The trial commenced in May 2021 and, at the time of publication, 95 sites had opened to recruitment.
Drosophila neuroblasts are a model system for studying stem cell self-renewal and the establishment of cortical polarity. Larval neuroblasts generate a large apical self-renewing neuroblast, and a ...small basal cell that differentiates. We performed a genetic screen to identify regulators of neuroblast self-renewal, and identified a mutation in sgt1 (suppressor-of-G2-allele-of-skp1) that had fewer neuroblasts. We found that sgt1 neuroblasts have two polarity phenotypes: failure to establish apical cortical polarity at prophase, and lack of cortical Scribble localization throughout the cell cycle. Apical cortical polarity was partially restored at metaphase by a microtubule-induced cortical polarity pathway. Double mutants lacking Sgt1 and Pins (a microtubule-induced polarity pathway component) resulted in neuroblasts without detectable cortical polarity and formation of “neuroblast tumors.” Mutants in hsp83 (encoding the predicted Sgt1-binding protein Hsp90), LKB1, or AMPKα all show similar prophase apical cortical polarity defects (but no Scribble phenotype), and activated AMPKα rescued the sgt1 mutant phenotype. We propose that an Sgt1/Hsp90–LKB1–AMPK pathway acts redundantly with a microtubule-induced polarity pathway to generate neuroblast cortical polarity, and the absence of neuroblast cortical polarity can produce neuroblast tumors.
► We used a novel sequence-capture genomic method to identify sgt1. ► Sgt1 is required for Bazooka localization in neuroblasts. ► Sgt1 is required for Scribble localization in neuroblasts. ► Sgt1 acts at the top of an Hsp90–LKB1–AMPK polarity pathway.
Airborne measurements from the Meteorological Research Flight's Hercules C-130 and the University of Washington's Convair C-131 A during the Monterey Area Ship Track field project are used to ...evaluate Twomey's analytic expression for cloud susceptibility, which describes the sensitivity of cloud albedo to changes in droplet concentrations. This expression incorporates assumptions about cloud physics, such as the independence of the cloud liquid water content and the width of the droplet size distribution on droplet concentrations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•High resolution infrared Fourier transform spectroscopy.•Absorption cross sections of n-butane, n-pentane, cyclopentane and cyclohexane.•For remote sensing in planetary atmospheres.
The infrared ...absorption cross sections of pure n-butane, n-pentane, cyclopentane and cyclohexane have been measured in the 3.3 µm region (and 6.8 µm region for cyclopentane) by high resolution Fourier transform spectroscopy. The samples had temperatures of 294 K and 230 K for n-butane, 294 K and 218 K for n-pentane, 296 K and 235 K for cyclopentane, and 294 K and 222 K for cyclohexane. These spectra are important for molecular identification in extraterrestrial environments such as Saturn's moon Titan, giant planets and exoplanets. All spectra are provided as data point files.
Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular ...signaling pathways, structure−activity studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortmannin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17β-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.
One of the primary aims of the North Atlantic regional Aerosol Characterisation Experiment (ACE‐2) was to quantify the physical and chemical processes affecting the evolution of the major aerosol ...types over the North Atlantic. The best, practical way of doing this is in a Lagrangian framework where a parcel of air is sampled over several tens of hours and its physical and chemical properties are intensively measured. During the intensive observational phase of ACE‐2, between 15 June 1997 and 24 July 1997, 3 cloudy Lagrangian experiments and 3 cloud‐free, Lagrangian experiments were undertaken between the south west tip of the Iberian Peninsula and the Canary Islands. This paper gives an overview of the aims and logistics of all of the Lagrangian experiments and compares and contrasts them to provide a framework for the more focused Lagrangian papers in this issue and future process modelling studies and parametrisation development. The characteristics of the cloudy Lagrangian experiments were remarkably different, enabling a wide range of different physical and chemical processes to be studied. In the 1st Lagrangian, a clean maritime air mass was sampled in which salt particle production, due to increased wind speed, dominated the change in the accumulation mode concentrations. In the 2nd Lagrangian, extensive cloud cover resulted in cloud processing of the aerosol in a polluted air mass, and entrainment of air from the free troposphere influenced the overall decrease in aerosol concentrations in the marine boundary layer (MBL). Very little change in aerosol characteristics was measured in the 3rd Lagrangian, where the pollution in the MBL was continually being topped up by entraining air from a residual continental boundary layer (CBL) above. From the analysis of all the Lagrangian experiments, it has been possible to formulate, and present here, a generalised description of a European continental outbreak of pollution over the sub‐tropical North Atlantic.
The effects of anthropogenic particulate emissions from ships on the radiative, microphysical, and chemical properties of moderately polluted marine stratiform clouds are examined. A case study of ...two ships in the same air mass is presented where one of the vessels caused a discernible ship track while the other did not.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A case study of the effects of ship emissions on the microphysical, radiative, and chemical properties of polluted marine boundary layer clouds is presented. Two ship tracks are discussed in detail. ...In situ measurements of cloud drop size distributions, liquid water content, and cloud radiative properties, as well as aerosol size distributions (outside-cloud, interstitial, and cloud droplet residual particles) and aerosol chemistry, are presented. These are related to remotely sensed measurements of cloud radiative properties.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During the 1st Lagrangian experiment of the North Atlantic Regional Aerosol Characterisation Experiment (ACE‐2), a parcel of air was tagged by releasing a smart, constant level balloon into it from ...the Research Vessel Vodyanitskiy. The Meteorological Research Flight's C‐130 aircraft then followed this parcel over a period of 30 h characterising the marine boundary layer (MBL), the cloud and the physical and chemical aerosol evolution. The air mass had originated over the northern North Atlantic and thus was clean and had low aerosol concentrations. At the beginning of the experiment the MBL was over 1500 m deep and made up of a surface mixed layer (SML) underlying a layer containing cloud beneath a subsidence inversion. Subsidence in the free troposphere caused the depth of the MBL to almost halve during the experiment and, after 26 h, the MBL became well mixed throughout its whole depth. Salt particle mass in the MBL increased as the surface wind speed increased from 8 m s−1 to 16 m s−1 and the accumulation mode (0.1μm to 3.0 μm) aerosol concentrations quadrupled from 50 cm−3 to 200 cm−3. However, at the same time the total condensation nuclei (>3 nm) decreased from over 1000 cm−3 to 750 cm−3. The changes in the accumulation mode aerosol concentrations had a significant effect on the observed cloud microphysics. Observational evidence suggests that the important processes in controlling the Aitken mode concentration which, dominated the total CN concentration, included, scavenging of interstitial aerosol by cloud droplets, enhanced coagulation of Aitken mode aerosol and accumulation mode aerosol due to the increased sea salt aerosol surface area, and dilution of the MBL by free tropospheric air.
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