We describe the synthesis of a series of sialic acid‐conjugated, polyglycerol‐based nanoparticles with diameters in the range of 1–100 nm. Particle sizes were varied along with the degree of ...functionalization to match the corresponding virus size and receptor multiplicity in order to achieve maximum efficiency. To build up these architectures, we used biocompatible, hyperbranched polyglycerols as scaffolds and recently developed polyglycerol‐based nanogels, the sizes of which can be varied between 2–4 nm and 40–100 nm, respectively. We demonstrate here that such multivalent nanoparticles inhibit influenza A virus cell binding and fusion and consequently infectivity. The potential of multivalency is evident from larger particles showing very efficient inhibition of viral infection up to 80 %. Indeed, both the size of the nanoparticle and the amount of ligand density are important determinants of inhibition efficiency. The inhibitory activity of the tested polymeric nanoparticles drastically increased with size. Particles with similar dimensions to the virus (50–100 nm) are exceedingly effective. We also observed a saturation point in degree of surface functionalization (i.e. ligand density), above which inhibition was not significantly improved. Our study emphasizes the importance of matching particle sizes and ligand densities to mimic biological surfaces and improve interactions; this is a vital concept underlying multivalent interactions.
Polyglycerol nanoparticles of diameter 50–70 nm were coated with sialic acid residues to afford excellent inhibitors of influenza virus binding and fusion, and hence infectivity of erythrocytes. This approach highlights the versatility and potential of a growing class of biocompatible, branched, polyether nanogels that benefit from a highly functionalizable, hydrophilic surface.
Hundreds of missense mutations in the coding region of PDX1 exist; however, if these mutations predispose to diabetes mellitus is unknown.
In this study, we screened a large cohort of subjects with ...increased risk for diabetes and identified two subjects with impaired glucose tolerance carrying common, heterozygous, missense mutations in the PDX1 coding region leading to single amino acid exchanges (P33T, C18R) in its transactivation domain. We generated iPSCs from patients with heterozygous PDX1P33T/+, PDX1C18R/+ mutations and engineered isogenic cell lines carrying homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations and a heterozygous PDX1 loss-of-function mutation (PDX1+/−).
Using an in vitro β-cell differentiation protocol, we demonstrated that both, heterozygous PDX1P33T/+, PDX1C18R/+ and homozygous PDX1P33T/P33T, PDX1C18R/C18R mutations impair β-cell differentiation and function. Furthermore, PDX1+/− and PDX1P33T/P33T mutations reduced differentiation efficiency of pancreatic progenitors (PPs), due to downregulation of PDX1-bound genes, including transcription factors MNX1 and PDX1 as well as insulin resistance gene CES1. Additionally, both PDX1P33T/+ and PDX1P33T/P33T mutations in PPs reduced the expression of PDX1-bound genes including the long-noncoding RNA, MEG3 and the imprinted gene NNAT, both involved in insulin synthesis and secretion.
Our results reveal mechanistic details of how common coding mutations in PDX1 impair human pancreatic endocrine lineage formation and β-cell function and contribute to the predisposition for diabetes.
•Missense mutations in the transactivation domain reduce PDX1 target gene expression.•Lack of PDX1 target gene activation impairs both β-cell development and function.•Common PDX1 coding mutations likely predispose for diabetes.
Abstract In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only ...tolypin, a mixture of closely related 16‐residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization by ultrahigh performance liquid chromatography coupled to high‐resolution mass spectrometry (UHPLC‐HR‐MS/MS) and ultrahigh performance liquid chromatography coupled to in‐source collision‐induced dissociation tandem mass spectrometry (UHPLC‐isCID‐HR‐MS/MS), revealing 12 partially co‐eluting individual peptides that were fully sequenced. Since tolypin‐related efrapeptins are potent inhibitors of F 1 /F o ‐ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella . We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4–5 log values, and that of an H3N2 strain by 1–2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella , supporting the inhibition of F 1 /F o ‐ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.
The copper electrochemical deposition (Cu-ECD) filling capability of high aspect ratio through silicon vias (HAR-TSVs) and homogeneity over 300 mm wafers were investigated on a film stack of thermal ...ALD (thALD) TaxNy barrier with thermal ALD Ru seed in comparison to TixNy barrier with a standard Cu i-PVD seed layer using a commercial 300 mm plating tool. As a first step, Cu-ECD was conducted on wafers with TSV blind holes with aspect ratios (AR) of 10 to 12. To achieve this, a thermal ALD film stack of approximately 6 nm TaxNy and 9 nm Ru (with a sheet resistance of 25.6 ± 1.4 Ω/ϒ) were deposited at 250 °C. The reactants for the barrier layer were (tert-butylimido)tris(diethylamino)tantalum(V) (TBTDET) and ammonia (NH3) as co-reactant. For the Ru seed layer deposition (ethylcyclopentadienyl)(pyrrolyl)ruthenium(II) (ECPR) and molecular oxygen as co-reactant were used supplemented by a hydrogen purge step after every third ALD cycle. The corresponding ALD growth was observed during the entire process by in-situ real-time spectroscopic ellipsometry (irtSE). Blister-free deposition and satisfactory film stack adhesion with no delamination was verified ex situ by scanning electron microscopy (SEM). The deposited copper inside the TSVs was analyzed by focused ion beam (FIB) imaging and X-ray tomography.
The Cu ECD filling capability in HAR-TSVs was shown on a film stack of thALD TaxNy thALD Ru seed using a commercial industry standard 300 mm plating tool. A novel blister-free ultra-thin Ru ALD film having good adhesion properties and unique advantages, e. g. high conformity in high-aspect-ratio through-silicon vias large-scale film uniformity over 300 mm wafers, as well as good reproducibility was developed.
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•We show a low temperature ultra-thin TaxNy-barrier and Ru-seed films by thermal ALD for high aspect ratio TSVs•A H2 purge between the ALD cycles prevent blister formation and guarantee good properties of the TaxNy |Ru film stack•TaxNy | Ru ultra thin (<10 nm) interface is uniformly, controllable, reproducible & reliable on 300 mm wafer level•ECD in high aspect ratio TSV after barrier/seed layer deposition by ALD on a commercial 300 mm AMAT Raider-S plating tool.
•Preoperative anemia is a negative predictor on survival and recurrence in OSCC.•Same for perioperative red blood cell transfusion (RBT) in a dose-dependent manner.•Unfavourable effects are mainly ...seen in perioperative RBT of non-anemic patients.•Transfusion strategy should be adapted depending on anemia status in OSCC patients.
To evaluate the prognostic effect of allogenic red blood cell transfusion (RBT) and preoperative anemia in patients with oral squamous cell carcinoma (OSCC) undergoing primary tumor resection.
We retrospectively analyzed a cohort of 621 patients, diagnosed with OSCC receiving tumor resection in curative intention. Preoperative anemia and perioperative RBT were evaluated according to WHO definition. Overall survival (OAS) as well as recurrence-free survival (RFS) was evaluated in transfused and non-transfused as well as in anemic and non-anemic patients. In addition, outcome parameters were calculated for distinct amounts of perioperatively administered RBTs. Data analysis was performed by uni- and multivariate statistics. Mean follow-up time was 7.3 years.
Preoperative anemia was diagnosed in 29% of OSCC patients. Anemic patients displayed a significantly decreased five-year OAS (44%) in comparison to non-anemic equivalents (69%). 70% of non-transfused OSCC patients were alive after five years, whereas in case of RBT five-year OAS was 41%. These findings were substantiated by subgroup analysis in patients without preoperative anemia. For anemic patients however, no deleterious effect on survival in case of perioperative RBT was seen. Increasing numbers of received RBTs were shown to worsen outcome of OSCC patients in a dose-dependent manner.
Preoperative anemia and RBT are significantly associated with impaired long-term outcome of patients suffering from OSCC. Future studies are needed to evaluate differentiated effects of RBTs in anemic and non-anemic OSCC patients and accordingly providing individual transfusion strategies to ameliorate outcome of patients suffering from OSCC.
Interactions between graphene, with its wide deployment in consumer products, and skin, the body's largest organ and first barrier, are highly relevant with respect to toxicology and dermal delivery. ...In this work, interaction of polyglycerol-functionalized graphene sheets, with 200 nm average lateral size and different surface charges, and human skin was studied and their potential as topical delivery systems were investigated. While neutral graphene sheets showed no significant skin interaction, their positively and negatively charged counterparts interacted with the skin, remaining in the stratum corneum. This efficient skin interaction bears a warning but also suggests a new topical drug delivery strategy based on the sheets' high loading capacity and photothermal property. Therefore, the immunosuppressive drug tacrolimus was loaded onto positively and negatively charged graphene sheets, and its release measured with and without laser irradiation using liquid chromatography tandem-mass spectrometry. Laser irradiation accelerated the release of tacrolimus, due to the photothermal property of graphene sheets. In addition, graphene sheets with positive and negative surface charges were loaded with Nile red, and their ability to deliver this cargo through the skin was investigated. Graphene sheets with positive surface charge were more efficient than the negatively charged ones in enhancing Nile red penetration into the skin.
Positively and negatively charged graphene sheets interacted with human skin and enhanced penetration of Nile red-loaded into the epidermal and dermal layers of the skin. Moreover, graphene's cargo was released more efficiently into the skin layers after laser exposure.
Abstract Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and ...impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
► New methodologies enable real-time geogas monitoring in Tau Tona gold mine. ► Geogas transport through an inactive fault system in 3.54
km depth was observed. ► CO
2, CH
4, He, and H
2 variations ...correlate with mining seismicity. ► Time series and data analysis identify two processes influencing gas composition. ► Monitoring system sensitive enough to quantify earthquake induced fluid transport.
An on-site gas monitoring study has been conducted in the framework of an earthquake laboratory (The International NELSAM–DAFGAS projects) at the TauTona gold mine, South Africa. Five boreholes up to 60
m long were drilled at 3.54
km depth into the highly fractured Pretorius Fault Zone and instruments for chemical and seismic monitoring installed therein. Over the span of 4
years sensitive gas monitoring devices were continuously improved to enable the direct observation of geogas concentration variations in the DAFGAS borehole. The major gas concentrations are constant and air-like with about 78% N
2, 21% O
2, 1% Ar. The geogas components CO
2, CH
4, He and H
2 show the most interesting trends and variations on the minute-by-minute basis and significantly correlate with seismic data, while the
222Rn activity remains constant. Time series and cross correlation analysis allow the identification of different gas components (geogas and tunnel air) and the identification of two processes influencing the borehole gas composition: (1) pumping-induced tunnel air breakthrough through networks of initially water-saturated fault fractures; and (2) seismicity induced permeability enhancement of fault fractures to above ∼5
×
10
-10
m
2. The current set-up of the gas monitoring system is sensitive enough to quantify the resulting geogas transport during periods of intense blasting activities (including recorded blasts with seismic moment ⩽1
×
10
9
Nm, located within 1000
m of the cubby) and, it is suggested, also during induced earthquakes, a final goal of the project.
This article presents and analyses the modular architecture and capabilities of CODE-DE (Copernicus Data and Exploitation Platform - Deutschland,
www.code-de.org
), the integrated German operational ...environment for accessing and processing Copernicus data and products, as well as the methodology to establish and operate the system. Since March 2017, CODE-DE has been online with access to Sentinel-1 and Sentinel-2 data, to Sentinel-3 data shortly after this time, and since March 2019 with access to Sentinel-5P data. These products are available and accessed by 1,682 registered users as of March 2019. During this period 654,895 products were downloaded and a global catalogue was continuously updated, featuring a data volume of 814 TByte based on a rolling archive concept supported by a reload mechanism from a long-term archive. Since November 2017, the element for big data processing has been operational, where registered users can process and analyse data themselves specifically assisted by methods for value-added product generation. Utilizing 195,467 core and 696,406 memory hours, 982,948 products of different applications were fully automatically generated in the cloud environment and made available as of March 2019. Special features include an improved visualization of available Sentinel-2 products, which are presented within the catalogue client at full 10 m resolution.
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