Protein processing characterized by a gel-free proteomics approach

We describe a method for the specific isolation of representative N-terminal peptides of proteins and their proteolytic fragments. Their isolation is based on a gel-free, peptidecentric proteomics approach using the principle of diagonal chromatography. We will indicate that the introduction of an altered chemical property to internal peptides holding a free α-N-terminus results in altered column retention of these peptides, thereby enabling the isolation and further characterization by mass spectrometry of N-terminal peptides. Besides pointing to changes in protein expression levels when performing such proteome surveys in a differential modus, protease specificity and substrate repertoires can be allocated since both are specified by neo-N-termini generated after a protease cleavage event. As such, our gel-free proteomics technology is widely applicable and amenable for a variety of proteome-driven protease degradomics research

The effect of climate type on timescales of drought propagation in an ensemble of global hydrological models

Drought is a natural hazard that occurs at many temporal and spatial scales and has severe environmental and socioeconomic impacts across the globe. The impacts of drought change as drought evolves from precipitation deficits to deficits in soil moisture or streamflow. Here, we quantified the time taken for drought to propagate from meteorological drought to soil moisture drought and from meteorological drought to hydrological drought. We did this by cross-correlating the Standardized Precipitation Index (SPI) against standardized indices (SIs) of soil moisture, runoff, and streamflow from an ensemble of global hydrological models (GHMs) forced by a consistent meteorological dataset. Drought propagation is strongly related to climate types, occurring at sub-seasonal timescales in tropical climates and at up to multi-annual timescales in continental and arid climates. Winter droughts are usually related to longer SPI accumulation periods than summer droughts, especially in continental and tropical savanna climates. The difference between the seasons is likely due to winter snow cover in the former and distinct wet and dry seasons in the latter. Model structure appears to play an important role in model variability, as drought propagation to soil moisture drought is slower in land surface models (LSMs) than in global hydrological models, but propagation to hydrological drought is faster in land surface models than in global hydrological models. The propagation time from SPI to hydrological drought in the models was evaluated against observed data at 127 in situ streamflow stations. On average, errors between observed and modeled drought propagation timescales are small and the model ensemble mean is preferred over the use of a single model. Nevertheless, there is ample opportunity for improvement as substantial differences in drought propagation are found at 10% of the study sites. A better understanding and representation of drought propagation in models may help improve seasonal drought forecasting as well as constrain drought variability under future climate scenarios

Immundefekte bei chronischer Rhinosinusitis : eine bedeutende und oft unterschätzte Ursache

Background Chronic rhinosinusitis (CRS) is one of the most frequent chronic diseases. Among these patients the prevalence of immune defects is higher than in the healthy general population. Methods A selective review of the literature was carried out in PubMed and Medline covering the period between 2008 and 2019. Additionally, recent German publications in journals not listed in the abovementioned databases were analyzed. Results The diagnostic workflow with respect to the immunodeficiency consists of a detailed anamnesis and physical examination, laboratory tests and the antibody reaction to polysaccharide vaccines and antigens. Beside antibiotic treatment, vaccinations and immunoglobulin replacement are available. Notwithstanding the above, functional endoscopic surgery of the paranasal sinuses should be performed according to guideline recommendations. Conclusion Patients with CRS who do not sufficiently respond to conservative and surgical treatment should be checked for underlying immunodeficiencies

The effect of climate type on timescales of drought propagation in an ensemble of global hydrological models

Drought is a natural hazard that occurs at many temporal and spatial scales and has severe environmental and socioeconomic impacts across the globe. The impacts of drought change as drought evolves from precipitation deficits to deficits in soil moisture or streamflow. Here, we quantified the time taken for drought to propagate from meteorological drought to soil moisture drought and from meteorological drought to hydrological drought. We did this by cross-correlating the Standardized Precipitation Index (SPI) against standardized indices (SIs) of soil moisture, runoff, and streamflow from an ensemble of global hydrological models (GHMs) forced by a consistent meteorological dataset. Drought propagation is strongly related to climate types, occurring at sub-seasonal timescales in tropical climates and at up to multi-annual timescales in continental and arid climates. Winter droughts are usually related to longer SPI accumulation periods than summer droughts, especially in continental and tropical savanna climates. The difference between the seasons is likely due to winter snow cover in the former and distinct wet and dry seasons in the latter. Model structure appears to play an important role in model variability, as drought propagation to soil moisture drought is slower in land surface models (LSMs) than in global hydrological models, but propagation to hydrological drought is faster in land surface models than in global hydrological models. The propagation time from SPI to hydrological drought in the models was evaluated against observed data at 127 in situ streamflow stations. On average, errors between observed and modeled drought propagation timescales are small and the model ensemble mean is preferred over the use of a single model. Nevertheless, there is ample opportunity for improvement as substantial differences in drought propagation are found at 10&thinsp;% of the study sites. A better understanding and representation of drought propagation in models may help improve seasonal drought forecasting as well as constrain drought variability under future climate scenarios.</p

Synaptotagmin 5 regulates Ca2+-dependent Weibel-Palade body exocytosis in human endothelial cells.

Membrane protein insertion is an essential cellular process. The broad biophysical and topological range of membrane proteins necessitates multiple insertion pathways, which remain incompletely defined. Here, we have discovered a new membrane protein insertion pathway, identified the class of substrates it handles, explained why other known pathways do not work for these substrates and reconstituted the pathway using purified components

Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau

Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer's disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer's disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau

Early targets of miR-34a in neuroblastoma

Several genes encoding for proteins involved in proliferation, invasion, and apoptosis are known to be direct miR-34a targets. Here, we used proteomics to screen for targets of miR-34a in neuroblastoma (NBL), a childhood cancer that originates from precursor cells of the sympathetic nervous system. We examined the effect of miR-34a overexpression using a tetracycline inducible system in two NBL cell lines (SHEP and SH-SY5Y) at early time points of expression (6, 12, and 24 h). Proteome analysis using post-metabolic labeling led to the identification of 2,082 proteins, and among these 186 were regulated (112 proteins down-regulated and 74 up-regulated). Prediction of miR-34a targets via bioinformatics showed that 32 transcripts held miR-34a seed sequences in their 3′-UTR. By combining the proteomics data with Kaplan Meier geneexpression studies, we identified seven new gene products (ALG13, TIMM13, TGM2, ABCF2, CTCF, Ki67, and LYAR) that were correlated with worse clinical outcomes. These were further validated in vitro by 3′-UTR seed sequence regulation. In addition, Michigan Molecular Interactions searches indicated that together these proteins affect signaling pathways that regulate cell cycle and proliferation, focal adhesions, and other cellular properties that overall enhance tumor progression (including signaling pathways such as TGF-β, WNT, MAPK, and FAK). In conclusion, proteome analysis has here identified early targets of miR-34a with relevance to NBL tumorigenesis. Along with the results of previous studies, our data strongly suggest miR-34a as a useful tool for improving the chance of therapeutic success with NBL

Annual phytoplankton succession results from niche-environment interaction

Annual plankton succession has been investigated for many decades and hypotheses ranging from abiotic to biotic mechanisms have been proposed to explain this recurrent pattern. Here, using data collected by the Continuous Plankton Recorder (CPR) survey and models originating from the MacroEcological Theory on the Arrangement of Life (METAL), we investigate annual phytoplankton succession in the North Sea at a species level. Our results show that this phenomenon can be well predicted by models combining photosynthetically active radiation, temperature and macro-nutrients. Our findings suggest that annual phytoplankton succession, at community level, originates from the interaction between species ecological niche and annual environmental fluctuations. We discuss our results in the context of traditional hypotheses formulated to explain this recurrent pattern in the marine field, including those on the initiation, the development and the termination of a typical extratropical spring bloom