A conceptual study of Hitler's development of the National Socialist democracy concept between 1919 and 1933 is presented. Despite the voluminous literature on Hitler and Nazism, our knowledge of the ...NS democracy concept is seriously incomplete. This article makes a substantial historiographical contribution by providing a more profound understanding of Hitler's NS democracy concept and his position in the broader Weimar debate on democracy. I argue that Hitler prioritized democracy as a core concept in NS ideology. Between 1920 and 1925, Hitler employed a Germanic democracy concept centred on a popularly elected Führer modelled in the reversed mirror image of his Jewish democracy concept. The allegedly Jewish interpretation of democracy was, according to Hitler's conspiracy theory, a precursor for the Jews to achieve a global dictatorship. Between 1925 and 1933 Hitler resettled for an anti-plebiscitary Volksherrschaft concept, abandoning his Germanic democracy, the election of the Führer, and elections per se. This new concept rested on a notion of a Volkswille, which purportedly accommodated a genuine will of the people that could not be expressed in plebiscites and was identical with Hitler's worldview. I contend that Hitler's changeover from Germanic democracy to Volksherrschaft contributed to a totalitarian turn in NS ideology.
Ubiquitin‐fold modifier 1 (UFM1) is a reversible post‐translational modifier that is covalently attached to target proteins through an enzymatic cascade and removed by designated proteases. ...Abnormalities in this process, referred to as Ufmylation, have been associated with a variety of human diseases. Given this, the UFM1‐specific enzymes represent potential therapeutic targets; however, understanding of their biological function has been hampered by the lack of chemical tools for activity profiling. To address this unmet need, a diversifiable platform for UFM1 activity‐based probes (ABPs) utilizing a native chemical ligation (NCL) strategy was developed, enabling the generation of a variety of tools to profile both UFM1 conjugating and deconjugating enzymes. The use of the probes is demonstrated in vitro and in vivo for monitoring UFM1 enzyme reactivity, opening new research avenues.
Introducing the UFM1 toolkit: A facile native chemical ligation strategy to enable the development of UFM1 reagents and activity‐based probes is presented. This toolkit permits the study of both UFM1‐specific proteases and conjugating enzymes in vitro and in cells, thereby opening new research avenues for the discovery of specific UFM1 inhibitors.
The development of recognition molecules with antibody-like properties is of great value to the biotechnological and bioanalytical communities. The recognition molecules presented here are peptides ...with a strong tendency to form β-hairpin structures, stabilized by alternate threonines, which are located at one face of the peptide. Amino acids at the other face of the peptide are available for interaction with the target molecule. Using this scaffold, we demonstrate that recognition molecules can efficiently be designed in silico toward four structurally unrelated proteins, GFP, IL-1β, IL-2, and IL-6. On solid support, 10 different antibody-mimetic recognition molecules were synthesized. They displayed high affinity and no cross-reactivity, as observed by fluorescence microscopy. Stabilized variants were readily obtained by incorporation of azido acids and propargylglycine followed by cyclization via the Cu(I)-catalyzed alkyne–azide cycloaddition reaction. As this new class of antibody mimics can be designed toward essentially any protein, the concept is believed to be useful to a wide range of technologies. Here, their use in protein separation and in the detection of proteins in a sandwich-type assay is demonstrated.
Fluorobenzene probes for protein profiling through selective cysteine labeling have been developed by rational reactivity tuning. Tuning was achieved by selecting an electron‐withdrawing para ...substituent in combination with variation of the number of fluorine substituents. Optimized probes chemoselectively arylated cysteine residues in proteins under aqueous conditions. Probes linked to azide, biotin, or a fluorophore were applicable to labeling of eGFP and albumin. Selective inhibition of cysteine proteases was also demonstrated with the probes. Additionally, probes were tuned for site‐selective labeling of cysteine residues and for activity‐based protein profiling in cell lysates.
Tuning in to cysteine: The reactivity of chemical probes for selective cysteine S‐arylation in proteins was tuned in a two‐dimensional fashion according to the number of fluorine substituents (see scheme) and the nature of an additional substituent. The optimized probes were suitable for protein labeling, the selective inhibition of cysteine proteases, and activity‐based protein profiling in cell lysates.
The incorporation of clickable noncanonical amino acids (ncAAs) has proven to an invaluable tool in chemical biology and protein science research. Nevertheless, the number of examples in which the ...method is used for preparative purposes is extremely limited. We report the synthesis of an active enzyme by quantitative, Cu(I)-catalyzed ligation of two inactive protein halves, expressed and equipped with an azide and alkyne moiety, respectively, through ncAA incorporation. The reported quantitative conversion is exceptional given the large size of the protein fragments and the fact that no linker or excess of either of the polypeptides was used. The triazole bridge formed between the ncAA side chains was shown to effectively mimic a natural protein loop, providing an enzyme with the same activity as its natural counterpart. We envision that this strategy, termed split-click protein chemistry, can be used for the production of proteins that are difficult to express as full-length entities. It also paves the way for the design of new proteins with tailor-made functionalities.
Complications to oesophageal and junctional cancer surgery are common and have not diminished much during the past ten years. An unusually high occurrence of anastomotic dehiscence occurred in ...Denmark in 2009 and 2010 as seen in the national database for oesophagus, cardiac and gastric (ECV) cancer.
In accordance with national guidelines, all patients resected for oesophageal and junctional cancer in Denmark from 2003 were prospectively entered into a national database. Data concerning anaesthesia, peri- and post-operative course, complications, re-operations and time spent in intensive care unit were obtained retrospectively from hospital records. An in-depth analysis of data from two high-volume centres performing ECV cancer surgery according to national guidelines was performed.
A total of 881 patients (Centre 1: 438; Centre 2: 443) were resected for oesophageal and junctional cancer. A total of 79 patients with anastomotic insufficiency (AI) were detected (Centre 1: 36; Centre 2: 43). By using a grading system, it was shown that AI was more severe and occurred earlier in one centre than in the other. Possible factors of influence are discussed, including neoadjuvant oncological therapy, use of thoracoscopically performed anastomosis and perioperative inotrophic drugs.
Thanks to the establishment of a nationwide database in pursuance of national guidelines, it was possible to detect variations in quality of surgery over time, evaluate serious complications early and undertake an in-depth analysis of possible aetiological factors. Particularly, comparison was facilitated by the use of a standardised grading system for complications.
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Site‐selective cysteine arylation has been achieved by rational 2D reactivity tuning of fluorobenzene probes. In their Communication on page 8022 ff., M. Meldal, F. Diness et al. demonstrate how ...probes may be tailored to selectively target cysteine‐containing proteins by adjusting the numbers of fluoro substituents (Fx) and by selecting substituents based on their electron‐withdrawing capacity represented by their Hammett σp constant.
•Nanofibrillated cellulose induced acute phase response and pulmonary inflammation.•Carboxylated nanofibrillated cellulose induced significantly lower responses.•Increased DNA damage levels were ...observed across doses and time points.•Pulmonary dosed nanofibrillated cellulose was observed in lung 28 days post-exposure.
We studied if the pulmonary and systemic toxicity of nanofibrillated celluloses can be reduced by carboxylation. Nanofibrillated celluloses administered at 6 or 18 μg to mice by intratracheal instillation were: 1) FINE NFC, 2–20 μm in length, 2–15 nm in width, 2) AS (−COOH), carboxylated, 0.5–10 μm in length, 4–10 nm in width, containing the biocide BIM MC4901 and 3) BIOCID FINE NFC: as (1) but containing BIM MC4901. FINE NFC administration increased neutrophil influx in BAL and induced SAA3 in plasma. AS (−COOH) produced lower neutrophil influx and systemic SAA3 levels than FINE NFC. Results obtained with BIOCID FINE NFC suggested that BIM MC4901 biocide did not explain the lowered response. Increased DNA damage levels were observed across materials, doses and time points. In conclusion, carboxylation of nanofibrillated cellulose was associated with reduced pulmonary and systemic toxicity, suggesting involvement of OH groups in the inflammatory and acute phase responses.
Chemical modification of proteins has numerous applications, but it has been challenging to achieve the required high degree of selectivity on lysine amino groups. Recently, we described the highly ...selective acylation of proteins with an N‐terminal Gly‐His6 segment. This tag promoted acylation of the N‐terminal Nα‐amine resulting in stable conjugates. Herein, we report the peptide sequences Hisn‐Lys‐Hism, which we term Lys‐His tags. In combination with simple acylating agents, they facilitate the acylation of the designated Lys Nϵ‐amine under mild conditions and with high selectivity over native Lys residues. We show that the Lys‐His tags, which are 7 to 10 amino acids in length and still act as conventional His tags, can be inserted in proteins at the C‐terminus or in loops, thus providing high flexibility regarding the site of modification. Finally, the selective and efficient acylation of the therapeutic antibody Rituximab, pure or mixed with other proteins, demonstrates the scope of the Lys‐His tag acylation method.
A short, designed Lys‐His tag can be inserted into proteins where it autocatalyzes the highly selective acylation of the Lys side‐chain amine with phenyl esters. The reaction conditions of this site‐selective, chemical protein modification method are mild, and no oxidative reagents, reductants nor enzymes are required.
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