Wie kleine Amyloid-β-Peptide zum großen Problem im Gehirn werden können

The formation of amyloid-β oligomers plays a key role in the onset of Alzheimer’s disease. We investigated the aggregation of amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing those structural properties, which lead to the formation of mature fibrils. We can show that the arrangement of the first oligomers is crucial for the topology of the resulting species, leading to the formation of non-toxic aggregates or fibrils

Improved Breaking Length Development of Unbleached Softwood Kraft Pulp in PFI Refining by Addition of Primary Fines

Nowadays the so called fines fraction is experiencing increasing interest for the papermaking society, as an essential component of any papermaking pulp. It shows distinctive properties affecting both production process and product properties to a large extent. Several research groups have experimented with either primary and/or secondary fines to assess their corresponding properties in the recent years. When it comes to the influence of primary fines on paper and process, these studies do not always show consistent results, attributed to different raw materials considered, to retention issues during sheet forming or maybe to formation issues arising at higher dosages. This work focuses on the clarification, how primary fines of unbleached softwood kraft pulp (Kappa number ~27) influence the product and process parameters, especially if the total fines amount is risen compared to the original stock. Primary fines are separated from the pulp using a laboratory pressure screen to be added again in controlled amounts afterwards. Thereby three pulp blends, showing a primary fines content of around 5%, 9% and 12% where prepared. These pulp blends were refined in a PFI mill at 1000, 4500 and 6000 revolutions and compared with the unbeaten reference. The refining treatment mainly resulted in fiber flexibilisation and internal fibrillation while barely any secondary fines were produced. Because retention of the fines material might be an issue, a Rapid-Köthen sheet former with white water recirculation was used. The results of paper testing show that the tensile index develops at lower specific refining energy when adding primary fines prior to refining due to increased densification of the sheets. The results also show increased dewatering resistance (Schopper-Riegler) at a given tensile index, while densification and air permeability (Gurley) are comparable. Considering the linear relationship between tensile index and sheet density – independent of the fines content – it can be concluded that fibre flexibilisation and primary fines both enhance fibre-fibre bonding and that both strategies result in the same increase in mechanical strength with the downside of slightly reduced dewatering in case of the introduction of primary fines.MoV4-(02) page 1MoV4-(02) page 55FFG - Österreichische Forschungsförderungs Gmb

Bacterial F-type ATP synthases follow a well-choreographed assembly pathway

F-type ATP synthases are multiprotein complexes composed of two separate coupled motors (F1 and FO) generating adenosine triphosphate (ATP) as the universal major energy source in a variety of relevant biological processes in mitochondria, bacteria and chloroplasts. While the structure of many ATPases is solved today, the precise assembly pathway of F1FO-ATP synthases is still largely unclear. Here, we probe the assembly of the F1 complex from Acetobacterium woodii. Using laser induced liquid bead ion desorption (LILBID) mass spectrometry, we study the self-assembly of purified F1 subunits in different environments under non-denaturing conditions. We report assembly requirements and identify important assembly intermediates in vitro and in cellula. Our data provide evidence that nucleotide binding is crucial for in vitro F1 assembly, whereas ATP hydrolysis appears to be less critical. We correlate our results with activity measurements and propose a model for the assembly pathway of a functional F1 complex

Direct C-H-Sulfonylation of 6-Membered Nitrogen-Heteroaromatics

Heterocyclic sulfones and sulfonamides represent important structural motives in medicinal chemistry and drug development. Therefore, efficient and reliable methods for their construction from simple building blocks are in high demand. Herein we report a novel approach for the direct C-H-sulfonylation of N heteroaromatics via N-activation with triflic anhydride (Tf2O), base-mediated addition of a sulfinate salt and subsequent rearomatization through trifluoromethanesulfinate elimination. This operationally simple one-pot protocol enables direct access to various sulfonylated 6-ring N-heterocycles. It is applicable to the late-stage functionalization of complex, drug-like molecules. The direct incorporation of sulfur dioxide with organometallic reagents as well as the utilization of a rongalite-based sulfonylation reagent provide opportunities for a highly modular synthesis of N-heterocyclic sulfones and sulfonamides from three different building blocks

Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer's disease related oligomers

The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular, we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here, we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers

Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation

MS Raw Data. Each MS raw spectrum was named, based on the used protein and the corresponding reaction. The assignment will be added shorty. Currently, the assignment can be provided by Philipp Hartmann ([email protected])

Author Correction: Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation

Hartmann P, Bohdan K, Hommrich M, et al. Author Correction: Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation. Nature chemistry. 2024

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia