The formation of the hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) of amyloid β (1-40) (Aβ(1-40)) is known to be an important step in the fibrillation of Aβ(1-40) peptides. Mutations of this putatively early molecular contact were shown to strongly influence the toxicity of Aβ(1-40) ( Das et al. ( 2015 ) ACS Chem. Neurosci. 6 , 1290 - 1295 ). Any mutation of residue F19 completely abolished the toxicity of Aβ(1-40), suggesting that a proper F19-L34 contact is crucial also for the formation of transient oligomers. In this work, we investigate a series of isomeric substitutions of L34, namely, d-leucine, isoleucine, and valine, to study further details of this molecular contact. These replacements represent very minor alterations in the Aβ(1-40) structure posing the question how these alterations challenge the fibrillation kinetics, structure, dynamics, and toxicity of the Aβ(1-40) aggregates. Our work involves kinetic studies using thioflavin T, transmission electron microscopy, X-ray diffraction for the analysis of the fibril morphology, and nuclear magnetic resonance experiments for local structure and molecular dynamics investigations. Combined with cell toxicity assays of the mutated Aβ(1-40) peptides, the physicochemical and biological importance of the early folding contact between F19 and L34 in Aβ(1-40) is underlined. This implies that the F19-L34 contact influences a broad range of different processes including the initiation of fibrillation, oligomer stability, fibril elongation, local fibril structure, and dynamics and cellular toxicity. These processes do not only cover a broad range of diverse mechanisms, but also proved to be highly sensitive to minor modulations of this crucial contact. Furthermore, our work shows that the contact is not simply mediated by general hydrophobic interactions, but also depends on stereospecific mechanisms.

Protein-protein interactions involving proteins with multiple globular domains present technical challenges for determining how such complexes form and how the domains are oriented/positioned. Here, a protocol with the potential for elucidating which specific domains mediate interactions in multicomponent system through ab initio modeling is described. A method for calculating solution structures of macromolecules and their assemblies is provided that involves integrating data from small angle X-ray scattering (SAXS), chromatography, and atomic resolution structures together in a hybrid approach. A specific example is that of the complex of full-length nidogen-1, which assembles extracellular matrix proteins and forms an extended, curved nanostructure. One of its globular domains attaches to laminin γ-1, which structures the basement membrane. This provides a basis for determining accurate structures of flexible multidomain protein complexes and is enabled by synchrotron sources coupled with automation robotics and size exclusion chromatography systems. This combination allows rapid analysis in which multiple oligomeric states are separated just prior to SAXS data collection. The analysis yields information on the radius of gyration, particle dimension, molecular shape and interdomain pairing. The protocol for generating 3D models of complexes by fitting high-resolution structures of the component proteins is also given.

Summary This systematic review and meta‐analysis evaluates metabolic and anthropometric outcomes of duodenal–jejunal bypass liners (DJBLs) compared to optimal medical management for the treatment of obesity and its associated metabolic complications. A systematic search of MEDLINE, Embase, Scopus, and Web of Science databases was conducted. Studies were reviewed and data were extracted following the PRISMA guidelines. The primary outcome was glycated hemoglobin (HbA1c) change at device explant with secondary outcomes including body mass index (BMI), weight, fasting plasma glucose (FPG), and adverse events. Twenty‐eight studies met inclusion criteria evaluating a total of 1229 patients undergoing DJBL treatment. When compared to medical management, DJBLs provided superior reductions in HbA1c (mean difference, MD −0.96%; 95% CI −1.43, −0.49; p < 0.0001), FPG (MD −1.76 mmol/L; 95% CI −2.80, −0.72; p = 0.0009), BMI (MD −2.80 kg/m2; 95% CI −4.18, −1.41; p < 0.0001), and weight (MD −5.45 kg; 95% CI −9.80, −1.09, p = 0.01). Post‐explant data reveals a gradual return to baseline status. Incidence of early device explant was 20.2%. Complications were resolved conservatively or with device explant without long‐term morbidity or mortality. We conclude that DJBLs provide significant metabolic and anthropometric improvements for patients with obesity. Uncertainty about the extent to which improvements are maintained after device removal may limit the use of DJBLs as a standalone treatment for obesity and associated metabolic complications.

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Mucous membrane plasmacytosis (MMP) is rare condition characterized by diffuse plasma cell infiltration of upper aerodigestive tract mucosa. It results in epithelial hyperplasia that has a classic papillary appearance. We describe a case of MMP primarily affect laryngeal and oropharyngeal mucosa resulting in progressive airway obstruction. We highlight airway management and histopathology. The patient had near complete clinical response with inhaled budesonide, which has not yet been described as a treatment option in the literature.