Первичный умлаут в немецком языке (на материале древних текстов)

Статья из специализированного выпуска научного журнала "Культура народов Причерноморья", материалы которого объединены общей темой "Язык и Мир" и посвящены общим вопросам Языкознания и приурочены к 80-летию со дня рождения Николая Александровича Рудякова.Стаття із спеціалізованого випуску наукового журналу "Культура народов Причерноморья", матеріали якого поєднані загальною темою "Мова і Світ" і присвячені загальним питанням мовознавства і приурочені до 80-річчя з дня народження Миколи Олександровича Рудякова

A gp41 MPER-specific Llama VHH Requires a Hydrophobic CDR3 for Neutralization but not for Antigen Recognition

The membrane proximal external region (MPER) of the HIV-1 glycoprotein gp41 is targeted by the broadly neutralizing antibodies 2F5 and 4E10. To date, no immunization regimen in animals or humans has produced HIV-1 neutralizing MPER-specific antibodies. We immunized llamas with gp41-MPER proteoliposomes and selected a MPER-specific single chain antibody (VHH), 2H10, whose epitope overlaps with that of mAb 2F5. Bi-2H10, a bivalent form of 2H10, which displayed an approximately 20-fold increased affinity compared to the monovalent 2H10, neutralized various sensitive and resistant HIV-1 strains, as well as SHIV strains in TZM-bl cells. X-ray and NMR analyses combined with mutagenesis and modeling revealed that 2H10 recognizes its gp41 epitope in a helical conformation. Notably, tryptophan 100 at the tip of the long CDR3 is not required for gp41 interaction but essential for neutralization. Thus bi-2H10 is an anti-MPER antibody generated by immunization that requires hydrophobic CDR3 determinants in addition to epitope recognition for neutralization similar to the mode of neutralization employed by mAbs 2F5 and 4E10

Emergence and spread of SARS-CoV-2 lineage B.1.620 with variant of concern-like mutations and deletions

Distinct SARS-CoV-2 lineages, discovered through various genomic surveillance initiatives, have emerged during the pandemic following unprecedented reductions in worldwide human mobility. We here describe a SARS-CoV-2 lineage - designated B.1.620 - discovered in Lithuania and carrying many mutations and deletions in the spike protein shared with widespread variants of concern (VOCs), including E484K, S477N and deletions HV69Delta, Y144Delta, and LLA241/243Delta. As well as documenting the suite of mutations this lineage carries, we also describe its potential to be resistant to neutralising antibodies, accompanying travel histories for a subset of European cases, evidence of local B.1.620 transmission in Europe with a focus on Lithuania, and significance of its prevalence in Central Africa owing to recent genome sequencing efforts there. We make a case for its likely Central African origin using advanced phylogeographic inference methodologies incorporating recorded travel histories of infected travellers

Scoring docking conformations using predicted protein interfaces

BACKGROUND: Since proteins function by interacting with other molecules, analysis of protein-protein interactions is essential for comprehending biological processes. Whereas understanding of atomic interactions within a complex is especially useful for drug design, limitations of experimental techniques have restricted their practical use. Despite progress in docking predictions, there is still room for improvement. In this study, we contribute to this topic by proposing T-PioDock, a framework for detection of a native-like docked complex 3D structure. T-PioDock supports the identification of near-native conformations from 3D models that docking software produced by scoring those models using binding interfaces predicted by the interface predictor, Template based Protein Interface Prediction (T-PIP). RESULTS: First, exhaustive evaluation of interface predictors demonstrates that T-PIP, whose predictions are customised to target complexity, is a state-of-the-art method. Second, comparative study between T-PioDock and other state-of-the-art scoring methods establishes T-PioDock as the best performing approach. Moreover, there is good correlation between T-PioDock performance and quality of docking models, which suggests that progress in docking will lead to even better results at recognising near-native conformations. CONCLUSION: Accurate identification of near-native conformations remains a challenging task. Although availability of 3D complexes will benefit from template-based methods such as T-PioDock, we have identified specific limitations which need to be addressed. First, docking software are still not able to produce native like models for every target. Second, current interface predictors do not explicitly consider pairwise residue interactions between proteins and their interacting partners which leaves ambiguity when assessing quality of complex conformations

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a.

Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptide-channel complexes using experimental methods is challenging. Thus structural models are often derived from combining experimental information with restraint-driven docking approaches. Using the complex formed by the venom peptide PcTx1 and the acid sensing ion channel (ASIC) 1a as a case study, we have examined the effect of different combinations of restraints and input structures on the statistical likelihood of (a) correctly predicting the structure of the binding interface and (b) the ability to predict which residues are involved in specific pairwise peptide-channel interactions. For this, we have analyzed over 200,000 water-refined docked structures obtained with various amounts and types of restraints of the peptide-channel complex predicted using the docking program HADDOCK. We found that increasing the number of restraints or even the use of pairwise interaction data resulted in only a modest improvement in the likelihood of finding a structure within a given accuracy. This suggests that shape complementarity and the force field make a large contribution to the accuracy of the predicted structure. The results also showed that there are large variations in the accuracy of the predicted structure depending on the precise combination of residues used as restraints. Finally, we reflect on the limitations of relying on geometric criteria such as root-mean square deviations to assess the accuracy of docking procedures. We propose that in addition to currently used measures, the likelihood of finding a structure within a given level of accuracy should be also used to evaluate docking methods

Hydration dynamics of the collagen triple helix by NMR

The hydration of the collagen-like Ac-(Gly-Pro-Hyp)(6)-NH2 triple-helical peptide in solution was investigated using an integrated set of high-resolution NMR hydration experiments, including different recently developed exchange-network editing methods. This approach was designed to explore the hydration dynamics in the proximity of labile groups, such as the hydroxyproline hydroxyl group, and revealed that the first shell of hydration in collagen-like triple helices is kinetically labile with upper Limits for water molecule residence times in the nanosecond to sub-nanosecond range. This result is consistent with a "hopping" hydration model in which solvent molecules are exchanged in and out of solvation sites at a rate that is not directly correlated to the degree of site localization. The hopping model thus reconciles the dynamic view of hydration revealed by NMR with the previously suggested partially ordered semi-clathrate-like cylinder of hydration. Ln addition, the nanosecond to sub-nanosecond upper limits for water molecule residence times imply that hydration-dehydration events are not likely to be the rate-limiting step for triple helix self-recognition, complementing previous investigations on water dynamics in collagen fibers. This study has also revealed labile proton features expected to facilitate the characterization of the structure and folding of triple helices in collagen peptides. (C) 2000 Academic Press

Hydration dynamics of the collagen triple helix by NMR

The hydration of the collagen-like Ac-(Gly-Pro-Hyp)(6)-NH2 triple-helical peptide in solution was investigated using an integrated set of high-resolution NMR hydration experiments, including different recently developed exchange-network editing methods. This approach was designed to explore the hydration dynamics in the proximity of labile groups, such as the hydroxyproline hydroxyl group, and revealed that the first shell of hydration in collagen-like triple helices is kinetically labile with upper Limits for water molecule residence times in the nanosecond to sub-nanosecond range. This result is consistent with a "hopping" hydration model in which solvent molecules are exchanged in and out of solvation sites at a rate that is not directly correlated to the degree of site localization. The hopping model thus reconciles the dynamic view of hydration revealed by NMR with the previously suggested partially ordered semi-clathrate-like cylinder of hydration. Ln addition, the nanosecond to sub-nanosecond upper limits for water molecule residence times imply that hydration-dehydration events are not likely to be the rate-limiting step for triple helix self-recognition, complementing previous investigations on water dynamics in collagen fibers. This study has also revealed labile proton features expected to facilitate the characterization of the structure and folding of triple helices in collagen peptides. (C) 2000 Academic Press

The orientations of cytochrome c in the highly dynamic complex with cytochrome b5 visualized by NMR and docking using HADDOCK

The interaction of bovine microsomal ferricytochrome b5 with yeast iso-1-ferri and ferrocytochrome c has been investigated using heteronuclear NMR techniques. Chemical-shift perturbations for 1H and 15N nuclei of both cytochromes, arising from the interactions with the unlabeled partner proteins, were used for mapping the interacting surfaces on both proteins. The similarity of the binding shifts observed for oxidized and reduced cytochrome c indicates that the complex formation is not influenced by the oxidation state of the cytochrome c. Protein-protein docking simulations have been performed for the binary cytochrome b5-cytochrome c and ternary (cytochrome b5)-(cytochrome c)2 complexes using a novel HADDOCK approach. The docking procedure, which makes use of the experimental data to drive the docking, identified a range of orientations assumed by the proteins in the complex. It is demonstrated that cytochrome c uses a confined surface patch for interaction with a much more extensive surface area of cytochrome b5. Taken together, the experimental data suggest the presence of a dynamic ensemble of conformations assumed by the proteins in the complex

The alpha-to-beta conformational transition of Alzheimer's A beta-(1-42) peptide in aqueous media is reversible: A step by step conformational analysis suggests the location of beta conformation seeding

Current views of the role of b-amyloid (Ab) peptide fibrils range from regarding them as the cause of Alzheimer’s pathology to having a protective function. In the last few years, it has also been suggested that soluble oligomers might be the most important toxic species. In all cases, the study of the conformational properties of Ab peptides in soluble form constitutes a basic approach to the design of molecules with “antiamyloid” activity. We have experimentally investigated the conformational path that can lead the Ab-(1-42) peptide from the native state, which is represented by an a helixembedd ed in the membrane, to the final state in the amyloid fibrils, which is characterized by bsheet structures. The conformational steps were monitored by using CD and NMR spectroscopy in media of varying polarities. This was achieved by changing the composition of water and hexafluoroisopropanol (HFIP). In the presence of HFIP, b conformations can be observed in solutions that have very high water content (up to 99% water; v/v). These can be turned back to a helices simply by adding the appropriate amount of HFIP. The transition of Ab-(1-42) from a to b conformations occurs when the amount of water is higher than 80% (v/v). The NMR structure solved in HFIP/H2O with high water content showed that, on going from very apolar to polar environments, the long N-terminal helixis essentially retained, whereas the shorter C-terminal helixis lost. The complete conformational path was investigated in detail with the aid of molecular-dynamics simulations in explicit solvent, which led to the localization of residues that might seed b conformations. The structures obtained might help to find regions that are more affected by environmental conditions in vivo. This could in turn aid the design of molecules able to inhibit fibril deposition or revert oligomerization processes