A complete, multi-level conformational clustering of antibody complementarity-determining regions

Classification of antibody complementarity-determining region (CDR) conformations is an important step that drives antibody modelling and engineering, prediction from sequence, directed mutagenesis and induced-fit studies, and allows inferences on sequence-to-structure relations. Most of the previous work performed conformational clustering on a reduced set of structures or after application of various structure pre-filtering criteria. In this study, it was judged that a clustering of every available CDR conformation would produce a complete and redundant repertoire, increase the number of sequence examples and allow better decisions on structure validity in the future. In order to cope with the potential increase in data noise, a first-level statistical clustering was performed using structure superposition Root-Mean-Square Deviation (RMSD) as a distance-criterion, coupled with second- and third-level clustering that employed Ramachandran regions for a deeper qualitative classification. The classification of a total of 12,712 CDR conformations is thus presented, along with rich annotation and cluster descriptions, and the results are compared to previous major studies. The present repertoire has procured an improved image of our current CDR Knowledge-Base, with a novel nesting of conformational sensitivity and specificity that can serve as a systematic framework for improved prediction from sequence as well as a number of future studies that would aid in knowledge-based antibody engineering such as humanisation

Disjoint combinations profiling (DCP): a new method for the prediction of antibody CDR conformation from sequence

The accurate prediction of the conformation of Complementarity-Determining Regions (CDRs) is important in modelling antibodies for protein engineering applications. Specifically, the Canonical paradigm has proved successful in predicting the CDR conformation in antibody variable regions. It relies on canonical templates which detail allowed residues at key positions in the variable region framework or in the CDR itself for 5 of the 6 CDRs. While no templates have as yet been defined for the hypervariable CDR-H3, instead, reliable sequence rules have been devised for predicting the base of the CDR-H3 loop. Here a new method termed Disjoint Combinations Profiling (DCP) is presented, which contributes a considerable advance in the prediction of CDR conformations. This novel method is explained and compared with canonical templates and sequence rules in a 3-way blind prediction. DCP achieved 93 accuracy over 951 blind predictions and showed an improvement in cumulative accuracy compared to predictions with canonical templates or sequence rules. In addition to its overall improvement in prediction accuracy, it is suggested that DCP is open to better implementations in the future and that it can improve as more antibody structures are deposited in the databank. In contrast, it is argued that canonical templates and sequence rules may have reached their peak

Η Εθνική Αρχή Διαφάνειας, κατά το ν. 4622/2019

H εργασία αποτελείται από 2 μέρη. Στο 1ο μέρος επιχειρείται προσέγγιση των εννοιών που σχετίζονται με την Εθνική Αρχή Διαφάνειας και συγκεκριμένα προσεγγίζονται : α) το κράτος πρόληψης, β) η διαφθορά, γ) οι διεθνείς συνθήκες για την διαφθορά, δ) οι προηγούμενοι θεσμοί που ενσωματώθηκαν από την ΕΑΔ, ε) ο έλεγχος της δημόσιας διοίκησης, στ) Οι Ανεξάρτητες Αρχές και το Νέο Δημόσιο Μάνατζμεντ και ζ) Η αρχή της διαφάνειας, κατά το ευρωπαϊκό και εθνικό δίκαιο. Στο 2 μέρος γίνεται παρουσίαση του θεσμικού πλαισίου της ΕΑΔ, με έμφαση : α) στην επιλογή του τύπου της Ανεξάρτητης Αρχής, β) στην ανεξαρτησία της Αρχής και των μελών της, γ) στον τρόπο επιλογής της διοίκησής της, δ) στις αρμοδιότητές της. Σχετικά με τις αρμοδιότητές της, υφίστανται κριτικές παρατηρήσεις για το εύρος των αρμοδιοτήτων αυτών. Στο 2ο μέρος παρουσιάζεται και μία πραγματική υπόθεση διαφάνειας, με συμμετοχή της ΕΑΔ και τέλος παρουσιάζονται τα συμπεράσματα της εργασίας : α) η ΕΑΔ ασχολείται με την πλευρά της διαφάνειας που σχετίζεται με την καταπολέμηση της διαφθοράς και όχι με άλλες σημαντικές πλευρές της έννοιας, όπως η "ανοιχτότητα", η συμμετοχή στην διοίκηση και η πρόσβαση στις δημόσιες πληροφορίες και τα έγγραφα, β) ανήκει στους θεσμούς του κράτους πρόληψης και του Νέου Δημόσιου Μάνατζμεντ, γ) υφίσταται μετασχηματισμός της δημόσιας διοίκησης που πλέον χρησιμοποιεί μεθόδους και εργαλεία διοίκησης προερχόμενα από τον ιδιωτικό τομέα, σε βαθμό αλλοίωσης του παραδοσιακού βεμπεριανού κράτους.Τhis dissertation comprises of 2 parts. In the 1st part, concepts related to the National Transparency Authority are approached : a) prevention state, b) corruption, c) the international conventions about corruption, d) previous institutions that have merged with the NTA, e) control of the public administration, f) Independent Authorities and New Public Management, and g) the principle of transparency, by the provisions of the European Law and the National Law. The 2nd part is a presentation of the statutory provisions regarding NTA. Emphasis is placed on : a) the choice of the form of an Independent Authority, b) the independence of the Authority and the independence of its members, c) the way the members of the administration are chosen, d) the powers of the Authority. As regards the powers of NTA, there are critical thoughts about the wide range of these powers. There is also a presentation of a transparency case study, with the participation of the NTA. At the end, the conclusions of the dissertation are presented : a) NTA deals with the aspect of transparency that is related to the fight against corruption and not with the aspects that are related to the openness, the citizen΄s participation in the administration and the access to the public information and documents. b) NTA belongs to the institutions of prevention state and to the institutions of NPM. c) There is a transformation of the public administration. Public administration tends to use methods and tools that stem from the private sector, to such extent as to alter the Weberian State

Commemorating the decipherment of Linear B and the discovery of Mycenaean Greek.

Includes image: 'St Cecilia', 1938.AbstractLinear B is the writing system used by the Mycenaean Greeks dur­ ing the Late Bronze Age, roughly between 1450 - 1200 BCE. Clay tablets inscribed in the Linear B script had been unearthed at the excavations of Knossos, Crete, in the early 1900s and subsequently at Pylos and Mycenae on the mainland of Greece,1 but they had remained largely unreadable for decades, until a British architect by the name of Michael Ventris, who had always had a keen interest in languages, announced on a BBC radio pro­ gramme, that was aired on 1st July 1952, that he had deciphered Linear B and that it represented the earliest surviving form of the Greek language.2 This was a major breakthrough, complementing the archaeological inves­ tigations of the time by giving scholars access to the textual information recorded in the Linear B tablets about the socio-political, economic and religious facets of life in the Mycenaean world. This paper commemorates the 60th anniversary of this important achievement in two ways: first, it outlines the unique contributions of the four main pioneers involved in the decipherment (Michael Ventris, Alice E. Kober, Emmett L. Bennett, Jr. and John Chadwick); second, it focuses on a small section of Linear B tablet PY Ep 704 in order to illustrate the detailed information contained in these texts and to consider the diachronic development of the Greek language by pointing to several key similarities and differences between Mycenaean and Modern Greek

Disjoint combinations profiling (DCP): a new method for the prediction of antibody CDR conformation from sequence.

The accurate prediction of the conformation of Complementarity-Determining Regions (CDRs) is important in modelling antibodies for protein engineering applications. Specifically, the Canonical paradigm has proved successful in predicting the CDR conformation in antibody variable regions. It relies on canonical templates which detail allowed residues at key positions in the variable region framework or in the CDR itself for 5 of the 6 CDRs. While no templates have as yet been defined for the hypervariable CDR-H3, instead, reliable sequence rules have been devised for predicting the base of the CDR-H3 loop. Here a new method termed Disjoint Combinations Profiling (DCP) is presented, which contributes a considerable advance in the prediction of CDR conformations. This novel method is explained and compared with canonical templates and sequence rules in a 3-way blind prediction. DCP achieved 93% accuracy over 951 blind predictions and showed an improvement in cumulative accuracy compared to predictions with canonical templates or sequence-rules. In addition to its overall improvement in prediction accuracy, it is suggested that DCP is open to better implementations in the future and that it can improve as more antibody structures are deposited in the databank. In contrast, it is argued that canonical templates and sequence rules may have reached their peak.</jats:p

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

A metabolome and transcriptome survey to tap the dynamics of fruit prolonged shelf-life and improved quality within Greek tomato germplasm

Introduction: Tomato is a high economic value crop worldwide with recognized nutritional properties and diverse postharvest potential. Nowadays, there is an emerging awareness about the exploitation and utilization of underutilized traditional germplasm in modern breeding programs. In this context, the existing diversity among Greek accessions in terms of their postharvest life and nutritional value remains largely unexplored. Methods: Herein, a detailed evaluation of 130 tomato Greek accessions for postharvest and nutritional characteristics was performed, using metabolomics and transcriptomics, leading to the selection of accessions with these interesting traits. Results: The results showed remarkable differences among tomato Greek accessions for overall ripening parameters (color, firmness) and weight loss. On the basis of their postharvest performance, a balance between short shelf life (SSL) and long shelf life (LSL) accessions was revealed. Metabolome analysis performed on 14 selected accessions with contrasting shelf-life potential identified a total of 206 phytonutrients and volatile compounds. In turn, transcriptome analysis in fruits from the best SSL and the best LSL accessions revealed remarkable differences in the expression profiles of transcripts involved in key metabolic pathways related to fruit quality and postharvest potential. Discussion: The pathways towards cell wall synthesis, polyamine synthesis, ABA catabolism, and steroidal alkaloids synthesis were mostly induced in the LSL accession, whereas those related to ethylene biosynthesis, cell wall degradation, isoprenoids, phenylpropanoids, ascorbic acid and aroma (TomloxC) were stimulated in the SSL accession. Overall, these data would provide valuable insights into the molecular mechanism towards enhancing shelf-life and improving flavor and aroma of modern tomato cultivars

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Atlas of phenotypic, genotypic and geographical diversity present in the European traditional tomato

The Mediterranean basin countries are considered secondary centres of tomato diversification. However, information on phenotypic and allelic variation of local tomato materials is still limited. Here we report on the evaluation of the largest traditional tomato collection, which includes 1499 accessions from Southern Europe. Analyses of 70 traits revealed a broad range of phenotypic variability with different distributions among countries, with the culinary end use within each country being the main driver of tomato diversification. Furthermore, eight main tomato types (phenoclusters) were defined by integrating phenotypic data, country of origin, and end use. Genome-wide association study (GWAS) meta-analyses identified associations in 211 loci, 159 of which were novel. The multidimensional integration of phenoclusters and the GWAS meta-analysis identified the molecular signatures for each traditional tomato type and indicated that signatures originated from differential combinations of loci, which in some cases converged in the same tomato phenotype. Our results provide a roadmap for studying and exploiting this untapped tomato diversity