Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity

International audienceBACKGROUND: Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community. RESULTS: We introduce a new approach (LigCSRre) to the 3D ligand similarity search of drug candidates. It combines a 3D maximum common substructure search algorithm independent on atom order with a tunable description of atomic compatibilities to prune the search and increase its physico-chemical relevance. We show, on 47 experimentally validated active compounds across five protein targets having different specificities, that for single compound search, the approach is able to recover on average 52% of the co-actives in the top 1% of the ranked list which is better than gold standards of the field. Moreover, the combination of several runs on a single protein target using different query active compounds shows a remarkable improvement in enrichment. Such Results demonstrate LigCSRre as a valuable tool for ligand-based screening. CONCLUSION: LigCSRre constitutes a new efficient and generic approach to the 3D similarity screening of small compounds, whose flexible design opens the door to many enhancements. The program is freely available to the academics for non-profit research at: http://bioserv.rpbs.univ-paris-diderot.fr/LigCSRre.html

In-situ synchrotron microtomography reveals multiple reaction pathways during soda-lime glass synthesis

Ultrafast synchrotron microtomography has been used to study in-situ and in real time the initial stages of silicate glass melt formation from crystalline granular raw materials. Significant and unexpected rearrangements of grains occur below the nominal eutectic temperature, and several drastically different solid-state reactions are observed to take place at different types of intergranular contacts. These reactions have a profound influence on the formation and the composition of the liquids produced, and control the formation of defects.Comment: 4 pages, 4 figure

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Bases de données relationnelles : une application web pour découvrir la concurrence d’accès

As part of an MOOC on relational databases launched in January 2016, we developed a web application allowing each learner to test a succession of SQL queries. This interface proposes to execute requests on two parallel transactions, it allows students to play with database concurrency.The authors of the MOOC wanted to have a solution integrated into their course so that students could grasp complex theoretical notions by the practice, without having to leave the platform on which they were. This also allowed them not to mention installing an SQL environment that can be unpleasant to students.Dans le cadre d’un MOOC sur les bases de données relationnelles lancé en janvier 2016, nous avons développé une application web permettant à chaque apprenant de tester simplement une succession de requêtes SQL. Cette interface proposait d’exécuter des requêtes sur deux transactions parallèles afin de donner aux étudiants la possibilité d’appréhender la concurrence d’accès sur une base de données.Les auteurs du MOOC souhaitaient disposer d’une solution intégrée à leur cours pour que les étudiants puissent appréhender des notions théoriques complexes par la pratique, sans avoir à quitter la plateforme sur laquelle ils étaient. Cela leur permettait également de ne pas évoquer l’installation d’un environnement SQL qui peut être lourd et rebutant pour les étudiants

Mécanismes physiques et chimiques mis en jeu lors de la fusion du mélange SiO2-Na2CO3

From the raw materials used to make glass, to the homogeneous liquid made out of the furnace, we may wonder about the steps by which the glass batch is being transformed into a homogeneous liquid. From a chronological point of view, glass making can be considered in three stages : The initial state before reaction of the granular mixture ; The step of chemical reactions between the different components ; A liquid with gaseous and solid inclusions (bubbles and residual quartz). Each of these steps relates to a specific field, with a strong coupling between physics and chemistry. Studying how these materials react together and how the microstructure can influence the overall reaction path followed by the batch is essential to know the mechanisms involved at every moment of the transformation. This understanding could fix some problems related to the making of an industrial glass (bubbles trapped in the liquid, quartz grains not dissolved into the liquid and the liquid chemical heterogeneity). The variety of phenomena involved during the fusion of an industrial glass batch push us to simplify the system, to be able to relate the evolution of the microstructure to the chemistry of the batch. This is why we decided to study the system SiO2-Na2CO3. We have also sieved grains in specific sizes in order to connect the chemical transformation of the mixture to the spatial distribution of the initial granular mixture.Entre l'enfournement des matières premières sur le bain liquide et le verre la sortie du four, on peut s'interroger sur les étapes par lesquelles le mélange vitrifiable passe avant d'être transformé en un liquide homogène. D'un point de vue chronologique, l'élaboration du verre peut être considérée en trois étapes : l'état initial du mélange granulaire avant réaction ; l'étape de réaction chimique entre les différents constituants ; un liquide avec ses inclusions gazeuses et solides (bulles et quartz résiduel). Chacune de ces étapes concerne un domaine spécifique, avec un fort couplage entre physique et chimie. Aborder la façon dont réagissent ces matières premières ensemble et comment la microstructure peut influencer le chemin réactionnel suivi globalement par le mélange est indispensable pour savoir a chaque moment de la transformation quels mécanismes sont mis en jeu. Cela permettrait de corriger certains problèmes liés à l'élaboration d'un verre industriel (bulles piégé es dans le liquide, grains de quartz non incorporés au liquide, hétérogénéité chimique du liquide). La variété de phénomènes possibles lors de la fusion d'un mélange vitrifiable industriel nous poussera à simplifier le système un maximum, afin d'être capable de relier l'évolution de la microstructure à celle de la chimie du matériau. C'est la raison pour laquelle nous avons décidé d'étudier le système SiO2-Na2CO3. Nous avons de plus utilisé des grains tamisés dans des tranches précises, afin de pouvoir relier la transformation chimique du mélange à la répartition spatiale initiale du mélange granulaire

Mécanismes physiques et chimiques mis en jeu lors de la fusion du mélange SiO2-Na2CO3

PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Pyogenic sacroiliitis in a 13-month-old child a case report and literature review

International audiencePyogenic sacroiliitis is exceptional in very young children. Diagnosis is difficult because clinical examination is misleading. FABER test is rarely helpful in very young children. Inflammatory syndrome is frequent. Bone scintigraphy and MRI are very sensitive for the diagnosis. Joint fluid aspiration and blood cultures are useful to identify the pathogen. Appropriate antibiotic therapy provides rapid regression of symptoms and healing. We report the case of pyogenic sacroiliitis in a 13-month-old child.Clinical, biological, and imaging data of this case were reviewed and reported retrospectively.A 13-month-old girl consulted for decreased weight bearing without fever or trauma. Clinical examination was not helpful. There was an inflammatory syndrome. Bone scintigraphy found a sacroiliitis, confirmed on MRI. Aspiration of the sacroiliac joint was performed. Empiric intravenous biantibiotic therapy was started. Patient rapidly recovered full weight bearing. On the 5th day, clinical examination and biological analysis returned to normal. Intravenous antibiotic therapy was switched for oral. One month later, clinical examination and biological analysis were normal and antibiotic therapy was stopped.Hematogenous osteoarticular infections are common in children but pyogenic sacroiliitis is rare and mainly affects older children. Diagnosis can be difficult because clinical examination is poor. Moreover, limping and decreased weight bearing are very common reasons for consultation. This may delay the diagnosis or refer misdiagnosis. Bone scintigraphy is useful to locate a bone or joint disease responsible for limping. In this observation, bone scintigraphy located the infection at the sacroiliac joint. Given the young age, MRI was performed to confirm the diagnosis. Despite the very young age of the patient, symptoms rapidly disappeared with appropriate antibiotic therapy.We report the case of pyogenic sacroiliitis in a 13-month-old child. It reminds the risk of misdiagnosing pyogenic sacroiliitis in children because it is exceptional and clinical examination is rarely helpful. It also highlights the usefulness of bone scintigraphy and MRI in osteoarticular infections in children