Fragment dissolved molecular dynamics: a systematic and efficient method to locate binding sites

Diverse computational methods to support Fragment-based drug discovery (FBDD) are available in the literature. Despite their demonstrated efficacy to support FBDD campaigns, they exhibit some drawbacks such as protein denaturation or ligand aggregation that have not been yet clearly overcome in the framework of biomolecular simulations. In the present work, we discuss a systematic semi-automatic novel computational procedure, designed to surpass these difficulties. The method, named fragment dissolved Molecular Dynamics (fdMD) utilizes simulation boxes of solvated small fragments, adding a repulsive Lennard-Jones potential term to avoid aggregation, which can be easily used to solvate the targets of interest. This method has the advantage of solvating the target with a low number of ligands, thus preventing this way denaturation of the target, while simultaneously generating a database of ligandsolvated boxes that can be used in further studies. A number of scripts are made available to analyze the results and obtain the descriptors proposed as a means of trustfully discard spurious binding sites. To test our method, four Test cases of different complexity have been solvated with ligand boxes and four molecular dynamics runs of 200 ns length have been run for each system, which have been extended up to 1 µs when needed. The reported results point that the selected number of replicas are enough to identify the correct binding sites irrespective of the initial structure, even in the case of proteins having several close binding sites for the same ligand. We also propose a set of descriptors to analyze the results, among which, the average MMGBSA and the average KDEEP energies emerge as the most robust ones.Peer ReviewedPostprint (author's final draft

The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2

Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manne

Split-Delivery Capacitated Arc-Routing Problem: Lower Bound and Metaheuristic

International audienceThis paper proposes lower and upper bounds for the split-delivery capacitated arc-routing problem (SDCARP), a variant of the capacitated arc-routing problem in which an edge can be serviced by several vehicles. Recent papers on related problems in node routing have shown that this policy can bring significant savings. It is also more realistic in applications such as urban refuse collection, where a vehicle can become full in the middle of a street segment. This work presents the first lower bound for the SDCARP, computed with a cutting plane algorithm and an evolutionary local search reinforced by a multistart procedure and a variable neighborhood descent. Tests on 126 instances show that the new metaheuristic outperforms on average a published memetic algorithm; achieves small deviations to the lower bound; and finds 44 optima, including 10 new ones

A Branch-and-Cut method for the Capacitated Location-Routing Problem

International audienceRecent researches in the design of logistic networks have shown that the overall distribution cost may be excessive if routing decisions are ignored when locating depots. The Location-Routing Problem (LRP) overcomes this drawback by simultaneously tackling location and routing decisions. The aim of this paper is to propose an exact approach based on a Branch-and-Cut algorithm for solving the LRP with capacity constraints on depots and vehicles. The proposed method is based on a zero-one linear model strengthened by new families of valid inequalities. The computational evaluation on three sets of instances (34 instances in total), with 5–10 potential depots and 20–88 customers, shows that 26 instances with five depots are solved to optimality, including all instances with up to 40 customers and three with 50 customers

Models and algorithms for a yard crane scheduling problem in container ports

[EN] This paper addresses the scheduling of a yard crane in an automated container block, considering its rela-tionships with the other terminal subsystems. Containers coming into the block to be stored have release times, indicating the moment at which they arrive from ships or trucks. Containers being retrieved have due times, indicating when they will be required by other subsystems. The problem can be seen as a pickup routing problem and also as a one-machine scheduling problem. As a starting point, integer linear models were developed for both approaches. Then, to obtain good solutions for large instances, several heuristic algorithms, coupled with a local search, were proposed. An extensive computational study, based on a newly generated benchmark, shows the limits of the exact methods and the quality of the solutions obtained by the heuristics.The authors are partially supported by the Spanish Ministry of Science and Innovation under the project "OPTEP-Port Terminal Operations Optimization" (No. RTI2018-094940-B-I00), partially financed with FEDER funds, by the Spanish Ministry of Science and Innovation under the project "OPRES-Realistic Optimization in Problems in Public Healt"(No. PID2021-124975OB-I00), partially financed with FEDER funds and by the Agencia Valenciana de la Innovacio (AVI) under the project "ireves (innovacion en vehiculos de emergencia sanitaria): una herramienta inteligente de decision" (No. INNACC/2021/26) partially financed with FEDER funds (interested readers can visit http://ireves.upv.es). Some of the authors are supported by the Faculty of Business Administration and Man-agement at the Universitat Politecnica de Valencia. Special thanks are due to Gerardo Gabriel Minella from Instituto Tecnologico de Informatica.Vallada Regalado, E.; Belenguer, JM.; Villa Juliá, MF.; Alvarez-Valdes, R. (2023). Models and algorithms for a yard crane scheduling problem in container ports. European Journal of Operational Research. 309(2):910-924. https://doi.org/10.1016/j.ejor.2023.01.047910924309

Cell population analysis of the adult murine subependymal neurogenic lineage by flow cytometry

Summary: This protocol provides a flow-cytometry-based procedure to classify and isolate all cells of the adult rodent subependymal zone (SEZ) neurogenic lineage, without the need for reporter mice, into different cell populations, including three neural stem cell (NSC) fractions with molecular signatures that are coherent with single-cell transcriptomics. Additionally, their cycling behavior can be assessed by means of 5-ethynyl-2′-deoxyuridine (EdU) incorporation. Our method allows the isolation of different NSC fractions and the functional assay of their cycling heterogeneity and quiescence-activation transitions.For complete details on the use, execution, and outcomes of this protocol, please refer to Belenguer et al. (2021)

Stent management of leaks after bariatric surgery: a systematic review and meta-analysis

BACKGROUND Despite the low rates of complications of bariatric surgery, gastrointestinal leaks are major adverse events that increase post-operative morbidity and mortality. Endoscopic treatment using self-expanding stents has been used in the therapeutic management of these complications with preliminary good results. METHODS We performed a systematic review and meta-analysis of self-expanding stents placement for the management of gastrointestinal leaks after obesity surgery. Overall proportion of successful leak closure, stent migration, and reoperation were analysed as primary outcomes. Secondary outcomes were patients’ clinical characteristics, duration and type of stent, other stent complications, and mortality. RESULTS A meta-analysis of studies reporting stents was performed, including 488 patients. The overall proportion of successful leak closure was 85.89% (95% CI, 82.52–89.25%), median interval between stent placement and its removal of 44 days. Stent migration was noted in 18.65% (95% CI, 14.32–22.98%) and the overall proportion of re-operation was in 13.54% (95% CI, 9.94–17.14%). The agreement between reviewers for the collected data gave a Cohen’s κ value of 1.0. No deaths were caused directly by complications with the stent placement. CONCLUSION Endoscopic placement of self-expanding stents can be used, in selected patients, for the management of leaks after bariatric surgery with a high rate of effectiveness and lowamortality rates. Nevertheless, reducing stent migration and re-operation rates representsaan important challenge for future studies

Raman spectroscopy, assisted by X-ray fluorescence and laser-induced breakdown spectroscopy, to characterise original and altered mineral phases in the NWA 2975 Martian shergottite

A fragment of the NWA 2975 Martian meteorite, an enriched basaltic shergottite, was analysed to complete its geochemical characterisation performed 10 years ago. By this means, the feasibility of the employed techniques in a combined way for present and future space exploration missions can be tested. For this aim, Raman spectroscopy was used supported by micro energy dispersive X-ray fluorescence (μ-EDXRF) and laser-induced breakdown spectroscopy (LIBS) for an accurate interpretation of molecular and elemental results. Raman spectroscopy results from two setups, InVia from Renishaw and RLS Simulator, were compared. The major minerals detected by Raman spectroscopy were pyroxenes (mainly augite, pigeonite and enstatite) and plagioclases (mainly shocked maskelynite). Raman spectroscopy allowed defining different metal compositions for these main minerals based on the secondary Raman spectroscopy bands in the 200–500 cm−1 region. In addition, other minerals were found such as merrillite, as well as pyrrhotite and apatite, in several veins and cracks of the meteorite, in agreement with the initial report by the Meteoritical Bulletin. Moreover, it should be highlighted that coesite was found for the very first time in this meteorite.Gobierno Vasco (España)Universidad del País Vasco (España)Ministerio de Economía y Competitividad de EspañaMinisterio de Ciencia e Innovación de EspañaEuropean Regional Development Fund (FEDER)Depto. de ÓpticaFac. de Óptica y OptometríaTRUEpu