MEPSA: Minimum energy pathway analysis for energy landscapes

From conformational studies to atomistic descriptions of enzymatic reactions, potential and free energy landscapes can be used to describe biomolecular systems in detail. However, extracting the relevant data of complex 3D energy surfaces can sometimes be laborious. In this article, we present MEPSA (Minimum Energy Path Surface Analysis), a cross-platform user friendly tool for the analysis of energy landscapes from a transition state theory perspective. Some of its most relevant features are: identification of all the barriers and minima of the landscape at once, description of maxima edge profiles, detection of the lowest energy path connecting two minima and generation of transition state theory diagrams along these paths. In addition to a built-in plotting system, MEPSA can save most of the generated data into easily parseable text files, allowing more versatile uses of MEPSA's output such as the generation of molecular dynamics restraints from a calculated path.Grant IPT2011-0964-900000 (Government of Spain).Peer Reviewe

Half-sandwich isocyanide, phosphine, methyl and phosphanido pentamethylcyclopentadienylniobium(V) complexes

[NbCp★Cl4] Cp★ = ν5-C5Me5) reacts with one molar equivalent of isocyanides and phosphines to give pseudo-octahedral adducts [NbCp★Cl4·L], (Full-size image (<1 K), 4) and the dinuclear complex [∗[NbCp★Cl4∗]2(μ-dmpe)], 5. Reactions of [NbCp★Cl4] with appropriate amounts of MgClMe yield the correspodning dimethyl [NbCp★Cl2Me2], 6, and tetramethyl [NbCp★Me4], 7 derivatives. Similarly, when [∗[NbCp★Cl3∗2(μ-O)] an and 3 are treated with the alkylating magnesium reagent, [∗[NbCp★Me3∗]2(μ-O)], 8, and [NbCp★Cl3Me(PMe2Ph)], 9, are obtained in high yields. A new phosphanido-niobium(V) complex [NbCp★Cl3(PPh2)] 10, is formed in the reaction of the starting tetrachloro complex with one equivalent of LiPPh2. All the complexes were characterized by IR and NMR spectroscopy, and most of them were studied by mass spectrometry

Two-step ATP-driven opening of cohesin head

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the "head" structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: I) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer

Short-course versus long-course therapy of the same antibiotic for community-acquired pneumonia in adolescent and adult outpatients.

Background Community-acquired pneumonia (CAP) is a lung infection that can be acquired during day-to-day activities in the community (not while receiving care in a hospital). Community-acquired pneumonia poses a significant public health burden in terms of mortality, morbidity, and costs. Shorter antibiotic courses for CAP may limit treatment costs and adverse effects, but the optimal duration of antibiotic treatment is uncertain. Objectives To evaluate the efficacy and safety of short-course versus longer-course treatment with the same antibiotic at the same daily dosage for CAP in non-hospitalised adolescents and adults (outpatients). We planned to investigate non-inferiority of short-course versus longerterm course treatment for efficacy outcomes, and superiority of short-course treatment for safety outcomes. Search methods We searched CENTRAL, which contains the Cochrane Acute Respiratory Infections Group Specialised Register,MEDLINE, Embase, five other databases, and three trials registers on 28 September 2017 together with conference proceedings, reference checking, and contact with experts and pharmaceutical companies.SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short- and long-courses of the same antibiotic for CAP in adolescent and adult outpatients. DATA COLLECTION AND ANALYSIS: We planned to use standard Cochrane methods. MAIN RESULTS: Our searches identified 5260 records. We did not identify any RCTs that compared short- and longer-courses of the same antibiotic for the treatment of adolescents and adult outpatients with CAP.We excluded two RCTs that compared short courses (five compared to seven days) of the same antibiotic at the same daily dose because they evaluated antibiotics (gemifloxacin and telithromycin) not commonly used in practice for the treatment of CAP. In particular, gemifloxacin is no longer approved for the treatment of mild-to-moderate CAP due to its questionable risk-benefit balance, and reported adverse effects. Moreover, the safety profile of telithromycin is also cause for concern.We found one ongoing study that we will assess for inclusion in future updates of the review. AUTHORS' CONCLUSIONS: We found no eligible RCTs that studied a short-course of antibiotic compared to a longer-course (with the same antibiotic at the same daily dosage) for CAP in adolescent and adult outpatients. The effects of antibiotic therapy duration for CAP in adolescent and adult outpatients remains unclear.pre-print547 K

Modulating the Synthesis of Dextran with the Acceptor Reaction Using Native and Encapsulated Dextransucrases

Dextransucrases are glucansucrases with broad applications in the food, cosmetics and pharmaceutical industries. Using sucrose as the glucosyl donor, they synthesize both high molecular weight (HMW) dextrans and potential prebiotic oligosaccharides. The process selectivity can be modulated by varying the reaction conditions. When no other molecule is present in the reaction, only dextrans are synthesized. In the presence of methyl α-D-glucopyranoside, the synthesis of methyl polyglucosides takes place, diminishing the transfer of glucose molecules to form dextran. In this work, the formation of HMW soluble dextran and methyl polyglucosides was studied with dextransucrases from Leuconostoc mesenteroides, strains B-512F and B-1299. The amount of dextran formed with dextransucrase B-512F was reduced up to 4 % with respect to the control in absence of acceptor, using a mass ratio of sucrose:methyl α-D-glucopyranoside of 1:4. The encapsulation in alginate retains the dextran inside the beads, causing a distortion of the biocatalyst and finally releasing the polysaccharides into the reaction medium

Advances in the modeling of the Iberian thermal lithosphere and perspectives on deep geothermal studies

Renewable energy sources are key to achieve the transition toward clean energy system. Among them, the geothermal energy has a production whose effectiveness requires sufficient understanding of the temperature distribution and fluid circulation at depth, as well as of the lithological and petrophysical properties of the crust. The focus of this paper is twofold: first, we summarize the main advances in the development of new methodologies and numerical codes to characterize the properties of the thermal lithosphere in terms of its, temperature, density and composition; second, based on the compilation of available thermal modelling results, we present the depth of the thermal Lithosphere-Asthenosphere Boundary (LAB) of the Iberian Peninsula and the temperature distribution at crustal depths of 5, 10, and 20 km, in addition to at Moho level. At 5 km depth, the temperature is above 110 °C with local anomalies (> 130 °C) located in the Iberian Massif and Cenozoic volcanic provinces. A similar pattern is observed at 10 and 20 km depth, where temperatures are above 190 °C and 350 °C, respectively. At 20 km depth, anomalies above > 500 °C, delineate the SE and NE Cenozoic volcanic provinces. At Moho depths, temperature ranges from 450 to 800 °C with hot regions mainly located along the Iberian Massif and the SE and NE volcanic provinces. The compiled results do not show any lithospheric anomaly that could give rise to high temperatures at shallow depths, but they do show an acceptable exploitation potential at intermediate depths. With regard to the direct use of district and greenhouse heating and for industrial processes, the potential is great throughout the Peninsula, the main challenges being the availability of groundwater and drilling costs

Two-step ATP-driven opening of cohesin head.

The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.post-print4709 K

Things are not always what they seem: From Cornelia de Lange to KBG phenotype in a girl with genetic variants in NIPBL and ANKRD11.

post-print509 K

Hubs and clusters approach to unlock the development of carbon capture and storage - Case study in Spain

Many countries have assigned an indispensable role for carbon capture and storage (CCS) in their national climate change mitigation pathways. However, CCS deployment has stalled in most countries with only limited commercial projects realised mainly in hydrocarbon-rich countries for enhanced oil recovery. If the Paris Agreement is to be met, then this progress must be replicated widely, including hydrocarbon-limited countries. In this study, we present a novel source-to-sink assessment methodology based on a hubs and clusters approach to identify favourable regions for CCS deployment and attract renewed public and political interest in viable deployment pathways. Here, we apply this methodology to Spain, where fifteen emission hubs from both the power and the hard-to-abate industrial sectors are identified as potential CO2 sources. A priority storage structure and two reserves for each hub are selected based on screening and ranking processes using a multi-criteria decision-making method. The priority source-to-sink clusters are identified indicating four potential development regions, with the North-Western and North-Eastern Spain recognised as priority regions due to resilience provided by different types of CO2 sources and geological structures. Up to 68.7 Mt CO2 per year, comprising around 21% of Spanish emissions can be connected to clusters linked to feasible storage. CCS, especially in the hard-to-abate sector, and in combination with other low-carbon energies (e.g., blue hydrogen and bioenergy), remains a significant and unavoidable contributor to the Paris Agreement's mid-century net-zero target. This study shows that the hubs and clusters approach can facilitate CCS deployment in Spain and other hydrocarbon-limited countries

Evaluating Face2Gene as a Tool to Identify Cornelia de Lange Syndrome by Facial Phenotypes

Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdL