A deep-learning sequence-based method to predict protein stability changes upon genetic variations

Several studies have linked disruptions of protein stability and its normal functions to disease. Therefore, during the last few decades, many tools have been developed to predict the free energy changes upon protein residue variations. Most of these methods require both sequence and structure information to obtain reliable predictions. However, the lower number of protein structures available with respect to their sequences, due to experimental issues, drastically limits the application of these tools. In addition, current methodologies ignore the antisymmetric property characterizing the thermodynamics of the protein stability: a variation from wild-type to a mutated form of the protein structure (XW→XM) and its reverse process (XM→XW) must have opposite values of the free energy difference (ΔΔGWM=−ΔΔGMW). Here we propose ACDC-NN-Seq, a deep neural network system that exploits the sequence information and is able to incorporate into its architecture the antisymmetry property. To our knowledge, this is the first convolutional neural network to predict protein stability changes relying solely on the protein sequence. We show that ACDC-NN-Seq compares favorably with the existing sequence-based methods

Ex-post evaluation of major infrastructure projects

Ex ante assessment of a project by means of cost-benefit analysis is quite common in transport. On the other hand, ex post evaluations are only done very infrequently, even though such analyses can be very useful. Ex post evaluation can be used to check whether projects really delivered the benefits expected from them at the time, and to learn which projects do better and which do worse than expected, and why. This paper reviews the literature for evaluating projects that have been completed (ex post evaluation). It also presents the methodology that was selected for the ex post evaluation of ten major transport infrastructure projects supported by the European Regional Development Fund (ERDF) and Cohesion Fund (CF) between 2000 and 2013. A conceptual framework on the impacts of a transport project on society has been developed and worked out in terms of an ex post assessment methodology. The conceptual framework includes a typology of effects for investment projects in the transport sector and the timeframe of effects. Ten case studies (major transport projects) have been carried out using this framework, and the outcomes for these case studies are reported

Foraminiferal biodiversity associated with cold-water coral carbonate mounds and open slope of SE Rockall Bank (Irish continental margin-NE Atlantic)

Cold-water coral (CWC) ecosystems are hotspots of macro- and microfaunal biodiversity and provide refuge for a wide variety of deep-sea species. We investigated how the abundance and biodiversity of 'live' (Rose Bengal stained) foraminifera varies with, and is related to, the occurrence of CWC on the Rockall Bank (NE Atlantic). Qualitative and quantitative analyses were performed on 21 replicate samples from 8 deep-sea stations, including 4 stations on CWC-covered carbonate mounds at depths of 567-657 m, and 4 stations on the adjacent slope at depths of 469-1958 m where CWC were absent. This sampling strategy enabled us to demonstrate that sediments surrounding the living CWC were characterised by higher foraminiferal abundance and biodiversity than open-slope sediments from the same area. A total of 163 foraminiferal species was identified. The dominant species in CWC sediments were: Spirillina vivipara, Allogromiid sp. 1. Globocassidulina subglobosa, Adercotryma wrighti, Eponides pusillus, Ehrenbergina carinata, Planulina ariminensis, Trochammina inflate and Paratrochammina challenged. Foraminifera were nearly absent in adjacent open slope areas subject to strong tidal currents and characterised by coarse grained deposits. We suggest that CWC create a heterogeneous three-dimensional substrate offering microhabitats to a diverse benthic foraminiferal community

Exploring cost-benefit analysis of research, development and innovation infrastructures: an evaluation framework

Governments, funding agencies and policy makers have high expectations on research, development and innovation (RDI) infrastructures in the context of science and innovation policies aimed at sustaining economic growth in the long term. The stakes associated with their selection and evaluation are therefore high. Cost-benefit analysis of RDI infrastructures is a new field. The intangible nature of some benefits and the uncertainty associated to the achievement of research results have often discouraged the use of a proper CBA for RDI infrastructures. Recently, some attempts to develop a CBA theoretical framework for RDI infrastructures have been made in the context of the use of Structural Funds by the Czech government and JASPERS. Moreover, the new Guide for the CBA of investment projects in the context of Cohesion Policy, recently adopted by the European Commission (2014) provides guidelines to appraise RDI projects, but also admits that \u2013 due to lack of experience and best practices \u2013 further steps are needed to improve the evaluation framework. This paper presents the results and the lessons learned on how to apply ex-ante CBA for major RDI infrastructures by a team of economists and scientists at the University of Milan and CSIL during a three-year research project supported by a EIBURS grant of the European Investment Bank Institute. Albeit the comprehensive conceptual framework presented in the paper builds on principles firmly rooted in CBA tradition, their application to the RDI sector is still in its infancy. So far, the model has been applied on two cases in physics involving particle accelerators (the Large Hadron Collider (LHC) at CERN and the National Centre for Oncological Treatment (CNAO) in Italy)). In a nutshell, the model presented break down benefits into two broad classes: i) use benefits, held by different categories of infrastructure\u2019s users such as scientists, firms, students and general public visitors, and ii) non-use benefits, denoting the social value for the discovery potential of the RDI infrastructure regardless of its actual or future use. We argue that the social value of discovery can be estimated with contingent valuation techniques. Another significant feature of our approach is the stochastic nature of the CBA model, intended to deal with the uncertainty and risk of optimism bias in the estimates

Cost-benefit analysis of applied research infrastructure : Evidence from health care

The present study aims at offering empirical evidence to improve existing knowledge and theory building on research infrastructure evaluation. Through an inductive case study research strategy, an innovative cost-benefit analysis framework has been used to assess the impact of an applied research infrastructure. The case study is the National Hadrontherapy Centre for Cancer Treatment (CNAO) located in Pavia (Italy). CNAO is an applied research facility specialised in hadrontherapy, an advanced oncological treatment showing clinical advantages as compared to traditional radiotherapy, at the same time being more expensive as it exploits non-commercial accelerators technology and sophisticated control and dose delivery systems. The analysis shows that with a fairly high probability the Centre provides a positive net contribution to society's welfare. Source of benefits are mainly health treatments to patients, for whom gains in terms of longer or better lives are guaranteed as compared to a counterfactual situation where they are treated with conventional therapies or they have no alternatives. Such benefits are the direct consequences of the application to end users of the knowledge developed in the Centre with research activities and are quantified and assessed on the basis of conventional cost-benefit analysis (CBA) approaches for health benefits. Additional benefits generated by the Centre are typical of research infrastructures in different scientific domains and refer to technological spillovers (namely creation of spin-offs, technological transfer to companies in the supply chain and to other similar facilities), knowledge creation (production of scientific outputs), human capital formation (training of doctoral students, technicians and professionals in the field of hadrontherapy) and cultural outreach (students, researchers and wider public visiting the facilities). Evidences show that the adopted CBA framework is a promising avenue as compared to existing alternative methodologies informing decision-making. Further research is however needed to fine tune the methodology, in particular for what concerns technological spillovers and knowledge creation benefits

Hafnium silicide formation on Si(100) upon annealing

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORHigh dielectric constant materials, such as HfO2, have been extensively studied as alternatives to SiO2 in new generations of Si based devices. Hf silicate/silicide formation has been reported in almost all literature studies of Hf based oxides on Si, using different methods of preparation. A silicate interface resembles close to the traditional Si/SiO2. The silicate very likely forms a very sharp interface between the Si substrate and the metal oxide, and would be suitable for device applications. However, the thermal instability of the interfacial silicate/oxide film leads to silicidation, causing a dramatic loss of the gate oxide integrity. Despite the importance of the Hf silicide surface and interface with Si, only a few studies of this surface are present in the literature, and a structural determination of the surface has not been reported. This paper reports a study of the Hf silicide formation upon annealing by using a combination of XPS, LEED, and x-ray photoelectron diffraction (XPD) analyses. Our results clearly indicate the formation of a unique ordered Hf silicide phase (HfSi2), which starts to crystallize when the annealing temperature is higher than 550 °C.High dielectric constant materials, such as HfO2, have been extensively studied as alternatives to SiO2 in new generations of Si based devices. Hf silicate/silicide formation has been reported in almost all literature studies of Hf based oxides on Si, using different methods of preparation. A silicate interface resembles close to the traditional Si/SiO2. The silicate very likely forms a very sharp interface between the Si substrate and the metal oxide, and would be suitable for device applications. However, the thermal instability of the interfacial silicate/oxide film leads to silicidation, causing a dramatic loss of the gate oxide integrity. Despite the importance of the Hf silicide surface and interface with Si, only a few studies of this surface are present in the literature, and a structural determination of the surface has not been reported. This paper reports a study of the Hf silicide formation upon annealing by using a combination of XPS, LEED, and x-ray photoelectron diffraction (XPD) analyses. Our results clearly indicate the formation of a unique ordered Hf silicide phase (HfSi2), which starts to crystallize when the annealing temperature is higher than 550 °C.747110FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORSem informaçãoSem informação170/04This work was financially supported by DAAD (PROBRAL D/03/23553) from Germany, and FAPESP, CNPq, and CAPES (PROBRAL 170/04) from Brazil. A.S. especially would like to thank CAPES for their support

Discovery of oxybisbenzoylamides as a new class of antimalarial agents

We have previously described several potent dual inhibitors of Plasmodium falciparum (Pf) growth characterized by the presence of statin, a \u3b2-hydroxyl amino acid able to inhibit parasite\u2019s plasmepsins (PLM). While investigating the mechanism of action of these inhibitors new compounds deprived of statin were synthetized which lost the ability to inhibit PLM, but retained a significant Pf growth inhibition. Further structural simplifications showed that the inhibition of Pf viability was to ascribe to a new pharmacophore never described before as antimalaria

Guideline Application in Real world: multi-Institutional Based survey of Adjuvant and first-Line pancreatic Ductal adenocarcinoma treatment in Italy. Primary analysis of the GARIBALDI survey

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% >75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine + capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel + gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nab-paclitaxel + gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing