Drug treatment efficiency depends on the initial state of activation in nonlinear pathways

An accurate prediction of the outcome of a given drug treatment requires quantitative values for all parameters and concentrations involved as well as a detailed characterization of the network of interactions where the target molecule is embedded. Here, we present a high-throughput in silico screening of all potential networks of three interacting nodes to study the effect of the initial conditions of the network in the efficiency of drug inhibition. Our study shows that most network topologies can induce multiple dose-response curves, where the treatment has an enhanced, reduced or even no effect depending on the initial conditions. The type of dual response observed depends on how the potential bistable regimes interplay with the inhibition of one of the nodes inside a nonlinear pathway architecture. We propose that this dependence of the strength of the drug on the initial state of activation of the pathway may be affecting the outcome and the reproducibility of drug studies and clinical trials.This work has been supported by the Ministry of Science and Technology of Spain via a Ramón y Cajal Fellowship (Ref. RYC-2010-07450), a grant from Plan Nacional framework (Ref. BFU2011-30303 and & BFU2014-53299-P) and a FPU fellowship. We thank Raúl Guantes, Juan Díaz Colunga, Marta Ibañes, Rosa Martínez Corral, Saúl Ares and Katherine Gonzales for invaluable help and technical assistance

Chapter A statistical information system in support of job policies orientation

A significant problem for labour market policies relies on the individuation of the most advisable skills to have and to enhance through focused training offers. Vocational training systems and institutions are called to answer the question posed by every person looking for a new job or professional opportunities: which are the skills-to-have to enhance the professional profile? Many efforts have been made to answer this question, mainly designing predictive models; however, these models are often limited to specific economic sectors and usually don’t adopt a country-specific perspective. This paper proposes a recommendation system oriented to specific users: once that the user has described his/her skills profile, the system suggests the skills that, once got, will fit with the most frequent job vacancies. In this proposal perspective, the skills are proposed regardless of the economic sector, and they are compatible with the characteristics of the specific country labour market. In this contribution, we will focus on the Italian market; the recommendation system is based on the job ads published by Italian companies on various websites for both 2019 and 2020 after the skills required for each job offer have been mapped to one of the skills presented in the classification of European Skills/ competence, qualifications ad Occupations (ESCO)

Chapter Big data analysis and labour market: an analysis of Italian online job vacancies data

Economists and social scientists are increasingly making use of web data to address socio-economic issues and to integrate existing sources of information. The data produced by online platforms and websites could produce a lot of useful and multidimensional information with a variety of potential applications in socio-economic analysis. In this respect, with the internet growth and knowledge, many aspects of job search have been transformed due to the availability of online tools for job searching, candidate searching and job matching. In European countries there is growing interest in designing and implementing real labour market information system applications for internet labour market data in order to support policy design and evaluation through evidence-based decision-making. The analysis of labour market web data could provide useful information for policy-makers to define labour market strategies as big data, jointly with official statistics, support policy makers in a pressing policy question namely “How to tackle the mismatch between jobs and skills?”. In this regard, the topic of skills gap, how to measure it and how to bridge it with education and continuous training have been tackled by using the big data collection, such as the Cedefop (European Center for the Development of Vocational Training) initiative and the Wollybi Project (made by Burning Glass). In this framework, this contribution focuses on the issues arising from the use (and the usefulness) of on-line job vacancy data to analyse the Italian labour market by using the Wollybi data available for the years 2019 and 2020. Furthermore, the availability of data for the year 2020, will allow us to evaluate whether there has been an impact of COVID19 in terms of needed skills and required occupations in the online job vacancies

Optical coherence tomography in Alzheimer's disease. A meta-analysis

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. METHODS AND FINDINGS: Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. RESULTS: 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). CONCLUSION: Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments

Oxidative Stress Induces Protein Phosphatase 2A-dependent Dephosphorylation of the Pocket Proteins pRb, p107, and p130

Oxidative stress induces cell death and growth arrest. In this study, the regulation and the functional role of the retinoblastoma family proteins pRb, p107, and p130 in the cellular response to oxidative stress were investigated. Treatment of endothelial cells with H2O2 induced rapid hypophosphorylation of the retinoblastoma family proteins. This event did not require p53 or p21Waf1/Cip1/Sdi1 and was not associated with cyclin/cyclin-dependent kinase down-modulation. Four lines of evidence indicate that H2O2-induced hypophosphorylation of pRb, p107, and p130 was because of the activity of protein phosphatase 2A (PP2A). First, cell treatment with two phosphatase inhibitors, okadaic acid and calyculin A, prevented the hypophosphorylation of the retinoblastoma family proteins, at concentrations that specifically inhibit PP2A. Second, SV40 small t, which binds and inhibits PP2A, when overexpressed prevented H2O2-induced dephosphorylation of the retinoblastoma family proteins, whereas a SV40 small t mutant unable to bind PP2A was totally inert. Third, PP2A core enzyme physically interacted with pRb and p107, both in H2O2-treated and untreated cells. Fourth, a PP2A phosphatase activity was co-immunoprecipitated with pRb, and the activity of pRb-associated PP2A was positively modulated by cell treatment with H2O2. Because DNA damaging agents inhibit DNA synthesis in a pRb-dependent manner, it was determined whether the PP2A-mediated dephosphorylation of the retinoblastoma family proteins played a role in this S-phase response. Indeed, it was found that inhibition of PP2A by SV40 small t over-expression prevented DNA synthesis inhibition induced by H2O2

Attempted Suicide in the Older Adults: A Case Series From the Psychiatry Ward of the University Hospital Maggiore Della Carità, Novara, Italy

: Introduction: As suicide rates increase with age, it is mandatory to carefully assess old age suicidal behaviors. Our aim was to describe the main socio-demographic and clinical features of a sample of suicide attempters aged 65 years and older, and to assess differences within the sample (men vs. women; patients with vs. without a previous history of suicide attempt; patients with vs. without a previous psychiatric history). Methods: Retrospective study conducted at the Maggiore della Carità University Hospital, Novara, Italy. Results: A higher percentage of female patients in our sample were treated by or referred to mental health services, while a greater percentage of male patients required a prolonged clinical observation in the Emergency Room (ER) or in non-psychiatric wards before psychiatric admission. The percentage of patients without previous psychiatric history taking anxiolytic and sedative medications was 25%. Conclusion: It is likely that different clusters and types of suicide attempters exist. Women in our sample appeared more proactive in asking for help, and more likely to be already treated by or referred to a psychiatric service, suggesting the need to facilitate the access to psychiatric services for the male population aged 65 years and older, or to offer support and care for the non-psychiatric reasons (comorbidities, pain, and loss of autonomy) possibly underlying suicidal behavior in this specific group. The use of medications deserves more attention considering the possible critical diagnostic issues in this age group

Correlation of Anti-Salmonella Antibodies Between Serum and Saliva Samples Collected From Finisher Pigs

Saliva samples obtained by using absorptive devices, can provide an alternative diagnostic matrix to serum for monitoring disease status in pigs. The aim of this study was to investigate the correlation of anti-Salmonella antibodies between serum and saliva samples collected from pigs. Twenty individual paired serum and saliva samples were collected from a single farm. Anti-Salmonella IgG was detected in individual serum samples using a commercial Salmonella ELISA kit, validated for sera. The same kit was used with a protocol modified by extending incubation time and increasing temperature to test individual saliva samples. Anti-Salmonella IgG antibodies in pig saliva were always detected at a lower level than in the matching serum samples. A correlation (rho = 0.66; p = 0.002) and a moderate agreement (K &gt; 0.62 p = 0.003) was found between individual Salmonella IgG in serum and saliva samples. Both correlation and the agreement levels are moderate. The size of this investigation was small, and further studies are necessary to further confirm these findings. The results of this work provide some evidence that saliva samples have the potential to be used for the diagnosis of Salmonella infection in pig farms

Intellectual property rights and the international transfer of climate change mitigating technologies

Our study is a quasi-replication of Dechezleprêtre et al. (2013), which was among the first studies to find a strong role for IPRs in explaining the international transfer of climate change and mitigation technologies (CCMTs). Their result is at odds with the received wisdom on the ambiguous role of IPRs in determining technology transfer to developing countries as strong IPRs can enable a market expansion effect and result in technology transfer but they may also strengthen monopoly power, increase value and reduce the incentive to transfer a large volume of technology. We extend the Dechezleprêtre et al. (2013) study by distinguishing between OECD and non-OECD groups of countries, including the effect of both de jure and de facto IPRs, and extending the period of study to include the years 2008–2018, when global trade and investment slowed down. Our exercise reveals that technology transfer to non-OECD countries is associated with a different set of policies compared to OECD countries. We also find that strong IP policies have not had the same beneficial CCMTs transfer outcomes in 2008–2018 as they did in the earlier period and in fact strong de facto IPR reduced the volume of CCMTs transfer to all countries

Therapeutic Peptides Targeting PPI in Clinical Development: Overview, Mechanism of Action and Perspectives

Targeting protein-protein interactions (PPIs) has been recently recognized as an emerging therapeutic approach for several diseases. Up today, more than half a million PPI dysregulations have been found to be involved in pathological events. The dynamic nature of these processes and the involvement of large protein surfaces discouraged anyway the scientific community in considering them promising therapeutic targets. More recently peptide drugs received renewed attention since drug discovery has offered a broad range of structural diverse sequences, moving from traditionally endogenous peptides to sequences possessing improved pharmaceutical profiles. About 70 peptides are currently on the marked but several others are in clinical development. In this review we want to report the update on these novel APIs, focusing our attention on the molecules in clinical development, representing the direct consequence of the drug discovery process of the last 10 years. The comprehensive collection will be classified in function of the structural characteristics (native, analogous, heterologous) and on the basis of the therapeutic targets. The mechanism of interference on PPI will also be reported to offer useful information for novel peptide desig