Variance component estimation with longitudinal data: a simulation study with alternative methods

A pedigree structure distributed in three different places was generated. For each offspring, phenotypicinformation was generated for five different ages (12, 30, 48, 66 and 84 months). The data file was simulated allowing someinformation to be lost (10, 20, 30 and 40%) by a random process and by selecting the ones with lower phenotypic values,representing the selection effect. Three alternative analysis were used, the repeatability model, random regression model andmultiple-trait model. Random regression showed to be more adequate to continually describe the covariance structure ofgrowth over time than single-trait and repeatability models, when the assumption of a correlation between successivemeasurements in the same individual was different from one another. Without selection, random regression and multiple-traitmodels were very similar

Pluvial flooding: high-resolution stochastic hazard mapping in urban areas by using fast-processing DEM-based algorithms

Climate change and rapid expansion of urban areas are expected to increase pluvial flood hazard and risk in the near future, and particularly so in large developed areas and cities. Therefore, large-scale and high-resolution pluvial flood hazard mapping is required to identify hotspots where mitigation measures may be applied to reduce flood risk. Depressions or low points in urban areas where runoff volumes can be stored are prone to pluvial flooding. The standard approach based on estimating synthetic design hyetographs assumes, in a given depression, that the T-year design storm generates the T-year pluvial flood. In addition, urban areas usually include several depressions even linked or nested that would require distinct design hyetographs instead of using a unique synthetic design storm. In this paper, a stochastic methodology is proposed to address the limitations of this standard approach, developing large-scale ~ 2 m-resolution pluvial flood hazard maps in urban areas with multiple depressions. The authors present an application of the proposed approach to the city of Pamplona in Spain (68.26 km2)

Stakeholder perspectives to improve risk management in European farming systems

The challenges faced by agricultural systems call for an advance in risk management (RM) assessments. This research identifies and discusses potential improvements to RM across 11 European Union (EU) farming systems (FS). The paper proposes a comprehensive, participatory approach that accounts for multi-stakeholder perspectives relying on 11 focus groups for brainstorming and gathering suggestions to improve RM. Data analysis is based on content analysis and coding of suggested improvements, and their assessment through the lenses of main challenges faced, farms’ flexibility, and dependence on subsidies. First, the results show that necessary improvements differ depending on whether they have their origin in sudden shocks or long-term pressures. Second, farm dependence on direct payments determines a stronger need to improve financial instruments, whereas farm flexibility suggests a need for more accessible and tailored tools for low-flexibility FS, and increased know-what and know-how for high-flexibility FS. Third, our findings indicate a potential for extending stakeholder involvement in RM to new or unconventional roles. Underlying specific improvements, the paper suggests and discusses three main avenues to improve RM as a whole: i) a developed learning and knowledge network; ii) new forms of collaboration; and iii) integrated financial and policy instruments

How do Stakeholders Perceive the Sustainability and Resilience of EU Farming Systems?

An increasing variety of stresses and shocks provides challenges and opportunities for EU farming systems. This article presents findings of a participatory assessment on the sustainability and resilience of eleven EU farming systems, to inform the design of adequate and relevant strategies and policies. According to stakeholders that participated in workshops, the main functions of farming systems are related to food production, economic viability and maintenance of natural resources. Performance of farming systems assessed with regard to these and five other functions was perceived to be moderate. Past strategies were often geared towards making the system more profitable, and to a lesser extent towards coupling production with local and natural resources, social self‐organisation, enhancing functional diversity, and facilitating infrastructure for innovation. Overall, the resilience of the studied farming systems was perceived as low to moderate, with robustness and adaptability often dominant over transformability. To allow for transformability, being reasonably profitable and having access to infrastructure for innovation were viewed as essential. To improve sustainability and resilience of EU farming systems, responses to short‐term processes should better consider long‐term processes. Technological innovation is required, but it should be accompanied with structural, social, agro‐ecological and institutional changes

Activity and high-order effective connectivity alterations in Sanfilippo C patient-specific neuronal networks

Induced pluripotent stem cell (iPSC) technology has been successfully used to recapitulate phenotypic traits of several human diseases in vitro. Patient-specific iPSC-based disease models are also expected to reveal early functional phenotypes, although this remains to be proved. Here, we generated iPSC lines from two patients with Sanfilippo type C syndrome, a lysosomal storage disorder with inheritable progressive neurodegeneration. Mature neurons obtained from patient-specific iPSC lines recapitulated the main known phenotypes of the disease, not present in genetically corrected patient-specific iPSC-derived cultures. Moreover, neuronal networks organized in vitro from mature patient-derived neurons showed early defects in neuronal activity, network-wide degradation, and altered effective connectivity. Our findings establish the importance of iPSC-based technology to identify early functional phenotypes, which can in turn shed light on the pathological mechanisms occurring in Sanfilippo syndrome. This technology also has the potential to provide valuable readouts to screen compounds, which can prevent the onset of neurodegeneration

Risk management and its role in enhancing perceived resilience capacities of farms and farming systems in Europe

In facing future challenges, risk management (RM) is essential for European farming systems (FS). This article synthesises lessons learned on RM based on a farm survey, interviews with farmers, and focus groups involving a range of FS actors. In contrast to previous literature, we broaden the definition of RM to include strategies that target long-term structural challenges, as well as expanding the level of analysis from the farm to the FS level. The results were consistent across the different methods. We found that farmers mainly worry about economic challenges: in particular long-term pressures. We also found that European farmers have implemented diverse RM strategies in the past 5 years, and that no single strategy has been applied by the vast majority of farmers. In line with perceptions of future challenges, there is a demand for the reorientation of RM strategies towards long-term pressures, rather than short-term shocks. FS actors were found to perceive RM as enhancing resilience capacities, especially adaptability. The results of interviews distinguished between major learning strategies and the attributes of farmers for enhancing robustness, adaptive, or transformative capacities. Focus group discussions revealed that the future development of RM strategies requires contributions by all FS actors

D5.6 Impacts of improved strategies and policy options on the resilience of farming systems across the EU

Resilience is the ability to deal with shocks and stresses, including the unknown and previously unimaginable, such as the Covid19 crisis. The aim of this paper is to assess responses of farming systems (FS) to this crisis and to assess them from the perspective of resilience thinking. We build on a resilience framework developed in the SURE‐Farm project and on ongoing resilience assessments in 11 FS across Europe through which we have an in‐depth understanding of the ‘pre‐Covid19 situation’ in each FS. This includes insights whether an FS has an enabling (or constraining) environment, who are the relevant system actors beyond farms, and what are the social, economic and ecological functions to be delivered by the system. The analysis allows us to understand which resilience resources and strategies were mobilised in different FS and thereby to explain differences in the ability of FS to cope with and respond to the crisis. Furthermore, the approach enables us to put crisis responses in a broader resilience perspective and to assess whether responses might enhance (or constrain) future resilience. Thus, our analysis allows to draw policy and industry relevant conclusions how to increase resilience of farming systems

May-Hegglin Anomaly, Sebastian Syndrome, Fechtner Syndrome, and Epstein Syndrome Are not Distinct Entities but Represent a Variable Expression of a Single Illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects

From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects

Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Ab42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognitionenhancing anti-AD lead