4-D Tomographic Inference: Application to SPECT and MR-driven PET

Emission tomographic imaging is framed in the Bayesian and information theoretic framework. The first part of the thesis is inspired by the new possibilities offered by PET-MR systems, formulating models and algorithms for 4-D tomography and for the integration of information from multiple imaging modalities. The second part of the thesis extends the models described in the first part, focusing on the imaging hardware. Three key aspects for the design of new imaging systems are investigated: criteria and efficient algorithms for the optimisation and real-time adaptation of the parameters of the imaging hardware; learning the characteristics of the imaging hardware; exploiting the rich information provided by depthof- interaction (DOI) and energy resolving devices. The document concludes with the description of the NiftyRec software toolkit, developed to enable 4-D multi-modal tomographic inference

Geo-hydrological hazard underlined by toponymy of Italian Military Geographycal Institute maps at 1:25,000 scale. Contributions to the knowledge of floodplain and hillslope dinamycs

Toponymy is a linguistic discipline, which has already been used as a tool for geographical studies in Italy and particularly in Liguria. Geographical studies have already classified the toponyms in several categories: physical geography, human geography and socio-economic geography. By selecting the place names connected to physical geography, we study those suggesting the presence of landslides or floods. We focussed on the Italian Military Geographic Institute maps at 1: 25.000 scale, edited between 1936-1939 and related to a territory approximately located between Genoa and Chiavari, in Ligurian coastal area, and Tortona and Piacenza in Po valley. On the Ligurian slopes we have examined the maps relating to the Polcevera, Bisagno and Entella streams catchments. For the Po side we dealt with maps of the Scrivia and Trebbia rivers catchments: From the Ligurian-Po watershed, these rivers flow into the Adriatic Sea. The place names have been compared with landslide and flood hazard maps of Basin Master Plans for geo-hydrological risk reduction. The toponyms feature a linguistic layer linked to different historical periods. In particular in the study area several layers have been recognized: the ancient Ligurian pre-Roman, Latin, ancient Lombard, vulgar Gaulish-Italic of local languages and Italian terms related to the twentieth century. The first three layers and the last one match in the entire area of study. The vulgar Gaulish-Italic is structured into two Ligurian and Emilian groups: the latter is further splitted into the Oltrepo variants of Tortona and Piacenza. The identified names were distinguished in related-landslides or floods. In addition, the toponyms have been further divided into three linguistic influence areas: Ligurian, from Ligurian Sea up to Novi Ligure and Bobbio, the language of Tortona, downstream of Novi Ligure and Piacenza from Bobbio to Po river. Overall, place names linked to physical geography features represent nearly 25% of toponyms with a density of about 0.5 per km2. Almost half of these are toponyms related to landslides, floods or predisposing factors such as erosion, steepness or water. The names of places linked to landsliding prevail in Liguria, while those related to the waters or floods in the Po areas are located in plain areas or in very gentle slopes. The most common names related to landslides or erosion are \u201cmoggia\u201d, \u201cliggia\u201d or \u201ccrosi\u201d and similar, which respectively mean swampy deposits, landslides or gullies. Names related to floods are \u201criva\u201d, \u201cpiana\u201d \u201cponte\u201d or \u201cisola\u201d which mean respectively edge of fluvial scarp, floodplain, bridge or isle. The comparison with the Basin Master Plan gave satisfying results: we found a good correspondence between names and geo-hydrological hazard. The use of toponyms allowed a geographycal interpretation of the slope and floodplain dynamics. It suggests a possible use of toponymys in land planning activities

A developmental evaluation approach to lesson study: exploring the impact of lesson study in London schools

This article presents a methodology for the developmental evaluation of a lesson study programme in primary and secondary schools. Our approach combined the principles of (i) user-focused evaluation, in which, as evaluators, we acted as participatory members of the innovation team and sought to involve users in the design and implementation of evaluation tools, (ii) a multi-level logical model to guide data collection and impact measurement and (iii) an ‘improving rather than proving’ approach to evaluation. The evaluation tools were used on a programme to promote lesson study in London schools involving 133 teachers and 33 schools. The evaluation methodology included outcomes at school leadership, teacher and student levels. Issues of internal and external validity are discussed and strengths and weaknesses are described. Findings showed promise in the use of our scale to measure changes in teacher pedagogical outcomes and in the recording of qualitative changes to both teachers and students as a result of the lesson study cycles. Suggestions for the future use and development of this methodology are proposed, including better use of control groups and quantitative measures to record changes in learning outcomes for students. List of Abbreviations: HE: Higher Education; LS: Lesson Study; PD: Professional Developmen

Cystic Fibrosis: A New Target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines

The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity

Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity.

Deletion of phenylalanine 508 (F508del) in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is the most frequent mutation causing cystic fibrosis (CF). F508del-CFTR is misfolded and prematurely degraded. Recently thymosin a-1 (Tα-1) was proposed as a single molecule-based therapy for CF, improving both F508del-CFTR maturation and function by restoring defective autophagy. However, three independent laboratories failed to reproduce these results. Lack of reproducibility has been ascribed by the authors of the original paper to the use of DMSO and to improper handling. Here, we address these potential issues by demonstrating that Tα-1 changes induced by DMSO are fully reversible and that Tα-1 peptides prepared from different stock solutions have equivalent biological activity. Considering the negative results here reported, six independent laboratories failed to demonstrate F508del-CFTR correction by Tα-1. This study also calls into question the autophagy modulator cysteamine, since no rescue of mutant CFTR function was detected following treatment with cysteamine, while deleterious effects were observed when bronchial epithelia were exposed to cysteamine plus the antioxidant food supplement EGCG. Although these studies do not exclude the possibility of beneficial immunomodulatory effects of thymosin α-1, they do not support its utility as a corrector of F508del-CFTR

‘Warrant’ revisited: Integrating mathematics teachers’ pedagogical and epistemological considerations into Toulmin’s model for argumentation

In this paper, we propose an approach to analysing teacher arguments that takes into account field dependence—namely, in Toulmin’s sense, the dependence of warrants deployed in an argument on the field of activity to which the argument relates. Freeman, to circumvent issues that emerge when we attempt to determine the field(s) that an argument relates to, proposed a classification of warrants (a priori, empirical, institutional and evaluative). Our approach to analysing teacher arguments proposes an adaptation of Freeman’s classification that distinguishes between: epistemological and pedagogical a priori warrants, professional and personal empirical warrants, epistemological and curricular institutional warrants, and evaluative warrants. Our proposition emerged from analyses conducted in the course of a written response and interview study that engages secondary mathematics teachers with classroom scenarios from the mathematical areas of analysis and algebra. The scenarios are hypothetical, grounded on seminal learning and teaching issues, and likely to occur in actual practice. To illustrate our proposed approach to analysing teacher arguments here, we draw on the data we collected through the use of one such scenario, the Tangent Task. We demonstrate how teacher arguments, not analysed for their mathematical accuracy only, can be reconsidered, arguably more productively, in the light of other teacher considerations and priorities: pedagogical, curricular, professional and personal

Siting marine protected areas based on habitat quality and extent provides the greatest benefit to spatially structured metapopulations

Connectivity and its role in the persistence and sustainability of marine metapopulations are attracting increased attention from the scientific community and coastal resource managers. Whether protection should prioritize the connectivity structure or demographic characteristics of a given patch is still unclear. We design a three-stage population model to analyze the relative importance of sources, sinks, quality and extent of juvenile and adult habitat, and node centralities (eigenvector, degree, closeness, and betweenness) as a basis for prioritizing sites. We use a logistic-type stage-structured model to describe the local dynamics of a population with a sessile adult stage and network models to elucidate propagule-exchange dynamics. Our results show that the coupled states of habitat extent and quality, which determine population carrying capacity, are good criteria for protection strategy. Protecting sites on the basis of sources, sinks, or other centrality measures of connectivity becomes optimal only in limited situations, that is, when larval production is not dependent on the adult population. Our findings are robust to a diverse set of larval pathway structures and levels of larval retention, which indicates that the network topology may not be as important as carrying capacity in determining the fate of the metapopulation. Protecting extensive, good quality habitat can help achieve both conservation and fisheries objectives

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro-or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma-and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients

Predictive fat mass equations for spinal muscular atrophy type I children: Development and internal validation

BACKGROUND: Body composition assessment is paramount for spinal muscular atrophy type I (SMA I) patients, as weight and BMI have proven to be misleading for these patients. Despite its importance, no disease-specific field method is currently available, and the assessment of body composition of SMA I patients requires reference methods available only in specialized settings. OBJECTIVE: To develop predictive fat mass equations for SMA I children based on simple measurements, and compare existing equations to the new disease-specific equations. DESIGN: Demographic, clinical and anthropometric data were examined as potential predictors of the best candidate response variable and non-linear relations were taken into account by transforming continuous predictors with restricted cubic splines. Alternative models were fitted including all the dimensions revealed by cluster analysis of the predictors. The best models were then internally validated, quantifying optimism of the obtained performance measures. The contribution of nusinersen treatment to the unexplained variability of the final models was also tested. RESULTS: A total of 153 SMA I patients were included in the study, as part of a longitudinal observational study in SMA children conducted at the International Center for the Assessment of Nutritional Status (ICANS), University of Milan. The sample equally represented both sexes (56% females) and a wide age range (from 3 months to 12 years, median 1.2 years). Four alternative models performed equally in predicting fat mass fraction (fat mass/body weight). The most convenient was selected and further presented. The selected model uses as predictors sex, age, calf circumference and the sum of triceps, suprailiac and calf skinfold thicknesses. The model showed high predictive ability (optimism corrected coefficient of determination, R2 = 0.72) and internal validation indicated little optimism both in performance measures and model calibration. The addition of nusinersen as a predictor variable did not improve the prediction. The disease-specific equation was more accurate than the available fat mass equations. CONCLUSIONS: The developed prediction model allows the assessment of body composition in SMA I children with simple and widely available measures and with reasonable accuracy

Growth patterns in children with spinal muscular atrophy

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. Results: Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4–1.6) and 4.1 (2.1–6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. Conclusions: These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth