The Integrated European Project "GEHA - GEnetics of Healthy Aging": recruitment, health status assessment and survival of the Italian 90+ sibpairs

The present study is part of the EU Integrated Project “GEHA – Genetics of Healthy Aging” (Franceschi C et al., Ann N Y Acad Sci. 1100: 21-45, 2007), whose aim is to identify genes involved in healthy aging and longevity, which allow individuals to survive to advanced age in good cognitive and physical function and in the absence of major age-related diseases. Aims The major aims of this thesis were the following: 1. to outline the recruitment procedure of 90+ Italian siblings performed by the recruiting units of the University of Bologna (UNIBO) and Rome (ISS). The procedures related to the following items necessary to perform the study were described and commented: identification of the eligible area for recruitment, demographic aspects related to the need of getting census lists of 90+siblings, mail and phone contact with 90+ subjects and their families, bioethics aspects of the whole procedure, standardization of the recruitment methodology and set-up of a detailed flow chart to be followed by the European recruitment centres (obtainment of the informed consent form, anonimization of data by using a special code, how to perform the interview, how to collect the blood, how to enter data in the GEHA Phenotypic Data Base hosted at Odense). 2. to provide an overview of the phenotypic characteristics of 90+ Italian siblings recruited by the recruiting units of the University of Bologna (UNIBO) and Rome (ISS). The following items were addressed: socio-demographic characteristics, health status, cognitive assessment, physical conditions (handgrip strength test, chair-stand test, physical ability including ADL, vision and hearing ability, movement ability and doing light housework), life-style information (smoking and drinking habits) and subjective well-being (attitude towards life). Moreover, haematological parameters collected in the 90+ sibpairs as optional parameters by the Bologna and Rome recruiting units were used for a more comprehensive evaluation of the results obtained using the above mentioned phenotypic characteristics reported in the GEHA questionnaire. 3. to assess 90+ Italian siblings as far as their health/functional status is concerned on the basis of three classification methods proposed in previous studies on centenarians, which are based on: • actual functional capabilities (ADL, SMMSE, visual and hearing abilities) (Gondo et al., J Gerontol. 61A (3): 305-310, 2006); • actual functional capabilities and morbidity (ADL, ability to walk, SMMSE, presence of cancer, ictus, renal failure, anaemia, and liver diseases) (Franceschi et al., Aging Clin Exp Res, 12:77-84, 2000); • retrospectively collected data about past history of morbidity and age of disease onset (hypertension, heart disease, diabetes, stroke, cancer, osteopororis, neurological diseases, chronic obstructive pulmonary disease and ocular diseases) (Evert et al., J Gerontol A Biol Sci Med Sci. 58A (3): 232-237, 2003). Firstly these available models to define the health status of long-living subjects were applied to the sample and, since the classifications by Gondo and Franceschi are both based on the present functional status, they were compared in order to better recognize the healthy aging phenotype and to identify the best group of 90+ subjects out of the entire studied population. 4. to investigate the concordance of health and functional status among 90+ siblings in order to divide sibpairs in three categories: the best (both sibs are in good shape), the worst (both sibs are in bad shape) and an intermediate group (one sib is in good shape and the other is in bad shape). Moreover, the evaluation wanted to discover which variables are concordant among siblings; thus, concordant variables could be considered as familiar variables (determined by the environment or by genetics). 5. to perform a survival analysis by using mortality data at 1st January 2009 from the follow-up as the main outcome and selected functional and clinical parameters as explanatory variables. Methods A total of 765 90+ Italian subjects recruited by UNIBO (549 90+ siblings, belonging to 258 families) and ISS (216 90+ siblings, belonging to 106 families) recruiting units are included in the analysis. Each subject was interviewed according to a standardized questionnaire, comprising extensively utilized questions that have been validated in previous European studies on elderly subjects and covering demographic information, life style, living conditions, cognitive status (SMMSE), mood, health status and anthropometric measurements. Moreover, subjects were asked to perform some physical tests (Hand Grip Strength test and Chair Standing test) and a sample of about 24 mL of blood was collected and then processed according to a common protocol for the preparation and storage of DNA aliquots. Results From the analysis the main findings are the following: - a standardized protocol to assess cognitive status, physical performances and health status of European nonagenarian subjects was set up, in respect to ethical requirements, and it is available as a reference for other studies in this field; - GEHA families are enriched in long-living members and extreme survival, and represent an appropriate model for the identification of genes involved in healthy aging and longevity; - two simplified sets of criteria to classify 90+ sibling according to their health status were proposed, as operational tools for distinguishing healthy from non healthy subjects; - cognitive and functional parameters have a major role in categorizing 90+ siblings for the health status; - parameters such as education and good physical abilities (500 metres walking ability, going up and down the stairs ability, high scores at hand grip and chair stand tests) are associated with a good health status (defined as “cognitive unimpairment and absence of disability”); - male nonagenarians show a more homogeneous phenotype than females, and, though far fewer in number, tend to be healthier than females; - in males the good health status is not protective for survival, confirming the male-female health survival paradox; - survival after age 90 was dependent mainly on intact cognitive status and absence of functional disabilities; - haemoglobin and creatinine levels are both associated with longevity; - the most concordant items among 90+ siblings are related to the functional status, indicating that they contain a familiar component. It is still to be investigated at what level this familiar component is determined by genetics or by environment or by the interaction between genetics, environment and chance (and at what level). Conclusions In conclusion, we could state that this study, in accordance with the main objectives of the whole GEHA project, represents one of the first attempt to identify the biological and non biological determinants of successful/unsuccessful aging and longevity. Here, the analysis was performed on 90+ siblings recruited in Northern and Central Italy and it could be used as a reference for others studies in this field on Italian population. Moreover, it contributed to the definition of “successful” and “unsuccessful” aging and categorising a very large cohort of our most elderly subjects into “successful” and “unsuccessful” groups provided an unrivalled opportunity to detect some of the basic genetic/molecular mechanisms which underpin good health as opposed to chronic disability. Discoveries in the topic of the biological determinants of healthy aging represent a real possibility to identify new markers to be utilized for the identification of subgroups of old European citizens having a higher risk to develop age-related diseases and disabilities and to direct major preventive medicine strategies for the new epidemic of chronic disease in the 21st century.

La creazione del distretto comunale: Il caso di Reggio Emilia (XII-prima metà XIII secolo)

L’oggetto della ricerca è stato il processo di creazione del distretto del Comune di Reggio Emilia tra il XII e l’inizio del XIII secolo, di cui sono stati analizzati diversi aspetti salienti, così come emergono in primo luogo dall’analisi del liber iurium reggiano, il Liber grossus antiquus. L’elaborato è suddiviso in due parti. Nella prima parte si è cercato di ricostruire le vicende, i legami e il patrimonio delle famiglie rurali reggiane nel corso del XII secolo in particolare e gli aspetti caratteristici del Comune cittadino nella sua fase iniziale. Nella seconda parte ci si è concentrati sull’analisi dei caratteri più rilevanti del processo di creazione del distretto comunale reggiano: il rapporto tra i signori del contado, i Comuni rurali e il Comune urbano; la difesa e l’incremento dei Communia cittadini; la fondazione di borghi franchi e nuovi. Il Comune di Reggio Emilia tentò di annettere l’intero territorio diocesano al distretto cittadino, non riuscendoci completamente e adottando una politica territoriale diversificata a seconda dei caratteri delle zone controllate.

Families Stories. Rappresentazioni di famiglie nella letteratura per l'infanzia in Europa e negli Stati Uniti

In questa tesi dottorale viene preso in analisi il tema della famiglia, uno degli elementi fondanti della riflessione pedagogica, crocevia di una molteplicità di nuclei interpretativi con diramazioni e contaminazioni, con mutamenti attraverso le epoche storiche, rappresentati in pagine contenute nei Classici della letteratura per l’infanzia e nei migliori libri di narrativa contemporanea. Si tratta di un tema di grande ampiezza che ha comportato una scelta mirata di Autori che, nei loro romanzi hanno trattato questioni riguardanti la famiglia nelle sue pluralità delle sue tante accezioni, dalla vita familiare agli abbandoni, dalle infanzie senza famiglia alle famiglie altre. Nelle diverse epoche storiche, le loro narrazioni hanno lasciato un segno per l'originalità interpretativa che ancora oggi ci raccontano storie di vie familiale Dai romanzi ottocenteschi alle saghe fantasy degli ultimi cinquant’anni, fino ai picturebook, destinati ai più piccoli, le families stories possono costituire un materiale pedagogico privilegiato, sia offrendo occasioni di scoperta e conoscenza di sé e del mondo, attraverso le quali i lettori bambini, enigmatici frontalieri, varcano soglie verso altrovi misteriosi, sia fornendo spunti agli studiosi per approfondire tematiche multiple e complesse. Le families stories riflettono spesso in maniera critica le divergenze che possono manifestarsi tra le prassi individuate e studiate dalle scienze umane e sociali e le metafore narrative proposte dai numerosi Autori della letteratura per l’infanzia. Proponendo una prospettiva spesso spiazzante, esse interpretano la realtà a fondo, cogliendo i più piccoli ed inosservati particolari che, invece, hanno la capacità di rompere gli schemi socio-educativi dell’epoca storica in cui le storie prendono vita.

Thermoelectric properties in phase-separated half-Heusler materials

The conversion of dissipated heat into electricity is the basic principle of thermoelectricity. In this context, half-Heusler (HH) compounds are promising thermoelectric (TE) materials for waste heat recovery. They meet all the requirements for commercial TE applications, ranging from good efficiencies via environmentally friendliness to being low cost materials. This work focused on the TE properties of Ti0.3Zr0.35Hf0.35NiSn-based HH materials. This compound undergoes an intrinsic phase separation into a Ti-poor and Ti-rich HH phase during a rapid solidification process. The resulting dendritic microstructure causes a drastic reduction of the thermal conductivity, leading to higher TE efficiencies in these materials. The TE properties and temperature dependence of the phase-separated Ti0.3Zr0.35Hf0.35NiSn compound were investigated. The TE properties can be adjusted depending on the annealing treatment. The extension of annealing time for 21 days at 1000 °C revealed a reduction of the thermal conductivity and thus an enhancement of the TE performance in this sample. An increase of annealing temperature caused a change of the phase fraction ratio in favor of the Ti-rich phase, leading to an improvement of the electronic properties. rnInspired by the TE properties of the Ti0.3Zr0.35Hf0.35NiSn HH compound, the performance of different n- and p-type materials, realized via site substitution with donor and acceptor elements was examined. The fabrication of a TE n- and p-type material pair based on one starting compound can guarantee similar TE and mechanical properties and is enormous beneficial for device engineering. As donor dopants V, Nb and Sb were tested. Depending on the lattice position small doping levels were sufficient to attain distinct improvement in their TE efficiency. Acceptor-induced doping with Sc, Y and Co caused a change in the transport behavior from n- to p- type conduction, revealing the highest Seebeck coefficients obtained in the MNiSn system. rnThen, the long-term stability of an exemplary n- and p-type HH compound was proven. Surprisingly, the dendritic microstructure can be maintained even after 500 cycles (1700 h) from 373 to 873 K. The TE performance of both n- and p-type materials showed no significant change under the long-term treatment, indicating the extraordinary temperature stability of these compounds. Furthermore both HH materials revealed similar temperature-dependence of their mechanical properties. This work demonstrates the excellent suitability of phase-separated HH materials for future TE applications in the moderate temperature range.rn

Investigation of acceptor dopants in ZrNiSn half-Heusler materials

Thermoelectric generators (TEG) are solid state devices and are able to convert thermal energy directly into electricity and thus could play an important role in waste heat recovery in the near future. Half-Heusler (HH) compounds with the general formula MNiSn (M = Ti, Zr, Hf) built a promising class of materials for these applications because of their high Seebeck coefficients, their environmentally friendliness and their cost advantage over conventional thermoelectric materials.rnrnMuch of the existing literature on HH deals with thermoelectric characterization of n-type MNiSn and p-type MCoSb compounds. Studies on p-type MNiSn-based HHs are far fewer in number. To fabricate high efficient thermoelectric modules based on HH compounds, high performance p-type MNiSn systems need to be developed that are compatible with the existing n-type HH compounds. This thesis explores synthesis strategies for p-type MNiSn based compounds. In particular, the efficacy of transition metals (Sc, La) and main group elements (Al, Ga, In) as acceptor dopants on the Sn-site in ZrNiSn, was investigated by evaluating their thermoelectric performance. The most promising p-type materials could be achieved with transition metal dopants, where the introduction of Sc on the Zr side, yielded the highest Seebeck coefficient in a ternary NiSn-based HH compound up to this date. Hall effect and band gap measurements of this system showed, that the high mobility of minority carrier electrons dominate the transport properties at temperatures above 500 K. It could be shown that this is the reason, why n-type HH are successful TE materials for high temperature applications, and that p-types are subjected to bipolar effects which will lead to diminished thermoelectric efficiencies at high temperatures.rnrnTo complement the experimental investigations on different metal dopants and their influence on the TE properties of HH compounds, numerical solutions to the Boltzmann transport equation were used to predict the optimum carrier concentration where the maximum TE efficiency occurs for p-type HH compounds. The results for p-type samples showed that can not be treated within a simple parabolic band model approach, due to bipolar and multi-band effects.rnrnThe parabolic band model is commonly used for bulk TE materials. It is most accurate when the transport properties are dominated by one single carrier type. Since the transport properties of n-type HH are dominated by only one carrier type (high mobility electrons), it could be shown, that the use of a simple parabolic band model lead to a successful prediction of the optimized carrier concentration and thermoelectric efficiency in n-type HH compounds. rn

Thermoelectric performance of p-type TiCoSb half-Heusler compounds - Intrinsic phase separation and charge carrier concentration optimization as key to high efficiency

The world's rising demand of energy turns the development of sustainable and more efficient technologies for energy production and storage into an inevitable task. Thermoelectric generators, composed of pairs of n-type and p-type semiconducting materials, di¬rectly transform waste heat into useful electricity. The efficiency of a thermoelectric mate¬rial depends on its electronic and lattice properties, summarized in its figure of merit ZT. Desirable are high electrical conductivity and Seebeck coefficients, and low thermal con¬ductivity. Half-Heusler materials are very promising candidates for thermoelectric applications in the medium¬ temperature range such as in industrial and automotive waste heat recovery. The advantage of Heusler compounds are excellent electronic properties and high thermal and mechanical stability, as well as their low toxicity and elemental abundance. Thus, the main obstacle to further enhance their thermoelectric performance is their relatively high thermal conductivity.rn rnIn this work, the thermoelectric properties of the p-type material (Ti/Zr/Hf)CoSb1-xSnx were optimized in a multistep process. The concept of an intrinsic phase separation has recently become a focus of research in the compatible n-type (Ti/Zr/Hf)NiSn system to achieve low thermal conductivities and boost the TE performance. This concept is successfully transferred to the TiCoSb system. The phase separation approach can form a significant alternative to the previous nanostructuring approach via ball milling and hot pressing, saving pro¬cessing time, energy consumption and increasing the thermoelectric efficiency. A fundamental concept to tune the performance of thermoelectric materials is charge carrier concentration optimization. The optimum carrier concentration is reached with a substitution level for Sn of x = 0.15, enhancing the ZT about 40% compared to previous state-of-the-art samples with x = 0.2. The TE performance can be enhanced further by a fine-tuning of the Ti-to-Hf ratio. A correlation of the microstructure and the thermoelectric properties is observed and a record figure of merit ZT = 1.2 at 710°C was reached with the composition Ti0.25Hf0.75CoSb0.85Sn0.15.rnTowards application, the long term stability of the material under actual conditions of operation are an important issue. The impact of such a heat treatment on the structural and thermoelectric properties is investigated. Particularly, the best and most reliable performance is achieved in Ti0.5Hf0.5CoSb0.85Sn0.15, which reached a maximum ZT of 1.1 at 700°C. The intrinsic phase separation and resulting microstructure is stable even after 500 heating and cooling cycles.

Inherited cavernous malformations of the central nervous system: clinical and genetic features in 19 Swiss families

Cavernous malformations (CCMs) are benign, well-circumscribed, and mulberry-like vascular malformations that may be found in the central nervous system in up to 0.5% of the population. Cavernous malformations can be sporadic or inherited. The common symptoms are epilepsy, hemorrhages, focal neurological deficits, and headaches. However, CCMs are often asymptomatic. The familiar form is associated with three gene loci, namely 7q21-q22 (CCM1), 7p13-p15 (CCM2), and 3q25.2-q27 (CCM3) and is inherited as an autosomal dominant trait with incomplete penetrance. The CCM genes are identified as Krit 1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3). Here, we present the clinical and genetic features of CCMs in 19 Swiss families. Furthermore, surgical aspects in such families are also discussed.

Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency

Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals. The aim of the present study was to screen for and analyse F13B gene defects in the German population. A total of 150 patients presenting with suspected FXIII deficiency and one patient with severe (homozygous) FXIII deficiency were screened for mutations in F13A and F13B genes. Twenty-five individuals presented with detectable heterozygous mutations, 12 of them in the F13A gene and 13 of them in the F13B gene. We report on the genotype-phenotype correlations of the individuals showing defects in the F13B gene. Direct sequencing revealed 12 unique mutations including seven missense mutations (Cys5Arg, Ile81Asn, Leu116Phe, Val217Ile, Cys316Phe, Val401Glu, Pro428Ser), two splice site mutations (IVS2-1G>C, IVS3-1G>C), two insertions (c.1155_1158dupACTT, c.1959insT) and one in-frame deletion (c.471-473delATT). Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358). Another three missense mutations, (Leu116Phe, Val401Glu, Pro428Ser) were located proximal to other cysteine disulphide bonds, therefore indicating that the region in and around these disulphide bonds is prone to functionally relevant mutations in the FXIII-B subunit. The present study reports on a fairly common prevalence of F13B gene defects in the German population. The regions in and around the cysteine disulphide bonds in the FXIII-B protein may be regions prone to frequent mutations.

The Search for Low Energy Conformational Families of Small Peptides: Searching for Active Conformations of Small Peptides in the Absence of a Known Receptor

Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Previous work revealed that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat model systems, interacting with an unknown receptor, while peptides smaller than eight amino acids did not inhibit breast cancer. We have shown that the use of replica exchange molecular dynamics predicts structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. These simulations identified smaller peptide analogs with a conserved turn, a β-turn formed in the larger peptides. These analogs inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition. We outline the computational methods that were tried and used with the experimental information that led to the successful completion of this research.

The Other Half

Leaders and faculty at private colleges and universities should support funding for public higher education.

Circulation dynamics and its influence on European and Mediterranean January-April climate over the past half millennium: results and insights from instrumental data, documentary evidence and coupled climate models

We use long instrumental temperature series together with available field reconstructions of sea-level pressure (SLP) and three-dimensional climate model simulations to analyze relations between temperature anomalies and atmospheric circulation patterns over much of Europe and the Mediterranean for the late winter/early spring (January–April, JFMA) season. A Canonical Correlation Analysis (CCA) investigates interannual to interdecadal covariability between a new gridded SLP field reconstruction and seven long instrumental temperature series covering the past 250 years. We then present and discuss prominent atmospheric circulation patterns related to anomalous warm and cold JFMA conditions within different European areas spanning the period 1760–2007. Next, using a data assimilation technique, we link gridded SLP data with a climate model (EC-Bilt-Clio) for a better dynamical understanding of the relationship between large scale circulation and European climate. We thus present an alternative approach to reconstruct climate for the pre-instrumental period based on the assimilated model simulations. Furthermore, we present an independent method to extend the dynamic circulation analysis for anomalously cold European JFMA conditions back to the sixteenth century. To this end, we use documentary records that are spatially representative for the long instrumental records and derive, through modern analogs, large-scale SLP, surface temperature and precipitation fields. The skill of the analog method is tested in the virtual world of two three-dimensional climate simulations (ECHO-G and HadCM3). This endeavor offers new possibilities to both constrain climate model into a reconstruction mode (through the assimilation approach) and to better asses documentary data in a quantitative way.

Biomechanics on the Half Shell: Functional Performance Influences Patterns of Morphological Variation in the Emydid Turtle carapace

This study uses the carapace of emydid turtles to address hypothesized differences between terrestrial and aquatic species. Geometric morphometrics are used to quantify shell shape, and performance is estimated for two shell functions: shell strength and hydrodynamics. Aquatic turtle shells differ in shape from terrestrial turtle shells and are characterized by lower frontal areas and presumably lower drag. Terrestrial turtle shells are stronger than those of aquatic turtles; many-to-one mapping of morphology to function does not entirely mitigate a functional trade-off between mechanical strength and hydrodynamic performance. Furthermore, areas of morphospace characterized by exceptionally poor performance in either of the functions are not occupied by any emydid species. Though aquatic and terrestrial species show no significant differences in the rate of morphological evolution, aquatic species show a higher lineage density, indicative of a greater amount of convergence in their evolutionary history. The techniques employed in this study, including the modeling of theoretical shapes to assess performance in unoccupied areas of morphospace, suggest a framework for future studies of morphological variation.