Die venezianische Fruhzeit des Sebastiano del Piombo : 1485-1510.

Thesis (doctoral)--Ruprecht-Carls-Universitat Heidelberg.

A versatile and reliable two-component system for tissue-specific gene induction in Arabidopsis

Developmental progression and differentiation of distinct cell types depend on the regulation of gene expression in space and time. Tools that allow spatial and temporal control of gene expression are crucial for the accurate elucidation of gene function. Most systems to manipulate gene expression allow control of only one factor, space or time, and currently available systems that control both temporal and spatial expression of genes have their limitations. We have developed a versatile two-component system that overcomes these limitations, providing reliable, conditional gene activation in restricted tissues or cell types. This system allows conditional tissue-specific ectopic gene expression and provides a tool for conditional cell type- or tissue-specific complementation of mutants. The chimeric transcription factor XVE, in conjunction with Gateway recombination cloning technology, was used to generate a tractable system that can efficiently and faithfully activate target genes in a variety of cell types. Six promoters/enhancers, each with different tissue specificities (including vascular tissue, trichomes, root, and reproductive cell types), were used in activation constructs to generate different expression patterns of XVE. Conditional transactivation of reporter genes was achieved in a predictable, tissue-specific pattern of expression, following the insertion of the activator or the responder T-DNA in a wide variety of positions in the genome. Expression patterns were faithfully replicated in independent transgenic plant lines. Results demonstrate that we can also induce mutant phenotypes using conditional ectopic gene expression. One of these mutant phenotypes could not have been identified using noninducible ectopic gene expression approaches.

A novel brain partition highlights the modular skeleton shared by structure and function

Elucidating the intricate relationship between brain structure and function, both in healthy and pathological conditions, is a key challenge for modern neuroscience. Recent progress in neuroimaging has helped advance our understanding of this important issue, with diffusion images providing information about structural connectivity (SC) and functional magnetic resonance imaging shedding light on resting state functional connectivity (rsFC). Here, we adopt a systems approach, relying on modular hierarchical clustering, to study together SC and rsFC datasets gathered independently from healthy human subjects. Our novel approach allows us to find a common skeleton shared by structure and function from which a new, optimal, brain partition can be extracted. We describe the emerging common structure-function modules (SFMs) in detail and compare them with commonly employed anatomical or functional parcellations. Our results underline the strong correspondence between brain structure and resting-state dynamics as well as the emerging coherent organization of the human brain.

Megaliths in Malta:Orme dei Giganti

Stoddart, S. K. F. and Malone, C. A. T. In: S. Tusa, C. Buccellato, and L. Biondo (eds.),, pp. 59–70. 2009. Palermo: Regione Siciliana---Assessorato dei beni culturali, ambientali e della pubblica istruzione---Dipartimento dei beni culturali e dell'educazione permanente

Environmental Aspects of Underground Construction and Exploration of Underground Structure – State of the Art

An underground work (such as a tunnel or a cavern) has many, well known, environmental qualities such as: no physical barriers crossing the land, less maintenance costs than an analogous surface structure, less expenses for heating and conditioning; a localized emission of noise, gas, dust during operation and, finally, a better protection against seismic actions.
It cannot be forgotten, anyway, that some negative environmental features are present such as, for example, : perturbation, pollution and drainage of the groundwater; settlements; disposal of waste rock.
In the paper the above mentioned concepts are discussed and analysed to give a global overview of all this aspects.

Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells

Increasingly invasive bladder cancer cells lines displayed insensitivity toward a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated nuclear receptor corepressor 1 (NCOR1) expression. Stable overexpression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses toward ligand. Similarly, silencing RNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by peroxisome proliferator-activated receptor (PPAR) gamma and vitamin D receptor (VDR) receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the histone deacetylase inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong-additive interactions toward the PPARgamma, VDR and Farnesoid X-activated receptors. Genome-wide microarray and microfluidic quantitative real-time, reverse transcription-polymerase chain reaction approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this corepressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPARgamma and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced.

Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.

Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. AIM OF THE STUDY: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O₂) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. CONCLUSIONS: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms.

Options chirurgicates pour l'insuffisance cardiaque terminale [Surgical options for terminal heart failure]

Terminal heart failure can be the cause or the result of major dysfunctions of the organisms. Although, the outcome of the natural history is the same in both situations, it is of prime importance to differentiate the two, as only heart failure as the primary cause allows for successful mechanical circulatory support as bridge to transplantation or towards recovery. Various objective parameters allow for the establishment of the diagnosis of terminal heart failure despite optimal medical treatment. A cardiac index <2.0 l/min, and a mixed venous oxygen saturation <60%, in combination with progressive renal failure, should trigger a diagnostic work-up in order to identify cardiac defects that can be corrected or to list the patient for transplantation with/without mechanical circulatory support.

Mitral regurgitation.

Mitral regurgitation (MR) involves systolic retrograde flow from the left ventricle into the left atrium. While trivial MR is frequent in healthy subjects, moderate to severe MR constitutes the second most prevalent valve disease after aortic valve stenosis. Major causes of severe MR in Western countries include degenerative valve disease (myxomatous disease, flail leaflet, annular calcification) and ischaemic heart disease, while rheumatic disease remains a major cause of MR in developing countries. Chronic MR typically progresses insidiously over many years. Once established, however, severe MR portends a poor prognosis. The severity of MR can be assessed by various techniques, Doppler echocardiography being the most widely used. Mitral valve surgery is the only treatment of proven efficacy. It alleviates clinical symptoms and prevents ventricular dilatation and heart failure (or, at least, it attenuates further progression of these abnormalities). Valve repair significantly improves clinical outcomes compared with valve replacement, reducing mortality by approximately 70%. Reverse LV remodelling after valve repair occurs in half of patients with functional MR. Percutaneous, catheter-based to mitral valve repair is a novel approach currently under clinical scrutiny, with encouraging preliminary results. This modality may provide a valuable alternative to mitral valve surgery, especially in critically ill patients.

Comparison of clinical and angiographic prognostic risk scores in elderly patients presenting with acute coronary syndrome and referred for percutaneous coronary intervention.

BACKGROUND: Multiple risk prediction models have been validated in all-age patients presenting with acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI); however, they have not been validated specifically in the elderly. METHODS: We calculated the GRACE (Global Registry of Acute Coronary Events) score, the logistic EuroSCORE, the AMIS (Acute Myocardial Infarction Swiss registry) score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score in a consecutive series of 114 patients ≥75 years presenting with ACS and treated with PCI within 24 hours of hospital admission. Patients were stratified according to score tertiles and analysed retrospectively by comparing the lower/mid tertiles as an aggregate group with the higher tertile group. The primary endpoint was 30-day mortality. Secondary endpoints were the composite of death and major adverse cardiovascular events (MACE) at 30 days, and 1-year MACE-free survival. Model discrimination ability was assessed using the area under receiver operating characteristic curve (AUC). RESULTS: Thirty-day mortality was higher in the upper tertile compared with the aggregate lower/mid tertiles according to the logistic EuroSCORE (42% vs 5%; odds ratio [OR] = 14, 95% confidence interval [CI] = 4-48; p <0.001; AUC = 0.79), the GRACE score (40% vs 4%; OR = 17, 95% CI = 4-64; p <0.001; AUC = 0.80), the AMIS score (40% vs 4%; OR = 16, 95% CI = 4-63; p <0.001; AUC = 0.80), and the SYNTAX score (37% vs 5%; OR = 11, 95% CI = 3-37; p <0.001; AUC = 0.77). CONCLUSIONS: In elderly patients presenting with ACS and referred to PCI within 24 hours of admission, the GRACE score, the EuroSCORE, the AMIS score, and the SYNTAX score predicted 30 day mortality. The predictive value of clinical scores was improved by using them in combination.

Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy.

The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.

Horae ad usum romanum

F. 1-12v. Calendrier en français, à l’encre rouge et noire, où l’on remarque des formes dialectales picardes et plusieurs saints du Nord : « sainte Audegonde » (30 janvier) ; « le Candelier » (2 févr.) ; « ste Gertrude » (17 mars) ; « saint Quentin » (2 mai) ; « saint Ernoulx » [ep. Suessonensis] (16 août) ; « saint Bertin » (5 septembre) ; « saint Lambert » (17 septembre) ; « saint Franchois » (4 oct.) ; « saint Gillain » [mart. in Hannonia] (16 oct., Ghislain); « le jour st Estievene » (26 déc., rouge). Une deuxième main très cursive ajouté d’autres saints, dont « s. Amand » (6 févr.) ; « s. Waleri » (1er avril) ; « s. Fuscien » [mart. Ambianensis] (27 juin et 10 déc.) ; « s. Firmin » [mart. Ambianensis] (25 septembre) ; « s. Bavon » (1er oct.). F. 13v-17v. « ... hore sancte Crucis». F. 18v-22v. « ... hore de sancto Spiritu ».F. 23v-85. « ... hore beate marie virginis secundum usum romanum ». F. 86v-94v. Office de la Vierge, selon les temps de l’année. « ... officum beate Marie virginis quod dicitur per totum adventum ad vesperas ».F.95-115. « ... septem psalmi penitentiales cum suis litaniis et precibus ». A noter « ... sancte Lamberte... sancte Rumolde [ep. Mechlinensis]... sancte Fursee [ab. Latiniacensis] ... sancte Amande... sancte Vedaste, sancte Bavo... sancte Philiberte... santa Ursula... sancta Brigida... sancta Aldegondis, sancta Gertrudis... ».F.116v-152v. « ... vigilie mortuorum » office des morts à l’usage de Sarum-Normandie-Metz ; cf. K. Ottosen, Responsories..., p. 242 (116v-151). — « Octo versus beati Bernardi ». « Illumina oculos meos ne umquam obdormiam... » ; cf. Leroquais, Livres d’heures, I, XXX-XXXI (151-152v).F.153-158v. « Initium sancti evvangelii secundum Johannem... secundum Lucam... secundum Matheum... secundum Marcum ».F. 158v-166. Suffrages aux saints : « Memoria de santo Johanne Baptista... ; devota oratio... » ; — « ... de sancto Adriano » ; — « ... de sancto Sebastiano » ; — « ... de sancto Anthonio » ; — « ... de sancto Quintino » ; — « ... de sancto Nicholae » ; — « ... de sancto Andrea » ; — « ... de sancto Fiacro ».F.166v-174v. Prières à la Vierge. « ... devotissima oratio ad beatem virginem Mariam ». « O intemerata... O Johannes... » (éd. Wilmart, Auteurs spirituels, 488-490) (166v-169v). — « Alia oratio ad beatam virginem Mariam ». « Obsecro te.... » (éd. Leroquais, Livres d’heures, II, 346-347) (169v-174). Les deux prières sont rédigées à la forme masculine. — « Laus Marie virginis ». « Salve regina... » (Analecta Hymnica, L, 318-319, n° 245) (174-174v). F. 175-184v. Suffrages aux saintes : « ... de santa Barbara » ; — « ... de sancta Margareta » ; — « ... de sancta Katerina » ; — « ... de sancta Maria Magdelena » ; — « ... de sancta Appolonia » ; — « ... de sancta Venicie [Venice, forme dérivée de Véronique] » « Veni sponsa Christi... Versus. Diffusa est gratia... Oratio. Exaudi nos Deus ut sicut de beate Venicie festivitate gaudemus, ita pie devotionis erudiamur. Per.... » ; sur le culte de sainte Véronique/Venice, en particulier à Paris, voir Gr. A. RUNNALS, Le mystère de sainte Venice, Exeter, 1980 (Textes littéraires) (175-180v). — Prières diverses : « ... quinque gaudia de beata virgine Maria » « Gaude Virgo mater Christi... » (éd. Leroquais, Livres d’heures, I, XXVI-XXVII) (180v-182). — « Oratio devota ad Jesum Christum ». « Ave domine Jhesu Christe verbum patris » (éd. Wilmart, Auteurs spirituels, 412 [III]) (182-183). — « Oratio devota que dicitur ad elevationem Domini ». « Ave verum corpus Domini nostri... » (éd. Szövérffy, Die Annalen , II, 298-299) (183-184). — « Memore de saint Miquiel », en latin (184-184v).