Nucleic-Acid Analogs with Restricted Conformational Flexibility in the Sugar-Phosphate Backbone (‘Bicyclo-DNA’). Part 5. Synthesis, Characterization, and Pairing Properties of Oligo-αlpha-D-(bicyclodeoxynucleotides) of the Bases Adenine and Thymine (αlpha-Bicyclo-DNA)

10.1002/hlca.19950780816.abs A conformational analysis of the (3′S,5′R)-2′-deoxy-3′,5′-ethano-α-D-ribonucleosides (a-D-bicyclodeoxynucleosides) based on the X-ray analysis of N4-benzoyl-α-D-(bicyclodeoxycytidine) 6 and on 1H-NMR analysis of the α-D-bicyclodeoxynucleoside derivatives 1-7 reveals a rigid sugar structure with the furanose units in the l′-exo/2′-endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α-D-bicyclothymidine and α-D-bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α-bcd(A10) and α-bcd(T10) (α = short form of α-D)efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β-d(A10) or β-d(T10)( β = short form ofβ-D). ii) The strand orientation in α-bicyclo-DNA/β-DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α-bicyclo-DNA/β-DNA duplexes compared to α-DNA/β-DNA duplexes. Furthermore, α-bicyclo-DNA is ca. 100-fold more resistant to the enzyme snake-venom phosphodiesterase with respect to β-DNA and about equally resistant as α-DNA.

Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis.

Thyroid transcription factor 1 (TTF-1) is encoded by the NKX2-1 homeobox gene. Besides specifying thyroid and pulmonary organogenesis, it is also temporarily expressed during embryonic development of the ventral forebrain. We recently observed widespread immunoreactivity for TTF-1 in a case of subependymal giant cell astrocytoma (SEGA, WHO grade I) – a defining lesion of the tuberous sclerosis complex (TSC). This prompted us to investigate additional SEGAs in this regard. We found tumor cells in all 7 specimens analyzed to be TTF-1 positive. In contrast, we did not find TTF-1 immunoreactivity in a cortical tuber or two renal angiomyolipomas resected from TSC patients. We propose our finding of consistent TTF-1 expression in SEGAs to indicate lineage-committed derivation of these tumors from a regionally specified cell of origin. The medial ganglionic eminence, ventral septal region, and preoptic area of the developing brain may represent candidates for the origin of SEGAs. Such lineagerestricted histogenesis may also explain the stereotypic distribution of SEGAs along the caudate nucleus in the lateral ventricles.

Optimal Confidence Bands for Shape-Restricted Curves

Let Y be a stochastic process on [0,1] satisfying dY(t)=n 1/2 f(t)dt+dW(t) , where n≥1 is a given scale parameter (`sample size'), W is standard Brownian motion and f is an unknown function. Utilizing suitable multiscale tests, we construct confidence bands for f with guaranteed given coverage probability, assuming that f is isotonic or convex. These confidence bands are computationally feasible and shown to be asymptotically sharp optimal in an appropriate sense.

Complex geomorphologic assemblage of terrains in association with the banded terrain in Hellas basin, Mars

Hellas basin acts as a major sink for the southern highlands of Mars and is likely to have recorded several episodes of sedimentation and erosion. The north-western part of the basin displays a potentially unique Amazonian landscape domain in the deepest part of Hellas, called “banded terrain”, which is a deposit characterized by an alternation of narrow band shapes and inter-bands displaying a sinuous and relatively smooth surface texture suggesting a viscous flow origin. Here we use high-resolution (HiRISE and CTX) images to assess the geomorphological interaction of the banded terrain with the surrounding geomorphologic domains in the NW interior of Hellas to gain a better understanding of the geological evolution of the region as a whole. Our analysis reveals that the banded terrain is associated with six geomorphologic domains: a central plateau named Alpheus Colles, plain deposits (P1 and P2), reticulate (RT1 and RT2) and honeycomb terrains. Based on the analysis of the geomorphology of these domains and their cross-cutting relationships, we show that no widespread deposition post-dates the formation of the banded terrain, which implies that this domain is the youngest and latest deposit of the interior of Hellas. Therefore, the level of geologic activity in the NW Hellas during the Amazonian appears to have been relatively low and restricted to modification of the landscape through mechanical weathering, aeolian and periglacial processes. Thermophysical data and cross-cutting relationships support hypotheses of modification of the honeycomb terrain via vertical rise of diapirs such as ice diapirism, and the formation of the plain deposits through deposition and remobilization of an ice-rich mantle deposit. Finally, the observed gradual transition between honeycomb and banded terrain suggests that the banded terrain may have covered a larger area of the NW interior of Hellas in the past than previously thought. This has implications on the understanding of the evolution of the deepest part of Hellas.

Domains of importance to the quality of life of older people from two Swiss regions

BACKGROUND Quality of life (QoL) is a subjective perception whose components may vary in importance between individuals. Little is known about which domains of QoL older people deem most important. OBJECTIVE This study investigated in community-dwelling older people the relationships between the importance given to domains defining their QoL and socioeconomic, demographic and health status. METHODS Data were compiled from older people enrolled in the Lc65+ cohort study and two additional, population-based, stratified random samples (n = 5,300). Principal components analysis (PCA) was used to determine the underlying domains among 28 items that participants defined as important to their QoL. The components extracted were used as dependent variables in multiple linear regression models to explore their associations with socioeconomic, demographic and health status. RESULTS PCA identified seven domains that older persons considered important to their QoL. In order of importance (highest to lowest): feeling of safety, health and mobility, autonomy, close entourage, material resources, esteem and recognition, and social and cultural life. A total of six and five domains of importance were significantly associated with education and depressive symptoms, respectively. The importance of material resources was significantly associated with a good financial situation (β = 0.16, P = 0.011), as was close entourage with living with others (β = 0.20, P = 0.007) and as was health and mobility with age (β = -0.16, P = 0.014). CONCLUSION The importance older people give to domains of their QoL appears strongly related to their actual resources and experienced losses. These findings may help clinicians, researchers and policy makers better adapt strategies to individuals' needs.

Conserved regulation of proximodistal limb axis development by Meis1/Hth.

Vertebrate limbs grow out from the flanks of embryos, with their main axis extending proximodistally from the trunk. Distinct limb domains, each with specific traits, are generated in a proximal-to-distal sequence during development. Diffusible factors expressed from signalling centres promote the outgrowth of limbs and specify their dorsoventral and anteroposterior axes. However, the molecular mechanism by which limb cells acquire their proximodistal (P-D) identity is unknown. Here we describe the role of the homeobox genes Meis1/2 and Pbx1 in the development of mouse, chicken and Drosophila limbs. We find that Meis1/2 expression is restricted to a proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus, and resembling the distribution of the Drosophila homologues homothorax (hth) and extradenticle (exd); that Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein; and that ectopic expression of Meis1 in chicken and hth in Drosophila disrupts distal limb development and induces distal-to-proximal transformations. We suggest that restriction of Meis1/Hth to proximal regions of the vertebrate and insect limb is essential to specify cell fates and differentiation patterns along the P-D axis of the limb.

Inherited structural controls on fault geometry, architecture and hydrothermal activity: an example from Grimsel Pass, Switzerland

Exhumed faults hosting hydrothermal systems provide direct insight into relationships between faulting and fluid flow, which in turn are valuable for making hydrogeological predictions in blind settings. The Grimsel Breccia Fault (Aar massif, Central Swiss Alps) is a late Neogene, exhumed dextral strike-slip fault with a maximum displacement of 25–45 m, and is associated with both fossil and active hydrothermal circulation. We mapped the fault system and modelled it in three dimensions, using the distinctive hydrothermal mineralisation as well as active thermal fluid discharge (the highest elevation documented in the Alps) to reveal the structural controls on fluid pathway extent and morphology. With progressive uplift and cooling, brittle deformation inherited the mylonitic shear zone network at Grimsel Pass; preconditioning fault geometry into segmented brittle reactivations of ductile shear zones and brittle inter-shear zone linkages. We describe ‘pipe’-like, vertically oriented fluid pathways: (1) within brittle fault linkage zones and (2) through alongstrike- restricted segments of formerly ductile shear zones reactivated by brittle deformation. In both cases, low-permeability mylonitic shear zones that escaped brittle reactivation provide important hydraulic seals. These observations show that fluid flow along brittle fault planes is not planar, but rather highly channelised into sub-vertical flow domains, with important implications for the exploration and exploitation of geothermal energy.

Opposing RA and FGF signals control proximodistal vertebrate limb development through regulation of Meis genes.

Vertebrate limbs develop in a temporal proximodistal sequence, with proximal regions specified and generated earlier than distal ones. Whereas considerable information is available on the mechanisms promoting limb growth, those involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activator of the proximal determinant genes Meis1 and Meis2. RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb. RA synthesis and signaling range, which initially span the entire lateral plate mesoderm, become restricted to proximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main molecule responsible for this AER activity and propose a model integrating the role of FGF in limb cell proliferation, with a specific function in promoting distalization through inhibition of RA production and signaling.