Screening the Structural Space of Bicyclo-DNA: Synthesis and Properties of Bicyclo-DNA Functionalized at C(6’)

The synthesis of a novel bicyclo-thymidine nucleoside bearing an ester functionality at C(6') (bc(alpha-alk)-nucleosides) is reported. This nucleoside was incorporated into oligodeoxynucleotides via solid phase phosphoramidite chemistry, and the ester moiety was post-synthetically converted to an amide or a carboxy group, or was left unchanged. Thermal melting data (T-m) with complementary DNA and RNA were collected and compared to natural DNA and to bc- and bc(ox)-DNA. It was found that single incorporations of bc(alpha-alk)-nucleosides in DNA duplexes were destabilizing by 0.5 to 2.5 degrees C/mod, whereas two consecutive bc(alpha-alk)-residues were less destabilizing, and in some cases even stabilizing by 0.5 degrees C/mod. In duplexes with complementary RNA, isolated bc(alpha-alk)-residues destabilized the duplex by -1.0 to -4.0 degrees C/mod, depending on the chemical nature of the substituent, whereas two consecutive modifications were only destabilizing by 0.3-1.0 degrees C/mod. The pairing selectivity was similar to that of unmodified or bc-DNA.

Parallel synthesis and nucleic acid binding properties of C(6')-[alpha]-functionalized bicyclo-DNA

Two novel bicyclo-T nucleosides carrying a hydroxyl or a carboxymethyl substituent in C(6')-[alpha]-position were prepared and incorporated into oligodeoxynucleotides. During oligonucleotide deprotection the carboxymethyl substituent was converted into different amide substituents in a parallel way. Tm-measurements showed no dramatic differences in both, thermal affinity and mismatch discrimination, compared to unmodified oligonucleotides. The post-synthetic modification of the carboxymethyl substituent allows in principle for a parallel preparation of a library of oligonucleotides carrying diverse substituents at C(6'). In addition, functional groups can be placed into unique positions in a DNA double helix.

PolySynthesis 6.0 -- bicentennial edition

Even 197 years after its introduction, the notion of polysynthesis remains one of the most intriguing and controversial tools in the (morphological) typologist's toolbox. Several --occasionally contradictory--definitions have been proposed, employed for various purposes, and debated to this very day, but neither practitioners nor theoreticians have reached a comfortable level of consensus regarding its most effective and efficient form yet. The present talk maps the evolution of the notion, discusses its usefulness, and contends that the tool can be made better by updating it minimally with respect to its form and substantially with respect to its conceptual foundations. The former aspect of the update consists of making the notion more precise via explicit qualification; the latter bears relation to our arguably problematic understanding of the pairs lexical vs. grammatical and word vs. clause.

Regional climate model simulations for Europe at 6 and 0.2 k BP: sensitivity to changes in anthropogenic deforestation

This study aims to evaluate the direct effects of anthropogenic deforestation on simulated climate at two contrasting periods in the Holocene, ~6 and ~0.2 k BP in Europe. We apply We apply the Rossby Centre regional climate model RCA3, a regional climate model with 50 km spatial resolution, for both time periods, considering three alternative descriptions of the past vegetation: (i) potential natural vegetation (V) simulated by the dynamic vegetation model LPJ-GUESS, (ii) potential vegetation with anthropogenic land use (deforestation) from the HYDE3.1 (History Database of the Global Environment) scenario (V + H3.1), and (iii) potential vegetation with anthropogenic land use from the KK10 scenario (V + KK10). The climate model results show that the simulated effects of deforestation depend on both local/regional climate and vegetation characteristics. At ~6 k BP the extent of simulated deforestation in Europe is generally small, but there are areas where deforestation is large enough to produce significant differences in summer temperatures of 0.5–1 °C. At ~0.2 k BP, extensive deforestation, particularly according to the KK10 model, leads to significant temperature differences in large parts of Europe in both winter and summer. In winter, deforestation leads to lower temperatures because of the differences in albedo between forested and unforested areas, particularly in the snow-covered regions. In summer, deforestation leads to higher temperatures in central and eastern Europe because evapotranspiration from unforested areas is lower than from forests. Summer evaporation is already limited in the southernmost parts of Europe under potential vegetation conditions and, therefore, cannot become much lower. Accordingly, the albedo effect dominates in southern Europe also in summer, which implies that deforestation causes a decrease in temperatures. Differences in summer temperature due to deforestation range from −1 °C in south-western Europe to +1 °C in eastern Europe. The choice of anthropogenic land-cover scenario has a significant influence on the simulated climate, but uncertainties in palaeoclimate proxy data for the two time periods do not allow for a definitive discrimination among climate model results.

Functional Imaging of Pheochromocytoma with Ga-DOTATOC and C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.

Visual hallucinations in dementia with Lewy bodies: a transcranial magnetic stimulation study

BACKGROUND: The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism. AIMS: To determine visual cortical excitability in people with dementia with Lewy bodies compared with aged-matched controls and also the relationship between visual cortical excitability and visual hallucinations in dementia with Lewy bodies. METHOD: Visual cortical excitability was determined by using transcranial magnetic stimulation (TMS) applied to the occiput to elicit phosphenes (transient subjective visual responses) in 21 patients with dementia with Lewy bodies and 19 age-matched controls. RESULTS: Phosphene parameters were similar between both groups. However, in the patients with dementia with Lewy bodies, TMS measures of visual cortical excitability correlated strongly with the severity of visual hallucinations (P = 0.005). Six patients with dementia with Lewy bodies experienced visual hallucination-like phosphenes (for example, seeing people or figures on stimulation) compared with none of the controls (P = 0.02). CONCLUSIONS: Increased visual cortical excitability in dementia with Lewy bodies does not appear to explain visual hallucinations but it may be a marker for their severity.

The S-1/S-2 exciton interaction in 2-pyridone center dot 6-methyl-2-pyridone: Davydov splitting, vibronic coupling, and vibronic quenching

The excitonic splitting between the S-1 and S-2 electronic states of the doubly hydrogen-bonded dimer 2-pyridone center dot 6-methyl-2-pyridone (2PY center dot 6M2PY) is studied in a supersonic jet, applying two-color resonant two-photon ionization (2C-R2PI), UV-UV depletion, and dispersed fluorescence spectroscopies. In contrast to the C-2h symmetric (2-pyridone) 2 homodimer, in which the S-1 <- S-0 transition is symmetry-forbidden but the S-2 <- S-0 transition is allowed, the symmetry-breaking by the additional methyl group in 2PY center dot 6M2PY leads to the appearance of both the S-1 and S-2 origins, which are separated by Delta(exp) = 154 cm(-1). When combined with the separation of the S-1 <- S-0 excitations of 6M2PY and 2PY, which is delta = 102 cm(-1), one obtains an S-1/S-2 exciton coupling matrix element of V-AB, el = 57 cm(-1) in a Frenkel-Davydov exciton model. The vibronic couplings in the S-1/S-2 <- S-0 spectrum of 2PY center dot 6M2PY are treated by the Fulton-Gouterman single-mode model. We consider independent couplings to the intramolecular 6a' vibration and to the intermolecular sigma' stretch, and obtain a semi-quantitative fit to the observed spectrum. The dimensionless excitonic couplings are C(6a') = 0.15 and C(sigma') = 0.05, which places this dimer in the weak-coupling limit. However, the S-1/S-2 state exciton splittings Delta(calc) calculated by the configuration interaction singles method (CIS), time-dependent Hartree-Fock (TD-HF), and approximate second-order coupled-cluster method (CC2) are between 1100 and 1450 cm(-1), or seven to nine times larger than observed. These huge errors result from the neglect of the coupling to the optically active intra-and intermolecular vibrations of the dimer, which lead to vibronic quenching of the purely electronic excitonic splitting. For 2PY center dot 6M2PY the electronic splitting is quenched by a factor of similar to 30 (i.e., the vibronic quenching factor is Gamma(exp) = 0.035), which brings the calculated splittings into close agreement with the experimentally observed value. The 2C-R2PI and fluorescence spectra of the tautomeric species 2-hydroxypyridine center dot 6-methyl-2-pyridone (2HP center dot 6M2PY) are also observed and assigned. (C) 2011 American Institute of Physics.

Effect of short-wave (6-22 MHz) magnetic fields on sleep quality and melatonin cycle in humans: the Schwarzenburg shut-down study

This paper describes the results of a unique "natural experiment" of the operation and cessation of a broadcast transmitter with its short-wave electromagnetic fields (6-22 MHz) on sleep quality and melatonin cycle in a general human population sample. In 1998, 54 volunteers (21 men, 33 women) were followed for 1 week each before and after shut-down of the short-wave radio transmitter at Schwarzenburg (Switzerland). Salivary melatonin was sampled five times a day and total daily excretion and acrophase were estimated using complex cosinor analysis. Sleep quality was recorded daily using a visual analogue scale. Before shut down, self-rated sleep quality was reduced by 3.9 units (95% CI: 1.7-6.0) per mA/m increase in magnetic field exposure. The corresponding decrease in melatonin excretion was 10% (95% CI: -32 to 20%). After shutdown, sleep quality improved by 1.7 units (95% CI: 0.1-3.4) per mA/m decrease in magnetic field exposure. Melatonin excretion increased by 15% (95% CI: -3 to 36%) compared to baseline values suggesting a rebound effect. Stratified analyses showed an exposure effect on melatonin excretion in poor sleepers (26% increase; 95% CI: 8-47%) but not in good sleepers. Change in sleep quality and melatonin excretion was related to the extent of magnetic field reduction after the transmitter's shut down in poor but not good sleepers. However, blinding of exposure was not possible in this observational study and this may have affected the outcome measurements in a direct or indirect (psychological) way.

[Photodynamic therapy of AMD for the first (better sight) and the second (worse sight) eyes]

BACKGROUND: Photodynamic therapy (PDT) is the standard treatment procedure for many forms of exudative and/or neovascular AMD. Despite therapy, visual acuity often drops to low vision levels. The cost efficiency of treating the eye in which vision is worse is therefore the subject of some controversy. PATIENTS AND METHODS: A retrospective case-control study was conducted in all patients who were treated with PDT at the Universitätsspital Zürich between September 1999 and November 2004. Each patient's first (with worse vision) and second (with better vision) eyes were compared for situation on presentation and course during treatment. RESULTS: In 117/228 cases (51.3%) visual acuity of the treated eye was better than (or identical to) that of the fellow eye at presentation. Visual acuity before therapy was an average of 0.58+/-0.27 logMAR [Snellen: 0.26 (0.14-0.49)] in the eyes with better visual acuity and 0.69+/-0.4 logMAR [Snellen 0.20 (0.08-0.51)] in the fellow eyes (p=0.015). After therapy there was no significant difference between the patient groups in visual acuity or in the magnitude of any change in visual acuity, or in lesion size or change in lesion size. CONCLUSION: The outcome of PDT of a second eye (with better visual acuity) is not significantly better than the result obtained in the first eye (the one with worse visual acuity initially).

Angiographic C-arm CT- versus MDCT-guided stereotactic punctures of liver lesions: nonrigid phantom study

OBJECTIVE Angiographic C-arm CT may allow performing percutaneous stereotactic tumor ablations in the interventional radiology suite. Our purpose was to evaluate the accuracy of using C-arm CT for single and multimodality image fusions and to compare the targeting accuracy of liver lesions with the reference standard of MDCT. MATERIALS AND METHODS C-arm CT and MDCT scans were obtained of a nonrigid rapid prototyping liver phantom containing five 1-mm targets that were placed under skin-simulating deformable plastic foam. Target registration errors of image fusion were evaluated for single-modality and multimodality image fusions. A navigation system and stereotactic aiming device were used to evaluate target positioning errors on postinterventional scans with the needles in place fused with the C-arm CT or MDCT planning images. RESULTS Target registration error of the image fusion showed no significant difference (p > 0.05) between both modalities. In five series with a total of 25 punctures for each modality, the lateral target positioning error (i.e., the lateral distance between the needle tip and the planned trajectory) was similar for C-arm CT (mean [± SD], 1.6 ± 0.6 mm) and MDCT (1.82 ± .97 mm) (p = 0.33). CONCLUSION In a nonrigid liver phantom, angiographic C-arm CT may provide similar image fusion accuracy for comparison of intra- and postprocedure control images with the planning images and enables stereotactic targeting accuracy similar to that of MDCT.

Detection efficiency of microchannel plates for e(-) and pi(-) in the momentum range from 17.5 to 345 MeV/c

High-energy e(-) and pi(-) were measured by the multichannel plate (MCP) detector at the PiM1 beam line of the High Intensity Proton Accelerator Facilities located at the Paul Scherrer Institute, Villigen, Switzerland. The measurements provide the absolute detection efficiencies for these particles: 5.8% +/- 0.5% for electrons in the beam momenta range 17.5-300 MeV/c and 6.0% +/- 1.3% for pions in the beam momenta range 172-345 MeV/c. The pulse height distribution determined from the measurements is close to an exponential function with negative exponent, indicating that the particles penetrated the MCP material before producing the signal somewhere inside the channel. Low charge extraction and nominal gains of the MCP detector observed in this study are consistent with the proposed mechanism of the signal formation by penetrating radiation. A very similar MCP ion detector will be used in the Neutral Ion Mass (NIM) spectrometer designed for the JUICE mission of European Space Agency (ESA) to the Jupiter system, to perform measurements of the chemical composition of the Galilean moon exospheres. The detection efficiency for penetrating radiation determined in the present studies is important for the optimisation of the radiation shielding of the NIM detector against the high-rate and high-energy electrons trapped in Jupiter's magnetic field. Furthermore, the current studies indicate that MCP detectors can be useful to measure high-energy particle beams at high temporal resolution. (C) 2015 AIP Publishing LLC.