Thallium isotopes reveal protracted anoxia during the Toarcian (Early Jurassic) associated with volcanism, carbon burial, and mass extinction

For this study, we generated thallium (Tl) isotope records from two anoxic basins to track the earliest changes in global bottom water oxygen contents over the Toarcian Oceanic Anoxic Event (TOAE; ∼183 Ma) of the Early Jurassic. The T-OAE, like other Mesozoic OAEs, has been interpreted as an expansion of marine oxygen depletion based on indirect methods such as organic-rich facies, carbon isotope excursions, and biological turnover. Our Tl isotope data, however, reveal explicit evidence for earlier global marine deoxygenation of ocean water, some 600 ka before the classically defined T-OAE. This antecedent deoxygenation occurs at the Pliensbachian/Toarcian boundary and is coeval with the onset of initial large igneous province (LIP) volcanism and the initiation of a marine mass extinction. Thallium isotopes are also perturbed during the T-OAE interval, as defined by carbon isotopes, reflecting a second deoxygenation event that coincides with the acme of elevated marine mass extinctions and the main phase of LIP volcanism. This suggests that the duration of widespread anoxic bottom waters was at least 1 million years in duration and spanned early to middle Toarcian time. Thus, the Tl data reveal a more nuanced record of marine oxygen depletion and its links to biological change during a period of climatic warming in Earth’s past and highlight the role of oxygen depletion on past biological evolution

Resolved quadrupolar transition in TiO2

We report an investigation of the direct forbidden absorption edge of TiO2. For the first time we have resolved the weak quadrupolar 1s exciton and measured its binding energy. Taking into account polaron effects, we estimated the bare electron effective mass in the Γ1 minimum of the conduction band and obtained a fairly reasonable value of 3m0

Theoretical analysis of the electronic structure of the stable and metastable c(2x2) phases of Na on Al(001): Comparison with angle-resolved ultra-violet photoemission spectra

Using Kohn-Sham wave functions and their energy levels obtained by density-functional-theory total-energy calculations, the electronic structure of the two c(2x2) phases of Na on Al(001) are analysed; namely, the metastable hollow-site structure formed when adsorption takes place at low temperature, and the stable substitutional structure appearing when the substrate is heated thereafter above ca. 180K or when adsorption takes place at room temperature from the beginning. The experimentally obtained two-dimensional band structures of the surface states or resonances are well reproduced by the calculations. With the help of charge density maps it is found that in both phases, two pronounced bands appear as the result of a characteristic coupling between the valence-state band of a free c(2x2)-Na monolayer and the surface-state/resonance band of the Al surfaces; that is, the clean (001) surface for the metastable phase and the unstable, reconstructed "vacancy" structure for the stable phase. The higher-lying band, being Na-derived, remains metallic for the unstable phase, whereas it lies completely above the Fermi level for the stable phase, leading to the formation of a surface-state/resonance band-structure resembling the bulk band-structure of an ionic crystal.Comment: 11 pages, 11 postscript figures, published in Phys. Rev. B 57, 15251 (1998). Other related publications can be found at http://www.rz-berlin.mpg.de/th/paper.htm

Anti-angiogenesis therapy in the Vx2 rabbit cancer model with a lipase-cleavable Sn 2 taxane phospholipid prodrug using αvβ3-targeted theranostic nanoparticles

In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of α(v)β(3)-integrin targeted perfluorocarbon (PFC) nanoparticles (α(v)β(3)-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of α(v)β(3)-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of α(v)β(3)-Dxtl-PD NP in endothelial cell culture was as effective as Taxol(®) or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of α(v)β(3)-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same α(v)β(3)-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane(®) given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that α(v)β(3)-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit

Synthesis of high-quality libraries of long (150mer) oligonucleotides by a novel depurination controlled process

We have achieved the ability to synthesize thousands of unique, long oligonucleotides (150mers) in fmol amounts using parallel synthesis of DNA on microarrays. The sequence accuracy of the oligonucleotides in such large-scale syntheses has been limited by the yields and side reactions of the DNA synthesis process used. While there has been significant demand for libraries of long oligos (150mer and more), the yields in conventional DNA synthesis and the associated side reactions have previously limited the availability of oligonucleotide pools to lengths <100 nt. Using novel array based depurination assays, we show that the depurination side reaction is the limiting factor for the synthesis of libraries of long oligonucleotides on Agilent Technologies’ SurePrint® DNA microarray platform. We also demonstrate how depurination can be controlled and reduced by a novel detritylation process to enable the synthesis of high quality, long (150mer) oligonucleotide libraries and we report the characterization of synthesis efficiency for such libraries. Oligonucleotide libraries prepared with this method have changed the economics and availability of several existing applications (e.g. targeted resequencing, preparation of shRNA libraries, site-directed mutagenesis), and have the potential to enable even more novel applications (e.g. high-complexity synthetic biology)

Comparisons between Chemical Mapping and Binding to Isoenergetic Oligonucleotide Microarrays Reveal Unexpected Patterns of Binding to the Bacillus subtilis RNase P RNA Specificity Domain†

ABSTRACT: Microarrays with isoenergetic pentamer and hexamer 20-O-methyl oligonucleotide probes with LNA (locked nucleic acid) and 2,6-diaminopurine substitutions were used to probe the binding sites on theRNase P RNA specificity domain of Bacillus subtilis. Unexpected binding patterns were revealed. Because of their enhanced binding free energies, isoenergetic probes can break short duplexes, merge adjacent loops, and/or induce refolding. This suggests new approaches to the rational design of short oligonucleotide therapeutics but limits the utility of microarrays for providing constraints for RNA structure determination. The microarray results are compared to results from chemical mapping experiments, which do provide constraints. Results from both types of experiments indicate that the RNase P RNA folds similarly in 1MNaþ and 10 mMMg2þ. Binding of RNA to RNA is important for many natural func-tions, includingproteinsynthesis (1,2), translationregulation (3,4), gene silencing (5, 6), metabolic regulation (7), RNAmodification (8, 9), etc. (10-13). Binding of oligonucleotides toRNAs is impor-tant for therapeutic approaches, such as siRNA, ribozymes, and antisense therapy (14, 15).Much remains to bediscovered, however, of the rules for predicting binding sites andpotential therapeutics

Quantitative cardiovascular magnetic resonance for molecular imaging

Cardiovascular magnetic resonance (CMR) molecular imaging aims to identify and map the expression of important biomarkers on a cellular scale utilizing contrast agents that are specifically targeted to the biochemical signatures of disease and are capable of generating sufficient image contrast. In some cases, the contrast agents may be designed to carry a drug payload or to be sensitive to important physiological factors, such as pH, temperature or oxygenation. In this review, examples will be presented that utilize a number of different molecular imaging quantification techniques, including measuring signal changes, calculating the area of contrast enhancement, mapping relaxation time changes or direct detection of contrast agents through multi-nuclear imaging or spectroscopy. The clinical application of CMR molecular imaging could offer far reaching benefits to patient populations, including early detection of therapeutic response, localizing ruptured atherosclerotic plaques, stratifying patients based on biochemical disease markers, tissue-specific drug delivery, confirmation and quantification of end-organ drug uptake, and noninvasive monitoring of disease recurrence. Eventually, such agents may play a leading role in reducing the human burden of cardiovascular disease, by providing early diagnosis, noninvasive monitoring and effective therapy with reduced side effects

A theoretical model for template-free synthesis of long DNA sequence

This theoretical scheme is intended to formulate a potential method for high fidelity synthesis of Nucleic Acid molecules towards a few thousand bases using an enzyme system. Terminal Deoxyribonucleotidyl Transferase, which adds a nucleotide to the 3′OH end of a Nucleic Acid molecule, may be used in combination with a controlled method for nucleotide addition and degradation, to synthesize a predefined Nucleic Acid sequence. A pH control system is suggested to regulate the sequential activity switching of different enzymes in the synthetic scheme. Current practice of synthetic biology is cumbersome, expensive and often error prone owing to the dependence on the ligation of short oligonucleotides to fabricate functional genetic parts. The projected scheme is likely to render synthetic genomics appreciably convenient and economic by providing longer DNA molecules to start with

Cytosolic 5'-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response.

International audienceBACKGROUND: Double stranded RNA (dsRNA) is widely accepted as an RNA motif recognized as a danger signal by the cellular sentries. However, the biology of non-segmented negative strand RNA viruses, or Mononegavirales, is hardly compatible with the production of such dsRNA. METHODOLOGY AND PRINCIPAL FINDINGS: During measles virus infection, the IFN-beta gene transcription was found to be paralleled by the virus transcription, but not by the virus replication. Since the expression of every individual viral mRNA failed to activate the IFN-beta gene, we postulated the involvement of the leader RNA, which is a small not capped and not polyadenylated RNA firstly transcribed by Mononegavirales. The measles virus leader RNA, synthesized both in vitro and in vivo, was efficient in inducing the IFN-beta expression, provided that it was delivered into the cytosol as a 5'-trisphosphate ended RNA. The use of a human cell line expressing a debilitated RIG-I molecule, together with overexpression studies of wild type RIG-I, showed that the IFN-beta induction by virus infection or by leader RNA required RIG-I to be functional. RIG-I binds to leader RNA independently from being 5-trisphosphate ended; while a point mutant, Q299A, predicted to establish contacts with the RNA, fails to bind to leader RNA. Since the 5'-triphosphate is required for optimal RIG-I activation but not for leader RNA binding, our data support that RIG-I is activated upon recognition of the 5'-triphosphate RNA end. CONCLUSIONS/SIGNIFICANCE: RIG-I is proposed to recognize Mononegavirales transcription, which occurs in the cytosol, while scanning cytosolic RNAs, and to trigger an IFN response when encountering a free 5'-triphosphate RNA resulting from a mislocated transcription activity, which is therefore considered as the hallmark of a foreign invader