Analysis of β-globin chromatin micro-environment using a novel 3C variant, 4Cv

Copyright: © 2010 Pink et al.Higher order chromatin folding is critical to a number of developmental processes, including the regulation of gene expression. Recently developed biochemical techniques such as RNA TRAP and chromosome conformation capture (3C) have provided us with the tools to probe chromosomal structures. These techniques have been applied to the β-globin locus, revealing a complex pattern of interactions with regions along the chromosome that the gene resides on. However, biochemical and microscopy data on the nature of β-globin interactions with other chromosomes is contradictory. Therefore we developed a novel 4C variant, Complete-genome 3C by vectorette amplification (4Cv), which allows an unbiased and quantitative method to examine chromosomal structure. We have used 4Cv to study the microenvironment of the β-globin locus in mice and show that a significant proportion of the interactions of β-globin are inter-chromosomal. Furthermore, our data show that in the liver, where the gene is active, β-globin is more likely to interact with other chromosomes, compared to the brain where the gene is silent and is more likely to interact with other regions along the same chromosome. Our data suggest that transcriptional activation of the β-globin locus leads to a change in nuclear position relative to the chromosome territory.Ryan Pink is supported by a grant from Action Medical Research; Daniel Caley is supported by a grant from The Dunhill Medical Trust; David Carter is supported by a grant from the British Society for Haematology

A Whole New Mind: Why Right-Brainers Will Rule The Future

This book describes a seismic-though as yet undetected-shift now under way in much of the advanced world. We are moving from an economy and a society built on the logical, linear, computerlike capabilities of the Information Age to an economy and a society built on the inventive, empathic, big-picture capabilities of what’s rising in its place, the Conceptual Age. This book is for anyone who wants to survive and thrive in this emerging world-people uneasy in their careers or dissatisfied with their lives, entrepreneurs and business leaders eager to say ahead of the next wave, parents who want to equip their children for the future, and the legions of emotionally astute and creatively adroit people whose distinctive abilities the Information Age has often overlooked and undervalued. In this book, you will learn the six essential aptitudes-what I call “the six senses”-on which professional success and personal satisfaction increasingly will depend. Design. Story. Symphony. Empathy. Play. Meaning. These are fundamentally human abilities that everyone can master-and helping you do that is my goal

Efficacy of Trabectedin in Patients with Advanced or Metastatic Alveolar Soft-Part Sarcoma

Background: Alveolar soft-part sarcoma (ASPS) is a rare sarcoma often occurring in young patients that is characterized by the unbalanced translocation der(17)t(X;17) (p11;q25). Although itusuallyshowsan indolent clinical course, the prognosis is usually poor in advanced disease. Since standard chemotherapy regimens used in soft-tissue sarcomas lack efficacy in ASPS, new therapeutic options are needed. We investigated the efficacy of trabectedin, which has demonstrated activity in a variety of cancer types including some of the most prevalent translocation-related sarcomas. Patients and Methods: 7 patients with metastatic or advanced ASPS treated with trabectedin in the Sarcoma Center Berlin-Brandenburg and the University Hospital of Greifswald were analyzed for median progression-free survival (mPFS), overall survival (OS), and therapy-related toxicity. Results: In 6 patients with documented disease progression, disease stabilization was reached with trabectedin; only 1 patient experienced progressive disease. The mPFS and OS were 7 months and 21 months, respectively, since the start of trabectedin treatment. Overall, no severe Common Toxicity Criteria (CTC) grade 3 or 4 toxicity was observed. Conclusions: The poor prognosis of patients with ASPS has so far been due to the unavailability of effective systemic treatments. Trabectedin can be considered the only currently registered drug with clinical activity in this disease

Intramembrane Congestion Effects on Lysenin Channel Voltage-Induced Gating

All cell membranes are packed with proteins. The ability to investigate the regulatory mechanisms of protein channels in experimental conditions mimicking their congested native environment is crucial for understanding the environmental physicochemical cues that may fundamentally contribute to their functionality in natural membranes. Here we report on investigations of the voltage-induced gating of lysenin channels in congested conditions experimentally achieved by increasing the number of channels inserted into planar lipid membranes. Typical electrophysiology measurements reveal congestion-induced changes to the voltage-induced gating, manifested as a significant reduction of the response to external voltage stimuli. Furthermore, we demonstrate a similar diminished voltage sensitivity for smaller populations of channels by reducing the amount of sphingomyelin in the membrane. Given lysenin’s preference for targeting lipid rafts, this result indicates the potential role of the heterogeneous organization of the membrane in modulating channel functionality. Our work indicates that local congestion within membranes may alter the energy landscape and the kinetics of conformational changes of lysenin channels in response to voltage stimuli. This level of understanding may be extended to better characterize the role of the specific membrane environment in modulating the biological functionality of protein channels in health and disease

Gemcitabine and Docetaxel for Epithelioid Sarcoma: Results from a Retrospective, Multi-Institutional Analysis

Objective: Epithelioid sarcoma (ES) presents unique clinical features in comparison to other sarcoma subtypes. Data regarding the benefits of chemotherapy are very limited. Combination regimens using gemcitabine and docetaxel (Gem/Doce) have proven to be effective, especially in uterine and nonuterine leiomyosarcoma. Yet, there is no available data on the efficacy of Gem/Doce in ES. Methods: A retrospective analysis of the three participating institutions was performed. Twenty-eight patients with an ES diagnosis presented at one of the participating institutions between 1989 and 2012. Of this group, 17 patients received chemotherapy. Results: Patients' median overall survival (OS) after the beginning of palliative chemotherapy was 21 months, and the 1-year OS was 87%. Twelve patients received Gem/Doce with a clinical benefit rate of 83%. The median progression-free survival (PFS) was 8 months for all patients receiving Gem/Doce. The best response was complete remission in 1 patient and partial remission in 6 patients. All 6 patients receiving Gem/Doce as a first-line treatment showed measurable responses with a median PFS of 9 months. Conclusions: In this retrospective study, Gem/Doce was an effective chemotherapeutic regimen for ES. Prospective studies are needed to better assess the effects of this combination drug therapy

The theory of exponential differential equations

This thesis is a model-theoretic study of exponential differential equations in the context of differential algebra. I define the theory of a set of differential equations and give an axiomatization for the theory of the exponential differential equations of split semiabelian varieties. In particular, this includes the theory of the equations satisfied by the usual complex exponential function and the Weierstrass p-functions. The theory consists of a description of the algebraic structure on the solution sets together with necessary and sufficient conditions for a system of equations to have solutions. These conditions are stated in terms of a dimension theory; their necessity generalizes Ax’s differential field version of Schanuel’s conjecture and their sufficiency generalizes recent work of Crampin. They are shown to apply to the solving of systems of equations in holomorphic functions away from singularities, as well as in the abstract setting. The theory can also be obtained by means of a Hrushovski-style amalgamation construction, and I give a category-theoretic account of the method. Restricting to the usual exponential differential equation, I show that a “blurring” of Zilber’s pseudo-exponentiation satisfies the same theory. I conjecture that this theory also holds for a suitable blurring of the complex exponential maps and partially resolve the question, proving the necessity but not the sufficiency of the aforementioned conditions. As an algebraic application, I prove a weak form of Zilber’s conjecture on intersections with subgroups (known as CIT) for semiabelian varieties. This in turn is used to show that the necessary and sufficient conditions are expressible in the appropriate first order language

A Mononuclear Fe(III) Single Molecule Magnet with a 3/2↔5/2 Spin Crossover

The air stable complex [(PNP)FeCl(2)] (1) (PNP = N[2-P(CHMe(2))(2)-4-methylphenyl](2)(−)), prepared from one-electron oxidation of [(PNP)FeCl] with ClCPh(3), displays an unusual S = 3/2 to S = 5/2 transition above 80 K as inferred by the dc SQUID magnetic susceptibility measurement. The ac SQUID magnetization data, at zero field and between frequencies 10 and 1042 Hz, clearly reveals complex 1 to undergo a frequency dependent of the out-of-phase signal and thus be a single molecular magnet with a thermally activated barrier of U(eff) = 32-36 cm(−1) (47 - 52 K). Variable temperature Mössbauer data also corroborate a significant temperature dependence in δ and ΔE(Q) values for 1, which is in agreement with the system undergoing a change in spin state. Likewise, variable temperature X-band EPR spectra of 1 reveals the S = 3/2 to be likely the ground state with the S = 5/2 being close in energy. Multi-edge XAS absorption spectra suggest the electronic structure of 1 to be highly covalent with an effective iron oxidation state that is more reduced than the typical ferric complexes due to the significant interaction of the phosphine groups in PNP and Cl ligands with iron. A variable temperature single crystal X-ray diffraction study of 1 collected between 30-300 K also reveals elongation of the Fe–P bond lengths and increment in the Cl–Fe–Cl angle as the S = 5/2 state is populated. Theoretical studies show overall similar orbital pictures except for the d(z(2)) orbital which is the most sensitivity to change in the geometry and bonding where the quartet ((4)B) and the sextet ((6)A) states are close in energy

Let’s get virtual! Reinventing a science festival during a pandemic: Limitations and insights

Non-formal, yet educative, activities such as science festivals can positively influence the public regarding their attitude towards Science, Technology, Engineering and Math (STEM) subjects and students’ willingness to pursue STEM-related careers. We evaluate the changes made to adapt the Oxford Brookes Science Bazaar, a science festival that has been delivered face-to-face since 2008, to a virtual format in 2021 due to the COVID-19 pandemic. The online festival included 28 pre-recorded and 12 live activities of different types (hands-on, demonstration, games, lectures, podcasts, virtual tours). Hands-on activities and virtual tours had the highest number of unique viewers, while lectures and podcasts were the least watched. The videos were watched also after the advertised date of the festival and reached a broader audience than the physical events. The number of participants, the holding time, and the proportion of people who filled the feedback forms, however, were lower in the online than the physical events. STEM organisations should consider hybrid events, with both virtual and in-person contents, to reach a broader audience and to create more inclusive events. We provide recommendations on how to maximise the benefit of virtual formats, including expanding blended virtual activities to reach a wider variety of age groups

A low spin manganese(IV) nitride single molecule magnet

Structural, spectroscopic and magnetic methods have been used to characterize the tris(carbene) borate compound PhB(MesIm)(3)Mn equivalent to N as a four-coordinate manganese(IV) complex with a low spin (S = 1/2) configuration. The slow relaxation of the magnetization in this complex, i.e. its single-molecule magnet (SMM) properties, is revealed under an applied dc field. Multireference quantum mechanical calculations indicate that this SMM behavior originates from an anisotropic ground doublet stabilized by spin-orbit coupling. Consistent theoretical and experiment data show that the resulting magnetization dynamics in this system is dominated by ground state quantum tunneling, while its temperature dependence is influenced by Raman relaxation