BioMagResBank (BMRB) as a partner in the Worldwide Protein Data Bank (wwPDB): new policies affecting biomolecular NMR depositions

We describe the role of the BioMagResBank (BMRB) within the Worldwide Protein Data Bank (wwPDB) and recent policies affecting the deposition of biomolecular NMR data. All PDB depositions of structures based on NMR data must now be accompanied by experimental restraints. A scheme has been devised that allows depositors to specify a representative structure and to define residues within that structure found experimentally to be largely unstructured. The BMRB now accepts coordinate sets representing three-dimensional structural models based on experimental NMR data of molecules of biological interest that fall outside the guidelines of the Protein Data Bank (i.e., the molecule is a peptide with 23 or fewer residues, a polynucleotide with 3 or fewer residues, a polysaccharide with 3 or fewer sugar residues, or a natural product), provided that the coordinates are accompanied by representation of the covalent structure of the molecule (atom connectivity), assigned NMR chemical shifts, and the structural restraints used in generating model. The BMRB now contains an archive of NMR data for metabolites and other small molecules found in biological systems

A L\'evy input fluid queue with input and workload regulation

We consider a queuing model with the workload evolving between consecutive i.i.d.\ exponential timers $\{e_q^{(i)}\}_{i=1,2,...}$ according to a spectrally positive L\'evy process $Y_i(t)$ that is reflected at zero, and where the environment $i$ equals 0 or 1. When the exponential clock $e_q^{(i)}$ ends, the workload, as well as the L\'evy input process, are modified; this modification may depend on the current value of the workload, the maximum and the minimum workload observed during the previous cycle, and the environment $i$ of the L\'evy input process itself during the previous cycle. We analyse the steady-state workload distribution for this model. The main theme of the analysis is the systematic application of non-trivial functionals, derived within the framework of fluctuation theory of L\'evy processes, to workload and queuing models

Management of trypanosomiasis and leishmaniasis

<p>Background: The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.</p> <p>Sources of data: PubMed.</p> <p>Areas of Agreement: There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.</p> <p>Areas of controversy: Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.</p> <p>Growing points: There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.</p> <p>Areas timely for developing research: Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.</p&gt

Regulation of nitrogen metabolism in the marine diazotroph Trichodesmium IMS101 under varying temperatures and atmospheric CO2 concentrations

We examined the influence of forecasted changes in global temperatures and pCO2 on N2 fixation and assimilation in the ecologically important cyanobacterium Trichodesmium spp. Changes of mRNA transcripts (nifH, glnA, hetR, psbA, psaB), protein (nitrogenase, glutamine synthetase) pools and enzymatic activity (nitrogenase) were measured under varying pCO2 and temperatures. High pCO2 shifted transcript patterns of all genes, resulting in a more synchronized diel expression. Under the same conditions, we did not observe any significant changes in the protein pools or in total cellular allocations of carbon and nitrogen (i.e. C : N ratio remained stable). Independently of temperature, high pCO2 (900 µatm) elevated N2 fixation rates. Levels of the key enzymes, nitrogenase and glutamine synthetase that mediate nitrogen assimilation did not increase, implying that the high pCO2 allowed higher reaction turnover rates through these key enzymes. Moreover, increased temperatures and high pCO2 resulted in higher C : P ratios. The plasticity in phosphorous stoichiometry combined with higher enzymatic efficiencies lead to higher growth rates. In cyanobacteria photosynthesis, carbon uptake, respiration, N2 fixation and nitrogen assimilation share cellular components. We propose that shifted cellular resource and energy allocation among those components will enable Trichodesmium grown at elevated temperatures and pCO2 to extend its niche in the future ocean, through both tolerance of a broader temperature range and higher P plasticity

Expanding the parameters of academia

This paper draws on qualitative data gathered from two studies funded by the UK Leadership Foundation for Higher Education to examine the expansion of academic identities in higher education. It builds on Whitchurch’s earlier work, which focused primarily on professional staff, to suggest that the emergence of broadly based projects such as widening participation, learning support and community partnership is also impacting on academic identities. Thus, academic as well as professional staff are increasingly likely to work in multi-professional teams across a variety of constituencies, as well as with external partners, and the binary distinction between ‘academic’ and ‘non-academic’ roles and activities is no longer clear-cut. Moreover, there is evidence from the studies of an intentionality about deviations from mainstream academic career routes among respondents who could have gone either way. Consideration is therefore given to factors that influence individuals to work in more project-oriented areas, as well as to variables that affect ways in which these roles and identities develop. Finally, three models of academically oriented project activity are identified, and the implications of an expansion of academic identities are reviewed

Is Paromomycin an Effective and Safe Treatment against Cutaneous Leishmaniasis? A Meta-Analysis of 14 Randomized Controlled Trials

Millions of people worldwide are suffering from cutaneous leishmaniasis that is caused by parasites of the genus Leishmania. Although pentavalent antimony compounds are the treatment of choice, their use is limited by high cost, poor compliance, and systemic toxicity. Paromomycin was developed to overcome such limitations. However, there is no consensus on its efficacy. This meta-analysis assessed the efficacy and safety of paromomycin compared with placebo and pentavalent antimony compounds. Fourteen randomized controlled trials, including 1,221 patients, met our selection criteria. Topical paromomycin appeared to have therapeutic activity against the old world and new world cutaneous leishmaniasis, with increased local reactions, when combined with methylbenzethonium chloride. Topical paromomycin was not significantly different from intralesional pentavalent antimony compounds in treating the old world form, whereas it was inferior to parenteral pentavalent antimony compounds in treating the new world form. However, a similar efficacy was found between parenteral paromomycin and pentavalent antimony compounds in treating the new world form. Fewer systemic side effects were observed with topical and parenteral paromomycin than pentavalent antimony compounds. These results suggest that topical paromomycin with methylbenzethonium chloride could be a therapeutic alternative to pentavalent antimony compounds for selected cases of the old world cutaneous leishmaniasis

An ice-rich flow origin for the banded terrain in the Hellas basin, Mars

The interior of Hellas Basin displays a complex landscape and a variety of geomorphological domains. One of these domains, the enigmatic banded terrain covers much of the northwestern part of the basin. We use high-resolution (Context Camera and High-Resolution Imaging Science Experiment) Digital Terrain Models to show that most of the complex viscous flowing behavior exhibited by the banded terrain is controlled by topography and flow-like interactions between neighboring banded terrain. Furthermore, the interior of the basin hosts several landforms suggestive of the presence of near-surface ice, which include polygonal patterns with elongated pits, scalloped depressions, isolated mounds, and collapse structures. We suggest that thermal contraction cracking and sublimation of near-surface ice are responsible for the formation and the development of most of the ice-related landforms documented in Hellas. The relatively pristine form, lack of superposed craters, and strong association with the banded terrain, suggest an Amazonian (<3 Ga) age of formation for these landforms. Finally, relatively high surface pressures (above the triple point of water) expected in Hellas and summertime temperatures often exceeding the melting point of water ice suggest that the basin may have recorded relatively “temperate” climatic conditions compared to other places on Mars. Therefore, the potentially ice-rich banded terrain may have deformed with lower viscosity and stresses compared to other locations on Mars, which may account for its unique morphology

Long-range effects of histone point mutations on DNA remodeling revealed from computational analyses of SIN-mutant nucleosome structures

The packaging of DNA into nucleosomes impedes the binding and access of molecules involved in its processing. The SWI/SNF multi-protein assembly, found in yeast, is one of many regulatory factors that stimulate the remodeling of DNA required for its transcription. Amino-acid point mutations in histones H3 or H4 partially bypass the requirement of the SWI/SNF complex in this system. The mechanisms underlying the observed remodeling, however, are difficult to discern from the crystal structures of nucleosomes bearing these so-called SIN (SWI/SNF INdependent) mutations. Here, we report detailed analyses of the conformations and interactions of the histones and DNA in these assemblies. We find that the loss of direct protein–DNA contacts near point-mutation sites, reported previously, is coupled to unexpected additional long-range effects, i.e. loss of intermolecular contacts and accompanying DNA conformational changes at sequentially and spatially distant sites. The SIN mutations seemingly transmit information relevant to DNA binding across the nucleosome. The energetic cost of deforming the DNA to the states found in the SIN-mutant structures helps to distinguish the mutants that show phenotypes in yeast from those that do not. Models incorporating these deformed dimer steps suggest ways that nucleosomal DNA may be remodeled during its biological processing

3D Carbon Scaffolds for Neural Stem Cell Culture and Magnetic Resonance Imaging

3D glassy carbon structures with percolated macropores are obtained by pyrolysis of chemically synthesized cryogels featuring tunable porosity. These batch-fabricated structures are used as scaffolds for culturing neural stem cells (NSCs) and are characterized by magnetic resonance imaging (MRI). With the aid of MRI, the successful cultivation of NSCs on a glassy carbon surface and the precise 3D locations of these cell clusters within the opaque scaffold are demonstrated. MRI also yields pore morphology and porosity analyses, pre- and post-pyrolysis. This integrated approach yields a complete 3D dataset of the NSC network, which enables the visual inspection of the morphological details of individual cell clusters without disturbing them or destroying the scaffold. Reported experimental methodology is expected to have an impact on studies designed to understand the mechanism of neurodegenerative disease (ND) development, and can serve as a protocol for the culture of various other types of cells that display compatibility with glassy carbon surfaces