Synthetic considerations in the self-assembly of coordination polymers of pyridine-functionalised hybrid Mn-Anderson polyoxometalates

The incorporation of polyoxometalates (POMs) as structural units into ordered porous constructs such as metal-organic frameworks (MOFs) is desirable for a range of applications where intrinsic properties inherited from both the MOF and POM are utilised, including catalysis and magnetic data storage. The controlled self-assembly of targeted MOF topologies containing POM units is hampered by the wide range of oxo and hydroxo units on the peripheries of POMs that can act as coordinating groups towards linking metal cations leading to a diverse range of structures, but incorporation of organic donor units into hybrid POMs offers an alternative methodology to programmably synthesise POM/MOF conjugates. Herein, we report six coordination polymers obtained serendipitously wherein Zn2+ and Cu2+ link pyridine-appended Mn-Anderson clusters into two- and three-dimensional network solids with complex connectivities and topologies. Careful inspection of their solid-state structures has allowed us to identify common structure-directing features across these coordination polymers, including a square motif where two Zn2+ cations bridge two POMs. By correlating certain structural motifs with synthetic conditions we have formulated a series of design considerations for the self-assembly of coordination polymers of hybrid POMs, encompassing the selection of reaction conditions, co-ligands and linking metal cations. We anticipate that these synthetic guidelines will inform the future assembly of hybrid POMs into functional MOF materials

Dynamic flow distortion investigation in an S-duct using DDES and SPIV data

The dynamic flow distortion generated within convoluted aero-engine intakes can affect the performance and operability of the engine. There is a need for a better understanding of the main flow mechanisms which promote flow distortion at the exit of S-shaped intakes. This paper presents a detailed analysis of the main coherent structures in an S-duct flow field based on a Delayed Detached Eddy Simulation (DDES). The DDES capability to capture the characteristics of the highly unsteady flow field is demonstrated against high resolution, synchronous Stereoscopic Particle Image Velocimetry (SPIV) measurements at the Aerodynamic Interface Plane (AIP). The flow field mechanisms responsible for the main AIP perturbations are identified. Clockwise and counter-clockwise stream-wise vortices are alternately generated around the separation region at a frequency of St=0.53, which promotes the swirl switching at the AIP. Spanwise vortices are also shed from the separation region at a frequency of St=1.06, and convect downstream along the separated centreline shear layer. This results in a vertical modulation of the main loss region and a fluctuation of the velocity gradient between the high and low velocity flow at the AIP

Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy.

Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms

The Earliest Phases of Galaxy Evolution

In this paper we study the very early phases of the evolution of our Galaxy by means of a chemical evolution model which reproduces most of the observational constraints in the solar vicinity and in the disk. We have restricted our analysis to the solar neighborhood and present the predicted abundances of several elements (C, N, O, Mg, Si, S, Ca, Fe) over an extended range of metallicities $[Fe/H] = -4.0$ to $[Fe/H] = 0.0$ compared to previous models. We adopted the most recent yield calculations for massive stars taken from different authors (Woosley & Weaver 1995 and Thielemann et al. 1996) and compared the results with a very large sample of data, one of the largest ever used to this purpose. These data have been analysed with a new and powerful statistical method which allows us to quantify the observational spread in measured elemental abundances and obtain a more meaningful comparison with the predictions from our chemical evolution model. Our analysis shows that the ``plateau'' observed for the [$\alpha$/Fe] ratios at low metallicities ($-3.0< [Fe/H] <-1.0$) is not perfectly constant but it shows a slope, especially for oxygen. This slope is very well reproduced by our model with both sets of yields. This is not surprising since realistic chemical evolution models, taking into account in detail stellar lifetimes, never predicted a completely flat plateau. This is due either to the fact that massive stars of different mass produce a slightly different O/Fe ratio or to the often forgotten fact that supernovae of type Ia, originating from white dwarfs, start appearing already at a galactic age of 30 million years and reach their maximum at 1 Gyr.Comment: 32 pages, 9 figures, to be published in Ap

Grouping Pig-Specific Responses to Mitogen with Similar Responder Animals may Facilitate the Interpretation of Results Obtained in an Out-Bred Animal Model

Copyright: © 2014 J. Alex Pasternak, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Peer ReviewedPig peripheral blood-derived mononuclear cells (PBMCs) and lamina propria mononuclear cells (LPMCs) stimulated with mitogens ex vivo can show significant animal-to-animal variation lead to difficulty in interpreting responses in an out-bred animal species. Mixed-cell populations were stimulated ex vivo with 2.5 μg/ml Con A or 2.5 ng/ml PMA plus 250 ng/ml ionomycin (PMAi; (LPCMs only)) or media alone for 72 hours. Supernatants were then tested for cytokine production using a Bioplex assay for porcine IFNα, IFNγ, IL-10, and IL-12. Unstimulated PBMCs had significant levels of IL-10 and the median value for this group decreased in the presence of Con A. Con A did, however, induce production of IFNα and IFNγ, but not IL-12 in this cell population. In contrast, unstimulated and Con A-stimulated LPMCs produced negligible IL-10, IFNα, IFNγ, and the majority of animals’ LPMCs showed negligible IL-12 production in response to Con A. In contrast, LPMCs stimulated with PMAi produced IFNγ suggesting cytokine production is mitogen–specific response. When we tracked animal-specific responses, we observed that discrete subsets of animal’s PBMCs responded to Con A with significantly increased or decreased IL-10 production relative to unstimulated cells. Further, in the LPMCs, some cells produced no IL-12 in response to Con A but showed augmented production in response to PMAi, while others showed production of IL-12 in response to Con A but no response to PMAi. Flow cytometric analysis showed that the PBMCs were a mixture of CD3+ T cells>CD21+ B cells>CD172+ myeloid cells whereas the LPMCs consisted of mainly Cytotoxic T cells and Natural Killer cells. The percentage of CD8α+CD4+ antigen-experienced T cells was greater in the LPMCs relative to the PBMCs. As expected in an out-bred species, animal-specific differences in cytokine production in response to stimulants exist and may confound interpretation of results unless tracked individually

Small but Crucial: The Novel Small Heat Shock Protein Hsp21 Mediates Stress Adaptation and Virulence in \u3ci\u3eCandida albicans\u3c/i\u3e

Small heat shock proteins (sHsps) have multiple cellular functions. However, the biological function of sHsps in pathogenic microorganisms is largely unknown. In the present study we identified and characterized the novel sHsp Hsp21 of the human fungal pathogen Candida albicans. Using a reverse genetics approach we demonstrate the importance of Hsp21 for resistance of C. albicans to specific stresses, including thermal and oxidative stress. Furthermore, a hsp21∆/∆ mutant was defective in invasive growth and formed significantly shorter filaments compared to the wild type under various filamentinducing conditions. Although adhesion to and invasion into human-derived endothelial and oral epithelial cells was unaltered, the hsp21∆/∆ mutant exhibited a strongly reduced capacity to damage both cell lines. Furthermore, Hsp21 was required for resisting killing by human neutrophils. Measurements of intracellular levels of stress protective molecules demonstrated that Hsp21 is involved in both glycerol and glycogen regulation and plays a major role in trehalose homeostasis in response to elevated temperatures. Mutants defective in trehalose and, to a lesser extent, glycerol synthesis phenocopied HSP21 deletion in terms of increased susceptibility to environmental stress, strongly impaired capacity to damage epithelial cells and increased sensitivity to the killing activities of human primary neutrophils. Via systematic analysis of the three main C. albicans stress-responsive kinases (Mkc1, Cek1, Hog1) under a range of stressors, we demonstrate Hsp21-dependent phosphorylation of Cek1 in response to elevated temperatures. Finally, the hsp21∆/∆mutant displayed strongly attenuated virulence in two in vivo infection models. Taken together, Hsp21 mediates adaptation to specific stresses via fine-tuning homeostasis of compatible solutes and activation of the Cek1 pathway, and is crucial for multiple stages of C. albicans pathogenicity. Hsp21 therefore represents the first reported example of a small heat shock protein functioning as a virulence factor in a eukaryotic pathogen

Dynamic Models of Aquaculture of Wolffish with Multiple Outputs: Invest in Growth Parameters or Invest in Biomolecule Production?

Most aquaculture rotation models deal with growing out a species to market size or to the optimum rotation age. Owners of these technologies often are also interested in investing in the growth parameters of the species, in order to shorten rotations. However, some species like the spotted and the Atlantic wolffish (Anarhichas minor & A. lupus) have potential to produce a number of by-products such as bio-molecules from mucus, blood or gastric enzymes, in addition to the production of high-quality products for human consumption (flesh & leather). We explore the implications of investing in growth parameters for meat production, versus investing in breeding programs that are more appropriate for bio-molecule markets and production of flesh. The problem is first cast as a classical Faustmann model with an investment function in growth parameters, and then as a less orthodox problem where no investment in growth parameters is made, but rather the owner invests in breeding programs that produce animals that can be used in sustainable blood extraction for antifreeze protein type III and mucus extraction for antimicrobial polypeptides, which would be sold on bio-molecule markets. The authors explore the possible effects on optimal rotations of these alternative strategies for maximizing profit for a firm. An example is presented based upon available data from the province of Quebec, Canada and Norway

IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes

Intraepithelial lymphocytes (IEL) respond to IL-15 complexed with IL-15Ra but how this intrinsically affects IEL is unclear. Here the authors use proteomics analyses of the main mouse IEL subsets and identify PIM kinases as essential for IEL proliferation, metabolism and effector function downstream of IL-15

Developing a rapid-response program for health system decision-makers in Canada: findings from an issue brief and stakeholder dialogue

Background: There is currently no mechanism in place outside of government to provide rapid syntheses of the best available research evidence about problems, options and/or implementation considerations related to a specific health system challenge that Canadian health system decision-makers need to address in a timely manner. A ‘rapid-response’ program could address this gap by providing access to optimally packaged, relevant and high-quality research evidence over short periods of time (i.e. days or weeks). Methods: We prepared an issue brief that describes the best available research evidence related to the problem, three broad features of a program that addresses the problem and implementation considerations. We identified systematic reviews by searching for organization-targeted implementation strategies in Health Systems Evidence (www.healthsystemsevidence.org) and drew on an existing analytical framework for how knowledge-brokering organizations can organize themselves to operationalize the program features. The issue brief was then used to inform a half-day stakeholder dialogue about whether and how to develop a rapid-response program for health system decision-makers in Canada. We thematically synthesized the deliberations. Results: We found very few relevant systematic reviews but used frameworks and examples from existing programs to 1) outline key considerations for organizing a rapid-response program,, 2) determine what can be done in timelines ranging from 3 to 10 and 30 business days, and 3) define success and measure it. The 11 dialogue participants from across Canada largely agreed with the content presented in the brief, but noted two key challenges to consider: securing stable, long-term funding and finding a way to effectively and equitably manage the expected demand. Recommendations and suggestions for next steps from dialogue participants included taking an ‘organic’ approach to developing a pan-Canadian network and including jurisdictional scans as a type of product to deliver through the program (rather than only syntheses of research evidence). Conclusions: Dialogue participants clearly signalled that there is an appetite for a rapid-response program for health system decision-makers in Canada. To ‘organically’ build such a program, we are currently engaging in efforts to build partnerships and secure funding to support the creation of a pan-Canadian network for conducting rapid syntheses for health system decision-makers in Canada. Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0009-3) contains supplementary material, which is available to authorized users

Managing healthcare budgets in times of austerity: the role of program budgeting and marginal analysis

Given limited resources, priority setting or choice making will remain a reality at all levels of publicly funded healthcare across countries for many years to come. The pressures may well be even more acute as the impact of the economic crisis of 2008 continues to play out but, even as economies begin to turn around, resources within healthcare will be limited, thus some form of rationing will be required. Over the last few decades, research on healthcare priority setting has focused on methods of implementation as well as on the development of approaches related to fairness and legitimacy and on more technical aspects of decision making including the use of multi-criteria decision analysis. Recently, research has led to better understanding of evaluating priority setting activity including defining ‘success’ and articulating key elements for high performance. This body of research, however, often goes untapped by those charged with making challenging decisions and as such, in line with prevailing public sector incentives, decisions are often reliant on historical allocation patterns and/or political negotiation. These archaic and ineffective approaches not only lead to poor decisions in terms of value for money but further do not reflect basic ethical conditions that can lead to fairness in the decision-making process. The purpose of this paper is to outline a comprehensive approach to priority setting and resource allocation that has been used in different contexts across countries. This will provide decision makers with a single point of access for a basic understanding of relevant tools when faced with having to make difficult decisions about what healthcare services to fund and what not to fund. The paper also addresses several key issues related to priority setting including how health technology assessments can be used, how performance can be improved at a practical level, and what ongoing resource management practice should look like. In terms of future research, one of the most important areas of priority setting that needs further attention is how best to engage public members