Energy Minimization of Discrete Protein Titration State Models Using Graph Theory

There are several applications in computational biophysics which require the optimization of discrete interacting states; e.g., amino acid titration states, ligand oxidation states, or discrete rotamer angles. Such optimization can be very time-consuming as it scales exponentially in the number of sites to be optimized. In this paper, we describe a new polynomial-time algorithm for optimization of discrete states in macromolecular systems. This algorithm was adapted from image processing and uses techniques from discrete mathematics and graph theory to restate the optimization problem in terms of "maximum flow-minimum cut" graph analysis. The interaction energy graph, a graph in which vertices (amino acids) and edges (interactions) are weighted with their respective energies, is transformed into a flow network in which the value of the minimum cut in the network equals the minimum free energy of the protein, and the cut itself encodes the state that achieves the minimum free energy. Because of its deterministic nature and polynomial-time performance, this algorithm has the potential to allow for the ionization state of larger proteins to be discovered

Exploring young child feeding practices and perceptions in Tower Hamlets, with a focus on sugar World Nutrition

Introduction: The aim of this qualitative research was to gain a greater understanding of the factors that influence young child feeding perceptions and practices in families with children under the age of five years old in London Borough of Tower Hamlets, in the context of rising childhood obesity levels in England. Methodology: The target group were mothers with children under five, mother in laws, service providers and carers. The participants were selected using purposeful, convenience and snowball sampling methods. Data were collected from 21 key informant interviews, 2 direct observations of health promotion sessions and 18 focus groups. The focus group discussions included 119 participants: 95 women who were mothers, 3 mother in laws and 21 service providers. A thematic analysis was used to identify four themes: knowledge not leading to changes, communication challenges, barriers to improving family healthy eating practices, and the lack of public health nutrition services. Findings: Knowledge had not led to behaviour change: Participants demonstrated high levels of knowledge on what constitutes healthy eating such as increasing the amount of fruit and vegetables their children eat while reducing sugar, salt and fat intake. Information was sought mainly from the internet, friends and family, but participants would prefer a one-to-one session with a health worker. Communication challenges: Misleading messages negatively affected food choices. Participants raised the problem of mixed messages regarding what was a healthy snack, as many food labels targeting young children carry misleading health claims such as “two of your five a day” or “organic,” despite having extremely high levels of sugar. Barriers to improving family healthy eating practices: The challenges experienced when trying to improve their children’s eating habits included the cost of healthy food options, the lack of time to buy and prepare healthy options, unhealthy treats given by family and friends, and the unhealthy takeaway food environment. Lack of public health nutrition services and support: There was a lack of clarity regarding who mothers and service providers should refer to regarding nutrition problems such as fussy eating, portion sizes, and diet diversity. Half of the early years’ service providers that were interviewed had no training on healthy eating guidelines, although training had been planned. Parents did not think the sugar tax would have a significant impact on the consumption of sugar or on childhood obesity levels

Reducing in-stent restenosis therapeutic manipulation of miRNA in vascular remodeling and inflammation

Background: Drug-eluting stents reduce the incidence of in-stent restenosis, but they result in delayed arterial healing and are associated with a chronic inflammatory response and hypersensitivity reactions. Identifying novel interventions to enhance wound healing and reduce the inflammatory response may improve long-term clinical outcomes. Micro–ribonucleic acids (miRNAs) are noncoding small ribonucleic acids that play a prominent role in the initiation and resolution of inflammation after vascular injury.<p></p> Objectives: This study sought to identify miRNA regulation and function after implantation of bare-metal and drug-eluting stents.<p></p> Methods: Pig, mouse, and in vitro models were used to investigate the role of miRNA in in-stent restenosis.<p></p> Results: We documented a subset of inflammatory miRNAs activated after stenting in pigs, including the miR-21 stem loop miRNAs. Genetic ablation of the miR-21 stem loop attenuated neointimal formation in mice post-stenting. This occurred via enhanced levels of anti-inflammatory M2 macrophages coupled with an impaired sensitivity of smooth muscle cells to respond to vascular activation.<p></p> Conclusions: MiR-21 plays a prominent role in promoting vascular inflammation and remodeling after stent injury. MiRNA-mediated modulation of the inflammatory response post-stenting may have therapeutic potential to accelerate wound healing and enhance the clinical efficacy of stenting

Change and continuity at PPA

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record.In June 2017, Public Policy and Administration (PPA) received its first Impact Factor of 1.529 in 2016 Journal Citation Reports®. It is a fantastic score, even more so considering this has been the very first year the journal was included in the index. As a result, PPA is now ranked 19/47 in the field ‘Public Administration’! This is major change for PPA, which this year celebrates its 30th year, and bodes very well for its future. And so, we want to take this opportunity to send a strong message of continuity to our readership and all the prospective contributors. [...

Polyphosphoinositides-dependent regulation of the osteoclast actin cytoskeleton and bone resorption

BACKGROUND: Gelsolin, an actin capping protein of osteoclast podosomes, has a unique function in regulating assembly and disassembly of the podosome actin filament. Previously, we have reported that osteopontin (OPN) binding to integrin α(v)β(3 )increased the levels of gelsolin-associated polyphosphoinositides, podosome assembly/disassembly, and actin filament formation. The present study was undertaken to identify the possible role of polyphosphoinositides and phosphoinositides binding domains (PBDs) of gelsolin in the osteoclast cytoskeletal structural organization and osteoclast function. RESULTS: Transduction of TAT/full-length gelsolin and PBDs containing gelsolin peptides into osteoclasts demonstrated: 1) F-actin enriched patches; 2) disruption of actin ring; 3) an increase in the association polyphosphoinositides (PPIs) with the transduced peptides containing PBDs. The above-mentioned effects were more pronounced with gelsolin peptide containing 2 tandem repeats of PBDs (PBD (2)). Binding of PPIs to the transduced peptides has resulted in reduced levels of PPIs association with the endogenous gelsolin, and thereby disrupted the actin remodeling processes in terms of podosome organization in the clear zone area and actin ring formation. These peptides also exhibited a dominant negative effect in the formation of WASP-Arp2/3 complex indicating the role of phosphoinositides in WASP activation. The TAT-PBD gelsolin peptides transduced osteoclasts are functionally defective in terms of motility and bone resorption. CONCLUSIONS: Taken together, these data demonstrate that transduction of PBD gelsolin peptides into osteoclasts produced a dominant negative effect on actin assembly, motility, and bone resorption. These findings indicate that phosphoinositide-mediated signaling mechanisms regulate osteoclast cytoskeleton, podosome assembly/disassembly, actin ring formation and bone resorption activity of osteoclasts

A new chapter for PPA!

publication-status: Publishedtypes: Editorial CommentOver the past three decades Public Policy and Administration (PPA) has established itself as one of the leading outlets for international quality research in the study of public policy, management and administration and cognate sub-fields. PPA has a strong identity providing a forum for debate, and the editorial line has been extremely successful in att racting high quality papers from a wide cross-secti on of policy fields addressing a range of contemporary issues. A particular strength of the journal under McTavish and Johnston-Miller has been its commitment to UK-related public administration at multiple levels

Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline

<b>Objective</b>: MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown.<p></p> <b>Methods and Results</b>: We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH.<p></p> <b>Conclusion</b>: Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention.<p></p&gt

Detection of prions in the faeces of sheep naturally infected with classical scrapie

Classical scrapie is a naturally transmitted prion disease of sheep and goats. Contaminated environments may contribute to the spread of disease and evidence from animal models has implicated urine, blood, saliva, placenta and faeces as possible sources of the infection. Here we sought to determine whether sheep naturally infected with classical scrapie shed prions in their faeces. We used serial protein misfolding cyclic amplification (sPMCA) along with two extraction methods to examine faeces from sheep during both the clinical and preclinical phases of the disease and showed amplification of PrPSc in 7 of 15 and 14 of 14 sheep respectively. However PrPSc was not amplified from the faeces of 25 sheep not exposed to scrapie. These data represent the first demonstration of prion shedding in faeces from a naturally infected host and thus a likely source of prion contamination in the environment

Aerosol trace metal leaching and impacts on marine microorganisms

Metal dissolution from atmospheric aerosol deposition to the oceans is important in enhancing and inhibiting phytoplankton growth rates and modifying plankton community structure, thus impacting marine biogeochemistry. Here we review the current state of knowledge on the causes and effects of the leaching of multiple trace metals from natural and anthropogenic aerosols. Aerosol deposition is considered both on short timescales over which phytoplankton respond directly to aerosol metal inputs, as well as longer timescales over which biogeochemical cycles are affected by aerosols

Ecospheric life cycle impacts of annual global space activities

This paper presents a first-order approximation of ecospheric life cycle impacts from annual global space activities across two scenarios using a streamlined Life Cycle Sustainability Assessment (LCSA). The first scenario considers all space missions launched throughout the 2018 calendar year whilst the second is a futuristic scenario where affordable access to space significantly increases the prevalence of space operations. A new space-specific life cycle database and sustainable design tool called the Strathclyde Space Systems Database (SSSD) has been used to compile the inventory of each scenario and generate results across numerous impact categories. The results for each scenario are then compared against normalised values to portray their contribution towards annual worldwide impacts and their severity in terms of planetary boundaries. This allows the relative life cycle sustainability impacts of space activities to be benchmarked for the first time, forming a basis for evaluation and discussion. Overall, the study highlights that despite the relatively small footprint of the space industry at present, this will likely become much more meaningful in the future based on predicted trends. This places an added importance on addressing potential adverse life cycle impacts within the design process of future space technologies and products