GPS for QSP: A Summary of the ACoP6 Symposium on Quantitative Systems Pharmacology and a Stage for Near-Term Efforts in the Field

Quantitative Systems Pharmacology (QSP) is experiencing increased application in the drug discovery and development process. Like its older sibling, systems biology, the QSP field is comprised of a mix of established disciplines and methods, from molecular biology to engineering to pharmacometrics.[1] As a result, there exist critical segments of the discipline that differ dramatically in approach and a need to bring these groups together toward a common goal

Evolution of strigolactone receptors by gradual neofunctionalization of KAI2 paralogues

Background: Strigolactones (SLs) are a class of plant hormones that control many aspects of plant growth. The SL signalling mechanism is homologous to that of karrikins (KARs), smoke-derived compounds that stimulate seed germination. In angiosperms, the SL receptor is an a/p hydrolase known as DWARF14 (D14); its close homologue, KARRIKIN INSENSITIVE2 (KAI2), functions as a KAR receptor, and likely recognizes an uncharacterized, endogenous signal (‘KL’). Previous phylogenetic analyses have suggested that the KAI2 lineage is ancestral in land plants, and that canonical D14-type SL receptors only arose in seed plants; this is paradoxical, however, as nonvascular plants synthesize and respond to SLs. Results: We have used a combination of phylogenetic and structural approaches to re-assess the evolution of the D14/KAI2 family in land plants. We analyzed 339 members of the D14/KAI2 family from land plants and charophyte algae. Our phylogenetic analyses show that the divergence between the eu-KAI2 lineage and the DDK (D14/DLK2/KAI2) lineage that includes D14 occurred very early in land plant evolution. We show that eu-KAI2 proteins are highly conserved, and have unique features not found in DDK proteins. Conversely, we show that DDK proteins show considerable sequence and structural variation to each other, and lack clearly definable characteristics. We use homology modelling to show that the earliest members of the DDK lineage structurally resemble KAI2, and that SL receptors in non-seed plants likely do not have D14-like structure. We also show that certain groups of DDK proteins lack the otherwise conserved MAX2-interface, and may thus function independently of MAX2, which we show is highly conserved throughout land plant evolution. Conclusions: Our results suggest D14-like structure is not required for SL perception, and that SL perception has relatively relaxed structural requirements compared to KAI2-mediated signalling. We suggest that SL perception gradually evolved by neo-functionalization within the DDK lineage, and that the transition from KAI2-like to D14-like protein may have been driven by interactions with protein partners, rather than being required for SL perception per se

Microcolony Imaging of Aspergillus fumigatus Treated with Echinocandins Reveals Both Fungistatic and Fungicidal Activities

Background: The echinocandins are lipopeptides that can be employed as antifungal drugs that inhibit the synthesis of 1,3b-glucans within the fungal cell wall. Anidulafungin and caspofungin are echinocandins used in the treatment of Candida infections and have activity against other fungi including Aspergillus fumigatus. The echinocandins are generally considered fungistatic against Aspergillus species. Methods: Culture of A. fumigatus from conidia to microcolonies on a support of porous aluminium oxide (PAO), combined with fluorescence microscopy and scanning electron microscopy, was used to investigate the effects of anidulafungin and caspofungin. The PAO was an effective matrix for conidial germination and microcolony growth. Additionally, PAO supports could be moved between agar plates containing different concentrations of echinocandins to change dosage and to investigate the recovery of fungal microcolonies from these drugs. Culture on PAO combined with microscopy and image analysis permits quantitative studies on microcolony growth with the flexibility of adding or removing antifungal agents, dyes, fixatives or osmotic stresses during growth with minimal disturbance of fungal microcolonies. Significance: Anidulafungin and caspofungin reduced but did not halt growth at the microcony level; additionally both drugs killed individual cells, particularly at concentrations around the MIC. Intact but not lysed cells showed rapid recovery when the drugs were removed. The classification of these drugs as either fungistatic or fungicidal is simplistic. Microcolon

Effect of nickel on the microstructure and mechanical property of die-cast Al–Mg–Si–Mn alloy

The effect of nickel on the microstructure and mechanical properties of a die-cast Al–Mg–Si–Mn alloy has been investigated. The results show that the presence of Ni in the alloy promotes the formation of Ni-rich intermetallics. These occur consistently during solidification in the die-cast Al–Mg–Si–Mn alloy across different levels of Ni content. The Ni-rich intermetallics exhibit dendritic morphology during the primary solidification and lamellar morphology during the eutectic solidification stage. Ni was found to be always associated with iron forming AlFeMnSiNi intermetallics, and no Al3Ni intermetallic was observed when Ni concentrations were up to 2.06 wt% in the alloy. Although with different morphologies, the Ni-rich intermetallics were identified as the same AlFeMnSiNi phase bearing a typical composition of Al[100–140](Fe,Mn)[2–7]SiNi[4–9]. With increasing Ni content, the spacing of the α-Al–Mg2Si eutectic phase was enlarged in the Al–Mg–Si–Mn alloy. The addition of Ni to the alloy resulted in a slight increase in the yield strength, but a significant decrease in the elongation. The ultimate tensile strength (UTS) increased slightly from 300 to 320 MPa when a small amount (e.g. 0.16 wt%) of Ni was added to the alloy, but further increase of the Ni content resulted in a decrease of the UTS.The Engineering and Physical Sciences Research Council (EPSRC), Technology Strategy Board (TSB) and Jaguar Land Rover (JLR) in the United Kingdom

Yours ever (well, maybe): Studies and signposts in letter writing

Electronic mail and other digital communications technologies seemingly threaten to end the era of handwritten and typed letters, now affectionately seen as part of snail mail. In this essay, I analyze a group of popular and scholarly studies about letter writing-including examples of pundits critiquing the use of e-mail, etiquette manuals advising why the handwritten letter still possesses value, historians and literary scholars studying the role of letters in the past and what it tells us about our present attitudes about digital communications technologies, and futurists predicting how we will function as personal archivists maintaining every document including e-mail. These are useful guideposts for archivists, providing both a sense of the present and the past in the role, value and nature of letters and their successors. They also provide insights into how such documents should be studied, expanding our gaze beyond the particular letters, to the tools used to create them and the traditions dictating their form and function. We also can discern a role for archivists, both for contributing to the literature about documents and in using these studies and commentaries, suggesting not a new disciplinary realm but opportunities for new interdisciplinary work. Examining a documentary form makes us more sensitive to both the innovations and traditions as it shifts from the analog to the digital; we can learn not to be caught up in hysteria or nostalgia about one form over another and archivists can learn about what they might expect in their labors to document society and its institutions. At one time, paper was part of an innovative technology, with roles very similar to the Internet and e-mail today. It may be that the shifts are far less revolutionary than is often assumed. Reading such works also suggests, finally, that archivists ought to rethink how they view their own knowledge and how it is constructed and used. © 2010 Springer Science+Business Media B.V

In ovo exposure to o,p -DDE affects sexual development but not sexual differentiation in Japanese medaka (Oryzias latipes).

Despite being banned in many countries, dichlorodiphenyltrichloroethane (DDT) and its metabolites dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) continue to be found in fish tissues at concentrations of concern. Like o,p -DDT, o,p -DDE is estrogenic and is believed to exert its effects through binding to the estrogen receptor. The limited toxicologic data for o,p -DDE suggest that it decreases fecundity and fertility of fishes. We conducted an egg injection study using the d-rR strain of medaka and environmentally relevant concentrations of o,p -DDE to examine its effects on sexual differentiation and development. The gonads of exposed fish showed no evidence of sex reversal or intersex. However, other gonad abnormalities occurred in exposed individuals. Females exhibited few vitellogenic oocytes and increased atresia. Male testes appeared morphologically normal but were very small. Gonadosomatic index values for both sexes were lower for exposed fish. Our observations of abnormal female and very small male gonads after in ovo o,p -DDE exposure may be indicative of effects on early endocrine processes important for normal ovarian and testicular development

Wave attenuation at a salt marsh margin: A case study of an exposed coast on the Yangtze estuary

To quantify wave attenuation by (introduced) Spartina alterniflora vegetation at an exposed macrotidal coast in the Yangtze Estuary, China, wave parameters and water depth were measured during 13 consecutive tides at nine locations ranging from 10 m seaward to 50 m landward of the low marsh edge. During this period, the incident wave height ranged from <0.1 to 1.5 m, the maximum of which is much higher than observed in other marsh areas around the world. Our measurements and calculations showed that the wave attenuation rate per unit distance was 1 to 2 magnitudes higher over the marsh than over an adjacent mudflat. Although the elevation gradient of the marsh margin was significantly higher than that of the adjacent mudflat, more than 80% of wave attenuation was ascribed to the presence of vegetation, suggesting that shoaling effects were of minor importance. On average, waves reaching the marsh were eliminated over a distance of similar to 80 m, although a marsh distance of >= 100 m was needed before the maximum height waves were fully attenuated during high tides. These attenuation distances were longer than those previously found in American salt marshes, mainly due to the macrotidal and exposed conditions at the present site. The ratio of water depth to plant height showed an inverse correlation with wave attenuation rate, indicating that plant height is a crucial factor determining the efficiency of wave attenuation. Consequently, the tall shoots of the introduced S. alterniflora makes this species much more efficient at attenuating waves than the shorter, native pioneer species in the Yangtze Estuary, and should therefore be considered as a factor in coastal management during the present era of sea-level rise and global change. We also found that wave attenuation across the salt marsh can be predicted using published models when a suitable coefficient is incorporated to account for drag, which varies in place and time due to differences in plant characteristics and abiotic conditions (i.e., bed gradient, initial water depth, and wave action).

Design and testing of hydrophobic core/hydrophilic shell nano/micro particles for drug-eluting stent coating

In this study, we designed a novel drug-eluting coating for vascular implants consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21. The core/shell structure was sprayed onto the surface of 316L stainless steel stents using a coaxial electrospray process with the aim of creating a coating that exhibited a differential release of the two drugs. The prepared stents displayed a uniform coating consisting of nano/micro particles. In vitro drug release experiments were performed, and we demonstrated that a biphasic mathematical model was capable of capturing the data, indicating that the release of the two drugs conformed to a diffusion-controlled release system. We demonstrated that our coating was capable of inhibiting the adhesion and activation of platelets, as well as the proliferation and migration of smooth muscle cells (SMCs), indicating its good biocompatibility and anti-proliferation qualities. In an in vivo porcine coronary artery model, the SZ-21/DTX drug-loaded hydrophobic core/hydrophilic shell particle coating stents were observed to promote re-endothelialization and inhibit neointimal hyperplasia. This core/shell particle-coated stent may serve as part of a new strategy for the differential release of different functional drugs to sequentially target thrombosis and in-stent restenosis during the vascular repair process and ensure rapid re-endothelialization in the field of cardiovascular disease

Validity, reliability and stability of the portable Cortex Metamax 3B gas analysis system

This study investigated the performance of the portable Cortex Metamax 3B (MM3B) automated gas analysis system during both simulated and human exercise using adolescents. Repeated measures using a Gas Exchange System Validator (GESV) across a range of simulated metabolic rates, showed the MM3B to be adequately reliable (both percentage errors, and percentage technical error of measurements <2%) for measuring expired ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2). Over a 3 h period, the MM3B was shown to be acceptably stable in measuring gas fractions, as well as VE, VO2, and VCO2 generated by the GESV, especially at moderate and high metabolic rates (drifts <2% and of minor physiological significance). Using eight healthy adolescents during rest, moderate, and vigorous cycle ergometry, the validity of the MM3B was tested against the primary criterion Douglas bag method (DBM) and a secondary criterion machine known to be accurate, the Jaeger Oxycon Pro system. No significant errors in VE were noted, yet the MM3B significantly overestimated both VO2 and VCO2 by approximately 10–17% at moderate and vigorous exercise as compared to the DBM and at all exercise levels compared to the Oxycon Pro. No significant differences were seen in any metabolic variable between the two criterion systems (DBM and Oxycon Pro). It is concluded the MM3B produces acceptably stable and reliable results, but is not adequately valid during moderate and vigorous exercise without some further correction of VO2 and VCO2

Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia

Immune-mediated haemolytic anaemia (IMHA) is reported to be the most common autoimmune disease of dogs, resulting in significant morbidity and mortality in affected animals. Haemolysis is caused by the action of autoantibodies, but the immunological changes that result in their production have not been elucidated.To investigate the frequency of regulatory T cells (Tregs) and other lymphocyte subsets and to measure serum concentrations of cytokines and peripheral blood mononuclear cell expression of cytokine genes in dogs with IMHA, healthy dogs and dogs with inflammatory diseases.19 dogs with primary IMHA, 22 dogs with inflammatory diseases and 32 healthy control dogs.Residual EDTA-anti-coagulated blood samples were stained with fluorophore-conjugated monoclonal antibodies and analysed by flow cytometry to identify Tregs and other lymphocyte subsets. Total RNA was also extracted from peripheral blood mononuclear cells to investigate cytokine gene expression, and concentrations of serum cytokines (interleukins 2, 6 10, CXCL-8 and tumour necrosis factor α) were measured using enhanced chemiluminescent assays. Principal component analysis was used to investigate latent variables that might explain variability in the entire dataset.There was no difference in the frequency or absolute numbers of Tregs among groups, nor in the proportions of other lymphocyte subsets. The concentrations of pro-inflammatory cytokines were greater in dogs with IMHA compared to healthy controls, but the concentration of IL-10 and the expression of cytokine genes did not differ between groups. Principal component analysis identified four components that explained the majority of the variability in the dataset, which seemed to correspond to different aspects of the immune response.The immunophenotype of dogs with IMHA differed from that of dogs with inflammatory diseases and from healthy control dogs; some of these changes could suggest abnormalities in peripheral tolerance that permit development of autoimmune disease. The frequency of Tregs did not differ between groups, suggesting that deficiency in the number of these cells is not responsible for development of IMHA