The macroecology of sustainability

The discipline of sustainability science has emerged in response to concerns of natural and social scientists, policymakers, and lay people about whether the Earth can continue to support human population growth and economic prosperity. Yet, sustainability science has developed largely independently from and with little reference to key ecological principles that govern life on Earth. A macroecological perspective highlights three principles that should be integral to sustainability science: 1) physical conservation laws govern the flows of energy and materials between human systems and the environment, 2) smaller systems are connected by these flows to larger systems in which they are embedded, and 3) global constraints ultimately limit flows at smaller scales. Over the past few decades, decreasing per capita rates of consumption of petroleum, phosphate, agricultural land, fresh water, fish, and wood indicate that the growing human population has surpassed the capacity of the Earth to supply enough of these essential resources to sustain even the current population and level of socioeconomic development.     

Diverse Lifestyles and Strategies of Plant Pathogenesis Encoded in the Genomes of Eighteen Dothideomycetes Fungi

The class Dothideomycetes is one of the largest groups of fungi with a high level of ecological diversity including many plant pathogens infecting a broad range of hosts. Here, we compare genome features of 18 members of this class, including 6 necrotrophs, 9 (hemi)biotrophs and 3 saprotrophs, to analyze genome structure, evolution, and the diverse strategies of pathogenesis. The Dothideomycetes most likely evolved from a common ancestor more than 280 million years ago. The 18 genome sequences differ dramatically in size due to variation in repetitive content, but show much less variation in number of (core) genes. Gene order appears to have been rearranged mostly within chromosomal boundaries by multiple inversions, in extant genomes frequently demarcated by adjacent simple repeats. Several Dothideomycetes contain one or more gene-poor, transposable element (TE)-rich putatively dispensable chromosomes of unknown function. The 18 Dothideomycetes offer an extensive catalogue of genes involved in cellulose degradation, proteolysis, secondary metabolism, and cysteine-rich small secreted proteins. Ancestors of the two major orders of plant pathogens in the Dothideomycetes, the Capnodiales and Pleosporales, may have had different modes of pathogenesis, with the former having fewer of these genes than the latter. Many of these genes are enriched in proximity to transposable elements, suggesting faster evolution because of the effects of repeat induced point (RIP) mutations. A syntenic block of genes, including oxidoreductases, is conserved in most Dothideomycetes and upregulated during infection in L. maculans, suggesting a possible function in response to oxidative stress.     

Enhancement of Chemokine Function as an Immunomodulatory Strategy Employed by Human Herpesviruses

Herpes simplex virus (HSV) types 1 and 2 are highly prevalent human neurotropic pathogens that cause a variety of diseases, including lethal encephalitis. The relationship between HSV and the host immune system is one of the main determinants of the infection outcome. Chemokines play relevant roles in antiviral response and immunopathology, but the modulation of chemokine function by HSV is not well understood. We have addressed the modulation of chemokine function mediated by HSV. By using surface plasmon resonance and crosslinking assays we show that secreted glycoprotein G (SgG) from both HSV-1 and HSV-2 binds chemokines with high affinity. Chemokine binding activity was also observed in the supernatant of HSV-2 infected cells and in the plasma membrane of cells infected with HSV-1 wild type but not with a gG deficient HSV-1 mutant. Cell-binding and competition experiments indicate that the interaction takes place through the glycosaminoglycan-binding domain of the chemokine. The functional relevance of the interaction was determined both in vitro, by performing transwell assays, time-lapse microscopy, and signal transduction experiments; and in vivo, using the air pouch model of inflammation. Interestingly, and in contrast to what has been observed for previously described viral chemokine binding proteins, HSV SgGs do not inhibit chemokine function. On the contrary, HSV SgGs enhance chemotaxis both in vitro and in vivo through increasing directionality, potency and receptor signaling. This is the first report, to our knowledge, of a viral chemokine binding protein from a human pathogen that increases chemokine function and points towards a previously undescribed strategy of immune modulation mediated by viruses.     

Intestinal aspartate proteases TiCatD and TiCatD2 of the haematophagous bug Triatoma infestans (Reduviidae): sequence characterisation, expression pattern and characterisation of proteolytic activity

Two aspartate protease encoding complementary deoxyribonucleic acids (cDNA) were characterised from the small intestine (posterior midgut) of Triatoma infestans and the corresponding genes were named TiCatD and TiCatD2. The deduced 390 and 393 amino acid sequences of both enzymes contain two regions characteristic for cathepsin D proteases and the conserved catalytic aspartate residues forming the catalytic dyad, but only TiCatD2 possesses an entire C-terminal proline loop. The amino acid sequences of TiCatD and TiCatD2 show 51-58% similarity to other insect cathepsin D-like proteases and, respectively, 88 and 58% similarity to the aspartate protease ASP25 from T. infestans available in the GenBank database. In phylogenetic analysis, TiCatD and ASP25 clearly separate from cathepsin D-like sequences of other insects, TiCatD2 groups with cathepsin D-like proteases with proline loop. The activity of purified TiCatD and TiCatD2 was highest between pH 2 and 4, respectively, and hence, deviate from the pH values of the lumen of the small intestine, which varied in correlation with the time after feeding between pH 5.2 and 6.7 as determined by means of micro pH electrodes. Both cathepsins, TiCatD and TiCatD2, were purified from the lumen of the small intestine using pepstatin affinity chromatography and identified by nanoLC-ESI-MS/MS analysis as those encoded by the cDNAs. The proteolytic activity of the purified enzymes is highest at pH 3 and the respective genes are expressed in the both regions of the midgut, stomach (anterior midgut) and small intestine, not in the rectum, salivary glands, Malpighian tubules or haemocytes. The temporal expression pattern of both genes in the small intestine after feeding revealed a feeding dependent regulation for TiCatD but not for TiCatD2.     

Acyl-sulfamates target the essential glycerol-phosphate acyltransferase (PlsY) in Gram-positive bacteria

PlsY is the essential first step in membrane phospholipid synthesis of Gram-positive pathogens. PlsY catalyzes the transfer of the fatty acid from acyl-phosphate to the 1-position of glycerol-3-phosphate to form the first intermediate in membrane biogenesis. A series of non-metabolizable, acyl-sulfamate analogs of the acyl-phosphate PlsY substrate were prepared and evaluated as inhibitors of Staphylococcus aureus PlsY and for their Gram-positive antibacterial activities. From this series phenyl (8-phenyloctanoyl) sulfamate had the best overall profile, selectively inhibiting S. aureus phospholipid biosynthesis and causing the accumulation of both long-chain fatty acids and acyl-acyl carrier protein intermediates demonstrating that PlsY was the primary cellular target. Bacillus anthracis was unique in being more potently inhibited by long chain acyl-sulfamates than other bacterial species. However, it is shown that Bacillus anthracis PlsY is not more sensitive to the acyl-sulfamates than S. aureus PlsY. Metabolic profiling showed that B. anthracis growth inhibition by the acyl-sulfamates was not specific for lipid synthesis illustrating that the amphipathic acyl-sulfamates can also have off-target effects in Gram-positive bacteria. Nonetheless, this study further advances PlsY as a druggable target for the development of novel antibacterial therapeutics, through the discovery and validation of the probe compound phenyl (8-phenyloctanoyl) sulfamate as a S. aureus PlsY inhibitor.     

Pharmacokinetic and -dynamic modelling of G-CSF derivatives in humans

ABSTRACT: BACKGROUND: The human granulocyte colony-stimulating factor (G-CSF) is routinely applied to support recovery of granulopoiesis during the course of cytotoxic chemotherapies. However, optimal use of the drug is largely unknown. We showed in the past that a biomathematical compartment model of human granulopoiesis can be used to make clinically relevant predictions regarding new, yet untested chemotherapy regimen. In the present paper, we aim to extend this model by a detailed pharmacokinetic and -dynamic modelling of two commonly used G-CSF derivatives Filgrastim and Pegfilgrastim. RESULTS: Model equations are based on our physiological understanding of the drugs which are delayed absorption of G-CSF when applied to the subcutaneous tissue, dose-dependent bioavailability, unspecific first order elimination, specific elimination in dependence on granulocyte counts and reversible protein binding. Pharmacokinetic differences between Filgrastim and Pegfilgrastim were modelled as different parameter sets. Our former cell-kinetic model of granulopoiesis was essentially preserved, except for a few additional assumptions and simplifications. We assumed a delayed action of G-CSF on the bone marrow, a delayed action of chemotherapy and differences between Filgrastim and Pegfilgrastim with respect to stimulation potency of the bone marrow. Additionally, we incorporated a model of combined action of Pegfilgrastim and Filgrastim or endogenous G-CSF which interact via concurrent receptor binding. Unknown pharmacokinetic or cell-kinetic parameters were determined by fitting the predictions of the model to available datasets of G-CSF applications, chemotherapy applications or combinations of it. Data were either extracted from the literature or were received from cooperating clinical study groups. Model predictions fitted well to both, datasets used for parameter estimation and validation scenarios as well. A unique set of parameters was identified which is valid for all scenarios considered. Differences in pharmacokinetic parameter estimates between Filgrastim and Pegfilgrastim were biologically plausible throughout. CONCLUSION: We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis under chemotherapy and applications of two different G-CSF derivatives. We aim to apply the model to a large variety of chemotherapy regimen in the future in order to optimize corresponding G-CSF schedules or to individualize G-CSF treatment according to the granulotoxic risk of a patient.     

TissuePatch™ as a novel synthetic sealant for repair of superficial lung defect: in vitro tests results

Controversies surrounding the efficacy of surgical sealants against alveolar air leaks (AAL) in lung surgery abound in the literature. We sought to test the sealing efficacy of a novel synthetic sealant, TissuePatch? in an in vitro lung model. The lower lobe of freshly excised swine lung (n?=?10) was intubated and ventilated. A superficial parenchymal defect (40?×?25 mm) was created, followed by AAL assessment. After sealant application, AAL was assessed again until burst failure occurred. The length of defect was recorded to evaluate the elasticity of the sealant. Superficial parenchymal defects resulted in AAL increasing disproportionally with ascending maximal inspiratory pressure (Pmax). Multiple linear regression analysis revealed strong correlation between AAL and Pmax, compliance, resistance. After sealant application, AAL was sealed in all ten tests at an inspired tidal volume (TVi) of 400 ml, in nine tests at TVi?=?500 ml, in seven at TVi?=?600 ml and in five at TVi?=?700 ml. The mean burst pressure was 42?±?9 mBar. Adhesive and cohesive sealant failures were found in six and three tests respectively. The length of defect before sealant failure was 8.9?±?4.9% larger than that at TVi?=?400 ml, demonstrating an adequate elasticity of this sealant film. TissuePatch? may be a reliable sealant for alternative or adjunctive treatment for repair of superficial parenchymal defects in lung surgery. The clinical benefits of this sealant should be confirmed by prospective, randomised controlled clinical trials. Die Wirksamkeit von chirurgischen Klebstoffen zur Prävention von alveolo-pleuralem Luftleck (APL) ist trotz zunehmenden klinischen Anwendungen in Lungenchirurgie immer noch kontrovers diskutiert. Wir evaluierten die Abdichtungswirksamkeit von einem neuartigen synthetischen Kleber, TissuePatch? mittels eines in vitro Lungenmodels. Der Unterlappen von frisch entnommenen Schweinlungen (n?=?10) wurde intubiert und beatmet. Eine pleurale Läsion (40?×?25 mm) wurde erstellt und APL mit steigendem inspiratorischem Tidalvolumen (TVi) untersucht. Nach Applikation von TissuePatch? wurde APL auf die gleiche Weise gemessen bis zur Auftritt von Kleberbruch. Zur Untersuchung der Elastizität des Klebers wurde die Länge der pleuralen Läsion gemessen. Pleurale Läsion führte bei aufsteigendem maximalem inspiratorischem Druck (Pmax) zu überproportionalem Anstieg von APL. Multiple lineare Regressionsanalyse ergab eine starke Korrelation zwischen APL und Pmax, Lungencompliance sowie Widerstand. Nach der Applikation von Klebstoff wurde APL bei TVi?=?400 ml in allen zehn Testen versiegelt, bei TVi?=?500 ml in neun Testen, bei TVi?=?600 ml in sieben und bei TVi?=?700 ml in fünf Testen. Der mittlere Pmax, der zu Kleberbruch führte, betrug 42?±?9 mBar. Bei den Versuchen wurden adhäsiver und kohäsiver Kleberbruch in jeweils sechs und drei Testen gefunden. Die Länge der pleuralen Läsion vor dem Kleberbruch war 8,9?±?4,9% größer als die bei TVi?=?400 ml. Unsere Versuche zeigten eine zuverlässige Versiegelung von TissuePatch? unter mechanischer Ventilation. Die klinische Nützlichkeit vom Kleber als unterstützende Maßnahme zur Prävention von alveolo-pleuralem Luftleck in Lungenchirurgie sollte durch prospektive, randomisierte kontrollierte klinische Studien bestätigt werden.