Illmensee inquiry: fraud charge unproven, researcher resumes duties

A summary is provided of the report of an international commission set up by the University of Geneva to investigate allegations of fraud against a leading embryologist, Professor Karl Illmensee. Illmensee is being allowed to resume his faculty duties because the report, while highly critical of the researcher's experimental records, found no compelling evidence that he fabricated his data.     

U.S. agrigenetics: suit filed against NIH

Three environmental groups have filed suit against the National Institutes of Health in an attempt to block an experiment approved in April by the NIH Recombinant DNA Advisory Committee. The experiment, designed by researchers at the University of California, Berkeley, to enhance the frost resistance of crops, would release genetically engineered organisms into the general environment for the first time. The suit, filed in a federal court in the District of Columbia, claims that releasing frost-resistant bacteria into the environment could have damaging ecological consequences, that NIH should have issued an environmental impact assessment before approving any experiment involving the release of genetically engineered organisms, and that the Recombinant DNA Advisory Committee lacks the expertise to assess environmental risks.     

Dynamic Dominating Set and Turbo-Charging Greedy Heuristics

The main purpose of this paper is to exposit two very different, but very general, motivational schemes in the art of parameterization and a concrete example connecting them. We introduce a dynamic version of the DOMINATING SET problem and prove that it is fixed-parameter tractable（FPT）. The problem is motivated by settings where problem instances evolve. It also arises in the quest to improve a natural greedy heuristic for the DOMINATING SET problem.     

Inconsistent idealizations and inferentialism about scientific representation

Inferentialists about scientific representation hold that an apparatus's representing a target system consists in the apparatus allowing “surrogative inferences” about the target. I argue that a serious problem for inferentialism arises from the fact that many scientific theories and models contain internal inconsistencies. Inferentialism, left unamended, implies that inconsistent scientific models have unlimited representational power, since an inconsistency permits any conclusion to be inferred. I consider a number of ways that inferentialists can respond to this challenge before suggesting my own solution. I develop an analogy to exploitable glitches in a game. Even though inconsistent representational apparatuses may in some sense allow for contradictions to be generated within them, doing so violates the intended function of the apparatus's parts and hence violates representational “gameplay”.     

The stoichiometry of peptide-heparan sulfate binding as a determinant of uptake efficiency of cell-penetrating peptides

Binding to negatively charged heparan sulfates (HS) at the cell surface is considered the first step in the internalization of cationic cell-penetrating peptides (CPPs). However, little is known about the relation of the characteristics of the HS-CPP interaction such as affinity, stoichiometry, and clustering with uptake. In this study, we investigated a collection of mutants of a cyclic CPP derived from human lactoferrin with respect to HS binding and uptake. The thermodynamic parameters of HS binding were determined by isothermal titration calorimetry, clustering of HS was investigated by dynamic light scattering, and cellular uptake by flow cytometry and confocal microscopy. Whereas mutations of non-arginine amino acids that are conserved across lactoferrins of different mammalia only had a minor effect on uptake efficiency, changes in the number of arginine residues influenced the uptake significantly. In general, introduction of arginine residues and cyclization improved the HS affinity and the ability to cluster HS. In particular, there was a strong negative correlation between stoichiometry and uptake, indicating that crosslinking of HS is the driving force for the uptake of arginine-rich CPPs. Using glycan microarrays presenting a collection of synthetic HS, we show that a minimal chain length of HS is required for peptide binding.     

West Nile virus emergence and large-scale declines of North American bird populations

Emerging infectious diseases present a formidable challenge to the conservation of native species in the twenty-first century. Diseases caused by introduced pathogens have had large impacts on species abundances, including the American chestnut, Hawaiian bird species and many amphibians. Changes in host population sizes can lead to marked shifts in community composition and ecosystem functioning. However, identifying the impacts of an introduced disease and distinguishing it from other forces that influence population dynamics (for example, climate) is challenging and requires abundance data that extend before and after the introduction. Here we use 26 yr of Breeding Bird Survey (BBS) data to determine the impact of West Nile virus (WNV) on 20 potential avian hosts across North America. We demonstrate significant changes in population trajectories for seven species from four families that concur with a priori predictions and the spatio-temporal intensity of pathogen transmission. The American crow population declined by up to 45% since WNV arrival, and only two of the seven species with documented impact recovered to pre-WNV levels by 2005. Our findings demonstrate the potential impacts of an invasive species on a diverse faunal assemblage across broad geographical scales, and underscore the complexity of subsequent community response.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Identification of stem cells in small intestine and colon by marker gene Lgr5

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.     

Attribution of observed surface humidity changes to human influence

Water vapour is the most important contributor to the natural greenhouse effect, and the amount of water vapour in the atmosphere is expected to increase under conditions of greenhouse-gas-induced warming, leading to a significant feedback on anthropogenic climate change. Theoretical and modelling studies predict that relative humidity will remain approximately constant at the global scale as the climate warms, leading to an increase in specific humidity. Although significant increases in surface specific humidity have been identified in several regions, and on the global scale in non-homogenized data, it has not been shown whether these changes are due to natural or human influences on climate. Here we use a new quality-controlled and homogenized gridded observational data set of surface humidity, with output from a coupled climate model, to identify and explore the causes of changes in surface specific humidity over the late twentieth century. We identify a significant global-scale increase in surface specific humidity that is attributable mainly to human influence. Specific humidity is found to have increased in response to rising temperatures, with relative humidity remaining approximately constant. These changes may have important implications, because atmospheric humidity is a key variable in determining the geographical distribution and maximum intensity of precipitation, the potential maximum intensity of tropical cyclones, and human heat stress, and has important effects on the biosphere and surface hydrology.