Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways

Rab family guanosine triphosphatases (GTPases) together with their regulators define specific pathways of membrane traffic within eukaryotic cells. In this study, we have investigated which Rab GTPase-activating proteins (GAPs) can interfere with the trafficking of Shiga toxin from the cell surface to the Golgi apparatus and studied transport of the epidermal growth factor (EGF) from the cell surface to endosomes. This screen identifies 6 (EVI5, RN-tre/USP6NL, TBC1D10A–C, and TBC1D17) of 39 predicted human Rab GAPs as specific regulators of Shiga toxin but not EGF uptake. We show that Rab43 is the target of RN-tre and is required for Shiga toxin uptake. In contrast, RabGAP-5, a Rab5 GAP, was unique among the GAPs tested and reduced the uptake of EGF but not Shiga toxin. These results suggest that Shiga toxin trafficking to the Golgi is a multistep process controlled by several Rab GAPs and their target Rabs and that this process is discrete from ligand-induced EGF receptor trafficking

Understanding self-reported difficulties in decision-making by people with autism spectrum disorders.

Autobiographical accounts and a limited research literature suggest that adults with autism spectrum disorders can experience difficulties with decision-making. We examined whether some of the difficulties they describe correspond to quantifiable differences in decision-making when compared to adults in the general population. The participants (38 intellectually able adults with autism spectrum disorders and 40 neurotypical adults) were assessed on three tasks of decision-making (Iowa Gambling Task, Cambridge Gamble Task and Information Sampling Task), which quantified, respectively, decision-making performance and relative attention to negative and positive outcomes, speed and flexibility, and information sampling. As a caution, all analyses were repeated with a subset of participants ( nASD = 29 and nneurotypical = 39) who were not taking antidepressant or anxiolytic medication. Compared to the neurotypical participants, participants with autism spectrum disorders demonstrated slower decision-making on the Cambridge Gamble Task, and superior performance on the Iowa Gambling Task. When those taking the medications were excluded, participants with autism spectrum disorders also sampled more information. There were no other differences between the groups. These processing tendencies may contribute to the difficulties self-reported in some contexts; however, the results also highlight strengths in autism spectrum disorders, such as a more logical approach to, and care in, decision-making. The findings lead to recommendations for how adults with autism spectrum disorders may be better supported with decision-making.The research reported here was carried out by the first author (Lydia Vella, née Luke) as part of her PhD in the Department of Psychiatry, University of Cambridge, and was supported by a Pinsent Darwin Studentship in Mental Health; University of Cambridge Domestic Research Studentship; the Charles Slater Fund; and the Marmaduke Sheild Fund. IC was supported during the preparation of this paper by the National Institute of Health Research (NIHR) Collaboration for Applied Health Research and Care (CLAHRC) East of England at Cambridgeshire & Peterborough NHS Foundation Trust. We are grateful to all our funders for their support. The paper describes independent research and the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health

Gravitational Waves from Binary Neutron Star Mergers with a Spectral Equation of State

In numerical simulations of binary neutron star systems, the equation of state of the dense neutron star matter is an important factor in determining both the physical realism and the numerical accuracy of the simulations. Some equations of state used in simulations are $C^2$ or smoother in the pressure/density relationship function, such as a polytropic equation of state, but may not have the flexibility to model stars or remnants of different masses while keeping their radii within known astrophysical constraints. Other equations of state, such as tabular or piece-wise polytropic, may be flexible enough to model additional physics and multiple stars' masses and radii within known constraints, but are not as smooth, resulting in additional numerical error. We will study in this paper a recently developed family of equation of state, using a spectral expansion with sufficient free parameters to allow for a larger flexibility than current polytropic equations of state, and with sufficient smoothness to reduce numerical errors compared to tabulated or piece-wise polytropic equations of state. We perform simulations at three mass ratios with a common chirp mass, using two distinct spectral equations of state, and at multiple numerical resolutions. We evaluate the gravitational waves produced from these simulations, comparing the phase error between resolutions and equations of state, as well as with respect to analytical models. From our simulations we estimate that the phase difference at merger for binaries with a dimensionless weighted tidal deformability difference greater than $\Delta \tilde{\Lambda} = 55$ can be captured by the SpEC code for these equations of state.Comment: 13 pages, 8 figure

Use of satellite telemetry data, GIS, and HTML to create an interactive display of caribou movements

The use of animation clearly reveals the large annual variation in wintering areas and large differences in daily movement rates for this herd. This interactive display can be adapted for school groups, subsistence hunters, the general public, or scientists

Use of satellite telemetry to evaluate movements of caribou within subsistence hunting areas in northern Alaska

Caribou from the Teshekpuk Herd (TH) are an important subsistence resource for residents of Inupiaq villages in northern Alaska. In recent years the use of satellite telemetry has increased the understanding of the herd's annual movements and interactions with other herds. Most caribou of the TH are within the National Petroleum Reserve—Alaska (NPRA) throughout the year. The northeastern portion of NPRA has undergone two lease sales for oil and gas exploration, and lease sales are tentatively scheduled for the central/northwest portion of the NPRA in 2004. During 1990—1999, the movements of 27 caribou from the TH were tracked using satellite collars. We evaluated the proportion of time caribou were available to Inupiaq hunters by incorporating maps depicting subsistence-use areas for each of seven Inupiaq villages, and then examining seasonal and annual movements of caribou relative to those areas. By combining caribou locations with subsistence hunting areas, we were able to explore spatial and temporal patterns in caribou availability to subsistence hunters. This information is useful for managers to set appropriate hunting regulations and for devising sensible alternatives and mitigation of likely petroleum development in NPRA

Destination characteristics that drive hotel performance:a state-of-the-art global analysis

Abstract The increased market saturation and competition in both domestic and international tourism destinations have renewed interest among hotel operators in identifying the key drivers of hotel performance. This paper presents a comprehensive analysis of the determinants of hotel performance and their relative importance across multiple tourist destinations. We employ a two-step estimation method to identify key determinants of hotel performance, using a rich sample of international hotels. Our empirical analyses show that the main drivers of hotel performance are the quality of the educational system, government support, disposable income, and number of international arrivals within a tourism destination. Results indicate that the most important barriers to hotel performance are the competition among accommodation providers, tax rate and fuel price. We argue for the need for hotel providers to develop strategies that take cognisance of the key drivers and barriers to enhancing hotel performance in an ever-changing global tourism sector

Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development

We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development

Sampling nucleotide diversity in cotton

<p>Abstract</p> <p>Background</p> <p>Cultivated cotton is an annual fiber crop derived mainly from two perennial species, <it>Gossypium hirsutum </it>L. or upland cotton, and <it>G. barbadense </it>L., extra long-staple fiber Pima or Egyptian cotton. These two cultivated species are among five allotetraploid species presumably derived monophyletically between <it>G. arboreum </it>and <it>G. raimondii</it>. Genomic-based approaches have been hindered by the limited variation within species. Yet, population-based methods are being used for genome-wide introgression of novel alleles from <it>G. mustelinum </it>and <it>G. tomentosum </it>into <it>G. hirsutum </it>using combinations of backcrossing, selfing, and inter-mating. Recombinant inbred line populations between genetics standards TM-1, (<it>G. hirsutum</it>) × 3-79 (<it>G. barbadense</it>) have been developed to allow high-density genetic mapping of traits.</p> <p>Results</p> <p>This paper describes a strategy to efficiently characterize genomic variation (SNPs and indels) within and among cotton species. Over 1000 SNPs from 270 loci and 279 indels from 92 loci segregating in <it>G. hirsutum </it>and <it>G. barbadense </it>were genotyped across a standard panel of 24 lines, 16 of which are elite cotton breeding lines and 8 mapping parents of populations from six cotton species. Over 200 loci were genetically mapped in a core mapping population derived from TM-1 and 3-79 and in <it>G. hirsutum </it>breeding germplasm.</p> <p>Conclusion</p> <p>In this research, SNP and indel diversity is characterized for 270 single-copy polymorphic loci in cotton. A strategy for SNP discovery is defined to pre-screen loci for copy number and polymorphism. Our data indicate that the A and D genomes in both diploid and tetraploid cotton remain distinct from each such that paralogs can be distinguished. This research provides mapped DNA markers for intra-specific crosses and introgression of exotic germplasm in cotton.</p

Do Null-Type Mutation Operators Help Prevent Null-Type Faults?

The null-type is a major source of faults in Java programs, and its overuse has a severe impact on software maintenance. Unfortunately traditional mutation testing operators do not cover null-type faults by default, hence cannot be used as a preventive measure. We address this problem by designing four new mutation operators which model null-type faults explicitly. We show how these mutation operators are capable of revealing the missing tests, and we demonstrate that these mutation operators are useful in practice. For the latter, we analyze the test suites of 15 open-source projects to describe the trade-offs related to the adoption of these operators to strengthen the test suite