1,564 research outputs found
Unexpected features of branched flow through high-mobility two-dimensional electron gases
GaAs-based two-dimensional electron gases (2DEGs) show a wealth of remarkable
electronic states, and serve as the basis for fast transistors, research on
electrons in nanostructures, and prototypes of quantum-computing schemes. All
these uses depend on the extremely low levels of disorder in GaAs 2DEGs, with
low-temperature mean free paths ranging from microns to hundreds of microns.
Here we study how disorder affects the spatial structure of electron transport
by imaging electron flow in three different GaAs/AlGaAs 2DEGs, whose mobilities
range over an order of magnitude. As expected, electrons flow along narrow
branches that we find remain straight over a distance roughly proportional to
the mean free path. We also observe two unanticipated phenomena in
high-mobility samples. In our highest-mobility sample we observe an almost
complete absence of sharp impurity or defect scattering, indicated by the
complete suppression of quantum coherent interference fringes. Also, branched
flow through the chaotic potential of a high-mobility sample remains stable to
significant changes to the initial conditions of injected electrons.Comment: 22 pages, 4 figures, 1 tabl
Self-Organization, Layered Structure, and Aggregation Enhance Persistence of a Synthetic Biofilm Consortium
Microbial consortia constitute a majority of the earthβs biomass, but little is known about how these cooperating
communities persist despite competition among community members. Theory suggests that non-random spatial structures
contribute to the persistence of mixed communities; when particular structures form, they may provide associated
community members with a growth advantage over unassociated members. If true, this has implications for the rise and
persistence of multi-cellular organisms. However, this theory is difficult to study because we rarely observe initial instances
of non-random physical structure in natural populations. Using two engineered strains of Escherichia coli that constitute a
synthetic symbiotic microbial consortium, we fortuitously observed such spatial self-organization. This consortium forms a
biofilm and, after several days, adopts a defined layered structure that is associated with two unexpected, measurable
growth advantages. First, the consortium cannot successfully colonize a new, downstream environment until it selforganizes
in the initial environment; in other words, the structure enhances the ability of the consortium to survive
environmental disruptions. Second, when the layered structure forms in downstream environments the consortium
accumulates significantly more biomass than it did in the initial environment; in other words, the structure enhances the
global productivity of the consortium. We also observed that the layered structure only assembles in downstream
environments that are colonized by aggregates from a previous, structured community. These results demonstrate roles for
self-organization and aggregation in persistence of multi-cellular communities, and also illustrate a role for the techniques
of synthetic biology in elucidating fundamental biological principles
Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment
BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. METHODS: OT-I CTL were adoptively transferred to C57BL/6 mice 21 β 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. RESULTS: Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. CONCLUSIONS: Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer
Investigation of mass transport processes in a microstructured membrane reactor for the direct synthesis of hydrogen peroxide
Microstructured membrane reactors present a promising approach to master the productivity and safety challenges during the direct synthesis of hydrogen peroxide. However, various mass transport processes occur in this complex system. In order to gain a deeper understanding of these processes, the saturation and desaturation behaviour of the liquid reaction medium with the gaseous reactants is investigated experimentally to examine possible cross-contamination. Moreover, the employed PDMS membraneβs permeances to hydrogen and oxygen are researched at different pressures, by using a variable-pressure/constant-volume setup for the behaviour at ambient pressure and a constant-pressure/variable-volume setup for the behaviour at elevated pressures. A mathematical model in MATLAB is applied to simulate the results. It is shown that a certain desaturation of the gasses through the membrane occurs, and the results are underlined by the modelled ones using a solution-diffusion model in MATLAB. Thus a constant flushing of the gas channels of the reactor is required for safety reasons. Moreover, the measured permeance values indicate that the species transport is mainly limited by the diffusion in the liquid phase and not the membrane resistance
Lateral Gene Expression in Drosophila Early Embryos Is Supported by Grainyhead-Mediated Activation and Tiers of Dorsally-Localized Repression
The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal-ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence (βthe A-boxβ) present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a βswitch-likeβ response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-Ξ² signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo
Exosome-Related Multi-Pass Transmembrane Protein TSAP6 Is a Target of Rhomboid Protease RHBDD1-Induced Proteolysis
We have previously reported that rhomboid domain containing 1 (RHBDD1), a mammalian rhomboid protease highly expressed in the testis, can cleave the Bcl-2 protein Bik. In this study, we identified a multi-pass transmembrane protein, tumor suppressor activated pathway-6 (TSAP6) as a potential substrate of RHBDD1. RHBDD1 was found to induce the proteolysis of TSAP6 in a dose- and activity-dependent manner. The cleavage of TSAP6 was not restricted to its glycosylated form and occurred in three different regions. In addition, mass spectrometry and mutagenesis analyses both indicated that the major cleavage site laid in the C-terminal of the third transmembrane domain of TSAP6. A somatic cell knock-in approach was used to genetically inactivate the endogenous RHBDD1 in HCT116 and RKO colon cancer cells. Exosome secretion was significantly elevated when RHBDD1 was inactivated in the two cells lines. The increased exosome secretion was verfied through the detection of certain exosomal components, including Tsg101, Tf-R, FasL and Trail. In addition, the elevation of exosome secretion by RHBDD1 inactivation was reduced when TSAP6 was knocked down, indicating that the role of RHBDD1 in regulating exosomal trafficking is very likely to be TSAP6-dependent. We found that the increase in FasL and Trail increased exosome-induced apoptosis in Jurkat cells. Taken together, our findings suggest that RHBDD1 is involved in the regulation of a nonclassical exosomal secretion pathway through the restriction of TSAP6
Schistosomiasis in european travelers and migrants: Analysis of 14 years tropnet surveillance data
Quantitative Mass Spectrometry Evaluation of Human Retinol Binding Protein 4 and Related Variants
Background: Retinol Binding Protein 4 (RBP4) is an exciting new biomarker for the determination of insulin resistance and type 2 diabetes. It is known that circulating RBP4 resides in multiple variants which may provide enhanced clinical utility, but conventional immunoassay methods are blind to such differences. A Mass Spectrometric immunoassay (MSIA) technology that can quantitate total RBP4 as well as individual isoforms may provide an enhanced analysis for this biomarker. Methods: RBP4 was isolated and detected from 0.5 uL of human plasma using MSIA technology, for the simultaneous quantification and differentiation of endogenous human RBP4 and its variants. Results: The linear range of the assay was 7.81β500 ug/mL, and the limit of detection and limit of quantification were 3.36 ug/mL and 6.52 ug/mL, respectively. The intra-assay CVs were determined to be 5.1 % and the inter-assay CVs were 9.6%. The percent recovery of the RBP4-MSIA ranged from 95 β 105%. Method comparison of the RBP4 MSIA vs the Immun Diagnostik ELISA yielded a Passing & Bablok fit of MSIA = 1.056 ELISA β 3.09, while the Cusum linearity p-value was.0.1 and the mean bias determined by the Altman Bland test was 1.2%. Conclusion: The novel RBP4 MSIA provided a fast, accurate and precise quantitative protein measurement as compared to the standard commercially available ELISA. Moreover, this method also allowed for the detection of RBP4 variants that are present in each sample, which may in the future provide a new dimension in the clinical utility of this biomarker
Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based chemotherapy in small-cell lung cancer
This randomised trial compared platinum-based to anthracycline-based chemotherapy in patients with small-cell lung cancer (limited or extensive stage) and β©½2 adverse prognostic factors. Patients were randomised to receive six cycles of either ACE (doxorubicin 50βmg/m2 i.v., cyclophosphamide 1βg/m2 i.v. and etoposide 120βmg/m2 i.v. on day 1, then etoposide 240βmg/m2 orally for 2 days) or PE (cisplatin 80βmg/m2 and etoposide 120βmg/m2 i.v. on day 1, then etoposide 240βmg/m2 orally for 2 days) given for every 3 weeks. For patients where cisplatin was not suitable, carboplatin (AUC6) was substituted. A total of 280 patients were included (139 ACE, 141 PE). The response rates were 72% for ACE and 77% for PE. One-year survival rates were 34 and 38% (P=0.497), respectively and 2-year survival was the same (12%) for both arms. For LD patients, the median survival was 10.9 months for ACE and 12.6 months for PE (P=0.51); for ED patients median survival was 8.3 months and 7.5 months, respectively. More grades 3 and 4 neutropenia (90 vs 57%, P<0.005) and grades 3 and 4 infections (73 vs 29%, P<0.005) occurred with ACE, resulting in more days of hospitalisation and greater i.v. antibiotic use. ACE was associated with a higher risk of neutropenic sepsis than PE and with a trend towards worse outcome in patients with LD, and should not be studied further in this group of patients
Production of benzylisoquinoline alkaloids in Saccharomyces cerevisiae
The benzylisoquinoline alkaloids (BIAs) are a diverse class of metabolites that exhibit a broad range of pharmacological activities and are synthesized through plant biosynthetic pathways comprised of complex enzyme activities and regulatory strategies. We have engineered yeast to produce the key intermediate reticuline and downstream BIA metabolites from a commercially available substrate. An enzyme tuning strategy was implemented that identified activity differences between variants from different plants and determined optimal expression levels. By synthesizing both stereoisomer forms of reticuline and integrating enzyme activities from three plant sources and humans, we demonstrated the synthesis of metabolites in the sanguinarine/berberine and morphinan branches. We also demonstrated that a human P450 enzyme exhibits a novel activity in the conversion of (R)-reticuline to the morphinan alkaloid salutaridine. Our engineered microbial hosts offer access to a rich group of BIA molecules and associated activities that will be further expanded through synthetic chemistry and biology approaches
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