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Search Results: 1 - 10 of 349137 matches for " Robert S. Haltiwanger "
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O-fucosylation of the Notch Ligand mDLL1 by POFUT1 Is Dispensable for Ligand Function
Julia Müller, Nadia A. Rana, Katrin Serth, Shinako Kakuda, Robert S. Haltiwanger, Achim Gossler
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088571
Abstract: Fucosylation of Epidermal Growth Factor-like (EGF) repeats by protein O-fucosyltransferase 1 (POFUT1 in vertebrates, OFUT1 in Drosophila) is pivotal for NOTCH function. In Drosophila OFUT1 also acts as chaperone for Notch independent from its enzymatic activity. NOTCH ligands are also substrates for POFUT1, but in Drosophila OFUT1 is not essential for ligand function. In vertebrates the significance of POFUT1 for ligand function and subcellular localization is unclear. Here, we analyze the importance of O-fucosylation and POFUT1 for the mouse NOTCH ligand Delta-like 1 (DLL1). We show by mass spectral glycoproteomic analyses that DLL1 is O-fucosylated at the consensus motif C2XXXX(S/T)C3 (where C2 and C3 are the second and third conserved cysteines within the EGF repeats) found in EGF repeats 3, 4, 7 and 8. A putative site with only three amino acids between the second cysteine and the hydroxy amino acid within EGF repeat 2 is not modified. DLL1 proteins with mutated O-fucosylation sites reach the cell surface and accumulate intracellularly. Likewise, in presomitic mesoderm cells of POFUT1 deficient embryos DLL1 is present on the cell surface, and in mouse embryonic fibroblasts lacking POFUT1 the same relative amount of overexpressed wild type DLL1 reaches the cell surface as in wild type embryonic fibroblasts. DLL1 expressed in POFUT1 mutant cells can activate NOTCH, indicating that POFUT1 is not required for DLL1 function as a Notch ligand.
The Protein O-glucosyltransferase Rumi Modifies Eyes Shut to Promote Rhabdomere Separation in Drosophila
Amanda R. Haltom equal contributor,Tom V. Lee equal contributor,Beth M. Harvey,Jessica Leonardi,Yi-Jiun Chen,Yang Hong,Robert S. Haltiwanger,Hamed Jafar-Nejad
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004795
Abstract: The protein O-glucosyltransferase Rumi/POGLUT1 regulates Drosophila Notch signaling by adding O-glucose residues to the Notch extracellular domain. Rumi has other predicted targets including Crumbs (Crb) and Eyes shut (Eys), both of which are involved in photoreceptor development. However, whether Rumi is required for the function of Crb and Eys remains unknown. Here we report that in the absence of Rumi or its enzymatic activity, several rhabdomeres in each ommatidium fail to separate from one another in a Notch-independent manner. Mass spectral analysis indicates the presence of O-glucose on Crb and Eys. However, mutating all O-glucosylation sites in a crb knock-in allele does not cause rhabdomere attachment, ruling out Crb as a biologically-relevant Rumi target in this process. In contrast, eys and rumi exhibit a dosage-sensitive genetic interaction. In addition, although in wild-type ommatidia most of the Eys protein is found in the inter-rhabdomeral space (IRS), in rumi mutants a significant fraction of Eys remains in the photoreceptor cells. The intracellular accumulation of Eys and the IRS defect worsen in rumi mutants raised at a higher temperature, and are accompanied by a ~50% decrease in the total level of Eys. Moreover, removing one copy of an endoplasmic reticulum chaperone enhances the rhabdomere attachment in rumi mutant animals. Altogether, our data suggest that O-glucosylation of Eys by Rumi ensures rhabdomere separation by promoting proper Eys folding and stability in a critical time window during the mid-pupal stage. Human EYS, which is mutated in patients with autosomal recessive retinitis pigmentosa, also harbors multiple Rumi target sites. Therefore, the role of O-glucose in regulating Eys may be conserved.
Negative Regulation of Notch Signaling by Xylose
Tom V. Lee,Maya K. Sethi equal contributor,Jessica Leonardi equal contributor,Nadia A. Rana equal contributor,Falk F. R. Buettner,Robert S. Haltiwanger,Hans Bakker,Hamed Jafar-Nejad
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003547
Abstract: The Notch signaling pathway controls a large number of processes during animal development and adult homeostasis. One of the conserved post-translational modifications of the Notch receptors is the addition of an O-linked glucose to epidermal growth factor-like (EGF) repeats with a C-X-S-X-(P/A)-C motif by Protein O-glucosyltransferase 1 (POGLUT1; Rumi in Drosophila). Genetic experiments in flies and mice, and in vivo structure-function analysis in flies indicate that O-glucose residues promote Notch signaling. The O-glucose residues on mammalian Notch1 and Notch2 proteins are efficiently extended by the addition of one or two xylose residues through the function of specific mammalian xylosyltransferases. However, the contribution of xylosylation to Notch signaling is not known. Here, we identify the Drosophila enzyme Shams responsible for the addition of xylose to O-glucose on EGF repeats. Surprisingly, loss- and gain-of-function experiments strongly suggest that xylose negatively regulates Notch signaling, opposite to the role played by glucose residues. Mass spectrometric analysis of Drosophila Notch indicates that addition of xylose to O-glucosylated Notch EGF repeats is limited to EGF14–20. A Notch transgene with mutations in the O-glucosylation sites of Notch EGF16–20 recapitulates the shams loss-of-function phenotypes, and suppresses the phenotypes caused by the overexpression of human xylosyltransferases. Antibody staining in animals with decreased Notch xylosylation indicates that xylose residues on EGF16–20 negatively regulate the surface expression of the Notch receptor. Our studies uncover a specific role for xylose in the regulation of the Drosophila Notch signaling, and suggest a previously unrecognized regulatory role for EGF16–20 of Notch.
A New Rechargeable Battery Design Based on Magnesium and Persulfate  [PDF]
Robert S. Disselkamp
Journal of Power and Energy Engineering (JPEE) , 2015, DOI: 10.4236/jpee.2015.33002
Abstract: A battery concept based on the chemical system of magnesium (anode) and persulfate (cathode) is presented. A complete procedure is given to prepare the battery for testing, although no experimental data is presented herein. The similarities of this system to a well-tested Li||LiFePO4 system lend strong credibility to the concept, and the estimated performance characteristics presented. The advantages of this design include the following many areas. First, inexpensive, and available, battery reagents exist. Second, by analogy to the lithium ion battery for which comparisons are made, the full fabrication process for battery separator design is known and efficient; and both the kJ/kg and Amps/kg values are estimated to be substantially larger than the lithium ion battery (e.g., Li||LiFePO4) experimental design. Finally, flammability of the Mg||MgS2O8 system can be expected to provide less of a potential flammability concern, compared to comparable lithium ion batteries. This is because lithium metal, as with any alkali metal, is aggressively flammable even under reduced moisture environments. The proposed magnesium persulfate battery calculated metrics yield an improvement of 194% greater output power (W/cm2·kg), and 154% greater stored energy (MJ/kg) than state-of-the-art lithium iron phosphate batteries.
The Pediatric Emergency Department: A Substitute for Primary Care?
Haltiwanger, Katherine A,Pines, Jesse M.,Martin, Marcus L
Western Journal of Emergency Medicine : Integrating Emergency Care with Population Health , 2006,
Abstract: Objectives: Pediatric emergency department (PED) patients often present with non-urgent complaints. We attempted to estimate the perceived degree of urgency of the visit and to identify reasons for seeking non-urgent care in the PED by patients and parents. Methods: A prospective survey was completed by parents (for children 17 and younger) and patients (18-21) presenting to a suburban academic PED that sees approximately 15,000 patients per year. A convenience sample of participants was enrolled. Results: Three hundred and five of 334 surveys were completed (91% response rate) over a 3-month period. Twenty-four percent of the chief complaints were perceived by those surveyed as emergent or possibly life-threatening, 23% were felt to be very urgent, and 52% were deemed somewhat urgent or minor. Twenty-five percent of those with minor or somewhat urgent complaints arrived by ambulance. Weekend visits and minority race correlated with a lower degree of perceived urgency. Overall, 79% of those surveyed identified a primary care provider (PCP) for themselves or their child. Of those, 54% had attempted to contact the PCP prior to coming to the PED. Six percent of those who attempted to reach their primary care providers were able to contact them and 52% were told to come to the PED. Conclusions: More than half of patients and parents presenting to the PED believed they had minor or somewhat urgent complaints. While the majority of patients have a regular provider, limited access to timely primary care and convenience may make the PED a more attractive care option than primary care for many parents and patients.
Recent Energy Balance of Earth  [PDF]
Robert S. Knox, David H. Douglass
International Journal of Geosciences (IJG) , 2010, DOI: 10.4236/ijg.2010.13013
Abstract: A recently published estimate of Earth’s global warming trend is 0.63 ± 0.28 W/m2, as calculated from ocean heat content anomaly data spanning 1993-2008. This value is not representative of the recent (2003-2008) warming/cooling rate because of a “flattening” that occurred around 2001-2002. Using only 2003-2008 data from Argo floats, we find by four different algorithms that the recent trend ranges from –0.010 to –0.161 W/m2 with a typical error bar of ±0.2 W/m2. These results fail to support the existence of a frequently-cited large positive computed radiative imbalance.
Entecavir for treatment of chronic hepatitis B: A clinical update for the treatment of patients with decompensated cirrhosis  [PDF]
P. Patrick Basu, Robert S. Brown Jr.
Open Journal of Internal Medicine (OJIM) , 2012, DOI: 10.4236/ojim.2012.22012
Abstract: The introduction of nucleos(t)ide analogues for the treatment of chronic hepatitis B virus (HBV) infection was transformative in reducing morbidity and mortality. Entecavir, a potent selective nucleoside analogue first approved in 2005 for treatment of chronic HBV, is associated with significant antiviral, biochemical, serologic, and histologic responses. Rapid reductions in HBV DNA levels, low risk of resistance development, and a favorable adverse event profile have contributed to its clinical usefulness. Re-cent developments in the use of entecavir have increased its utility in the management of difficult-to-treat patients with chronic HBV, including those patients with decompensated liver disease. Recent studies in this population have demonstrated that entecavir 1.0 mg/d given for up to 48 weeks had superior antiviral activity when compared with adefovir and was generally safe and well tolerated. Long-term outcomes of entecavir in difficult-to-treat populations are eagerly anticipated.
System for High Throughput Water Extraction from Soil Material for Stable Isotope Analysis of Water  [PDF]
Timothy S. Goebel, Robert J. Lascano
Journal of Analytical Sciences, Methods and Instrumentation (JASMI) , 2012, DOI: 10.4236/jasmi.2012.24031

A major limitation in the use of stable isotope of water in ecological studies is the time that is required to extract water from soil and plant samples. Using vacuum distillation the extraction time can be less than one hour per sample. Therefore, assembling a distillation system that can process multiple samples simultaneously is advantageous and necessary for ecological or hydrological investigations. Presented here is a vacuum distillation apparatus, having six ports, that can process up to 30 samples per day. The distillation system coupled with the Los Gatos Research DLT-100 Liquid Water Isotope Analyzer is capable of analyzing all of the samples that are generated by vacuum distillation. These two systems allow larger sampling rates making investigations into water movement through an ecological system possible at higher temporal and spatial resolution.

Time for cotton to uptake water of a known isotopic signature as measured in leaf petioles  [PDF]
Timothy S. Goebel, Robert J. Lascano
Agricultural Sciences (AS) , 2014, DOI: 10.4236/as.2014.52021

While stable isotopes of water have been used to study water movement through the environment, they generally have not been used to examine shorter, more transient events, e.g., rainfall of <25 mm. With the development of robust methods that use isotope ratio infrared spectrometry, evaluating samples has become faster and simpler, allowing more soil and plant samples to be collected and analyzed. Using larger sampling rates can therefore increase the resolution of changes in stable isotopes within an ecosystem, and allows for a better understanding of how quickly rainwater that enters the soil by infiltration is transpired by a plant via root-water uptake. Quantifying rainwater uptake by plants is essential to increase crop production in rainfed agriculture. Thus the objective of this study was to measure the time required by a plant to transpire water from a source of water with a different isotopic signature than the water that the plant was irrigated. To this end, cotton (Gossypium hirsutum (L.)) plants were grown in a greenhouse and the time required for the enriched water added the soil to show up in the meristematic petioles of cotton leaves was measured. The initial divergence from the irrigation water signature occurred as quickly as 4 hours. The water from the sampled petioles then reached equilibrium with the new source water within 12 hours.

Using Engineered microRNAs as Vectors for Animal RNA Interference: Promises and Challenges  [PDF]
Jerry S. Chen, Robert W. Zeller
Advances in Bioscience and Biotechnology (ABB) , 2014, DOI: 10.4236/abb.2014.54037

microRNAs are post-transcriptional regulators of gene expression that recruit RNA silencing complexes to target transcripts to prevent translation and promote their degradation. Experimental studies suggest that microRNA binding to target transcripts can result in as much as a 90% decrease in gene expression. Because of this feature, the microRNA pathway has been utilized as a vehicle for potent RNA interference (RNAi). In recent years, significant advances have been made in engineering artificial microRNA vectors for RNAi in a number of biological systems, with the most progress in plants but also some success in mouse and human cell lines. In this mini-review, we provide a brief discussion of the potential of this technology in comparison with other RNAi strategies, and the current challenges in the design of microRNA-based RNAi vectors, particularly for animal systems.

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