71 research outputs found

    Synthesis of Quasi-Freestanding Graphene Films Using Radical Species Formed in Cold Plasmas

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    For over a decade, the Stinespring laboratory has investigated scalable, plasma assisted synthesis (PAS) methods for the growth of graphene films on silicon carbide (SiC). These typically utilized CF4-based inductively coupled plasma (ICP) with reactive ion etching (RIE) to selectively etch silicon from the SiC lattice. This yielded a halogenated carbon-rich surface layer which was then annealed to produce the graphene layers. The thickness of the films was controlled by the plasma parameters, and overall, the process was readily scalable to the diameter of the SiC wafer. The PAS process reproducibly yielded two- to three-layer thick graphene films that were highly tethered to the underlying SiC substrate via an intermediate buffer layer. The buffer layer was compositionally similar to graphene. However, a significant number of graphene carbons were covalently bound to silicon atoms in the underlying substrate. This tethering lead to mixing of the film and substrate energy bands which degraded many of graphene’s most desirable electrical properties. The research described in this dissertation was aimed at improving graphene quality by reducing the extent of tethering using a fundamentally different plasma etching mechanism while maintaining scalability. In the ICP-RIE process, the etchant species include F and CFx (x = 1-3) radicals and their corresponding positive ions. These radicals are classified as “cold plasma species” in the sense that they are nominally in thermal equilibrium with the substrate and walls of the system. In contrast, the electrons exist at extremely high temperature (energy), and the ionic species are accelerated to energies on the order of several hundred electron volts by the plasma bias voltage that exists between the plasma and substrate. As a result, the ionic species create a directional, high rate etch that is dominated by physical etching characterized by energy and momentum transfer. In contrast, the neutral radicals chemically etch the surface at a much lower rate. In this work, the effects of physical etching due to high energy ions were eliminated by shielding the SiC substrate using a mask (e.g., quartz) supported by silicon posts. In this way, a microplasma consisting of chemically reactive cold plasma species was created in the small space between the substrate surface and the backside of the quartz mask. This process, referred to here as microplasma assisted synthesis (MPAS), was used to produce graphene films. A parametric investigation was conducted to determine the influence of MPAS operating parameters on graphene quality. The key parameters investigated included ICP power, RIE power, etch time, various mask materials, microreactor height, substrate cooling, initial surface morphology and SiC polytype. The resulting graphene films were characterized by x-ray photoelectron spectroscopy (XPS), Raman spectroscopy, and atomic force microscopy (AFM). Following optimization of the MPAS process, some tethering of the graphene films remained. However, films produced by MPAS consistently exhibited significantly less tethering than those produced using the PAS process. Moreover, both XPS and Raman spectroscopy indicated that these films were quasi-free standing, and, in some cases, they approached free standing graphene. From a wide view, the results of these studies demonstrate the potential of MPAS as a technique for realizing the controlled synthesis of high-quality, lightly tethered mono-, and few-layer graphene films directly on an insulating substrate. On a more fundamental level, the results of these studies provide insight into the surface chemistry of radical species

    Free Energy of an Inhomogeneous Superconductor: a Wave Function Approach

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    A new method for calculating the free energy of an inhomogeneous superconductor is presented. This method is based on the quasiclassical limit (or Andreev approximation) of the Bogoliubov-de Gennes (or wave function) formulation of the theory of weakly coupled superconductors. The method is applicable to any pure bulk superconductor described by a pair potential with arbitrary spatial dependence, in the presence of supercurrents and external magnetic field. We find that both the local density of states and the free energy density of an inhomogeneous superconductor can be expressed in terms of the diagonal resolvent of the corresponding Andreev Hamiltonian, resolvent which obeys the so-called Gelfand-Dikii equation. Also, the connection between the well known Eilenberger equation for the quasiclassical Green's function and the less known Gelfand-Dikii equation for the diagonal resolvent of the Andreev Hamiltonian is established. These results are used to construct a general algorithm for calculating the (gauge invariant) gradient expansion of the free energy density of an inhomogeneous superconductor at arbitrary temperatures.Comment: REVTeX, 28 page

    Dynamic Patterns of Circulating Seasonal and Pandemic A(H1N1)pdm09 Influenza Viruses From 2007–2010 in and around Delhi, India

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    Influenza surveillance was carried out in a subset of patients with influenza-like illness (ILI) presenting at an Employee Health Clinic (EHS) at All India Institute of Medical Sciences (AIIMS), New Delhi (urban) and pediatric out patients department of civil hospital at Ballabhgarh (peri-urban), under the Comprehensive Rural Health Services Project (CRHSP) of AIIMS, in Delhi region from January 2007 to December 2010. Of the 3264 samples tested, 541 (17%) were positive for influenza viruses, of which 221 (41%) were pandemic Influenza A(H1N1)pdm09, 168 (31%) were seasonal influenza A, and 152 (28%) were influenza B. While the Influenza viruses were detected year-round, their types/subtypes varied remarkably. While there was an equal distribution of seasonal A(H1N1) and influenza B in 2007, predominance of influenza B was observed in 2008. At the beginning of 2009, circulation of influenza A(H3N2) viruses was observed, followed later by emergence of Influenza A(H1N1)pdm09 with co-circulation of influenza B viruses. Influenza B was dominant subtype in early 2010, with second wave of Influenza A(H1N1)pdm09 in August-September, 2010. With the exception of pandemic H1N1 emergence in 2009, the peaks of influenza activity coincided primarily with monsoon season, followed by minor peak in winter at both urban and rural sites. Age group analysis of influenza positivity revealed that the percent positivity of Influenza A(H1N1)pdm09 influenza virus was highest in >5–18 years age groups (OR 2.5; CI = 1.2–5.0; p = 0.009) when compared to seasonal influenza. Phylogenetic analysis of Influenza A(H1N1)pdm09 from urban and rural sites did not reveal any major divergence from other Indian strains or viruses circulating worldwide. Continued surveillance globally will help define regional differences in influenza seasonality, as well as, to determine optimal periods to implement influenza vaccination programs among priority populations

    Transcriptome-Wide Prediction of miRNA Targets in Human and Mouse Using FASTH

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    Transcriptional regulation by microRNAs (miRNAs) involves complementary base-pairing at target sites on mRNAs, yielding complex secondary structures. Here we introduce an efficient computational approach and software (FASTH) for genome-scale prediction of miRNA target sites based on minimizing the free energy of duplex structure. We apply our approach to identify miRNA target sites in the human and mouse transcriptomes. Our results show that short sequence motifs in the 5′ end of miRNAs frequently match mRNAs perfectly, not only at validated target sites but additionally at many other, energetically favourable sites. High-quality matching regions are abundant and occur at similar frequencies in all mRNA regions, not only the 3′UTR. About one-third of potential miRNA target sites are reassigned to different mRNA regions, or gained or lost altogether, among different transcript isoforms from the same gene. Many potential miRNA target sites predicted in human are not found in mouse, and vice-versa, but among those that do occur in orthologous human and mouse mRNAs most are situated in corresponding mRNA regions, i.e. these sites are themselves orthologous. Using a luciferase assay in HEK293 cells, we validate four of six predicted miRNA-mRNA interactions, with the mRNA level reduced by an average of 73%. We demonstrate that a thermodynamically based computational approach to prediction of miRNA binding sites on mRNAs can be scaled to analyse complete mammalian transcriptome datasets. These results confirm and extend the scope of miRNA-mediated species- and transcript-specific regulation in different cell types, tissues and developmental conditions

    Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

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    Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes

    Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

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    Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides

    Positive Darwinian Selection in the Piston That Powers Proton Pumps in Complex I of the Mitochondria of Pacific Salmon

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    The mechanism of oxidative phosphorylation is well understood, but evolution of the proteins involved is not. We combined phylogenetic, genomic, and structural biology analyses to examine the evolution of twelve mitochondrial encoded proteins of closely related, yet phenotypically diverse, Pacific salmon. Two separate analyses identified the same seven positively selected sites in ND5. A strong signal was also detected at three sites of ND2. An energetic coupling analysis revealed several structures in the ND5 protein that may have co-evolved with the selected sites. These data implicate Complex I, specifically the piston arm of ND5 where it connects the proton pumps, as important in the evolution of Pacific salmon. Lastly, the lineage to Chinook experienced rapid evolution at the piston arm

    Mammalian MicroRNA Prediction through a Support Vector Machine Model of Sequence and Structure

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    BACKGROUND: MicroRNAs (miRNAs) are endogenous small noncoding RNA gene products, on average 22 nt long, found in a wide variety of organisms. They play important regulatory roles by targeting mRNAs for degradation or translational repression. There are 377 known mouse miRNAs and 475 known human miRNAs in the May 2007 release of the miRBase database, the majority of which are conserved between the two species. A number of recent reports imply that it is likely that many mammalian miRNAs remain to be discovered. The possibility that there are more of them expressed at lower levels or in more specialized expression contexts calls for the exploitation of genome sequence information to accelerate their discovery. METHODOLOGY/PRINCIPAL FINDINGS: In this article, we describe a computational method-mirCoS-that uses three support vector machine models sequentially to discover new miRNA candidates in mammalian genomes based on sequence, secondary structure, and conservation. mirCoS can efficiently detect the majority of known miRNAs and predicts an extensive set of hairpin structures based on human-mouse comparisons. In total, 3476 mouse candidates and 3441 human candidates were found. These hairpins are more similar to known miRNAs than to negative controls in several aspects not considered by the prediction algorithm. A significant fraction of predictions is supported by existing expression evidence. CONCLUSIONS/SIGNIFICANCE: Using a novel approach, mirCoS performs comparably to or better than existing miRNA prediction methods, and contributes a significant number of new candidate miRNAs for experimental verification

    An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

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    There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups