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The Institute for Pharmacogenomics and Individualized Therapy (IPIT) at the University of North Carolina at Chapel Hill (NC, USA) is a collaborative, multidisciplinary unit that brings together faculty from different disciplines and crosses the traditional departmental/school structure to perform pharmacogenomics research. IPIT investigators work together towards the goal of developing therapies to enable the delivery of individualized medical care. The NIH-supported Comprehensive Research on Expressed Alleles in Therapeutic Evaluation (CREATE) group leads the field in the evaluation of pathways regulating drug activity, and also provides a foundation for future IPIT research. IPIT members perform bench research, clinical cohort analysis and prospective clinical intervention studies, research on the integration of pharmacogenomic therapy into practice and research to foster global health pharmacogenomics application through the Pharmacogenetics for Every Nation Initiative. IPIT Investigators are actively incorporating a pharmacogenomics curriculum into existing teaching programs at all levels.

Chemical (solution) methods of nanomaterial synthesis offer the advantages of simplicity, stoichiometric control, ease of scale-up, and the possibilities of size control and narrow size distributions. Of the many solution methods of making nanoparticles, the reduction of metal salts by alkalides or electrides, generally referred to as alkalide reduction, is particularly promising due to its ability to protect highly oxyphilic elements and its use of the most power reductants possible in any given solvent. This makes it general across the periodic table including the early transition metals and rare earth elements. In fact, to date, it is the only solution method shown to be capable of synthesizing lanthanide metal nanoparticles. Binary and higher order phase nanomaterials are also possible by the simultaneous alkalide reduction of multiple elements. Nanoscale oxides and nitrides can be formed by reacting nanomaterials made by alkalide reduction with the appropriate gas. Spheroidal nanoparticles as small as ∼1 nm in diameter can be synthesized by this method as can rods up to ∼1 µm in length. The current practice and capabilities of highly versatile synthetic routes to nanomaterials are outlined in this article. Keywords: alkalide; electride; nano; magnetic; phosphor; alloy; carbide; oxide; nitride; rod

While pharmacogenetics – the correlation of genotype and response to medicines – currently has a small but measurable impact on the prescribing practice of clinicians, the advent of the ‘personal genome’ is likely to change this significantly. Advances in high-throughput technologies aimed at characterizing human genetic variation, including chip-based genotyping and next-generation sequencing, are poised to provide a flood of information that will affect both pharmacogenetic discovery and pharmacogenetic application in clinical practice. In order for this flood of information to not overwhelm both researchers and clinicians alike, a variety of new and expanded information management tools will be needed, including electronic medical records, bioinformatic algorithms for analyzing sequence data, information management systems for storing, retrieving and interpreting whole-genome sequence data, and pharmacogenetic decision tools for prescribers.

This report culminates a three year project to develop appropriately parameterized and validated physiologically-based pharmacokinetic (PBPK) models for representative components of jet fuel JP-8, and combine them into a complex mixture interaction model of JP-8 itself for use in a mechanism-based assessment of human health effects resulting from exposure to aerosol, vapor and (via skin) liquid. Single chemical models of selected representative components (nonane, decane and naphthalene) were used to predict systemic dose for dose-response assessment using kinetic data from in-house and published studies. To harmonize single chemical models, we developed a modeling framework that included generic tissue compartments in which we have combined diffusion limitation and deep tissue (global tissue model). We also applied a QSAR approach for estimating blood and tissue partition coefficients, and in integrating our kinetic model with exposure models. A complex mixture model of jet fuel was developed for an arbitrarily large number of components, in which interactions are modeled for the specific case of competitive metabolic inhibition of a specific enzyme (P450-2E1). Applications of this approach include the ability to integrate animal, human and in vitro data in a form that allows internal dose and health effects predictions to be made concerning specific real-world exposures to JP-8 and new alternative fuels.

Li alloying metals have much greater specific and volumetric energy densities than current state of the art graphite used in commercial Li ion batteries. However, the extremely large volumetric changes that the metals undergo when alloying with Li lead to the structural degradation of the electrode with consequent poor cycle life. We are attempting to make stable Li alloying metal electrodes, specifically with gallium arsenide, by akalide reduction on carbon matrices. Arsenic has been largely ignored as a candidate for Li alloying anode materials despite having the third best gravimetric capacity of the alloying metals and being abundant and inexpensive, on par with the cost of bulk silicon1. Gallium, a lithium alloying metal that melts at 29.8°C, has shown promise because of its self-healing ability at increased temperatures2, although it suffers from a lower gravimetric capacity than some of its more popular lithium alloying counterparts. Here we show the synthesis of Gallium Arsenide by akalide reduction. It is characterized by powder x-ray diffraction, transmission electron microscopy, thermo-gravimetric analysis, and x-ray fluorescence spectroscopy. Electrochemical testing of lithium half-cells, cycled from 0.02 to 1.5V versus lithium at a rate of C/10, showed a reversible capacity of 630 mAh/g with good capacity retention. (1) Nitta, N.; Yushin, G. Particle & Particle Systems Characterization, 31, 317-336. (2) Deshpande, R. D.; Li, J. C.; Cheng, Y. T.; Verbrugge, M. W. Journal of the Electrochemical Society, 158, A845-A849. Figure 1

Since their introduction, lithium ion batteries have become ubiquitous for powering portable electronic devices. However, the charging rate of graphite (by far the most common anode material) is relatively slow due to long lithium diffusion pathlengths. Highly graphitic hollow carbon nanospheres (HCNS) have a tremendous advantage over micron-sized graphite particles as the diffusion path length is on the nanoscale, 3 orders of magnitude shorter than graphite’s, facilitating rapid charging within a few minutes, rather than many hours. In addition, HCNS anodes cycle stably in inexpensive low melting point electrolytes, cycling with excellent capacity retention and high rate at temperatures as low as -50 ˚C. Unfortunately, HCNS anodes have lower specific capacity compared to those made with graphite (~220 mAh/g vs. 372 mAh/g).(1) However, the high surface area, good electrical conductivity and excellent electrochemical stability of HCNS make it a promising support material for other high capacity lithium alloying materials, suggesting the possibility of significantly higher specific capacities, much better low temperature performance and charging rates than graphite-based anodes. Here we present our studies to date on the incorporation of germanium metal, second only to Si in gravimetric capacity as a Li alloying material (1385 mAh/g) and nearly equal to it in volumetric capacity (7372 mAh/mL), into HCNS anodes. Syntheses were performed at room temperature by solution phase reduction of germanium precursors in the presence of the HCNS to produce conductive composites of Ge nanoparticles supported on HCNS. When cycling from 1.5 to 0.02 V vs. Li, a stable capacity of ~600 mAh/g electrode ( ~1200 mAh/g Ge) was obtained with average capacity fade of 0.03% per cycle. Long-term coulombic efficiency values were 99.9 and 99.6% for 20 and 40% Ge/HCNS, respectively. Owing to the high volumetric capacity of Ge and porous structure of the HCNS, areal capacities of ~2.5 mAh/cm2 could be obtained by slurry casted techniques. Performance comparisons of multiple Ge/HCNS compositions with differing cycling environments will be presented. (1) Michael J. Wagner, J. Thomas McKinnon, J. Cox and K. Gneshin, “Hollow Carbon Naonsphere Based Secondary Cell Electrodes”, United States Patent 8,262,942, September 11, 2012. Figure 1

Li alloying metals have much greater specific and volumetric energy densities than current state of the art graphite used in commercial Li ion batteries. However, the extremely large volumetric changes that the metals undergo when alloying with Li lead to the structural degradation of the electrode with consequent poor cycle life. We are attempting to make stable Li alloying metal electrodes, specifically with gallium arsenide, by akalide reduction on carbon matrices. Arsenic has been largely ignored as a candidate for Li alloying anode materials despite having the third best gravimetric capacity of the alloying metals and being abundant and inexpensive, on par with the cost of bulk silicon1. Gallium, a lithium alloying metal that melts at 29.8°C, has shown promise because of its self-healing ability at increased temperatures2, although it suffers from a lower gravimetric capacity than some of its more popular lithium alloying counterparts. Here we show the synthesis of Gallium Arsenide by akalide reduction. It is characterized by powder x-ray diffraction, transmission electron microscopy, thermo-gravimetric analysis, and x-ray fluorescence spectroscopy. Electrochemical testing of lithium half-cells, cycled from 0.02 to 1.5V versus lithium at a rate of C/10, showed a reversible capacity of 1365 mAh/g with good capacity retention. (1) Nitta, N.; Yushin, G. Particle & Particle Systems Characterization, 31, 317-336. (2) Deshpande, R. D.; Li, J. C.; Cheng, Y. T.; Verbrugge, M. W. Journal of the Electrochemical Society, 158, A845-A849. Figure 1

Related individuals collected for use in linkage studies may be used in case-control linkage disequilibrium analysis, provided one takes into account correlations between individuals due to identity-by-descent (IBD) sharing. We account for these correlations by calculating a weight for each individual. The weights are used in constructing a composite likelihood, which is maximized iteratively to form likelihood ratio tests for single-marker and haplotypic associations. The method scales well with increasing pedigree size and complexity, and is applicable to both autosomal and X chromosomes. We apply the approach to an analysis of association between type 2 diabetes and single-nucleotide polymorphism markers in the PPAR-g gene. Simulated data are used to check validity of the test and examine power. Analysis of related cases has better power than analysis of population-based cases because of the increased frequencies of disease-susceptibility alleles in pedigrees with multiple cases compared to the frequencies of these alleles in population-based cases. Also, utilizing all cases in a pedigree rather than just one per pedigree improves power by increasing the effective sample size. We demonstrate that our method has power at least as great as that of several competing methods, while offering advantages in the ability to handle missing data and perform haplotypic analysis. Genet. Epidemiol. 28:110–122, 2005. & 2004 Wiley-Liss, Inc.

CoFe2O4 nanocrystallites have been synthesized by alkalide reduction of Co2+ and Fe3+ to form nanoscale CoFe2, followed by oxidation with aerated water at room-temperature resulting in the nanocrystalline ferrite. As produced, the material consists of 2−4 nm nanocrystals that are superparamagnetic with an average blocking temperature of ∼350 K. Annealing at 100 °C in air results in a decrease in the blocking temperature to ∼250 K, with no detectable nanocrystallite growth. The dramatic change in the magnetic properties upon annealing is probably due to removal of crystal defects, namely oxygen vacancies. Further annealing to temperatures as high as 400 °C results in little change in the nanocrystallite size or the magnetic properties. Annealing at 500 °C results in the onset of significant growth in the nanocrystallite size, reaching 30 nm for material annealed at 1000 °C. The saturation magnetization, remanence, and squareness ratio, measured at 300 K, increase smoothly with increasing annealing temperat...

We performed multipoint linkage analysis using 83 markers from the SNP Consortium (TSC) SNP linkage map in 3 regions covering 190 cM previously scanned with microsatellite markers and found to be linked to type 2 diabetes. Since the average linkage disequilibrium present in the TSC SNP marker clusters is relatively low, we assumed the intracluster genetic distances were a reasonable small nonzero distance (0.03 cM) and performed linkage analysis using GENEHUNTER PLUS and ASM linkage analysis software. We found that for the pedigree structures and missing data patterns in our samples the average information content in all three regions and the LOD score curves in two regions obtained from the TSC SNP markers were similar to results obtained from microsatellite marker maps with 10 cM average spacing. We also give an algorithm which extends the Lander-Green algorithm to permit multipoint linkage analysis of clusters of tightly linked markers with arbitrarily high levels of intracluster linkage disequilibrium.

(Y0.95Eu0.05)2O3 nanoparticles have been synthesized by subambient homogeneous reduction using alkalide solutions and subsequent oxidation. As synthesized, the material consists of free-flowing agg...

We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.

Gadolinium nanoparticles have been produced at subambient temperature by alkalide reduction. The nanoparticles display maxima in the temperature dependence of their magnetization, cooled in the absence of an applied external field, at T(max) of 5.0 and 17.5 K for unheated samples and samples annealed at 1000 degrees C for 4 h, respectively. Field cooled behavior deviates at temperatures slightly above T(max), increasing at lower temperature. Curie-Weiss law fits of the high-temperature data yield magnetic moments in close agreement with those expected for noninteracting Gd(3+) ions, suggesting that the behavior seen is due to a magnetic transition rather than superparamagnetism. Magnetization is linearly dependent on field at temperatures higher than 7-8 times T(max) and shows remanence-free hysteresis at lower temperature, suggesting metamagnetism. Some annealed samples show evidence of additional ferromagnetic interactions below approximately 170 K. Magnetic entropy curves generated from magnetization data are consistent with that expected for a paramagnet.

Samples of the electride, Cs + (18-crown-6) 2 e - , with the previously published structure, are antiferromagnetic with a maximum magnetic susceptibility at about 50 K and with a stoichiometric number of trapped electrons. Allowing the temperature to increase above about 230 K changes the susceptibility to Curie-Weiss behavior with a Weiss constant of only -2.3 K but with retention of a nearly stoichiometric number of trapped electrons. The overall magnetic behavior is different from that found in previous studies, which characterized this electride as a Curie-Weiss paramagnet with up to about 80% of the expected unpaired spins. The difference is tentatively attributed to the presence of excess cesium in the previously studied samples. The earlier behavior could be reproduced by preparing samples by the previous technique

Since their introduction, lithium ion batteries have become ubiquitous for powering portable electronic devices. However, the charging rate of graphite (by far the most common anode material) is dependent on lithium diffusion into the material. Highly graphitic hollow carbon nanospheres (HCNS) have a tremendous advantage over micron-sized graphite particles as the diffusion path length is on the nanoscale, 3 orders of magnitude shorter than graphite’s, facilitating rapid charging within a few minutes, rather than many hours. In addition, HCNS anodes cycle stably in inexpensive low melting electrolytes, cycling with excellent capacity retention and high rate at temperatures as low as -50 ˚C. Unfortunately, HCNS anodes have lower specific capacity compared to those made with graphite (~220 mAh/g vs. ~330 mAh/g).(1) However, the high surface area, good electrical conductivity and excellent electrochemical stability of HCNS make it a promising support material for other high capacity lithium alloying metals, suggesting the possibility of significantly higher specific capacities, much better low temperature performance and charging rates than graphite-based anodes. Here we present our studies to date on the incorporation of germanium metal which is second only to Si in gravimetric capacity as a Li alloying material (1385 mAh/g) and nearly equal to it in volumetric capacity (7372 mAh/mL), into HCNS anodes. Syntheses were performed by multiple reduction methods of germanium precursors in the presence of HCNS to produce conductive composites of HCNS. Various Ge morphologies were observed from each synthesis method. Using these composites, electrodes were prepared with different binder materials and tested in different electrolytes at various potentials in attempt to obtain a high capacity, long cycle-life anode while maintaining nearly 100 % coulombic efficiency. A stable capacity of 950 mAh/g of Ge was obtained when cycling from 1.0 to 0.055 V and long-term coulombic efficiency values were greater than 99.7 %. TEM analysis revealed the HCNS particles to be coated with Ge. Performance comparisons of multiple Ge/HCNS composites with differing cycling environments will be presented. (1) Michael J. Wagner, J. Thomas McKinnon, J. Cox and K. Gneshin, “Hollow Carbon Naonsphere Based Secondary Cell Electrodes”, United States Patent 8,262,942, September 11, 2012.

Large-scale human genotyping requires technologies with a minimal number of steps, high accuracy, and the ability to automate at a reasonable cost. In this regard, we have developed a rapid, cost-effective readout method for single nucleotide polymorphism (SNP) genotyping that combines an easily automatable single-tube allele-specific primer extension (ASPE) with an efficient high throughput flow cytometric analysis performed on a Luminex 100 flow cytometer. This robust technique employs an ASPE reaction using PCR-derived target DNA containing the SNP and a pair of synthetic complementary capture probes that differ at their 3' end-nucleotide defining the alleles. Each capture probe has been synthesized to contain a unique 25-nucleotide identifying sequence (ZipCode) at its 5' end. An array of fluorescent microspheres, covalently coupled with complementary ZipCode sequences (cZipCodes), was hybridized to biotin-labeled ASPE reaction products, sequestering them for flow cytometric analysis. ASPE offers both an advantage of streamlining the SNP analysis protocol and an ability to perform multiplex SNP analysis on any mixture of allelic variants. All steps of the assay are simple additions of the solutions, incubations, and washes. This technique was used to assay 15 multiplexed SNPs on human chromosome 12 from 96 patients. Comparison of the microsphere-based ASPE assay results to gel-based oligonucleotide ligation assay (OLA) results showed 99.2% agreement in genotype assignments. In addition, the microsphere-based multiplex SNPs assay system was adapted for the identification of bacterial samples by both ASPE and single base chain extension (SBCE) assays. A series of probes designed for different variable sites of bacterial 16S rDNA permitted multiplex analysis and generated species- or genus-specific patterns. Seventeen bacterial species representing a broad range of gram-negative and gram-positive bacteria were analyzed within 16 variable sites of 16S rDNA sequence. The results were consistent with the published sequences and confirmed by direct DNA sequencing.

A new chemical precursor system to the YBa2Cu3O7–x(1–2–3) superconductor using acetic acid and 1,3-bis(dimethylamino)propan-2-ol (bdmapH) has been developed, a polynuclear complex [Cu4(OAc)6(bdmap)2(H2O)6]n with a two-dimensional network linked by hydrogen bonds has been isolated and characterized from this system.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to

Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389–395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association’s GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).

SummarySeveral authors have proposed algorithms to detect Mendelian errors in human genetic linkage data. Most currently available methods use likelihood-based methods on multiplex family data to identify typing or pedigree errors. These algorithms cannot be applied in many sib-pair collections, because of lack of parental-genotype information. Nonetheless, misspecifying the relationships between individuals has serious consequences for sib-pair linkage studies: false relationships bias the statistics designed to identify linkage with disease phenotypes. To test the hypothesis that two individuals are sibs, we propose a test statistic based on the summation, over a large number of genetic markers, of the number of alleles shared identical by state by a pair of individuals, for each marker. The test statistic has an approximately normal distribution under the null hypothesis, and extreme negative values correspond to nonsib pairs. Power and significance studies show that the test statistic calculated by use of 50 unlinked markers has 96% power to detect half-sibs and has 100% power to detect unrelated individuals as not full-sib pairs, with a 5% false-positive rate. Furthermore, extreme positive values of the test statistic identify sibs as MZ twins.

Hereditary multiple exostoses (EXT) is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3, respectively. Recently, the EXT1 gene has been isolated and partially characterized and appears to encode a tumor suppressor gene. We have identified six mutations in the human EXT1 gene from six unrelated multiple exostoses families segregating for the EXT gene on chromosome 8. One of the mutations we detected is the same 1-bp deletion in exon 6 that was previously reported in two independent EXT families. The other five mutations, in exons 1, 6, 9, and the splice junction at the 3′ end of exon 2, are novel. In each case, the mutation is likely to result in a truncated or nonfunctional EXT1 protein. These results corroborate and extend the previous report of mutations in this gene in two EXT families, and provide additional support for the EXT1 gene as the cause of hereditary multiple exostoses in families showing linkage to chromosome 8.

Hereditary predisposition to multiple exostoses is a genetically heterogeneous disease. Recently, we have reported the identification of the EXT1 gene on human chromosome 8. We have now isolated a cDNA clone from a human adult lung cDNA library and have determined the genomic organization and promoter structure of the EXT1 gene. The gene is composed of 11 exons, ranging from 90 to 1735 bp, and spans approximately 350 kb of genomic DNA. Sequence analysis of the promoter region revealed the presence of a CpG island containing GC and CAAT boxes, but no TATA box. Such a promoter is characteristic for housekeeping genes. This finding is in good agreement with the ubiquitous expression of the EXT1 gene.

We have developed an integrated physical map for human chromosome 8q23-q24.1 based on STS content analysis of somatic cell hybrids and YAC contigs. Among the 63 STSs used are markers from multiple genetic maps and several previously unmapped polymorphisms, thus integrating genetic markers from different sources into comprehensive, ordered sets based on their positions in the physical map. These maps will facilitate the isolation of genes causing human inherited diseases that map to these chromosomal regions.

The current-voltage (I-V) characteristics of the interfaces between boron-doped hydrogenated amorphous silicon (p-a-Si:H) and transparent conductive oxides (TCOs) such as tin oxide (SnO2) and indium tin oxide (ITO) are experimentally determined. The measurements are performed on especially developed Kelvin cross bridge structures which allow the direct sensing of the contact region. All contacts exhibit for high dopant concentrations an almost linear I-V characteristic. The values of the contact resistance depend on the TCO type and range between 0.5 and 4 Ω· cm2 at 25°C. Gradual reduction of the boron doping level leads to a remarkable increase of the contact resistance and finally to a rectifying behavior. The results indicate that tunnelling across the interface contributes significantly to the current transport. This conclusion is also supported by the behavior of the I-V characteristics at low temperatures. Regarding degradation of the contacts a systematic reduction of the contact resistance is observed after ageing them for 1000 hours at 80°C.

The Langer-Giedion syndrome (tricho-rhino-phalangeal syndrome type II, TRPS II) is characterized by craniofacial dysmorphism and skeletal abnormalities. It combines the clinical features of TRPS I and multiple cartilaginous exostoses (EXT). We have used YAC cloning, Southern blotting, PCR analysis, and fluorescence in situ hybridization to study chromosome 8 deletions, translocations, an inversion, and an insertion in patients with TRPS I, TRPS II or EXT. Our results indicate that the TRPS gene maps more than 1,000 kb proximal to the EXT1 gene and that both genes are affected in TRPS II. We conclude that TRPS II is not due to pleiotropic effects of mutations in a single gene, but that it is a true contiguous gene syndrome.

10061 Background: Limited clinical data on real-world practice patterns are available for care of pts with m/rSTS. This study evaluated drug tx patterns and outcomes in m/rSTS pts following failure of prior chemotherapy based on data from a U.S. referral academic cancer center. Methods: Data from medical records consented for research use were retrospectively reviewed at Dana-Farber Cancer Institute for pts with m/rSTS who were ≥18 years, commenced 2nd-line systemic therapy between 1/1/2000 and 2/4/2011, had confirmed disease progression on or after 1st-line therapy and had ≥3 months of observation. Pts were excluded if they had been diagnosed with gastrointestinal stromal tumor, bone sarcoma or dermatofibrosarcoma protuberans, or had ever been treated with pazopanib. Histologic subtype, tx type and duration, tx modifications (e.g., discontinuation) and reasons for modifications were examined. Overall survival, time to progression and clinician-assessed tumor response were collected. Results: Study pts had leiomyosarcoma (n=50), synovial cell sarcoma (n=7), liposarcoma (n=5) and other histologic subtypes (n=39). These 101 pts received an average 4 lines of tx (maximum=10 lines). Wide variations were noted in each line of tx (Table) with no consistent nor dominant regimens. Median 2nd-line tx duration was 4.1 months (95%CI 2.9-5.0). Among 98 pts who discontinued 2nd-line tx, 72 (73%) did so due to progressive disease, 10 due to “completion” of planned tx, and 6 to adverse events. Median progression-free survival from initiation of 2nd-line tx varied across regimens from 2.0 to 6.5 months (overall median 5.5 months). Conclusions: The wide variation in ≥2nd-line tx confirms there is no single “standard” of care for m/rSTS. The majority of pts discontinued 2nd-line tx due to progressive disease and often received additional lines of tx, indicating frequent physician and pt switching of tx. [Table: see text]

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The Werner syndrome locus (WRN) is located at 8p11-p12. To facilitate eventual cloning of the WRN gene, a 10,000-rad radiation-reduced hybrid (RH) cell panel was generated to map genetic markers, sequence-tagged sites (STSs), and genes in this region. A hamster cell line carrying an intact human chromosome 8 was fused with another hamster cell line. Two sets of hybrid cell panels from 2 separate fusions were generated; each panel consisted of 50 independent clones; 33 and 34 cell lines from the 2 fusions retained human chromosome material as determined by inter-Alu PCR. The combined panel was genotyped for 52 markers spanning the entire chromosome, including 10 genes, 29 anonymous polymorphic loci, and 13 STSs. Seventeen of these markers have not been previously described. Markers near the centromere were retained at a higher frequency than more distal markers. Fluorescence in situ hybridization was also used to localize and order a subset of the markers. An RH map of the WRN region was constructed using a maximum likelihood method, giving the following most likely order: D8S131 - D8S339(GSR) - D8S124 - D8S278 - D8S259 - (D8S71) - D8S283 - D8S87 - D8S105 - D8S135(FGFR1) - D8S135PB - D8S255 - ANK1. A geneticmore » map of 15 short tandem repeat polymorphic loci in the WRN region was also constructed. The marker orders from the genetic and RH maps were consistent. In addition, an integrated map of 24 loci in the WRN region was generated using information from both genetic and RH mapping methods. A 1000:1 framework map for 6 loci (LPL-D8S136-D8S137-D8S87-FGFR1-ANK1) was determined by genetic mapping, and the resulting locus order was fixed during analysis of the RH genotype data. The resulting integrated map contained more markers than could confidently be ordered by either genetic or RH mapping alone. 64 refs., 5 figs., 6 tab.« less

NaTaO3 nanorods were synthesized with high (>90%) yield by reduction of TaCl5 with THF solutions of the alkalide K+(15C5)2Na-, followed by product annealing under dynamic vacuum at 250 and 600 degrees C. In addition to the nanorods, the product is comprised of 5-10% approximately 10-nm diameter spheroidal NaTaO3 nanocrystals. The nanorods are generally longer than 500 nm, with some exceeding 1 mum, and 10-100 nm wide, with aspect ratios that vary between 10 and 20:1. Select area electron diffraction patterns of individual nanorods indicate that each nanorod is a single crystal with its axis oriented in the [010] direction.

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In an attempt to identify C/EBP-like transcription factors expressed in the prostate, a cDNA homologous to the mouse C/EBP delta (CRP3) and the rat CELF gene was isolated. A genomic clone containing the entire C/EBP delta gene was isolated using a cDNA fragment as a probe. The gene was characterized by restriction mapping and sequence analysis. By fluorescence in situ hybridization, using the biotinylated genomic clone as a probe, the C/EBP delta gene was assigned to the pericentromeric region of human chromosome 8, most probably to 8q11. This chromosomal localization was confirmed by analysis of a panel of human x hamster somatic cell hybrid DNA samples with a C/EBP delta-specific STS. As a result, the C/EBP delta gene could be positioned between the PLAT and the MOS loci.

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A linkage map consisting of 21 dinucleotide repeat polymorphisms, 1 tetranucleotide repeat polymorphism, and 3 RFLPs was constructed for human chromosome 8. The map spanned most of the chromosome length from near pter to q23-q24 on the distal portion of the long arm. The total 186 cM length of the female map was over two times the 84 cM length of the male map. Cytogenetic mapping of the polymorphisms using a panel of hybrids containing rearranged chromosomes was completely consistent with the linkage map. Special effort was made to remove as many genotyping errors, including parental phase errors, as possible. Removal of errors, in agreement with recent theoretical predictions, led to reduction of the total length of the sex-equal map by 10% from 145 to 130 cM.

Two nonallelic histone gene clusters were characterized in the marine copepod, Tigriopus californicus. The DNA sequence of one of the clusters reveals six genes in the contiguous arrangement of H2B, H1, H3, H4, H2B and H2A. The order of genes within the second cluster is H3, H4, H2B and H2A. There is no evidence for the presence of an H1 gene in this cluster. Comparison of the three copepod H2B genes reveals a high degree of similarity between the 5′ upstream regions and between the amino terminal halves of the two H2B genes found within the same cluster. From these data we infer that gene duplication and/or gene conversion events occurred within this cluster in the recent past.

We report the growth, structural characterization, and magnetic properties of ferromagnetic Fe0.8Ga0.2 nanowires that are grown on quartz substrates by electrospinning. Electrospun nanowires are annealed in ultrahigh purity argon-hydrogen gas mixture. Uniform, continuous, high aspect ratio FeGa nanowires with diameters in the range of 50–500 nm and lengths of up to 500 μm are grown. Hysteresis loops were measured with magnetic field applied perpendicular and parallel to the substrate plane at 4 and 300 K. The nanowires exhibit a quite large coercivity (380 Oe) at 4 K in the parallel field. At 300 K, they show lower coercivities than that of bulk FeGa in both directions.

Tetragonal alkali metal tungsten bronze and hexagonal alkali metaltungstate nanorods have been synthesized by sub-ambient reduction by alkalide solutions and subsequent oxidation. Tetragonal potassium tungsten bronze, K0.4WO3, nanorods result after post-reduction annealing at 250 °C for 3 h followed by 600 °C for 4 h in vacuum if the alkalide reduction is performed using K+(15-crown-5)2Na− and a mixed sodium/potassium tungsten bronze, Na0.3K0.2WO3, if K+(18-crown-6)2Na− is used. The rods are generally ∼40 nm wide and 400–500 nm long single crystals, their principal axis being in the [001] crystallographic direction. Annealing in air at 500 °C changes the material to a bronze-like hexagonal alkali metal tungstate, without substantial effect on its nanorod morphology. The hexagonal alkali metal tungstate, K0.3W0.95O3, nanorods can be made directly by heating to 400 °C rather than 600 °C in the 2-step annealing process, consistent with the tungstate being the first phase formed, transforming to the bronze at higher temperature.

Linkage mapping in a large, seven-generation family with type 2 autosomal dominant retinitis pigmentosa (ADRP) demonstrates linkage between the disease locus (RP1) and DNA markers on the short arm of human chromosome 8. Five markers were most informative for mapping ADRP in this family using two-point linkage analysis. The markers, their maximum lod scores, and recombination distances were ANK1 (ankyrin)--2.0 at 16%; D8S5 (TL11)--5.3 at 17%; D8S87 [a(CA)n repeat]--7.2 at 14%; LPL (lipoprotein lipase)--1.5 at 26%; and PLAT (plasminigen activator, tissue)--10.6 at 7%. Multipoint linkage analysis, using a simplified pedigree structure for the family (which contains 192 individuals and two inbreeding loops), gave a maximum lod score of 12.2 for RP1 at a distance 8.1 cM proximal to PLAT in the pericentric region of the chromosome. Based on linkage data from the CEPH (Paris) reference families and physical mapping information from a somatic cell hybrid panel of chromosome 8 fragments, the most likely order for four of these five loci and the diseases locus is 8pter-LPL-D8S5-D8S87-PLAT-RP1. (The precise location of ANK1 relative to PLAT in this map is not established). The most likely location for RP1 is in the pericentric region of the chromosome. Recently, several families with ADRP with tight linkage to the rhodopsin locus at 3q21-q24 were reported and a number of specific rhodopsin mutations in families with ADRP have since been reported. In other ADRP families, including the one in this study, linkage to rhodopsin has been excluded. Thus mutations at two different loci, at least, have been shown to cause ADRP. There is no remarkable clinical disparity in the expression of disease caused by these different loci.

We have obtained lymphoblastoid cell lines from three patients with Langer-Giedion syndrome who have over-lapping deletions in 8q24.1. To isolate the deletion chromosomes from their normal homologs, patient cell lines were fused with hamster cells and hybrid cells were selected for retention of human chromosome 8. These hybrid cell lines were screened for the presence of chromosome 8 by fluorescence in situ hybridization and by Southern blot hybridization. We have hybridized 31 recombinant DNA clones derived from the 8q22-qter region to Southern blots of the hybrid cell lines; 8 were found to lie within the deletion of at least one patient. One clone identified sequences that were missing from one copy of chromosome 8 in all three patients. These clones help to further define the deletions in these patients and will serve as starting points for detailed characterization of the region.

We have characterized a panel of somatic cell hybrids that carry fragments of human chromosome 8 and used this panel for the regional localization of anonymous clones derived from a chromosome 8 library. The hybrid panel includes 11 cell lines, which were characterized by Southern blot hybridization with chromosome 8-specific probes of known map location and by fluorescent in situ hybridization with a probe derived from a chromosome 8 library. The chromosome fragments in the hybrid cell lines divide the chromosome into 10 intervals. Using this mapping panel, we have mapped 56 newly derived anonymous clones to regions of chromosome 8. We have also obtained physical map locations for 7 loci from the genetic map of chromosome 8, thus aligning the genetic and physical maps of the chromosome.

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Nanocrystalline (Y0.95Tb0.05)2O3 has been synthesized by sub-ambient homogenous reduction using alkalide solutions, subsequent oxidation and annealing. As synthesized, the material consists of free flowing, agglomerates of ill-defined, amorphous or subnanocrystalline nanoparticles. Samples annealed at 500 °C or greater are crystalline, consisting of agglomerated nanocrystals. The nanocrystals grow from an average of ∼1–2 nm to 19 nm and the agglomerates break-up as the annealing temperature is raised from 500 to 1000 °C. The nanocrystalline product displays luminescence typical of the Tb3+ ion. The photoluminescence intensity of the green 5D4–7F4 transition increases with increasing annealing temperature, reaching a maximum of 4% for the nanophosphor annealed at 1000 °C. Evidence of quantum confinement luminescence enhancement is observed for the nanocrystallites annealed at 500 °C, but the quantum efficiency is low, presumably due to their very small size and consequent rapid surface recombination. The results of this study suggest that nanocrystallites of (Y0.95Tb0.05)2O3 with a large quantum confinement fluorescence enhancement may be accessible by appropriate annealing in the temperature range 500–600 °C.

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Arc-generated fullerene soot dramatically reduces the capacity fade of SFG-15 graphite electrodes in extended lithium ion cycling. Composite electrodes made by the addition of as little as 10% by mass fullerene soot exhibit less than 1.5% reduction in unload capacity over 200 cycles at a rate of C/2, whereas electrodes without the additive lose 79% of their capacity under the same conditions. The addition of the soot decreases the first cycle Coulombic efficiency of the electrodes, from 83.4% for graphite electrodes to 52.9% with the addition of 10% soot. However, the Coulombic efficiency of the composite electrodes surpasses that of the graphite electrodes after a few cycles and remains higher for subsequent cycles. The soot is estimated to increase the first cycle Coulombic losses by ∼ 2000 mAh/g of soot. The soot makes only modest contributions to the capacity of the electrodes, ∼85 mAh/g for compositions with 30% or more graphite content by mass, significantly less (∼25 mAh/g) for composite electrodes with lower graphite content. However, the soot apparently prevents the irreversible loss of electrode capacity, allowing the capacity of the graphite active material to approach its theoretical limit for lithium storage (372 mAh/g) for low soot content compositions.

Rationale The prevalence of asthma and other allergic diseases has risen to above 10% over the past 2 decades. Genome wide screens for asthma phenotypes have been completed in several populations. Overall results from these genome scans differ significantly, which could mainly be attributed to the sample size, and the choice of phenotypes/populations. We conducted a genome scan using a large population to identify asthma susceptibility genes. Methods An asthma Genetics program was initiated at GSK in 1998 which includes the Genetics of Asthma International network (GAIN) and two independent collections from Denmark and Minnesota. We collected ∼1500 families from 13 collection centers in Europe Australia and US. A genome scan using 735 families was performed with 390 markers representing an approximate 7-cM genome scan set (752 affected sib pairs for Physician's Diagnosis of Asthma, PDA). Multi-point linkage analysis was performed with Genehunter using four phenotypes; PDA, atopic asthma, BHR (bronchial hyper-responsiveness) and strict asthma (2 of 3 symptoms + BHR). Results Preliminary results showed the following 5 chromosomal regions with a LOD greater than 2.0, Chromosome 1, LOD score 2.014 for atopic asthma; Chromosome 2, LOD score 2.23 for strict asthma and/ BHR; chromosome 4, LOD score 2.43 for BHR; chromosome 6, LOD score 2.06 for strict asthma; and chromosome 12, LOD score 2.03 for physician's diagnosis of asthma. Conclusions The improved power associated with the better sample size has led to the identification of several genomic regions linked to asthma, including a potentially novel locus on chromosome 4.