3 - 14 Micron Spectroscopy of Comets C/2002 O4 (Honig), C/2002 V1 (NEAT), C/2002 X5 (Kudo-Fujikawa), C/2002 Y1 (Juels-Holvorcem), 69P/Taylor, and the Relationships among Grain Temperature, Silicate Band Strength and Structure among Comet Families

We report 3 - 13 micron spectroscopy of 4 comets observed between August 2002 and February 2003: C/2002 O4 (Honig) on August 1, 2002, C/2002 V1 (NEAT) on Jan. 9 and 10, 2003, C/2002 X5 (Kudo-Fujikawa) on Jan. 9 and 10, 2003, and C/2002 Y1 (Juels-Holvorcem) on Feb. 20, 2003. In addition, we include data obtained much earlier on 69P/Taylor (February 9, 1998) but not previously published. For Comets Taylor, Honig, NEAT, and Kudo-Fujikawa, the silicate emission band was detected, being approximately 23%, 12%, 15%, and 10%, respectively, above the continuum. The data for Comet Juels-Holvorcem were of insufficient quality to detect the presence of a silicate band of comparable strength to the other three objects, and we place an upper limit of 24% on this feature. The silicate features in both NEAT and Kudo-Fujikawa contained structure indicating the presence of crystalline material. Combining these data with those of other comets, we confirm the correlation between silicate band strength and grain temperature of Gehrz & Ney (1992) and Williams et al. (1997) for dynamically new and long period comets, but the majority of Jupiter family objects may deviate from this relation. The limited data available on Jupiter family objects suggest that they may have silicate bands that are slightly different from the former objects. Finally, when compared to the silicate emission bands observed in pre-main sequence stars, the dynamically new and long period comets most closely resemble the more evolved stellar systems, while the limited data (in quantity and quality) on Jupiter family objects seem to suggest that these have spectra more like the less-evolved stars.Comment: 45 pages, 12 figure

Mid-Infrared Spectrophotometric Observations of Fragments B and C of Comet 73P/Schwassmann-Wachmann 3

We present mid-infrared spectra and images from the GEMINI-N (+Michelle) observations of fragments SW3-[B] and SW3-[C] of the ecliptic (Jupiter Family) comet 73P/Schwassmann-Wachmann 3 pre-perihelion. We observed fragment B soon after an outburst event (between 2006 April 16 - 26 UT) and detected crystalline silicates. The mineralogy of both fragments was dominated by amorphous carbon and amorphous pyroxene. The grain size distribution (assuming a Hanner modified power-law) for fragment SW3-[B] has a peak grain radius of a_p ~ 0.5 micron, and for fragment SW3-[C], a_p ~ 0.3 micron; both values larger than the peak grain radius of the size distribution for the dust ejected from ecliptic comet 9P/Tempel 1 during the Deep Impact event (a_p = 0.2 micron. The silicate-to-carbon ratio and the silicate crystalline mass fraction for the submicron to micron-size portion of the grain size distribution on the nucleus of fragment SW3-[B] was 1.341 +0.250 -0.253 and 0.335 +0.089 -0.112, respectively, while on the nucleus of fragment SW3-[C] was 0.671 +0.076 -0.076 and 0.257 +0.039 -0.043, respectively. The similarity in mineralogy and grain properties between the two fragments implies that 73P/Schwassmann-Wachmann 3 is homogeneous in composition. The slight differences in grain size distribution and silicate-to-carbon ratio between the two fragments likely arises because SW3-[B] was actively fragmenting throughout its passage while the activity in SW3-[C] was primarily driven by jets. The lack of diverse mineralogy in the fragments SW3-[B] and SW3-[C] of 73P/Schwassmann-Wachmann 3 along with the relatively larger peak in the coma grain size distribution suggests the parent body of this comet may have formed in a region of the solar nebula with different environmental properties than the natal sites where comet C/1995 O1 (Hale-Bopp) and 9P/Tempel 1 nuclei aggregated.Comment: 31 pages, 5 figure, accepted for publication in A

A thermodynamic approach to PCR primer design

We developed a primer design method, Pythia, in which state of the art DNA binding affinity computations are directly integrated into the primer design process. We use chemical reaction equilibrium analysis to integrate multiple binding energy calculations into a conservative measure of polymerase chain reaction (PCR) efficiency, and a precomputed index on genomic sequences to evaluate primer specificity. We show that Pythia can design primers with success rates comparable with those of current methods, but yields much higher coverage in difficult genomic regions. For example, in RepeatMasked sequences in the human genome, Pythia achieved a median coverage of 89% as compared with a median coverage of 51% for Primer3. For parameter settings yielding sensitivities of 81%, our method has a recall of 97%, compared with the Primer3 recall of 48%. Because our primer design approach is based on the chemistry of DNA interactions, it has fewer and more physically meaningful parameters than current methods, and is therefore easier to adjust to specific experimental requirements. Our software is freely available at http://pythia.sourceforge.net

Dust Grain-Size Distributions From MRN to MEM

Employing the Maximum Entropy Method algorithm, we fit interstellar extinction measurements which span the wavelength range 0.125-3 micron. We present a uniform set of MEM model fits, all using the same grain materials, optical constants and abundance constraints. In addition, we are taking advantage of improved UV and IR data and better estimates of the gas-to-dust ratio. The model fits cover the entire range of extinction properties that have been seen in the Galaxy and the Magellanic Clouds. The grain models employed for this presentation are the simplistic homogeneous spheres models (i.e., Mathis, Rumpl, & Nordsieck 1977) with two (graphite, silicate) or three (graphite, silicate, amorphous carbon) components. Though such usage is only a first step, the results do provide interesting insight into the use of grain size as a diagnostic of dust environment. We find that the SMC Bar extinction curve cannot be fit using carbon grains alone. This is a challenge to the recent observational result indicating little silicon depletion in the SMC.Comment: 24 pages, 5 figures, accepted for publication in the Astrophysical Journa

Assaying the regulatory potential of mammalian conserved non-coding sequences in human cells

The fraction of experimentally active conserved non-coding sequences within any given cell type is low, so classical assays are unlikely to expose their potential

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD. Twenty-one members over 6 generations composed the pedigree. An extensive neurologic and neurocognitive examination was performed on 2 symptomatic individuals and 3 nonsymptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother. DNA was extracted from blood for these 5 individuals and whole-exome sequencing was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals, a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: (1) aggressive, symmetrical, and early-onset Parkinsonism; (2) late parkinsonism associated with FTD; and (3) progressive supranuclear palsy but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported

Somatic PDGFRB activating variants in fusiform cerebral aneurysms

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors

Rare loss of function variants in candidate genes and risk of colorectal cancer

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P

A dynamic Bayesian network for identifying protein-binding footprints from single molecule-based sequencing data

Motivation: A global map of transcription factor binding sites (TFBSs) is critical to understanding gene regulation and genome function. DNaseI digestion of chromatin coupled with massively parallel sequencing (digital genomic footprinting) enables the identification of protein-binding footprints with high resolution on a genome-wide scale. However, accurately inferring the locations of these footprints remains a challenging computational problem