Modeling Distances in Large-Scale Networks by Matrix Factorization

In this paper, we propose a model for representing and predicting distances in large-scale networks by matrix factorization. The model is useful for network distance sensitive applications, such as content distribution networks, topology-aware overlays, and server selections. Our approach overcomes several limitations of previous coordinates-based mechanisms, which cannot model sub-optimal routing or asymmetric routing policies. We describe two algorithms -- singular value decomposition (SVD) and nonnegative matrix factorization (NMF) -- for representing a matrix of network distances as the product of two smaller matrices. With such a representation, we build a scalable system -- Internet Distance Estimation Service (IDES) -- that predicts large numbers of network distances from limited numbers of measurements. Extensive simulations on real-world data sets show that IDES leads to more accurate, efficient and robust predictions of latencies in large-scale networks than previous approaches

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage

First Principles Calculations of the pK_a Values and Tautomers of Isoguanine and Xanthine

The accurate replication of DNA requires the formation of complementary hydrogen bonds between a template base and the base moiety of an incoming deoxynucleotide-5‘-triphosphate. Recent structural studies suggest that some DNA polymerases contribute additional constraints by interrogating the minor groove face of the incoming and template bases. Therefore, the hydrogen bond-donating or -accepting properties of the base pairing as well as minor groove faces of the bases could be important determinants of correct base selection. In this paper, we investigate two purines that could arise by endogenous damage of the normal DNA bases:  isoguanine (which can be generated by the oxidation of adenine) and xanthine (which can be generated by the deamination of guanine). In both cases, the potential exists for the placement of a proton in the N3 position, converting the N3 position from a hydrogen bond acceptor to a donor. In this paper, we use first principles quantum mechanical methods (density functional theory using the B3LYP functional and the 6-31G++G**basis set) to predict the ionization and tautomeric equilibria of both isoguanine and xanthine in the gas phase and aqueous solution. For isoguanine, we find that the N1H and N3H neutral tautomeric forms are about equally populated in aqueous solution, while the enol tauotomers are predominant in the gas phase. In contrast, we find that xanthine displays essentially no tautomeric shifts in aqueous solution but is nearly equally populated by both an anionic and a neutral form at physiological pH. To obtain these results, we carried out an extensive examination of the tautomeric and ionic configurations for both xanthine and isoguanine in solution and in the gas phase. The potential hydrogen-bonding characteristics of these damaged purines may be used to test predictions of the important components of base selection by different DNA polymerases during DNA replication

Exploratory Analysis of Outpatient Visits for US Adults Diagnosed with Lupus Erythematosus: Findings from the National Ambulatory Medical Care Survey 2006–2016

The study aims to assess office-based visit trends for lupus patients and evaluate their medication burden, chronic conditions, and comorbidities. This cross-sectional study used data from the National Ambulatory Medical Care Survey (NAMCS), a survey sample weighted to represent national estimates of outpatient visits. Adult patients diagnosed with lupus were included. Medications and comorbidities that were frequently recorded were identified and categorized. Descriptive statistics and bivariate analyses were used to characterize visits by sex, age, race/ethnicity, insurance type, region, and reason for visit. Comorbidities were identified using diagnosis codes documented at each encounter. There were 27,029,228 visits for lupus patients from 2006 to 2016, and 87% them were on or were prescribed medications. Most visits were for female (88%), white (79%), non-Hispanic (88%) patients with private insurance (53%). The majority of patients were seen for a chronic routine problem (75%), and 29% had lupus as the primary diagnosis. Frequent medications prescribed were hydroxychloroquine (30%), prednisone (23%), multivitamins (14%), and furosemide (9%). Common comorbidities observed included arthritis (88%), hypertension (25%), and depression (13%). Prescription patterns are reflective of comorbidities associated with lupus. By assessing medications most frequently prescribed and comorbid conditions among lupus patients, we showcase the complexity of disease management and the need for strategies to improve care

Sensitive Radio Observations of High Redshift Dusty QSOs

We present sensitive radio continuum imaging at 1.4 GHz and 4.9 GHz of seven high redshift QSOs selected for having a 240 GHz continuum detection, which is thought to be thermal dust emission. We detect radio continuum emission from four of the sources: BRI 0952-0115, BR 1202-0725, LBQS 1230+1627B, and BRI 1335-0417. The radio source in BR 1202-0725 is resolved into two components, coincident with the double mm and CO sources. We compare the results at 1.4 GHz and 240 GHz to empirical and semi-analytic spectral models based on star forming galaxies at low redshift. The radio-to-submm spectral energy distribution for BR 1202-0725, LBQS 1230+1627B, and BRI 1335-0417 are consistent with that expected for a massive starburst galaxy, with implied massive star formation rates of order 1000 solar masses per year (without correcting for possible amplification by gravitational lensing). The radio-to-submm spectral energy distribution for BRI 0952-0115 suggests a low-luminosity radio jet source driven by the AGN.Comment: 12 pages, Latex emulateapj format, including 1 table and 3 figures. The Astrophysical Journal, to appear in the January 2000 issu

Millimeter-Wave Spectroscopy and Mapping of Quasar Hosts, and the Status of ULIRGs as Quasar 2s

It is becoming possible to detect high redshift quasars in various molecular lines, and to show by mapping lensed objects that the strong dust and molecular emission arises in warm dense ~100 pc-scale "tori." The properties of ULIRGs, at least those with AGN-like narrow line regions, are very similar, as expected in the hidden quasar hypothesis. Several of the latter are in fact confirmed as "Quasar 2s" by spectropolarimetry.Comment: 7 page

Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial.

OBJECTIVE: To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine. BACKGROUND: Ubrogepant is an oral, calcitonin gene-related receptor antagonist in development for the acute treatment of migraine. The efficacy of ubrogepant was demonstrated in 2 phase 3 trials in which a significant improvement was observed in migraine headache pain, migraine-associated symptoms, and ability to function. METHODS: This was a phase 3, multicenter, randomized, open-label, 52-week extension trial. Adults with migraine with or without aura entered the trial after completing one of 2 phase 3 lead-in trials and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. Randomization to ubrogepant dose was blinded. Those randomized to usual care continued to treat migraine attacks with their own medication. The usual care arm was included in this trial to capture background rates of hepatic laboratory parameters and contextualize hepatic safety assessments. Safety and tolerability were the primary outcome measures. The safety population for the ubrogepant arms included all randomized participants who received at least 1 dose of treatment. All cases of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations of ≥3 times the upper limit of normal were adjudicated by an independent panel of liver experts who were blinded to dose. RESULTS: The safety population included 1230 participants (404 in the ubrogepant 50-mg group, 409 in the ubrogepant 100-mg group, and 417 in the usual care group). Participants were on average 42 years of age, 90% (1106/1230) female and 85% (1043/1230) white, with an average BMI of 30 kg/m CONCLUSIONS: Long-term intermittent use of ubrogepant 50 and 100 mg given as 1 or 2 doses per attack for the acute treatment of migraine was safe and well tolerated, as indicated by a low incidence of treatment-related TEAEs and SAEs and discontinuations due to adverse events in this 1-year trial