The c2d Spitzer Spectroscopic Survey of Ices Around Low-Mass Young Stellar Objects. IV. NH3 and CH3OH

NH3 and CH3OH are key molecules in astrochemical networks leading to the formation of more complex N- and O-bearing molecules, such as CH3CN and HCOOCH3. Despite a number of recent studies, little is known about their abundances in the solid state. (...) In this work, we investigate the ~ 8-10 micron region in the Spitzer IRS (InfraRed Spectrograph) spectra of 41 low-mass young stellar objects (YSOs). These data are part of a survey of interstellar ices in a sample of low-mass YSOs studied in earlier papers in this series. We used both an empirical and a local continuum method to correct for the contribution from the 10 micron silicate absorption in the recorded spectra. In addition, we conducted a systematic laboratory study of NH3- and CH3OH-containing ices to help interpret the astronomical spectra. We clearly detect a feature at ~9 micron in 24 low-mass YSOs. Within the uncertainty in continuum determination, we identify this feature with the NH3 nu_2 umbrella mode, and derive abundances with respect to water between ~2 and 15%. Simultaneously, we also revisited the case of CH3OH ice by studying the nu_4 C-O stretch mode of this molecule at ~9.7 micron in 16 objects, yielding abundances consistent with those derived by Boogert et al. 2008 (hereafter paper I) based on a simultaneous 9.75 and 3.53 micron data analysis. Our study indicates that NH3 is present primarily in H2O-rich ices, but that in some cases, such ices are insufficient to explain the observed narrow FWHM. The laboratory data point to CH3OH being in an almost pure methanol ice, or mixed mainly with CO or CO2, consistent with its formation through hydrogenation on grains. Finally, we use our derived NH3 abundances in combination with previously published abundances of other solid N-bearing species to find that up to 10-20 % of nitrogen is locked up in known ices.Comment: 31 pages, 15 figures, accepted for publication in Ap

Pomalidomide – An Appraisal of Its Clinical Development and Role in the Treatment of Relapsed/Refractory Multiple Myeloma

Pomalidomide is a distinct immunomodulatory agent with significant activity in relapsed/refractory multiple myeloma (RRMM). The optimal treatment schedule in patients with RRMM who have received multiple lines of treatment, including bortezomib and lenalidomide, is 4 mg/day on days 1–21 of a 28-day cycle in combination with weekly low-dose dexamethasone. Improved responses and outcomes relative to traditional therapies continue to be confirmed in recently completed and ongoing trials. Pomalidomide exhibits direct tumoricidal, immunomodulatory, anti-angiogenic and anti-inflammatory activities, which facilitate combination therapy with agents with complementary mechanisms of action, resulting in greater anti-myeloma effects than single-agent therapy or previous combination therapies. For example, in combination with proteasome inhibitors and traditional chemotherapeutic agents in doublet or triplet regimens, pomalidomide provides high rates of durable response, and represents an important new treatment option for patients with RRMM requiring effective new therapies. Additionally, pomalidomide maintains its efficacy and tolerability profile in difficult-to-treat patients, including the elderly, patients with poor cytogenetics and those with renal impairment. This review summarises the clinical development of pomalidomide and discusses this effective agent for the treatment of patients with RRMM in the context of current myeloma treatment options, as well as potential future directions to further improve patient outcomes

Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis

Immunoglobulin light-chain (AL) amyloidosis is a rare, incurable plasma cell disorder. Its therapy has benefited immensely from the expanding drug armamentarium available for multiple myeloma. Pomalidomide in combination with weekly dexamethasone (Pom/dex) is active among patients with relapsed myeloma. In the present study, we explored the Pom/dex combination in patients with previously treated AL. Patients were eligible for this prospective phase 2 trial if they had had at least one prior regimen and if they had reasonably preserved organ function. Patients were treated with oral Pom/dex. Thirty-three patients were enrolled. The median age was 66 years. Median time from diagnosis to on-study was 37 months. Eighty-two percent had cardiac involvement. The confirmed hematologic response rate was 48%, with a median time to response of 1.9 months. Organ improvement was documented in 5 patients. The median overall and progression-free survival rates were 28 and 14 months, respectively; the 1-year overall and progression-free survival rates were 76% and 59%, respectively. There was a discordance between the hematologic response and the N-terminal probrain natriuretic peptide response. The most common grade 3-5 adverse events, regardless of attribution, were neutropenia and fatigue. We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896. (Blood. 2012;119(23): 5397-5404

Prosodic structure and suprasegmental features:Short-vowel stød in Danish

This paper presents a phonological analysis of a glottalization phenomenon in dialects of Danish known as ‘short-vowel stød’. It is argued that both short-vowel stød and common Danish stød involve the attachment of a laryngeal feature to a prosodic node—specifically the mora. In the case of short-vowel stød that mora lacks segmental content, as it is projected top-down due to local prosodic requirements, not bottom-up by segmental material. I show that this device provides an account of the distribution of short-vowel stød as arising from the interplay of constraints on metrical structure (both lexically stored and computed by the grammar) and the requirement for morae to be featurally licensed. The analysis provides further evidence for the analysis of ‘tonal accents’ and related phenomena in terms of metrical structure rather than lexical tone or laryngeal features, and contributes to our understanding of the relationship between segmental and suprasegmental phonology in Germanic languages

Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence

Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells’ oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells’ hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress

Violent Behavior of Female Students in Middle Schools

This study was conducted to determine if middle school female students were exhibiting violent behavior in a large mid-south urban school district. The subjects were all middle school female students within 30 middle schools in a large mid-south urban school district from 2012-2013 until 2016-2017. Information about middle school female students’ behavior was taken from each school’s website as reported annually by district principals to the large mid-south urban school district. The information about middle school female students’ behavior was used to determine if there was an increase in suspensions per the number of discipline referrals for violent behavior which the female students received and if there were any statistically significant relationships between which middle school female students received the suspensions as gender, ethnicity, location, and the size of the schools which the students attended. The suspensions for middle school female students were examined to determine if there was an increase from the first school year to the last school year for each of the middle schools. Each school year was then compared to the next school year to determine if there was a yearly increase and five-year increase of suspensions. The male middle school data was obtained so that it could be compared with the female middle school data to ascertain if female middle school students were receiving the same amount of discipline referrals for the same reasons as the male middle school students. The results were that female middle school students were not suspended based on their gender for violent behavior

MATHEMATICAL BELIEFS AND PROBLEM SOLVING (SYSTEMS, ANXIETY, MOTIVATION, GIFTED)

The purpose of this study was to investigate the role of students\u27 mathematical beliefs in problem solving. The subjects were four junior high school students participating in Purdue University\u27s STAR program, a two-week intensive summer program for the mathematically and verbally talented. These subjects were enrolled in a Beginning Math Problem Solving with Computers class. The four subjects were individually interviewed throughout the program. In the interviews, the students were questioned about their classroom experiences in mathematics and were encouraged to discuss their beliefs about mathematics. However, most of the interview time was spent with the students using the think-aloud technique to solve problems. The interview data were analyzed qualitatively. At the time that this study was designed and implemented, the focus was on the role of mathematical beliefs in problem solving. Five general categories of mathematical beliefs were distinguished based on analysis of the interview data. These categories were: beliefs about one\u27s ability to do mathematics, beliefs about mathematics as a discipline, beliefs about where mathematical knowledge comes from, beliefs about solving mathematics problems, and beliefs about how mathematics should be taught and learned. Each type of belief was found to influence problem solving behavior. After preliminary analysis of the interview data it became apparent that other factors in addition to beliefs would have to be considered when explaining why these students did what they did when they solved problems. Mathematical problem solving, for these students at least, was conceptualized as being part of a larger framework. Components of this framework include the individual\u27s prior experiences in mathematics, his mathematical knowledge, and his mathematical beliefs, needs, and motivations. Mathematics myths (societal beliefs) are also part of the framework, since they influence the individual\u27s view of mathematics