The Weak Field Limit of the Magnetorotational Instability

We investigate the behavior of the magneto-rotational instability in the limit of extremely weak magnetic field, i.e., as the ratio of ion cyclotron frequency to orbital frequency (X) becomes small. Considered only in terms of cold two-fluid theory, instability persists to arbitrarily small values of X, and the maximum growth rate is of order the orbital frequency except for the range m_e/m_i < |X| < 1, where it can be rather smaller. In this range, field aligned with rotation (X > 0) produces slower growth than anti-aligned field (X < 0). The maximum growth rate is generally achieved at smaller and smaller wavelengths as |X| diminishes. When |X| < m_e/m_i, new unstable "electromagnetic-rotational" modes appear that do not depend on the equilibrium magnetic field. Because the most rapidly-growing modes have extremely short wavelengths when |X| is small, they are often subject to viscous or resistive damping, which can result in suppressing all but the longest wavelengths, for which growth is much slower. We find that this sort of damping is likely to curtail severely the frequently-invoked mechanism for cosmological magnetic field growth in which a magnetic field seeded by the Biermann battery is then amplified by the magneto-rotational instability. On the other hand, the small |X| case may introduce interesting effects in weakly-ionized disks in which dust grains carry most of the electric charge.Comment: 30 pages, including 4 figures; revised version resubmitted to Ap

Effects of Line-tying on Magnetohydrodynamic Instabilities and Current Sheet Formation

An overview of some recent progress on magnetohydrodynamic stability and current sheet formation in a line-tied system is given. Key results on the linear stability of the ideal internal kink mode and resistive tearing mode are summarized. For nonlinear problems, a counterexample to the recent demonstration of current sheet formation by Low \emph{et al}. [B. C. Low and \AA. M. Janse, Astrophys. J. \textbf{696}, 821 (2009)] is presented, and the governing equations for quasi-static evolution of a boundary driven, line-tied magnetic field are derived. Some open questions and possible strategies to resolve them are discussed.Comment: To appear in Phys. Plasma

Flux and Seasonality of Dissolved Organic Matter From the Northern Dvina (Severnaya Dvina) River, Russia

Pan‐Arctic riverine dissolved organic carbon (DOC) fluxes represent a major transfer of carbon from land‐to‐ocean, and past scaling estimates have been predominantly derived from the six major Arctic rivers. However, smaller watersheds are constrained to northern high‐latitude regions and, particularly with respect to the Eurasian Arctic, have received little attention. In this study, we evaluated the concentration of DOC and composition of dissolved organic matter (DOM) via optical parameters, biomarkers (lignin phenols), and ultrahigh resolution mass spectrometry in the Northern Dvina River (a midsized high‐latitude constrained river). Elevated DOC, lignin concentrations, and aromatic DOM indicators were observed throughout the year in comparison to the major Arctic rivers with seasonality exhibiting a clear spring freshet and also some years a secondary pulse in the autumn concurrent with the onset of freezing. Chromophoric DOM absorbance at a350 was strongly correlated to DOC and lignin across the hydrograph; however, the relationships did not fit previous models derived from the six major Arctic rivers. Updated DOC and lignin fluxes were derived for the pan‐Arctic watershed by scaling from the Northern Dvina resulting in increased DOC and lignin fluxes (50 Tg yr−1 and 216 Gg yr−1, respectively) compared to past estimates. This leads to a reduction in the residence time for terrestrial carbon in the Arctic Ocean (0.5 to 1.8 years). These findings suggest that constrained northern high‐latitude rivers are underrepresented in models of fluxes based from the six largest Arctic rivers with important ramifications for the export and fate of terrestrial carbon in the Arctic Ocean

Presenteeism and productivity: The role of biomarkers and hormones

Purpose. This study aimed to assess whether self-reported productivity despite presenteeism may be affected by biomarkers and hormones and how these physiological indicators can interact with each other to explain the presenteeism dimensions. Methods. This pilot study included 180 healthy participants with a mean age of 41.22 years (SD = 13.58), 76.11% of whom were female. The dependent variable included a self-reported measure of productivity loss due to presenteeism: the Stanford Presenteeism Scale 6. This study also includes physiological indicators such as biomarkers (C-reactive protein (CRP) and blood glucose) and hormones (cortisol and TSH thyroid hormone). Results. Multiple linear regression analyses revealed that CRP moderated the relationship between cortisol levels and productivity despite presenteeism. Moreover, the increase of TSH moderated the relationship between cortisol, glycemia, and employees’ capacity to complete work tasks while sick. Conclusions. The results highlight TSH’s moderating role in decreasing employees’ capacity to fulfill tasks when these individuals have high levels of glycemia and cortisol in their blood. These findings have practical and theoretical implications based on a fuller understanding of how biomarkers and hormones explain productivity despite presenteeism.info:eu-repo/semantics/publishedVersio

Whole Genome Analysis of Epidemiologically Closely Related Staphylococcus aureus Isolates

The change of the bacteria from colonizers to pathogens is accompanied by a drastic change in expression profiles. These changes may be due to environmental signals or to mutational changes. We therefore compared the whole genome sequences of four sets of S. aureus isolates. Three sets were from the same patients. The isolates of each pair (S1800/S1805, S2396/S2395, S2398/S2397, an isolate from colonization and an isolate from infection, respectively) were obtained within <30 days of each other and the isolate from infection caused skin infections. The isolates were then compared for differences in gene content and SNPs. In addition, a set of isolates from a colonized pig and a farmer from the same farm at the same time (S0462 and S0460) were analyzed. The isolates pair S1800/S1805 showed a difference in a prophage, but these are easily lost or acquired. However, S1805 contained an integrative conjugative element not present in S1800. In addition, 92 SNPs were present in a variety of genes and the isolates S1800 and S1805 were not considered a pair. Between S2395/S2396 two SNPs were present: one was in an intergenic region and one was a synonymous mutation in a putative membrane protein. Between S2397/S2398 only one synonymous mutation in a putative lipoprotein was found. The two farm isolates were very similar and showed 12 SNPs in genes that belong to a number of different functional categories. However, we cannot pinpoint any gene that explains the change from carrier status to infection. The data indicate that differences between the isolate from infection and the colonizing isolate for S2395/S2396 and S2397/S2398 exist as well as between isolates from different hosts, but S1800/S1805 are not clonal

Fast Reconnection in a Two-Stage Process

Magnetic reconnection plays an essential role in the generation and evolution of astrophysical magnetic fields. The best tested and most robust reconnection theory is that of Parker and Sweet. According to this theory, the reconnection rate scales with magnetic diffusivity lambda as lambda^0.5. In the interstellar medium, the Parker-Sweet reconnection rate is far too slow to be of interest. Thus, a mechanism for fast reconnection seems to be required. We have studied the magnetic merging of two oppositely directed flux systems in weakly ionized, but highly conducting, compressible gas. In such systems, ambipolar diffusion steepens the magnetic profile, leading to a thin current sheet. If the ion pressure is small enough, and the recombination of ions is fast enough, the resulting rate of magnetic merging is fast, and independent of lambda. Slow recombination or sufficiently large ion pressure leads to slower merging which scales with lambda as lambda^0.5. We derive a criterion for distinguishing these two regimes, and discuss applications to the weakly ionized ISM and to protoplanetary accretion disks.Comment: 21 pages, 13 figures, submitted to Ap

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

A Gene Optimization Strategy that Enhances Production of Fully Functional P-Glycoprotein in Pichia pastoris

Structural and biochemical studies of mammalian membrane proteins remain hampered by inefficient production of pure protein. We explored codon optimization based on highly expressed Pichia pastoris genes to enhance co-translational folding and production of P-glycoprotein (Pgp), an ATP-dependent drug efflux pump involved in multidrug resistance of cancers.Codon-optimized "Opti-Pgp" and wild-type Pgp, identical in primary protein sequence, were rigorously analyzed for differences in function or solution structure. Yeast expression levels and yield of purified protein from P. pastoris (∼130 mg per kg cells) were about three-fold higher for Opti-Pgp than for wild-type protein. Opti-Pgp conveyed full in vivo drug resistance against multiple anticancer and fungicidal drugs. ATP hydrolysis by purified Opti-Pgp was strongly stimulated ∼15-fold by verapamil and inhibited by cyclosporine A with binding constants of 4.2±2.2 µM and 1.1±0.26 µM, indistinguishable from wild-type Pgp. Maximum turnover number was 2.1±0.28 µmol/min/mg and was enhanced by 1.2-fold over wild-type Pgp, likely due to higher purity of Opti-Pgp preparations. Analysis of purified wild-type and Opti-Pgp by CD, DSC and limited proteolysis suggested similar secondary and ternary structure. Addition of lipid increased the thermal stability from T(m) ∼40 °C to 49 °C, and the total unfolding enthalpy. The increase in folded state may account for the increase in drug-stimulated ATPase activity seen in presence of lipids.The significantly higher yields of protein in the native folded state, higher purity and improved function establish the value of our gene optimization approach, and provide a basis to improve production of other membrane proteins

Clean Low-Biomass Procedures and Their Application to Ancient Ice Core Microorganisms

Microorganisms in glacier ice provide tens to hundreds of thousands of years archive for a changing climate and microbial responses to it. Analyzing ancient ice is impeded by technical issues, including limited ice, low biomass, and contamination. While many approaches have been evaluated and advanced to remove contaminants on ice core surfaces, few studies leverage modern sequencing to establish in silico decontamination protocols for glacier ice. Here we sought to apply such “clean” sampling techniques with in silico decontamination approaches used elsewhere to investigate microorganisms archived in ice at ~41 (D41, ~20,000 years) and ~49 m (D49, ~30,000 years) depth in an ice core (GS3) from the summit of the Guliya ice cap in the northwestern Tibetan Plateau. Four “background” controls were established – a co-processed sterile water artificial ice core, two air samples collected from the ice processing laboratories, and a blank, sterile water sample – and used to assess contaminant microbial diversity and abundances. Amplicon sequencing revealed 29 microbial genera in these controls, but quantitative PCR showed that the controls contained about 50–100-times less 16S DNA than the glacial ice samples. As in prior work, we interpreted these low-abundance taxa in controls as “contaminants” and proportionally removed them in silico from the GS3 ice amplicon data. Because of the low biomass in the controls, we also compared prokaryotic 16S DNA amplicons from pre-amplified (by re-conditioning PCR) and standard amplicon sequencing, and found the resulting microbial profiles to be repeatable and nearly identical. Ecologically, the contaminant-controlled ice microbial profiles revealed significantly different microorganisms across the two depths in the GS3 ice core, which is consistent with changing climate, as reported for other glacier ice samples. Many GS3 ice core genera, including Methylobacterium, Sphingomonas, Flavobacterium, Janthinobacterium, Polaromonas, and Rhodobacter, were also abundant in previously studied ice cores, which suggests wide distribution across glacier environments. Together these findings help further establish “clean” procedures for studying low-biomass ice microbial communities and contribute to a baseline understanding of microorganisms archived in glacier ice