The Effect of 53 \u3cem\u3eμ\u3c/em\u3em IR Radiation on 18 cm OH Megamaser Emission

OH megamasers (OHMs) emit primarily in the main lines at 1667 and 1665 MHz and differ from their Galactic counterparts due to their immense luminosities, large line widths, and 1667/1665 MHz flux ratios, which are always greater than 1. We find that these maser properties result from strong 53 μm radiative pumping combined with line overlap effects caused by turbulent line widths ~20 km s-1 pumping calculations that do not include line overlap are unreliable. A minimum dust temperature of ~45 K is needed for inversion, and maximum maser efficiency occurs for dust temperatures ~80-140 K. We find that warmer dust can support inversion at lower IR luminosities, in agreement with observations. Our results are in good agreement with a clumpy model of OHMs, with clouds sizes ≲1 pc and OH column densities ~5 × 1016 cm-2, that is able to explain both the diffuse and compact emission observed for OHMs. We suggest that all OH main-line masers may be pumped by far-IR radiation, with the major differences between OHMs and Galactic OH masers caused by differences in line width produced by line overlap. Small Galactic maser line widths tend to produce stronger 1665 MHz emission. The large OHM line widths lead to inverted ground-state transitions having approximately the same excitation temperature, producing 1667/1665 MHz flux ratios greater than 1 and weak satellite line emission. Finally, the small observed ratio of pumping radiation to dense molecular gas, as traced by HCN and HCO+, is a possible reason for the lack of OH megamaser emission in NGC 6240

Modeling SiO Maser Emission from Late-Type Stars

We have performed a thorough study of both radiative and collisional pumping of the SiO masers around late-type stars, carefully considering the combined and separate actions of each type of pump in order to gauge its effectiveness. We find that collisional pumping is severely underestimated when the model calculations use a small number (less than about 18) of rotational levels in each vibrational state. We have developed a procedure that corrects this problem and gives results that are nearly independent of the number of levels utilized in the calculations. We recognize, but do not solve, an important problem that afflicts all escape probability treatments which include maser saturation effects on the level populations. Maser radiation is strongly beamed and the functional form of the beaming angle must be known to properly calculate the maser escape probability. However, the beam pattern for saturated masers in the presence of large velocity gradients has yet to be studied in the literature. Our model is based on observations and theoretical arguments that place the SiO masers in high-density clumps rather than in the smooth stellar wind. Significantly, general conclusions can be reached which are independent of the pumping mechanism. Most importantly, the overall molecular density is restricted to lie between ~109-1010 cm-3, regardless of the type of pumping. In addition, both collisional and radiative pumps result in the production of a maser chain within each vibrational state, as observed. There are some important differences, however, between the pumping mechanisms. All pumps based on stellar radiation become less efficient with distance from the star because of the rapid decline in pump rate. This prevents any radiative pump from being able to produce the observed maser emission over most of the observed maser region. The only feasible radiative pumps require fine tuning of physical conditions and produce inversion only over a narrow range of optical depths that depends sensitively on the size of the velocity gradient and the form of the escape probability expression. In addition, these radiative pumps have difficulty in explaining the simultaneous production of masers in the same rotational transitions of adjacent vibrational states as is observed. We find that collisional pumping produces the strongest maser emission and, in contrast to radiative pumping, generates maser radiation over the entire observed region and does not require fine tuning of the physical parameters for its operation. Furthermore, there is a significant range of overlapping column densities where collisional pumping produces maser emission in the same rotational transitions of adjacent vibrational states, as observed. Collisional pumping thus appears to be the primary pumping mechanism responsible for the SiO maser phenomenon

Redesigned and chemically-modified hammerhead ribozymes with improved activity and serum stability

BACKGROUND: Hammerhead ribozymes are RNA-based molecules which bind and cleave other RNAs specifically. As such they have potential as laboratory reagents, diagnostics and therapeutics. Despite having been extensively studied for 15 years or so, their wide application is hampered by their instability in biological media, and by the poor translation of cleavage studies on short substrates to long RNA molecules. This work describes a systematic study aimed at addressing these two issues. RESULTS: A series of hammerhead ribozyme derivatives, varying in their hybridising arm length and size of helix II, were tested in vitro for cleavage of RNA derived from the carbamoyl phosphate synthetase II gene of Plasmodium falciparum. Against a 550-nt transcript the most efficient (t(1/2 )= 26 seconds) was a miniribozyme with helix II reduced to a single G-C base pair and with twelve nucleotides in each hybridising arm. Miniribozymes of this general design were targeted to three further sites, and they demonstrated exceptional cleavage activity. A series of chemically modified derivatives was prepared and examined for cleavage activity and stability in human serum. One derivative showed a 10(3)-fold increase in serum stability and a doubling in cleavage efficiency compared to the unmodified miniribozyme. A second was almost 10(4)-fold more stable and only 7-fold less active than the unmodified parent. CONCLUSION: Hammerhead ribozyme derivatives in which helix II is reduced to a single G-C base pair cleave long RNA substrates very efficiently in vitro. Using commonly available phosphoramidites and reagents, two patterns of nucleotide substitution in this derivative were identified which conferred both good cleavage activity against long RNA targets and good stability in human serum

Excited-State OH Masers and Supernova Remnants

The collisionally pumped, ground-state 1720 MHz maser line of OH is widely recognized as a tracer for shocked regions and observed in star-forming regions and supernova remnants. Whereas some lines of excited states of OH have been detected and studied in star-forming regions, the subject of excited-state OH in supernova remnants-where high collision rates are to be expected-is only recently being addressed. Modeling of collisional excitation of OH demonstrates that 1720, 4765, and 6049 MHz masers can occur under similar conditions in regions of shocked gas. In particular, the 6049 and 4765 MHz masers become more significant at increased OH column densities where the 1720 MHz masers begin to be quenched. In supernova remnants, the detection of excited-state OH line maser emission could therefore serve as a probe of regions of higher column densities. Using the Very Large Array, we searched for excited-state OH in the 4.7, 7.8, 8.2, and 23.8 GHz lines in four well-studied supernova remnants with strong 1720 MHz maser emission (Sgr A East, W28, W44 and IC 443). No detections were made, at typical detection limits of around 10 mJy beam-1. The search for the 6 GHz lines were done using Effelsberg since the VLA receivers did not cover those frequencies, and are reported on in an accompanying letter (Fish and coworkers). We also cross-correlated the positions of known supernova remnants with the positions of 1612 MHz maser emission obtained from blind surveys. No probable associations were found, perhaps except in the Sgr A East region. The lack of detections of excited-state OH indicates that the OH column densities suffice for 1720 MHz inversion but not for inversion of excited-state transitions, consistent with the expected results for C-type shocks

The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand

Auf das Wasser kommt es an: Konservierte Bindungsgeometrie, enthalpiegetriebene Bindungsweise und nichtunterscheidbare Bindungsaffinitäten für fluorierte und nichtfluorierte Liganden von humaner Carbonsäureanhydrase (siehe Bild) stützen die Theorie, dass das Schlüssel-Schloss-Modell einen wichtigen Bestandteil des Bindungsvorgangs unbeachtet lässt: das Wasser, das die Bindungstasche des Proteins füllt und den Liganden umgibt.Chemistry and Chemical Biolog

The Effect of 53 micron IR Radiation on 18 cm OH Megamaser Emission

OH megamasers (OHMs) emit primarily in the main lines at 1667 and 1665 MHz, and differ from their Galactic counterparts due to their immense luminosities, large linewidths and 1667/1665 MHz flux ratios, which are always greater than one. We find that these maser properties result from strong 53 micron radiative pumping combined with line overlap effects caused by turbulent linewidths of about 20 km/s; pumping calculations that do not include line overlap are unreliable. A minimum dust temperature of about 45 K is needed for inversion, and maximum maser efficiency occurs for dust temperatures in the range 80 - 140 K. We find that warmer dust can support inversion at lower IR luminosities, in agreement with observations. Our results are in good agreement with a clumpy model of OHMs, with clouds sizes about 1 pc and OH column densities about 5e16 cm^2, that is able to explain both the diffuse and compact emission observed for OHMs. We suggest that all OH main line masers may be pumped by far-IR radiation, with the major differences between OHMs and Galactic OH masers caused by differences in linewidth produced by line overlap. Small Galactic maser linewidths tend to produce stronger 1665 MHz emission. The large OHM linewidths lead to inverted ground state transitions having approximately the same excitation temperature, producing 1667/1665 MHz flux ratios greater than one and weak satellite line emission. Finally, the small observed ratio of pumping radiation to dense molecular gas, as traced by HCN and HCO$^+$, is a possible reason for the lack of OH megamaser emission in NGC 6240.Comment: Accepted to ApJ, 26 pages including 1 table and 7 figure

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Broad and strong memory CD4(+)and CD8(+)T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale