Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no ...nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
In response to different stimuli many transcription factors (TFs) display different activation dynamics that trigger the expression of specific sets of target genes, suggesting that ...promoters have a way to decode dynamics. Here, we use optogenetics to directly manipulate the nuclear localization of a synthetic TF in mammalian cells without affecting other processes. We generate pulsatile or sustained TF dynamics and employ live cell microscopy and mathematical modelling to analyse the behaviour of a library of reporter constructs. We find decoding of TF dynamics occurs only when the coupling between TF binding and transcription pre-initiation complex formation is inefficient and that the ability of a promoter to decode TF dynamics gets amplified by inefficient translation initiation. Using the knowledge acquired, we build a synthetic circuit that allows obtaining two gene expression programs depending solely on TF dynamics. Finally, we show that some of the promoter features identified in our study can be used to distinguish natural promoters that have previously been experimentally characterized as responsive to either sustained or pulsatile p53 and NF-κB signals. These results help elucidate how gene expression is regulated in mammalian cells and open up the possibility to build complex synthetic circuits steered by TF dynamics.
Graphical Abstract
Graphical Abstract
Mammalian promoters decode transcription factor dynamics. DifferentTF dynamics are distinguished by promoters characterized by inefficientcoupling between TF binding and PIC formation and stabilization.
Extended gas clouds have been previously detected surrounding the brightest known close-in transiting hot Jupiter exoplanets, HD 209458 b and HD 189733 b; we observed the distant but more extreme ...close-in hot Jupiter system, WASP-12, with Hubble Space Telescope (HST). Near-UV (NUV) transits up to three times deeper than the optical transit of WASP-12 b reveal extensive diffuse gas, extending well beyond the Roche lobe. Our spectra reveal significantly enhanced absorption (greater than 3sigma below the median) at ~200 individual wavelengths on each of two HST visits; 65 of these wavelengths are consistent between the two visits, using a strict criterion for velocity matching that excludes matches with velocity shifts exceeding ~20 km s super(-1). Our Visit 2 NUV light curves show evidence for a stellar flare. We show that some of the possible transit detections in resonance lines of rare elements may be due instead to non-resonant transitions in common species. We present optical observations and update the transit ephemeris.
Groundwater stored in weathered basement aquifers (WBAs) is a strategic water resource. In this study, we investigate the productivity of WBAs and sustainability of groundwater ions using a novel ...process‐based stochastic modeling approach, which is applied to simulate ions in the Precambrian basement aquifer in Ghana. The statistical distribution of the generated synthetic yield data was found in very good agreement with observed yield data from the same Ghanaian aquifer. Further analysis provided robust insights regarding how different hydrogeological parameters of the WBA, and their interplay, control aquifer productivity and sustainability. Results indicate that 97% of the simulated ions could sustain the yield of a hand pump (6 L/min), approximately 30% could also sustain yields >60 L/min, while only 1% could sustain yields greater than 300 L/min. The model indicates that an aquifer transmissivity value of approximately 1.4 m2/day is required for a successful hand‐pumped borehole, while a higher yielding source (60 L/min) requires a transmissivity value of at least 9.5 m2/day. A global sensitivity analysis of 13 model input parameters shows that the thickness of the regolith and the maximum hydraulic conductivity developed at the base of the saprolite are the critical factors controlling success and sustainability for low yielding hand‐pumped boreholes. For higher yielding supplies, the net recharge, the depth to groundwater, and the aquifer extent become increasingly significant. Results from this work have important implications for the potential for increased development of groundwater from WBAs in tropical Africa.
Key Points
Realistic simulations of groundwater ion in weathered basement aquifers
Identified critical parameters for different classes of productivity
Transmissivity of 1.4 m2/day found as threshold for hand pumps
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We report on the discovery of WASP-12b, a new transiting extrasolar planet with R pl = 1.79+0.09 -0.09 RJ and M pl = 1.41+0.10 -0.10 M J. The planet and host star properties were derived from a Monte ...Carlo Markov Chain analysis of the transit photometry and radial velocity data. Furthermore, by comparing the stellar spectrum with theoretical spectra and stellar evolution models, we determined that the host star is a supersolar metallicity (M/H = 0.3+0.05 -0.15), late-F (T eff = 6300+200 -100 K) star which is evolving off the zero-age main sequence. The planet has an equilibrium temperature of T eq = 2516 K caused by its very short period orbit (P = 1.09 days) around the hot, twelfth magnitude host star. WASP-12b has the largest radius of any transiting planet yet detected. It is also the most heavily irradiated and the shortest period planet in the literature.
To search for a novel thermostable esterase for optimized industrial applications, esterase from a thermophilic eubacterium species,
MB4, was purified and characterized in this work. Sequence ...analysis of
esterase with other homologous esterases of the same family revealed an apparent tail at the C-terminal that is not conserved across the esterase family. Hence, it was hypothesized that the tail is unlikely to have an essential structural or catalytic role. However, there is no documented report of any role for this tail region. We probed the role of the C-terminal domain on the catalytic activity and substrate preference of
esterase EstA3 with a view to see how it could be engineered for enhanced properties. To achieve this, we cloned, expressed, and purified the wild-type and the truncated versions of the enzyme. In addition, a naturally occurring member of the family (from
) that lacks the C-terminal tail was also made. In vitro characterization of the purified enzymes showed that the C-terminal domain contributes significantly to the catalytic activity and distinct substrate preference of
esterase EstA3. All three recombinant enzymes showed the highest preference for paranitrophenyl butyrate (pNPC4), which suggests they are true esterases, not lipases. Kinetic data revealed that truncation had a slight effect on the substrate-binding affinity. Thus, the drop in preference towards long-chain substrates might not be a result of substrate binding affinity alone. The findings from this work could form the basis for future protein engineering allowing the modification of esterase catalytic properties through domain swapping or by attaching a modular protein domain.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Protein tyrosine phosphatases (PTPs) of the polymerase and histidinol phosphatase (PHP) superfamily with characteristic phosphatase activity dependent on divalent metal ions are found in many ...Gram-positive bacteria. Although members of this family are co-purified with metal ions, they still require the exogenous supply of metal ions for full activation. However, the specific roles these metal ions play during catalysis are yet to be well understood. Here, we report the metal ion requirement for phosphatase activities of
Cap8C and
Wzb. AlphaFold-predicted structures of the two PTPs suggest that they are members of the PHP family. Like other PHP phosphatases, the two enzymes have a catalytic preference for Mn
, Co
and Ni
ions. Cap8C and Wzb show an unusual thermophilic property with optimum activities over 75 °C. Consistent with this model, the activity-temperature profiles of the two enzymes are dependent on the divalent metal ion activating the enzyme.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We present the discovery of four new transiting hot Jupiters, detected mainly from SuperWASP-North and SOPHIE observations. These new planets, WASP-52b, WASP-58b, WASP-59b, and WASP-60b, have orbital ...periods ranging from 1.7 to 7.9 days, masses between 0.46 and 0.94 MJup, and radii between 0.73 and 1.49 RJup. Their G1 to K5 dwarf host stars have V magnitudes in the range 11.7−13.0. The depths of the transits are between 0.6 and 2.7%, depending on the target. With their large radii, WASP-52b and WASP-58b are new cases of low-density, inflated planets, whereas WASP-59b is likely to have a large, dense core. WASP-60 shows shallow transits. In the case of WASP-52 we also detected the Rossiter-McLaughlin anomaly via time-resolved spectroscopy of a transit. We measured the sky-projected obliquity λ = 24° +17-9, indicating that WASP-52b orbits in the same direction as its host star isrotating and that this prograde orbit is slightly misaligned with the stellar equator. These four new planetary systems increase our statistics on hot Jupiters and provide new targets for follow-up studies.
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FMFMET, NUK, UL, UM, UPUK
The 'hot Jupiters' that abound in lists of known extrasolar planets are thought to have formed far from their host stars, but migrate inwards through interactions with the proto-planetary disk from ...which they were born, or by an alternative mechanism such as planet-planet scattering. The hot Jupiters closest to their parent stars, at orbital distances of only ∼0.02 astronomical units, have strong tidal interactions, and systems such as OGLE-TR-56 have been suggested as tests of tidal dissipation theory. Here we report the discovery of planet WASP-18b with an orbital period of 0.94 days and a mass of ten Jupiter masses (10 MJup), resulting in a tidal interaction an order of magnitude stronger than that of planet OGLE-TR-56b. Under the assumption that the tidal-dissipation parameter Q of the host star is of the order of 106, as measured for Solar System bodies and binary stars and as often applied to extrasolar planets, WASP-18b will be spiralling inwards on a timescale less than a thousandth that of the lifetime of its host star. Therefore either WASP-18 is in a rare, exceptionally short-lived state, or the tidal dissipation in this system (and possibly other hot-Jupiter systems) must be much weaker than in the Solar System.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An adult alpaca (Vicugna pacos) with a history of colic and anorexia was euthanized because of failure to respond to treatment. Macroscopically, pale-tan, multifocal to coalescing, firm nodules and ...plaques markedly expanded the omentum, mesentery and the parietal and visceral peritoneum of multiple abdominal organs, especially the right oviduct and associated mesosalpinx. Abundant dark-red watery digesta were present in the duodenum and jejunum. Histological evaluation of the right oviduct, abdominal visceral nodules and plaques and mesenteric lymph nodes revealed transmural expansion and replacement by an epithelial malignant neoplasm, comprised of tubules and acini of ciliated columnar cells supported by abundant fibrous connective tissue. Both ovaries were histologically normal. On the basis of the ciliated morphology of the neoplastic cells, the focus on the proximal reproductive tract and the unremarkable ovaries, a reproductive tubal adenocarcinoma with carcinomatosis was diagnosed, with both the endometrium and oviduct considered as the tissues of origin. The prominent ciliated morphology of the neoplastic cells and the classification of human fallopian tube (oviduct) neoplasia lead us to propose oviductal adenocarcinoma with widespread carcinomatosis as the definitive diagnosis. The lamina propria of the small intestine was infiltrated segmentally by lymphocytes, plasma cells and neutrophils, and Clostridium perfringens with beta2 toxin production was identified by polymerase chain reaction in the small intestinal contents. To our knowledge, this is the first report of these two distinct diseases in an alpaca.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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