MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant
GABAA receptors with comparable high affinity (0.21–0.40 nM).
However, MRK-409 has greater agonist efficacy at the α3 compared with ...α1 subtypes
(respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This
compound readily penetrates the brain in rats and occupies the benzodiazepine site of
GABAA receptors, measured using an in vivo 3Hflumazenil binding assay,
with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50
of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409
produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of
anxiety with minimum effective doses corresponding to occupancies, depending on the particular
model, ranging from ∼35% to 65% yet there were minimal overt signs of
sedation at occupancies greater than 90%. In humans, however, safety and tolerability
studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a
maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a
Cmax
plasma concentration of 28 ng/mL, which, based on
the rodent plasma EC50 for occupancy of 115 ng/mL, suggested that sedation
in humans occurs at low levels of occupancy. This was confirmed in human positron emission
tomography studies, in which 11Cflumazenil uptake following a single dose of
1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of
GABAA receptor benzodiazepine binding sites by MRK-409 was below the limits of
detection (i.e. <10%). Taken together, these data show that MRK-409 causes
sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably
less than those predicted from rodent models to be required for anxiolytic efficacy
(∼35–65%). Thus, the preclinical non-sedating anxiolytic profile of
MRK-409 did not translate into humans and further development of this compound was halted.
Microbial mat communities possess extensive taxonomic and functional diversity, which drive high metabolic rates and rapid cycling of major elements. Modern microbial mats occurring in hypersaline ...environments are considered as analogs to extinct geobiological formations dating back to ∼ 3.5 Gyr ago. Despite efforts to understand the diversity and metabolic potential of hypersaline microbial mats in Shark Bay, Western Australia, there has yet to be molecular analyses at the transcriptional level in these microbial communities. In this study, we generated metatranscriptomes for the first time from actively growing mats comparing the type of mat, as well as the influence of diel and seasonal cycles. We observed that the overall gene transcription is strongly influenced by microbial community structure and seasonality. The most transcribed genes were associated with tackling the low nutrient conditions by the uptake of fatty acids, phosphorus, iron, and nickel from the environment as well as with protective mechanisms against elevated salinity conditions and to prevent build-up of ammonium produced by nitrate reducing microorganisms. A range of pathways involved in carbon, nitrogen, and sulfur cycles were identified in mat metatranscriptomes, with anoxygenic photosynthesis and chemoautotrophy using the Arnon-Buchanan cycle inferred as major pathways involved in the carbon cycle. Furthermore, enrichment of active anaerobic pathways (e.g., sulfate reduction, methanogenesis, Wood-Ljungdahl) in smooth mats corroborates previous metagenomic studies and further advocates the potential of these communities as modern analogs of ancient microbialites.
Constellation Observing System for Meteorology, Ionosphere and Climate, Ionosonde, and Global Ultraviolet Imager data have been used to investigate the solar cycle changes in the winter anomaly (the ...winter anomaly is defined as the enhancement of the F2 peak electron density in the winter hemisphere over that in the summer hemisphere) in the last solar cycle. There is no winter anomaly in solar minimum, and an enhancement of about 50% in winter over summer ones on the same day of the year at solar maximum. This solar cycle variation in the winter anomaly is primarily due to greater winter to summer differences of O/N2 in solar maximum than in solar minimum, with a secondary contribution from the effects of temperature on the recombination coefficient between O+ and the molecular neutral gas. The greater winter increases in electron density in the Northern Hemisphere than in the Southern Hemisphere appear to be related to the greater annual variation of O/N2 in the north than in the south.
Key Points
No winter anomaly during solar minimum, but there is one at solar maximum
Solar cycle variation due to greater winter to summer changes of O/N2 in solar maximum that in solar minimum
South and north different
•Burn center volume does not affect mortality in Germany.•Patients treated in large volume burn centers received more surgeries.•Patients treated in large volume burn centers showed an increased ...length of hospital stay.
Hospital volume has been identified as an independent outcome parameter for a number of medical fields and surgical procedures, and there is a tendency to increase required patient numbers for center verification. However, the existing literature does not support a clear correlation between patient load and clinical outcome in adult burn care and recent data from Germany does not exist. We therefore evaluated the effect of patient volume in German burn centers on clinical outcome. Patient data was extracted from the German Burn Registry from 2015 to 2018. For better inter-center comparability, solely burn patients with a TBSA ≥ 10% were included. Mortality, number of surgeries and length of stay (LOS) were evaluated with respect to burn center patient volume. Burn center volume was divided into two and three groups. A total of 2718 patients with a TBSA ≥ 10% were admitted to the participating 17 burn centers. Independent from the division of patient data into either 2 or 3 groups, the TBSA and ABSI score-related severity of burn injuries were comparable between groups. There was no significant difference in mortality due to center size. Nevertheless, patients treated in large volume burn centers showed a significantly increased LOS (+4.5 days, 1.9–7.2 CI, p = 0.001) and required significantly more surgeries (+0.5 surgeries 0.2–0.8 CI, p = 0.002) when compared to the small volume centers. A similar phenomenon regarding mortality and LOS (p 0.001) was observed after dividing the centers into two groups. Interestingly a division into three groups showed significant differences with the best outcome for patients in medium-volume centers. Nevertheless, mortality did not differ significantly. Therefore, our data demonstrates that in contrast to many other medical fields, outcome and mortality are not automatically improved in burn care by simply increasing the patient load, at least in centers treating 20–100 BICU patients/year.
Green infrastructure strategies are often cited as best practice for urban water management; however, limited research has been undertaken to compare intervention effectiveness during moderate to ...extreme intensity rainfall events which are typically responsible for surface water flooding. This research responds to this through applying a cellular automata-based rapid scenario screening framework to predict the flood management performance of green infrastructure strategies across an urban catchment in Melbourne City Centre (Australia). Key findings indicate an intensive application of green infrastructure could substantially reduce flood depth and velocity in the catchment but that residual risk remains, particularly during extreme flood events. The best performing intervention strategy in the study area was found to be catchment-wide decentralised rainwater capture. The research also evidences the utility of rapid scenario screening tools to complement existing flood modelling approaches through screening management strategies, exploring scenarios and engaging a wide range of multi-disciplinary stakeholders.
Abstract
We present James Webb Space Telescope (JWST) and Hubble Space Telescope (HST) observations of the afterglow of GRB 221009A, the brightest gamma-ray burst (GRB) ever observed. This includes ...the first mid-IR spectra of any GRB, obtained with JWST/Near Infrared Spectrograph (0.6–5.5 micron) and Mid-Infrared Instrument (5–12 micron), 12 days after the burst. Assuming that the intrinsic spectral slope is a single power law, with
F
ν
∝
ν
−
β
, we obtain
β
≈ 0.35, modified by substantial dust extinction with
A
V
= 4.9. This suggests extinction above the notional Galactic value, possibly due to patchy extinction within the Milky Way or dust in the GRB host galaxy. It further implies that the X-ray and optical/IR regimes are not on the same segment of the synchrotron spectrum of the afterglow. If the cooling break lies between the X-ray and optical/IR, then the temporal decay rates would only match a post-jet-break model, with electron index
p
< 2, and with the jet expanding into a uniform ISM medium. The shape of the JWST spectrum is near-identical in the optical/near-IR to X-SHOOTER spectroscopy obtained at 0.5 days and to later time observations with HST. The lack of spectral evolution suggests that any accompanying supernova (SN) is either substantially fainter or bluer than SN 1998bw, the proto-type GRB-SN. Our HST observations also reveal a disk-like host galaxy, viewed close to edge-on, that further complicates the isolation of any SN component. The host galaxy appears rather typical among long-GRB hosts and suggests that the extreme properties of GRB 221009A are not directly tied to its galaxy-scale environment.
Iron overload, primarily related to RBC transfusions, is a relatively common complication in hematopoietic cell transplant (HCT) recipients. Iron overload increases the risk of infections, ...veno-occlusive disease and hepatic dysfunction post transplant. Elevated pretransplant ferritin levels have been reported to increase the risk of nonrelapse mortality following HCT and might influence the risk of acute and chronic GVHD. Serum ferritin is sensitive but not specific for iron overload and is a poor predictor of body iron burden. Estimation of hepatic iron content with a liver biopsy or magnetic resonance imaging should be considered prior to initiating therapy for post transplant iron overload. A subgroup of transplant survivors with mild iron overload and no end-organ damage may not need therapy. Phlebotomy is the treatment of choice with iron-chelation therapy reserved for patients not eligible for phlebotomy. Natural history, evolution and treatment of iron overload in transplant survivors have not been adequately investigated and more studies are needed to determine its impact on short-term and long-term morbidity and mortality.
The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who ...participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.
Summary
Background
Insulin dysregulation, obesity, and exposure to high‐nonstructural carbohydrate (NSC) forage are risk factors for equine metabolic syndrome‐associated laminitis (EMSAL); high ...systemic insulin concentrations in EMSAL are proposed to induce cellular dysregulation in the digital lamellae through activation of the insulin‐like growth factor‐1 receptor.
Objectives
To use a dietary challenge model (DCM) and a euglycaemic–hyperinsulinaemic clamp (EHC) model to assess lamellar growth factor‐related signalling.
Study design
Lamellar phospho (P)‐protein concentrations of signalling proteins important in growth factor‐related signalling were assessed in 2 models: 1) lean and obese ponies on a low‐ or high‐NSC diet; and 2) EHC model using Standardbred horses.
Methods
Ponies stratified for body condition (lean LN, n = 11 and obese OB, n = 11) were exposed to a low‐NSC diet (LO, n = 5 per group for LN LO and OB LO) or a high NSC diet (HI, n = 6 per group for LN HI and OB HI groups) for 7 days. For the EHC model, horses were administered insulin (constant rate infusion 6 mIU/kg bwt/min combined with 50% dextrose, EHC group, n = 8) or saline (0.57 mL/kg bwt/h, CON group, n = 8) for 48 h. Immunoblotting was employed to assess concentrations of activated/phosphorylated and total protein for members of the PI3K/Akt/mTORC1 and Ras/ERK pathways in lamellar samples from both models.
Results
In the DCM, lamellar P‐(Ser 240/244) RPS6 was increased in OB HI ponies (vs. OB LO, P<0.05); positive correlations existed (P<0.05; r>0.5) between Day 7 basal serum insulin concentrations and lamellar concentrations of P‐p70S6K and P‐(Ser 240/244) RPS6. In the EHC model, lamellar concentrations of P‐Akt, P‐p70S6K, P‐ERK 1/2, P‐p90RSK, and both P‐(Ser 235/236) and P‐(Ser 240/244) RPS6 were increased in the EHC group (vs. CON, P<0.05).
Main limitations
The primary limitations of this study are the small number of animals per group in the DCM study, and the fact that many animals did not develop laminitis as that was not the endpoint of either study.
Conclusions
These results support further investigation of mTORC1/RPS6 signalling as a potential therapeutic target(s) in EMSAL.
The Summary is available in Chinese – see Supporting Information.
A comprehensive set of optical and near-infrared (NIR) photometry and spectroscopy is presented for the faint and fast 2008ha-like supernova (SN) 2010ae. Contingent on the adopted value of host ...extinction, SN 2010ae reached a peak brightness of −13.8 > MV > −15.3 mag, while modeling of the UVOIR light curve suggests it produced 0.003–0.007 M⊙ of 56Ni, ejected 0.30−0.60 M⊙ of material, and had an explosion energy of 0.04–0.30 × 1051 erg. The values of these explosion parameters are similar to the peculiar SN 2008ha –for which we also present previously unpublished early phase optical and NIR light curves – and places these two transients at the faint end of the 2002cx-like SN population. Detailed inspection of the post-maximum NIR spectroscopic sequence indicates the presence of a multitude of spectral features, which are identified through SYNAPPS modeling to be mainly attributed to Co ii. Comparison with a collection of published and unpublished NIR spectra of other 2002cx-like SNe, reveals that a Co ii footprint is ubiquitous to this subclass of transients, providing a link to Type Ia SNe. A visual-wavelength spectrum of SN 2010ae obtained at +252 days past maximum shows a striking resemblance to a similar epoch spectrum of SN 2002cx. However, subtle differences in the strength and ratio of calcium emission features, as well as diversity among similar epoch spectra of other 2002cx-like SNe indicates a range of physical conditions of the ejecta, highlighting the heterogeneous nature of thispeculiar class of transients.
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