With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of ...desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
Darwin's finches are a clade of 19 species of passerine birds native to the Galápagos Islands, whose biogeography, specialized beak morphologies, and dietary choices-ranging from seeds to blood-make ...them a classic example of adaptive radiation. While these iconic birds have been intensely studied, the composition of their gut microbiome and the factors influencing it, including host species, diet, and biogeography, has not yet been explored.
We characterized the microbial community associated with 12 species of Darwin's finches using high-throughput 16S rRNA sequencing of fecal samples from 114 individuals across nine islands, including the unusual blood-feeding vampire finch (Geospiza septentrionalis) from Darwin and Wolf Islands. The phylum-level core gut microbiome for Darwin's finches included the Firmicutes, Gammaproteobacteria, and Actinobacteria, with members of the Bacteroidetes at conspicuously low abundance. The gut microbiome was surprisingly well conserved across the diversity of finch species, with one exception-the vampire finch-which harbored bacteria that were either absent or extremely rare in other finches, including Fusobacterium, Cetobacterium, Ureaplasma, Mucispirillum, Campylobacter, and various members of the Clostridia-bacteria known from the guts of carnivorous birds and reptiles. Complementary stable isotope analysis of feathers revealed exceptionally high δ
N isotope values in the vampire finch, resembling top marine predators. The Galápagos archipelago is also known for extreme wet and dry seasons, and we observed a significant seasonal shift in the gut microbial community of five additional finch species sampled during both seasons.
This study demonstrates the overall conservatism of the finch gut microbiome over short (< 1 Ma) divergence timescales, except in the most extreme case of dietary specialization, and elevates the evolutionary importance of seasonal shifts in driving not only species adaptation, but also gut microbiome composition.
This study aimed to identify risk factors for relapse (psychiatric emergency department visits or hospitalization) and lack of follow-up with outpatient psychiatric care in the 12 months after ending ...services in an urban safety net coordinated specialty care (CSC) program for first episode psychosis (FEP).
The study population (n = 143) were individuals with FEP who had any CSC care between 2014 and 2021. To identify risk factors for relapse and follow up after exit, multivariable logistic regression was performed using data from electronic health records and linked insurance claims data.
Individuals with any emergency department visit or hospitalization 12 months prior to ending CSC (aOR = 4.69, 95 % CI 1.78–12.34) and those who were using cannabis at last CSC contact (aOR = 4.06, 95 % CI 1.56–10.56) had a higher risk of relapse after ending CSC services. Cannabis use at last contact was also associated with lower rates of outpatient psychiatric follow-up (aOR = 0.32, 95 % CI 0.12–0.94), while CSC duration in months had a small positive association with post-CSC psychiatric follow-up. There were no differences in relapse or follow-up by race or ethnicity, primary diagnosis, or medication usage.
Prior relapse during CSC predicted relapse in the 12 months after ending CSC services, but not outpatient follow up. Cannabis use predicted both a higher rate of relapse and a lower rate of follow up after ending services. There were no differences by race or ethnicity in our sample, suggesting that once individuals engaged in FEP care there were no evident disparities in the observed outcomes.
No large group of recently extinct placental mammals remains as evolutionarily cryptic as the approximately 280 genera grouped as 'South American native ungulates'. To Charles Darwin, who first ...collected their remains, they included perhaps the 'strangest animals ever discovered'. Today, much like 180 years ago, it is no clearer whether they had one origin or several, arose before or after the Cretaceous/Palaeogene transition 66.2 million years ago, or are more likely to belong with the elephants and sirenians of superorder Afrotheria than with the euungulates (cattle, horses, and allies) of superorder Laurasiatheria. Morphology-based analyses have proved unconvincing because convergences are pervasive among unrelated ungulate-like placentals. Approaches using ancient DNA have also been unsuccessful, probably because of rapid DNA degradation in semitropical and temperate deposits. Here we apply proteomic analysis to screen bone samples of the Late Quaternary South American native ungulate taxa Toxodon (Notoungulata) and Macrauchenia (Litopterna) for phylogenetically informative protein sequences. For each ungulate, we obtain approximately 90% direct sequence coverage of type I collagen α1- and α2-chains, representing approximately 900 of 1,140 amino-acid residues for each subunit. A phylogeny is estimated from an alignment of these fossil sequences with collagen (I) gene transcripts from available mammalian genomes or mass spectrometrically derived sequence data obtained for this study. The resulting consensus tree agrees well with recent higher-level mammalian phylogenies. Toxodon and Macrauchenia form a monophyletic group whose sister taxon is not Afrotheria or any of its constituent clades as recently claimed, but instead crown Perissodactyla (horses, tapirs, and rhinoceroses). These results are consistent with the origin of at least some South American native ungulates from 'condylarths', a paraphyletic assembly of archaic placentals. With ongoing improvements in instrumentation and analytical procedures, proteomics may produce a revolution in systematics such as that achieved by genomics, but with the possibility of reaching much further back in time.
Deep-sea cold seeps are dynamic sources of methane release and unique habitats supporting ocean biodiversity and productivity. Here, we describe newly discovered animal-bacterial symbioses fueled by ...methane, between two species of annelid (a serpulid
and sabellid
) and distinct aerobic methane-oxidizing bacteria belonging to the Methylococcales, localized to the host respiratory crown. Worm tissue δ
C of -44 to -58‰ are consistent with methane-fueled nutrition for both species, and shipboard stable isotope labeling experiments revealed active assimilation of
C-labeled methane into animal biomass, which occurs via the engulfment of methanotrophic bacteria across the crown epidermal surface. These worms represent a new addition to the few animals known to intimately associate with methane-oxidizing bacteria and may further explain their enigmatic mass occurrence at 150-million year-old fossil seeps. High-resolution seafloor surveys document significant coverage by these symbioses, beyond typical obligate seep fauna. These findings uncover novel consumers of methane in the deep sea and, by expanding the known spatial extent of methane seeps, may have important implications for deep-sea conservation.
Ecotones have been described as “biodiversity hotspots” from myriad environments, yet have not been studied extensively in the deep ocean. While physiologically challenging, deep‐water methane seeps ...host highly productive communities fueled predominantly by chemosynthetic pathways. We hypothesized that the biological and geochemical influence of methane seeps extends into background habitats, resulting in the formation of a “chemotone” where chemosynthesis‐based and photosynthesis‐based communities overlap. To investigate this, we analyzed the macrofaunal assemblages and geochemical properties of sediments collected from “active,” “transition” (potential chemotone), and “background” habitats surrounding five Costa Rican methane seeps (depth range 377–1908 m). Sediment geochemistry demonstrated a clear distinction between active and transition habitats, but not between transition and background habitats. In contrast, biological variables confirmed the presence of a chemotone, characterized by intermediate biomass, a distinct species composition (including habitat endemics and species from both active and background habitats), and enhanced variability in species composition among samples. However, chemotone assemblages were not distinct from active and/or background assemblages in terms of faunal density, biological trait composition, or diversity. Biomass and faunal stable isotope data suggest that chemotones are driven by a gradient in food delivery, receiving supplements from chemosynthetic production in addition to available photosynthetic‐based resources. Sediment geochemistry suggests that chemosynthetic food supplements are delivered across the chemotone at least in part through the water column, as opposed to reflecting exclusively in situ chemosynthetic production in sediments. Management efforts should be cognisant of the ecological attributes and spatial extent of the chemotone that surrounds deep‐sea chemosynthetic environments.
This study aimed to examine the COVID-19 pandemic's impact on fire service safety culture, behavior and morale, levers of well-being, and well-being outcomes.
Two samples (Stress and Violence against ...fire-based EMS Responders SAVER, consisting of 3 metropolitan departments, and Fire service Organizational Culture of Safety FOCUS, a geographically stratified random sample of 17 departments) were assessed monthly from May to October 2020. Fire department-specific and pooled scores were calculated. Linear regression was used to model trends.
We observed concerningly low and decreasing scores on management commitment to safety, leadership communication, supervisor sensegiving, and decision-making. We observed increasing and concerning scores for burnout, intent to leave the profession, and percentage at high risk for anxiety and depression.
Our findings suggest that organizational attributes remained generally stable but low during the pandemic and impacted well-being outcomes, job satisfaction, and engagement. Improving safety culture can address the mental health burden of this work.
Searches for new resonances are performed using an unsupervised anomaly-detection technique. Events with at least one electron or muon are selected from 140 fb-1 of pp collisions at $\sqrt{s}$ =13 ...TeV recorded by ATLAS at the Large Hadron Collider. The approach involves training an autoencoder on data, and subsequently defining anomalous regions based on the reconstruction loss of the decoder. Studies focus on nine invariant mass spectra that contain pairs of objects consisting of one light jet or b jet and either one lepton (e,μ), photon, or second light jet or b jet in the anomalous regions. No significant deviations from the background hypotheses are observed. Limits on contributions from generic Gaussian signals with various widths of the resonance mass are obtained for nine invariant masses in the anomalous regions.
Objectives:
To determine intra-rater and inter-rater reliability of functional outcome measures in adults with neurofibromatosis 1 and to ascertain how closely objective and subjective measures ...align.
Methods:
A total of 49 ambulant adults with neurofibromatosis 1 aged 16 years and over were included in this observational study: median age 31 years (range: 16–66 years), 29 females, 20 males. Participants were video-recorded or photographed performing four functional outcome measures. Four raters from the neurofibromatosis centre multi-disciplinary team independently scored the measures to determine inter-rater reliability. One rater scored the measures a second time on a separate occasion to determine intra-rater reliability. The measures evaluated were the functional reach, timed up and go, 10 m walk and a modified nine-hole peg tests. Participants also completed a disease-specific quality-of-life questionnaire.
Results:
Inter-rater reliability and intra-rater reliability scores (intra-class coefficient) were similar for each outcome measure. Excellent rater agreement (intra-class coefficient, r ⩾ 0.9) was found for the functional reach, timed up and go and the 10 m walk tests. Rater agreement was good for the modified nine-hole peg test: intra-class coefficient r = 0.75 for intra-rater reliability and 0.76 for inter-rater reliability. The timed up and go and the 10 m walk tests correlated highly with perceived mobility challenges in the quality-of-life questionnaire.
Conclusion:
The functional reach, timed up and go and 10 m walk tests are potentially useful outcome measures for monitoring neurofibromatosis 1 treatment and will be assessed in multi-centre and longitudinal studies.
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