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Our data are consistent with the oscillation model of specialization, and a parallel narrowing of the edaphic, climatic, and mutualistic dimensions of the host species niche. Our findings provide novel evidence that the evolution of specialization in mutualism is accompanied by specialization in other niche dimensions.Clinical trials show that tyrosine kinase inhibitor (TKI) treatment can be discontinued in selected patients with chronic myeloid leukaemia (CML). Although updated CML guidelines support such procedure in clinical routine, data on TKI stopping outside clinical trials are limited. In this retrospective study utilising the Swedish CML registry, we examined TKI discontinuation in a population-based setting. Out of 584 patients diagnosed with chronic-phase CML (CML-CP) in 2007-2012, 548 had evaluable information on TKI discontinuation. With a median follow-up of nine years from diagnosis, 128 (23%) discontinued TKI therapy (≥1 month) due to achieving a DMR (deep molecular response) and 107 (20%) due to other causes (adverse events, allogeneic stem cell transplant, pregnancy, etc). Among those stopping in DMR, 49% re-initiated TKI treatment (median time to restart 4·8 months). In all, 38 patients stopped TKI within a clinical study and 90 outside a study. After 24 months 41·1% of patients discontinuing outside a study had re-initiated TKI treatment. TKI treatment duration pre-stop was longer and proportion treated with second-generation TKI slightly higher outside studies, conceivably affecting the clinical outcome. In summary we show that TKI discontinuation in CML in clinical practice is common and feasible and may be just as successful as when performed within a clinical trial.
We leverage recent bioarchaeological approaches and life history theory to address the implications of the osteological paradox in a study population. The goal of this article is to evaluate morbidity and mortality patterns as well as variability in the risk of disease and death during the Late Intermediate period (LIP; 950-1450 C.E.) in the Nasca highlands of Peru. We demonstrate how the concurrent use of multiple analytical techniques and life history theory can engage the osteological paradox and provide salient insights into the study of stress, frailty, and resilience in past populations.
Crania from LIP burial contexts in the Nasca highlands were examined for cribra orbitalia (n = 325) and porotic hyperostosis (n = 270). All age groups and both sexes are represented in the sample. Survivor/nonsurvivor analysis assessed demographic differences in lesion frequency and severity. Hazard models were generated to assess differences in survivorship. The relationship between dietary diversity and heterogeneles or increased female fertility rates may explain these differences.Structural dynamics of calcified cartilage (CC) are poorly understood. Conventionally, CC structure is analyzed using histological sections. Micro-computed tomography (µCT) allows for three-dimensional (3D) imaging of mineralized tissues; however, the segmentation between bone and mineralized cartilage is challenging. Here, we present state-of-the-art deep learning segmentation for µCT images to assess 3D CC morphology. The sample includes 16 knees from 12 New Zealand White rabbits dissected into osteochondral samples from six anatomical regions lateral and medial femoral condyles, lateral and medial tibial plateaus, femoral groove, and patella (n = 96). The samples were imaged with µCT and processed for conventional histology. Manually segmented CC from the images was used to train segmentation models with different encoder-decoder architectures. The models with the greatest out-of-fold evaluation Dice score were selected. CC thickness was compared across 24 regions, co-registered between the imaging modalitpecially when analyzing dynamic changes in cartilage mineralization. It could also provide further understanding of 3D morphological changes that may occur in mineralized cartilage, such as thickening of the subchondral plate in osteoarthritis and other joint diseases.
The μ-opioid receptor (μ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM μ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-μ receptors to further our understanding of the pharmacodynamic properties of μ receptors.
We performed virtual screening of the ZINC Drug Now library of compounds using in silico 7TM- and 6TM-μ receptor structural models and identified potential compounds that are selective for 6TM- and/or 7TM-μ receptors. Subsequently, we characterized the most promising candidate compounds in functional in vitro studies using Be2C neuroblastoma transfected cells, behavioural in vivo pain assays using various knockout mice and in ex vivo electrophysiology studies.
Our virtual screen identified 30 potential candidate compounds. Subsequent functional in vitro cellular assays shortlisted four compounds (#5, 10, 11 and 25) that demonstrated 6TM- or 7TM-μ receptor-dependent NO release. In in vivo pain assays these compounds also produced dose-dependent hyperalgesic responses. Studies using mice that lack specific opioid receptors further established the μ receptor-dependent nature of identified novel ligands. Ex vivo electrophysiological studies on spontaneous excitatory postsynaptic currents in isolated spinal cord slices also validated the hyperalgesic properties of the most potent 6TM- (#10) and 7TM-μ receptor (#5) ligands.
Our novel compounds represent a new class of ligands for μ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.
Our novel compounds represent a new class of ligands for μ receptors and will serve as valuable research tools to facilitate the development of opioids with significant analgesic efficacy and fewer side-effects.
Melanoma incidence has been dramatically increasing worldwide. Psoralen, a known photocarcinogen, is naturally abundant in citrus products, leading to the hypothesis that high citrus consumption may increase melanoma risk.
To investigate the association between total citrus consumption and melanoma risk, and the association between individual citrus products and melanoma risk, and to test for interactions between total citrus intake and established melanoma risk factors.
Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between citrus consumption and melanoma risk among 1592 cases and 197372 controls from the UK Biobank cohort. Myrcludex B order Citrus consumption data were collected via five rounds of 24-h recall questionnaires. International Classification of Diseases codes were used to determine melanoma outcome.
After adjusting for potential confounders, participants in the highest category of total citrus intake (> 2 servings per day) had a significantly increased risk of melanoma (OR 1·63, 95% CI 1·24-2·12) relative to those with no consumption.
