Notes

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Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.14-O-[(4,6-Diaminopyrimidine-2-yl)thioacetyl] mutilin (DPTM) is a promising drug candidate with excellent antibacterial activity against Gram-positive bacteria. The present study was designed to characterize its Cytochrome P450 (CYP) enzymes inhibition activities and the genotoxicity with the standard Ames test. We determined the inhibitory effects of DPTM on CYP1A2, CYP2D1/6, CYP2E1, CYP2C11/9 and CYP3A/4 in rat liver microsomes (RLMs) and in human liver microsomes (HLMs). The mRNA expressions of the above CYP isoforms and their transcriptional regulators were also evaluated using the Hep G2 cell model. The results showed DPTM exhibited a moderate inhibitory potential against CYP3A/4 (IC50 values of 10 ± 2 and 8 ± 2 μM, respectively) and weak against the other CYP enzymes based on their IC50 values. Compared to the control, CYP isoforms and their transcriptional regulators mRNA expressions significantly increased when the Hep G2 cells were treated with DPTM for a certain period of time. In the Ames test, Salmonella strains TA97, TA98, TA100, TA102 and TA1535 were treated with or without the metabolic activation (S9). Analysis showed the average number of revertant colonies per plate was less in double in the groups treated with DPTM than that in the negative control plate and showed no dose-related increase.As defined by the World Health Organization, an endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)populations. Traditional experimental testing regimens to identify toxicants that induce endocrine disruption can be expensive and time-consuming. Computational modeling has emerged as a promising and cost-effective alternative method for screening and prioritizing potentially endocrine-active compounds. The efficient identification of suitable chemical descriptors and machine-learning algorithms, including deep learning, is a considerable challenge for computational toxicology studies. Here, we sought to apply classic machine-learning algorithms and deep-learning approaches to a panel of over 7500 compounds tested against 18 Toxicity Forecaster assays related to nuclear estrogen receptor (ERα and ERβ) activity. Three binary fingerprints (Extended Connectivity FingerPriistically related endpoints. Consensus predictions based on the average values of individual models remain the best modeling strategy for computational toxicity evaluations.In this study, we propose a contagion model as a simple and powerful mathematical approach for predicting the spatial spread and temporal evolution of the onset and recession of floodwaters in urban road networks. A network of urban roads resilient to flooding events is essential for the provision of public services and for emergency response. The spread of floodwaters in urban networks is a complex spatial-temporal phenomenon. This study presents a mathematical contagion model to describe the spatial-temporal spread and recession process of floodwaters in urban road networks. The evolution of floods within networks can be captured based on three macroscopic characteristics-flood propagation rate ([Formula see text]), flood incubation rate ([Formula see text]), and recovery rate ([Formula see text])-in a system of ordinary differential equations analogous to the Susceptible-Exposed-Infected-Recovered (SEIR) model. We integrated the flood contagion model with the network percolation process in which the probability of flooding of a road segment depends on the degree to which the nearby road segments are flooded. The application of the proposed model is verified using high-resolution historical data of road flooding in Harris County during Hurricane Harvey in 2017. The results show that the model can monitor and predict the fraction of flooded roads over time. Additionally, the proposed model can achieve 90% precision and recall for the spatial spread of the flooded roads at the majority of tested time intervals. The findings suggest that the proposed mathematical contagion model offers great potential to support emergency managers, public officials, citizens, first responders, and other decision-makers for flood forecast in road networks.Duck meat enjoys growing popularity among consumers. Alternative protein sources to soybean are being investigated to eliminate genetically modified components from the poultry' diet. The aim of this study was to compare growth performance, quality of meat, and fatty acid composition in subcutaneous and abdominal fat from ducks fed a diet based on yellow lupin and rapeseed meal, sources of protein alternative to soybean meal (SBM). Ducks were allocated to different dietary treatment groups and reared for 8 weeks (N = 102 per group). Group A received a diet based on SBM, while group B was fed a diet based on yellow lupin with the addition of rapeseed meal. Both groups were divided into two subgroups, of male and female birds. Growth performance parameters and zoometric traits of ducks were monitored during the growth period. After 8 weeks selected birds were slaughtered and dissected (N = 10 per group). Carcass composition was calculated and selected traits of meat quality important for further processing were analysed. Subcutaneous and abdominal fat were collected to analyse fatty acid composition. The alternative diet had no negative effect on ducks' growth performance parameters and dressing percentage. The replacement of SBM with yellow lupin and rapeseed meal increased n-3 fatty acid content, which is important for consumers. In conclusion, SBM can be replaced with feed containing 60.10% of yellow lupin and 14.00% of rapeseed meal in concentrate. These sources of protein are mainly recommended for small poultry farms, which do not always have access to SBM and prepare poultry feed from their own crops.Tick cell lines are an easy-to-handle system for the study of viral and bacterial infections and other aspects of tick cellular processes. Tick cell cultures are often continuously cultivated, as freezing can affect their viability. Selleck AZD5069 However, the long-term cultivation of tick cells can influence their genome stability. In the present study, we investigated karyotype and genome size of tick cell lines. Though 16S rDNA sequencing showed the similarity between Ixodes spp. cell lines at different passages, their karyotypes differed from 2n = 28 chromosomes for parental Ixodes spp. ticks, and both increase and decrease in chromosome numbers were observed. For example, the highly passaged Ixodes scapularis cell line ISE18 and Ixodes ricinus cell lines IRE/CTVM19 and IRE/CTVM20 had modal chromosome numbers 48, 23 and 48, respectively. Also, the Ornithodoros moubata cell line OME/CTVM22 had the modal chromosome number 33 instead of 2n = 20 chromosomes for Ornithodoros spp. ticks. All studied tick cell lines had a larger genome size in comparison to the genomes of the parental ticks. Thus, highly passaged tick cell lines can be used for research purposes, but possible differences in encoded genetic information and downstream cellular processes, between different cell populations, should be taken into account.Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.Individuals found at bars in slums have several risk factors for HIV and tuberculosis (TB). To determine the prevalence of HIV and TB among individuals found at bars in slums of Kampala, Uganda, we enrolled adults found at bars that provided written informed consent. Individuals with alcohol intoxication were excluded. We performed HIV testing using immunochromatographic antibody tests (Alere Determine HIV-1/2 and Chembio HIV 1/2 STAT-PAK). TB was confirmed using the Xpert MTB/RIF Ultra assay, performed on single spot sputum samples. We enrolled 272 participants from 42 bars in 5 slums. The prevalence of HIV and TB was 11.4% (95% CI 8.1-15.8) and 15 (95% CI 6-39) per 1,000 population respectively. Predictors of HIV were female sex (aOR 5.87, 95% CI 2.05-16.83), current cigarette smoking (aOR 3.23, 95% CI 1.02-10.26), history of TB treatment (aOR 10.19, 95% CI 3.17-32.82) and CAGE scores of 2-3 (aOR 3.90, 95% CI 1.11-13.70) and 4 (aOR 4.77, 95% CI 1.07-21.35). The prevalence of HIV and TB was twice and four times the national averages respectively. These findings highlight the need for concurrent programmatic screening for both HIV and TB among high risk populations in slums.Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved.
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