Combining 1,3-Ditriazolylbenzene and Quinoline to Discover a New G-Quadruplex-Interactive Small Molecule Active against Cancer Stem-Like Cells

Quadruplex nucleic acids are promising targets for cancer therapy. In this study we used a fragment‐based approach to create new flexible G‐quadruplex (G4) DNA‐interactive small molecules with good calculated oral drug‐like properties, based on quinoline and triazole heterocycles. G4 melting temperature and polymerase chain reaction (PCR)‐stop assays showed that two of these compounds are selective G4 ligands, as they were able to induce and stabilize G4s in a dose‐ and DNA sequence‐dependent manner. Molecular docking studies have suggested plausible quadruplex binding to both the G‐quartet and groove, with the quinoline module playing the major role. Compounds were screened for cytotoxicity against four cancer cell lines, where 4,4′‐(4,4′‐(1,3‐phenylene)bis(1H‐1,2,3‐triazole‐4,1‐diyl))bis(1‐methylquinolin‐1‐ium) (1 d) showed the greater activity. Importantly, dose–response curves show that 1 d is cytotoxic in the human colon cancer HT‐29 cell line enriched in cancer stem‐like cells, a subpopulation of cells implicated in chemoresistance. Overall, this study identified a new small molecule as a promising lead for the development of drugs targeting G4 in cancer stem cells

Tracking Holocene palaeostratification and productivity changes in the Western Irish Sea: A multi-proxy record

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.The Western Irish Sea preserves an exceptionally thick (ca. 40 m) Holocene succession that is ideally suited to understanding the pattern of palaeostratification and water mass productivity changes in the region, and their relationship with sea level, sedimentation, and biota. Additionally, the presence of shallow-buried methane provides an opportunity to explore its potential impact on the local pattern of Holocene marine environmental change. Multi-proxy investigation of a cored borehole succession through the Holocene interval tracks changes from mixed to seasonally stratified conditions. In the earliest Holocene (11.2–10 ka), high productivity, mixed water conditions prevailed, with abundant and diverse foraminifera and dominant heterotrophic dinoflagellate cysts. Productivity was probably driven by high nutrient fluxes related to high rates of sedimentation (>1600 cm/kyr), in turn influenced by relatively low sea level and restricted sediment accommodation space across shelf areas to the east of the borehole site (eastern Irish Sea Basin). With rising sea level in the later part of the Early Holocene, the region evolved into a relatively lower productivity mixed water mass system, with significant changes in ecology revealed by dinoflagellate cysts and foraminifera. In the latest Early Holocene and earliest Mid Holocene (ca. 8.4–8.2 ka) a return to higher productivity is signalled by dinoflagellate cyst data; a result of seasonal stratification becoming established, evidenced by sharply increased summer sea surface temperature estimates (typically 16–17 °C) that contrast with an opposite (more positive) trend in δ18O values for benthic foraminifera. Reductions in turbulent mixing associated with stratification might have exacerbated the palaeoecological impact of shallow-buried methane associated with the borehole site, potentially evidenced by a significant change in dominant benthic foraminifera and strong, localised excursions in the benthic δ13C/δ18O record

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML

Social interaction, noise and antibiotic-mediated switches in the intestinal microbiota

The intestinal microbiota plays important roles in digestion and resistance against entero-pathogens. As with other ecosystems, its species composition is resilient against small disturbances but strong perturbations such as antibiotics can affect the consortium dramatically. Antibiotic cessation does not necessarily restore pre-treatment conditions and disturbed microbiota are often susceptible to pathogen invasion. Here we propose a mathematical model to explain how antibiotic-mediated switches in the microbiota composition can result from simple social interactions between antibiotic-tolerant and antibiotic-sensitive bacterial groups. We build a two-species (e.g. two functional-groups) model and identify regions of domination by antibiotic-sensitive or antibiotic-tolerant bacteria, as well as a region of multistability where domination by either group is possible. Using a new framework that we derived from statistical physics, we calculate the duration of each microbiota composition state. This is shown to depend on the balance between random fluctuations in the bacterial densities and the strength of microbial interactions. The singular value decomposition of recent metagenomic data confirms our assumption of grouping microbes as antibiotic-tolerant or antibiotic-sensitive in response to a single antibiotic. Our methodology can be extended to multiple bacterial groups and thus it provides an ecological formalism to help interpret the present surge in microbiome data.Comment: 20 pages, 5 figures accepted for publication in Plos Comp Bio. Supplementary video and information availabl

Evaluation of the psychometric properties of the London Measure of Unplanned Pregnancy in Brazilian Portuguese

Background: Estimates of unplanned pregnancy worldwide are of concern, especially in low and middle-income countries, including Brazil. Although the contraceptive prevalence rate is high in Brazil, almost half of all pregnancies are reported as unintended. The only source of nationally representative data about pregnancy intention is the Demographic and Health Survey, as with many other countries. In more recent years, however, it has been realized that concept of unintended pregnancy is potentially more complex and requires more sophisticated measurement strategies, such as the London Measure of Unplanned Pregnancy (LMUP). The LMUP has been translated and validated in other languages, but not Portuguese yet. In this study, we evaluate the psychometric properties of the LMUP in the Portuguese language, Brazilian version. Methods: A Brazilian Portuguese version of the LMUP was produced via translation and back-translation. After piloting, the mode of administration was changed from self-completion to interviewer-administration. The measure was field tested with pregnant, postpartum, and postabortion women recruited at maternity and primary health care services in Sao Paulo city. Reliability (internal consistency) was assessed using Cronbach’s alpha and item-total correlations. Construct validity was assessed using principal components analysis and hypothesis testing. Scaling was assessed with Mokken analysis. Results: 759 women aged 15–44 completed the Brazilian Portuguese LMUP. There were no missing data. The measure was acceptable and well targeted. Reliability testing demonstrated good internal consistency (alpha = 0.81, all item-rest correlations >0.2). Validity testing confirmed that the measure was unidimensional and that all hypotheses were met: there were lower LMUP median scores among women in the extreme age groups (p<0.001), among non-married women (p<0.001) and those with lower educational attainment (p<0.001). The Loevinger H coefficient was 0.60, indicating a strong scale. Conclusion: The Brazilian Portuguese LMUP is a valid and reliable measure of pregnancy planning/intention that is now available for use in Brazil. It represents a useful addition to the public health research and surveillance toolkit in Brazil

Genetic diversity of carotenoid-rich bananas evaluated by Diversity Arrays Technology (DArT)

The aim of this work was to evaluate the carotenoid content and genetic variability of banana accessions from the Musa germplasm collection held at Embrapa Cassava and Tropical Fruits, Brazil. Forty-two samples were analyzed, including 21 diploids, 19 triploids and two tetraploids. The carotenoid content was analyzed spectrophotometrically and genetic variability was estimated using 653 DArT markers. The average carotenoid content was 4.73 μg.g -1 , and ranged from 1.06 μg.g -1 for the triploid Nanica (Cavendish group) to 19.24 μg.g -1 for the triploid Saney. The diploids Modok Gier and NBA-14 and the triploid Saney had a carotenoid content that was, respectively, 7-fold, 6-fold and 9-fold greater than that of cultivars from the Cavendish group (2.19 μg.g -1). The mean similarity among the 42 accessions was 0.63 (range: 0.24 to 1.00). DArT analysis revealed extensive genetic variability in accessions from the Embrapa Musa germplasm bank

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing ‘depression-like’ shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = −3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997–1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10−4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men