Star Poly( N

New star poly(N-isopropylacrylamide)-b-polyhedral oligomeric silsesquioxane (PNIPAm-b-POSS) copolymers were synthesized from octa-azido functionalized POSS (N3-POSS) and alkyne-PNIPAm, which was prepared using an alkyne-functionalized atom transfer radical polymerization (ATRP) initiator (propargyl 2-bromo-2-methylpropionamide), via click chemistry. These star PNIPAm-b-POSS copolymers undergo a sharp coil-globule transition in water at above 32°C changing from a hydrophilic state below this temperature to a hydrophobic state above it, which is similar to linear PNIPAm homopolymers. More interestingly, we found that these star polymers exhibited strong blue photoluminescence in water above a lower critical solution temperature (LCST). This photoluminescence was likely due to the constrained geometric freedom and relatively rigid structure caused by intramolecular hydrogen bonding within the star PNIPAm polymers, which exhibit an intrinsic fluorescent behavior

The promiscuous development of an unconventional Qa1b-restricted T cell population

MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αβ+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αβ intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αβ T cells. QFL T cells require the MHC I subunit β-2 microglobulin (β2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αβ+CD4- pathway for development of CD8αα IELs

Metabolic health status and fecundability in a Singapore preconception cohort study

Background: Obesity compromises metabolic health and female fertility, yet not all obese women are similar in metabolic status. The extent to which fecundability is influenced by the metabolic health status of women who are overweight or obese before conception is unknown. Objective: This study aimed to: (1) determine the metabolic health status, and (2) examine the association between metabolic health status and fecundability of overweight and obese women trying to conceive in the Singapore PREconception Study of long-Term maternal and child Outcomes cohort study. Study Design: We conducted a prospective preconception cohort study of Asian women (Chinese, Malay, and Indian) aged 18 to 45 years trying to conceive who were treated from 2015 to 2017 in KK Women's and Children's Hospital in Singapore (n=834). We defined women to have metabolically unhealthy status if they: (1) met 3 or more modified Joint Interim Statement metabolic syndrome criteria; or (2) had homeostasis model assessment-insulin resistance index ≥2.5. Body mass index was categorized as normal (18.5–22.9 kg/m2), overweight (23–27.4 kg/m2), or obese (≥27.5 kg/m2) on the basis of cutoff points for Asian populations. Fecundability was measured by time to pregnancy in menstrual cycles within a year of enrolment. Discrete-time proportional hazards models were used to estimate fecundability odds ratios, with adjustment for confounders and accounting for left truncation and right censoring. Results: Of 232 overweight women, 28 (12.1%) and 25 (10.8%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Of 175 obese women, 54 (30.9%) and 93 (53.1%) were metabolically unhealthy by metabolic syndrome ≥3 criteria and homeostasis model assessment-insulin resistance ≥2.5, respectively. Compared with metabolically healthy normal-weight women, lower fecundability was observed in metabolically unhealthy overweight women on the basis of metabolic syndrome criteria (fecundability odds ratios, 0.38 [95% confidence interval, 0.15–0.92]) and homeostasis model assessment-insulin resistance (fecundability odds ratios, 0.68 [95% confidence interval, 0.33–1.39]), with metabolic syndrome criteria showing a stronger association. Metabolically unhealthy obese women showed lower fecundability than the healthy normal-weight reference group by both metabolic syndrome (fecundability odds ratios, 0.35; 95% confidence interval, 0.17–0.72) and homeostasis model assessment-insulin resistance criteria (fecundability odds ratios, 0.43; 95% confidence interval, 0.26–0.71). Reduced fecundability was not observed in overweight or obese women who showed healthy metabolic profiles by either definition. Conclusion: Overweight or obesity was not synonymous with having metabolic syndrome or insulin resistance. In our preconception cohort, metabolically unhealthy overweight and obese women showed reduced fecundability, unlike their counterparts who were metabolically healthy. These findings suggest that metabolic health status, rather than simply being overweight and obese per se, plays an important role in fecundability.acceptedVersionPeer reviewe

Comparing feature selection and machine learning approaches for predicting CYP2D6 methylation from genetic variation

IntroductionPharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort.MethodsBuffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models’ performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites.ResultsOverall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model.DiscussionThe development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing

Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR(+)) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR(+) chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy

Role of cultural values and protean orientation on career success criteria.

This study examines the role of cultural values, using Hofstede’s 5 cultural dimensions, and protean orientation on career success criteria. This study also examines the predictive role of protean orientation as an independent variable and as a mediator in the relationship between cultural values and career success criteria

Differences between children and adults with otitis media with effusion treated with CO2 laser myringotomy

Background: The safety and advantages of CO2 laser myringotomy for otitis media with effusion (OME) are well described. The goal of such treatment is to avoid unnecessary ventilation tube insertion. Comparisons between different age groups treated with this modality are lacking, and prognostic factors for treatment outcomes are not available. Methods: We conducted a retrospective cohort study that included 130 children (160 ears) and 96 adults (108 ears) with OME persisting after conservative antibiotic treatment. In eligible patients, we performed laser myringotomy in the affected ear. Follow-up was scheduled every week for 1 month and then every month for 6 months. Results for 233 ears were available for analysis; 24 ears were excluded (19 due to cancer, four due to a cleft palate, and one due to Down syndrome) and 10 patients (11 ears) were lost during follow-up. A logistic regression model was used for analysis, with success of therapy as the binary outcome. Results: Adult patients had more unilateral lesions (p < 0.001) and serous fluid effusions (p < 0.001) than did the pediatric patients. However, there was no significant difference in the cure rate (children: 58.1%; adults: 64.7%) and positive culture rate (children: 15.1%; adults: 14.3%) between patient groups. Three factors were found to be associated with a poor prognosis: multiple occurrences in children (p < 0.001), mucoid effusion (p = 0.04), and a history of ventilation tube use in adults (p < 0.001). No other variables predicted treatment outcome. Conclusion: Our findings suggest that CO2 laser myringotomy is a useful treatment modality for OME in children and adults, except for children with multiple occurrences and in adults with mucoid effusions and a history of ventilation tube use