A Study of Short-Chain Fatty Acids During the Canalicular and Early Saccular Phases of Fetal Lung Development and Childhood Asthma.

Background: Emerging literature indicates that the microbiome and its byproducts, such as short-chain fatty acids (SCFAs), play an important role in childhood diseases such as allergies and asthma. Specifically, there is evidence suggesting that SCFAs play a critical role in fetal immunoprogramming during the late saccular phase of fetal lung development. An increase in acetate during the late saccular phase is known to play a critical role in inhibiting histone deacetylases (HDACs), resulting in a cascade of events, including Treg immune regulation, involved in fetal immunoprogramming, and reduction in the asthma phenotype.

Youden index estimation based on group-tested data.

Youden index, a linear function of sensitivity and specificity, provides a direct measurement of the highest diagnostic accuracy achievable by a biomarker. It is maximized at the cut-off point that optimizes the biomarker's overall classification rate while assigning equal weight to sensitivity and specificity. In this paper, we consider the problem of estimating the Youden index when only group-tested data are available.

Socioeconomic mobility, metabolic health, and diet: mediation via subjective socioeconomic status.

Objective: Socioeconomic mobility, i.e., changing socioeconomic status (SES) between adolescence and adulthood, may impact health through changing resources, social status, and health-related behaviors.

Epigenetic implications of socioeconomic status and education on sperm DNA methylation patterns.

Objective: To identify differentially methylated regions and assess epigenetic age and instability scores within each cohort of differing income levels and educational attainment.

Design: Retrospective analysis of epigenetic data.

Setting: University.

Do maternal and paternal education protect against developmental delays?

Background: Parental education is linked to child development and wellbeing, but unique and combined contributions of maternal and paternal education have rarely been studied.

Aims: This study assessed the individual and joint associations of maternal and paternal education on children's odds of a probable developmental delay.

Methods And Procedures: Mothers (N = 3566) from the Upstate KIDS cohort study reported on theirs and the father's highest level of education and completed the Ages and Stages Questionnaires up to 7 times when the child was 4- to 36-months-old.

How is tailored implementation undertaken using a self-guided toolkit? Qualitative study of the ItFits-toolkit in the ImpleMentAll project.

Background: The process of tailored implementation is ill-defined and under-explored. The ItFits-toolkit was developed and subsequently tested as a self-guided online platform to facilitate implementation of tailored strategies for internet-based cognitive behavioural therapy (iCBT) services. In ImpleMentAll, ItFits-toolkit had a small but positive effect on the primary outcome of iCBT normalisation.

Preconception Phthalate Exposure and Women's Reproductive Health: Pregnancy, Pregnancy Loss, and Underlying Mechanisms.

Background: Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive.

Objectives: We aimed to determine the relationship of preconception phthalate metabolite exposure with ) fecundability and pregnancy loss and ) markers of potential biological mechanisms, including reproductive hormones, inflammation, and oxidative stress.

Towards an Implementation-STakeholder Engagement Model (I-STEM) for improving health and social care services.

Background: The implementation science literature acknowledges a need for engagement of key stakeholders when designing, delivering and evaluating implementation work. To date, the literature reports minimal or focused stakeholder engagement, where stakeholders are engaged in either barrier identification and/or barrier prioritisation. This paper begins to answer calls from the literature for the development of tools and guidance to support comprehensive stakeholder engagement in implementation research and practice.

A Cell-Based Optimised Approach for Rapid and Efficient Gene Editing of Human Pluripotent Stem Cells.

Introducing or correcting disease-causing mutations through genome editing in human pluripotent stem cells (hPSCs) followed by tissue-specific differentiation provide sustainable models of multiorgan diseases, such as cystic fibrosis (CF). However, low editing efficiency resulting in extended cell culture periods and the use of specialised equipment for fluorescence activated cell sorting (FACS) make hPSC genome editing still challenging. We aimed to investigate whether a combination of cell cycle synchronisation, single-stranded oligodeoxyribonucleotides, transient selection, manual clonal isolation, and rapid screening can improve the generation of correctly modified hPSCs.

The Relationship of Preconception and Early Pregnancy Isoprostanes with Fecundability and Pregnancy Loss.

Background: Although redox stress likely plays an important role in reproductive health, the utility of peripheral biomarkers of oxidative stress, such as isoprostanes, during the periconception period remains underexplored. We evaluated the relationship between isoprostanes during preconception and gestational week 4 and women's reproductive health outcomes.

Methods: The Effects of Aspirin in Gestation and Reproduction trial (2007-2011) enrolled 1228 women attempting pregnancy and followed them for up to 6 menstrual cycles and throughout pregnancy if they became pregnant.

Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

Background: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants.

The Role of Maternal Preconception Adiposity in Human Offspring Sex and Sex Ratio.

We evaluated relationships between preconception adiposity and human offspring sex and sex ratio. Using data from a prospective preconception cohort nested within a randomized controlled trial based at 4 US clinical sites (2006-2012), we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for male:female sex ratio, and log-identity regression to estimate risk differences (RDs) and 95% CIs for male and female livebirth according to preconception adiposity measures. Inverse-probability weights accounted for potential selection bias.

Claspin haploinsufficiency leads to defects in fertility, hyperplasia and an increased oncogenic potential.

Claspin is an adaptor protein required for ATR-dependent phosphorylation of CHK1 during S-phase following DNA replication stress. Claspin expression is highly variable in cancer, with low levels frequently correlating with poor patient survival. To learn more about the biological consequences of reduced Claspin expression and its effects on tumorigenesis, we investigated mice with a heterozygous knockout of the Clspn gene.

Up-regulation of the PI3K/AKT and RHO/RAC/PAK signalling pathways in CHK1 inhibitor resistant Eµ-Myc lymphoma cells.

The development of resistance and the activation of bypass pathway signalling represents a major problem for the clinical application of protein kinase inhibitors. While investigating the effect of either a c-Rel deletion or RelAT505A phosphosite knockin on the Eµ-Myc mouse model of B-cell lymphoma, we discovered that both NF-κB subunit mutations resulted in CHK1 inhibitor resistance, arising from either loss or alteration of CHK1 activity, respectively. However, since Eµ-Myc lymphomas depend on CHK1 activity to cope with high levels of DNA replication stress and consequent genomic instability, it was not clear how these mutant NF-κB subunit lymphomas were able to survive.

Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.

Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747.

Longitudinal semen parameter assessments and live birth: variability and implications for treatment strategies.

Objective: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability.

Design: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort.

Setting: Four US reproductive endocrinology and infertility care study centers, 2013-2017.

The Catalytic Reactivity of Alloys; Ethanol and Formic Acid Decomposition on Cu-Pd(110).

The effect of alloying Cu and Pd on the reactivity pattern for formic acid and for ethanol has been examined. The electronic structure of the material is strongly affected by the alloying, with the d-band lowered in energy and filled, compared with Pd alone. Hence the reactivity would be expected to be strongly affected by the alloying.

c-Rel-dependent Chk2 signaling regulates the DNA damage response limiting hepatocarcinogenesis.

Background And Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. The NF-κB transcription factor family subunit c-Rel is typically protumorigenic; however, it has recently been reported as a tumor suppressor. Here, we investigated the role of c-Rel in HCC.

Alphabetti kinase Spaghetti: the complex roles of IKKα and β in the canonical NF-κB pathway.

Numerous studies, published over many years, have established the key role that the IκB kinase (IKK) subunits, α and β, play in regulating the Nuclear Factor κB (NF-κB) pathway. This research generally concluded that their functions can be separated, with IKKβ being the critical regulator of the canonical NF-κB pathway, while IKKα functions as the key activating kinase for the non-canonical pathway. However, other roles for these kinases have been described and several reports concluded that this separation of their functions may not always be the case.

A multistate competing risks framework for preconception prediction of pregnancy outcomes.

Background: Preconception pregnancy risk profiles-characterizing the likelihood that a pregnancy attempt results in a full-term birth, preterm birth, clinical pregnancy loss, or failure to conceive-can provide critical information during the early stages of a pregnancy attempt, when obstetricians are best positioned to intervene to improve the chances of successful conception and full-term live birth. Yet the task of constructing and validating risk assessment tools for this earlier intervention window is complicated by several statistical features: the final outcome of the pregnancy attempt is multinomial in nature, and it summarizes the results of two intermediate stages, conception and gestation, whose outcomes are subject to competing risks, measured on different time scales, and governed by different biological processes. In light of this complexity, existing pregnancy risk assessment tools largely focus on predicting a single adverse pregnancy outcome, and make these predictions at some later, post-conception time point.

Increased migration and motility in XIAP-null cells mediated by the C-RAF protein kinase.

The product encoded by the X-linked inhibitor of apoptosis (XIAP) gene is a multi-functional protein which not only controls caspase-dependent cell death, but also participates in inflammatory signalling, copper homeostasis, response to hypoxia and control of cell migration. Deregulation of XIAP, either by elevated expression or inherited genetic deletion, is associated with several human disease states. Reconciling XIAP-dependent signalling pathways with its role in disease progression is essential to understand how XIAP promotes the progression of human pathologies.

Preconception hemoglobin A1c concentration in healthy women is not associated with fecundability or pregnancy loss.

Objective: To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2-3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases.

Design: A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial.

Setting: Four US academic medical centers.