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The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
A fiber optic probe-based Raman spectroscopy system using a single laser module with two excitation wavelengths, at 680 and 785 nm, has been developed for measuring the fingerprint and high wavenumber regions using a single detector. This system is simpler and less expensive than previously reported configurations of combined fingerprint and high wavenumber Raman systems, and its probe-based implementation facilitates numerous in vivo applications. The high wavenumber region of the Raman spectrum ranges from 2800-3800 cm-1 and contains valuable information corresponding to the molecular vibrations of proteins, lipids, and water, which is complimentary to the biochemical signatures found in the fingerprint region (800-1800 cm-1), which probes DNA, lipids, and proteins. The efficacy of the system is demonstrated by tracking changes in water content in tissue-mimicking phantoms, where Voigtian decomposition of the high wavenumber water peak revealed a correlation between the water content and type of water-tissue interactions in the samples. This dual wavelength system was then used for in vivo assessment of cervical remodeling during mouse pregnancy, a physiologic process with known changes in tissue hydration. The system shows that Raman spectroscopy is sensitive to changes in collagen content in the fingerprint region and hydration state in the high wavenumber region, which was verified using an ex vivo comparison of wet and dry weight. Simultaneous fingerprint and high wavenumber Raman spectroscopy will allow precise in vivo quantification of tissue water content in the high wavenumber region, paired with the high biochemical specificity of the fingerprint region.
OBJECTIVE - Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.
DESIGN - We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.
RESULTS - The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.
CONCLUSION - The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
Pregnancy produces important health-related needs, and expectant families have turned to technologies to meet them. The ability to predict needs and technology preferences might aid in connecting families with resources. This study examined the relationships among Multidimensional Health Locus of Control (MHLC) scores, information-seeking behaviors, and health-related needs in 71 pregnant women and 29 caregivers. Internal MHLC scores were positively correlated with information-seeking behaviors, including website and patient portal use. Higher Chance scores were associated with decreased portal or pregnancy website use (p=0.002), with the exception of FitPregnancy.com (p=0.02). MHLC scores were not significantly correlated with number of health-related needs or whether needs were met. Individuals with needs about disease management had higher Powerful Others scores (p=0.01); those with questions about tests had lower Powerful Others scores (p=0.008). MHLC scores might be used to identify individuals less likely to seek information and to predict need types.
Bacterial DNA has been reported in the placenta and amniotic fluid by several independent groups of investigators. However, it's taxonomic overlap with fetal and maternal bacterial DNA in different sites has been poorly characterized. Here, we determined the presence of bacterial DNA in the intestines and placentas of fetal mice at gestational day 17 (n = 13). These were compared to newborn intestines (n = 15), maternal sites (mouth, n = 6; vagina, n = 6; colon, n = 7; feces, n = 8), and negative controls to rule out contamination. The V4 region of the bacterial 16S rRNA gene indicated a pattern of bacterial DNA in fetal intestine similar to placenta but with higher phylogenetic diversity than placenta or newborn intestine. Firmicutes were the most frequently assignable phylum. SourceTracker analysis suggested the placenta as the most commonly identifiable origin for fetal bacterial DNA, but also over 75% of fetal gut genera overlapped with maternal oral and vaginal taxa but not with maternal or newborn feces. These data provide evidence for the presence of bacterial DNA in the mouse fetus.
Preterm birth affects approximately 1 out of every 10 births in the United States, leading to high rates of mortality and long-term negative health consequences. To investigate the mechanisms leading to preterm birth so as to develop prevention strategies, researchers have developed numerous mouse models of preterm birth. However, the lack of standard definitions for preterm birth in mice limits our field's ability to compare models and make inferences about preterm birth in humans. In this review, we discuss numerous mouse preterm birth models, propose guidelines for experiments and reporting, and suggest markers that can be used to assess whether pups are premature or mature. We argue that adoption of these recommendations will enhance the utility of mice as models for preterm birth.
In mouse models used to study parturition or pre-clinical therapeutic testing, measurement of uterine contractions is limited to either isometric tension or operative intrauterine pressure (IUP). The goal of this study was to: (1) develop a method for transcervical insertion of a pressure catheter to measure intrauterine contractile pressure during mouse pregnancy, (2) determine whether this method can be utilized numerous times in a single mouse pregnancy without affecting the timing of delivery or fetal outcome and (3) compare the contractile activity between mouse models of term and preterm labor (PTL). Visualization of the cervix allowed intrauterine pressure catheter (IUPC) placement into anesthetized pregnant mice (plug = day 1, delivery = day 19.5). The amplitude, frequency, duration and area under the curve (AUC) of IUP was lowest on days 16-18, increased significantly ( < 0.05) on the morning of day 19 and reached maximal levels during by the afternoon of day 19 and into the intrapartum period. An AUC threshold of 2.77 mmHg discriminated between inactive labor (day 19 am) and active labor (day 19 pm and intrapartum period). Mice examined on a single vs every experimental timepoint did not have significantly different IUP, timing of delivery, offspring number or fetal/neonatal weight. The IUP was significantly greater in LPS-treated and RU486-treated mouse models of PTL compared to time-matched vehicle control mice. Intrapartum IUP was not significantly different between term and preterm mice. We conclude that utilization of a transcervical IUPC allows sensitive assessment of uterine contractile activity and labor progression in mouse models without the need for operative approaches.
© 2018 Society for Reproduction and Fertility.
New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-g glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86-5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.
Copyright © 2018 Elsevier Ltd. All rights reserved.
BACKGROUND - The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications.
OBJECTIVE - The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair.
STUDY DESIGN - In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6-week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses.
RESULTS - Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm) and cholesterol (1447 cm) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals.
CONCLUSION - Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth.
Copyright © 2018. Published by Elsevier Inc.
PROBLEM - Premature birth complicates 10%-12% of deliveries. Infection and inflammation are the most common etiologies and are associated with increased offspring morbidity and mortality. We hypothesize that lipopolysaccharide (LPS)-induced maternal inflammation causes direct placenta injury and subsequent injury to the fetal intestine.
METHOD OF STUDY - Pregnant C57Bl6 mice were injected intraperitoneally on day 15.5 with 100 μg/kg LPS or saline. Maternal serum, amniotic fluid, placental samples, and ileal samples of offspring were obtained assessed for inflammation and/or injury. Maternal placental ultrasounds were performed. Placental DNA was isolated for microbiome analysis.
RESULTS - Maternal injection with LPS caused elevated IL-1β, IL-10, IL-6, KC-GRO, and TNF. Placental tissue showed increased IL-1β, IL-6, and KC-GRO and decreased IL-10, but no changes were observed in amniotic fluid. Placental histology demonstrated LPS-induced increases in mineralization and necrosis, but no difference in placental blood flow. Most placentas had no detectable microbiome. Exposure to maternal LPS induced significant injury to the ilea of the offspring.
CONCLUSION - Lipopolysaccharide causes a maternal inflammatory response that is mirrored in the placenta. Placental histology demonstrates structural changes; however, placental blood flow is preserved. LPS also induces an indirect intestinal injury in the offspring that lasts beyond the neonatal period.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.