Late Pregnancy Exposures to Disinfection By-products and Growth-Related Birth Outcomes

Toxicologic studies have demonstrated associations between growth-related birth outcomes and exposure to high concentrations of disinfection by-products (DBPs), including specific tri-halomethane (THM) and haloacetic acid (HAA) chemical subspecies. Few prior investigations of DBPs have evaluated exposure during the third trimester of pregnancy, the time period of gestation when fetal growth may be most sensitive to environmental influences. We conducted a retrospective cohort study to examine the effects of exposure to THMs and HAAs during the third trimester and during individual weeks and months of late gestation on the risks for term low birth weight, intrauterine growth retardation, and very preterm and preterm births. The study population (n = 48,119) included all live births and fetal deaths occurring from January 1998 through March 2003 to women whose residence was served by one of three community water treatment facilities. We found evidence of associations between exposure to specific HAAs and term low birth weight as well as intrauterine growth retardation and for exposure to the five regulated HAAs (HAA5) and term low birth weight. Our findings suggest a critical window of exposure with respect to fetal development during weeks 33–40 for the effects of dibromoacetic acid and during weeks 37–40 for the effects of dichloroacetic acid. Adjustment for potential confounders did not affect the conclusions

High-Frequency in Situ Optical Measurements During a Storm Event: Assessing Relationships Between Dissolved Organic Matter, Sediment Concentrations, and Hydrologic Processes

Dissolved organic matter (DOM) dynamics during storm events has received considerable attention in forested watersheds, but the extent to which storms impart rapid changes in DOM concentration and composition in highly disturbed agricultural watersheds remains poorly understood. In this study, we used identical in situ optical sensors for DOM fluorescence (FDOM) with and without filtration to continuously evaluate surface water DOM dynamics in a 415 km(2) agricultural watershed over a 4 week period containing a short-duration rainfall event. Peak turbidity preceded peak discharge by 4 h and increased by over 2 orders of magnitude, while the peak filtered FDOM lagged behind peak turbidity by 15 h. FDOM values reported using the filtered in situ fluorometer increased nearly fourfold and were highly correlated with dissolved organic carbon (DOC) concentrations (r(2) = 0.97), providing a highly resolved proxy for DOC throughout the study period. Discrete optical properties including specific UV absorbance (SUVA(254)), spectral slope (S(290-350)), and fluorescence index (FI) were also strongly correlated with in situ FDOM and indicate a shift toward aromatic, high molecular weight DOM from terrestrially derived sources during the storm. The lag of the peak in FDOM behind peak discharge presumably reflects the draining of watershed soils from natural and agricultural landscapes. Field and experimental evidence showed that unfiltered FDOM measurements underestimated filtered FDOM concentrations by up to similar to 60% at particle concentrations typical of many riverine systems during hydrologic events. Together, laboratory and in situ data provide insights into the timing and magnitude of changes in DOM quantity and quality during storm events in an agricultural watershed, and indicate the need for sample filtration in systems with moderate to high suspended sediment loads

Managed Aquifer Recharge as a Tool to Enhance Sustainable Groundwater Management in California

A growing population and an increased demand for water resources have resulted in a global trend of groundwater depletion. Arid and semi-arid climates are particularly susceptible, often relying on groundwater to support large population centers or irrigated agriculture in the absence of sufficient surface water resources. In an effort to increase the security of groundwater resources, managed aquifer recharge (MAR) programs have been developed and implemented globally. MAR is the approach of intentionally harvesting and infiltrating water to recharge depleted aquifer storage. California is a prime example of this growing problem, with three cities that have over a million residents and an agricultural industry that was valued at 47 billion dollars in 2015. The present-day groundwater overdraft of over 100 km3 (since 1962) indicates a clear disparity between surface water supply and water demand within the state. In the face of groundwater overdraft and the anticipated effects of climate change, many new MAR projects are being constructed or investigated throughout California, adding to those that have existed for decades. Some common MAR types utilized in California include injection wells, infiltration basins (also known as spreading basins, percolation basins, or recharge basins), and low-impact development. An emerging MAR type that is actively being investigated is the winter flooding of agricultural fields using existing irrigation infrastructure and excess surface water resources, known as agricultural MAR. California therefore provides an excellent case study to look at the historical use and performance of MAR, ongoing and emerging challenges, novel MAR applications, and the potential for expansion of MAR. Effective MAR projects are an essential tool for increasing groundwater security, both in California and on a global scale. This chapter aims to provide an overview of the most common MAR types and applications within the State of California and neighboring semi-arid regions

RTOG/NRG 1115 Quality of Life of Phase III Dose Escalated Radiation Therapy (RT) and Standard Androgen Deprivation Therapy (ADT) with GnRH Agonist vs. Dose Escalated RT and ADT with GnRH Agonist and Orteronel (TAK-700) for Men with High-Risk Prostate

Purpose/Objective(s): Quality of life (QOL) was assessed with the hypothesis that QOL and fatigue scores would not differ significantly between the ADT + RT (Arm A) and the experimental group receiving ADT + RT + oreteronel (Arm B). Materials/Methods: In both arms, ADT with GnRH agonist was given for 24 mos, and dose escalated RT started 8-10 wks after initiation of ADT. In Arm B, oreteronel was given BID for 24 mos. QOL was measured with Expanded Prostate Cancer Index Composite (EPIC) and EQ-5D global QOL assessment. EPIC has 4 domains: bowel, urinary, sexual, and hormonal. EQ-5D index score was calculated using health states obtained from 5 dimensions, and a visual analog score (VAS). For EPIC, EQ-5D index and VAS, higher scores indicate better QOL. Fatigue was measured by the 7-item Patient-Reported Outcome Measurement Information System (PROMIS) short form. Total score is standardized into a T-score with mean of 50 and standard deviation of 10 with higher score representing more fatigue. Change scores, calculated as follow-up minus baseline, were compared between arms. Longitudinal analysis using repeated measures mixed effects models was conducted (prior to ADT [baseline], one wk prior to starting RT, last wk of RT, and 1 and 2.5 yrs after initiation of therapy). Results: Of 231 eligible patients, 196 consented to QOL, 102 on Arm A and 94 on Arm B. Compliance prior to start of RT and end of RT was 83%. At 1 and 2.5 yrs, 80% and 62% of pts, respectively, completed the EPIC. There were no differences between any EPIC domain between arms from the start of RT through the end of follow-up. Men on oreteronel had a significantly greater decline in bowel score prior to starting RT then control patients (-6.12, 95% confidence interval [CI]: -9.24, -3.01 vs. -1.93, 95% CI: -4.48, 0.63, respectively, p=0.038). Arm B patients also had a statistically significant and clinically meaningful worse change in urinary score vs control from baseline to pre-RT (-2.33, 95% CI: -5.02, 0.36 vs. 1.38, 95% CI: -1.07, 3.83, respectively, p=0.043). No other timepoints were significant. The only sig. between arm difference in EPIC sexual and hormonal scores was also at pre-RT in favor of Arm A over Arm B; p=0.024 and p=0.0024 respectively). Fatigue was also greater in the oreteronel patients prior to starting RT (3.81, 95% CI: 1.88, 5.74 vs. 1.18, 95% CI: -0.23, 2.60, p=0.028). Conclusion: The addition of oreteronel to RT and ADT resulted in greater declines in QOL prior to the start of RT but did not result in significant differences at any other time points. Although oreteronel development has been halted, the QOL results are encouraging for other drugs in this class that remain under investigation. In ongoing prospective trials, QOL impacts should be measured in conjunction with changes in clinical outcome and survival. This project was supported by grants UG1CA189867, U10CA180868, U10CA180822 from the National Cancer Institute and Takeda Pharmaceutical

Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators

Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on differential single-cell gene expression analysis of mesenchymal osteolineage cells close to and further removed from hematopoietic stem/progenitor cells to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. Amongst the genes which were preferentially expressed in proximal cells, we functionally examined three secreted or cell surface molecules not previously connected to HSPC biology: the secreted RNase Angiogenin, the cytokine IL18 and the adhesion molecule Embigin and discovered that all of these factors are HSPC quiescence regulators. Our proximity-based differential single cell approach therefore reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance understanding of microenvironmental regulation of stem cell function

Warming Can Boost Denitrification Disproportionately Due to Altered Oxygen Dynamics

Background: Global warming and the alteration of the global nitrogen cycle are major anthropogenic threats to the environment. Denitrification, the biological conversion of nitrate to gaseous nitrogen, removes a substantial fraction of the nitrogen from aquatic ecosystems, and can therefore help to reduce eutrophication effects. However, potential responses of denitrification to warming are poorly understood. Although several studies have reported increased denitrification rates with rising temperature, the impact of temperature on denitrification seems to vary widely between systems. Methodology/Principal Findings: We explored the effects of warming on denitrification rates using microcosm experiments, field measurements and a simple model approach. Our results suggest that a three degree temperature rise will double denitrification rates. By performing experiments at fixed oxygen concentrations as well as with oxygen concentrations varying freely with temperature, we demonstrate that this strong temperature dependence of denitrification can be explained by a systematic decrease of oxygen concentrations with rising temperature. Warming decreases oxygen concentrations due to reduced solubility, and more importantly, because respiration rates rise more steeply with temperature than photosynthesis. Conclusions/Significance: Our results show that denitrification rates in aquatic ecosystems are strongly temperature dependent, and that this is amplified by the temperature dependencies of photosynthesis and respiration. Our result

Cotranscriptional recruitment of the nuclear poly(A)-binding protein Pab2 to nascent transcripts and association with translating mRNPs

Synthesis of the pre-mRNA poly(A) tail in the nucleus has important consequences on the translational activity of the mature mRNA in the cytoplasm. In most eukaryotes, nuclear polyadenylation of pre-mRNAs is thought to require the nuclear poly(A)-binding protein (PABP2/PABPN1) for poly(A) tail synthesis and ultimate length control. As yet, however, the extent of the association between PABP2 and the exported mRNA remains poorly understood. Here, we used chromatin immunoprecipitation (ChIP) assays to show that the fission yeast ortholog of mammalian PABP2 (Pab2) is cotranscriptionally recruited to active genes. Notably, the association of Pab2 to genes precedes that of a typical 3′-processing/polyadenylation factor, suggesting that Pab2 recruitment during the transcription cycle precedes polyadenylation. The inclusion of an RNase step in our ChIP and immunoprecipitation assays suggests that Pab2 is cotranscriptionally recruited via nascent mRNA ribonucleoprotein (mRNPs). Tandem affinity purification coupled with mass spectrometry also revealed that Pab2 associates with several ribosomal proteins as well as general translation factors. Importantly, whereas previous results suggest that the nuclear poly(A)-binding protein is not present on cytoplasmic mRNAs, we show that fission yeast Pab2 is associated with polysomes. Our findings suggest that Pab2 is recruited to nascent mRNPs during transcription and remains associated with translated mRNPs after nuclear export