Increased C3 productivity in Midwestern lawns since 1982 revealed by carbon isotopes in Amanita thiersii

How climate and rising carbon dioxide concentrations (pCO2) have influenced competition between C3 and C4 plants over the last 50 years is a critical uncertainty in climate change research. Here we used carbon isotope (δ13C) values of the saprotrophic lawn fungus Amanita thiersii to integrate the signal of C3 and C4 carbon in samples collected between 1982 and 2009 from the Midwestern USA. We then calculated 13C fractionation (Δ) to assess the balance between C3 and C4 photosynthesis as influenced by mean annual temperature (MAT), mean annual precipitation over a 30 year period (MAP‐30), and pCO2. Sporocarp Δ correlated negatively with MAT (−1.74‰ °C−1, 79% of variance) and positively with MAP (9.52‰ m−1, 15% of variance), reflecting the relative productivity of C3 and C4 grasses in lawns. In addition, Δ values correlated positively with pCO2 (0.072‰ ppm−1, 5% of variance). Reduced photorespiration with rising pCO2 accounted for 20% of this increased Δ, but the remaining 80% is consistent with increased assimilation of C3‐derived carbon by Amanita thiersii resulting from increased productivity of C3 grasses with rising pCO2. Between 1982 and 2009, pCO2 rose by 46 ppm and the relative contribution of C3 photosynthesis to Amanita thiersii carbon increased 18.5%. The δ13C value of Amanita thiersii may integrate both lawn maintenance practices and the physiological responses of turf grasses to rising CO2 concentrations

The Carbon Isotope Organic Geochemistry of Early Ordovician Rocks from the Annascaul Formation, County Kerry

Ireland is well known to geologists as containing some of the thickest successions of Early Ordovician (485-470 Ma; Walker et al. 2012) sedimentary rocks in the world. The carbon stable isotope compositions (δ13C value) of similarly aged rocks have been reported for only very few places in the world (i.e., Argentina, southern China, and southern France), and no such analyses have been performed on the Early Ordovician, organic-rich rocks of Ireland. Here we report the δ13C values of bulk organic material and organic isolates recovered from the Annascaul Formation of Southwestern Ireland. Members of the Annascaul Formation spanning the Early Ordovician were sampled at multiple sites within five localities on the Dingle Peninsula, County Kerry. Mean bulk organic δ13C values for the organic matter within rocks of the Farranacarriga, Tinal, Illaunglass, Bealacoon, and Killelton Members ranged from -28.7‰ (Farranacarriga) to -22.1‰ (Illaunglass); the average δ13C values of organics isolated from the Farranacarriga and Bealacoon Members were -29.0 and -28.4‰, respectively. No statistical difference was observed between the δ13C value of isolates and the δ13C value of bulk sediment from which organics had been isolated (P-0.85, Farranacarriga, n-6; P-0.81, Bealacoon, n-5; paired t-test). The δ13C values we present here agree well with the previously published δ13C values for Early Ordovician organic carbon (average = -28.4, -25.4, -25.5‰) from Argentina, southern China, and southern France (respectively). Our new data from the Annascaul Formation are ∼3.3‰ higher than the average value reported for δ13C values of organic matter of marine origin for the same period, raising the possibility that terrestrial bryophytes (or other terrestrial photosynthesizers) contributed to these Early Ordovician sediments. Further equivocal evidence is provided by the abundant organic macerals found within the Farranacarriga Member with possible vitrinite origin. The δ13C values of palynomorphsized organic isolates from the Annascaul Formation reflect a marine origin for these organisms, consistent with their previous identification as acritarchs. Given the recognition of the earliest thalloid macrofossils and land-plant cryptospores in the Middle Ordovician sediments of the Appalachian basin (USA) and Argentina, respectively, our results highlight the Early-Middle Ordovician boundary as a potentially crucial time of terrestrial ecosystem expansion and development

Nd Isotopic Structure of the Pacific Ocean 70-30 and Numerical Evidence for Vigorous Ocean Circulation and Ocean Heat Transport in a Greenhouse World

The oceanic meridional overturning circulation (MOC) is a crucial component of the climate system, impacting heat and nutrient transport, and global carbon cycling. Past greenhouse climate intervals present a paradox because their weak equator-to-pole temperature gradients imply a weaker MOC, yet increased poleward oceanic heat transport appears to be required to maintain these weak gradients. To investigate the mode of MOC that operated during the early Cenozoic, we compare new Nd isotope data with Nd tracer-enabled numerical ocean circulation and coupled climate model simulations. Assimilation of new Nd isotope data from South Pacific Deep Sea Drilling Project and Ocean Drilling Program Sites 323, 463, 596, 865, and 869 with previously published data confirm the hypothesized MOC characterized by vigorous sinking in the South and North Pacific ~70 to 30 Ma. Compilation of all Pacific Nd isotope data indicates vigorous, distinct, and separate overturning circulations in each basin until ~40 Ma. Simulations consistently reproduce South Pacific and North Pacific deep convection over a broad range of conditions, but cases using strong deep ocean vertical mixing produced the best data-model match. Strong mixing, potentially resulting from enhanced abyssal tidal dissipation, greater interaction of wind-driven internal wave activity with submarine plateaus, or higher than modern values of the geothermal heat flux enable models to achieve enhanced MOC circulation rates with resulting Nd isotope distributions consistent with the proxy data. The consequent poleward heat transport may resolve the paradox of warmer worlds with reduced temperature gradients

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women

Background Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. Objective We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. Study Design Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days’ and 22 weeks 6 days’ gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. Results Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. Conclusion In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies

Hairpin ribozyme-antisense RNA constructs can act as molecular lassos

We have developed a novel class of antisense agents, RNA Lassos, which are capable of binding to and circularizing around complementary target RNAs. The RNA Lasso consists of a fixed sequence derived from the hairpin ribozyme and an antisense segment whose size and sequence can be varied to base pair with accessible sites in the target RNA. The ribozyme catalyzes self-processing of the 5′- and 3′-ends of a transcribed Lasso precursor and ligates the processed ends to produce a circular RNA. The circular and linear forms of the self-processed Lasso coexist in an equilibrium that is dependent on both the Lasso sequence and the solution conditions. Lassos form strong, noncovalent complexes with linear target RNAs and form true topological linkages with circular targets. Lasso complexes with linear RNA targets were detected by denaturing gel electrophoresis and were found to be more stable than ordinary RNA duplexes. We show that expression of a fusion mRNA consisting of a sequence from the murine tumor necrosis factor-α (TNF-α) gene linked to luciferase reporter can be specifically and efficiently blocked by an anti-TNF Lasso. We also show in cell culture experiments that Lassos directed against Fas pre-mRNA were able to induce a change in alternative splicing patterns

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists