Anatomy of the 2017 air quality emergency in Delhi.

The Indian capital Delhi experienced an environmental emergency in early November 2017 when levels of toxic PM2.5 particles surpassed WHO guidelines by 25 times (11 times by Indian Standards) for a prolonged period of a week (peak 24 h average ~650 µg/m3). We hereby demonstrate the role that monsoon dynamics played in linking and mixing dust emitted from a large natural dust storm, 3000 km away in the Middle East, with smoke from agriculture fires in northwest India. This dust and smoke rich air was then transported to Delhi where, under stagnant conditions, it mixed with local emissions resulting in very high pollution levels. The heavy aerosol-laden air altered the land-skin surface air temperature difference resulting in increased surface wind speeds, favouring faster dispersion and an unusual sharp decline in PM2.5 (PM2.5-110 µg/m3). Understanding the multi-scale nature of such events is important in improving our abilities to forecast these events and in developing effective air quality management strategies for the mega cities.

Key Issues for Seamless Integrated Chemistry-Meteorology Modeling.

Online coupled meteorology-atmospheric chemistry models have greatly evolved in recent years. Although mainly developed by the air quality modeling community, these integrated models are also of interest for numerical weather prediction and climate modeling, as they can consider both the effects of meteorology on air quality and the potentially important effects of atmospheric composition on weather. This paper summarizes the main conclusions from the "Symposium on Coupled Chemistry-Meteorology/Climate Modelling: Status and Relevance for Numerical Weather Prediction, Air Quality and Climate Research," which was initiated by the European COST Action ES1004 "European Framework for Online Integrated Air Quality and Meteorology Modelling (EuMetChem)." It offers a brief review of the current status of online coupled meteorology and atmospheric chemistry modeling and a survey of processes relevant to the interactions between atmospheric physics, dynamics, and composition. In addition, it highlights scientific issues and emerging challenges that require proper consideration to improve the reliability and usability of these models for three main application areas: air quality, meteorology (including weather prediction), and climate modeling. It presents a synthesis of scientific progress in the form of answers to nine key questions, and provides recommendations for future research directions and priorities in the development, application, and evaluation of online coupled models.

Metformin alters DNA methylation genome-wide via the H19/SAHH axis.

The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells.

The restoration of traumatized teeth.

The restoration of a traumatized tooth may require minimally invasive or more extensive treatment options. The majority of injuries occur in the younger population, so management should consider the long-term outcome, failure and future treatment needs over the course of, often, many decades. The aim should be to provide a tooth-restoration complex that closely mimics the functional and aesthetic qualities of an intact tooth for as long as possible. This narrative review will assess the relevant literature pertinent to restoration of traumatized teeth in order to provide guidance for the practising clinician.

Biofuels that cause land-use change may have much larger non-GHG air quality emissions than fossil fuels.

Although biofuels present an opportunity for renewable energy production, significant land-use change resulting from biofuels may contribute to negative environmental, economic, and social impacts. Here we examined non-GHG air pollution impacts from both indirect and direct land-use change caused by the anticipated expansion of Brazilian biofuels production. We synthesized information on fuel loading, combustion completeness, and emission factors, and developed a spatially explicit approach with uncertainty and sensitivity analyses to estimate air pollution emissions. The land-use change emissions, ranging from 6.7 to 26.4 Tg PM(2.5), were dominated by deforestation burning practices associated with indirect land-use change. We also found Brazilian sugar cane ethanol and soybean biodiesel including direct and indirect land-use change effects have much larger life-cycle emissions than conventional fossil fuels for six regulated air pollutants. The emissions magnitude and uncertainty decrease with longer life-cycle integration periods. Results are conditional to the single LUC scenario employed here. After LUC uncertainty, the largest source of uncertainty in LUC emissions stems from the combustion completeness during deforestation. While current biofuels cropland burning policies in Brazil seek to reduce life-cycle emissions, these policies do not address the large emissions caused by indirect land-use change.

Photosynthetic control of atmospheric carbonyl sulfide during the growing season.

Climate models incorporate photosynthesis-climate feedbacks, yet we lack robust tools for large-scale assessments of these processes. Recent work suggests that carbonyl sulfide (COS), a trace gas consumed by plants, could provide a valuable constraint on photosynthesis. Here we analyze airborne observations of COS and carbon dioxide concentrations during the growing season over North America with a three-dimensional atmospheric transport model. We successfully modeled the persistent vertical drawdown of atmospheric COS using the quantitative relation between COS and photosynthesis that has been measured in plant chamber experiments. Furthermore, this drawdown is driven by plant uptake rather than other continental and oceanic fluxes in the model. These results provide quantitative evidence that COS gradients in the continental growing season may have broad use as a measurement-based photosynthesis tracer.

How a small DNA virus uses dsRNA but not RNAi to regulate its life cycle.

Mouse polyomavirus contains a circular DNA genome, with early and late genes transcribed from opposite strands. At early times after infection, genes encoded from the early transcription unit are predominantly expressed. After the onset of viral DNA replication, expression of genes encoded from the late transcription unit increases dramatically. At late times, late primary transcripts are inefficiently polyadenylated, leading to the generation of multigenomic RNAs that are precursors to mature mRNAs. These transcripts contain sequences complementary to the early RNAs and downregulate early-strand gene expression by inducing RNA editing. Our recent work leads to a model where the production of the multigenomic late RNAs is also controlled by the editing of poly(A) signals, directed by overlapping primary transcripts.

The effect of the limited availability of H2O2 in the competitive deposition of sulfur and oxidized nitrogen.

To understand the influence of the reduction of SO2 emissions from a single source in the S and N deposition around its local environment, the application of the Sulphur Transport Eulerian Model 2 (STEM-II) was introduced in this paper. Observed local deposition patterns were analysed and explained in terms of the main processes involved in the pollutants deposition. It was necessary to take into account the limited availability of H2O2 because of its influence on both S(IV) and oxidized nitrogen deposition. In order to estimate the quantitative relationship between the SO2 emissions reduction and the observed S and N deposition patterns, these processes were simulated for different meteorological conditions. Simulation results were in agreement with both observed deposition patterns and limited availability of H2O2, specially if significant changes in the S deposition patterns were considered. Both observed and estimated S deposition patterns changed their top value location from the Southwest (1990) to the Northwest (1997) of the domain, because of the reduction of dry deposition. The global reduction of total S depositions, estimated and observed, were in good agreement too. Model simulations could explain the higher S dry deposition reduction, considering the emissions reduction strategy applied.

The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs.

How do cells discriminate between selectively edited mRNAs that encode new protein isoforms, and dsRNA-induced, promiscuously edited RNAs that encode nonfunctional, mutant proteins? We have developed a Xenopus oocyte model system which shows that a variety of hyperedited, inosine-containing RNAs are specifically retained in the nucleus. To uncover the mechanism of inosine-induced retention, HeLa cell nuclear extracts were used to isolate a multiprotein complex that binds specifically and cooperatively to inosine-containing RNAs. This complex contains the inosine-specific RNA binding protein p54(nrb), the splicing factor PSF, and the inner nuclear matrix structural protein matrin 3. We provide evidence that one function of the complex identified here is to anchor hyperedited RNAs to the nuclear matrix, while allowing selectively edited mRNAs to be exported.

Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation.

Hormones and growth factors induce protein translation in part by phosphorylation of the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). The rapamycin and FK506-binding protein (FKBP)-target 1 (RAFT1, also known as FRAP) is a mammalian homolog of the Saccharomyces cerevisiae target of rapamycin proteins (mTOR) that regulates 4E-BP1. However, the molecular mechanisms involved in growth factor-initiated phosphorylation of 4E-BP1 are not well understood. Here we demonstrate that protein kinase Cdelta (PKCdelta) associates with RAFT1 and that PKCdelta is required for the phosphorylation and inactivation of 4E-BP1. PKCdelta-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. As shown for serum, phosphorylation of 4E-BP1 by PKCdelta inhibits the interaction between 4E-BP1 and eIF4E and stimulates cap-dependent translation. Moreover, a dominant-negative mutant of PKCdelta inhibits serum-induced phosphorylation of 4E-BP1. These findings demonstrate that PKCdelta associates with RAFT1 and thereby regulates phosphorylation of 4E-BP1 and cap-dependent initiation of protein translation.

Acid rain and acidification in China: the importance of base cation deposition.

Acid deposition has been recognized as a serious environmental problem in China. Most acid deposition studies have focused on sulfur deposition and the pH of precipitation. However, as high concentration of alkaline dust is an important feature of the atmosphere in large parts of China, base cation deposition must be taken into account when discussing possible effects on soils and vegetation from acid deposition. We estimate the deposition of sulfur as well as calcium, i.e. the dominating anion and cation, on a regional scale in China using data both from measurements and modeling. The ratio of sulfur/calcium in deposition is then used as an indicator for identifying areas where deposition acidity exceeds alkalinity, and where soils may be at risk to acidification. The dynamic soil acidification model MAGIC is applied with data from two sites receiving high deposition loads in southwest China. The model predictions indicate that considerable soil acidification has been going on for the last decades due to acid deposition inputs. Effects on the spatial distribution of acidic deposition in China, using different future deposition scenarios, are illustrated. As the size of the anthropogenic fraction of the base cation deposition is unknown, different possible future trends in calcium deposition were used. Soil response, according to the model, using different combinations of sulfur and calcium deposition scenarios is shown. Applying the most strict measures to reduce sulfur emission will almost eliminate the acid deposition problem; however, such a scenario is not economically feasible in the short term. A strict, but possibly realistic, future scenario for sulfur may be enough to keep the situation at the present level, assuming only moderate reductions in calcium deposition. With large decreases in base cation deposition, increased soil acidification can be expected even with considerable sulfur emission reductions.

Regulation of the rapamycin and FKBP-target 1/mammalian target of rapamycin and cap-dependent initiation of translation by the c-Abl protein-tyrosine kinase.

The c-Abl protein-tyrosine kinase is activated by ionizing radiation and certain other DNA-damaging agents. The rapamycin and FKBP-target 1 (RAFT1), also known as FKBP12-rapamycin-associated protein (FRAP, mTOR), regulates the p70S6 kinase (p70(S6k)) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). The present results demonstrate that c-Abl binds directly to RAFT1 and phosphorylates RAFT1 in vitro and in vivo. c-Abl inhibits autophosphorylation of RAFT1 and RAFT1-mediated phosphorylation p70(S6k). The functional significance of the c-Abl-RAFT1 interaction is further supported by the finding that eIF4E-dependent translation in mouse embryo fibroblasts from Abl(-/-) mice is significantly higher than that compared in wild-type cells. The results also demonstrate that exposure of cells to ionizing radiation is associated with c-Abl-mediated binding of 4E-BP1 to eIF4E and inhibition of translation. These findings with the c-Abl tyrosine kinase represent the first demonstration of a negative physiologic regulator of RAFT1-mediated 5' cap-dependent translation.

A modification to enable controlled progressive advancement of the Twin Block appliance.

A modification of the Twin block appliance has been developed to facilitate controlled gradual advancement of the mandibular position during the treatment of Class II division I malocclusions. This features the incorporation of stainless steel screws with conical heads into the blocks of the upper appliance to provide the inclined plane effect. Advancement is by the addition of polyacetal spacers between the screw heads and the upper blocks. The system is designed to improve the clinical flexibility of the appliance and to enhance patient acceptance in cases where mandibular protrusion is limited initially. Another possible application is gradual reactivation for Class III correction. Other advantages are reduced laboratory and clinical time during reactivation of the appliance, and perhaps a more physiological response to the growth modification process. The design and construction of the advancement system is illustrated, and its clinical use discussed.

Intronless mRNA transport elements may affect multiple steps of pre-mRNA processing.

We have reported recently that a small element within the mouse histone H2a-coding region permits efficient cytoplasmic accumulation of intronless beta-globin cDNA transcripts. This sequence lowers the levels of spliced products from intron-containing constructs and can functionally replace Rev and the Rev-responsive element (RRE) in the nuclear export of unspliced HIV-1-related mRNAs. In work reported here, we further investigate the molecular mechanisms by which this element might work. We demonstrate here through both in vivo and in vitro assays that, in addition to promoting mRNA nuclear export, this element acts as a polyadenylation enhancer and as a potent inhibitor of splicing. Surprisingly, two other described intronless mRNA transport elements (from the herpes simplex virus thymidine kinase gene and hepatitis B virus) appear to function in a similar manner. These findings prompt us to suggest that a general feature of intronless mRNA transport elements might be a collection of phenotypes, including the inhibition of splicing and the enhancement of both polyadenylation and mRNA export.

Antisense RNA: function and fate of duplex RNA in cells of higher eukaryotes.

There is ample evidence that cells of higher eukaryotes express double-stranded RNA molecules (dsRNAs) either naturally or as the result of viral infection or aberrant, bidirectional transcriptional readthrough. These duplex molecules can exist in either the cytoplasmic or nuclear compartments. Cells have evolved distinct ways of responding to dsRNAs, depending on the nature and location of the duplexes. Since dsRNA molecules are not thought to exist naturally within the cytoplasm, dsRNA in this compartment is most often associated with viral infections. Cells have evolved defensive strategies against such molecules, primarily involving the interferon response pathway. Nuclear dsRNA, however, does not induce interferons and may play an important posttranscriptional regulatory role. Nuclear dsRNA appears to be the substrate for enzymes which deaminate adenosine residues to inosine residues within the polynucleotide structure, resulting in partial or full unwinding. Extensively modified RNAs are either rapidly degraded or retained within the nucleus, whereas transcripts with few modifications may be transported to the cytoplasm, where they serve to produce altered proteins. This review summarizes our current knowledge about the function and fate of dsRNA in cells of higher eukaryotes and its potential manipulation as a research and therapeutic tool.