Analysis of Nitrogen Loading Reductions for Wastewater Treatment Facilities and Non-Point Sources in the Great Bay Estuary Watershed

In 2009, the New Hampshire Department of Environmental Services (DES) published a proposal for numeric nutrient criteria for the Great Bay Estuary. The report found that total nitrogen concentrations in most of the estuary needed to be less than 0.3 mg N/L to prevent loss of eelgrass habitat and less than 0.45 mg N/L to prevent occurrences of low dissolved oxygen. Based on these criteria and an analysis of a compilation of data from at least seven different sources, DES concluded that 11 of the 18 subestuaries in the Great Bay Estuary were impaired for nitrogen. Under the Clean Water Act, if a water body is determined to be impaired, a study must be completed to determine the existing loads of the pollutant and the load reductions that would be needed to meet the water quality standard. Therefore, DES developed models to determine existing nitrogen loads and nitrogen loading thresholds for the subestuaries to comply with the numeric nutrient criteria. DES also evaluated the effects of different permitting scenarios for wastewater treatment facilities on nitrogen loads and the costs for wastewater treatment facility upgrades. This modeling exercise showed that: Nitrogen loads to the Great Bay, Little Bay, and the Upper Piscataqua River need to be reduced by 30 to 45 percent to attain the numeric nutrient criteria. Both wastewater treatment facilities and non-point sources will need to reduce nitrogen loads to attain the numeric nutrient criteria. The percent reduction targets for nitrogen loads only change minimally between wet and dry years. Wastewater treatment facility upgrades to remove nitrogen will be costly; however, the average cost per pound of nitrogen removed from the estuary due to wastewater facility upgrades is lower than for non-point source controls. The permitting options for some wastewater treatment facilities will be limited by requirements to not increase pollutant loads to impaired waterbodies. The numeric nutrient criteria and models used by DES are sufficiently accurate for calculating nitrogen loading thresholds for the Great Bay watershed. Additional monitoring and modeling is needed to better characterize conditions and nitrogen loading thresholds for the Lower Piscataqua River. This nitrogen loading analysis for Great Bay may provide a framework for setting nitrogen permit limits for wastewater treatment facilities and developing watershed implementation plans to reduce nitrogen loads

Great Bay Nitrogen Non-Point Source Study

The Great Bay Estuary is 21 square miles of tidal waters located in southeastern New Hampshire. It is one of 28 “estuaries of national significance” established under the Environmental Protection Agency’s National Estuary Program. The estuary is experiencing the signs of eutrophication, specifically, low dissolved oxygen, macroalgae blooms, and declining eelgrass habitat (DES, 2012). Sixty-eight percent of the nitrogen that ends up in the Great Bay Estuary originates from sources spread across the watershed; the remainder derives from direct discharges of municipal wastewater treatment facilities (DES, 2010; PREP, 2013). In this report, these sources of nitrogen are called non-point sources and consist of atmospheric deposition, fertilizers, human waste disposed into septic systems, and animal waste. The purpose of this study is to determine how much nitrogen each non-point source type contributes to the estuary. The nitrogen loads from municipal wastewater treatment facilities have been reported elsewhere (DES, 2010; PREP, 2012; PREP, 2013) and, therefore, are not included in this study except to provide context. The intended use of this study is for planning purposes, and is not meant for regulatory allocations or specific reduction requirements. The results of the model may be useful for towns or watershed groups for prioritizing nitrogen reduction efforts or as a starting point for more detailed studies of non-point sources. However, more detailed inventories of non-point sources will be needed to track the effects of nitrogen reduction efforts in smaller areas. In addition, the model makes no conclusions about the benefits of nitrogen reductions to receiving waters or overall estuarine health

Why Is Cardiac Morbidity and Mortality Greater Around Christmas, New Year’s, Monday Mornings and in the Morning Hours: Potential Roles of Unrecognized Ionized Hypomagnesemia and Release of Ceramides?

The following is the introduction to this article: There is a growing incidence of lethal cardiac events around Christmas, New Year’s and in the morning hours from 4:00 to 10:00 a.m. which is well-established in the USA and in The Southern Hemisphere [1-7]. In addition, many cardiac deaths often occur on Mondays with no satisfactory explanation [2,3]. Many of these deaths are, for the most part, unexplained and listed as “death from “natural causes”. Although in the USA, the deaths which occur around Christmas and New Years happen in the cold –winter months, this does not account for many cardiac incidences which occur throughout the year in the early a.m. hours or on Mondays. A number of explanations have been offered to explain the higher morbidities and mortalities at these special times of the year, morning hours and on Mondays, such as emotional stresses, too much ingestion of alcoholic beverages, improper medical facilities, diet, and/or changes in the physical environments [1-7]

A comparison of the development of audiovisual integration in children with autism spectrum disorders and typically developing children

This study aimed to investigate the development of audiovisual integration in children with Autism Spectrum Disorder (ASD). Audiovisual integration was measured using the McGurk effect in children with ASD aged 7–16 years and typically developing children (control group) matched approximately for age, sex, nonverbal ability and verbal ability. Results showed that the children with ASD were delayed in visual accuracy and audiovisual integration compared to the control group. However, in the audiovisual integration measure, children with ASD appeared to ‘catch-up’ with their typically developing peers at the older age ranges. The suggestion that children with ASD show a deficit in audiovisual integration which diminishes with age has clinical implications for those assessing and treating these children

Singularly Perturbed Monotone Systems and an Application to Double Phosphorylation Cycles

The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation ``futile cycle'' motif which plays a central role in eukaryotic cell signaling.Comment: 21 pages, 3 figures, corrected typos, references remove

Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene

G protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH β-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH(2)-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH β-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH(2)-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH β-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline

In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes

Hexamerization-enhanced CD20 antibody mediates complement-dependent cytotoxicity in serum genetically deficient in C9

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2 + during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2 + to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2 + signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2 + influx represents the most proximate mediator of cell death by CDC