HESS Opinions: "Climate, hydrology, energy, water: recognizing uncertainty and seeking sustainability"

Since 1990 extensive funds have been spent on research in climate change. Although Earth Sciences, including climatology and hydrology, have benefited significantly, progress has proved incommensurate with the effort and funds, perhaps because these disciplines were perceived as “tools” subservient to the needs of the climate change enterprise rather than autonomous sciences. At the same time, research was misleadingly focused more on the “symptom”, i.e. the emission of greenhouse gases, than on the “illness”, i.e. the unsustainability of fossil fuel-based energy production. Unless energy saving and use of renewable resources become the norm, there is a real risk of severe socioeconomic crisis in the not-too-distant future. A framework for drastic paradigm change is needed, in which water plays a central role, due to its unique link to all forms of renewable energy, from production (hydro and wave power) to storage (for time-varying wind and solar sources), to biofuel production (irrigation). The extended role of water should be considered in parallel to its other uses, domestic, agricultural and industrial. Hydrology, the science of water on Earth, must move towards this new paradigm by radically rethinking its fundamentals, which are unjustifiably trapped in the 19thcentury myths of deterministic theories and the zeal to eliminate uncertainty. Guidance is offered by modern statistical and quantum physics, which reveal the intrinsic character of uncertainty/entropy in nature, thus advancing towards a new understanding and modelling of physical processes, which is central to the effective use of renewable energy and water resources

Resolving conflicting objectives in the management of the Plastiras Lake: Can we quantify beauty?

The possible water management of the Plastiras Lake, an artificial reservoir in central Greece, is examined. The lake and surrounding landscape are aesthetically degraded when the water level drops, and the requirement of maintaining a high quality of the scenery constitutes one of the several conflicting water uses, the other ones being irrigation, water supply, and power production. This environmental water use, and, to a lesser extent, the requirement for adequate water quality, results in constraining the annual release. Thus, the allowed fluctuation of reservoir stage is not defined by the physical and technical characteristics of the reservoir, but by a multi-criteria decision, the three criteria being maximising water release, ensuring adequate water quality, and maintaining a high quality of the natural landscape. Each of these criteria is analyzed separately. The results are then put together in a multicriterion tableau, which helps understand the implications of the possible alternative decisions. Several conflict resolution methods are overviewed, namely willingness to pay, hedonic prices, and multi-criteria decision analysis. All these methods attempt to quantify non-quantifiable qualities, and it is concluded that they don't necessarily offer any advantage over merely making a choice based on understanding

A Case of Pulmonary-Renal Syndrome Leading to the Diagnosis of Legionnaires’ Disease

We report a case of a 51-year-old Caucasian man referred at our department due to acute renal failure (ARF) complicating respiratory failure during hospitalization in a regional hospital. The patient was previously started on steroids due to the suspicion of rapidly progressive glomerulonephritis (RPGN) in the context of Goodpasture syndrome. However, clinical and laboratory findings did not support this diagnosis; instead a careful evaluation limited differential diagnosis of the renal insult to acute tubular necrosis or acute interstitial nephritis (AIN) following respiratory infection. With lung function fully improved but renal function not recovering, a renal biopsy revealed AIN, a finding leading to further diagnostic testing and finally to the diagnosis of Legionnaires’ disease as a cause of this patient’s pulmonary-renal syndrome. The management consisted of progressive tapering of oral steroids associated with full recovery of the patient’s renal function. This is a rare case of Legionnaires’ disease causing immune-mediated AIN and highlights the possibility of Legionella infection as a cause of pulmonary-renal syndrome

3D superimposition of craniofacial imaging—The utility of multicentre collaborations

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149360/1/ocr12281.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149360/2/ocr12281_am.pd

Combination of RNA interference and U1 inhibition leads to increased inhibition of gene expression

RNA interference (RNAi) has been revolutionary for the specific inhibition of gene expression. However, the application of RNAi has been hampered by the fact that many siRNAs induce dose-dependent unwanted secondary effects. Therefore, new methods to increase inhibition of gene expression with low doses of inhibitors are required. We have tested the combination of RNAi and U1i (U1 small nuclear RNA—snRNA—interference). U1i is based on U1 inhibitors (U1in), U1 snRNA molecules modified to target a pre-mRNA and inhibit its gene expression by blocking nuclear polyadenylation. The combination of RNAi and U1i resulted in stronger inhibition of reporter or endogenous genes than that obtained using either of the techniques alone. The increased inhibition observed is stable over time and allows higher inhibition than the best obtained with either of the inhibitors alone even with decreased doses of the inhibitors. We believe that the combination of RNAi and U1i will be of interest when higher inhibition is required or when potent inhibitors are not available. Also, the combination of these techniques would allow functional inhibition with a decreased dose of inhibitors, avoiding toxicity due to dose-dependent unwanted effects

Development of operating rules for a complex multireservoir system by coupling genetic algorithms and network optimization

This is an Accepted Manuscript of an article published in Hydrological Sciences Journal on MAY 1 2013, available online: http://dx.doi.org/10.1080/02626667.2013.779777[EN] An alternative procedure for assessment of reservoir Operation Rules (ORs) under drought situations is proposed. The definition of ORs for multi-reservoir water resources systems (WRSs) is a topic that has been widely studied by means of optimization and simulation techniques. A traditional approach is to link optimization methods with simulation models. Thus the objective here is to obtain drought ORs for a real and complex WRS: the Júcar River basin in Spain, in which one of the main issues is the resource allocation among agricultural demands in periods of drought. To deal with this problem, a method based on the combined use of genetic algorithms (GA) and network flow optimization (NFO) is presented. The GA used was PIKAIA, which has previously been used in other water resources related fields. This algorithm was linked to the SIMGES simulation model, a part of the AQUATOOL decision support system (DSS). Several tests were developed for defining the parameters of the GA. The optimization of various ORs was analysed with the objective of minimizing short-term and long-term water deficits. The results show that simple ORs produce similar results to more sophisticated ones. The usefulness of this approach in the assessment of ORs for complex multi-reservoir systems is demonstrated.The authors wish to thank the Confederacion Hidrogrofica del Jucar (Spanish Ministry of the Environment) for the data provided in developing this study and the Comision Interministerial de Ciencia y Tecnologia, CICYT (Spanish Ministry of Science and Innovation) for funding the projects INTEGRAME (contract CGL2009-11798) and SCARCE (programme Consolider-Ingenio 2010, project CSD2009-00065). The authors also thank the European Commission (Directorate-General for Research and Innovation) for funding the project DROUGHT-R&SPI (programme FP7-ENV-2011, project 282769) and the Seventh Framework Programme of the European Commission for funding the project SIRIUS (FP7-SPACE-2010-1, project 262902). We are grateful to the reviewers for their valuable comments, which have improved this paper.Lerma Elvira, N.; Paredes Arquiola, J.; Andreu Álvarez, J.; Solera Solera, A. (2013). Development of operating rules for a complex multireservoir system by coupling genetic algorithms and network optimization. Hydrological Sciences Journal. 58(4):797-812. https://doi.org/10.1080/02626667.2013.779777S79781258

A statistical method for excluding non-variable CpG sites in high-throughput DNA methylation profiling

<p>Abstract</p> <p>Background</p> <p>High-throughput DNA methylation arrays are likely to accelerate the pace of methylation biomarker discovery for a wide variety of diseases. A potential problem with a standard set of probes measuring the methylation status of CpG sites across the whole genome is that many sites may not show inter-individual methylation variation among the biosamples for the disease outcome being studied. Inclusion of these so-called "non-variable sites" will increase the risk of false discoveries and reduce statistical power to detect biologically relevant methylation markers.</p> <p>Results</p> <p>We propose a method to estimate the proportion of non-variable CpG sites and eliminate those sites from further analyses. Our method is illustrated using data obtained by hybridizing DNA extracted from the peripheral blood mononuclear cells of 311 samples to an array assaying 1505 CpG sites. Results showed that a large proportion of the CpG sites did not show inter-individual variation in methylation.</p> <p>Conclusions</p> <p>Our method resulted in a substantial improvement in association signals between methylation sites and outcome variables while controlling the false discovery rate at the same level.</p

Deletion Hotspots in AMACR Promoter CpG Island Are cis-Regulatory Elements Controlling the Gene Expression in the Colon

Alpha-methylacyl-coenzyme A racemase (AMACR) regulates peroxisomal β-oxidation of phytol-derived, branched-chain fatty acids from red meat and dairy products — suspected risk factors for colon carcinoma (CCa). AMACR was first found overexpressed in prostate cancer but not in benign glands and is now an established diagnostic marker for prostate cancer. Aberrant expression of AMACR was recently reported in Cca; however, little is known about how this gene is abnormally activated in cancer. By using a panel of immunostained-laser-capture-microdissected clinical samples comprising the entire colon adenoma–carcinoma sequence, we show that deregulation of AMACR during colon carcinogenesis involves two nonrandom events, resulting in the mutually exclusive existence of double-deletion at CG3 and CG10 and deletion of CG12-16 in a newly identified CpG island within the core promoter of AMACR. The double-deletion at CG3 and CG10 was found to be a somatic lesion. It existed in histologically normal colonic glands and tubular adenomas with low AMACR expression and was absent in villous adenomas and all CCas expressing variable levels of AMACR. In contrast, deletion of CG12-16 was shown to be a constitutional allele with a frequency of 43% in a general population. Its prevalence reached 89% in moderately differentiated CCas strongly expressing AMACR but only existed at 14% in poorly differentiated CCas expressing little or no AMACR. The DNA sequences housing these deletions were found to be putative cis-regulatory elements for Sp1 at CG3 and CG10, and ZNF202 at CG12-16. Chromatin immunoprecipitation, siRNA knockdown, gel shift assay, ectopic expression, and promoter analyses supported the regulation by Sp1 and ZNF202 of AMACR gene expression in an opposite manner. Our findings identified key in vivo events and novel transcription factors responsible for AMACR regulation in CCas and suggested these AMACR deletions may have diagnostic/prognostic value for colon carcinogenesis

Chemotherapy induces Notch1-dependent MRP1 up-regulation, inhibition of which sensitizes breast cancer cells to chemotherapy

Background Multi-drug Resistance associated Protein-1 (MRP1) can export chemotherapeutics from cancer cells and is implicated in chemoresistance, particularly as is it known to be up-regulated by chemotherapeutics. Our aims in this study were to determine whether activation of Notch signalling is responsible for chemotherapy-induced MRP1 expression Notch in breast cancers, and whether this pathway can be manipulated with an inhibitor of Notch activity. Methods MRP1 and Notch1 were investigated in 29 patients treated with neoadjuvant chemotherapy (NAC) for breast cancer, using immunohistochemistry on matched biopsy (pre-NAC) and surgical samples (post-NAC). Breast epithelial cell cultures (T47D, HB2) were treated with doxorubicin in the presence and absence of functional Notch1, and qPCR, siRNA, Western blots, ELISAs and flow-cytometry were used to establish interactions. Results In clinical samples, Notch1 was activated by neoadjuvant chemotherapy (Wilcoxon signed-rank p < 0.0001) and this correlated with induction of MRP1 expression (rho = 0.6 p = 0.0008). In breast cell lines, doxorubicin induced MRP1 expression and function (non-linear regression p < 0.004). In the breast cancer line T47D, doxorubicin activated Notch1 and, critically, inhibition of Notch1 activation with the γ-secretase inhibitor DAPT abolished the doxorubicin-induced increase in MRP1 expression and function (t-test p < 0.05), resulting in enhanced cellular retention of doxorubicin and increased doxorubicin-induced apoptosis (t-test p = 0.0002). In HB2 cells, an immortal but non-cancer derived breast cell line, Notch1-independent MRP1 induction was noted and DAPT did not enhance doxorubicin-induced apoptosis. Conclusions Notch inhibitors may have potential in sensitizing breast cancer cells to chemotherapeutics and therefore in tackling chemoresistance

Identification of Sequence Variants in Genetic Disease-Causing Genes Using Targeted Next-Generation Sequencing

Identification of gene variants plays an important role in research on and diagnosis of genetic diseases. A combination of enrichment of targeted genes and next-generation sequencing (targeted DNA-HiSeq) results in both high efficiency and low cost for targeted sequencing of genes of interest.To identify mutations associated with genetic diseases, we designed an array-based gene chip to capture all of the exons of 193 genes involved in 103 genetic diseases. To evaluate this technology, we selected 7 samples from seven patients with six different genetic diseases resulting from six disease-causing genes and 100 samples from normal human adults as controls. The data obtained showed that on average, 99.14% of 3,382 exons with more than 30-fold coverage were successfully detected using Targeted DNA-HiSeq technology, and we found six known variants in four disease-causing genes and two novel mutations in two other disease-causing genes (the STS gene for XLI and the FBN1 gene for MFS) as well as one exon deletion mutation in the DMD gene. These results were confirmed in their entirety using either the Sanger sequencing method or real-time PCR.Targeted DNA-HiSeq combines next-generation sequencing with the capture of sequences from a relevant subset of high-interest genes. This method was tested by capturing sequences from a DNA library through hybridization to oligonucleotide probes specific for genetic disorder-related genes and was found to show high selectivity, improve the detection of mutations, enabling the discovery of novel variants, and provide additional indel data. Thus, targeted DNA-HiSeq can be used to analyze the gene variant profiles of monogenic diseases with high sensitivity, fidelity, throughput and speed