ALBERT

Description: We investigate how the choice of injection mode impacts transport properties in kilometer-scale three-dimensional discrete fracture networks (DFN). The choice of injection mode, resident or flux-weighted, is designed to mimic different physical phenomena. It has been hypothesized that solute plumes injected under resident conditions evolve to behave similarly to solutes injected under flux-weighted conditions. Previously, computational limitations have prohibited the large scale simulations required to investigate this hypothesis. We investigate this hypothesis by using a high performance DFN suite, dfnWorks , to simulate flow in kilometer-scale three-dimensional DFNs based on fractured granite at the Forsmark site in Sweden, and adopt a Lagrangian approach to simulate transport therein. Results show that after traveling through a pre-equilibrium region both injection methods exhibit linear scaling of the first moment of travel time and power law scaling of the breakthrough curve with similar exponents, slightly larger than two. The physical mechanisms behind this evolution appear to be the combination of in-network channeling of mass into larger fractures, which offer reduced resistance to flow, and in-fracture channeling, which results from the topology of the DFN. This article is protected by copyright. All rights reserved.

Description: Hydrologic ensemble forecasts driven by atmospheric ensemble prediction systems need statistical post-processing in order to account for systematic errors in terms of both location and spread. Runoff is an inherently multivariate process with typical events lasting from hours in case of floods to weeks or even months in case of droughts. This calls for multivariate post-processing techniques that yield well calibrated forecasts in univariate terms and ensure a realistic temporal dependence structure at the same time. To this end, the univariate ensemble model output statistics (EMOS) post-processing method is combined with two different copula approaches that ensure multivariate calibration throughout the entire forecast horizon. The domain of this study covers three sub-catchments of the river Rhine that represent different sizes and hydrological regimes: the Upper Rhine up to the gauge Maxau, the river Moselle up to the gauge Trier, and the river Lahn up to the gauge Kalkofen. In this study the two approaches to model the temporal dependence structure are ensemble copula coupling (ECC), which preserves the dependence structure of the raw ensemble, and a Gaussian copula approach (GCA), which estimates the temporal correlations from training observations. The results indicate that both methods are suitable for modelling the temporal dependencies of probabilistic hydrologic forecasts. This article is protected by copyright. All rights reserved.

Description: A three-dimensional mathematical model that describes transport of contaminant in a horizontal aquifer with simultaneous diffusion into a fractured clay formation is proposed. A group of semi-analytical solutions is derived based on specific initial and boundary conditions as well as various source functions. The analytical model solutions are evaluated by numerical Laplace inverse transformation and analytical Fourier inverse transformation. The model solutions can be used to study the fate and transport in a three-dimensional spatial domain in which a non-aqueous phase liquid exists as a pool atop a fractured low permeability clay layer. The non-aqueous phase liquid gradually dissolves into the groundwater flowing past the pool, while simultaneously diffusing into the fractured clay formation below the aquifer. Mass transfer of the contaminant into the clay formation is demonstrated to be significantly enhanced by the existence of the fractures, even though the volume of fractures is relatively small compared to the volume of the clay matrix. The model solution is a useful tool in assessing contaminant attenuation processes in a confined aquifer underlain by a fractured clay formation. This article is protected by copyright. All rights reserved.

Description: World Health Organization reports that methicillin-resistant Staphylococcus aureus (MRSA) is the origin of higher proportion of hospital acquired infections. In order to combat the effect of MRSA infection, an ideal drug should stimulate the allosteric exposure of active site, prompting penicillin binding proteins (PBP2a) to bind with that particular compound. Ceftaroline shows high binding affinity towards PBP2a and also confers resistance against degrading enzymes. Recently, two amino acid alterations in the allosteric site of PBP2a, asparagine (N) to lysine (K) at position 146 and glutamic acid (E) to lysine at position 150 are reported to confer resistance against ceftaroline resulting in the rise of ceftaroline-resistant MRSA strains. The present study focuses on the identification of potential ligands that can effectively bind with allosteric site of PBP2a, that leads to the access of active site and entry of a β-lactam antibiotic for effective inhibition. The results obtained from our study will be useful for designing effective compounds with potential therapeutic effects against ceftaroline resistant MRSA strains. This article is protected by copyright. All rights reserved

Description: The human protein kinase X gene (PRKX) and cAMP-dependent protein kinase (PKA) are both c-AMP-dependent serine/threonine protein kinases within the protein kinase AGC subgroup. Of all the protein kinases in this group, PRKX is the least studied. PRKX has been isolated from patients with chondrodysplasia punctate and is involved in numerous processes, including sexual differentiation and fertilization, normal kidney development, and autosomal dominant polycystic kidney disease (ADPKD), blood maturation, neural development and angiogenesis in vitro. Although the role of PRKX in development and disease has been reported recently, the underlying mechanism of PRKX activity is largely unknown. In addition, based on the expression pattern of PRKX and the extensive role of PKA in disease and development, PRKX might have additional crucial functions that have not been addressed in the literature. In this review, we summarize the characteristics and developmental functions of PRKX that have been reported by recent studies. In particular, we elucidate the structural and functional differences between PRKX and PKA, as well as the possible roles of PRKX in development and related diseases. Finally, we propose future studies that could lead to important discoveries of more PRKX functions and the underlying mechanisms involved. This article is protected by copyright. All rights reserved

Description: Several key transcription factors regulate cell growth, survival, and differentiation during neural crest and melanoblast development in the embryo, and these same pathways may be reactivated in tumors arising from the progenitors of these cells. The transcription factors PAX3 and FOXD3 have essential roles in melanoblasts and melanoma. In this study, we define a regulatory pathway where FOXD3 promotes the expression of PAX3. Both factors are expressed in melanoma cells and there is a positive correlation between the transcript levels of PAX3 and FOXD3. The PAX3 gene contains two FOX binding motifs within highly conserved enhancer regulatory elements that are essential for neural crest development. FOXD3 binds to both of these motifs in vitro but only one of these sites is preferentially utilized in melanoma cells. Overexpression of FOXD3 upregulates PAX3 levels while inhibition of FOXD3 function does not alter PAX3 protein levels, supporting that FOXD3 is sufficient but not necessary to drive PAX3 expression in melanoma cells. Here, we identify a molecular pathway where FOXD3 upregulates PAX3 expression and therefore contributes to melanoma progression. This article is protected by copyright. All rights reserved

Description: Metabolic networks are significantly altered in neoplastic cells. This altered metabolic program leads to increased glycolysis and lipogenesis and decreased dependence on oxidative phosphorylation and oxygen consumption. Despite their limited mitochondrial respiration, cancer cells, nonetheless, derive sufficient energy from alternative carbon sources and metabolic pathways to maintain cell proliferation. They do so, in part, by utilizing fatty acids, amino acids, ketone bodies and acetate, in addition to glucose. The alternative pathways used in the metabolism of these carbon sources provide opportunities for therapeutic manipulation. Acetate, in particular, has garnered increased attention in the context of cancer as both an epigenetic regulator of posttranslational protein modification, and as a carbon source for cancer cell biomass accumulation. However, to date, the data have not provided a clear understanding of the precise roles that protein acetylation and acetate oxidation play in carcinogenesis, cancer progression or treatment. This review highlights some of the major issues, discrepancies and opportunities associated with the manipulation of acetate metabolism and acetylation-based signaling in cancer development and treatment. This article is protected by copyright. All rights reserved

Description: Adipogenesis comprises a complex network of signaling pathways and transcriptional cascades; the GSK3β-C/EBPβ- srebf1a axis is a critical signaling pathway at early stages leading to the expression of PPARγ2, the master regulator of adipose differentiation. Previous work has demonstrated that retinoic acid inhibits adipogenesis affecting different signaling pathways. Here, we evaluated the anti-adipogenic effect of retinoic acid on the adipogenic transcriptional cascade, and the expression of adipogenic genes cebpb , srebf1a , srebf1c , pparg2 , and cebpa . Our results demonstrate that retinoic acid blocks adipose differentiation during commitment, returning cells to an apparent non-committed state, since they have to be newly induced to adipose conversion after the retinoid is removed from the culture medium. Retinoic acid down regulates the expression of the adipogenic genes, srebf1a, srebf1c , pparg2 , and cebpa . Retinoic acid did not down regulate the expression of cebpb , but it inhibited C/EBPβ phosphorylation at Thr188, a critical step for the progression of the adipogenic program. We also found that RA inhibition of adipogenesis did not increase the expression of dlk1 , the gene encoding for Pref1, a well-known anti-adipogenic transcription factor. This article is protected by copyright. All rights reserved

Description: ABSTRACT Platelets are important in hemostasis, but also detect particles and pathogens in the circulation. Phagocytic and endocytic activities of platelets are widely recognized, however, receptors and mechanisms involved remain poorly understood. We previously demonstrated that platelets internalize and store phospholipid microvesicles enriched in human tissue factor (TF + MVs) and that platelet-associated TF enhances thrombus formation at sites of vascular damage. Here we investigate the mechanisms implied in the interactions of TF + MVs with platelets and the effects of specific inhibitory strategies. Aggregometry and electron microscopy were used to assess platelet activation and TF + MVs uptake. Cytoskeletal assembly and activation of phosphoinositide 3-kinase (PI3K) and RhoA were analyzed by western blot and ELISA. Exposure of platelets to TF + MVs caused reversible platelet aggregation, actin polymerization and association of contractile proteins to the cytoskeleton being maximal at 1 min. The same kinetics were observed for activation of PI3K and translocation of RhoA to the cytoskeleton. Inhibitory strategies to block glycoprotein IIb-IIIa (GPIIb-IIIa), scavenger receptor CD36, serotonin transporter (SERT) and PI3K, fully prevented platelet aggregation by TF + MVs. Ultrastructural techniques revealed that uptake of TF + MVs was efficiently prevented by anti-CD36 and SERT inhibitor, but only moderately interfered by GPIIb-IIIa blockade. We conclude that internalization of TF + MVs by platelets occurs independently of receptors related to their main hemostatic function (GPIIb-IIIa), involves the scavenger receptor CD36, SERT and engages PI3-Kinase activation and cytoskeletal assembly. CD36 and SERT appear as potential therapeutic targets to interfere with the association of TF + MVs with platelets and possibly downregulate their prothrombotic phenotype. This article is protected by copyright. All rights reserved

Description: Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non-myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3 to 2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin. This article is protected by copyright. All rights reserved

Description: This work focuses on the implementation of a Shallow Water-Exner model for compound natural channels with complex geometry and movable bed within the finite volume framework. The model is devised for compound channels modeling: cross-section overbanks are treated with fixed bed conditions, while the main channel is left free to modify its morphology. A capacitive approach is used for bedload transport modeling, in which the solid flow rates are estimated with bedload transport formulas. The model equations pose some numerical issues in the case of natural channels, where bedload transport may occur for both subcritical and supercritical flows and geometry varies in space. An explicit path-conservative scheme, designed to overcome all these issues, is presented in the paper. The scheme solves liquid and solid phases dynamics in a coupled manner, in order to correctly model near critical currents/channel interactions and is well-balanced, that is able to properly reproduce steady states. The Roe and Osher Riemann solvers are implemented, so as to take into account the spatial geometry variations of natural channels. The scheme reaches up to 2 nd order accuracy. Validation is performed with fixed and movable bed test cases whose analytical solution is known, and with flume experimental data. An application of the model to a real case study is also shown. This article is protected by copyright. All rights reserved.

Description: In this paper we use a physical modelling approach to explore the effect of lateral confinement on gravel bed river planform style, bed morphology, and sediment transport processes. A set of 27 runs was performed in a large flume (25 m long, 2.9 m wide), with constant longitudinal slope (0.01) and uniform grain size (1 mm), changing the water discharge (1.5 to 2.5 l/s) and the channel width (0.15 m to 1.5 m) to model a wide range of channel configurations, from narrow, straight, embanked channels to wide braided networks. The outcomes of each run were characterized by a detailed digital elevation model describing channel morphology, a map of dry areas and areas actively transporting sediment within the channel, and continuous monitoring of the amount of sediment transported through the flume outlet. Analysis reveals strong relationships between unit stream power and parameters describing the channel morphology. In particular, a smooth transition is observed between narrow channels with an almost rectangular cross section profile (with sediment transport occurring across the entire channel width) and complex braided networks where only a limited proportion (30%) of the bed is active. This transition is captured by descriptors of the bed elevation frequency distribution, e.g. standard deviation, skewness and kurtosis. These summary statistics represent potentially useful indicators of bed morphology that are compared with other commonly used summary indicators such as the braiding index and the type and number of bars. This article is protected by copyright. All rights reserved.

Description: We believe that there are too many models in hydrology and we should ask ourselves the question, if we are currently wasting time and effort in developing another model again instead of focusing on the development of a community hydrological model. In other fields this kind of models have been quite successful, but due to several reasons, no single community model has been developed in the field of hydrology yet. The concept, strength and weakness of a community model was discussed at the Chapman Conference on Catchment Spatial Behaviour and Complex Organisation held in Luxembourg in September 2014. This discussion as well as out own opinions about the potential of a community models, or at least the necessary discussion to establish one are debated in this commentary. This article is protected by copyright. All rights reserved.

Description: Soil surface sealing is a widespread natural process occurring frequently in bare soil areas between vegetation patches. The low hydraulic conductivity that characterizes the seal layer reduces both infiltration and evaporation fluxes from the soil, and thus has the potential to affect local vegetation water uptake (VWU). This effect is investigated here using experimental data, 2D physically based modelling and a long-term climatic dataset from three dry sites presenting a climatic gradient in the Negev Desert, Israel. The Feddes VWU parameters for the dominant shrub at the study site ( Sarcopoterium spinosum ) were acquired using lysimeter experiments. The results indicate that during the season surface sealing could either increase or decrease VWU depending on initial soil water content, rainfall intensity, and the duration of the subsequent drying intervals. These factors have a marked effect on inter-annual variability of the seal layer effect on VWU, which on average was found to be 26% higher under sealed conditions than in the case of unsealed soil surfaces. The seal layer was found to reduce the period where the vegetation was under water stress by 31% compared with unsealed conditions. This effect was more pronounced for seasons with total rainfall depth higher than 10 cm/y, and was affected by interseasonal climatic variability. These results shed light on the importance of surface sealing in dry environments and its contribution to the resilience of woody vegetation. This article is protected by copyright. All rights reserved.

Description: Female salmonids bury and lay their eggs in streambeds by digging a pit, which is then covered with sediment from a second pit. The spawning process alters streambed topography, winnows fine sediment, and mixes sediment in the active layer. The resulting egg nests (redds) contain coarser and looser sediments than those of unspawned streambed areas, and display a dune-like shape with an amplitude and length that vary with fish size, substrate conditions, and flow conditions. Redds increase local bed surface roughness (〈10 −1 channel width, W ), but may reduce the size of macro-bedforms by eroding reach scale topography (10 ° -10 1 W ). Research has suggested that spawning may increase flow resistance due to redd form drag, resulting in lower grain shear stress and less particle mobility. Spawning however also prevents streambed armoring through surface and subsurface material mixing, potentially increasing particle mobility. Here, we use 2-dimensional hydraulic modeling with detailed pre- and post-spawning bathymetries and field observations to test the effect of small spawning salmonids on sediment transport. Our results show that topographical roughness added by small-bodied salmon redds has negligible effects on shear stress at the reach-unit scale, and limited effects at the local scale. Conversely, our results indicate sediment mixing reduces armoring and enhances sediment mobility, which increases potential bed load transport by subsequent floods. River restoration in fish-bearing streams should take into consideration the effects of redd excavation on channel stability. This is particularly important for streams that historically supported salmonids, and at present are the focus of habitat restoration actions. This article is protected by copyright. All rights reserved.

Description: Floods are a natural hazard that affect communities worldwide, but to date the vast majority of flood hazard research and mapping has been undertaken by wealthy developed nations. As populations and economies have grown across the developing world, so too has demand from governments, businesses and NGOs for modelled flood hazard data in these data-scarce regions. We identify six key challenges faced when developing a flood hazard model that can be applied globally, and present a framework methodology that leverages recent cross-disciplinary advances to tackle each challenge. The model produces return period flood hazard maps at ∼90 m resolution for the whole terrestrial land surface between 56˚S and 60˚N, and results are validated against high resolution government flood hazard datasets from the UK and Canada. The global model is shown to capture between two thirds and three quarters of the area determined to be at risk in the benchmark data without generating excessive false positive predictions. When aggregated to ∼1 km, mean absolute error in flooded fraction falls to ∼5%. The full complexity global model contains an automatically parameterised subgrid channel network, and comparison to both a simplified 2D only variant and an independently developed pan-European model shows the explicit inclusion of channels to be a critical contributor to improved model performance. Whilst careful processing of existing global terrain datasets enables reasonable model performance in urban areas, adoption of forthcoming next-generation global terrain datasets will offer the best prospect for a step-change improvement in model performance. This article is protected by copyright. All rights reserved.

Description: Understanding how channel bed morphology affects flow conditions (and vice versa) is important for a wide range of fluvial processes and practical applications. We investigated interactions between bed roughness and flow velocity in a steep, glacier-fed mountain stream (Riedbach, Ct. Valais, Switzerland) with almost flume-like boundary conditions. Bed gradient increases along the 1-km study reach by roughly one order of magnitude ( S =3-41%), with a corresponding increase in streambed roughness, while flow discharge and width remain approximately constant due to the glacial runoff regime. Streambed roughness was characterized by semi-variograms and standard deviations of point clouds derived from terrestrial laser scanning. Reach-averaged flow velocity was derived from dye tracer breakthrough curves measured by 10 fluorometers installed along the channel. Commonly used flow resistance approaches (Darcy-Weisbach equation and dimensionless hydraulic geometry) were used to relate the measured bulk velocity to bed characteristics. As a roughness measure, D 84 yielded comparable results to more laborious measures derived from point clouds. Flow resistance behavior across this large range of steep slopes agreed with patterns established in previous studies for both lower-gradient and steep reaches, regardless of which roughness measures were used. We linked empirical critical shear stress approaches to the variable power equation for flow resistance to investigate the change of bed roughness with channel slope. The predicted increase in D 84 with increasing channel slope was in good agreement with field observations. This article is protected by copyright. All rights reserved.

Description: Large wood governs channel morphology, as well as the availability of in-stream habitat, in many forested streams. In this paper we use a stochastic, physically based model to simulate wood recruitment and in-stream geomorphic processes, in order to explore the influence of disturbance history on the availability of aquatic habitat. Specifically, we consider the effects of fire on a range of stream sizes by varying the rate of tree toppling over time in a simulated forest characterized by a tree height of 30 m. We also consider the effects of forest harvesting with various riparian buffer sizes, by limiting the lateral extent of the riparian stand. Our results show that pulsed inputs of wood increase the availability and variability of physical habitat in the post-fire period; reach-averaged pool area and deposit area double in small streams, while side-channels increase by over 50% in intermediate-sized channels. By contrast, forest harvesting reduces the availability of habitat within the reach, though the effects diminish with increasing buffer size or stream width; in laterally stable streams the effects are minimal so long as buffer width is large enough for key pieces to be recruited to the reach. This research emphasizes the importance of natural disturbance in creating and maintaining habitat heterogeneity and shows that scenario-based numerical modeling provides a useful tool for assessing the historical range of variability associated with natural disturbance, as well as changes in habitat relevant to fish. It can be also used to inform forest harvesting and management. This article is protected by copyright. All rights reserved.

Description: Spreading of conservative solutes in groundwater due to aquifer heterogeneity is quantified by the macrodispersivity, which was found to be scale dependent. It increases with travel distance, stabilizing eventually at a constant value. However, the question of its asymptotic behaviour at very large scale is still a matter of debate. It was surmised in the literature that macrodispersivity scales up following a unique scaling law. Attempts to define such a law were made by fitting a regression line in the log-log representation of an ensemble of macrodispersivities from multiple experiments. The functional relationships differ among the authors, based on the choice of data. Our study revisits the data basis, used for inferring unique scaling, through a detailed analysis of literature marcodispersivities. In addition, values were collected from the most recent tracer tests reported in the literature. We specified a system of criteria for reliability and re-evaluated the reliability of the reported values. The final collection of reliable estimates of macrodispersivity does not support a unique scaling law relationship. On the contrary, our results indicate, that the field data can be explained as a collection of macrodispersivities of aquifers with varying degree of heterogeneity where each exhibits its own constant asymptotic value. Our investigation concludes that transport, and particularly the macrodispersivity, is formation-specific, and that modeling of transport cannot be relegated to a unique scaling law. Instead, transport requires characterization of aquifer properties, e.g. spatial distribution of hydraulic conductivity, and the use of adequate models. This article is protected by copyright. All rights reserved.

Description: For the past few decades, heat has been used to estimate river-aquifer exchange flux at discrete locations by comparison of river and groundwater temperature. In recent years, heat has also been employed to estimate reach-scale river-aquifer exchange flux based only on river temperature. However, there are many more parameters that govern heat exchange and transport in surface water than in groundwater. In this study, we analyzed the sensitivities of surface water temperature to various parameters and assessed the accuracy of temperature-based estimates of exchange flux in two synthetic rivers and in a field setting. For the large synthetic river with a flow rate of 63 m 3 s −1 (i.e., 5.44 × 10 6 m 3 d −1 ), the upper and lower bounds of the groundwater inflow rate can be determined when the actual groundwater inflow is around 100 m 2 d −1 . For higher and lower fluxes, only minimum and maximum bounds respectively can be determined. For the small synthetic river with the flow rate of 0.63 m 3 s −1 (i.e., 5.44 × 10 4 m 3 d −1 ), the bounds of the groundwater inflow rate can only be estimated when the actual groundwater inflow rate is near 10 m 2 d −1 . In the field setting, results show that the inflow rate must be less than 100 m 2 d −1 , but a lower bound for groundwater inflow cannot be determined. The large ranges of estimated groundwater inflow rates in both theoretical and field settings indicate the need to reduce parameter errors and combine heat measurements with other isotopic and/or chemical methods. This article is protected by copyright. All rights reserved.

Description: Climate state can be an important predictor of future hydrologic conditions. In ensemble streamflow forecasting, where historical weather inputs or streamflow observations are used to generate the ensemble, climate index weighting is one way to represent the influence of climate state. Using a climate index, each forecast variable member of the ensemble is selectively weighted to reflect the climate state at the time of the forecast. A new approach to climate index weighting of ensemble forecasts is presented. The method is based on a sampling-resampling approach for Bayesian updating. The original hydrologic ensemble members define a sample drawn from the prior distribution; the relationship between the climate index and the ensemble member forecast variable is used to estimate a likelihood function. Given an observation of the climate index at the time of the forecast, the estimated likelihood function is then used to assign weights to each ensemble member. The weights define the probability of each ensemble member outcome given the observed climate index. The weighted ensemble forecast is then used to estimate the posterior distribution of the forecast variable conditioned on the climate index. The Bayesian climate index weighting approach is easy to apply to hydrologic ensemble forecasts; its parameters do not require calibration with hindcasts, and it adapts to the strength of the relation between climate and the forecast variable, defaulting to equal weighting of ensemble members when no relationship exists. A hydrologic forecasting application illustrates the approach and contrasts it with traditional climate index weighting approaches. This article is protected by copyright. All rights reserved.

Description: Profilin (Pfn1) regulates cytoskeletal reorganization and migration, but its role in osteoblasts is not known. BMPs (bone morphogenetic proteins) aree a multifunctional cytokine involved in osteoblastic differentiation and promote bone regeneration and repair. Although several molecules are known to modulate BMP signaling, mechanisms that determine the levels of BMP action in osteoblastic function are still incompletely understood. We therefore examine the expression of Pfn1 in osteoblasts and its role in BMP-induced differentiation in osteoblasts. In osteoblastic MC3T3-E1(MC) cells, Pfn1 mRNA is expressed constitutively and its expression levels are declined during the culture in a time dependent manner in contrast to the increase in alkaline phosphatase activity revealing that Pfn1 expression is down regulated along with differentiation. To test the effects of osteoblastic differentiation on Pfn1expression further, MC cells are treated with BMP. BMP treatment suppresses the levels of Pfn1 mRNA. This suppressive effect of BMP is time dependent and further down regulation of Pfn1 mRNA levels is observed when the BMP treatment is continued for a longer period of time. Pfn1mRNA knock down (KD) by siRNAs enhances BMP-induced increase in alkaline phosphatase (Alp) activity in MC cells. To analyze the regulatory mechanism, Alp mRNA levels are examined and Pfn1 KD enhances the BMP-induced increase in the levels of Alp mRNA expression. Furthermore, Pfn1 KD enhances BMP-induced transcriptional expression of luciferase reporter activity via BMP response element in osteoblasts. These data indicate that Pfn1 is a novel target of BMP and suppresses BMP-induced differentiation of osteoblasts at least in part via transcriptional event. This article is protected by copyright. All rights reserved

Description: Field hydrology is on the decline. Meanwhile, the need for new field-derived insight into the age, origin and pathway of water in the headwaters, where most runoff is generated, is more needed than ever. Water Resources Research (WRR) has included some of the most influential papers in field-based runoff process understanding, particularly in the formative years when the knowledge base was developing rapidly. Here, we take advantage of this 50 th anniversary of the journal to highlight a few of these important field-based papers and show how field scientists have posed strong and sometimes outrageous hypotheses—approaches so needed in an era of largely model-only research. We chronicle the decline in field work and note that it is not only the quantity of field work that is diminishing but its character is changing too: from discovery science to data collection for model parameterisation. While the latter is a necessary activity, the loss of the former is a major concern if we are to advance the science of watershed hydrology. We outline a vision for field research to seek new fundamental understanding, new mechanistic explanations of how watershed systems work, particularly outside the regions of traditional focus. This article is protected by copyright. All rights reserved.

Description: One of the major features of neurodegenerative disease is the selective vulnerability of different neuronal populations that are affected in a progressive and often stereotyped manner. Despite the susceptible neuronal population varies between diseases, oxidative stress is implicated as the major pathogenic process in all of them. Natural Extract of Castanea sativa Mill . bark (ENC), recently characterized in its phenolic composition, acts as antioxidant and cardioprotective agent. Its neuroprotettive properties, however, have never been investigated. The aim of this study was to assess neuroprotection of ENC in in vitro models of oxidative-stress-mediate injury. Human neuroblastoma SH-SY5Y cells treated with glutamate (50 mM for 24h) or hydrogen peroxide (25 µM for 1h followed by 24 with medium) were used. The results showed that the addition of ENC (1-50 µg/ml) to cell medium before the neuronal damage provided neuroprotection in both experimental models used, while its addition after the injury was ineffective. In conclusion, the present results suggest that ENC could be a valuable support as dietary supplement, combining beneficial preventive neuroprotettive effects with a high antioxidant activity. This article is protected by copyright. All rights reserved

Description: PKR-like ER-resident kinase (PERK) phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α) under endoplasmic reticulum (ER) stress; this results in repression of general translation and induction of specific gene expression, such as activating transcription factor 4 (ATF4). We previously showed that, upon ER stress, transducin (beta)-like 2 (TBL2) was an ER-localized transmembrane protein and interacted with PERK and that TBL2 was involved in ATF4 expression and cell survival. Here, we show that TBL2 is able to associate with ATF4 mRNA and regulate its translation. The RNA-immunoprecipitation analysis using several TBL2 deletion mutants revealed that the WD40 domain was essential for association with ATF4 mRNA. Importantly, suppression of TBL2 by knockdown or overexpression of the TBL2 mutant with a defective WD40 domain diminished ATF4 induction at the translational level. Thus, our findings indicate that, under ER stress, TBL2 participates in ATF4 translation through its association with the mRNA. This article is protected by copyright. All rights reserved

Description: Toll-like receptor 2 (TLR2)-mediated signaling cascades and gene regulation are mainly involved in diseases such as immunity and inflammation. In this study microarray analysis was performed using bone marrow-derived macrophages (BMDM) and Raw 264.7 cells to identify novel proteins involved in the TLR2-mediated cellular response. We found that pleckstrin homology-like domain family, member 1 (PHLDA1) is a novel gene up-regulated by TLR2 stimulation and determined the unique signaling pathway for its expression. Treatment with TLR2 agonist Pam 3 CSK 4 increased mRNA, protein, and fluorescence staining of PHLDA1. Induction of PHLDA1 by TLR2 stimulation disappeared from TLR2 KO mice-derived BMDM. Among janus kinase (JAK) family members, JAK2 was involved in TLR2-stimulated PHLDA1 expression. Signal transducer and activator of transcription 3 (STAT3) also participated in PHLDA1 expression downstream of the JAK2. Interestingly, ERK1/2 was an intermediate between JAK2 and STAT3. In silico analysis revealed the presence of highly conserved γ-activated sites within mouse PHLDA1 promoter and confirmed the JAK2-STAT3 pathway is important to Pam 3 CSK 4 -induced PHLDA1 transcription. These findings suggest that the JAK2-ERK1/2-STAT3 pathway is an important signaling pathway for PHLDA1 expression and that these proteins may play a critical role in eliciting TLR2-mediated immune and inflammatory response. This article is protected by copyright. All rights reserved

Description: Autophagy is a catabolic cellular mechanism involving lysosomal degradation of unwanted cellular components. Interaction between Beclin-1 and Bcl-2 proteins is known to play a critical role in the initiation of autophagy. We report that malignantly transformed lung epithelial cells are resistant to autophagy, and express lower basal levels of autophagic proteins Beclin-1 and LC3-II as compared to non-tumorigenic cells. Additionally, increased levels of nitric oxide (NO) and Bcl-2 were observed in transformed cells. NO was found to negatively regulate autophagy initiation and autophagic flux by nitrosylating Bcl-2 and stabilizing its interaction with Beclin-1, resulting in inhibition of Beclin-1 activity. An increase in the apoptotic initiator caspase-9 and the apoptosis and autophagy-associated kinase p38/MAPK in both cell types indicated possible autophagy-apoptosis crosstalk. Pre-treatments with ABT-737 (Bcl-2 inhibitor) and aminoguanidine (NO inhibitor), and transfection with a non-nitrosylable Bcl-2 cysteine double-mutant plasmid resulted in increased autophagic flux (LC3-II/p62 upregulation) corresponding with decreased S -nitrocysteine expression, thus corroborating the regulatory role of Bcl-2 S -nitrosylation in autophagy. In conclusion, our study reveals a novel mechanism of autophagy resistance via post-translational modification of Bcl-2 protein by NO, which may be critical in driving cellular tumorigenesis. This article is protected by copyright. All rights reserved

Description: We present a novel inverse modeling strategy to estimate spatially distributed parameters of nonlinear models. The maximum a posteriori (MAP) estimators of these parameters are based on a likelihood functional, which contains spatially discrete measurements of the system parameters and spatio-temporally discrete measurements of the transient system states. The piecewise continuity prior for the parameters is expressed via Total Variation (TV) regularization. The MAP estimator is computed by minimizing a non-quadratic objective equipped with the TV operator. We apply this inversion algorithm to estimate hydraulic conductivity of a synthetic confined aquifer from measurements of conductivity and hydraulic head. The synthetic conductivity field is composed of a low-conductivity heterogeneous intrusion into a high-conductivity heterogeneous medium. Our algorithm accurately reconstructs the location, orientation and extent of the intrusion from the steady-state data only. Addition of transient measurements of hydraulic head improves the parameter estimation, accurately reconstructing the conductivity field in the vicinity of observation locations. This article is protected by copyright. All rights reserved.

Description: Human societies are increasingly altering the water and biogeochemical cycles to both improve ecosystem productivity and reduce risks associated with the unpredictable variability of climatic drivers. These alterations, however, often cause large negative environmental consequences, raising the question as to how societies can ensure a sustainable use of natural resources for the future. Here we discuss how ecohydrological modeling may address these broad questions with special attention to agroecosystems. The challenges related to modeling the two-way interaction between society and environment are illustrated by means of a dynamical model in which soil and water quality supports the growth of human society but is also degraded by excessive pressure, leading to critical transitions and sustained societal growth-collapse cycles. We then focus on the coupled dynamics of soil water and solutes (nutrients or contaminants), emphasizing the modeling challenges, presented by the strong nonlinearities in the soil and plant system and the unpredictable hydro-climatic forcing, that need to be overcome to quantitatively analyze problems of soil water sustainability in both natural and agricultural ecosystems. We discuss applications of this framework to problems of irrigation, soil salinization, and fertilization and emphasize how optimal solutions for large-scale, long-term planning of soil and water resources in agroecosystems under uncertainty could be provided by methods from stochastic control, informed by physically and mathematically sound descriptions of ecohydrological and biogeochemical interactions. This article is protected by copyright. All rights reserved.

Description: Water resource management (WRM) through dams or reservoirs is worldwide necessary to support key human-related activities, ranging from hydropower production to water allocation and flood risk mitigation. Designing of reservoir operations aims primarily to fulfil the main purpose (or purposes) for which the structure has been built. However, it is well known that reservoirs strongly influence river geomorphic processes, causing sediment deficits downstream, altering water and sediment fluxes, leading to river bed incision and causing infrastructure instability and ecological degradation. We propose a framework that, by combining physically based modelling, surrogate modelling techniques and Multi-Objective (MO) optimization, allows to include fluvial geomorphology into MO optimization whose main objectives is the maximization of hydropower revenue and the minimization of river bed degradation. The case study is a run-of-the-river power plant on the River Po (Italy). A 1D mobile-bed hydro-morphological model simulated the river bed evolution over a ten year horizon for alternatives operation rules of the power plant. The knowledge provided by such a physically based model is integrated into a MO optimization routine via surrogate modelling using the response surface methodology. Hence, this framework overcomes the high computational costs that so far hindered the integration of river geomorphology into WRM. We provided numerical proof that river morphologic processes and hydropower production are indeed in conflict, but that the conflict may be mitigated with appropriate control strategies. This article is protected by copyright. All rights reserved.

Description: This paper addresses how much flood water can be conserved for use after the flood season through the operation of reservoir by taking into account the residual flood control capacity (the difference between flood conveyance capacity and the expected inflow in a lead time). A two-stage model for dynamic control of the flood limited water level (the maximum allowed water level during the flood season, DC-FLWL) is established considering forecast uncertainty and acceptable flood risk. It is found that DC-FLWL is applicable when the reservoir inflow ranges from small to medium levels of the historical records, while both forecast uncertainty and acceptable risk in the downstream affect the feasible space of DC-FLWL. As forecast uncertainty increases (under a given risk level) or as acceptable risk level decreases (under a given forecast uncertainty level), the minimum required safety margin for flood control increases, and the chance for DC-FLWL decreases. The derived hedging rules from the modeling framework illustrate either the dominant role of water conservation or flood control or the tradeoff between the two objectives under different levels of forecast uncertainty and acceptable risk. These rules may provide useful guidelines for conserving water from flood, especially in the area with heavy water stress. The analysis is illustrated via a case study with a real-world reservoir in northeastern China. This article is protected by copyright. All rights reserved.

Description: Although the mechanism which regulates transcription in the 5'-UTR of the mu opioid receptor (MOR) gene (OPRM1) in lymphocytes has been well studied, a question remains as to whether there is post-transcriptional regulation of MOR gene OPRM1 gene in lymphocytes. In this study, we describe both the role played by miRNAs and the impact of SIVmac239 infection on post-transcriptional regulation of MOR gene OPRM1 gene in CEM x174 cells. Our results show that miR-16 is able to bind the target site in the range of 8699-8719 nt from the stop coden in MOR gene MOR-1 mRNA 3'-UTR and suppress the expression of MOR OPRM1 gene. Mutation of this target site reduces the effect of miR-16. Morphine (1 µM) inhibites the expression of miR-16, and this effect is reversed by the antagonist naloxone. Thus, morphine may up-regulate MOR receptor level by both stimulating MOR OPRM1 gene transcription and stabilizing its mRNA. SIVmac239 infection results in an apparent elevation of miR-16 and gradual reduction of MOR OPRM1 gene expression. The inverse correlation of elevated miR-16 and reduced MOR OPRM1 gene expression under viral loading confirmed the effect of SIVmac239 on post-transcriptional regulation of MOR OPRM1 gene in lymphocytes. We conclude that miR-16 is a primary factor in post-transcriptional regulation of MOR OPRM1 gene. SIVmac239 upregulates miR-16 levels and consequently suppresses MOR OPRM1 gene expression. This finding will be helpful for full understanding of the regulatory mechanism of MOR OPRM1 gene in lymphocytes, as well as the synergistic mechanism of HIV infection and morphine addiction in the pathogenesis of AIDS.

Description: Structural stability of Oldenlandia affinis cyclotide, kalata B1 of native (1NB1) and two mutants 2F2I ([P20D, V21K] kB1) and 2F2J ([W19K, P20N, V21K] kB1) was investigated. Single model analysis showed high number of intra-molecular interactions followed by more proportion of beta sheet contents in [P20D, V21K] kB1 as compared to that of native and the other mutant of kalata B1. Further, the modern conformational sampling approach, an alternate to classical molecular dynamics was introduced, which revealed that the [P20D, V21K] kB1 was identified as structurally stable one, substantiated by various structural events viz., root mean square deviation, root mean square fluctuation and angular deviation by Ramachandran plot. Moreover, the statistically validated contours of polar surface area, hydrogen bond distribution and the distance of disulfide bridges also supported the priority of [P20D, V21K] kB1 with respect to stability. From this work, it is proposed that the [P20D, V21K] kB1 (2F2I) could be the best template for scaffolding peptide based drug design.

Description: Inhibition of metabolic features which distinguish cancer cells from their non-malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted towards glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here we show that the transition from the 2-D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed.

Description: We investigated the effects of exogenous sodium pyruvate (SP) on adipocyte differentiation, lipid accumulation, and the mRNA expression levels of adipogenesis-related genes in 3T3-L1 pre-adipocytes. Differentiation of pre-adipocytes was induced by MDI (3-isobutyl-1-methylxanthine: IBMX, dexamethasone: DEX, and insulin), in the presence or absence of SP. Adipogenesis was stimulated by SP in a concentration-dependent manner. SP also induced the expression of genes encoding aP2, GLUT4, and adiponectin, but had no effect on cell proliferation. Exogenous glucose did not promote adipogenesis or lipid accumulation. 2-deoxy-D-glucose inhibited adipogenesis initiated by MDI, but failed to influence the effects of SP on adipogenesis, whereas 3-bromopyruvate inhibited adipogenesis regardless of whether SP was present. The pro-adipogenic properties of SP were limited to the early events of adipogenesis. To determine whether SP mimics the adipogenic action of dexamethasone or insulin, we examined the effects of SP on adipogenesis with combinations of IBMX, DEX, and insulin. SP did not improve incomplete lipid accumulation observed in cells grown under IBMX-, DEX-, or insulin-free conditions. Insulin-stimulated ERK1/2 phosphorylation was diminished by SP, while phosphorylation of Akt was increased, correlating with increased glucose uptake in response to insulin. We also observed that SP stimulated immediate early expression of C/EBPβ and C/EBPδ. The PPARγ antagonist GW9662 inhibited adipogenesis. Our findings highlight the adipogenic function of exogenous SP by stimulating early events of adipogenesis.

Description: Diabetic nephropathy is characterized by inordinate secretion of extracellular matrix (ECM) proteins from mesangial cells (MCs), which is tightly associated with excessive activation of TGF-β signaling. The forkhead transcription factor O1 (FoxO1) protects mesangial cells from hyperglycemia-induced oxidative stress, which may be involved in ameliorating the redundant secretion of ECM proteins under high glucose conditions. Here we reported that high glucose elevated the level of p-Akt to attenuate endogenous FoxO1 bioactivities in MCs, accompanied with decreases in the mRNA expressions of catalase (CAT) and superoxide dismutase 2 (SOD2). Meanwhile, the expression of major ECM proteins-FN and Col I- increased under high glucose condition, in consistent with the activation of TGF-β/Smad signaling. By contrast, overexpression of nucleus-localized FoxO1 (insensitive to Akt phosphorylation) directly up-regulated the expressions of anti-oxidative enzymes, accompanied with inactivation of TGF-β/Smad3 pathway, as well as decreases of extracellular matrix proteins. Moreover, similar to those MCs overexpressed of nucleus-localized FoxO1 in high glucose conditions, MCs with down-regulation of FoxO1 by small interference-RNA under normal glucose conditions showed increased FN level and activated TGF-β/Smad3 pathway. Our findings link the anti-oxidative activity of FoxO1 and the TGF-β-induced secretion of ECM proteins, indicating the novel role of FoxO1 in protecting MCs under high glucose conditions.

Description: We present a co-evolutionary view of hydrologic systems, revolving around feedbacks between environmental and social processes operating across different time scales. This brings to the fore an emphasis on emergent phenomena in changing water systems, such as the levee effect, adaptation to change, system lock-in, and system collapse due to resource depletion. Changing human values play a key role in the emergence of these phenomena and should therefore be considered as internal to the system. Guidance is provided for the framing and modeling of these phenomena to test alternative hypotheses about how they arose. A plurality of co-evolutionary models, from stylized to comprehensive system-of-system models, may assist strategic water management for long time scales through facilitating stakeholder participation, exploring the possibility space of alternative futures, and helping to synthesize the observed dynamics in a wide range of case studies. Future research opportunities lie in exploring emergent phenomena arising from time scale interactions through historical, comparative and process studies of human-water feedbacks. This article is protected by copyright. All rights reserved.

Description: ABSTRACT Multiphase-fluid distribution and flow is inherent in numerous areas of hydrology. Yet, pore-scale characterization of transitions between two and three immiscible-fluids is limited. The objective of this study was to examine the impact of such transitions on the pore-scale configuration of organic liquid in a multi-fluid system comprising natural porous media. Three-dimensional images of an organic liquid (trichloroethene) in two-phase (organic-liquid/water) and three-phase (air/organic-liquid/water) systems were obtained using X-ray microtomography before and after drainage and imbibition. Upon transition from a two-phase to a three-phase system, a significant portion of the organic liquid (intermediate wetting fluid) was observed to exist as lenses and films in contact with air (nonwetting fluid). In these cases, the air was either encased by or contiguous to the organic liquid. The presence of air resulted in an increase in the surface-area-to-volume ratios for the organic-liquid blobs. Upon imbibition, the air was displaced downgradient, and concomitantly, the morphology of the organic-liquid blobs no longer in contact with air reverted to that characteristic of a two-phase distribution (i.e., more spherical blobs and ganglia). This change in morphology resulted in a reduction in the surface-area-to-volume ratio. These results illustrate the impact of transitions between two-phase and three-phase conditions on fluid configuration, and they demonstrate the malleable nature of fluid configuration under dynamic, multiphase-flow conditions. The results have implications for characterizing and modeling pore-scale flow and mass-transfer processes. This article is protected by copyright. All rights reserved.

Description: We performed power-spectral analyses on 133 globally distributed lake-level time series after removing annual variability. Lake-level power spectra are found to be power-law functions of frequency over the range of 20 days -1 to 27 years -1 , suggesting that lake levels are globally a f -β -type noise. The spectral exponent (β), i.e. the best-fit slope of the logarithm of the power spectrum to the logarithm of frequency, is a nonlinear function of lake surface area, indicating that lake size is an important control on the magnitude of water-level variability over the range of time scales we considered. A simple cellular model for lake-level fluctuations that reproduces the observed spectral-scaling properties is presented. The model (an adaptation of a surface-growth model with random deposition and relaxation) is based on the equations governing flow in an unconfined aquifer with stochastic inputs and outputs of water (e.g. random storms). The agreement between observation and simulation suggests that lake surface area, spatio-temporal stochastic forcing, and diffusion of the groundwater table are the primary factors controlling lake water-level variability in natural (unmanaged) lakes. Water-level variability is generally considered to be a manifestation of climate trends or climate change, yet our work shows that an input with short or no memory (i.e. weather) gives rise to a long-memory non-stationary output (lake water-level). This work forms the basis for a null hypothesis of lake water-level variability that should be disproven before water-level trends are to be attributed to climate. This article is protected by copyright. All rights reserved.

Description: Describing convective nonwetting phase flow in unsaturated porous media requires knowledge of the nonwetting phase relative permeability. This study was conducted to formulate and derive a generalized expression for the nonwetting phase relative permeability via combining with the Kosugi water retention function. This generalized formulation is then used to flexibly investigate the Burdine, Mualem and Alexander and Skaggs models' prediction accuracy for relative nonwetting phase permeability. The model and data comparison results show that these three permeability models, if used in their original form, but applied to the nonwetting phase, could not predict the experimental data well. The optimum pore tortuosity and connectivity value is thus obtained for the improved prediction of relative nonwetting phase permeability. As a result, the effective parametrization of (α,β,η) parameters in the modified Burdine, modified Mualem and modified Alexander and Skaggs permeability models were found to be (2.5, 2, 1), (2, 1, 2) and (2.5, 1, 1), respectively. These three suggested models display the highest accuracy among the nine relative permeability models investigated in this study. However, the corresponding discontinuous nonwetting phase and the liquid film flow should be accounted for in future for the improved prediction of nonwetting phase relative permeability at very high and very low water saturation range, respectively. This article is protected by copyright. All rights reserved.

Description: A new optical remote sensing technique for estimating water depth from an oblique camera view is described. The water surface and the bed were imaged simultaneously to create time-dependent maps of the water surface velocities and the bed elevations that can be used to validate numerical models at high spatial and temporal resolution. The technique was applied in a sandy meander bend at the University of Minnesota Saint Anthony Falls Laboratory Outdoor StreamLab. The root mean square differences between optical estimates of the bed and in situ observations ranged between 0.01 and 0.03 m. Mean bedform wavelength was 0.73 m and mean crest height was 0.07 m, but both varied with distance around the meander bend. Bedform classification varied with distance downstream, and sinuosity of bedforms varied with local radius of curvature. Bedform roughness scaled similarly to other natural riverine environments although wavelength and height magnitude and variability were larger than predicted by empirical formulations for straight reaches. Bedform translation rate varied between 1 and 5 mm s −1 . Estimates of velocity from particle image velocimetry (PIV) on the water surface were ∼10% higher than in situ observations collected ∼0.05 m below the water surface. Using the PIV observations to drive simple equations for bedload sediment flux, we explained up to 72% of the observed variance in downstream sediment flux. The new methodology described here provides non-intrusive, high spatial and temporal resolution measurements of both the bed and the flow. This article is protected by copyright. All rights reserved.

Description: We study the influence of topography on groundwater fluxes and water table depths across the Contiguous United States (CONUS). Groundwater tables are often conceptualized as subdued replicas of topography. While it is well known that groundwater configuration is also controlled by geology and climate, nonlinear interactions between these drivers within large real world systems are not well understood and are difficult to characterize given sparse groundwater observations. We address this limitation using the fully integrated physical hydrology model ParFlow to directly simulate groundwater fluxes and water table depths within a complex heterogeneous domain that incorporates all three primary groundwater drivers. Analysis is based on a first of its kind, continental scale, high-resolution (1km), groundwater-surface water simulation spanning more than 6.3 million km 2 . Results show that groundwater fluxes are most strongly driven by topographic gradients (as opposed to gradients in pressure head) in humid regions with small topographic gradients or low conductivity. These regions are generally consistent with the topographically controlled groundwater regions identified in previous studies. However, we also show that areas where topographic slopes drive groundwater flux do not generally have strong correlations between water table depth and elevation. Nonlinear relationships between topography and water table depth are consistent with groundwater flow systems that are dominated by local convergence and could also be influenced by local variability in geology and climate. One of the strengths of the numerical modeling approach is its ability to evaluate continental scale groundwater behavior at a high resolution not possible with other techniques. This article is protected by copyright. All rights reserved.

Description: Hydrology is an integrative discipline linking the broad array of water-related research with physical, ecological, and social sciences. The increasing breadth of hydrological research, often where subdisciplines of hydrology partner with related sciences, reflects the central importance of water to environmental science, while highlighting the fractured nature of the discipline itself. This lack of coordination among hydrologic subdisciplines has hindered the development of hydrologic theory and integrated models capable of predicting hydrologic partitioning across time and space. The recent development of the concept of the critical zone (CZ), an open system extending from the top of the canopy to the base of groundwater, brings together multiple hydrological subdisciplines with related physical and ecological sciences. Observations obtained by CZ researchers provide a diverse range of complementary process and structural data to evaluate both conceptual and numerical models. Consequently, a cross-site focus on “critical zone hydrology” has potential to advance the discipline of hydrology and to facilitate the transition of CZ observatories into a research network with immediate societal relevance. Here we review recent work in catchment hydrology and hydrochemistry, hydrogeology, and ecohydrology that highlights a common knowledge gap in how precipitation is partitioned in the critical zone: “ how is the amount, routing, and residence time of water in the subsurface related to the biogeophysical structure of the CZ? ” Addressing this question will require coordination among hydrologic subdisciplines and interfacing sciences, and catalyze rapid progress in understanding current CZ structure and predicting how climate and land cover changes will affect hydrologic partitioning. This article is protected by copyright. All rights reserved.

Description: The effect of targeted expression of an anabolic isoform of basic fibroblast growth factor (FGF2) in osteoblastic lineage on tibial fracture healing was assessed in mice. Closed fracture of the tibiae was performed in Col3.6-18kDa Fgf2 -IRES-GFPsaph mice in which a 3.6 kb fragment of type I collagen promoter (Col3.6) drives the expression of only the 18kD isoform of FGF2 (18kDa Fgf2/ LMW) with green fluorescent protein-sapphire (GFPsaph) as well as Vector mice (Col3.6-IRES-GFPsaph, Vector) that did not harbor the FGF2 transgene. Radiographic, micro-CT, DEXA and histologic analysis of fracture healing of tibiae harvested at 3, 10 and 20 days showed a smaller fracture callus but accelerated fracture healing in LMWTg compared with Vector mice. At post fracture day 3, FGF receptor 3 and Sox 9 mRNA were significantly increased in LMWTg compared with Vector. Accelerated fracture healing was associated with higher FGF receptor 1, platelet derived growth factors B, C and D, type X collagen, vascular endothelial cell growth factor, matrix metalloproteinase 9, tartrate resistant acid phosphatase, cathepsin K, runt-related transcription factor-2, Osterix and Osteocalcin and lower Sox9, and type 2 collagen expression at 10 days post fracture. We postulate that overexpression of LMW FGF2 accelerated the fracture healing process due to its effects on factors that are important in chondrocyte and osteoblast differentiation and vascular invasion. This article is protected by copyright. All rights reserved

Description: In the last decades significant technological advances together with improved modeling capabilities fostered a rapid development of geophysical monitoring techniques in support of hydrological modeling. Geophysical monitoring offers the attractive possibility to acquire spatially distributed information on state variables. These provide complementary information about the functioning of the hydrological system to that provided by standard hydrological measurements, which are either intrinsically local or the result of a complex spatial averaging process. Soil water content is an example of state variable, which is relatively simple to measure pointwise (locally) but with a vanishing constraining effect on catchment-scale modeling, while streamflow data, the typical hydrological measurement, offer limited possibility to disentangle the controlling processes. The objective of this work is to analyze the advantages offered by coupling traditional hydrological data with unconventional geophysical information in inverse modeling of hydrological systems. In particular, we explored how the use of time-lapse, spatially distributed microgravity measurements may improve the conceptual model identification of a topographically complex Alpine catchment (the Vermigliana catchment, South-Eastern Alps, Italy). The inclusion of microgravity data resulted in a better constraint of the inversion procedure and an improved capability to identify limitations of concurring conceptual models to a level that would be impossible relying only on streamflow data. This allowed for a better identification of model parameters and a more reliable description of the controlling hydrological processes, with a significant reduction of uncertainty in water storage dynamics with respect to the case when only streamflow data are used. This article is protected by copyright. All rights reserved.

Description: TCERG1 was characterized previously as a repressor of the transcription factor C/EBPα through a mechanism that involved relocalization of TCERG1 from nuclear speckles to pericentromeric regions. The inhibitory activity as well as the relocalization activity has been demonstrated to lie in the amino terminal half of the protein, which contains several discrete motifs including an imperfect glutamine-alanine (QA) repeat. In the present study, we showed that deletion of this domain completely abrogated the ability of TCERG1 to inhibit the growth arrest activity of C/EBPα. Moreover, the QA repeat deletion mutant of TCERG1 lost the ability to be relocalized from nuclear speckles to pericentromeric regions, and caused an increase in the average size of individual speckles. We also showed that deletion of the QA repeat abrogated the complex formation between TCERG1 and C/EBPα. Examination of mutants with varying numbers of QA repeats indicated that a minimal number of repeats are required for inhibitory activity as well as relocalization ability. These data contribute to our overall understanding of how TCERG1 can have gene-specific effects in addition to its more general roles in coordinating transcription elongation and splicing. This article is protected by copyright. All rights reserved

Description: We present new measurements of bedload tracer transport in a mountain stream over several snowmelt seasons. Cumulative displacements were measured using passive tracers, which consisted of gravel and cobbles embedded with radio frequency identification tags. The timing of bedload motion during eleven transporting events was quantified with active tracers, i.e., accelerometer-embedded cobbles. Probabilities of cobble transport increased with discharge above a threshold, and exhibited slight to moderate hysteresis during snowmelt hydrographs. Dividing cumulative displacements by the number of movements recorded by each active tracer constrained average step lengths. Average step lengths increased with discharge, and distributions of average step lengths and cumulative displacements were thin-tailed. Distributions of rest times followed heavy-tailed power law scaling. Rest time scaling varied somewhat with discharge and with the degree to which tracers were incorporated into the stream bed. The combination of thin-tailed displacement distributions and heavy-tailed rest time distributions predict superdiffusive dispersion. This article is protected by copyright. All rights reserved.

Description: Gas transfer processes are fundamental to the biogeochemical and water quality functions of wetlands, yet there is limited knowledge of the rates and pathways of soil - atmosphere exchange for gases other than oxygen and methane (CH 4 ). In this study we use a novel push-pull technique with sulfur hexafluoride (SF 6 ) and helium (He) as dissolved gas tracers to quantify the kinetics of root-mediated gas transfer, which is a critical efflux pathway for gases from wetland soils. This tracer approach disentangles the effects of physical transport from simultaneous reaction in saturated, vegetated wetland soils. We measured significant seasonal variation in first-order gas exchange rate constants, with smaller spatial variations between different soil depths and vegetation zones in a New Jersey tidal marsh. Gas transfer rates for most biogeochemical trace gases are expected to be bracketed by the rate constants for SF 6 and He, which ranged from ∼10 −2 to 2x10 −1 h −1 at our site. A modified Damköhler number analysis is used to evaluate the balance between biochemical reaction and root-driven gas exchange in governing the fate of environmental trace gases in rooted, anaerobic soils. This approach confirmed the importance of plant gas transport for CH 4 , and showed that root-driven transport may affect nitrous oxide (N 2 O) balances in settings where N 2 O reduction rates are slow This article is protected by copyright. All rights reserved.

Description: Measuring vertically nested temperatures at the streambed interface poses practical challenges that are addressed here with a new discrete subsurface temperature profiling probe. We describe a new temperature probe and its application for heat as a tracer investigations to demonstrate the probe's utility. Accuracy and response time of temperature measurements made at 6 discrete depths in the probe were analyzed in the laboratory using temperature bath experiments. We find the temperature probe to be an accurate and robust instrument that allows for easily installation and long-term monitoring in highly variable environments. Because the probe is inexpensive and versatile, it is useful for many environmental applications that require temperature data collection for periods of several months in environments that are difficult to access or require minimal disturbance. This article is protected by copyright. All rights reserved.

Description: Nanoparticle deposition behavior observed at the Darcy scale represents an average of the processes occurring at the pore scale. Hence, the effect of various pore-scale parameters on nanoparticle deposition can be understood by studying nanoparticle transport at pore scale and upscaling the results to the Darcy scale. In this work, correlation equations for the deposition rate coefficients of nanoparticles in a cylindrical pore are developed as a function of nine pore-scale parameters: the pore radius, nanoparticle radius, mean flow velocity, solution ionic strength, viscosity, temperature, solution dielectric constant, and nanoparticle and collector surface potentials. Based on dominant processes, the pore space is divided into three different regions, namely, bulk, diffusion, and potential regions. Advection-diffusion equations for nanoparticle transport are prescribed for the bulk and diffusion regions, while the interaction between the diffusion and potential regions is included as a boundary condition. This interaction is modeled as a first-order reversible kinetic adsorption. The expressions for the mass transfer rate coefficients between the diffusion and the potential regions are derived in terms of the interaction energy profile. Among other effects, we account for nanoparticle-collector interaction forces on nanoparticle deposition. The resulting equations are solved numerically for a range of values of pore-scale parameters. The nanoparticle concentration profile obtained for the cylindrical pore is averaged over a moving averaging volume within the pore in order to get the 1D concentration field. The latter is fitted to the 1D advection-dispersion equation with an equilibrium or kinetic adsorption model to determine the values of the average deposition rate coefficients. In this study, pore-scale simulations are performed for three values of Péclet number, Pe = 0.05, 5 and 50. We find that under unfavorable conditions, the nanoparticle deposition at pore scale is best described by an equilibrium model at low Péclet numbers ( Pe = 0.05), and by a kinetic model at high Péclet numbers ( Pe = 50). But, at an intermediate Pe (e.g., near Pe = 5), both equilibrium and kinetic models fit the 1D concentration field. Correlation equations for the pore-averaged nanoparticle deposition rate coefficients under unfavorable conditions are derived by performing a multiple-linear regression analysis between the estimated deposition rate coefficients for a single pore and various pore-scale parameters. The correlation equations, which follow a power law relation with nine pore-scale parameters, are found to be consistent with the column-scale and pore-scale experimental results, and qualitatively agree with the colloid filtration theory. These equations can be incorporated into pore network models to study the effect of pore-scale parameters on nanoparticle deposition at larger length scales such as Darcy scale. This article is protected by copyright. All rights reserved.

Description: Safe drinking water is critical to human health and development. In rural sub-Saharan Africa, most improved water sources are boreholes with handpumps; studies suggest that up to one third of these handpumps are non-functional at any given time. This work presents findings from a secondary analysis of cross-sectional data from 1509 water sources in 570 communities in the rural Greater Afram Plains (GAP) region of Ghana; one of the largest studies of its kind. 79.4% of enumerated water sources were functional when visited; in multivariable regressions, functionality depended on source age, management, the number of other sources in the community, and the district. A Bayesian network (BN) model developed using the same dataset found strong dependencies of functionality on implementer, pump type, management, and the availability of tools, with synergistic effects from management determinants on functionality, increasing the likelihood of a source being functional from a baseline of 72% to more than 97% with optimal management and available tools. We suggest that functionality may be a dynamic equilibrium between regular breakdowns and repairs, with management a key determinant of repair rate. Management variables may interact synergistically in ways better captured by BN analysis than by logistic regressions. These qualitative findings may prove generalizable beyond the study area, and may offer new approaches to understanding and increasing handpump functionality and safe water access. This article is protected by copyright. All rights reserved.

Description: Process controls on water, sediment, nutrient and organic carbon exports from the landscape through runoff are not fully understood. This paper provides analyses from 446 sites worldwide to evaluate the impact of environmental factors (MAP and MAT: mean annual precipitation and temperature; CLAY and BD: soil clay content and bulk density; S: slope gradient and LU: land use) on annual exports (R C : runoff coefficients; SL: sediment loads; TOC L : organic carbon losses; TN L : nitrogen losses and TP L : phosphorus losses) from different spatial scales. R C was found to increase, on average, from 18% at local scale (in headwaters), 25% at micro and subcatchment scale (mid-reaches) to 41% at catchment scale (lower reaches of river basins) in response to multiple factors. SL increased from microplots (468 g m −2 yr −1 ) to plots (901 g m −2 yr −1 ), accompanied by decreasing TOC L and TN L . Climate was a major control masking the effects of other factors. For example, R C , SL, TOC L , TN L and TP L tended to increase with MAP at all spatial scales. These variables, however, decreased with MAT. The impact of CLAY, BD, LU and S on erosion variables was largely confined to the hillslope scale, where R C, SL and TOC L decreased with CLAY, while TNL and TP L increased. The results contribute to better understanding of water, nutrient and carbon cycles in terrestrial ecosystems, and should inform river basin modelling and ecosystem management. The important role of spatial climate variability points to a need for comparative research in specific environments at nested spatio-temporal scales. This article is protected by copyright. All rights reserved.

Description: G-protein-coupled receptor 30 (GPR30) is an estrogen receptor that initiates several rapid, non-genomic signaling events triggered by E2. GPR30 has recently been identified in C2C12 cells; however, little is known about the intracelular distribution and its role in C2C12 myoblasts and myotubes. By western blotting and immunohistochemistry, we evidenced expression of GPR30. While in C2C12 myoblasts the receptor was present in nucleus, mitochondria and endoplasmic reticulum, in C2C12 myotubes it was additionally found in cytoplasm. Using trypan blue uptake assay to determine cellular death and fluorescent microscopy to evaluate picnotic nuclei and mitochondrial distribution, we demonstated that treatment of C2C12 myoblasts with G1 (GPR30 agonist) did not protect the cells against apoptosis induced by H 2 O 2 as E2. However, when G15 (GPR30 antagonist) was used, E2 could not prevent the damage caused by the oxidative stress. Further, some of the molecular mechanisms involved were investigated by wertern blot assays. Thus, E2 was able to induce AKT phosphorylation in apoptotic conditions and ERK phosphorylation in proliferating C2C12 cells but not when the cultures were incubated with G15. Additionally, using G15 antagonist we have found that GPR30 participates in the myogenin expression and creatine kinase activity stimulated by E2 in the first steps of C2C12 differentiation. Althogether these findings provide evidences showing that GPR30 is expressed in diverse intracellular compartments in undifferentiated and differentiated C2C12 cells and mediates E2 actions. This article is protected by copyright. All rights reserved

Description: Chd5 is an essential factor for neuronal differentiation and spermatogenesis, and known as a tumor suppressor. H3K27me3 and H3K4un are modifications recognized by Chd5; however, it remains unclear how Chd5 remodels chromatin structure. We completely disrupted the Chd5 locus using the CRISPR-Cas9 system to generate a 52 kbp long deletion, and analyzed Chd5 function in mouse embryonic stem cells. Our findings show that Chd5 represses murine endogenous retrovirus-L (MuERV-L/MERVL), an endogenous retrovirus-derived retrotransposon, by regulating H3K27me3 and H3.1/H3.2 function. This article is protected by copyright. All rights reserved

Description: Previous studies have shown that promyelocytic leukemia zinc finger (PLZF), chemokine (C-X-C motif) receptor 4 (CXCR4) and mir146a were associated with the self-renewal of mouse spermatogonial stem cells (SSCs); however, there is little information on their effects on the fate of livestock SSCs. Here, we have identified a regulatory pathway in dairy goat mGSCs, involving PLZF, mir146a and the SDF-1 receptor CXCR4. PLZF overexpression downregulated mir146a and simultaneously upregulated the expression of CXCR4 protein, whereas PLZF knockdown (siPLZF) induced the specifically opposite effects. The in vitro assays demonstrated that PLZF specifically interacts with and suppresses the mir146a promoter, and mir146a targets CXCR4 to impede its translation. The levels of ERK1/2 phosphorylation in the mGSCs overexpressed CXCR4 and PLZF were upregulated, respectively, whereas mir146a expression was decreased and CXCR4 protein was increased. Mir146a overexpression and siPLZF impaired mGSC proliferation and differentiation, however, Mir146a knockdown induced the opposite effects. The effects of PLZF and mir146a were mediated regulation by mir146a and CXCR4, respectively. Overexpression of CXCR4 or addition of CXCL12 in cultures of dairy goat mGSCs resulted in the upregulation of their signaling, and the phosphorylation of ERK1/2 was increased. Collectively, these findings indicate that PLZF is an important transcription factor in the regulation of the expression of CXCR4 to promote dairy goat mGSC proliferation by targeting mir146a. This article is protected by copyright. All rights reserved

Description: Bacterial lipopolysaccharide (LPS) is the most important contributing factor in pathogenesis of bacterial infection in male accessory glands; and it has shown to inhibit testicular steroidogenesis and induce apoptosis. The present study demonstrates that LPS causes mitochondrial dysfunction via suppression of sirtuin 4 (SIRT4); which in turn affects Leydig cell function by modulating steroidogenesis and apoptosis. LC-540 Leydig cells treated with LPS (10µg/ml) showed impaired steroidogenesis and increased cellular apoptosis. The mRNA and protein expression of SIRT4 were decreased in LPS treated cells when compared to controls. The obtained data suggest that the c-Jun N-terminal kinase (JNK) activation suppresses SIRT4 expression in LPS treated Leydig cells. Furthermore, the overexpression of SIRT4 prevented LPS induced impaired steroidogenesis and cellular apoptosis by improving mitochondrial function. These findings provide valuable information that SIRT4 regulates LPS mediated Leydig cell dysfunction. This article is protected by copyright. All rights reserved

Description: Ketamine, a dissociative anesthetic, is misused and abused worldwide as an illegal recreational drug. In addition to its neuropathic toxicity, ketamine abuse has numerous effects, including renal failure; however, the underlying mechanism is poorly understood. The process called epithelial phenotypic changes (EPCs) causes the loss of cell-cell adhesion and cell polarity in renal diseases, as well as the acquisition of migratory and invasive properties. Madin-Darby canine kidney cells, an in vitro cell model, were subjected to experimental manipulation to investigate whether ketamine could promote EPCs. Our data showed that ketamine dramatically decreased transepithelial electrical resistance and increased paracellular permeability and junction disruption, which were coupled to decreased levels of apical junctional proteins (ZO-1, Occludin and E-cadherin). Consistent with the downregulation of epithelial markers, the mesenchymal markers N-cadherin, Fibronectin and Vimentin were markedly upregulated following ketamine stimulation. Of the E-cadherin repressor complexes tested, the mRNA levels of Snail, Slug, Twist, and ZEB1 were elevated. Moreover, ketamine significantly enhanced migration and invasion. Ketamine-mediated changes were at least partly caused by the inhibition of GSK-3β activity through Ser-9 phosphorylation by the PI3K/Akt pathway. Inhibiting PI3K/Akt with LY294002 reactivated GSK-3β and suppressed ketamine-enhanced permeability, EPCs and motility. These findings were recapitulated by the inactivation of GSK-3β using the inhibitor 3F8. Taken together, these results provide evidence that ketamine induces renal distal tubular EPCs through the downregulation of several junction proteins, the upregulation of mesenchymal markers, the activation of Akt, and the inactivation of GSK-3β. This article is protected by copyright. All rights reserved

Description: CCN2/connective tissue growth factor (CTGF) is a multifunctional molecule that promotes harmonized development and regeneration of cartilage through its matricellular interaction with a variety of extracellular biomolecules. Thus, deficiency in CCN2 supply profoundly affects a variety of cellular activities including basic metabolism. A previous study showed that the expression of a number of ribosomal protein genes was markedly enhanced in Ccn2 -null chondrocytes. Therefore, in this study, we analyzed the impact of CCN2 on amino acid and protein metabolism in chondrocytes. Comparative metabolome analysis of the amino acids in Ccn2 -null and wild type mouse chondrocytes revealed stable decreases in the cellular levels of all of the essential amino acids. Unexpectedly, uptake of such amino acids was rather enhanced in Ccn2 -null chondrocytes, and the addition of exogenous CCN2 to human chondrocytic cells resulted in decreased amino acid uptake. However, as expected, amino acid consumption by protein synthesis was also accelerated in Ccn2 -null chondrocytes. Furthermore, we newly found that expression of 2 genes encoding 2 glycolytic enzymes, as well as the previously reported Eno 1 gene, was repressed in those cells. Considering the impaired glycolysis and retained mitochondrial membrane potential in Ccn2 -null chondrocytes, these findings suggest that Ccn2 deficiency induces amino acid shortage in chondrocytes by accelerated amino acid consumption through protein synthesis and acquisition of aerobic energy. Interestingly, CCN2 was found to capture such free amino acids in vitro . Under physiological conditions, CCN2 may be regulating the levels of free amino acids in the extracellular matrix of cartilage. This article is protected by copyright. All rights reserved

Description: ABSTRACT Some cord blood banks freeze entire pieces of UC (mixed cord, MC) which after post-thaw yields mixed heterogeneous populations of mesenchymal stem cells (MSCs) from all its microanatomical compartments. Freezing of such entire tissues results in sub-optimal post-thaw cell recovery because of poor cryoprotectant diffusion and intracellular ice-formation, heat and water transport issues and damage to intercellular junctions. To develop a simple method of harvesting pure homogeneous MSCs for cord blood banks we compared the post-thaw behavior of three groups of frozen UC tissues (i) freshly harvested WJ without cell separation, (ii) MSCs isolated from WJ (WJSC) and (iii) MC. WJ and WJSC produced high post-thaw cell survival rates (93.52 ± 6.12% to 90.83 ± 4.51%) and epithelioid monolayers within 24h in primary culture whereas post-thaw MC explants showed slow growth with mixed epithelioid and fibroblastic cell outgrowths after several days. Viability and proliferation rates of post-thawed WJ and hWJSC were significantly greater than MC. Post-thaw WJ and WJSC produced significantly greater CD24 + and CD108 + fluorescence intensities and significantly lower CD40 + contaminants. Post-thaw WJ and WJSC produced significantly lesser annexin-V-positive and sub-G1 cells and greater degrees of osteogenic and chondrogenic differentiation compared to MC. qRT-PCR analysis of post-thaw MC showed significant decreases in anti-apoptotic gene expression (SURVIVIN, BCL2) and increases in pro-apoptotic (BAX) and cell cycle regulator genes (P53, P21, ROCK 1) compared to WJ and WJSC. We conclude that freezing of fresh WJ is a simple and reliable method of generating large numbers of clinically utilizable MSCs for cell-based therapies. This article is protected by copyright. All rights reserved

Description: The Wnt ligands are a family of secreted signaling proteins which play key roles in a number of cellular processes under physiological and pathological conditions. Wnts bind to their membrane receptors and initiate a signaling cascade which leads to the nuclear localization and transcriptional activity of β-catenin. The development of purified recombinant Wnt ligands has greatly aided in our understanding of Wnt signaling and its functions in development and disease. In the current study, we identified non-Wnt related signaling activities which were present in commercially available preparations of recombinant Wnt3a. Specifically, we found that treatment of cultured fibroblasts with recombinant Wnt3a induced immediate activation of TGF-β and BMP signaling and this activity appeared to be independent of the Wnt ligand itself. Therefore, while purified recombinant Wnt ligands continue to be a useful tool for studying this signaling pathway, one must exercise a degree of caution when analyzing the results of experiments that utilize purified recombinant Wnt ligands. This article is protected by copyright. All rights reserved

Description: The wettability of CO 2 -brine-rock systems will have a major impact on the management of carbon sequestration in subsurface geological formations. Recent contact angle measurement studies have reported sensitivity in wetting behaviour of this system to pressure, temperature and brine salinity. We report observations of the impact of reservoir conditions on the capillary pressure characteristic curve and and relative permeability of a single Berea sandstone during drainage - CO 2 displacing brine - through effects on the wetting state. Eight reservoir condition drainage capillary pressure characteristic curves were measured using CO 2 and brine in a single fired Berea sandstone at pressures (5 to 20 MPa), temperatures (25 to 50°C) and ionic strengths (0 to 5 mol kg −1 NaCl). A ninth measurement using a N 2 -water system provided a benchmark for capillarity with a strongly water wet system. The capillary pressure curves from each of the tests were found to be similar to the N 2 -water curve when scaled by the interfacial tension. Reservoir conditions were not found to have a significant impact on the capillary strength of the CO 2 -brine system during drainage through a variation in the wetting state. Two steady-state relative permeability measurements with CO 2 and brine and one with N 2 and brine similarly show little variation between conditions, consistent with the observation that the CO 2 -brine-sandstone system is water wetting and multiphase flow properties invariant across a wide range of reservoir conditions. This article is protected by copyright. All rights reserved.

Description: Hillslope-scale rainfall-runoff processes leading to a fast catchment response are not explicitly included in land surface models (LSMs) for use in earth system models (ESMs) due to computational constraints. This study presents a hybrid-3D hillslope hydrological model (h3D) that couples a 1D vertical soil column model with a lateral pseudo-2D saturated zone and overland flow model for use in ESMs. By representing vertical and lateral responses separately at different spatial resolutions, h3D is computationally efficient. The h3D model was first tested for three different hillslope planforms (uniform, convergent and divergent). We then compared h3D (with single and multiple soil columns) with a complex physically-based 3D model and a simple 1D soil moisture model coupled with an unconfined aquifer (as typically used in LSMs). It is found that simulations obtained by the simple 1D model vary considerably from the complex 3D model and are not able to represent hillslope-scale variations in the lateral flow response. In contrast, the single soil column h3D model shows a much better performance and saves computational time by 2-3 orders of magnitude compared with the complex 3D model. When multiple vertical soil columns are implemented, the resulting hydrological responses (soil moisture, water table depth, and baseflow along the hillslope) from h3D are nearly identical to those predicted by the complex 3D model, but still saves computational time. As such, the computational efficiency of the h3D model provides a valuable and promising approach to incorporating hillslope-scale hydrological processes into continental and global-scale ESMs. This article is protected by copyright. All rights reserved.

Description: We investigated potential source areas of dissolved organic carbon (DOC) in headwater streams by examining DOC concentrations in lysimeter, shallow well, and streamwater samples from a reference catchment at the Hubbard Brook Experimental Forest. These observations were then compared to high frequency temporal variations in fluorescent dissolved organic matter (FDOM) at the catchment outlet and the predicted spatial extent of shallow groundwater in soils throughout the catchment. While near-stream soils are generally considered a DOC source in forested catchments, DOC concentrations in near-stream groundwater were low (mean = 2.4 mg/L, standard error = 0.6 mg/L), less than hillslope groundwater farther from the channel (mean = 5.7 mg/L, standard error = 0.4 mg/L). Furthermore, water tables in near-stream soils did not rise into the carbon rich upper B or O horizons even during events. In contrast, soils below bedrock outcrops near channel heads where lateral soil formation processes dominate had much higher DOC concentrations. Soils immediately downslope of bedrock areas had thick eluvial horizons indicative of leaching of organic materials, Fe, and Al and had similarly high DOC concentrations in groundwater (mean = 14.5 mg/L, standard error = 0.8 mg/L). Flow from bedrock outcrops partially covered by organic soil horizons produced the highest groundwater DOC concentrations (mean = 20.0 mg/L, standard error = 4.6 mg/L) measured in the catchment. Correspondingly, streamwater in channel heads sourced in part by shallow soils and bedrock outcrops had the highest stream DOC concentrations measured in the catchment. Variation in FDOM concentrations at the catchment outlet followed water table fluctuations in shallow to bedrock soils near channel heads. We show that shallow hillslope soils receiving runoff from organic matter-covered bedrock outcrops may be a major source of DOC in headwater catchments in forested mountainous regions where catchments have exposed or shallow bedrock near channel heads. This article is protected by copyright. All rights reserved.

Description: ABSTRACT Multiple scenarios of upward CO 2 migration driven by both injection-induced pressure and buoyancy force were investigated in a horizontally and vertically stratified core utilizing a core-flooding system with a 2D X-ray scanner. Two reservoir type scenarios were considered: (1) the terrestrial reservoir scenario (10 MPa and 50°C), where CO 2 exists in a supercritical state and (2) the deep-sea sediment reservoir scenario (28 MPa and 25°C), where CO 2 is stored in the liquid phase. The core-flooding experiments showed a 36% increase in migration rate in the vertical core setting compared with the horizontal setting, indicating the significance of the buoyancy force under the terrestrial reservoir scenario. Under both reservoir conditions, the injected CO 2 tended to find a preferential flow path (low capillary entry pressure and high-permeability (high- k ) path) and bypass the unfavorable pathways, leaving low CO 2 saturation in the low-permeability (low- k ) layers. No distinctive fingering was observed as the CO 2 moved upward, and the CO 2 movement was primarily controlled by media heterogeneity. The CO 2 saturation in the low- k layers exhibited a more sensitive response to injection rates, implying that the increase in CO 2 injection rates could be more effective in terms of storage capacity in the low- k layers in a stratified reservoir. Under the deep-sea sediment condition, the storage potential of liquid CO 2 was more than twice as high as that of supercritical CO 2 under the terrestrial reservoir scenario. In the end, multiphase transport simulations were conducted to assess the effects of heterogeneity on the spatial variation of pressure build-up, CO 2 saturation and CO 2 flux. Finally, we showed that a high gravity number () tended to be more influenced by the heterogeneity of the porous media. This article is protected by copyright. All rights reserved.

Description: Lake water storage change (Δ S w ) is an important indicator of the hydrologic cycle and greatly influences lake expansion/shrinkage over the Tibetan Plateau (TP). Accurate estimation of Δ S w will contribute to improved understanding of lake variations in the TP. Based on a water balance, this study explored the variations of Δ S w for the Lake Selin Co (the largest closed lake on the TP) during 2003-2012 using the Water and Energy Budget-based Distributed Hydrological Model (WEB-DHM) together with two different evapotranspiration (ET) algorithms (the Penman-Monteith method and a simple sublimation estimation approach for water area in unfrozen and frozen period). The contributions of basin discharge and climate causes to the Δ S w are also quantitatively analyzed. The results showed that WEB-DHM could well reproduce daily discharge, the spatial pattern and basin-averaged values of MODIS land surface temperature (LST) during nighttime and daytime. Compared with the ET reference values estimated from the basin-wide water balance, our ET estimates showed better performance than three global ET products in reproducing basin-averaged ET. The modeled ET at point scale matches well with short-term in situ daily measurements (RMSE = 0.82 mm/day). Lake inflows and precipitation over the water area had stronger relationships with Δ S w in the warm season and monthly scale, whereas evaporation from the water area had remarkable effects on Δ S w in the cold season. The total contribution of the three factors to Δ S w was about 90%, and accounting for 49.5%, 22.1% and 18.3%, respectively. This article is protected by copyright. All rights reserved.

Description: Predicting hydro(geo)logical or environmental systems is subject to high levels of uncertainties, especially if appropriate data for model calibration are lacking. For subsurface systems, where data acquisition is cost intensive and time demanding, it is especially important to collect only those data that provide the largest amount of relevant information. The high expenses call for optimal experimental design, which is widely recognized for maximizing the efficiency of experiments. In model-based design of experiments, the analysis of the design efficiency and the resulting optimal design are based on the initial state of knowledge about the modeled system. Joint optimization of multi-measurement designs is a well known challenge and the usefulness of global optimization approaches is widely recognized in this context. However, we will show that the benefit for such global optimization becomes questionable when measurement data become available sequentially. Instead, the optimization effort should be invested within an interactive design approach. Today's fast telecommunication, global connectivity and high-performance computing allow to consider such interactive coupling. This study will use a synthetic case study to compare the standard en-bloc global optimization approach to two interactive design approaches. The approaches are implemented in a Bayesian framework and are compared based on their complexity and overall performance. The key conclusion confirms a previously untested presumption: for models that trigger nonlinear parameter inference problems, interaction (which may come at a loss of global optimization) is more beneficial than global optimization based on the initial state of knowledge (which typically implies the impossibility of interactivity). This article is protected by copyright. All rights reserved.

Description: ABSTRACT Environmental tracers provide information on groundwater age, recharge conditions, and flow processes which can be helpful for evaluating groundwater sustainability and vulnerability. Dissolved noble gas data have proven particularly useful in mountainous terrain because they can be used to determine recharge elevation. However, tracer-derived recharge elevations have not been utilized as calibration targets for numerical groundwater flow models. Herein we constrain and calibrate a regional groundwater flow model with noble-gas-derived recharge elevations for the first time. Tritium and noble gas tracer results improved the site conceptual model by identifying a previously uncertain contribution of mountain-block recharge from the Coast Mountains to an alluvial coastal aquifer in humid southwestern British Columbia. The revised conceptual model was integrated into a three-dimensional numerical groundwater flow model and calibrated to hydraulic head data in addition to recharge elevations estimated from noble gas recharge temperatures. Recharge elevations proved to be imperative for constraining hydraulic conductivity, recharge location and bedrock geometry, and thus minimizing model non-uniqueness. Results indicate that 45% of recharge to the aquifer is mountain-block recharge. A similar match between measured and modeled heads was achieved in a second numerical model that excludes the mountain block (no mountain block recharge), demonstrating that hydraulic head data alone are incapable of quantifying mountain block recharge. This result has significant implications for understanding and managing source water protection in recharge areas, potential effects of climate change, the overall water budget, and ultimately ensuring groundwater sustainability. This article is protected by copyright. All rights reserved.

Description: CIZ/NMP4 (Cas interacting zinc finger protein, Nmp4, Zfp384) is a transcription factor that is known to regulate matrix related-proteins. To explore the possible pathophysiological role of CIZ/NMP4 in arthritis, we examined CIZ/NMP4 expression in articular cartilage in arthritis model. CIZ/NMP4 was expressed in the articular chondrocytes of mice at low levels while its expression was enhanced when arthritis was induced. Arthritis induction increased clinical score in wild type mice. In contrast, CIZ/NMP4 deficiency suppressed such rise in the levels of arthritis score and swelling of soft tissue. CIZ/NMP4 deficiency also reduced invasion of inflammatory cells in joint tissue. Quantitative PCR analyses of mRNA from joints revealed that arthritis-induced increase in expressions of IL-1β was suppressed by CIZ/NMP4 deficiency. CIZ/NMP4 bound to IL-1β promoter and activated its transcription. The increase in CIZ/NMP4 in arthritis was also associated with enhancement in bone resorption and cartilage matrix degradation. In fact, RANKL, a signaling molecule prerequisite for osteoclastogenesis and, MMP-3, a clinical marker for arthritis were increased in joints upon arthritis induction. In contrast, CIZ/NMP4 deficiency suppressed the arthritis-induced increase in bone resorption, expression of RANKL and MMP-3 mRNA. Thus, CIZ/NMP4 plays a role in the development of arthritis at least in part through regulation of key molecules related to the arthritis. This article is protected by copyright. All rights reserved

Description: The probability that new hydraulically fractured wells drilled within the area of New York underlain by the Marcellus Shale will intersect existing an wellbore is calculated using a statistical model, which incorporates: the depth of a new fracturing well, the vertical growth of induced fractures, and the depths and locations of existing nearby wells. The model first calculates the probability of encountering an existing well in plan view and combines this with the probability of an existing well being at sufficient depth to intersect the fractured region. Average probability estimates for the entire region of New York underlain by the Marcellus Shale range from 0.00% to 3.45% based upon the input parameters used. The largest contributing parameter on the probability value calculated is the nearby density of wells meaning that due diligence by oil and gas companies during construction in identifying all nearby wells will have the greatest effect in reducing the probability of interwellbore communication. This article is protected by copyright. All rights reserved.

Description: The idea of complementary evaporative fluxes, first advanced by Bouchet in 1963 is reformulated as a general polynomial, satisfying boundary conditions based on strictly physical considerations. Experimental evidence supports the validity of the imposed constraints. Earlier complementary relationships are shown to be special cases which satisfy only one of the necessary conditions. The new formulation provides a more rigorous base for the complementary principle. This article is protected by copyright. All rights reserved.

Description: A levee failure occurred along the Secchia River, Northern Italy, on January 19, 2014, resulting in flood damage in excess of $500 Million. In response to this failure, immediate surveillance of other levees in the region led to the identification of a second breach developing on the neighboring Panaro River, where rapid mitigation efforts were successful in averting a full levee failure. The paired breach events that occurred along the Secchia and Panaro Rivers provided an excellent window on an emerging levee failure mechanism. In the Secchia River, by combining the information content of photographs taken from helicopters in the early stage of breach development and 10-cm resolution aerial photographs taken in 2010 and 2012, animal burrows were found to exist in the precise levee location where the breach originated. In the Panaro River, internal erosion was observed to occur at a location where a crested porcupine den was known to exist and this erosion led to the collapse of the levee top. This paper uses detailed numerical modeling of rainfall, river flow, and variably saturated flow in the levee to explore the hydraulic and geotechnical mechanisms that were triggered along the Secchia and Panaro Rivers by activities of burrowing animals leading to levee failures. As habitats become more fragmented and constrained along river corridors it is possible that this failure mechanism could become more prevalent and, therefore, will demand greater attention in both the design and maintenance of earthen hydraulic structures as well as in wildlife management. This article is protected by copyright. All rights reserved.

Description: Future water demand is a main consideration in water system management. Consequently, water demand models (WDMs) have evolved in past decades, identifying principal demand-generating factors and modeling their influence on water demand. Regional water systems serve consumers of various types (e.g., municipalities, farmers, industrial regions) and consumption patterns. Thus, one of the challenges in regional water demand modeling is the heterogeneity of the consumers served by the water system. When a high-resolution, regional WDM is desired, accounting for this heterogeneity becomes all the more important. This paper presents a novel approach to regional water demand modeling. The two-step approach includes aggregating the dataset into groups of consumers having similar consumption characteristics, and developing a WDM for each homogeneous group. The development of WDMs is widely applied in the literature and thus, the focus of this paper is to discuss the first step of data aggregation. The research hypothesis is that water consumption records in their original or transformed form can provide a basis for aggregating the dataset into groups of consumers with similar consumption characteristics. This paper presents a methodology for water consumption data clustering by comparing several data representation methods (termed Feature Vectors): monthly normalized average, monthly consumption coefficient of variation, a combination of the monthly average and monthly variation, and the autocorrelation coefficients of the consumption time-series. Clustering using solely normalized monthly average provided homogeneous and distinct clusters with respect to monthly consumption, which succeed in capturing different consumer characteristics (water use, geographical location) that were not specified a-priori. Clustering using the monthly coefficient of variation provided different, yet homogeneous clusters, clustering consumers characterized by similar variation trends that were closely related to consumer water use type. The concatenation of these two Feature Vectors provided further insight into the relationship between consumption patterns and variability of consumers. An autocorrelation Feature Vector provided results that can form a basis for constructing a time-series model that is based on a group of resembling time-series. The approaches presented here are steps towards utilizing the increasing amount of available water consumption data and data analysis techniques to facilitate the modeling of water demands in larger and heterogeneous regions with sufficient resolution. This article is protected by copyright. All rights reserved.

Description: Most of the human appropriation of freshwater resources is for agriculture. Water availability is a major constraint to mankind's ability to produce food. The notion of virtual water content ( VWC ), also known as crop water footprint, provides an effective tool to investigate the linkage between food and water resources as a function of climate, soil and agricultural practices. The spatial variability in the virtual water content of crops is here explored, disentagling its dependency on climate and crop yields, and assessing the sensitivity of VWC estimates to parameter variability and uncertainty. Here we calculate the virtual water content of four staple crops (i.e., wheat, rice, maize, and soybean) for the entire world developing a high-resolution (5 by 5 arc minute) model, and we evaluate the VWC sensitivity to input-parameters. We find that food production almost entirely depends on green water (〉90%), but, when applied, irrigation makes crop production more water efficient, thus requiring less water. The spatial variability of the VWC is mostly controlled by the spatial patterns of crop yields with an average correlation coefficient of 0.83. The results of the sensitivity analysis show that wheat is most sensitive to the length of the growing period, rice to reference evapotranspiration, maize and soybean to the crop planting date. The VWC sensitivity varies not only among crops, but also across the harvested areas of the world, even at the sub-national scale. This article is protected by copyright. All rights reserved.

Description: The dissolution rate of non-aqueous phase liquid (NAPL) often governs the remediation time frame at subsurface hazardous waste sites. Most formulations for estimating this rate are empirical and assume that the NAPL is the non-wetting fluid. However, field evidence suggests that some waste sites might be organic-wet. Thus, formulations that assume the NAPL is non-wetting may be inappropriate for estimating the rates of NAPL dissolution. An exact solution to the Young-Laplace equation, assuming NAPL resides as pendular rings around the contact points of porous media idealized as spherical particles in a hexagonal close packing arrangement, is presented in this work to provide a theoretical prediction for NAPL-water interfacial area. This analytic expression for interfacial area is then coupled with an exact solution to the advection-diffusion equation in a capillary tube assuming Hagen-Poiseuille flow to provide a theoretical means of calculating the mass transfer rate coefficient for dissolution at the NAPL-water interface in an organic-wet system. A comparison of the predictions from this theoretical model with predictions from empirically-derived formulations from the literature for water-wet systems showed a consistent range of values for the mass transfer rate coefficient, despite the significant differences in model foundations (water-wetting vs NAPL-wetting, theoretical vs. empirical). This finding implies that, under these system conditions, the important parameter is interfacial area, with a lesser role played by NAPL configuration. This article is protected by copyright. All rights reserved.

Description: A number of important candidate CO 2 reservoirs exhibit sedimentary architecture reflecting fluvial deposition. Recent studies have led to new conceptual and quantitative models for sedimentary architecture in fluvial deposits over a range of scales that are relevant to CO 2 injection and storage. We used a geocellular modelling approach to represent this multi-scaled and hierarchical sedimentary architecture. With this model, we investigated the dynamics of CO 2 plumes, during and after injection, in such reservoirs. The physical mechanism of CO 2 trapping by capillary trapping incorporates a number of related processes, i.e. residual trapping, trapping due to hysteresis of the relative permeability, and trapping due to hysteresis of the capillary pressure. Additionally CO 2 may be trapped due to differences in capillary entry pressure for different textural sedimentary facies (e.g. coarser- vs. finer-grained cross-sets). The amount of CO 2 trapped by these processes depends upon a complex system of non-linear and hysteretic characteristic relationships including how relative permeability and capillary pressure vary with brine and CO 2 saturation. The results strongly suggest that representing small-scale features (decimeter to meter), including their organization within a hierarchy of larger-scale features, and representing their differences in characteristic relationships, can all be critical to understanding trapping processes in some important candidate CO 2 reservoirs. This article is protected by copyright. All rights reserved.

Description: Under changing environments, not only univariate but also multivariate hydrological series might become nonstationary. Nonstationarity, in forms of change-point or trend, has been widely studied for univariate hydrological series, while it attracts attention only recently for multivariate hydrological series. For multivariate series, two types of change-point need to be distinguished, i.e. change-point in marginal distributions and change-point in the dependence structure among individual variables. In this paper, a three-step framework is proposed to separately detect two types of change-point in multivariate hydrological series, i.e. change-point detection for individual univariate series, estimation of marginal distributions, and change-point detection for dependence structure. The last step is implemented using both the Cramér-von Mises statistic (CvM) method and the copula-based likelihood-ratio test (CLR) method. For CLR, three kinds of copula model (symmetric, asymmetric, and pair-copula) are employed to construct the dependence structure of multivariate series. Monte Carlo experiments indicate that CLR is far more powerful than CvM in detecting the change-point of dependence structure. This framework is applied to the trivariate flood series composed of annual maxima daily discharge (AMDD), annual maxima 3-day flood volume and annual maxima 15-day flood volume of the Upper Hanjiang River, China. It is found that each individual univariate flood series has a significant change-point; and the trivariate series presents a significant change-point in dependence structure due to the abrupt change in the dependence structure between AMDD and annual maxima 3-day flood volume. All these changes are caused by the construction of the Ankang Reservoir. This article is protected by copyright. All rights reserved.

Description: An output-feedback control strategy for pollution mitigation in combined sewer networks is presented. The proposed strategy provides means to apply model-based predictive control to large-scale sewer networks, in-spite of the lack of measurements at most of the network sewers. In previous works, the authors presented a hybrid linear control-oriented model for sewer networks together with the formulation of Optimal Control Problems (OCP) and State Estimation Problems (SEP). By iteratively solving these problems, preliminary Receding Horizon Control with Moving Horizon Estimation (RHC/MHE) results, based on flow measurements, were also obtained. In this work, the RHC/MHE algorithm has been extended to take into account both flow and water level measurements and the resulting control loop has been extensively simulated to assess the system performance according different measurement availability scenarios and rain events. All simulations have been carried out using a detailed physically-based model of a real case-study network as virtual reality. This article is protected by copyright. All rights reserved.

Description: This paper investigates nonpayment behavior in Guatemala. Determinants of nonpayment behavior are identified through zero-inflated negative binomial regression models in order to take into account particular distributional characteristics of the amount of outstanding payments. Findings indicate that nonpayment behavior is a demonstration of consumer dissatisfaction with current water services. The amount of outstanding bill payments also responds to system unreliability. Results also suggest that nonpayment behaviors are more prominent in community-managed systems than in municipal systems. No evidence was found on a potential relationship between nonpayment behavior and household income. Policy implications are discussed. This article is protected by copyright. All rights reserved.

Description: Agricultural practices have altered watershed-scale dissolved organic matter (DOM) dynamics, including in-stream concentration, biodegradability, and total catchment export. However, mechanisms responsible for these changes are not clear, and field-scale processes are rarely directly linked to the magnitude and quality of DOM that is transported to surface water. In a small (12 ha) agricultural catchment in eastern Washington State, we tested the hypothesis that hydrologic connectivity in a catchment is the dominant control over the concentration and quality of DOM exported to surface water via artificial subsurface drainage. Concentrations of dissolved organic carbon (DOC) and humic-like components of DOM decreased while the Fluorescence Index and Freshness Index increased with depth through the soil profile. In drain discharge, these characteristics were significantly correlated with drain flow across seasons and years, with drain DOM resembling deep sources during low flow and shallow sources during high flow, suggesting that DOM from shallow sources bypasses removal processes when hydrologic connectivity in the catchment is greatest. Assuming changes in streamflow projected for the Palouse River (which contains the study catchment) under the A1B climate scenario (rapid growth, dependence on fossil fuel and renewable energy sources) apply to the study catchment, we project greater interannual variability in annual DOC export in the future, with significant increases in the driest years. This study highlights the variability in DOM inputs from agricultural soil to surface water on daily to interannual timescales, pointing to the need for a more nuanced understanding of agricultural impacts on DOM dynamics in surface water. This article is protected by copyright. All rights reserved.

Description: In basement catchments of sub-humid West Africa, baseflow is the main component of annual streamflow. However, the important heterogeneity of lithology hinders the understanding of baseflow generation processes. Since these processes are linked with water storage changes (WSCs) across the catchment, we propose the use of hybrid gravity data in addition to neutron probe-derived water content and water levels to monitor spatiotemporal WSC of a typical crystalline basement headwater catchment (16 ha) in Benin. These behaviors are shown to provide insights into hydrological processes in terms of water redistribution toward the catchment outlet. Hybrid gravimetry produces gravity change observations from time-lapse microgravity surveys coupled with gravity changes monitored at a base station using a superconducting gravimeter and/or an absolute gravimeter. A dense microgravity campaign (70 surveys of 14 stations) covering three contrasted years was set up with a rigorous protocol, leading to low uncertainties (〈 2.5 µGal) on station gravity determinations (with respect to the network reference station). Empirical orthogonal function analyses of both gravity changes and WSCs from neutron probe data show similar spatial patterns in the seasonal signal. Areas where storage and water table show a capping behavior (when data reach a plateau during the wet season), suggesting threshold-governed fast subsurface redistribution, are identified. This observed storage dynamics, together with geological structures investigated by electrical resistivity tomography and drill log analysis make it possible to derive a conceptual model for the catchment hydrology. This article is protected by copyright. All rights reserved.

Description: Groundwater and surface water contain interfaces across which hydrologic functions are discontinuous. Thin elements with high hydraulic conductivity in a porous media focus groundwater, which flows through such inhomogeneities and causes an abrupt change in stream function across their interfaces, and elements with low conductivity retards flow with discontinuous head. Baseflow interactions at the interface between groundwater and surface water transport water between these stores and generate a discontinuous normal component of flow. Thin objects in surface water with Kutta condition generates circulation by the discontinuous tangential component of flow across their interface. These discontinuities across hydrologic interfaces are quantified and visualized using the Analytic Element Method, where slit elements are formulated using the Joukowsky transformation with Laurent series and new influence functions to represent sinks and circulation, and methods are developed for these applications expressing discontinuities as Fourier series. The specific geometries illustrate solutions for a randomly generated heterogeneous porous media with non-intersecting inhomogeneities, for groundwater/surface water interaction in a synthetic river network, and for a slender body with geometry similar to the wings of the Wright Brothers. The mathematical details are reduced to series solutions and matrix multiplications, which are easily extensible to other geometries and applications. This article is protected by copyright. All rights reserved.

Description: Both flow field heterogeneity and mass transfer between mobile and immobile domains have been studied separately for explaining observed anomalous transport. Here, we investigate non-Fickian transport using high-resolution 3D X-ray micro-tomographic images of Berea sandstone containing microporous cement with pore size below the setup resolution. Transport is computed for a set of representative elementary volumes and results from advection and diffusion in the resolved macroporosity (mobile domain) and diffusion in the microporous phase (immobile domain) where the effective diffusion coefficient is calculated from the measured local porosity using a phenomenological model that includes a porosity threshold ( ɸ ϴ ) below which diffusion is null and the exponent n that characterizes tortuosity-porosity power-law relationship. We show that both flow field heterogeneity and microporosity trigger anomalous transport. Breakthrough curve (BTC) tailing is positively correlated to microporosity volume and mobile-immobile interface area. The sensitivity analysis showed that the BTC tailing increases with the value of ɸ ϴ , due to the increase of the diffusion path tortuosity until the volume of the microporosity becomes negligible. Furthermore, increasing the value of n leads to an increase in the standard deviation of the distribution of effective diffusion coefficients, which in turn results in an increase of the BTC tailing. Finally, we propose a continuous time random walk upscaled model where the transition time is the sum of independently distributed random variables characterized by specific distributions. It allows modeling a 1D equivalent macroscopic transport honoring both the control of the flow field heterogeneity and the multi-rate mass transfer between mobile and immobile domains. This article is protected by copyright. All rights reserved.

Description: ABSTRACT Immune responses are outcomes of complex molecular machinery which occur inside the cells. Unravelling the cellular mechanisms induced by immune stimulating molecules such as glycans and determining their structure-function relationship are therefore important factors to be assessed. With this viewpoint, the present study identifies the functional receptor binding unit of a well characterized heteroglycan and also delineates the cellular and molecular processes that are induced upon heteroglycan binding to specific cell surface receptors in immune cells. The heteroglycan was acid hydrolysed and it was revealed that 10-30 kDa fractions served as the functional receptor binding unit of the molecule. Increasing the size of 10-30 kDa heteroglycan showed prominent immune activity. The whole soluble heteroglycan was also conjugated with hyperbranched dendrimers so as to generate a particulate form of the molecule. Dectin-1 and TLR2 were identified as the major receptors in macrophages that bind to particulate as well as soluble form of the heteroglycan and subsequently caused downstream signaling molecules such as NF-κβ and MAPK to get activated. High levels of 1L-1β and IL-10 mRNA were observed in particulate heteroglycan treated macrophages, signifying that increasing the size and availability of the heteroglycan to its specific receptors is pertinent to its biological functioning. Upregulated expression of PKC and iNOS were also noted in particulate heteroglycan treated RAW 264.7 cells than the soluble forms. Taken together, our results indicate that biological functions of immunomodulatory heteroglycan are dependent on their size and molecular weight. This article is protected by copyright. All rights reserved

Description: Polyphenols are a class of natural compounds whose potential as antioxidant, anti-inflammatory and anti-angiogenesis has been reported in many pathological conditions. Red raspberry extract, rich in polyphenols, has been reported to exert anti-inflammatory effects and prevent cell proliferation in distinct animal models. However, the signalling pathways involved remain unknown. Herein, we used human microvascular endothelial cells (HMVECs) to determine the influence of red raspberry phenolic compound extract concentrations, ranging from 10-250 µg gallic acid equivalents (GAE)/mL, on endothelium viability (MTS assay), proliferation (BrdU incorporation), migration (injury assay) and capillary-like structures formation (Matrigel assay). Protein expression in cell lysates was determined by Western blot analysis. We showed that red raspberry extracts reduced cell viability (GI 50  = 87,64 ± 6,59 µg GAE/mL) and proliferation in a dose-dependent manner. A significant abrogation of cells ability to migrate to injured areas, even at low concentrations, was observed by injury assay. Cell assembly into capillary-like structures on Matrigel also decreased in a dose dependent-manner for higher extract concentrations, as well as the number of branching points per unit of area. Protein expression analysis showed a dose-dependent decrease in Phospho-VEGFR2 expression, implying abrogation of VEGF signalling activity. We also showed for the first time that red raspberry phenolic compounds induce the rearrangement of filamentous actin cytoskeleton, with an isotropy increase found for higher testing concentrations. Taken together, our findings corroborate the anti-angiogenic potential of red raspberry phenolic compounds and provide new insights into their mode of action upon endothelium. This article is protected by copyright. All rights reserved

Description: Using airborne thermal infrared imaging and horizontally-resolved in situ temperature monitoring at the lake surface we estimated strength and duration of regular wind-driven upwelling of dense deep water to the lake surface in two small (in terms of Rossby radius) temperate lakes during the initial phase of summer thermal stratification. The onset and duration of the upwelling events correlated well with the balance between stratification (in terms of Schmidt Stability) and wind forcing, as expressed by Lake and Wedderburn Numbers: The period of regular upwelling appearances lasted 7-15 days, identified by Schmidt stabilities around 30 J m −2 and Lake Numbers between 0 and 1, and resulted in persistent temperature gradients of up to 2°C across the lake surface. Our results suggest that spring upwelling should inevitably take place in all freshwater temperate lakes with mean temperatures crossing the maximum density value of freshwater on annual cycle, whereas duration and intensity of the upwelling would vary depending on lake morphometry and weather conditions. Our results suggest major contribution of upwelling in nutrient supply to the upper waters, oxygenation of the deep water column, and air-lake gas exchange, in particular, the release of the sediment-produced methane into the atmosphere. This article is protected by copyright. All rights reserved.

Description: We provide a comprehensive experimental study of steady state, drainage relative permeability curves with CO 2 -brine and N 2 -deionised water, on a single Bentheimer sandstone core with a simple two-layer heterogeneity. We demonstrate that, if measured in the viscous limit, relative permeability is invariant with changing reservoir conditions, and is consistent with the continuum scale multiphase flow theory for water wet systems. Furthermore, we show that under capillary limited conditions, the CO 2 -brine system is very sensitive to heterogeneity in capillary pressure, and by performing core floods under capillary limited conditions, we produce effective relative permeability curves that are flow rate and fluid parameter dependent. We suggest that the major uncertainty in past observations of CO 2 -brine relative permeability curves is due to the interaction of CO 2 flow with pore space heterogeneity under capillary limited conditions and is not due to the effects of changing reservoir conditions. We show that the appropriate conditions for measuring intrinsic or effective relative permeability curves can be selected simply by scaling the driving force for flow by a quantification of capillary heterogeneity. Measuring one or two effective curves on a core with capillary heterogeneity that is representative of the reservoir will be sufficient for reservoir simulation This article is protected by copyright. All rights reserved.

Description: We examine the prediction capability of two approximate models (Multi Rate Mass Transfer, MRMT, and Continuous Time Random Walk, CTRW) of non-Fickian transport, by comparison with accurate 2D and 3D numerical simulations. Both non-local in time approaches circumvent the need to solve the flow and transport equations by using proxy models to advection, providing the breakthrough curves (BTC) at control planes at any x , depending on a vector of 5 unknown parameters. Although underlain by different mechanisms, the two models have an identical structure in the Laplace Transform domain and have the Markovian property of independent transitions. We show that also the numerical BTCs enjoy the Markovian property. Following the procedure recommended in the literature, along a practitioner perspective, we first calibrate the parameters values by a best fit with the numerical BTC at a control plane at x 1 , close to the injection plane, and subsequently use it for prediction at further control planes for a few values of . Due to a similar structure and Markovian property, the two methods perform equally well in matching the numerical BTC. The identified parameters are generally not unique, making their identification somewhat arbitrary. The inverse Gaussian model and the recently developed Multi Indicator model (MIM), which does not require any fitting as it relates the BTC to the permeability structure, are also discussed. The application of the proxy models for prediction requires carrying out transport field tests of large plumes for a long duration. This article is protected by copyright. All rights reserved.

Description: Virus removal during rapid transport in an unconfined, low-temperature (6°C) sand and gravel aquifer was investigated at a riverbank field site, 25 km south of Trondheim in central Norway. The data from bacteriophage MS2 inactivation and transport experiments were applied in a two-site kinetic transport model using HYDRUS-1D, to evaluate the mechanisms of virus removal and whether these mechanisms were sufficient to protect the groundwater supplies. The results demonstrated that inactivation was negligible to the overall removal, and that irreversible MS2 attachment to aquifer grains, coated with iron precipitates, played a dominant role in the removal of MS2; 4.1 log units of MS2 were removed by attachment during 38 m travel distance and less than 2 days residence time. Although the total removal was high, pathways capable of allowing virus migration at rapid velocities were present in the aquifer. The risk of rapid transport of viable viruses should be recognized, particularly for water supplies without permanent disinfection. This article is protected by copyright. All rights reserved.

Description: Upstream source control and Stormwater Treatment Areas (STAs) have reduced phosphorus (P) loads to Water Conservation Area 2A (WCA-2A), a northern Everglades wetland, by three-quarters since year 2000. Nevertheless, large storages of P remain in enriched peat soils and it is unclear how legacy stores will impact spatial and temporal scales of recovery. We re-measured soil P enrichment along a well-studied eutrophication gradient in WCA-2A and applied a profile modeling approach with uncertainty analysis to assess changes in longitudinal soil P gradients 13-years after load reductions. We then analyzed existing internal water P data, using a novel data screening approach, for evidence of lowest possible water P concentrations independent from inflows. We interpret such water P limits as evidence of the strength of internal loading at a location. Results indicate that soil P enrichment persists in the ∼7.5 km long “impacted” zone, with no significant evidence of net advancement or recession, while a large pool of labile P in the flocculent layer consolidated and diminished. There is indeed evidence, both spatial and temporal, that this extensive zone of enriched soil P continues to elevate lowest achievable water P concentrations. The corresponding gradient of elevated water P limits is both receding and diminishing since load reductions, thus providing further evidence toward recovery. However, results also suggest that these “transitory P limits” due to internal loading are likely to persist for decades above water quality targets. These results advance our understanding of recovery in impacted wetlands and are relevant to Everglades restoration. This article is protected by copyright. All rights reserved.

Description: Numerical modeling approaches with varying complexity were explored to investigate coupled groundwater flow and geochemical processes in saline basins. Long-term model simulations of a playa system gain insights into the complex feedback mechanisms between density driven flow and the spatio-temporal patterns of precipitating evaporites and evolving brines. Using a reactive multicomponent transport model approach the simulations reproduced, for the first time in a numerical study, the evaporite precipitation sequences frequently observed in saline basins (“bull's eyes”). Playa-specific flow, evapo-concentration and chemical divides were found to be the primary controls for the location of evaporites formed, and the resulting brine chemistry. Comparative simulations with the computationally far less demanding surrogate single-species transport models showed that these were still able to replicate the major flow patterns obtained by the more complex reactive transport simulations. However, the simulated degree of salinization was clearly lower than in reactive multicomponent transport simulations. For example, in the late stages of the simulations, when the brine becomes halite-saturated, the non-reactive simulation overestimated the solute mass by almost 20%. The simulations highlight the importance of the consideration of reactive transport processes for understanding and quantifying geochemical patterns, concentrations of individual dissolved solutes and evaporite evolution. This article is protected by copyright. All rights reserved.

Description: Evodiamine (Evo), extracted from the Chinese herbal medicine Evodia rutaecarpa, has cytotoxic effects on different types of human cancer cells. However, its effects on drug resistance and their molecular mechanism and therapeutic target in colorectal cancer are not well understood. In the present study, we observed that Evo inhibited cell growth and induced apoptosis in adose-and time-dependent mannner in HCT-116/L-OHP cells. Moreover, Evo treatment reduced Rhodamine 123 accumulation and ATPase activity in HCT-116/L-OHP cells, indicating that Evo decreased the efflux function in HCT-116/L-OHP cells. Interestingly, phosphorylation of NF-κB pathway, particularly p50/p65, was also inhibited by Evo treatment. Furthermore the effect of Evo in reversing drug resistance and suppressing phosphorylation of NF-κB pathway were attenuated after treatment with the NF-κB activator (LPS). Additionally, Evo inhibited the tumor growth in a colorectal MDR cancer xenograft model and down regulated p-NF-κB level in vivo . Our study provided the first direct evidence that Evo can attenuate multidrug resistance by blocking p-NF-κB signaling pathway in human colorectal cancer. Evo could be a potential candidate for cancer chemotherapy. This article is protected by copyright. All rights reserved

Description: Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n = 20 placentas; SOP, n = 24; C, n = 12), 24 h (LIG, n = 28; SOP, n = 20; C, n = 12) and 72 h (LIG, n = 20; SOP, n = 20; C, n = 24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. This article is protected by copyright. All rights reserved

Description: ABSTRACT A method is presented for using dissolved CFCs or SF 6 to estimate the apparent age of stream base flow by indirectly estimating the mean concentration of the tracer in the inflowing groundwater. The mean value is estimated simultaneously with the mean residence times of the gas and water in the stream by sampling the stream for one or both age tracers, along with dissolved nitrogen and argon at a single location over a period of approximately 12-14 hours. The data are fitted to an equation representing the temporal in-stream gas exchange as it responds to the diurnal temperature fluctuation. The efficacy of the method is demonstrated by collecting and analyzing samples at six different stream locations across parts of northern Virginia, USA. The studied streams drain watersheds with areas of between 2 and 122 km 2 during periods when the diurnal stream temperature ranged between 2 and 5°C. The method has the advantage of estimating the mean groundwater residence time of discharge from the watershed to the stream without the need for the collection of groundwater infiltrating to streambeds or local groundwater sampled from shallow observation wells near the stream. This article is protected by copyright. All rights reserved.

Description: ABSTRACT A between-groups experimental design examined public acceptance for managed aquifer recharge of stormwater for indirect potable and non-potable reuse; acceptance was based on five policy-related variables (fairness, effectiveness, trust, importance of safety assurances, and importance of communication activities). Results showed that public acceptance (N = 408) for managed aquifer recharge of stormwater was higher for non-potable applications, as was the importance of safety assurances. Analyses of variance also showed that perceptions of fairness and effectiveness were higher for a non-potable scheme, but not trust. A three-step hierarchical regression (Step 1: age, gender, education, income; Step 2: type of use; Step 3: fairness, effectiveness, trust, safety assurance, communication activities) demonstrated that type of stormwater use and the policy related factors accounted for 73% of the variance in acceptance of stormwater ( R 2 = .74, adjusted R 2 = .74, F (10, 397) = 113.919, p  〈 .001). Age, type of use and three of the five policy-related factors were also significant individual predictors of acceptance. The most important predictors were perceptions of trust in water authorities, perceptions of effectiveness, and perceptions of fairness. Interestingly, while safety assurance was important in attitudinal acceptance of managed aquifer recharge based on type of use, safety assurance was not found to be significant predictor of acceptance. This research suggests that policy-makers should look to address matters of greater public importance and drive such as fairness, trust and effectiveness of stormwater programs and advocate these at the forefront of their policies, rather than solely on education campaigns. This article is protected by copyright. All rights reserved.

Description: Previously, we reported that brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration by inducing periodontal ligament cell proliferation in vivo . In addition, the down growth of gingival epithelial cells, which comprises a major obstacle to the regeneration was not observed. However, the underlying molecular mechanism is still unclear. Therefore, this study aimed to investigate the effect of BDNF on cell proliferation and apoptosis in human periodontal ligament cells (HPL cells) and human gingival epithelial cells (OBA9 cells) and to explore the molecular mechanism in vitro . HPL cells dominantly expressed a BDNF receptor, TrkB, and BDNF increased cell proliferation and ERK phosphorylation. However, its proliferative effect was diminished by a MEK1/2 inhibitor (U0126) and TrkB siRNA transfection. Otherwise, OBA9 cells showed a higher expression level of p75, which is a pan-neurotrophin receptor, than that of HPL cells. BDNF facilitated not cell proliferation but cell apoptosis and JNK phosphorylation in OBA9 cells. A JNK inhibitor (SP600125) and p75 siRNA transfection attenuated the BDNF-induced cell apoptosis. Moreover, OBA9 cells pretreated with SP600125 or p75 siRNA showed cell proliferation by BDNF stimulation, though it was reduced by U0126 and TrkB siRNA. Interestingly, overexpression of p75 in HPL cells up-regulated cell apoptosis and JNK phosphorylation by BDNF treatment. These results indicated that TrkB-ERK signaling regulates BDNF-induced cell proliferation, whereas p75-JNK signaling plays roles in cell apoptotic and cytostatic effect of BDNF. Overall, BDNF activates periodontal ligament cells proliferation and inhibits the gingival epithelial cells growth via the distinct pathway. This article is protected by copyright. All rights reserved

Description: Observations at the field, catchment, and continental scales across a range of arid and semiarid climates and latitudes reveal aspect-controlled patterns in soil properties, vegetation types, ecohydrologic fluxes, and hillslope morphology. Although the global distribution of solar radiation on earth's surface and its implications on vegetation dynamics are well documented, we know little about how variation of solar radiation across latitudes influence landscape evolution and resulting geomorphic difference. Here, we used a landscape evolution model that couples the continuity equations for water, sediment, and aboveground vegetation biomass at each model element in order to explore the controls of latitude and mean annual precipitation (MAP) on the development of hillslope asymmetry (HA). In our model, asymmetric hillslopes emerged from the competition between soil creep and vegetation-modulated fluvial transport, driven by spatial distribution of solar radiation. Latitude was a primary driver of HA because of its effects on the global distribution of solar radiation. In the Northern Hemisphere, north-facing slopes (NFS), which support more vegetation cover and have lower transport efficiency, get steeper toward the North Pole while south-facing slopes (SFS) get gentler. In the Southern Hemisphere, the patterns are reversed and SFS get steeper towards the South Pole. For any given latitude, MAP is found to have minor control on HA. Our results underscore the potential influence of solar radiation as a global control on the development of asymmetric hillslopes in fluvial landscapes. This article is protected by copyright. All rights reserved.

Description: Temporal dynamics of sediment transport in steep channels using two experiments performed in a steep flume (8%) with natural sediment composed of 12 grain sizes are studied. High-resolution (1 sec) time series of sediment transport were measured for individual grain size classes at the outlet of the flume for different combinations of sediment input rates and flow discharges. Our aim in this paper is to quantify (a) the relation of discharge and sediment transport, and (b) the nature and strength of memory in grain-size dependent transport. None of the simple statistical descriptors of sediment transport (mean, extreme values, quantiles) display a clear relation with water discharge, in fact a large variability between discharge and sediment transport is observed. Instantaneous transport rates have probability density functions with heavy tails and bedload bursts have a coarser grain-size distribution than that of the entire experiment. We quantify the strength and nature of memory in sediment transport rates by estimating the Hurst exponent and the autocorrelation coefficient of the time series for different grain sizes. Our results show the presence of the Hurst phenomenon in transport rates, indicating long-term memory which is grain-size dependent. The short-term memory in coarse-grain transport increases with temporal aggregation and this reveals the importance of the sampling duration of bedload transport rates in natural streams, especially for large fractions. This article is protected by copyright. All rights reserved.

Description: In-channel structures are often installed in alluvial rivers during restoration to steer currents, but they also modify the streambed morphology and water surface profile, and alter hydraulic gradients driving ecologically important hyporheic exchange. Although river features before and after restoration need to be compared, few studies have collected detailed observations to facilitate this comparison. We created a laboratory mobile-bed alluvial meandering river and collected detailed measurements in the highly sinuous meander before and after installation of in-channel structures, which included one cross-vane and six J-hooks situated along one bar unit. Measurements of streambed and water surface elevation with sub-millimeter vertical accuracy and horizontal resolution were obtained using close-range photogrammetry. Compared to the smooth gradually varied water surface profile for control runs without structures, the structures created rapidly varied flow with sub- to super-critical flow transitions, as well as backwater and forced-morphology pools, which increased volumetric storage by 74% in the entire stream reach. The J-hooks, located along the outer bank of the meander bend and downstream of the cross-vane, created stepwise patterns in the streambed and water surface longitudinal profiles. The pooling of water behind the cross-vane increased the hydraulic gradient across the meander neck by 1% and increased local groundwater gradients by 4%, with smaller increases across other transects through the intra-meander zone. Scour pools developed downstream of the cross-vane and around the J-hooks situated near the meander apex. In-channel structures significantly changed meander bend hydraulic gradients, and the detailed streambed and water surface 3D maps provide valuable data for computational modeling of changes to hyporheic exchange. This article is protected by copyright. All rights reserved.