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Small ponds-farm ponds, detention ponds, or impoundments below 0.01 km(2)-serve important human needs throughout most large river basins. Yet the role of small ponds in regional nutrient and sediment budgets is essentially unknown, currently making it impossible to evaluate their management potential to achieve water quality objectives. Here we used new hydrography data sets and found that small ponds, depending on their spatial position within both their local catchments and the larger river network, can dominate the retention of nitrogen, phosphorus, and sediment compared to rivers, lakes, and reservoirs. Over 300,000 small ponds are collectively responsible for 34%, 69%, and 12% of the mean annual retention of nitrogen, phosphorus, and sediment in the Northeastern United States, respectively, with a dominant influence in headwater catchments (54%, 85%, and 50%, respectively). Small ponds play a critical role among the many aquatic features in long-term nutrient and sediment loading to downstream waters. Plain Language Summary Reservoirs created by river damming have extensive impacts on downstream water quality but are not necessarily the most important elements of a diverse aquatic landscape. Many more small ponds have been constructed to serve important human needs ranging from farm irrigation in agricultural areas to flood control and trapping of nutrients and fine sediment in urban areas. The number of human-influenced small ponds is projected to rise worldwide, yet their role in the delivery of nutrients and sediment from headwaters to oceans is currently unresolved. Here we used new data sets and found that small ponds are collectively responsible for trapping a substantial amount of the nutrients and sediment that are exported annually from headwaters. These findings support the need to jointly consider features such as urban detention ponds, farm ponds, and beaver ponds in managing headwaters to decrease long-term nutrient and sediment loading to downstream waters and sensitive coastal areas. U.S. Geological SurveyUnited States Geological Survey; National Science Foundation Hydrologic Sciences ProgramNational Science Foundation (NSF)NSF - Directorate for Geosciences (GEO); Water Mission Area The ideas for this work were formulated during meetings of the John Wesley Powell Center River Corridor Working Group, supported by U.S. Geological Survey and National Science Foundation Hydrologic Sciences Program. The work was carried out at the USGS where N. M. S. is a USGS Mendenhall postdoctoral fellow funded by the Water Mission Area. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. We used publicly available, nationally consistent data sets (see Table S2 for data sources). The SPARROW model source code is also publicly available (https://water.usgs.gov/nawqa/sparrow/). The authors declare no conflict of interest. Public domain – authored by a U.S. government employee

Downstream flow in rivers is repeatedly delayed by hydrologic exchange with off-channel storage zones where biogeochemical processing occurs. We present a dimensionless metric that quantifies river connectivity as the balance between downstream flow and the exchange of water with the bed, banks, and floodplains. The degree of connectivity directly influences downstream water quality - too little connectivity limits the amount of river water exchanged and leads to biogeochemically inactive water storage, while too much connectivity limits the contact time with sediments for reactions to proceed. Using a metric of reaction significance based on river connectivity, we provide evidence that intermediate levels of connectivity, rather than the highest or lowest levels, are the most efficient in removing nitrogen from Northeastern United States' rivers. Intermediate connectivity balances the frequency, residence time, and contact volume with reactive sediments, which can maximize the reactive processing of dissolved contaminants and the protection of downstream water quality. Our simulations suggest denitrification dominantly occurs in riverbed hyporheic zones of streams and small rivers, whereas vertical turbulent mixing in contact with sediments dominates in mid-size to large rivers. The metrics of connectivity and reaction significance presented here can facilitate scientifically based prioritizations of river management strategies to protect the values and functions of river corridors. U.S. Geological SurveyUnited States Geological Survey; National Science Foundation Hydrologic Sciences ProgramNational Science Foundation (NSF)NSF - Directorate for Geosciences (GEO); USGS National Water Quality Program; DOE Office of Biological and Environmental Research (BER) in the Subsurface Biogeochemistry Program (SBR) as part of SBR's Scientific Focus Area at the Pacific Northwest National Laboratory (PNNL) The work is a product of the John Wesley Powell Center River Corridor Synthesis Group, supported by U.S. Geological Survey and National Science Foundation Hydrologic Sciences Program. USGS authors received additional support from the USGS National Water Quality Program. Gomez-Velez received additional support from the DOE Office of Biological and Environmental Research (BER) in the Subsurface Biogeochemistry Program (SBR) as part of SBR's Scientific Focus Area at the Pacific Northwest National Laboratory (PNNL). The synthesis is based entirely on analysis of published information and publicly available data sources. Any use of trade, firm, or product is for descriptive purposes only and does not imply endorsement by the U.S. Government. Public domain – authored by a U.S. government employee

Lakes, reservoirs, and other ponded waters are ubiquitous features of the aquatic landscape, yet their cumulative role in nitrogen removal in large river basins is often unclear. Here we use predictive modeling, together with comprehensive river water quality, land use, and hydrography datasets, to examine and explain the influences of more than 18,000 ponded waters on nitrogen removal through river networks of the Northeastern United States. Thresholds in pond density where ponded waters become important features to regional nitrogen removal are identified and shown to vary according to a ponded waters’ relative size, network position, and degree of connectivity to the river network, which suggests worldwide importance of these new metrics. Consideration of the interacting physical and biological factors, along with thresholds in connectivity, reveal where, why, and how much ponded waters function differently than streams in removing nitrogen, what regional water quality outcomes may result, and in what capacity management strategies could most effectively achieve desired nitrogen loading reduction., Lakes, reservoirs, and other ponded waters are common in large river basins yet their influence on nitrogen budgets is often indistinct. Here, the authors show how a ponded waters’ relative size, shape, and degree of connectivity to the river network control nitrogen removal.

We previously reported that miR-1 is among the most consistently down-regulated miRs in primary human prostate tumors. In this follow-up study, we further corroborated this finding in an independent data set and made the novel observation that miR-1 expression is further reduced in distant metastasis and is a candidate predictor of disease recurrence. Moreover, we performed in vitro experiments to explore the tumor suppressor function of miR-1. Cell-based assays showed that miR-1 is epigenetically silenced in human prostate cancer. Overexpression of miR-1 in these cells led to growth inhibition and down-regulation of genes in pathways regulating cell cycle progression, mitosis, DNA replication/repair and actin dynamics. This observation was further corroborated with protein expression analysis and 3'-UTR-based reporter assays, indicating that genes in these pathways are either direct or indirect targets of miR-1. A gene set enrichment analysis revealed that the miR-1-mediated tumor suppressor effects are globally similar to those of histone deacetylase inhibitors. Lastly, we obtained preliminary evidence that miR-1 alters the cellular organization of F-actin and inhibits tumor cell invasion and filipodia formation. In conclusion, our findings indicate that miR-1 acts as a tumor suppressor in prostate cancer by influencing multiple cancer-related processes and by inhibiting cell proliferation and motility.

Background Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic. Methods This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006-2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed. Results Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIH-CPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo ( P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and subscores ( P P = .02), and improvement in total McGill Pain Questionnaire score ( P = .01). Results for the other outcomes did not differ between groups. Conclusion Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS. Trial Registration clinicaltrials.gov Identifier:NCT00371033

We conducted a clinical trial of peptide prostate specific antigen (PSA): 154-163 (155L) vaccination in human leukocyte antigen (HLA)-A2 patients with detectable and rising serum PSA after radical prostatectomy for prostate cancer (Clinicaltrials.gov identifier NCT00109811). The trial was a single dose-level, phase 2 pilot trial of 1 mg of PSA: 154-163 (155L) emulsified with adjuvant (Montanide ISA-51). The primary endpoint was the determination of immunogenicity of the vaccine; secondary outcomes were determination of toxicity and effect on serum PSA. The vaccine was given subcutaneously 7 times on weeks 0, 2, 4, 6, 10, 14, and 18. Peptide-specific CD8 T-cell responses in the peripheral blood mononuclear cells (PBMC) of patients were measured by interferon (IFN)-gamma enzyme-linked immunosorbent spot assay. CD8 T-cell cultures were also established by in vitro stimulation with the peptide presented by autologous dendritic cells. Five patients were enrolled and completed all vaccinations. No IFN-gamma response to PSA: 154-163 (155L) was detected in unfractioned PBMC in any patient either before or after vaccination. Three of 5 patients demonstrated strong IFN-gamma responses to PSA: 154-163 (155L) and native PSA: 154-163 peptides in CD8 T-cell cultures derived from postvaccination PBMC. However, peptide-specific T cells failed to recognize HLA-A2 positive targets expressing endogenous PSA. There were no significant changes in serum PSA level in any subject. No serious adverse events were observed. PSA: 154-163 (155L) is not an effective immunogen when given with Montanide ISA-51. The PSA: 154-163 peptide is poorly processed from endogenous PSA and therefore represents a cryptic epitope of PSA in HLA-A2 antigen-presenting cells.

The importance of lotic systems as sinks for nitrogen inputs is well recognized. A fraction of nitrogen in streamflow is removed to the atmosphere via denitrification with the remainder exported in streamflow as nitrogen loads. At the watershed scale, there is a keen interest in understanding the factors that control the fate of nitrogen throughout the stream channel network, with particular attention to the processes that deliver large nitrogen loads to sensitive coastal ecosystems. We use a dynamic stream transport model to assess biogeochemical (nitrate loadings, concentration, temperature) and hydrological (discharge, depth, velocity) effects on reach-scale denitrification and nitrate removal in the river networks of two watersheds having widely differing levels of nitrate enrichment but nearly identical discharges. Stream denitrification is estimated by regression as a nonlinear function of nitrate concentration, streamflow, and temperature, using more than 300 published measurements from a variety of US streams. These relations are used in the stream transport model to characterize nitrate dynamics related to denitrification at a monthly time scale in the stream reaches of the two watersheds. Results indicate that the nitrate removal efficiency of streams, as measured by the percentage of the stream nitrate flux removed via denitrification per unit length of channel, is appreciably reduced during months with high discharge and nitrate flux and increases during months of low-discharge and flux. Biogeochemical factors, including land use, nitrate inputs, and stream concentrations, are a major control on reach-scale denitrification, evidenced by the disproportionately lower nitrate removal efficiency in streams of the highly nitrate-enriched watershed as compared with that in similarly sized streams in the less nitrate-enriched watershed. Sensitivity analyses reveal that these important biogeochemical factors and physical hydrological factors contribute nearly equally to seasonal and stream-size related variations in the percentage of the stream nitrate flux removed in each watershed.

Prostate cancer is the second most frequently diagnosed cancer in men worldwide and sixth leading cancer-related cause of death in males. Treatments for recurrent prostate cancer are only rarely curative, and the majority of patients eventually demonstrate progressive disease. Animal and clinical studies suggested that immunological approaches can be useful for prostate cancer treatment and prevention. The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate-specific differentiation antigens is an attractive concept. Prostate specific antigen (PSA) is a serine protease of the glandular kallikrein gene family with highly restricted expression on prostate tumor cells and normal prostate. Previous attempts to develop PSA-based vaccines for prostate cancer primarily using poxvirus and adenovirus vectors resulted in promising clinical and immune responses. However, these approaches had limitations due to pre-existing antibody responses to viral vectors and insufficient safety. Previously we have constructed novel non-replicative alphavirus vector platform derived from live attenuated human TC-83 IND vaccine against Venezuelan equine encephalitis (VEE) virus infection. In earlier studies, vaccines based on alphaviruses demonstrated efficiency in targeted gene delivery to DC and induction of protective CTL immunity against several human viral pathogens and breast cancer in a rodent animal model. In this study we tested novel TC-83 based PSA-encoding alphavirus vaccine (vVLP-PSA) against prostate cancer using transgenic mouse model with established neonatal tolerance to human PSA. Preventive vaccination using vVLP-PSA demonstrated induction of strong PSA-specific CD8+ T-cell response as detected by IFNγ ELISPOT assay and intracellular cytokine staining. Potent expansion of PSA-specific CD8+ effector T-cells was found in peripheral blood and spleens of vaccinated mice using PSA peptide-loaded MHC I dextramers. vVLP-PSA vaccination also induced PSA-specific antibody production in immunized mice. Injection of TRAMP tumor cells expressing PSA into vaccinated mice resulted in elevated infiltration of tumor site with CD8+ T-cells and rapid elimination of PSA-expressing tumor cells during first several weeks after tumor challenge. Tumor survival analysis revealed tendency for delayed tumor growth in vVLP-PSA immunized mice. Altogether, our data demonstrate that TC83-based vaccine encoding PSA induces strong PSA-specific CTL response and mediates efficient elimination of antigen-expressing prostate tumor cells promptly after tumor challenge.