River catchments worldwide are heavily fragmented by anthropogenic barriers, reducing their longitudinal connectivity and contributing to the decline of migratory fish populations. Direct impacts of ...individual barriers on migratory fish are well-established, but barrier impacts on onward migration are poorly understood, despite their relevance to evidence-based, catchment-scale, management of threatened species. This study investigated the upstream spawning migration of 352 acoustic tagged river lamprey (Lampetra fluviatilis), translocated upstream of two key barriers (R2: n = 60 & 59; R3: n = 59 & 52) compared to a control group (R1: n = 61 & 59), across two contrasting (dry and wet, n = 180 and 172) years in the River Yorkshire Ouse, England, to reveal the impact of barriers on the onward migration of upstream migrating fish. Release further upstream increased the degree of catchment penetration, with median distance upstream of R1 56.1% and 68.6% greater for lamprey released at R2 and R3 respectively. Median delays at the two downstream-most main river barriers by the control group were 23.8 and 5.4 days (2018/19) and 9.3 and 11.4 days (2019/20). However, impacts of delay were only observed on the time to reach spawning habitat, time to reach final assumed spawning location and speed of movement in one upper catchment tributary during 2019/20 whilst they were only observed on time to reach spawning habitat during 2018/19 and on assumed spawning location distance during 2019/20 in the other. Ultimately, limited impacts of delay at barriers on onward fish migration post-passage were observed but median catchment penetration was increased with consecutive release upstream. This study demonstrated the importance of a true understanding of barrier impacts to inform catchment-wide planning, evidence vital for management worldwide. Although the findings of this study do support the use of trap and transport as a measure to remediate barrier impacts on migration, fish passage engineering improvements or barrier removal, at structures shown to be the most inhibiting to fish migration should be considered the best and most sustainable option to improve barrier passage.
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•The impact of two river barriers on onward fish migration compared to controls.•Anadromous river lamprey (n = 352) tracked in two contrasting years (dry and wet).•Translocation past downstream-most barriers increased catchment penetration.•Migration delays at downstream-most barriers increased during dry conditions.•Limited impacts of delay on onward fish migration post-passage were observed.
Information on movement ecology and susceptibility to fishing gears is becoming increasingly employed in the management of commercial fisheries. This study combined acoustic telemetry (n = 51 and 52) ...and a simple passive integrated transponder (PIT) tag (n = 1499 and 1113) mark-recapture study, across two successive years on a commercial river lamprey (Lampetra fluviatilis) fishery, to inform exploitation rates and the influence of conditional capture probability on expected catch-per-unit-effort (CPUE). The movements of acoustic-tagged lamprey were used to refine estimates of the number of PIT-marked individuals vulnerable to the fishery. In 2018, this increased the recapture rate estimation by 0.99% and reduced the estimated run size by 152,101 (21.6%; 95% CL, 148,683, 155,688) individuals, with corresponding values of 0.12% and 114,639 (25.0%; 95% CL, 112,900, 116,448) in 2019. Lamprey movements were similar between years, with the number of trap line encounters by individuals between trap lifts used to inform expected CPUE for each lift. Conditional capture probability was mainly dependent on environmental conditions (e.g., river flow) with most trap lifts in the expected CPUE range, although the impacts of behaviour on vulnerability to capture were difficult to disentangle. This study highlights how the incorporation of acoustic telemetry increased the accuracy of, validated, and complemented mark-recapture data, without which management decisions (e.g., quota size) would have been based upon over 100,000 more individuals (27.5% higher than the adjusted run size in 2018 and 33.3% higher in 2019), with potentially severe consequences for the population. These findings demonstrate the importance of understanding fish movement to improve and inform fishery management. The study also presents a framework to quantify conditional capture probability and its influence on CPUE; knowledge that is widely applicable across aquatic systems for management and sustainability of fisheries.
Objectives. To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). Methods. We compared a CBM (Sativex) with placebo in a randomized, ...double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. Results. Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (s.d.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. Conclusions. In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.
This report compared plazomicin with colistin for the treatment of severe (bloodstream or pneumonia) infection with carbapenem-resistant Enterobacteriaceae. The trial was stopped early for futility, ...but a suggestion of activity of plazomicin was identified.
Accurate and precise analyses of oil and gas (O&G) wastewaters and solids (
e.g.
, sediments and sludge) are important for the regulatory monitoring of O&G development and tracing potential O&G ...contamination in the environment. In this study, 15 laboratories participated in an inter-laboratory comparison on the chemical characterization of three O&G wastewaters from the Appalachian Basin and four solids impacted by O&G development, with the goal of evaluating the quality of data and the accuracy of measurements for various analytes of concern. Using a variety of different methods, analytes in the wastewaters with high concentrations (
i.e.
, >5 mg L
−1
) were easily detectable with relatively high accuracy, often within ±10% of the most probable value (MPV). In contrast, often less than 7 of the 15 labs were able to report detectable trace metal(loid) concentrations (
i.e.
, Cr, Ni, Cu, Zn, As, and Pb) with accuracies of approximately ±40%. Despite most labs using inductively coupled plasma mass spectrometry (ICP-MS) with low instrument detection capabilities for trace metal analyses, large dilution factors during sample preparation and low trace metal concentrations in the wastewaters limited the number of quantifiable determinations and likely influenced analytical accuracy. In contrast, all the labs measuring Ra in the wastewaters were able to report detectable concentrations using a variety of methods including gamma spectroscopy and wet chemical approaches following Environmental Protection Agency (EPA) standard methods. However, the reported radium activities were often greater than ±30% different to the MPV possibly due to calibration inconsistencies among labs, radon leakage, or failing to correct for self-attenuation. Reported radium activities in solid materials had less variability (±20% from MPV) but accuracy could likely be improved by using certified radium standards and accounting for self-attenuation that results from matrix interferences or a density difference between the calibration standard and the unknown sample. This inter-laboratory comparison illustrates that numerous methods can be used to measure major cation, minor cation, and anion concentrations in O&G wastewaters with relatively high accuracy while trace metal(loid) and radioactivity analyses in liquids may often be over ±20% different from the MPV.
Results from this inter-laboratory comparison indicate that O&G waste analyses can be inaccurate and imprecise.
Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well ...defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid-induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.
Inhibition of the kinase activity of leucine-rich repeat kinase 2 (LRRK2) is under investigation as a possible treatment for Parkinson's disease. However, there is no clinical validation as yet, and ...the safety implications of targeting LRRK2 kinase activity are not well understood. We evaluated the potential safety risks by comparing human and mouse LRRK2 mRNA tissue expression, by analyzing a Lrrk2 knockout mouse model, and by testing selective brain-penetrating LRRK2 kinase inhibitors in multiple species. LRRK2 mRNA tissue expression was comparable between species. Phenotypic analysis of Lrrk2 knockout mice revealed morphologic changes in lungs and kidneys, similar to those reported previously. However, in preclinical toxicity assessments in rodents, no pulmonary or renal changes were induced by two distinct LRRK2 kinase inhibitors. Both of these kinase inhibitors induced abnormal cytoplasmic accumulation of secretory lysosome-related organelles known as lamellar bodies in type II pneumocytes of the lung in nonhuman primates, but no lysosomal abnormality was observed in the kidney. The pulmonary change resembled the phenotype of Lrrk2 knockout mice, suggesting that this was LRRK2-mediated rather than a nonspecific or off-target effect. A biomarker of lysosomal dysregulation, di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP), was also decreased in the urine of Lrrk2 knockout mice and nonhuman primates treated with LRRK2 kinase inhibitors. Our results suggest a role for LRRK2 in regulating lysosome-related lamellar bodies and that pulmonary toxicity may be a critical safety liability for LRRK2 kinase inhibitors in patients.
Background: A recent phase III trial showed that the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, to first-line irinotecan, 5-fluorouracil, and leucovorin ...(IFL) prolonged median survival in patients with metastatic colorectal cancer. We carried out a retrospective analysis of patients in the trial to evaluate whether mutation status of k-ras, b-raf, or p53 or P53 expression could predict which patients were more likely to respond to bevacizumab. Methods: Microdissected tumors from 295 patients (274 primary tumors, 21 metastases) were subject to DNA sequence analysis to identify mutations in k-ras, b-raf, and p53. Nuclear P53 expression was determined by immunohistochemistry. Hazard ratios and 95% confidence intervals (CI) for overall survival were estimated using Cox regression analysis. Results: In all biomarker subgroups, estimated hazard ratios for risk of death were less than 1 for bevacizumab-treated patients as compared with those for placebo-treated patients. Mutations in k-ras and/or b-raf were observed in 88 of 213 patients (41%). Hazard ratios for death among patients with tumors with wild-type k-ras/b-raf status, as compared with those of patients with mutations in one or both genes, were 0.51 (95% CI = 0.28 to 0.95) among those treated with IFL plus bevacizumab and 0.66 (95% CI = 0.37 to 1.18) among those treated with IFL plus placebo. Mutations in p53 were found in 139 of 205 patients (68%), and P53 was overexpressed in 191 of 266 patients (72%); neither p53 mutation nor P53 overexpression was statistically significantly associated with survival. Conclusions: We did not find a statistically significant relationship between mutations of k-ras, b-raf, or p53 and the increase in median survival associated with the addition of bevacizumab to IFL in metastatic colorectal cancer.
To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary ...human tissues. From this approach, we have found that maternal embryonic leucine zipper kinase (Melk), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. In situ hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the ApcMin and Apc1638N murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference-mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth in vitro as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.
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