Search

Wastewater treatment plant (WWTP) effluents alter stream water chemistry and metabolic activity. Yet, essential aspects influencing the biogeochemical response of receiving streams such as hydrology and diel oscillations of light and temperature remain largely unexplored. We measured day vs night water chemistry and in-stream net nutrient uptake velocity (V f ) in an intermittent forested stream, upstream and downstream of a WWTP effluent under contrasting hydrological conditions. The WWTP effluent negatively influenced stream water chemistry, especially during the dry period. Despite large diel oscillations in light inputs, day-night differences in nutrient and oxygen concentrations were small, suggesting that heterotrophic respiration drove stream metabolism with a minor contribution of gross primary production. The magnitude of V f was similar between day and night at the two reaches. Yet, at the downstream reach, in-stream net DIN uptake occurred more often at night, and values of V f for ammonia and nitrite indicated enhanced in-stream nitrification. The two reaches showed a small capacity to retain DIN and soluble reactive phosphorus from the water column. Positive values of in-stream net nutrient uptake (i.e. uptake > release) occurred mostly during the dry period, highlighting that in-stream biogeochemical processing can contribute to improve water quality in streams receiving point-sources effluents in regions with low water availability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Biogeochemical gradients in streambeds are steep and can vary over short distances often making adequate characterisation of sediment biogeochemical processes challenging. This paper provides an overview and comparison of streambed pore-water sampling methods, highlighting their capacity to address gaps in our understanding of streambed biogeochemical processes. This work reviews and critiques available pore-water sampling techniques to characterise streambed biogeochemical conditions, including their characteristic spatial and temporal resolutions, and associated advantages and limitations. A field study comparing three commonly-used pore-water sampling techniques (multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gels) was conducted to assess differences in observed nitrate and ammonium concentration profiles. Pore-water nitrate concentrations did not differ significantly between sampling methods (p-value = 0.54) with mean concentrations of 2.53, 4.08 and 4.02 mg l - 1 observed with the multilevel mini-piezometers, miniature drivepoint samplers and diffusive equilibrium in thin-film gel samplers, respectively. Pore-water ammonium concentrations, however, were significantly higher in pore-water extracted by multilevel mini-piezometers (3.83 mg l - 1 ) and significantly lower where sampled with miniature drivepoint samplers (1.05 mg l - 1 , p-values <0.01). Differences in observed pore-water ammonium concentration profiles between active (suction: multilevel mini-piezometers) and passive (equilibrium; diffusive equilibrium in thin-film gels) samplers were further explored under laboratory conditions. Measured pore-water ammonium concentrations were significantly greater when sampled by diffusive equilibrium in thin-film gels than with multilevel mini-piezometers (all p-values ≤0.02). The findings of this study have critical implications for the interpretation of field-based research on hyporheic zone biogeochemical cycling and highlight the need for more systematic testing of sampling protocols. For the first time, the impact of different active and passive pore-water sampling methods is addressed systematically here, highlighting to what degree the choice of pore-water sampling methods affects research outcomes, with relevance for the interpretation of previously published work as well as future studies., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest, either financial or personal, that may be perceived to influence this work., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist., Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis., Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH)., Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Sézary syndrome is a rare leukemic form of cutaneous T cell lymphoma characterized by generalized redness, scaling, itching and increased numbers of circulating atypical T lymphocytes. It is rarely curable, with poor prognosis. Here we present a multiplatform genomic analysis of 37 patients with Sézary syndrome that implicates dysregulation of cell cycle checkpoint and T cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1 and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly one-third of patients. ZEB1, encoding a transcription repressor essential for T cell differentiation, was deleted in over one-half of patients. IL32 and IL2RG were overexpressed in nearly all cases. Our results demonstrate profound disruption of key signaling pathways in Sézary syndrome and suggest potential targets for new therapies.

Background: Liver disease is an important complication in CF., Aims: To determine if CFLD is a risk factor for mortality in CF, and which baseline characteristics predict all-cause mortality., Methods: Irish children with CFLD, and their age and gender matched controls were enrolled at baseline and reviewed after 10years to determine which characteristics predict mortality., Results: 72/84 (85.71%) participants were followed, (mean age Cases 21.71yrs SD 6.5, CF controls 23.62 SD 5.6, 22 (61%) males), with no difference in duration of follow-up. Nineteen participants (26.4%) died, 38.9% (14/36) with CFLD and 13.89% (5/36) CF controls (Odds Ratio (OR) 3.94 95% CI:1.23-12.56 p=0.005). In logistic regression, liver disease (OR 4.28 95% CI 1.07-17.16) female gender (OR 12.25 95% CI 2.37-63.24), reduced pulmonary function, (OR 5.11 95% CI 1.09-23.81) were each independent risk factors for mortality in CF., Conclusions: Liver disease is an independent risk factor for mortality in CF., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

We report on a secreted protein found in mammalian cochlear outer hair cells (OHC) that is a member of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of adhesion proteins. Ceacam16 mRNA is expressed in OHC, and its protein product localizes to the tips of the tallest stereocilia and the tectorial membrane (TM). This specific localization suggests a role in maintaining the integrity of the TM as well as in the connection between the OHC stereocilia and TM, a linkage essential for mechanical amplification. In agreement with this role, CEACAM16 colocalizes and coimmunoprecipitates with the TM protein α-tectorin. In addition, we show that mutation of CEACAM16 leads to autosomal dominant nonsyndromic deafness (ADNSHL) at the autosomal dominant hearing loss (DFNA4) locus. In aggregate, these data identify CEACAM16 as an α-tectorin-interacting protein that concentrates at the point of attachment of the TM to the stereocilia and, when mutated, results in ADNSHL at the DFNA4 locus.

Transverse myelitis (TM) is an immune-mediated spinal cord disorder associated with inflammation, demyelination, and axonal damage. We investigated the soluble immune derangements present in TM patients and found that IL-6 levels were selectively and dramatically elevated in the cerebrospinal fluid and directly correlated with markers of tissue injury and sustained clinical disability. IL-6 was necessary and sufficient to mediate cellular injury in spinal cord organotypic tissue culture sections through activation of the JAK/STAT pathway, resulting in increased activity of iNOS and poly(ADP-ribose) polymerase (PARP). Rats intrathecally infused with IL-6 developed progressive weakness and spinal cord inflammation, demyelination, and axonal damage, which were blocked by PARP inhibition. Addition of IL-6 to brain organotypic cultures or into the cerebral ventricles of adult rats did not activate the JAK/STAT pathway, which is potentially due to increased expression of soluble IL-6 receptor in the brain relative to the spinal cord that may antagonize IL-6 signaling in this context. The spatially distinct responses to IL-6 may underlie regional vulnerability of different parts of the CNS to inflammatory injury. The elucidation of this pathway identifies specific therapeutic targets in the management of CNS autoimmune conditions.

Background: Noninvasive mechanical ventilation (NIMV) is accepted as a life-saving treatment for patients presenting to the emergency department and other acute care settings with severe exacerbations of chronic obstructive pulmonary disease (COPD)., Objectives: It was hypothesized that there is marked national variability in the use of NIMV. Therefore, the use of NIMV for COPD exacerbations in urban centres across Canada was evaluated., Methods: All Canadian hospitals affiliated with a university training program were surveyed, and a request for involvement in this survey was posted on the Canadian Society of Respiratory Therapy professional practice listserv. Survey information was received from all 33 sites (100%) that were contacted., Results: Marked differences in the application of NIMV were identified across all regions in Canada, ranging from requiring extensive monitoring in the intensive care unit to application on a general internal medical unit with intermittent noninvasive blood pressure monitoring. There were sites that rarely used NIMV for COPD exacerbations and others where it was routine practice., Conclusions: NIMV is a life-saving treatment for acute exacerbations of COPD. Despite clear clinical evidence, its use has not penetrated throughout all the larger urban hospitals in Canada. This may be more problematic in sites without 24 h respiratory therapy support. There are barriers to the routine application of NIMV that can be overcome using established guidelines and available evidence.