Fox River Watershed Investigation: Stratton Dam to the Illinois River: Phase II Blackberry Creek and Poplar Creek Hydrologic and Water Quality Simulation Models: Executive Summary

Fox River Study Group, Inc.published or submitted for publicationis peer reviewe

Impaired NDRG1 functions in Schwann cells cause demyelinating neuropathy in a dog model of Charcot-Marie-Tooth type 4D

Mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause degenerative polyneuropathy in ways that are poorly understood. We have investigated Alaskan Malamute dogs with neuropathy caused by a missense mutation in NDRG1. In affected animals, nerve levels of NDRG1 protein were reduced by more than 70% (p < 0.03). Nerve fibers were thinly myelinated, loss of large myelinated fibers was pronounced and teased fiber preparations showed both demyelination and remyelination. Inclusions of filamentous material containing actin were present in adaxonal Schwann cell cytoplasm and Schmidt-Lanterman clefts. This condition strongly resembles the human Charcot-MarieTooth type 4D. However, the focally folded myelin with adaxonal infoldings segregating the axon found in this study are ultrastructural changes not described in the human disease. Furthermore, lipidomic analysis revealed a profound loss of peripheral nerve lipids. Our data suggest that the low levels of mutant NDRG1 is insufficient to support Schwann cells in maintaining myelin homeostasis. (C) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license

Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers

<p>Abstract</p> <p>Background</p> <p>Depending on the population studied, large genomic rearrangements (LGRs) of the mismatch repair (<it>MMR</it>) genes constitute various proportions of the germline mutations that predispose to hereditary non-polyposis colorectal cancer (HNPCC). It has been reported that loss of heterozygosity (LOH) at the LGR region occurs through a gene conversion mechanism in tumors from <it>MLH1</it>/<it>MSH2 </it>deletion carriers; however, the converted tracts were delineated only by extragenic microsatellite markers. We sought to determine the frequency of LGRs in Slovak HNPCC patients and to study LOH in tumors from LGR carriers at the LGR region, as well as at other heterozygous markers within the gene to more precisely define conversion tracts.</p> <p>Methods</p> <p>The main <it>MMR </it>genes responsible for HNPCC, <it>MLH1</it>, <it>MSH2</it>, <it>MSH6</it>, and <it>PMS2</it>, were analyzed by MLPA (multiplex ligation-dependent probe amplification) in a total of 37 unrelated HNPCC-suspected patients whose <it>MLH1/MSH2 </it>genes gave negative results in previous sequencing experiments. An LOH study was performed on six tumors from LGR carriers by combining MLPA to assess LOH at LGR regions and sequencing to examine LOH at 28 SNP markers from the <it>MLH1 </it>and <it>MSH2 </it>genes.</p> <p>Results</p> <p>We found six rearrangements in the <it>MSH2 </it>gene (five deletions and dup5-6), and one aberration in the <it>MLH1 </it>gene (del5-6). The <it>MSH2 </it>deletions were of three types (del1, del1-3, del1-7). We detected LOH at the LGR region in the single <it>MLH1 </it>case, which was determined in a previous study to be LOH-negative in the intragenic D3S1611 marker. Three tumors displayed LOH of at least one SNP marker, including two cases that were LOH-negative at the LGR region.</p> <p>Conclusion</p> <p>LGRs accounted for 25% of germline <it>MMR </it>mutations identified in 28 Slovakian HNPCC families. A high frequency of LGRs among the <it>MSH2 </it>mutations provides a rationale for a MLPA screening of the Slovakian HNPCC families prior scanning by DNA sequencing. LOH at part of the informative loci confined to the <it>MLH1 </it>or <it>MSH2 </it>gene (heterozygous LGR region, SNP, or microsatellite) is a novel finding and can be regarded as a partial LOH. The conversion begins within the gene, and the details of conversion tracts are discussed for each case.</p

Expression of a novel carbonic anhydrase, CA XIII, in normal and neoplastic colorectal mucosa

BACKGROUND: Carbonic anhydrase (CA) isozymes may have an important role in cancer development. Some isozymes control pH homeostasis in tumors that appears to modulate the behaviour of cancer cells. CA XIII is the newest member of the CA gene family. It is a cytosolic isozyme which is expressed in a number of normal tissues. The present study was designed to investigate CA XIII expression in prospectively collected colorectal tumor samples. METHODS: Both neoplastic and normal tissue specimens were obtained from the same patients. The analyses were performed using CA XIII-specific antibodies and an immunohistochemical staining method. For comparison, the tissue sections were immunostained for other cytosolic isozymes, CA I and II. RESULTS: The results indicated that the expression of CA XIII is down-regulated in tumor cells compared to the normal tissue. The lowest signal was detected in carcinoma samples. This pattern of expression was quite parallel for CA I and II. CONCLUSION: The down-regulation of cytosolic CA I, II and XIII in colorectal cancer may result from reduced levels of a common transcription factor or loss of closely linked CA1, CA2 and CA13 alleles on chromosome 8. Their possible role as tumor suppressors should be further evaluated

Reduced microvascular density in omental biopsies of children with chronic kidney disease

Endothelial dysfunction is an early manifestation of cardiovascular disease (CVD) and consistently observed in patients with chronic kidney disease (CKD). We hypothesized that CKD is associated with systemic damage to the microcirculation, preceding macrovascular pathology. To assess the degree of "uremic microangiopathy", we have measured microvascular density in biopsies of the omentum of children with CKD.Omental tissue was collected from 32 healthy children (0-18 years) undergoing elective abdominal surgery and from 23 age-matched cases with stage 5 CKD at the time of catheter insertion for initiation of peritoneal dialysis. Biopsies were analyzed by independent observers using either a manual or an automated imaging system for the assessment of microvascular density. Quantitative immunohistochemistry was performed for markers of autophagy and apoptosis, and for the abundance of the angiogenesis-regulating proteins VEGF-A, VEGF-R2, Angpt1 and Angpt2.Microvascular density was significantly reduced in uremic children compared to healthy controls, both by manual imaging with a digital microscope (median surface area 0.61% vs. 0.95%, p<0.0021 and by automated quantification (total microvascular surface area 0.89% vs. 1.17% p = 0.01). Density measured by manual imaging was significantly associated with age, height, weight and body surface area in CKD patients and healthy controls. In multivariate analysis, age and serum creatinine level were the only independent, significant predictors of microvascular density (r2 = 0.73). There was no immunohistochemical evidence for apoptosis or autophagy. Quantitative staining showed similar expression levels of the angiogenesis regulators VEGF-A, VEGF-receptor 2 and Angpt1 (p = 0.11), but Angpt2 was significantly lower in CKD children (p = 0.01).Microvascular density is profoundly reduced in omental biopsies of children with stage 5 CKD and associated with diminished Angpt2 signaling. Microvascular rarefaction could be an early systemic manifestation of CKD-induced cardiovascular disease

Climate change in the Baltic Sea region : a summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge of the effects of global warming on past and future changes in climate of the Baltic Sea region is summarised and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focuses on the atmosphere, land, cryosphere, ocean, sediments, and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in palaeo-, historical, and future regional climate research, we find that the main conclusions from earlier assessments still remain valid. However, new long-term, homogenous observational records, for example, for Scandinavian glacier inventories, sea-level-driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution, and new scenario simulations with improved models, for example, for glaciers, lake ice, and marine food web, have become available. In many cases, uncertainties can now be better estimated than before because more models were included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth system have been studied, and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication, and climate change. New datasets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal timescales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first palaeoclimate simulations regionalised for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA), and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics are dominated by tides, the Baltic Sea is characterised by brackish water, a perennial vertical stratification in the southern subbasins, and a seasonal sea ice cover in the northern subbasins.Peer reviewe

What evidence exists on ecotechnologies for recycling carbon and nutrients from domestic wastewater? a systematic map

Abstract: Background: Eutrophication of the Baltic Sea, and many other water bodies, is partly the result of point-source emissions of nutrients and carbon from wastewater. At the same time, nitrogen and phosphorus planetary boundaries have been breached. There is a need for more efficient resource management, including the recovery and reuse of nutrients and carbon in waste. The aim of this paper is to collate evidence on ecotechnologies intended for use in the wastewater sector globally to facilitate the recovery or reuse of carbon and/or nutrients. Methods: Searches were performed on literature published between 2013 and 2017 and in 5 bibliographic databases, 1 search engine, and 38 specialist websites. Database searches were performed in English. Searches in specialist websites were also performed in Finnish, Polish and Swedish. There was no geographical limitation. Screening was conducted at title and abstract level, and on full texts. Apart from bibliographical information, we extracted information on ecotechnology type, intervention, details of the recovery or reuse, the type of wastewater stream to which the ecotechnology is applied, the study location, type and design. Prior to screening and coding, we conducted consistency checks amongst reviewers. We generated a searchable database of coded studies. Findings were synthesised narratively and visualised in a geographical information system (i.e. an evidence atlas). We identified a series of knowledge gaps and clusters that warrant further research. Results: The search resulted in 4024 records, out of which 413 articles were retained after the screening process. In addition, 35 pre-screened studies from the specialist website searches were added. Together, these 448 articles contained 474 individual studies of 28 types of ecotechnologies. A combination of ecotechnologies (16.7%), followed by microalgae cultivation (14.1%) were the most frequent ecotechnologies in the evidence base. Ecotechnologies for recovery composed 72.6% of the evidence base. The most common wastewater streams for recovery were mixed wastewater and sludge (73.8%). There was a relative lack of studies on recovery from source-separated wastewater. The most common type of recovery was energy (27.3%), followed by simultaneous recovery of nitrogen and phosphorus (22.1%). Reuse of recovered substances was described in 22.8% of the studies. The most common type of reuse was of nitrogen and phosphorus (57.4%), followed by joint reuse of organic carbon, nitrogen and phosphorus (35.2%). Reuse ecotechnologies were mostly focused on the use of wastewater for irrigation or reuse of biosolids, and not on the nutrients that had been extracted through e.g. precipitation of struvite. In 22 studies both recovery and reuse were described. In total, 60 different study countries were reported in the evidence base, and the most common study location was China

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1α, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients

Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

INTRODUCTION: Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance of HIF-1α and its downstream targets in phyllodes tumors and fibroadenomas of the breast. METHODS: The expression of HIF-1α, CAIX, VEGF and p53 was investigated by immunohistochemistry in a group of 37 primary phyllodes tumors and 30 fibroadenomas with known clinical follow-up. The tumor microvasculature was visualized by immunohistochemistry for CD31. Proliferation was assessed by Ki67 immunostaining and mitotic counts. Being biphasic tumors, immunoquantification was performed in the stroma and epithelium. RESULTS: Only two fibroadenomas displayed low-level stromal HIF-1α reactivity in the absence of CAIX expression. Stromal HIF-1α expression was positively correlated with phyllodes tumor grade (P = 0.001), with proliferation as measured by Ki67 expression (P < 0.001) and number of mitoses (P < 0.001), with p53 accumulation (P = 0.003), and with global (P = 0.015) and hot-spot (P = 0.031) microvessel counts, but not with CAIX expression. Interestingly, concerted CAIX and HIF-1α expression was frequently found in morphologically normal epithelium of phyllodes tumors. The distance from the epithelium to the nearest microvessels was higher in phyllodes tumors as compared with in fibroadenomas. Microvessel counts as such did not differ between fibroadenomas and phyllodes tumors, however. High expression of VEGF was regularly found in both tumors, with only a positive relation between stromal VEGF and grade in phyllodes tumors (P = 0.016). Stromal HIF-1α overexpression in phyllodes tumors was predictive of disease-free survival (P = 0.032). CONCLUSION: These results indicate that HIF-1α expression is associated with diminished disease-free survival and may play an important role in stromal progression of breast phyllodes tumors. In view of the absence of stromal CAIX expression in phyllodes tumors, stromal upregulation of HIF-1α most probably arises from hypoxia-independent pathways, with p53 inactivation as one possible cause. In contrast, coexpression of HIF-1α and CAIX in the epithelium in phyllodes tumors points to epithelial hypoxia, most probably caused by relatively distant blood vessels. On the other hand, HIF-1α and CAIX seem to be of minor relevance in breast fibroadenomas