A field study assessing the impact of on-site wastewater treatment systems on surface water quality in a Co. Monaghan catchment

Poorly functioning on-site wastewater treatment systems (OSWTS) can be among the many sources of pollution to groundwater and surface water, which are of critical concern owing to potential human and ecological health risks. An investigation into the effects of on-site wastewater treatment systems (OSWTS) on surface water quality has been undertaken at several sites within a catchment in Co. Monaghan. The study sites were located in areas of 'low’ permeability, suggesting that run-off usually dominates over infiltration. Poor treatment performance of OSWTS within the catchment were found to be the result of several factors, including location in areas with unsuitable soil and site characteristics, incorrect installation, poor maintenance and inappropriate operation by the home owner.

Doonloughan: a seasonal settlement site on the Connemara coast

A series of shell middens and miscellaneous habitation sites, located in a dune
system in west County Galway, have been exposed and are slowly disappearing
through wind, wave and surface erosion. In 1992 a project was initiated to
record, sample and date some of these sites and the radiocarbon results
demonstrated that activity in the area spanned the Early Bronze Age through to
the Iron Age and into the early and post medieval periods. This preliminary
fieldwork was succeeded by the excavation of three of the better-preserved sites; a Bronze Age midden in 1994 and two early medieval sites (the subject of this paper), in 1997. The medieval sites dated to the late-seventh to ninth century adand were represented by a sub-circular stone hut with a hearth and the charred remains of a more ephemeral wooden tent-like structure. The discovery of a bronze penannular brooch of ninth/tenth century date at the latter site wouldsuggest that the settlements are not the remains of transient, impoverishedpeoples of the lower classes of society, eking out a living along the coast. The calcareous sands ensured good preservation of organic remains*fish and mammal bones, charred cereal grains, seeds and seaweed, and marine molluscs. Analyses of these indicated exploitation of marine resources but, otherwise, were comparable with the diet and economy represented by assemblages from established contemporary site types of the period. Unlike raths, cranno´gs and monastic settlements, however, the volume of material represented at the Galway sites was slight, despite the excellent preservation conditions. A range of seasonal indicators also suggested temporary habitation: probable latespring/summer occupation of the stone hut site and autumnal occupancy of the second, less substantial site. It is suggested that the machair plain, beside which the dunes are located, was most probably the attraction for settlers to the area and was exploited as an alternative pasture for the seasonal grazing of livestock.
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Environmental indifference? A critique of environmentally deterministic theories of peatland archaeological site construction in Ireland

Climate change, whether gradual or sudden, has frequently been invoked as a causal factor to explain many aspects of cultural change during the prehistoric and early historic periods. Critiquing such theories has often proven difficult, not least because of the imprecise dating of many aspects of the palaeoclimate or archaeological records and the difficulties of merging the two strands of research. Here we consider one example of the archaeological record – peatland site construction in Ireland – which has previously been interpreted in terms of social response to climate change and examine whether close scrutiny of the archaeological and palaeoenvironmental records uphold the climatically deterministic hypotheses. We evaluate evidence for phasing in the temporal distribution of trackways and related sites in Irish peatlands, of which more than 3,500 examples have been recorded, through the examination of ~350 dendrochronological and 14C dates from these structures. The role of climate change in influencing when such sites were constructed is assessed by comparing visually and statistically the frequency of sites over the last 4,500 years with well-dated, multi-proxy climate reconstructions from Irish peatlands. We demonstrate that national patterns of “peatland activity” exist that indicate that the construction of sites in bogs was neither a constant nor random phenomenon. Phases of activity (i.e. periods in which the number of structures increased), as well as the ‘lulls’ that separate them, show no consistent correlation with periods of wetter or drier conditions on the bogs, suggesting that the impetus for the start or cessation of such activity was not climatically-determined. We propose that trigger(s) for peatland site construction in Ireland must instead also be sought within the wider, contemporary social background. Perhaps not surprisingly, a comparison with archaeological and palynological evidence shows that peatland activity tends to occur at times of more expansive settlement and land-use, suggesting that the bogs were used when the landscape was being more widely occupied. Interestingly, the lulls in peatland site construction coincide with transitional points between nominal archaeological phases, typically defined on the basis of their material culture, implying that there may indeed have been a cultural discontinuity at these times. © 2012 Elsevier Ltd. All rights reserved.

Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation

Alport syndrome (AS) is a clinically and genetically heterogeneous renal disorder, predominantly affecting the type IV collagen alpha 3/alpha 4/alpha 5 network of the glomerular basement membrane (GBM). AS can be caused by mutations in any of the three genes encoding these type IV collagen chains. The majority of AS families (85%) are X-linked (XL-AS) involving mutations in the COL4A5 gene. Mutations in the COL4A3 and COL4A4 genes cause autosomal recessive AS (AR-AS), accounting for approximately 14% of the cases. Recently, autosomal dominant AS (AD-AS) was linked to the COL4A3/COL4A4 locus in a large family.

Deregulated estrogen metabolism in BRCA1 deficient cells induces chromosomal instability.

Objectives: Germline mutations in BRCA1 predispose carriers to a high
incidence of breast and ovarian cancers. The BRCA1 protein functions to maintain
genomic stability via important roles in DNA repair, transcriptional regulation, and
post-replicative repair. Despite functions in processes essential in all cells, BRCA1
loss or mutation leads to tumours predominantly in estrogen-regulated tissues.
Here, we aim to determine if endogenous estrogen metabolites may be an initiator
of genomic instability in BRCA1 deficient cells.

Methods: We analysed DNA DSBs by ?H2AX, 53BP1, and pATM1981
foci and neutral comet assay, estrogen metabolite concentrations by LC-MS/MS,
and BRCA1 transcriptional regulation of metabolism genes by ChIP-chip, ChIP,
and qRT-PCR.

Results: We show that estrogen metabolism is perturbed in BRCA1 deficient
cells resulting in elevated production of 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2), and decreased production of the protective metabolite
4-methoxyestradiol. We demonstrate that 2-OHE2 and 4-OHE2 treatment leads
to DNA double strand breaks (DSBs) in breast cells, and these DSBs were exacerbated
in both BRCA1 depleted cells and BRCA1 heterozygous cells (harbouring
185delAG mutation). Furthermore, the DSBs were not repaired efficiently in either
BRCA1 depleted or heterozygous cells, and we found that 2-OHE2 and 4-OHE2
treatment generates chromosomal aberrations in BRCA1 depleted cells. We suggest
that the increase in DNA DSBs in BRCA1 deficient cells is due to loss of
both BRCA1 transcriptional repression of estrogen metabolising genes (such as
CYP1A1 and CYP3A4) and loss of transcriptional activation of detoxification
genes (such as COMT).

Conclusions: We suggest that BRCA1 loss results in estrogen driven tumourigenesis
through a combination of increased expression of estrogen metabolising
enzymes and reduced expression of protective enzymes, coupled with a defect in
the repair of DNA DSBs induced by endogenous estrogen metabolites. The overall
effect being an exacerbation of genomic instability in estrogen regulated tissues in
BRCA1 mutation carriers.

Optimization of an ether series of mGluR5 positive allosteric modulators: Molecular determinants of MPEP site interaction crossover

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) pos. allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topol. similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Discovery and SAR of a novel series of non-MPEP site mGlu(5) PAMs based on an aryl glycine sulfonammide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.

The M17 leucine aminopeptidase of the malaria parasite Plasmodium falciparum:importance of active site metal ions in the binding of substrates and inhibitors

The M17 leucine aminopeptidase of the intraerythrocytic stages of the malaria parasite Plasmodium falciparum (PfLAP) plays a role in releasing amino acids from host hemoglobin that are used for parasite protein synthesis, growth, and development. This enzyme represents a target at which new antimalarials could be designed since metalloaminopeptidase inhibitors prevent the growth of the parasites in vitro and in vivo. A study on the metal ion binding characteristics of recombinant P. falciparum M17 leucine aminopeptidase (rPfLAP) shows that the active site of this exopeptidase contains two metal-binding sites, a readily exchangeable site (site 1) and a tight binding site (site 2). The enzyme retains activity when the metal ion is removed from site 1, while removal of metal ions from both sites results in an inactive apoenzyme that cannot be reactivated by the addition of divalent metal cations. The metal ion at site 1 is readily exchangeable with several divalent metal ions and displays a preference in the order of preference Zn(2+) > Mn(2+) > Co(2+) > Mg(2+). While it is likely that native PfLAP contains a Zn(2+) in site 2, the metal ion located in site 1 may be dependent on the type and concentration of metal ions in the cytosolic compartment of the parasite. Importantly, the type of metal ion present at site 1 influences not only the catalytic efficiency of the enzyme for peptide substrates but also the mode of binding by bestatin, a metal-chelating inhibitor of M17 aminopeptidases with antimalarial activity.

Ancient manuring practices pollute arable soils at the St Kilda World Heritage Site, Scottish North Atlantic

The impact of ancient fertilization practices on the biogeochemistry of arable soils on the remote Scottish island of Hirta, St Kilda was investigated. The island was relatively unusual in that the inhabitants exploited seabird colonies for food, enabling high population densities to be sustained on a limited, and naturally poor, soil resource. A few other Scottish islands, the Faeroes and some Icelandic Islands, had similar cultural dependence on seabirds. Fertilization with human and animal waste streams (mainly peat ash and bird carcases) on Hirta over millennia has led to over-deepened, nutrient-rich soils (plaggen). This project set out to examine if this high rate of fertilization had adversely impacted the soil, and if so, to determine which waste streams were responsible. Arable soils were considerably elevated in Pb and Zn compared to non-arable soils. Using Pb isotope signatures and analysis of the waste streams, it was determined that this pollution came from peat and turf ash (Pb and Zn) and from bird carcases (Zn). This was also confirmed by (13)C and (15)N analysis of the profiles which showed that soil organic matter was highly enriched in marine-derived C and N compared to non-arable soils. The pollution of such a remote island may be typical of other 'bird culture' islands, and peat ash contamination of marginal arable soils at high latitudes may be widespread in terms of geographical area, but less intense at specific locations due to lower population densities than on Hirta.

Strategies for Effective Management of Health and Safety in Confined Site Construction

The overall aim of this research is to identify and catalogue the numerous managerial strategies for effective management of health and safety on a confined, urban, construction site. A mixed methods methodology was adopted using interviews and focus group discussions on three selected case studies of confined construction sites. In addition to these, a questionnaire survey was used based on the findings from the interviews and the focus group discussions. The top five key strategies include (1) Employ safe system of work plans to mitigate personnel health and safety issues; (2) Inform personnel, before starting on-site, of the potential issues using site inductions; (3) Effective communication among site personnel; (4) Draft and implement an effective design site layout prior to starting on-site; and (5) Use of banksman (traffic co-ordinator) to segregate personnel from vehicular traffic. The construction sector is one of the leading industries in accident causation and with the continued development and regeneration of our urban centres, confined site construction is quickly becoming the norm - an environment which only fuels accident creation within the construction sector. This research aids on-site management that requires direction and assistance in the identification and implementation of key strategies for the management of health and safety, particularly in confined construction site environments.

Clinicopathological features of homologous recombination-deficient epithelial ovarian cancers: Sensitivity to PARP inhibitors, platinum, and survival

Up to 50% of epithelial ovarian cancers (EOC) display defects in the homologous recombination (HR) pathway. We sought to determine the ramifications of the homologous recombination-deficient (HRD) status on the clinicopathologic features, chemotherapy response, and survival outcomes of patients with EOCs. HR status was determined in primary cultures from ascitic fluid in 50 chemotherapy-naïve patients by a functional RAD51 immunofluorescence assay and correlated with in vitro sensitivity to the PARP inhibitor (PARPi), rucaparib. All patients went on to receive platinum-based chemotherapy; platinum sensitivity, tumor progression, and overall survival were compared prospectively in HR-competent versus HRD patients. Compared with HR-competent patients, the HRD group was predominantly serous with a higher median CA125 at presentation. HRD was associated with higher ex vivo PARPi sensitivity and clinical platinum sensitivity. Median follow-up duration was 14 months; patients in the HRD group had lower tumor progression rates at 6 months, lower overall/disease-specific death rates at 12 months, and higher median survival. We therefore suggest that HRD as predicted by a functional RAD51 assay correlates with in vitro PARPi sensitivity, clinical platinum sensitivity, and improved survival outcome.

Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

PURPOSE:
To investigate the role of the Fractalkine receptor CX3CR1 pathway in oxidative insults-mediated retinal degeneration and immune activation.
METHODS:
A prooxidant, paraquat (0.75 µM) was injected into the vitreous of C57BL/6J, CX3CR1(gpf/+), and CX3CR1(gfp/gfp) mice. Retinal lesions were investigated clinically by topic endoscopic fundus imaging and fluorescence angiography, and pathologically by light- and electron microscopy. Retinal immune gene expression was determined by real-time RT-PCR. Microglial activation and immune cell infiltration were examined by confocal microscopy of retinal flatmounts.
RESULTS:
Intravitreal injection of paraquat (0.75 µM) resulted in acute retinal capillary nonperfusion within 2 days, which improved from 4 days to 4 weeks postinjection (p.i.). Panretinal degeneration was observed at 4 days p.i. and progressed further at 4 weeks p.i. In the absence of CX3CR1, retinal degeneration was exaggerated and was accompanied by increased TNF-a, iNOS, IL-1ß, Ccl2, and Casp-1 gene expression. Confocal microscopy of retinal flatmounts revealed microglial activation and CD44(+)MHC-II(+) monocyte and GR1(+) neutrophil infiltration in paraquat-injected eyes. The number of activated microglia and infiltrating leukocytes was significantly higher in CX3CR1(gfp/gfp) mice than in CX3CR1(gfp/+) mice.
CONCLUSIONS:
Our results suggest that the CX3CR1 signaling pathway may play an important role in controlling retinal inflammation under oxidative and ischemia/reperfusion conditions. In the absence of CX3CR1, uncontrolled retinal inflammation results in exaggerated retinal degeneration.

Organization specific predictors of job satisfaction: findings from a Canadian multi-site quality of work life cross-sectional survey

Background: Organizational features can affect how staff view their quality of work life. Determining staff perceptions about quality of work life is an important consideration for employers interested in improving employee job satisfaction. The purpose of this study was to identify organization specific predictors of job satisfaction within a health care system that consisted of six independent health care organizations.

Methods: 5,486 full, part and causal time (non-physician) staff on active payroll within six organizations (2 community hospitals, 1 community hospital/long-term care facility, 1 long-term care facility, 1 tertiary care/community health centre, and 1 visiting nursing agency) located in five communities in Central West Ontario, Canada were asked to complete a 65-item quality of work life survey. The self-administered questionnaires collected staff perceptions of: co-worker and supervisor support; teamwork and communication; job demands and decision authority; organization characteristics; patient/resident care; compensation and benefits; staff training and development; and impressions of the organization. Socio-demographic data were also collected.

Results: Depending on the organization, between 15 and 30 (of the 40 potential predictor) variables were found to be statistically associated with job satisfaction (univariate analyses). Logistic regression analyses identified the best predictors of job satisfaction and these are presented for each of the six organizations and for all organizations combined.

Conclusions: The findings indicate that job satisfaction is a multidimensional construct and although there appear to be some commonalities across organizations, some predictors of job satisfaction appear to be organization and context specific.

The Palisades is a key reference site for the middle Pleistocene of eastern Beringia: New evidence from paleomagnetics and regional tephrostratigraphy

The Palisades, in central Alaska, is one of the most prominent exposures of Quaternary sediments on the Yukon River. Perennially-frozen silt and sand at the Palisades are presently thought to preserve paleoenvironmental records from the Holocene to ~Marine Isotope Stage (MIS) 8 and, beneath a major unconformity, the earliest Pleistocene (~2 Ma). We present new paleomagnetic and tephrochronologic constraints that substantially revise the age of the sediments at the Palisades. We describe 15 new tephra beds, including five beds below the prominent PAL tephra that correlate to known tephra with independent age control from other sites in eastern Beringia. These five known tephra include Chester Bluff tephra, which is present in east-central Alaska and the Yukon, and the newly named Alyeska Pipeline and Taylor Highway tephra from central Alaska; all are constrained to the middle Pleistocene. Paleomagnetic transects from the base of the bluff to the MIS 5e forest bed yield normal polarity, with the exception of a brief reversal event between Old Crow tephra (124 ± 10 ka) and the MIS 5e forest bed that is likely the first documentation of the Blake paleomagnetic event in Alaskan loess. The detailed tephrostratigraphy and paleomagnetic data collectively suggest that most of the sedimentary record at the Palisades is middle Pleistocene in age. The Palisades thus preserves a rare record of late to middle Pleistocene paleoenvironments with multiple regionally distributed tephra beds. © 2013 Elsevier Ltd.