Potential Failure Mode Analysis for Mineral Extraction Near Reservoirs

This research was performed to develop a method of determining the potential hazard of underground mining near surface bodies of water. Underground mining creates a void within the subsurface that is eventually filled by overburden material. This strain movement perpetrates through the strata layers through fracturing and bedding plane separation, creating a depression above the mined seam (subsidence). The effect of subsidence may occur rapidly over the course of several weeks to months (longwall mining, pillar extraction) or may occur slowly (room and pillar mining); in some cases over one hundred years. These strain movements may affect the physical properties of the overlying rock layers, specifically hydraulic conductivity as it pertains to this research. Hydraulic conductivity is the ability for a medium to transmit water when submitted to a hydraulic gradient. The change in hydraulic conductivity may permanently alter the local groundwater table, or create a pathway from a surface body of water into the mine void. This may lead to erosion around the reservoir rim, potentially causing uncontrolled water loss within the reservoir.;This research was performed to develop a methodology to determine potential seepage failure modes due to changes in hydraulic conductivity in overburden, caused by underground coal mining. The research is separated into four tasks: 1) literature review of mine subsidence prediction and empirical assessment, 2) a method to develop potential seepage failure mode analysis of a mine site, 3) numerical analysis assessing seepage at a field site, and 4) semi-quantitative sensitivity analysis of risk based events for seepage mode failure near reservoirs.;Analysis shows that subsidence due to underground mining affects the hydraulic conductivity of the overlying medium, affecting the localized groundwater table and creating a cone of depression where hydraulic conductivity is increased. The extent of the cone of depression from the mine void is referred to as the Angle of Groundwater Influence. If this angle intersects with a reservoir pool level, seepage from the reservoir may cause uncontrolled drawdown or erosion.;Computer model analysis was performed on a field site to show how this methodology is applied. It was analyzed for three different lateral offset distances based on various pool levels. The numerical modeling results show that the reservoir pool has minimal impact if it lies beyond the affected overburden of the mine. However, if the reservoir rim intersects the impacted area, the increased flow rate may initiate erosion in the subsurface potentially leading to a failure mode for the reservoir. Within the subsurface, the controlling factor is the rock layer with the highest initial hydraulic conductivity located above the fractured zone. At the modeled field site, the changes in groundwater flow rate below the reservoir rim increased beyond one order of magnitude at Probable Maximum Flood (PMF) pool level. The findings developed within the sensitivity and field site analyses were used to develop practical application of the methodology to aid in determining the potential hazard from underground mining on surface bodies of water

THE ROLE OF PASSENGER LEUKOCYTES IN THE ANOMALOUS SURVIVAL OF NEONATAL SKIN GRAFTS IN MICE

The anomalous survival of neonatal C3H skin grafts on CBA mice is correlated with the emigration of passenger leukocytes from the graft vasculature. Thus, newborn homografts whose leukocyte populations are eliminated by X-irradiation or by transient sojourn on an intermediate adult C3H host, do not display prolonged survival. Moreover, the continued presence of the newborn grafts is not requisite to the maintenance of the unresponsive state, an observation consonant with the demonstration that CBA mice bearing long-term neonatal C3H skin grafts are leukocyte chimeras. In contrast, neonatal male C57 skin grafts may persist on C57 females after heavy irradiation of the donor, or after passage on an intermediate adult male host. In addition, tolerance is broken by removal of long-persistant newborn grafts from hitherto unresponsive females, and chimerism is not detectable in female C57 mice tolerant of infant male isografts. Finally, leukocytes of neonatal C3H origin, inoculated subcutaneously into CBA males, may occasionally render these animals unresponsive to subsequent adult C3H skin homografts, whereas those taken from infant C57 males usually sensitize their adult female hosts. Thus, passenger leukocytes are implicated in the extended survival of C3H neonatal homografts on CBA recipients, but not in the persistence of H-Y-incompatible neonatal skin isografts on C57 females

SKIN HOMOGRAFTS: TOLEROGENIC VERSUS IMMUNOGENIC INFLUENCES IN MICE

In strain combinations involving multiple non-H-2 disparities, neonatal skin grafts may survive significantly longer than adult grafts of similar genotype on normal adult hosts, and repeatedly outlive grafts of adult origin on immunosuppressed recipients. Moreover, newborn grafts of long-standing may render their hosts unresponsive to adult skin grafts from the same donor strain. With some H-2-compatible strain combinations in which homozygous neonatal grafts are rejected, F1 hybrid (heterozygous) grafts of similar age not only may survive indefinitely, but also may induce tolerance of subsequent adult parental strain homografts. These tolerogenic and gene dosage effects, although much weaker, can likewise be revealed with H-2-incompatible neonatal skin grafts

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease

The neuropeptide complement of the marine annelid Platynereis dumerilii.

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: The marine annelid Platynereis dumerilii is emerging as a powerful lophotrochozoan experimental model for evolutionary developmental biology (evo-devo) and neurobiology. Recent studies revealed the presence of conserved neuropeptidergic signaling in Platynereis, including vasotocin/neurophysin, myoinhibitory peptide and opioid peptidergic systems. Despite these advances, comprehensive peptidome resources have yet to be reported. RESULTS: The present work describes the neuropeptidome of Platynereis. We established a large transcriptome resource, consisting of stage-specific next-generation sequencing datasets and 77,419 expressed sequence tags. Using this information and a combination of bioinformatic searches and mass spectrometry analyses, we increased the known proneuropeptide (pNP) complement of Platynereis to 98. Based on sequence homology to metazoan pNPs, Platynereis pNPs were grouped into ancient eumetazoan, bilaterian, protostome, lophotrochozoan, and annelid families, and pNPs only found in Platynereis. Compared to the planarian Schmidtea mediterranea, the only other lophotrochozoan with a large-scale pNP resource, Platynereis has a remarkably full complement of conserved pNPs, with 53 pNPs belonging to ancient eumetazoan or bilaterian families. Our comprehensive search strategy, combined with analyses of sequence conservation, also allowed us to define several novel lophotrochozoan and annelid pNP families. The stage-specific transcriptome datasets also allowed us to map changes in pNP expression throughout the Platynereis life cycle. CONCLUSION: The large repertoire of conserved pNPs in Platynereis highlights the usefulness of annelids in comparative neuroendocrinology. This work establishes a reference dataset for comparative peptidomics in lophotrochozoans and provides the basis for future studies of Platynereis peptidergic signaling.This work was supported by Max Planck Society Sequencing Grant M.IF.A.ENTW8050 to GJ. The research leading to these results was supported by the European Research Council under European Union Seventh Framework Program FP7/2007–2013 and European Research Council Grant Agreement 260821

Evaluation of a Low-Cost, PC-Based Driving Simulator to Assess Persons with Cognitive Impairments Due to Brain Injury

Brain injury due to accident or stroke frequently results in cognitive impairment, reducing an individual’s ability to judge driving situations accurately. Rehabilitation professionals typically use a combination of clinical and on-road tests to determine whether an individual is safe to drive. Weighing the safety of the community, the candidate, and the driving evaluator, these on-road tests are often conducted under road, traffic and weather conditions less demanding than those that a driver might face in the “real world,” and thus may offer less than complete information regarding the candidate’s responses to such real-world driving challenges. Indeed, individuals with mild cognitive deficits may perform adequately under such testing conditions but unsafely when driving challenges increase. Complicating this situation further, those with mild to moderate acquired cognitive impairments may be largely unaware of their own limitations, and thus more intolerant of perceived delays or challenges to their desire to drive again. Although continuing advances have improved performance and fidelity while significantly reducing costs, most interactive driving simulators remain too expensive for widespread clinical application. In a project funded by the National Center for Medical Rehabilitation Research, National Institutes of Health, we sought to determine, on a pilot basis, whether a low-cost, PC-based driving simulator could provide clinicians with information useful to their efforts to assess the safe ability to drive of individuals with cognitive impairments. We developed two comprehensive simulator-based driving scenarios, one quite basic and one more challenging, and pilot-tested them on ten subjects – five with moderate cognitive impairments, and five age and sex matched-controls without impairment. The “simple” scenario was developed to match the essential demands of the first half of an existing on-road driving evaluation; the “complex” scenario was based on the second half of the on-road evaluation into which more demanding, but still common, driving challenges were integrated. Road types, lane widths, pavement markings, traffic signals, horizontal and vertical curvature, and the proximal built environment were all created in simulation to provide a convincing generic representation of the on-road test. Challenges incorporated into the “complex” phase of the scenario, which were absent from the “simple” phase, included traffic events such as: cross-traffic failing to stop at a STOP sign; pedestrians crossing the driver’s path; vehicles suddenly pulling out in front of the subject from the road shoulder; opposing thru traffic appearing suddenly from behind slower moving vehicles as the subject attempted to turn left; slower moving lead vehicles causing passing decisions; traffic streams forcing gap acceptance decisions; etc. Results from the simulator were compared to results from the on-road evaluation. In addition, data gathered from subject exit interviews was used to judge simulator verisimilitude and efficacy in changing self-awareness of deficit. Because the cognitive impairments associated with brain injury often reduce the individual’s awareness of his or her own limitations, we looked at evidence that performance on the simulator could contribute to an individual’s own understanding of his or her driving strengths and weaknesses. The results of the pilot study will lead to an enhancement of simulator capabilities, and to a comprehensive clinical trial at multiple sites. This paper will present the findings of this pilot investigation and an overview of the expanded clinical study

Pancreas Cancer Survival in the Gemcitabine Era

After multiple positive studies, gemcitabine, approved for the treatment of pancreas cancer by the FDA in 1977, became standard of care. Whether this therapeutic advance has translated into longer survival for pancreas cancer patients in general has not been established. This study, derived from SEER (Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute) data, compared the survival experiences of the gemcitabine (1998–2004) and pre-gemcitabine (1988–1997) eras for 7,151 patients who had metastatic disease and did not undergo extirpative surgery, 14,369 patients who had not undergone surgery and had metastases, 5,042 patients who had undergone surgery and did not have metastases, and 5,011 patients who had undergone surgery and had metastases. Calculated survival time ratios (TR) were adjusted for radiotherapy history, grade, nodal status, loco-regional extent of disease, age, race, and gender. For those who did not undergo extirpative surgery, improvements in survival in the gemcitabine era (1998–2004) versus the prior time period (1988–1997) seen for patients with metastatic cancer (TR = 1.20, 95% c.i. 1.15–1.25) were not seen for those without metastatic cancer (TR = 1.05, 95% c.i. 1.00–1.15). For those who did undergo extirpative surgery, improvements were much more dramatic for those with metastatic cancer (TR = 1.61, 95% c.i. 1.45–1.80) than those without metastases (TR = 1.23, 95% c.i. 1.15–1.31). The results are consistent with the notion that the promising findings with respect to gemcitabine in the controlled clinical trials have found expression in the general population of patients with pancreas cancer

CRISPR activation screen identifies TGFβ-associated PEG10 as a crucial tumor suppressor in Ewing sarcoma

As the second most common pediatric bone and soft tissue tumor, Ewing sarcoma (ES) is an aggressive disease with a pathognomonic chromosomal translocation t(11;22) resulting in expression of EWS-FLI1, an "undruggable" fusion protein acting as transcriptional modulator. EWS-FLI1 rewires the protein expression in cancer cells by activating and repressing a multitude of genes. The role and contribution of most repressed genes remains unknown to date. To address this, we established a CRISPR activation system in clonal SKNMC cell lines and interrogated a custom focused library covering 871 genes repressed by EWS-FLI1. Among the hits several members of the TGFβ pathway were identified, where PEG10 emerged as prime candidate due to its strong antiproliferative effect. Mechanistic investigations revealed that PEG10 overexpression caused cellular dropout via induction of cell death. Furthermore, non-canonical TGFβ pathways such as RAF/MEK/ERK, MKK/JNK, MKK/P38, known to lead to apoptosis or autophagy, were highly activated upon PEG10 overexpression. Our study sheds new light onto the contribution of TGFβ signalling pathway repression to ES tumorigenesis and suggest that its re-activation might constitute a novel therapeutic strategy