Geochemistry of mine pool discharges in the Pittsburgh coal basin

Seventy-two mine water discharges from flooded underground mines of the Pittsburgh coal bed were sampled for chemistry during 2012. Statistical techniques including correlation, principal component analysis (PCA), and cluster analysis (CA) were utilized to evaluate geochemical relationships. The distributions of most solute concentrations are non-parametric. Strong correlations were observed between constituents of pyrite and carbonate dissolution (Fe, SO 4, Ca, Mg) as well as Na, Sr, and K. Several waters with high scores on PC1 are moderately saline with average concentrations of Na (1199 mg/L), Cl (350 mg/L), Br (1.69 mg/L), and Sr (4.13 mg/L). Waters with highly negative scores on PC2 are acidic with maximum concentrations of Fe3+ (35.3mg/L) and Al (23.3 mg/L) and discharge from shallow mines along the eastern margin of the coal subcrop. Waters with highly positive scores on PC2 are alkaline waters from deep, fully flooded mines with pH (6.3) and alkalinity (876 mg/L). PC3 has high scores primarily due to elevated Ba. Pittsburgh coal bed waters display, on average, SO4 (923 mg/L), Na (267 mg/L), alkalinity (226 mg/L as CaCO3), Ca (245 mg/L), Cl (100 mg/L), and Fe (45 mg/L) with traces of brine constituents. Diagnostic variations in concentrations of Ba, Br, Sr, Cl, and Al reveal spatial trends and partitioning into six clusters

Den site selection and movement patterns of female raccoons following removal and exclusion from residences

Raccoons (Procyon lotor) are one of many wildlife species that have adapted to survive in urban/suburban environments. Classified as a rabies vector species in many eastern states, their disposition after being handled by wildlife specialists is often dictated by this human health concern. Specifically, some states prohibit relocation and mandate that raccoons be released on site or euthanized. Although management using nonlethal means is often preferred by some segments of the human population, several questions remain to be addressed before appropriate agency policies regarding the handling of urban wildlife can be determined. There is little information available regarding the fate of lactating raccoons and their offspring that are trapped and released on site or excluded from human structures. Therefore, our objective was to determine habitat use, home range size, and fate of adult females and their offspring following capture, exclusion, and subsequent release on site. Nineteen adult female raccoons were live-trapped, anesthetized, fitted with radio-collars, and released. Raccoons were captured in Hartford County, Connecticut between April and June of 1998 and 1999. Movements and den-site selection were monitored weekly using radio-telemetry equipment. Home ranges averaged 10.5 ha. Sixty-two percent of the raccoons selected human occupied structures for den sites immediately after release. In total, 73% of the den sites selected were human built. Further insight into nuisance raccoon behavior will permit state wildlife agencies to better develop management policies

Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations

Low-temperature far-infrared ellipsometry of convergent beam

Development of an ellipsometry to the case of a coherent far infrared irradiation, low temperatures and small samples is described, including a decision of the direct and inverse problems of the convergent beam ellipsometry for an arbitrary wavelength, measurement technique and a compensating orientation of cryostat windows. Experimental results are presented: for a gold film and UBe13 single crystal at room temperature (lambda=119 um), temperature dependencies of the complex dielectric function of SrTiO3 (lambda=119, 84 and 28 um) and of YBa2Cu3O7-delta ceramic (lambda=119 um).Comment: 14 pages, 6 figure

Introduction of GI Wellness Committee to reduce GI fellow burnout and improve wellness.

Gastroenterology (GI) fellowship is an arduous process which predisposes fellows to fatigue and burnout. Our baseline survey showed a large number of our fellows to be in danger of burnout. Aims for Improvement To improve the overall wellness of GI fellows, identify stressors and reduce incidence of burnout. The goal for the first 6 months of operation is to demonstrate improvement in Mini ReZ survey scores by 25% at starting from Sept 1st, 2020

Cognitive Control Errors in Nonhuman Primates Resembling Those in Schizophrenia Reflect Opposing Effects of NMDA Receptor Blockade on Causal Interactions Between Cells and Circuits in Prefrontal and Parietal Cortices

Background: The causal biology underlying schizophrenia is not well understood, but it is likely to involve a malfunction in how neurons adjust synaptic connections in response to patterns of activity in networks. We examined statistical dependencies between neural signals at the cell, local circuit, and distributed network levels in prefrontal and parietal cortices of monkeys performing a variant of the AX continuous performance task paradigm. We then quantified changes in the pattern of neural interactions across levels of scale following NMDA receptor (NMDAR) blockade and related these changes to a pattern of cognitive control errors closely matching the performance of patients with schizophrenia. Methods: We recorded the spiking activity of 1762 neurons along with local field potentials at multiple electrode sites in prefrontal and parietal cortices concurrently, and we generated binary time series indicating the presence or absence of spikes in single neurons or local field potential power above or below a threshold. We then applied causal discovery analysis to the time series to detect statistical dependencies between the signals (causal interactions) and compared the pattern of these interactions before and after NMDAR blockade. Results: Global blockade of NMDAR produced distinctive and frequently opposite changes in neural interactions at the cell, local circuit, and network levels in prefrontal and parietal cortices. Cognitive control errors were associated with decreased interactions at the cell level and with opposite changes at the network level in prefrontal and parietal cortices. Conclusions: NMDAR synaptic deficits change causal interactions between neural signals at different levels of scale that correlate with schizophrenia-like deficits in cognitive control

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dys-regulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism

Spin Foams and Noncommutative Geometry

We extend the formalism of embedded spin networks and spin foams to include topological data that encode the underlying three-manifold or four-manifold as a branched cover. These data are expressed as monodromies, in a way similar to the encoding of the gravitational field via holonomies. We then describe convolution algebras of spin networks and spin foams, based on the different ways in which the same topology can be realized as a branched covering via covering moves, and on possible composition operations on spin foams. We illustrate the case of the groupoid algebra of the equivalence relation determined by covering moves and a 2-semigroupoid algebra arising from a 2-category of spin foams with composition operations corresponding to a fibered product of the branched coverings and the gluing of cobordisms. The spin foam amplitudes then give rise to dynamical flows on these algebras, and the existence of low temperature equilibrium states of Gibbs form is related to questions on the existence of topological invariants of embedded graphs and embedded two-complexes with given properties. We end by sketching a possible approach to combining the spin network and spin foam formalism with matter within the framework of spectral triples in noncommutative geometry.Comment: 48 pages LaTeX, 30 PDF figure

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics