Hydrology and Water Quality in the Central Kentucky Karst: Phase 1

Study of springs and cave streams has shown that heavy metal-rich effluent from a wastewater treatment plant can be traced to Hidden River Cave (beneath the city of Horse Cave) and thence 4 to 5 miles north to a group of 39 springs at 14 locations along a 5-mile reach of Green River. Nickel, chromium, copper and zinc in these effluent-bearing springs are in concentrations of as much as 30 times greater than other springs upstream and downstream from this reach, 20 times greater than the Green River, and 60 times greater than in shallow domestic wells between Horse Cave and the river. Mean concentration ratios, based on samples taken during moderate to flood flow, are considerably lower. Although the heavy metal content of the effluent-bearing stream in Hidden River Cave greatly exceeds various maximum concentrations set by current standards, the concentrations in the effluent-bearing springs do not exceed current maximums allowed for public water supplies. None of the domestic shallow wells between the cave and the river intercept this effluent-rich water. The distributary system that was postulated to feed the 39 springs was entered by digging in June 1975; 14.6 miles of this floodwater maze has been mapped. Water tracing over distances of as much as 15 miles has made it possible to delineate thirteen groundwater basins, eleven of them characterized by distributary flow. Study of the water quality· of five adjacent groundwater basins showed that they could be geochemically differentiated. One of these, the Three-Springs Groundwater Basin, has a distributary complex that is 2.4 miles wide and its discharge is believed to be affected by brines released by drilling. Dendritic flow paths, identified by dye-traces to and from caves (and mapping of these caves), have been recognized in the Turnhole Spring Groundwater Basin (Quinlan, 1976) and the Graham Springs Groundwater Basin. Flow converges to trunk streams as much as 40 ft wide that may rise and fall as much as 100 ft in response to heavy rains. Groundwater velocities in the upper part of the principal aquifer range from 30 ft per hour to 1300 ft per hour, depending upon the duration and intensity of rains. Recommendations are made for: 1) the use of drainage basin maps for regional planning and protection of water supplies, 2) protection of other water supplies, and 3) development of specific springs as potential public water supplies

Hydrology and Water Quality in the Central Kentucky Karst: Phase II Part A: Preliminary Summary of the Hydrogeology of the Mill Hole Sub-Basin of the Turnhole Spring Groundwater Basin

Water from upland areas flows to small ephemeral and perennial springs that feed sinking streams that are tributary to low-order cave streams. These cave streams, also recharged by diffuse percolation, are part of a dendritic network in which intermediate-order streams join high-order streams that flow to major trunk streams. The trunk in the Mill Hole Sub-basin flows across the bottom of a large karst window, Mill Hole, and joins the trunk of the Patoka Creek Sub-basin. Their combined discharge bifurcates, flows around the collapsed central core of a larger karst window, Cedar Sink, and re-joins to flow as one to Turnhole Spring, along the south bank of Green River. The location of the major trunk streams can be inferred from the position and orientation of well-defined troughs in the piezometric surface. Flow velocities over the same 5-mile distance, erroneously assuming a straight path from Parker Cave to Mill Hole, range from 60 to 1100 ft per hour--depending on whether discharge is at flood or base flow conditions. Actual velocity extremes are probably lower and higher

Approximating Nearest Neighbor Distances

Several researchers proposed using non-Euclidean metrics on point sets in Euclidean space for clustering noisy data. Almost always, a distance function is desired that recognizes the closeness of the points in the same cluster, even if the Euclidean cluster diameter is large. Therefore, it is preferred to assign smaller costs to the paths that stay close to the input points. In this paper, we consider the most natural metric with this property, which we call the nearest neighbor metric. Given a point set P and a path $\gamma$, our metric charges each point of $\gamma$ with its distance to P. The total charge along $\gamma$ determines its nearest neighbor length, which is formally defined as the integral of the distance to the input points along the curve. We describe a $(3+\varepsilon)$-approximation algorithm and a $(1+\varepsilon)$-approximation algorithm to compute the nearest neighbor metric. Both approximation algorithms work in near-linear time. The former uses shortest paths on a sparse graph using only the input points. The latter uses a sparse sample of the ambient space, to find good approximate geodesic paths.Comment: corrected author nam

All Six Planets Known to Orbit Kepler-11 Have Low Densities

The Kepler-11 planetary system contains six transiting planets ranging in size from 1.8 to 4.2 times the radius of Earth. Five of these planets orbit in a tightly-packed configuration with periods between 10 and 47 days. We perform a dynamical analysis of the system based upon transit timing variations observed in more than three years of \ik photometric data. Stellar parameters are derived using a combination of spectral classification and constraints on the star's density derived from transit profiles together with planetary eccentricity vectors provided by our dynamical study. Combining masses of the planets relative to the star from our dynamical study and radii of the planets relative to the star from transit depths together with deduced stellar properties yields measurements of the radii of all six planets, masses of the five inner planets, and an upper bound to the mass of the outermost planet, whose orbital period is 118 days. We find mass-radius combinations for all six planets that imply that substantial fractions of their volumes are occupied by constituents that are less dense than rock. The Kepler-11 system contains the lowest mass exoplanets for which both mass and radius have been measured.Comment: 39 pages, 10 figure

Generalizations of entanglement based on coherent states and convex sets

Unentangled pure states on a bipartite system are exactly the coherent states with respect to the group of local transformations. What aspects of the study of entanglement are applicable to generalized coherent states? Conversely, what can be learned about entanglement from the well-studied theory of coherent states? With these questions in mind, we characterize unentangled pure states as extremal states when considered as linear functionals on the local Lie algebra. As a result, a relativized notion of purity emerges, showing that there is a close relationship between purity, coherence and (non-)entanglement. To a large extent, these concepts can be defined and studied in the even more general setting of convex cones of states. Based on the idea that entanglement is relative, we suggest considering these notions in the context of partially ordered families of Lie algebras or convex cones, such as those that arise naturally for multipartite systems. The study of entanglement includes notions of local operations and, for information-theoretic purposes, entanglement measures and ways of scaling systems to enable asymptotic developments. We propose ways in which these may be generalized to the Lie-algebraic setting, and to a lesser extent to the convex-cones setting. One of our original motivations for this program is to understand the role of entanglement-like concepts in condensed matter. We discuss how our work provides tools for analyzing the correlations involved in quantum phase transitions and other aspects of condensed-matter systems.Comment: 37 page

Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators (“potentiators” and “correctors”), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called “stabilizers”) that rescue ΔF508-CFTR activity. To design the “stabilizers”, we extended our structural ensemble-based computational protein redesign algorithm to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods

Computational and Serologic Analysis of Novel and Known Viruses in Species Human Adenovirus D in Which Serology and Genomics Do Not Correlate

In November of 2007 a human adenovirus (HAdV) was isolated from a bronchoalveolar lavage (BAL) sample recovered from a biopsy of an AIDS patient who presented with fever, cough, tachycardia, and expiratory wheezes. To better understand the isolated virus, the genome was sequenced and analyzed using bioinformatic and phylogenomic analysis. The results suggest that this novel virus, which is provisionally named HAdV-D59, may have been created from multiple recombination events. Specifically, the penton, hexon, and fiber genes have high nucleotide identity to HAdV-D19C, HAdV-D25, and HAdV-D56, respectively. Serological results demonstrated that HAdV-D59 has a neutralization profile that is similar yet not identical to that of HAdV-D25. Furthermore, we observed a two-fold difference between the ability of HAdV-D15 and HAdV-D25 to be neutralized by reciprocal antiserum indicating that the two hexon proteins may be more similar in epitopic conformation than previously assumed. In contrast, hexon loops 1 and 2 of HAdV-D15 and HAdV-D25 share 79.13 and 92.56 percent nucleotide identity, respectively. These data suggest that serology and genomics do not always correlate

Properly Folded Bacterially Expressed H1N1 Hemagglutinin Globular Head and Ectodomain Vaccines Protect Ferrets against H1N1 Pandemic Influenza Virus

Background: In the face of impending influenza pandemic, a rapid vaccine production and mass vaccination is the most effective approach to prevent the large scale mortality and morbidity that was associated with the 1918 "Spanish Flu". The traditional process of influenza vaccine production in eggs is time consuming and may not meet the demands of rapid global vaccination required to curtail influenza pandemic. Methodology/Principal Findings: Recombinant technology can be used to express the hemagglutinin (HA) of the emerging new influenza strain in a variety of systems including mammalian, insect, and bacterial cells. In this study, two forms of HA proteins derived from the currently circulating novel H1N1 A/California/07/2009 virus, HA1 (1-330) and HA (1- 480), were expressed and purified from E. coli under controlled redox refolding conditions that favoured proper protein folding. However, only the recombinant HA1 (1-330) protein formed oligomers, including functional trimers that bound receptor and caused agglutination of human red blood cells. These proteins were used to vaccinate ferrets prior to challenge with the A/California/07/2009 virus. Both proteins induced neutralizing antibodies, and reduced viral loads in nasal washes. However, the HA1 (1-330) protein that had higher content of multimeric forms provided better protection from fever and weight loss at a lower vaccine dose compared with HA (1-480). Protein yield for the HA1 (1-330) ranged around 40 mg/Liter, while the HA (1-480) yield was 0.4-0.8 mg/Liter. Conclusions/Significance: This is the first study that describes production in bacterial system of properly folded functional globular HA1 domain trimers, lacking the HA2 transmembrane protein, that elicit potent neutralizing antibody responses following vaccination and protect ferrets from in vivo challenge. The combination of bacterial expression system with established quality control methods could provide a mechanism for rapid large scale production of influenza vaccines in the face of influenza pandemic threat

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

IMPORTANCE: Patients with atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson’s disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes, but have not been prospectively studied. OBJECTIVE: To define the distinguishing features of PSP and CBS, and to assess their usefulness in facilitating early diagnosis and separation from PD. DESIGN, SETTING, PARTICIPANTS: Cohort study which recruited APS and PD patients from movement disorder clinics across the UK from September 2015 to December 2018, and will follow up patients over 5 years. APS patients were stratified into PSP-Richardson syndrome, PSP-subcortical (including PSP-parkinsonism and PSP-progressive gait freezing cases), PSP-cortical (including PSP-frontal and PSP/CBS overlap cases), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer’s and CBS-non-Alzheimer’s groups. MAIN OUTCOME MEASURES: Baseline group comparisons were conducted using: 1) Clinical trajectory; 2) Cognitive screening scales; 3) Serum neurofilament light chain (NF-L); 4) TRIM11, ApoE and MAPT genotypes; 5) Volumetric MRI. RESULTS: 222 APS cases (101 PSP, 55 MSA, 40 CBS and 26 indeterminate) were recruited (58% male; mean age at recruitment, 68.3 years). Age-matched controls (n=76) and PD cases (n=1967) were also included. Concordance between the ante-mortem clinical diagnosis and pathological diagnosis was achieved in 12/13 (92%) of PSP and CBS cases coming to post-mortem. Applying the MDS PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP. 49/101 (49%) of reclassified PSP patients did not have classical PSP-Richardson syndrome. PSP-subcortical patients had a longer diagnostic latency and a more benign clinical trajectory than PSP-Richardson syndrome and PSP-cortical (p<0.05). PSP-subcortical was distinguished from PSP-cortical and PSP-Richardson syndrome by cortical volumetric MRI measures (AUC 0.84-0.89), cognitive profile (AUC 0.80-0.83), serum NF-L (AUC 0.75-0.83) and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP subtypes. 8/17 (47%) of CBS patients with CSF analysis were identified as having CBS-Alzheimer’s. CBS-Alzheimer’s patients had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment and higher APOE-ε4 allele frequency than CBS-non-Alzheimer’s (p<0.05, AUC 0.80-0.87). Serum NF-L levels distinguished PD from PSP and CBS (p<0.05, AUC 0.80). CONCLUSIONS AND RELEVANCE: Clinical, therapeutic and epidemiological studies focusing on PSP-Richardson syndrome are likely to miss a large number of patients with underlying PSP-tau pathology. CSF analysis defines a distinct CBS-Alzheimer’s subgroup. PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis