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A hallmark of human and experimental heart failure is deficient sarcoplasmic reticulum (SR) Ca-uptake reflecting impaired contractile function. This is at least partially attributed to dephosphorylation of phospholamban by increased protein phosphatase 1 (PP1) activity. Indeed inhibition of PP1 by transgenic overexpression or gene-transfer of constitutively active inhibitor-1 improved Ca-cycling, preserved function and decreased fibrosis in small and large animal models of heart failure, suggesting that inhibitor-1 may represent a potential therapeutic target. We recently identified a novel human polymorphism (G109E) in the inhibitor-1 gene with a frequency of 7% in either normal or heart failure patients. Transgenic mice, harboring cardiac-specific expression of G109E inhibitor-1, exhibited decreases in contractility, Ca-kinetics and SR Ca-load. These depressive effects were relieved by isoproterenol stimulation. Furthermore, stress conditions (2 Hz +/- Iso) induced increases in Ca-sparks, Ca-waves (60% of G109E versus 20% in wild types) and after-contractions (76% of G109E versus 23% of wild types) in mutant cardiomyocytes. Similar findings were obtained by acute expression of the G109E variant in adult cardiomyocytes in the absence or presence of endogenous inhibitor-1. The underlying mechanisms included reduced binding of mutant inhibitor-1 to PP1, increased PP1 activity, and dephosphorylation of phospholamban at Ser16 and Thr17. However, phosphorylation of the ryanodine receptor at Ser2808 was not altered while phosphorylation at Ser2814 was increased, consistent with increased activation of Ca/calmodulin-dependent protein kinase II (CaMKII), promoting aberrant SR Ca-release. Parallel in vivo studies revealed that mutant mice developed ventricular ectopy and complex ventricular arrhythmias (including bigeminy, trigeminy and ventricular tachycardia), when challenged with isoproterenol. Inhibition of CaMKII activity by KN-93 prevented the increased propensity to arrhythmias. These findings suggest that the human G109E inhibitor-1 variant impairs SR Ca-cycling and promotes arrhythmogenesis under stress conditions, which may present an additional insult in the compromised function of heart failure carriers. © 2015 Elsevier Ltd.

We investigate the ongoing seismicity in the Raton Basin and find that the deep injection of wastewater from the coal‐bed methane field is responsible for inducing the majority of the seismicity since 2001. Many lines of evidence indicate that this earthquake sequence was induced by wastewater injection. First, there was a marked increase in seismicity shortly after major fluid injection began in the Raton Basin in 1999. From 1972 through July 2001, there was one M≥4 earthquake in the Raton Basin, whereas 12 occurred between August 2001 and 2013. The statistical likelihood that such a rate change would occur if earthquakes behaved randomly in time is 3.0%. Moreover, this rate change is limited to the area of industrial activity. Earthquake rates remain low in the surrounding area. Second, the vast majority of the seismicity is within 5 km of active disposal wells and is shallow, ranging between 2 and 8 km depth. The two most carefully studied earthquake sequences in 2001 and 2011 have earthquakes within 2 km of high‐volume, high‐injection‐rate wells. Third, injection wells in the area are commonly very high volume and high rate. Two wells adjacent to the August 2011 M 5.3 earthquake injected about 4.9 million cubic meters of wastewater before the earthquake, more than seven times the amount injected at the Rocky Mountain Arsenal well that caused damaging earthquakes near Denver, Colorado, in the 1960s. The August 2011 M 5.3 event is the second‐largest earthquake to date for which there is clear evidence that the earthquake sequence was induced by fluid injection.

The homeomorphism problem is, given two compact n-manifolds, is there an algorithm to decide if the manifolds are homeomorphic or not. The homeomorphism problem has been solved for many important classes of 3-manifolds - especially those with embedded 2-sided incompressible surfaces (cf [12], [15], [16]), which are called Haken manifolds. It is also well-known that the homeomorphism problem is easily solvable for two 3-manifolds which admit geometries in the sense of Thurston [36], [31]. Hence the recognition problem, to decide if a 3-manifold has a geometric structure, is a significant problem. The recognition problem has been solved for all geometric classes, except for the class of small Seifert fibered spaces, which either have finite fundamental group or have fundamental groups which are extensions of Z by a triangle group and have finite abelianisation. Our aim in this paper is to give an algorithm to recognise these last classes of 3-manifolds, i.e to decide if a given 3-manifold is homeomorphic to one in this class. A completely different solution has been announced recently by Tao Li [22]. Also Perelman's announcement of a solution of the geometrisation conjecture would enable a complete solution of the homeomorphism problem; by identifying which geometric structure a given manifold admits. However it is worth noting that practical algorithms for the homeomorphism and recogntion problems, which can be implemented via software, are very useful for experimentation in 3-manifold topology. (See for example [5], [39]).

OBJECTIVE: The short-term diagnostic stability of schizophrenic and other psychotic disorders was examined in first-admission patients, with attention to the principal reasons for diagnostic change. METHOD: Hospitalized first-admission patients (N = 278) participating in an epidemiologic study were interviewed at baseline and after 6 months with the Structured Clinical Interview for DSM-III-R. A best estimate diagnosis was made at both time points with the use of all available sources of information. Reasons for changes in diagnosis were determined by two psychiatrists. RESULTS: Affective psychosis and schizophrenic disorders were relatively stable broad diagnostic categories over the 6-month period, with 86.5%-88.9% of the patients remaining in the same category, although findings for specific diagnoses within these categories ranged from 61.5% to 85.7%. The groups with unknown and nonspecific diagnoses showed less stability; the diagnoses of more than one-third of these patients remained unknown or nonspecific at the 6-month evaluation. If the 6-month diagnoses are used as the research standard, somewhat lower percentages of patients received the same diagnoses at baseline. Forty-three percent of the changes in diagnosis were attributed to the clinical course of illness; the rest were attributed to the diagnostic process itself. CONCLUSIONS: A longitudinal diagnostic assessment based on multiple sources of information is crucial for categorizing first-admission psychotic patients, particularly those who do not initially fit into a DSM-III-R category. The short-term stability of a diagnosis is a function of multiple factors, including the changing clinical picture, additional sources of information, and new interpretations of original data.