ANOTHER LOOK AT CLARK\u27S ADIT-SILVER SERIES

The empirical semivariogram for Clark\u27s adit-silver series has been the subject of several publications. Its use in the literature along with some other discussed considerations makes this series a suitable selection for a classroom or workshop semivariogram modeling exercise. My emphasis in this exercise is on estimating the scale of fluctuation (8). Alternative unbounded, bounded asymptotic, and bounded transitional models are developed via weighted least-squares estimation for both regular and integral semivariogram parameterizations (ISV). Results are compared with Clark\u27s recommendation along with some other traditional models, nonparametric models, and ad hoc numerical methods. When a given model fits well using the regular method, generally the ISV does also. When a given model fits poorly using the regular method, however, generally the ISV form fits much worse, or gives unrealistic parameter estimates, or diverges. While an unbounded rational polynomial exponential performs well and presents some interesting existence considerations, for practical purposes the series can be considered bounded and a hyperbolic tangent is selected as the best performing simple parameterization. The ISV for the hyperbolic tangent gives parameter and 8 estimates closest to ad hoc independent values for them. In the spirit of non parametric models, however, splined-line segments can perform extremely well if parameter parsimony and parameter interpretation are not deemed important considerations by a given modeler

CHARACTERIZING THE STATISTICAL DISTRIBUTION OF ORGANIC CARBON AND EXTRACTABLE PHOSPHORUS AT A REGIONAL SCALE

Greater awareness of potential environmental problems has created the need to monitor total organic carbon (TOC) and extractable phosphorus (P) concentrations at a regional scale. The probability distribution of these soil properties can have a significant effect on the power of statistical tests and the quality of inferences applied to these properties. The objectives of this study were to: (1) evaluate the probability distribution of TOC and extractable P at the regional scale in three Major Land Resource Areas (MLRA), and (2) identify appropriate transformations that will result in a normal distribution. Both TOC and extractable P were non-normally distributed in all three MLRAs. Suggested power transformations did not result in normality, but a natural log and negative binomial transformation did produce distributions that met the assumptions of normality in most cases. Statistical analysis of TOC and extractable P data at the regional scale will need to take into account the non-normal distribution of these properties for accurate and precise estimates

Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters

The p53 tumour suppressor is induced by various stress stimuli and coordinates an adaptive gene expression programme leading to growth arrest or cell death. Some stimuli, such as DNA damage, lead to rapid and substantial multisite phosphorylation of p53, nucleated initially through phosphorylation of serine 15. Other stimuli, such as hyper-proliferation, do not stimulate p53-phosphorylation, raising questions regarding the physiological role for phosphorylation. Here, we show that a basal level of Ser15 phosphorylation occurs in both unstimulated cells and cells stimulated pharmacologically to induce p53. p53 in which Ser15 is substituted by alanine (S15A) fails to mediate p53-dependent transcription or growth arrest but can be rescued by substitution with aspartate (S15D: a phospho-mimic). Chromatin immunoprecipitation (ChIP) analyses show that, while wt- and S15A-p53 are detectable on the CDKN1A (p21) promoter (as a representative p53-responsive promoter), S15A-p53 does not stimulate histone acetylation (a measure of chromatin relaxation), nor is its recruitment stimulated, in response to a DNA damage or pharmacological stimulus. These data demonstrate that Ser15 phosphorylation is required for p53 function in the physiological context of p53-responsive promoters and suggest a key and possibly universal role even for low levels of this modification in promoting p53-transcription function

Managing the entanglement: complexity leadership in public sector systems

Complexity in public sector systems requires leaders to balance the administrative practices necessary to be aligned and efficient in the management of routine challenges and the adaptive practices required to respond to dynamic circumstances. Conventional notions of leadership in the field of public administration do not fully explain the role of leadership in balancing the entanglement of formal, top-down, administrative functions and informal, emergent, adaptive functions within public sector settings with different levels of complexity. Drawing on and extending existing complexity leadership constructs, this article explores how leadership is enacted over the duration of six urban regeneration projects representing high, medium, and low levels of project complexity. The article suggests that greater attention needs to be paid to the tensions inherent in enabling leadership if actors are to cope with the complex, collaborative, cross-boundary, adaptive work in which they are increasingly engage

Author Correction:The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation (Scientific Reports (2017) DOI: 10.1038/s41598-017-16394-2)

The original version of this Article contained a typographical error in the spelling of the author Adrian T. Saurin, which was incorrectly given as Adrian Saurin. This has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material

Maintaining Personal Resiliency: Lessons Learned from Evangelical Protestant Clergy

Despite the prominence of clergy in providing human services, and the work-related stressors they experience, clergy health and coping responses have rarely been the focus of psychological research. We report two studies. In the first, we evaluated responses of 398 senior pastors to three open-ended questions regarding personal coping, structural support for their work, and remediation efforts in times of distress. In the second study, Christian mental health professionals and Christian education professionals identified Protestant Christian clergy who exemplify emotional and spiritual health. Twenty-six participated in individual 30-minute interviews. Respondents emphasized the importance of being intentional in maintaining balance in life and developing healthy relationships. They also value a vital spiritual life, emphasizing both their sense of calling into ministry the importance of spiritual disciplines, and an ongoing awareness of God's grace. We suggest ways that Christian mental health professionals can support pastors in preventive and remedial roles. </jats:p

Obesity is associated with higher complication rates in revision total hip arthroplasty

We examined differences in complication rates between obese and non-obese patients undergoing revision total hip arthroplasty. Sixty-five patients with a BMI ≥30 kg/m2 and 54 patients with a BMI of <30 kg/m2 were identified. Obese patients were 2.5 times more likely to suffer a complication than non-obese (38.4% cf 14.8%, p = 0.02). Obese patients were more likely to experience dislocation, leg length discrepancy, fracture, implant loosening, infection and pulmonary embolus. The obese group had a significantly higher revision rate (12.3% cf 1.8%, p = 0.039). Obese patients should be counselled pre-operatively on their elevated risk

FGF19 Action in the Brain Induces Insulin-Independent Glucose Lowering

Insulin-independent glucose disposal (referred to as glucose effectiveness [GE]) is crucial for glucose homeostasis and, until recently, was thought to be invariable. However, GE is reduced in type 2 diabetes and markedly decreased in leptin-deficient ob/ob mice. Strategies aimed at increasing GE should therefore be capable of improving glucose tolerance in these animals. The gut-derived hormone FGF19 has previously been shown to exert potent antidiabetic effects in ob/ob mice. In ob/ob mice, we found that systemic FGF19 administration improved glucose tolerance through its action in the brain and that a single, low-dose i.c.v. injection of FGF19 dramatically improved glucose intolerance within 2 hours. Minimal model analysis of glucose and insulin data obtained during a frequently sampled i.v. glucose tolerance test showed that the antidiabetic effect of i.c.v. FGF19 was solely due to increased GE and not to changes of either insulin secretion or insulin sensitivity. The mechanism underlying this effect appears to involve increased metabolism of glucose to lactate. Together, these findings implicate the brain in the antidiabetic action of systemic FGF19 and establish the brain’s capacity to rapidly, potently, and selectively increase insulin-independent glucose disposal

The primary familial brain calcification associated protein MYORG is an α-galactosidase with restricted substrate specificity

Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG

LRH-1 drives colon cancer cell growth by repressing the expression of the <i>CDKN1A</i> gene in a p53-dependent manner

Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that has been implicated in the progression of breast, pancreatic and colorectal cancer (CRC). To determine mechanisms underlying growth promotion by LRH-1 in CRC, we undertook global expression profiling following siRNA-mediated LRH-1 knockdown in HCT116 cells, which require LRH-1 for growth and in HT29 cells, in which LRH-1 does not regulate growth. Interestingly, expression of the cell cycle inhibitor p21 (CDKN1A) was regulated by LRH-1 in HCT116 cells. p21 regulation was not observed in HT29 cells, where p53 is mutated. p53 dependence for the regulation of p21 by LRH-1 was confirmed by p53 knockdown with siRNA, while LRH-1-regulation of p21 was not evident in HCT116 cells where p53 had been deleted. We demonstrate that LRH-1-mediated p21 regulation in HCT116 cells does not involve altered p53 protein or phosphorylation, and we show that LRH-1 inhibits p53 recruitment to the p21 promoter, likely through a mechanism involving chromatin remodelling. Our study suggests an important role for LRH-1 in the growth of CRC cells that retain wild-type p53