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The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, hemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data. We used computer simulations to model the factors that influence the slopes derived from the population data, and then matched these simulations with the empirically derived slopes. Our simulations showed that changes to the population distribution of feedback loop limbs may alter the slopes of correlations within population data in specific ways. Non-random (interdependent) associations of the limbs of feedback loops may also have this effect, as well as producing discrepancies between the slopes of feedback limb loops determined experimentally and the same slopes determined by derivation from population data. Our corresponding empirical findings were consistent with the presence of such interdependence in the free thyroxine/thyrotropin, hemoglobin/erythropoietin, and glucose/insulin systems. The glucose/insulin data provided evidence consistent with increasing interdependence with age in childhood. Our findings therefore provide strong evidence that the interdependence of the limbs of feedback loops is a general feature of endocrine homeostatic regulation. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages. [ABSTRACT FROM AUTHOR]

International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden1. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2. Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.Whole-genome sequencing of 962 clear cell renal cell carcinomas from 11 countries shows geographic variations in somatic mutation profiles, including a mutational signature of unknown cause in 70% of cases from Japan. [ABSTRACT FROM AUTHOR]

Coxiella burnetii is an important zoonotic bacterial pathogen of global importance, causing the disease Q fever in a wide range of animal hosts. Ruminant livestock, in particular sheep and goats, are considered the main reservoir of human infection. Vaccination is a key control measure, and two commercial vaccines based on formalin-inactivated C. burnetii bacterins are currently available for use in livestock and humans. However, their deployment is limited due to significant reactogenicity in individuals previously sensitized to C. burnetii antigens. Furthermore, these vaccines interfere with available serodiagnostic tests which are also based on C. burnetii bacterin antigens. Defined subunit antigen vaccines offer significant advantages, as they can be engineered to reduce reactogenicity and co-designed with serodiagnostic tests to allow discrimination between vaccinated and infected individuals. This study aimed to investigate the diversity of antibody responses to C. burnetii vaccination and/or infection in cattle, goats, humans, and sheep through genome-wide linear epitope mapping to identify candidate vaccine and diagnostic antigens within the predicted bacterial proteome. Using high-density peptide microarrays, we analyzed the seroreactivity in 156 serum samples from vaccinated and infected individuals to peptides derived from 2,092 open-reading frames in the C. burnetii genome. We found significant diversity in the antibody responses within and between species and across different types of C. burnetii exposure. Through the implementation of three different vaccine candidate selection methods, we identified 493 candidate protein antigens for protein subunit vaccine design or serodiagnostic evaluation, of which 65 have been previously described. This is the first study to investigate multi-species seroreactivity against the entire C. burnetii proteome presented as overlapping linear peptides and provides the basis for the selection of antigen targets for next-generation Q fever vaccines and diagnostic tests. [ABSTRACT FROM AUTHOR]

Forest management decisions affect carbon stock and rates of sequestration. One subject of debate is the rotation age that will optimize sequestration over extended periods. Some argue that shorter rotations facilitate greater sequestration rates due to the accelerated growth rates of younger trees compared to mature or old-growth trees. Others maintain that frequent harvesting will not allow forest carbon to rebound after each subsequent rotation, and thus more extended periods between clearcutting is the superior choice. These contrasting viewpoints are mirrored regarding the impact of thinning treatments, in that either thinning will enhance forest carbon uptake by facilitating improved and sustained r growth of residual trees or removing any above-ground biomass will outweigh the yields. This study aims to compare the different suites of management decisions and identify practical combinations of rotation ages and thinning applications that will optimize carbon sequestration while meeting other objectives over a 240-year projection timeframe. Stand development under different harvest rotations and thinning specifications was modeled using a Forest Vegetation Simulator (FVS). We found that site productivity was the primary determinant in stand-above-ground carbon dynamics under various management scenarios. Thus, the optimal rotation age/thinning treatment combinations differed between site classes. High productivity stands were estimated to sequester the most above-ground live carbon with 60-year rotations with a low-intensity thin at age 40. Moderately productive stands performed the best with 80-year rotations when two low-intensity thinning treatments were applied between harvests. For high and moderate productivity stands, estimates of gross carbon increased when two low or moderate-intensity thinning treatments were applied within 80- or 120-year rotations. High-intensity thinning treatments reduced total carbon sequestered over the 240-year projection timeframe for all productivity levels and rotation ages, except for low productivity stands under 120-year rotations. [ABSTRACT FROM AUTHOR]

Simple Summary: Shiga toxin-producing E. coli (STEC) serogroup O157 can cause serious infections in humans, with symptoms ranging from bloody diarrhoea to kidney failure, and, in some instances, can be life-threatening. The natural reservoir for these bacteria is livestock, particularly cattle; however, there is an increasing number of human cases associated with wildlife species such as deer. In Scotland, a human STEC O157 outbreak in 2015 that was associated with the consumption of venison prompted us to investigate the prevalence of STEC O157 in Scottish wild deer species. Although the estimated prevalence was low (0.28%), we found that STEC O157 isolates were shed at high levels from positive deer and that these isolates had the potential to cause severe disease in humans. Furthermore, retrospective analysis identified an isolate from this study as the likely source of another Scottish human outbreak in 2017. Shiga toxin-producing E. coli (STEC) infections associated with wildlife are increasing globally, highlighting many 'spillover' species as important reservoirs for these zoonotic pathogens. A human outbreak of STEC serogroup O157 in 2015 in Scotland, associated with the consumption of venison meat products, highlighted several knowledge gaps, including the prevalence of STEC O157 in Scottish wild deer and the potential risk to humans from wild deer isolates. In this study, we undertook a nationwide survey of wild deer in Scotland and determined that the prevalence of STEC O157 in wild deer is low 0.28% (95% confidence interval = 0.06–0.80). Despite the low prevalence of STEC O157 in Scottish wild deer, identified isolates were present in deer faeces at high levels (>104 colony forming units/g faeces) and had high human pathogenic potential based on whole genome sequencing and virulence gene profiling. A retrospective epidemiological investigation also identified one wild deer isolate from this study as a possible source of a Scottish human outbreak in 2017. These results emphasise the importance of food hygiene practices during the processing of wild deer carcasses for human consumption. [ABSTRACT FROM AUTHOR]

Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson's disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated factors released from neurons provides a rationale for investigating ER stress biomarkers in the blood to aid diagnosis of PD. The levels of ER stress-regulated proteins in serum collected from 29 PD patients and 24 non-PD controls were measured using enzyme-linked immunosorbent assays. A panel of four biomarkers, protein disulfide-isomerase A1, protein disulfide-isomerase A3, mesencephalic astrocyte-derived neurotrophic factor, and clusterin, together with age and gender had higher ability (area under the curve 0.64, sensitivity 66%, specificity 57%) and net benefit to discriminate PD patients from the non-PD group compared with other analyzed models. Addition of oligomeric and total α-synuclein to the model did not improve the diagnostic power of the biomarker panel. We provide evidence that ER stress-regulated proteins merit further investigation for their potential as diagnostic biomarkers of PD. [ABSTRACT FROM AUTHOR]

The bacterium Coxiella burnetii can cause the disease Q-fever in a wide range of animal hosts. Ruminants, including sheep, are thought to play a pivotal role in the transmission of C. burnetii to humans; however, the only existing livestock vaccine, namely, Coxevac® (Ceva Animal Health Ltd., Libourne, France), a killed bacterin vaccine based on phase I C. burnetii strain Nine-Mile, is only approved for use in goats and cattle. In this study, a pregnant ewe challenge model was used to determine the protective effects of Coxevac® and an experimental bacterin vaccine based on phase II C. burnetii against C. burnetii challenge. Prior to mating, ewes (n = 20 per group) were vaccinated subcutaneously with either Coxevac®, the phase II vaccine, or were unvaccinated. A subset of pregnant ewes (n = 6) from each group was then challenged 151 days later (~100 days of gestation) with 106 infectious mouse doses of C. burnetii, Nine-Mile strain RSA493. Both vaccines provided protection against C. burnetii challenge as measured by reductions in bacterial shedding in faeces, milk and vaginal mucus, and reduced abnormal pregnancies, compared to unvaccinated controls. This work highlights that the phase I vaccine Coxevac® can protect ewes against C. burnetii infection. Furthermore, the phase II vaccine provided comparable levels of protection and may offer a safer and cost-effective alternative to the currently licensed vaccine. [ABSTRACT FROM AUTHOR]

Objectives: The sensitivities of the pituitary to thyroxine feedback, and the thyroid to thyrotropin stimulation determine the free thyroxine /thyrotropin feedback loop and can be described mathematically by two curves. It is not well understood how the two curves combine in a healthy population with normal thyroid function to express the individual balance points that are observed. This study was directed at this issue testing the possibilities of random combination and directed linkage between the two curves. Methods: We reverse-engineered two sets of population data, on the assumption of independent combinations of thyroid and pituitary sensitivities, to obtain estimates of the curve describing thyroid sensitivity. Sensitivity studies were performed. Results: No analysis resulted in a physiologically feasible estimate of the curve describing thyroid sensitivity. There was evidence of linkage of the two curves in terms of their combination throughout the normal range. Thyroid response curves reflecting a low free thyroxine response to thyrotropin tended to be combined in individuals with thyrotropin curves reflecting a high thyrotropin response to free thyroxine, and vice versa. Conclusions: Thyroid and pituitary sensitivities are linked, being combined in individuals in a non-random directed pattern. Direct mutual interaction may contribute to this linkage. This linkage precludes the derivation of the curves describing these sensitivities from population data of the free thyroxine and thyrotropin relationship and complicates their derivation by physiological experimentation. This linkage and probable interaction may also bestow evolutionary advantage by minimising inter-individual variation in free thyroxine levels and by augmenting homeostasis. [ABSTRACT FROM AUTHOR]

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Aims: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. Materials and Methods: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub‐cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi‐squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso‐based binominal regression analysis. Results: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. Conclusions: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN25823942. [ABSTRACT FROM AUTHOR]

Recently proposed concepts regarding the nature and assessment of the thyroid state have provided a model more consistent with empiric evidence. It now appears likely that there are no such entities as thyroid set points and individual euthyroidism. Rather than there being discrete thyroid states, peripheral organ parameters are associated with thyroid function in a continuous manner. Thyroid hormone levels and, in particular, levels of free thyroxine now appear to be superior to thyrotropin levels as indicators of the thyroid state. Complicating the assessment of the correlations of the thyroid state with pregnancy outcomes are the contribution of the placenta to maternal thyroid function, fetal thyroid development, the multiple potential pathways to any particular outcome, the likely presence of small critical periods of time, the differing genetics of fetal and maternal tissues, and the unreliability of thyroid hormone assays. Nevertheless, there is no apparent reason for there to be a change in pregnancy to the basic principles of thyroid hormone action. The relationships between mild abnormalities of the thyroid state and pregnancy outcomes and the value of treating such mild abnormalities remain uncertain and controversial. The evidence suggests that further investigation of these clinical questions might better be based on thyroid hormone, particularly free thyroxine, levels. In the investigation of borderline low thyroid states, the categories of subclinical hypothyroidism and isolated hypothyroxinemia might both be abandoned with attention being directed to low free thyroxine levels regardless of the thyroid-stimulating hormone (TSH) levels. For these changes to occur, there would ideally be improvements in the assays for free thyroxine in pregnancy. The evidence suggests that, just as in the non-pregnant situation, pregnancy guidelines based on thyrotropin levels may need revision. [ABSTRACT FROM AUTHOR]

Inhibition of IRE1 RNase activity sensitizes patient-derived acute myeloid leukaemia cells to proteasome inhibitors The cells that were most responsive to MKC8866 plus CFZ co-treatment when compared with CFZ treatment alone had the highest XBP1s and vice versa. Significantly increased AML cell death was observed in the combination treatments that included CFZ ( I p i < 0.0001); increased cell death was observed in the combination treatments with BTZ but this was not significant (Figure 1D,E, right panels). We demonstrate that an IRE1 RNase inhibitor (MKC8866), in combination with proteasome inhibitors, significantly decreases XBP1s levels and increases cell death in AML cell lines and patient-derived AML cells. [Extracted from the article]

In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that 'subclinical hypothyroidism' (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy. [ABSTRACT FROM AUTHOR]

The value of non‐commodity ecosystem services provided by forests is widely recognized, but intensive forest management practices are increasing, with uncertain consequences for a multitude of these services. Quantitative relationships among biodiversity conservation, timber production and other ecosystem services remain poorly understood, especially during the early‐successional period of intensively managed forestlands.We manipulated management intensity in regenerating forest plantations to test the prediction that treatments aimed at maximizing timber production decrease biodiversity conservation and non‐timber services. We measured species richness of 3 taxonomic groups and 13 proxies for provisioning, cultural and regulating services within stands randomly assigned to one of the three herbicide application intensities or an untreated control.Herbicides increased allocation of net primary production to crop trees, increasing projected timber volume and revenues at 40‐ and 60‐year harvest ages. Commonly used herbicide prescriptions reduced culturally valued plants by 71%, wild‐ungulate forage by 41%, avian richness by 20% and pollinator floral resources by 42%, the latter being associated with 38% fewer pollinator species. However, agriculturally valued bumblebees, pollination of blueberries, avian‐mediated arthropod control, wild ungulate observations and regulation services tied to forest productivity appeared unaffected by increasing management intensity and timber production.Species richness and flora‐provided services in young forest plantations exhibited strong trade‐offs with projected timber production, whereas post‐treatment vegetation regeneration and site‐level variation likely maintained a range of other services. Although vegetation recovery is important for supporting wildlife and some ecosystem services on industrial forestlands, it is unlikely that any single prescription can optimize both timber and non‐timber benefits to society across managed forest landscapes. Instead, producing different services in discrete portions of the landscape may be necessary.Synthesis and applications. We tested the effects of intensive forest management via herbicides on ecosystem services and found that biodiversity responses and services from early‐successional vegetation trade‐off against timber production. A number of services appeared to be compatible with timber production, although no single prescription optimized the full range of services. Stand‐level biodiversity conservation and a variety of services could potentially be provided by treatment skips and less‐intensive management on productive sites, although it is unlikely that all services can be optimized without landscape‐level planning. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor of the journal Thyroid, discussing the clinical and laboratory status of measuring thyrotropin (TSH) and thyroid hormone concentrations. The authors argue that there is no robust empirical evidence to support the longstanding recommendation that TSH concentration is the best blood test for assessing thyroid status. They suggest that thyroid hormone concentrations, particularly free thyroxine (fT4), may be superior to TSH concentrations in terms of correlation with clinical outcomes. The authors also question the theoretical basis for the superiority of TSH concentrations and propose that recommendations regarding the assessment of thyroid status be updated based on recent evidence. [Extracted from the article]

Purpose: Recently published papers have demonstrated that particularly in untreated individuals, clinical parameters more often associate with thyroid hormone, particularly free thyroxine (FT4), levels than with thyrotropin (TSH) levels. Clinical and research assessments of the thyroid state of peripheral tissues would therefore be more precise if they were based on FT4 levels rather than on TSH levels. In this paper we describe implications of, and opportunities provided by, this discovery. Conclusions: The FT4 level may be the best single test of thyroid function. The addition of free triiodothyronine (FT3) and TSH levels would further enhance test sensitivity and distinguish primary from secondary thyroid dysfunction respectively. There are opportunities to reconsider testing algorithms. Additional potential thyroidology research subjects include the peripheral differences between circulating FT4 and FT3 action, and outcomes in patients on thyroid replacement therapy in terms of thyroid hormone levels. Previously performed negative studies of therapy for subclinical thyroid dysfunction could be repeated using thyroid hormone levels rather than TSH levels for subject selection and the monitoring of treatment. Studies of outcomes in older individuals with treatment of high normal FT4 levels, and pregnant women with borderline high or low FT4 levels would appear to be the most likely to show positive results. There are fresh indications to critically re-analyse the physiological rationale for the current preference for TSH levels in the assessment of the thyroid state of the peripheral tissues. There may be opportunities to apply these research principles to analogous parameters in other endocrine systems. [ABSTRACT FROM AUTHOR]

Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need for a biopsy to diagnose prostate cancer. Peripheral blood serum obtained from 436 men undergoing transrectal ultrasound guided biopsy were assessed for a panel of 18 inflammatory serum biomarkers in addition to Total and Free Prostate Specific Antigen (PSA). This panel was integrated into a previously developed Irish clinical risk calculator (IPRC) for the detection of prostate cancer and high-grade prostate cancer (Gleason Score ≥ 7). Using logistic regression and multinomial regression methods, two models (Logst-RC and Multi-RC) were developed considering linear and nonlinear effects of the panel in conjunction with clinical and demographic parameters for determination of the two endpoints. Both models significantly improved the predictive ability of the clinical model for detection of prostate cancer (from 0.656 to 0.731 for Logst-RC and 0.713 for Multi-RC) and high-grade prostate cancer (from 0.716 to 0.785 for Logst-RC and 0.767 for Multi-RC) and demonstrated higher clinical net benefit. This improved discriminatory power and clinical utility may allow for individualised risk stratification improving clinical decision making. [ABSTRACT FROM AUTHOR]

Host adaptation of pathogens may increase intra- and interspecies transmission. We showed previously that the passage of a clinically isolated enterohemorrhagic Escherichia coli (EHEC) O157 strain (125/99) through the gastrointestinal tract of mice increases its pathogenicity in the same host. In this work, we aimed to elucidate the underlying mechanism( s) involved in the patho-adaptation of the stool-recovered (125RR) strain.We assessed the global transcription profile by microarray and found almost 100 differentially expressed genes in 125RR strain compared with 125/99 strain.We detected an overexpression of Type Three Secretion System (TTSS) proteins at the mRNA and protein levels and demonstrated increased adhesion to epithelial cell lines for the 125RR strain. Additional key attributes of the 125RR strain were: increased motility on semisolid agar, which correlated with an increased fliC mRNA level; reduced Stx2 production at the mRNA and protein levels; increased survival at pH 2.5, as determined by acid resistance assays. We tested whether the overexpression of the LEE-encoded regulator (ler) in trans in the 125/99 strain could recreate the increased pathogenicity observed in the 125RR strain. As anticipated ler overexpression led to increased expression of TTSS proteins and bacterial adhesion to epithelial cells in vitro but also increased mortality and intestinal colonization in vivo.We conclude that this host-adaptation process required changes in several mechanisms that improved EHEC O157 fitness in the new host. The research highlights some of the bacterial mechanisms required for horizontal transmission of these zoonotic pathogens between their animal and human populations. [ABSTRACT FROM AUTHOR]

Background: Though the functional states of other endocrine systems are not defined on the basis of levels of controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone thyrotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine (fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status. Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was performed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for quality by using a modified Newcastle–Ottawa score. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters. Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were associated with thyroid hormone levels significantly more often than with TSH levels—the converse was not true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels were 53% and 23% (p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were comparably associated with clinical parameters (p = 0.71). More sophisticated statistical analyses, however, indicated that the associations with TT3/fT3 were not as robust as the associations with fT4. Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong negative population correlation between thyroid hormones and TSH. Clinical and research components of thyroidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration. [ABSTRACT FROM AUTHOR]

We report rigorous quantum five-dimensional (5D) calculations of the coupled translation-rotation (TR) energy levels and wave functions of an H2 molecule, in the ground (ν = 0) and vibrationally excited (ν = 1) states, confined inside the octahedral interstitial site of solid C60 with S6 symmetry. Translational and rotational excitations of H2 in this nanocavity have been measured by the inelastic neutron scattering (INS) and infrared (IR) spectroscopy, enabling direct comparison between theory and experiment. A pairwise additive 5D intermolecular potential energy surface (PES) was employed in the calculations. The quantum calculations cover the range of energies and types of translational and rotational excitations of the guest molecule which go substantially beyond those considered in the earlier theoretical investigations of this system, revealing new information about the TR energy level structure. The computed j = 1 and j = 2 rotational levels and their splittings, as well as the translational fundamental, are in semi-quantitative agreement with the available INS and IR data, indicating the need for a more accurate intermolecular PES. Our calculations reveal a strong dependence of the TR energy levels, in particular their splittings, on the setting angle which defines the orientation of the C60 molecules relative to their local threefold axes. [ABSTRACT FROM AUTHOR]

Background: Decreased expression of thrombomodulin (TM) in bladder cancer tissue has been shown to be associated with cell proliferation, increased malignancy and a poor prognosis. The aim of this study was to investigate the immunoexpression of TM in bladder tissue cores by immunohistochemistry (IHC) and the relationship between TM score and patient survival for the following pathologies: transitional cell papillary carcinoma (TCPC), transitional cell carcinoma (non-papillary) (TCC), squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma. TM immunoexpression was also evaluated in normal adjacent bladder tissue cores. Methods: TM immunoexpression was assessed in n=185 formalin-fixed paraffin-embedded (FFPE) bladder tissue cores from n=98 patients by IHC. Tissue cores included TCPC (n=29), TCC (n=85), SCC (n=21), adenocarcinoma (n=12), sarcoma (n=4), and normal tissue cores (n=34). Results: TM immunoexpression scores are stronger in TCPC, TCC and SCC bladder cancer tissue cores with respect to adenocarcinoma and sarcoma (mean TM immunoexpression scores: 3.04, 2.57, 2.55, 1.55 and 1.19, respectively) (Kruskal–Wallis p< 0.001). TM immunoexpression scores significantly decreased in bladder cancer tissue cores across both stage (p< 0.001) and grade (p< 0.001) (Kruskal–Wallis). Survival data were available for n=45 bladder cancer patients (mean follow-up of 34 months). Applying a TM immunoexpression cut-off score of 3.0 demonstrated that patients with bladder cancer who had a TM immunoexpression score < 3.0 had lower survival rates (median survival 23.5 months). In contrast, patients with TM immunoexpression scores ≥ 3.0 had longer survival rates (median survival 40 months) (log-rank; p=0.045). Conclusion: TM immunoexpression in bladder cancer tissue may be a clinically relevant predictor of tumor progression and survival. Low expression of TM in bladder cancer biopsies or in recurrent bladder cancer may be indicative of a poor prognosis. TM immunoexpression could be used to guide clinical decision making. [ABSTRACT FROM AUTHOR]

Background: Olfactory receptor (OR) genes are the largest multi-gene family in the mammalian genome, with 874 in human and 1483 loci in mouse (including pseudogenes). The expansion of the OR gene repertoire has occurred through numerous duplication events followed by diversification, resulting in a large number of highly similar paralogous genes. These characteristics have made the annotation of the complete OR gene repertoire a complex task. Most OR genes have been predicted in silico and are typically annotated as intronless coding sequences. Results: Here we have developed an expert curation pipeline to analyse and annotate every OR gene in the human and mouse reference genomes. By combining evidence from structural features, evolutionary conservation and experimental data, we have unified the annotation of these gene families, and have systematically determined the protein-coding potential of each locus. We have defined the non-coding regions of many OR genes, enabling us to generate full-length transcript models. We found that 13 human and 41 mouse OR loci have coding sequences that are split across two exons. These split OR genes are conserved across mammals, and are expressed at the same level as protein-coding OR genes with an intronless coding region. Our findings challenge the long-standing and widespread notion that the coding region of a vertebrate OR gene is contained within a single exon. Conclusions: This work provides the most comprehensive curation effort of the human and mouse OR gene repertoires to date. The complete annotation has been integrated into the GENCODE reference gene set, for immediate availability to the research community. [ABSTRACT FROM AUTHOR]

Cable-assisted (or tethered) mechanized harvesting has recently been introduced to the Pacific Northwest of the United States, and is rapidly being adopted by the forest industry. However, potential environmental impacts, productivity and cost of the new harvesting systems have not been well-assessed. This study aims to examine the effects of cable assistance on soil compaction, system productivity and cost through a field-based experiment. A harvester-forwarder system was used to thin a harvest unit on dry soils in western Oregon, with and without cable-assistance. We conducted a detailed time study during operations and collected soil measurements before and after machine passes. Machine productivity ranged from 28.75 to 92.36 m3 per scheduled machine hour, with resulting unit costs for untethered and tethered systems ranging from $13.19 to $18.13/m3. Our results showed reduced soil impacts in both extent and degree of soil compaction when cable assistance was employed. The reduced extent of soil impacts is attributed to a reduction in track wander owing to the operative tensions of the tether cable, and the smaller increase in soil density appears to be attributed to combined effects of initially denser soil conditions and reduced shear displacement as a result of cable-assistance. [ABSTRACT FROM AUTHOR]

Specific Escherichia coli isolates lysogenised with prophages that express Shiga toxin (Stx) can be a threat to human health, with cattle being an important natural reservoir. In many countries the most severe pathology is associated with enterohaemorrhagic E. coli (EHEC) serogroups that express Stx subtype 2a. In the United Kingdom, phage type (PT) 21/28 O157 strains have emerged as the predominant cause of life-threatening EHEC infections and this phage type commonly encodes both Stx2a and Stx2c toxin types. PT21/28 is also epidemiologically linked to super-shedding (>103 cfu/g of faeces) which is significant for inter-animal transmission and human infection as demonstrated using modelling studies. We demonstrate that Stx2a is the main toxin produced by stx2a+/stx2c+ PT21/28 strains induced with mitomycin C and this is associated with more rapid induction of gene expression from the Stx2a-encoding prophage compared to that from the Stx2c-encoding prophage. Bacterial supernatants containing either Stx2a and/or Stx2c were demonstrated to restrict growth of bovine gastrointestinal organoids with no restriction when toxin production was not induced or prevented by mutation. Isogenic strains that differed in their capacity to produce Stx2a were selected for experimental oral colonisation of calves to assess the significance of Stx2a for both super-shedding and transmission between animals. Restoration of Stx2a expression in a PT21/28 background significantly increased animal-to-animal transmission and the number of sentinel animals that became super-shedders. We propose that while both Stx2a and Stx2c can restrict regeneration of the epithelium, it is the relatively rapid and higher levels of Stx2a induction, compared to Stx2c, that have contributed to the successful emergence of Stx2a+ E. coli isolates in cattle in the last 40 years. We propose a model in which Stx2a enhances E. coli O157 colonisation of in-contact animals by restricting regeneration and turnover of the colonised gastrointestinal epithelium. [ABSTRACT FROM AUTHOR]

Partial results of a NIOSH-funded study for "Protecting the Logging Workforce: Development of Innovative Logging Techniques for a Safer Work Environment" by a team of researchers at Oregon State University are presented that review safety in steep slope logging. Comparisons are made for hazards and exposures of "conventional" and new technologies for steep slopes. Hazards of new technologies are identified. Safety assessments are addressed for forestry sectors internationally, for the firm and for workers. Important questions of technical feasibility, economic viability and environmental performance are raised. Ongoing research on operators using tethered and untethered systems are described. Results will help inform training and selecting operators. New Best Operating Practices and safety code regulations will result from the research. New technologies will reduce worker hazards and exposures for steep slope logging. [ABSTRACT FROM AUTHOR]

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The physiological functions of Thyroid Stimulating Hormone (TSH) autoregulation, the ultra-short feedback loop inhibition of TSH by TSH itself, have not been determined. In this work we explored the role of TSH autoregulation in thyroid homeostasis. We synthesized the known physiology of autoregulation with theknown physiological relationships between thyroid hormones; in particular between free thyroxine and TSH. We analysed the implications of TSH autoregulation, on the generation of the TSH response to free thyroxine (the 'TSH curve'), and on the variation inthis response, which might result from variations in hypothalamopituitary or thyroid gland function. Our analysis demonstrated that, in the circumstances of inter-individual and intra-individual variations to hypothalamo-pituitary function TSH autoregulation lessens variation in the TSH curve. This in turn enhances the probability of generating and maintaining a euthyroid free thyroxine value. This contribution of TSH autoregulation to the stabilisation of thyroid physiology offers a logical explanation for the evolutionary selection of this physiological process. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) is a key player in lipid transport and metabolism and exists in three common isoforms: APOE2, APOE3 and APOE4. The presence of the E4 allelic variant is recognized as a major genetic risk factor for dementia and other chronic (neuro) degenerative diseases. The availability of a validated assay for rapid and reliable APOE4 classification is therefore advantageous. Methods: Biochip array technology (BAT) was successfully applied to identify directly the APOE4 status from plasma within 3 h, through simultaneous immunoassay-based detection of both specific APOE4 and total APOE levels. Results: Samples (n = 432) were first genotyped by polymerase chain reaction (PCR), and thereafter, using BAT, the corresponding plasma was identified as null, heterozygous or homozygous for the E4 allele by calculating the ratio of APOE4 to total APOE protein. Two centers based in Austria and Ireland correctly classified 170 and 262 samples, respectively, and achieved 100% sensitivity and specificity. Conclusions: This chemiluminescent biochip-based sandwich immunoarray provides a novel platform to detect rapidly and accurately an individual's APOE4 status directly from plasma. The E4 genotype of individuals has been shown previously to affect presymptomatic risk, prognosis and treatment response for a variety of diseases, including Alzheimer's disease. The biochip's potential for being incorporated in quantitative protein biomarker arrays capable of analyzing disease stages makes it a superior alternative to PCR-based APOE genotyping and may deliver additional protein-specific information on a variety of diseases in the future. [ABSTRACT FROM AUTHOR]

Abstract: The prevailing teaching regarding homeostasis, and in particular endocrine homeostasis, includes the fundamental concept of a “set point,” which represents a target or optimum level defended by physiological control mechanisms. Analogies for the description and teaching of this concept have included thermostats and cruise controls. We previously demonstrated that such a set‐point model of regulation implies that in population data of parameter set point/controlling hormone levels, correlations between the parameter and its controlling hormone must be in the direction of the response of the parameter to its controlling hormone, and that in thyroid homeostasis this relationship is not observed. In this work we similarly examined population correlations, extracted from the literature, for the parameters glucose and calcium, and their controlling hormones. We found 10 correlations. Most were highly significant (P < 0.01). All were in the direction of the response of the controlling hormone to the parameter. Therefore, none were consistent with the pattern implied by a set‐point model of regulation. Instead all were consistent with an “equilibrium point” model of regulation, whereby ambient levels have no particular connotation to the individual, and result passively from the interplay of physiological processes. We conclude that glucose and calcium regulation, like thyroid regulation, are not centered on set points. This may reflect a general property of homeostasis. We provide an alternative mechanistic analogy, without a set point, for the heuristic description and teaching, of homeostasis. [ABSTRACT FROM AUTHOR]

Symmetry breaking has been recently observed in the endofullerenes M@C60 (M = H2, HF, H2O), manifesting in the splittings of the three-fold degenerate ground states of the endohedral ortho-H2, ortho-H2O and the j = 1 level of HF. The nature of the interaction causing the symmetry breaking is established in this study. A fragment of the solid C60 is considered, comprised of the central C60 molecule surrounded by twelve nearest-neighbor (NN) C60 molecules. The fullerenes have either P (major) or H (minor) orientational orderings, and are assumed to be rigid with Ih symmetry. Only the central C60 is occupied by the guest molecule M, while the NN fullerenes are all empty. The key proposition of the study is that the electrostatic interactions between the charge densities on the NN C60 molecules and that on M inside the central C60 give rise to the symmetry breaking responsible for the measured level splittings. Using this model, the M@C60 level splittings of interest are calculated variationally and using perturbation theory, for both the P and H orientations. Those obtained for the dominant P orientation are in excellent agreement with the experimental results, with respect to the splitting magnitudes and patterns, for all three M@C60 systems considered, pointing strongly to the quadrupolar M–NN interactions as the main cause of the symmetry breaking. The level splittings calculated for the H orientation are about 30 times smaller than the ones in the P orientation. [ABSTRACT FROM AUTHOR]

Background: The external validity, or generalizability, of trials and guidelines has been considered poor in the context of multiple morbidity. How multiple morbidity might affect the magnitude of benefit of a given treatment, and thereby external validity, has had little study. Objective: To provide a method of decision analysis to quantify the effects of age and comorbidity on the probability of deriving a given magnitude of treatment benefit. Design: We developed a method to calculate probabilistically the effect of all of a patient's comorbidities on their underlying utility, or well-being, at a future time point. From this, we derived a distribution of possible magnitudes of treatment benefit at that future time point. We then expressed this distribution as the probability of deriving at least a given magnitude of treatment benefit. To demonstrate the applicability of this method of decision analysis, we applied it to the treatment of hypercholesterolaemia in a geriatric population of 50 individuals. We highlighted the results of four of these individuals. Results: This method of analysis provided individualized quantifications of the effect of age and comorbidity on the probability of treatment benefit. The average probability of deriving a benefit, of at least 50% of the magnitude of benefit available to an individual without comorbidity, was only 0.8%. Conclusion: The effects of age and comorbidity on the probability of deriving significant treatment benefits can be quantified for any individual. Even without consideration of other factors affecting external validity, these effects may be sufficient to guide decision-making. [ABSTRACT FROM AUTHOR]

The environmental effect of extreme soil heating, such as occurs with the complete combustion of large downed wood during wildfires, is a post-fire management concern to forest managers. To address this knowledge gap, we stacked logs to create 'mega-log' burning conditions and compared the temperature, duration and penetration of the soil heat pulse in nine high intensity burned (HB) plots paired with adjacent masticated and broadcast burned low intensity burned (LB) plots at different soil depths (0, 5, 10 and 30 cm) in a Pinus ponderosa stand with volcanic pumice soils. Maximum soil surface temperatures ranges were 424-1168°C with a mean and standard error of 759 ± 9°C in the HB treatment and 42-360°C (107 ± 438C) in the LB treatment. In the HB treatment, temperatures causing fine root and soil organism mortality (>60°C) penetrated the soil to at least 10 cm, but were not recorded at 30 cm. In the HB treatment, mean duration above 608C at 0-10 cm persisted for 4-13 h (7.61 ± 1.02 h). Soils in the LB treatment experienced lethal temperatures at the surface for about an hour (1.19 ± 0.70 h) and at 5 cm were mostly well below lethal temperatures with the exception of one at 57°C and another at 100°C that remained above 60°C for 1.4 h. Large areas of high burn severity may affect long-term forest productivity. Our quantification of soil heating establishes conditions for ongoing studies investigating the effects of soil burn severity on tree seedling growth, soil fungi and nutrients. [ABSTRACT FROM AUTHOR]

Infections caused by Shiga toxin (Stx)-producing E. coli strains constitute a health problem, as they are problematic to treat. Stx production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimized compound interferes with the SOS response by directly affecting the activity and oligomerization of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants. [ABSTRACT FROM AUTHOR]

Context. Population studies of the distribution of T4/TSH set points suggest a more complex inverse relationship between T4 and TSH than that suggested by physiological studies. The reasons for the similarities and differences between the curves describing these relationships are unresolved. Methods. We subjected the curve, derived from empiric data, describing the TSH suppression response to T4, and the more mathematically derived curve describing the T4 response to TSH, to the different possible models of population variation. The implied consequences of these in terms of generating a population distribution of T4/TSH equilibrium points (a “population curve”) were generated and compared to the empiric population curve. The physiological responses to primary hypothyroidism and hyperthyroidism were incorporated into the analysis. Conclusions. Though the population curve shows a similarly inverse relationship, it is describing a different relationship than the curve describing the suppression of TSH by T4. The population curve is consistent with the physiological studies of the TSH response to T4 and implies a greater interindividual variation in the positive thyroid T4 response to TSH than in the central inhibitory TSH response to T4. The population curve in the dysthyroid states is consistent with known physiological responses to these states. [ABSTRACT FROM AUTHOR]

Evolution provides the unifying framework with which to understand biology. The coherent investigation of genic and genomic data often requires comparative genomics analyses based on whole-genome alignments, sets of homologous genes and other relevant datasets in order to evaluate and answer evolutionary-related questions. However, the complexity and computational requirements of producing such data are substantial: this has led to only a small number of reference resources that are used for most comparative analyses. The Ensembl comparative genomics resources are one such reference set that facilitates comprehensive and reproducible analysis of chordate genome data. Ensembl computes pairwise and multiple whole-genome alignments from which large-scale synteny, per-base conservation scores and constrained elements are obtained. Gene alignments are used to define Ensembl Protein Families, GeneTrees and homologies for both protein-coding and non-coding RNA genes. These resources are updated frequently and have a consistent informatics infrastructure and data presentation across all supported species. Specialized web-based visualizations are also available including synteny displays, collapsible gene tree plots, a gene family locator and different alignment views. The Ensembl comparative genomics infrastructure is extensively reused for the analysis of non-vertebrate species by other projects including Ensembl Genomes and Gramene and much of the information here is relevant to these projects. The consistency of the annotation across species and the focus on vertebrates makes Ensembl an ideal system to perform and support vertebrate comparative genomic analyses. We use robust software and pipelines to produce reference comparative data and make it freely available. [ABSTRACT FROM AUTHOR]

1,3,5-Tris(4-carboxyphenyl)benzene assembles into an intricate 8-fold polycatenated assembly of (6,3) hexagonal nets formed through hydrogen bonds and π-stacking. One polymorph features 56 independent molecules in the asymmetric unit, the largest Z′ reported to date. The framework is permanently porous, with a BET surface area of 1095 m2 g−1 and readily adsorbs N2, H2 and CO2. [ABSTRACT FROM AUTHOR]

Western land managers desire a method to discriminate between individual live and dead trees to support postfire management decisions such as salvage logging. Logistic regression models have been suggested for this purpose following prescribed fire and wildfire for ponderosa pine (Pinus ponderosa Dougl. Ex Laws.). Goodness of fit of the regression model is not sufficient for good discrimination. We demonstrate methods to evaluate discriminatory ability using six previously published logistic models and five data sets of postfire tree mortality. The area under the receiver operating characteristic curve (AUC) provides an average assessment of discriminatory ability over all false positive and false negative error rates. In management settings, it may be important to assess correct prediction rates for a maximum false positive rate rather than averaged over all false positive rates. Therefore, we suggest an additional statistic, CP∣FPD, the correct prediction rate for a fixed false positive rate, D. Both goodness of fit and discriminatory ability should be assessed to insure accurate discrimination. We further suggest that the sampling variation of the AUC and CP∣FPD statistics be small and that distributions be centered on values that are acceptable to practitioners. [ABSTRACT FROM AUTHOR]

Though we noted that TSH levels are a sensitive indicator of overt thyroid dysfunction, we did not mean to reassure practitioners that checking TSH levels should be the first step in clinical decision making. Physiologically, TSH levels do respond to the levels of thyroid hormones, but in the therapeutic situation just as in a "controlling" situation, any TSH level will correspond to a range of thyroid hormone values in the population ([7]). Only if we knew the TSH level that corresponded with mid-range thyroid hormone levels in a given individual, and we knew that TSH physiology had not been altered by the replacement therapy, would we have a suitable TSH target level for that individual, for that replacement therapy. [Extracted from the article]

The metaphor of shadow has provided a generative container for exploration of the scope and depth of Appreciative Inquiry theory and practice. The idea of shadow can be a useful tool for opening up important areas of discussion that carry anxiety and can amplify the liberation of energy for change. [ABSTRACT FROM AUTHOR]

Logistic regression models used to predict tree mortality are critical to post-fire management, planning prescribed burns and understanding disturbance ecology. We review literature concerning post-fire mortality prediction using logistic regression models for coniferous tree species in the western USA. We include synthesis and review of: methods to develop, evaluate and interpret logistic regression models; explanatory variables in logistic regression models; factors influencing scope of inference and model limitations; model validation; and management applications. Logistic regression is currently the most widely used and available technique for predicting post-fire tree mortality. Over 100 logistic regression models have been developed to predict post-fire tree mortality for 19 coniferous species following wild and prescribed fires. The most widely used explanatory variables in post-fire tree mortality logistic regression models have been measurements of crown (e.g. crown scorch) and stem (e.g. bole char) injury. Prediction of post-fire tree mortality improves when crown and stem variables are used collectively. Logistic regression models that predict post-fire tree mortality are the basis of simple field tools and contribute to larger fire-effects models. Future post-fire tree mortality prediction models should include consistent definition of model variables, model validation and direct incorporation of physiological responses that link to process modelling efforts. [ABSTRACT FROM AUTHOR]