Proof Orders for Decreasing Diagrams

We present and compare some well-founded proof orders for decreasing diagrams. These proof orders order a conversion above another conversion if the latter is obtained by filling any peak in the former by a (locally) decreasing diagram. Therefore each such proof order entails the decreasing diagrams technique for proving confluence. The proof orders differ with respect to monotonicity and complexity. Our results are developed in the setting of involutive monoids. We extend these results to obtain a decreasing diagrams technique for confluence modulo

Regional variation in the flexural properties of the equine hoof wall

The equine hoof wall is a hard, keratinous structure that transmits forces generated when the hoof connects the ground to the skeleton of the horse. During locomotion the hoof capsule is known to deform, resulting in an inward curvature of the dorsal wall and expansion of the heels. However, while researchers have studied the tensile and compressive properties, there is a lack of data on the flexural properties of the hoof wall in different locations around the hoof capsule. In this study, the flexural properties and hydration status of the hoof wall were investigated in two orthogonal directions, in different locations around the hoof capsule. The hoof was divided into three regions: the dorsal-most aspect (toe), the medial and lateral regions (quarters) and the heels caudally. Beams were cut both perpendicular (transverse) and parallel (longitudinal) to the orientation of the tubules. Differences in the mechanical properties were then investigated using three-point bending tests. There were considerable differences in the flexural properties around the hoof capsule; transverse beams from the heel were 45% more compliant than those from the toe region. This corresponded with changes in the hydration of the hoof wall; beams from the heel region were more hydrated (28.2 ± 0.60%) than those from the toe (24.2 ± 0.44%; P < 0.01). Regional variation in the water content is thought to help explain differences in the flexural properties. Mechanical data are further discussed in relation to variation in the structure and loading of the hoof wall

The parasitoid fly ormia ochracea (Diptera: Tachinidae) can use juvenile crickets as hosts

The parasitoid fly Ormia ochracea uses the calling song of its host Gryllus spp. to locate an area inhabited by potential hosts. Once a calling male has been located, O. ochracea deposits live larvae on the host, and on substrates surrounding the host to enable the larvae to attach to and enter individuals in the vicinity of the calling male. In Texas, where O. ochracea parasitizes the Texas field cricket Gryllus texensis, we observed juvenile crickets in the mating aggregations that form around calling males. Juvenile G. texensis crickets are, therefore, potentially susceptible to parasitism by O. ochracea. Here we investigated whether laboratory reared juvenile field crickets could successfully host O. ochracea larvae. We found that juvenile crickets were appropriate hosts for O. ochracea

Impact of Insulin Treatment on the Effect of Eplerenone:Insights From the EMPHASIS-HF Trial

BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and insulin-treated diabetes have a high risk of cardiovascular complications. Mineralocorticoid receptor antagonists may mitigate this risk. We aim to explore the effect of eplerenone on cardiovascular outcomes and all-cause mortality in HFrEF patients with diabetes, including those treated with insulin in the EMPHASIS-HF trial (Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms). METHODS: The primary outcome was the composite of heart failure hospitalization or cardiovascular death. Cox models with treatment-by-diabetes subgroup interaction terms were used. RESULTS: The median follow-up was 21 (10-33) months. Of the 2737 patients included, 623 (23%) had non-insulin-treated diabetes, 236 (9%) had insulin-treated diabetes and 1878 did not have diabetes. Patients with insulin-treated diabetes were younger, more often women, with higher body mass index, waist circumference, more frequent ischemic heart failure cause, impaired kidney function, and longer diabetes duration. Compared with patients without diabetes, those with insulintreated diabetes had a 2-fold higher risk of having a primary outcome event. The hazard ratio (95% CI) for the effect of eplerenone, compared with placebo, on the primary outcome was 0.31 (0.19-0.50) in insulin-treated diabetes, 0.69 (0.500.93) in non-insulin-treated diabetes, and 0.72 (0.58-0.88) in patients without diabetes; interaction P=0.007. The annualized number needed-to-treat-to-benefit with regards to the primary outcome was 3 (95% CI, 3-4) in patients with insulin-treated diabetes, 16 (13-19) in patients with diabetes not receiving insulin, and 26 (24-28) in patients without diabetes. CONCLUSIONS: Patients with insulin-treated diabetes experienced a greater benefit from eplerenone than those with diabetes not treated with insulin and people without diabetes

Renal function stratified dose comparisons of eplerenone versus placebo in the EMPHASIS-HF trial.

BACKGROUND: Current heart failure guidelines recommend target eplerenone dose of 50 mg/day. We have examined the effect of different eplerenone doses based on pre-specified renal function stratification in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). METHODS AND RESULTS: In EMPHASIS-HF, the target dose of eplerenone/placebo was stratified at randomization according to estimated glomerular filtration rate (eGFR): 50 mg/day if eGFR ≥ 50 mL/min/1.73 m2 and ≤ 25 mg/day if eGFR 30-49 mL/min/1.73 m2 . Patients remained within these dose ranges during the trial (as per stratification). The primary outcome was a composite of heart failure hospitalization or cardiovascular mortality. Eplerenone was superior to placebo within each respective eGFR stratum [eplerenone vs. placebo in the eGFR ≥ 50 mL/min/1.73 m2 stratum: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.45-0.74; and eplerenone vs. placebo in the eGFR 30-49 mL/min/1.73 m2 stratum: HR 0.62, 95% CI 0.49-0.78; Pinteraction  = 0.89]. Despite receiving lower eplerenone doses, patients in the eGFR 30-49 mL/min/1.73 m2 stratum more often had hyperkalaemia, renal failure events, and drug discontinuation. CONCLUSION: In EMPHASIS-HF the eplerenone dose was stratified according to renal function and the treatment effect was not influenced by renal function: 25 mg/day in patients with eGFR 30-49 mL/min/1.73 m2 was as effective as 50 mg/day in patients with eGFR > =50 mL/min/1.73 m2 . However, patients with impaired renal function experienced more adverse events, despite reveiving lower eplerenone doses. Current guidelines do not recommend tailoring the dose of eplereone according to renal function but the current data suggest they should

GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels

The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn’s disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [−0.198 (−0.332, −0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability

Genome-Wide ENU Mutagenesis in Combination with High Density SNP Analysis and Exome Sequencing Provides Rapid Identification of Novel Mouse Models of Developmental Disease

BACKGROUND Mice harbouring gene mutations that cause phenotypic abnormalities during organogenesis are invaluable tools for linking gene function to normal development and human disorders. To generate mouse models harbouring novel alleles that are involved in organogenesis we conducted a phenotype-driven, genome-wide mutagenesis screen in mice using the mutagen N-ethyl-N-nitrosourea (ENU). METHODOLOGY/PRINCIPAL FINDINGS ENU was injected into male C57BL/6 mice and the mutations transmitted through the germ-line. ENU-induced mutations were bred to homozygosity and G3 embryos screened at embryonic day (E) 13.5 and E18.5 for abnormalities in limb and craniofacial structures, skin, blood, vasculature, lungs, gut, kidneys, ureters and gonads. From 52 pedigrees screened 15 were detected with anomalies in one or more of the structures/organs screened. Using single nucleotide polymorphism (SNP)-based linkage analysis in conjunction with candidate gene or next-generation sequencing (NGS) we identified novel recessive alleles for Fras1, Ift140 and Lig1. CONCLUSIONS/SIGNIFICANCE In this study we have generated mouse models in which the anomalies closely mimic those seen in human disorders. The association between novel mutant alleles and phenotypes will lead to a better understanding of gene function in normal development and establish how their dysfunction causes human anomalies and disease.This work was enabled by the Australian Phenomics Network and partly supported by funding from the Australian Government’s National Collaborative Research Infrastructure Strategy, a Strategic Grant from the Faculty of Medicine, Nursing and Health Sciences at Monash University, and the Victorian Government’s Operational Infrastructure Support Program. IS acknowledges support through the NH&MRC R. Douglas Wright and ARC Future Fellowship schemes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating alpha-Klotho levels

The protein alpha-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, alpha-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating alpha-Klotho levels. Plasma alpha-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating alpha-Klotho levels at genome-wide significance (P 9% of the variation in circulating alpha-Klotho levels. MR analyses revealed no causal relationships between alpha-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on alpha-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on alpha-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on alpha-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: alpha-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-alpha-Klotho pathway. However, the role of the circulating form of alpha-Klotho, which is generated by cleavage of transmembrane alpha-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating alpha-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating alpha-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on alpha-Klotho levels, presumably by affecting protein turnover and stability