The mechanics of Arabidopsis seed germination

Germination is defined as the protrusion of the embryonic radicle through the seed coat layers (endosperm and testa). As the radicle elongates, the testa ruptures, followed by rupture of the endosperm. Arabidopsis seeds exhibit a two-step germination process with sequential rupture of the testa and endosperm. We are interested in exploring the physical process of germination. Whilst much effort has previously been placed on genetic networks, a mathematical approach for furthering the understanding of the physical/mechanical properties of germination has not yet been described. The Mathematics in Plant Sciences Study Group helped us to develop a better understanding of the problem. Several different mathematical models were generated for radicle growth and endosperm stretching. These models were developed on multiscale dimensions – looking at the organ, tissue and cellular levels. The outcomes of the study group have heightened our interest in the mechanical aspects of germination, and we are currently progressing with a grant proposal – a collaboration between the Schools of Biosciences and Engineering at the University of Nottingham, and a group from the Department of Biology at the University of Freiburg, Germany

Petition for a Writ of Certiorari. Opp v. Office of the State\u27s Attorney of Cook County, 565 U.S. 815 (2011) (No. 10-1163), 2011 U.S. LEXIS 6893

QUESTION PRESENTED Five major federal employment statutes, including in this case the Age Discrimination in Employment Act, exclude certain government workers at the policymaking level from the definition of employees protected by those laws. The question presented is: who is a worker on the policymaking level

Dynamic regulation of AtDAO1 and GH3 modulates auxin homeostasis

The hormone auxin is a key regulator of plant growth and development, and great progress has been made understanding auxin transport and signaling. Here we show that auxin metabolism and homeostasis are also regulated in a complex manner. The principal auxin degradation pathways in Arabidopsis include oxidation by AtDAO1/2 and conjugation by GH3s. Metabolic profiling of dao1-1 root tissues revealed a 50% decrease in the oxidation product oxIAA, an increase in the conjugated forms IAA-Asp and IAA-Glu of 438-fold and 240-fold respectively, while auxin remains close to wild type. By fitting parameter values to a mathematical model of these metabolic pathways we show that, in addition to reduced oxidation, both auxin biosynthesis and conjugation are increased in dao1-1. We then quantified gene expression in plantae, and found that transcripts of AtDAO1 and GH3 genes are increased in response to auxin, over different time scales and concentration ranges. Including this regulation of AtDAO1 and GH3 in an extended model reveals that auxin oxidation is more important for auxin homoeostasis at lower hormone concentrations, while auxin conjugation is most significant at high auxin levels. Finally, embedding our homeostasis model in a multicellular simulation to assess the spatial effect of the dao1-1 mutant shows that auxin increases in outer root tissues, in agreement with the dao1-1 mutant root hair phenotype. We conclude that auxin homeostasis is dependent on AtDAO1, acting in concert with GH3, to maintain auxin at optimal levels for plant growth and development

The auxin-regulated CrRLK1L kinase ERULUS controls cell wall composition during root hair tip growth

Root hairs facilitate a plant’s ability to acquire soil anchorage and nutrients. Root hair growth is regulated by the plant hormone auxin and dependent on localized synthesis, secretion and modification of the root hair tip cell wall. However, the exact well wall regulators in root hairs controlled by auxin have yet to be determined. In this study, we describe the characterization of ERULUS (ERU), an auxin-induced Arabidopsis receptor-like kinase whose expression is directly regulated by ARF7 and ARF19 transcription factors. ERU belongs to the Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE (CrRLK1L) subfamily of putative cell wall sensor proteins. Imaging of a fluorescent fusion protein revealed that ERU is localized to the apical root hair plasma membrane. ERU regulates cell wall composition in root hairs and modulates pectin dynamics through negative control of pectin methylesterase (PME) activity. Mutant eru (-/-) root hairs accumulate de-esterified homogalacturonan and exhibit aberrant pectin Ca²⁺ binding site oscillations and increased PME activity. Up to 80% of the eru root hair phenotype is rescued by pharmacological supplementation with a PME inhibiting catechin extract. ERU transcription is altered in specific cell wall-related root hair mutants, suggesting it is a target for feedback regulation. Loss of ERU alters the phosphorylation status of FERONIA and H⁺-ATPases 1/2, regulators of apoplastic pH. Furthermore, H⁺-ATPases 1/2 and ERU are differentially phosphorylated in response to auxin. We conclude that ERULUS is a key auxin-controlled regulator of cell wall composition and pectin dynamics during root hair tip growth

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Characterisation of a novel mutation in the control of germination in Arabidopsis thaliana

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High-Throughput Quantification of Root Growth Using a Novel Image-Analysis Tool1[C][W]

Measuring the dynamics of plant growth is fundamental to the understanding of plant development processes. This paper describes a high-throughput, automatic method to trace Arabidopsis (Arabidopsis thaliana) seedling roots grown on agarose plates. From the trace, additional software can quantify length, curvature, and stimulus response parameters such as onset of gravitropism. The method combines a particle-filtering algorithm with a graph-based method to trace the center line of a root. This top-down approach is robust to a variety of noise effects and is reasonably flexible across different image sets. The resulting tool requires minimal interaction from the user and is able to process long time-lapse sequences with user interaction only required on the first frame. The tool is described first, followed by its use on two sample data sets, one measuring root length and the other additionally analyzing the gravitropic response and curvature. The tool, RootTrace, is open source; both the program and source code will be available online