Observer-based offset-free internal model control

A linear feedback control structure is proposed that allows internal model control design principles to be applied to unstable and marginally stable plants. The control structure comprises an observer using an augmented plant model, state estimate feedback and disturbance estimate feedback. Conditions are given for both nominal internal stability and offset-free action even in the case of plant-model mismatch. The Youla parameterization is recovered as a limiting case with reduced order observers. The simple design methodology is illustrated for a marginally stable plant with delay

Critical Role of FLRT1 Phosphorylation in the Interdependent Regulation of FLRT1 Function and FGF Receptor Signalling

Background Fibronectin leucine rich transmembrane (FLRT) proteins have dual properties as regulators of cell adhesion and potentiators of fibroblast growth factor (FGF) mediated signalling. The mechanism by which the latter is achieved is still unknown and is the subject of this investigation. Principal Findings Here we show that FLRT1 is a target for tyrosine phosphorylation mediated by FGFR1 and implicate a non-receptor Src family kinase (SFK). We identify the target tyrosine residues in the cytoplasmic domain of FLRT1 and show that these are not direct substrates for Src kinase suggesting that the SFK may exert effects via potentiation of FGFR1 kinase activity. We show that whilst FLRT1 expression results in a ligand-dependent elevation of MAP kinase activity, a mutant version of FLRT1, defective as an FGFR1 kinase substrate (Y3F-FLRT1), has the property of eliciting ligand-independent chronic activation of the MAP kinase pathway which is suppressed by pharmacological inhibition of either FGFR1 or Src kinase. Functional investigation of FGFR1 and FLRT1 signalling in SH-SY5Y neuroblastoma cells reveals that FLRT1 alone acts to induce a multi-polar phenotype whereas the combination of FLRT1 and FGFR activation, or expression of Y3F-FLRT1, acts to induce neurite outgrowth via MAPK activation. Similar results were obtained in a dendrite outgrowth assay in primary hippocampal neurons. We also show that FGFR1, FLRT1 and activated Src are co-localized and this complex is trafficked toward the soma of the cell. The presence of Y3F-FLRT1 rather than FLRT1 resulted in prolonged localization of this complex within the neuritic arbour. Conclusions This study shows that the phosphorylation state of FLRT1, which is itself FGFR1 dependent, may play a critical role in the potentiation of FGFR1 signalling and may also depend on a SFK-dependent phosphorylation mechanism acting via the FGFR. This is consistent with an ‘in vivo’ role for FLRT1 regulation of FGF signalling via SFKs. Furthermore, the phosphorylation-dependent futile cycle mechanism controlling FGFR1 signalling is concurrently crucial for regulation of FLRT1-mediated neurite outgrowth

Fatalities due to intestinal obstruction following the ingestion of foreign bodies

Two fatalities due to an occlusive ileus following the ingestion of foreign bodies in patients with psychiatric disorders are described. A severely mentally handicapped young man developed a temperature and died 1 h after admission to a surgical ward. At autopsy, not, vert, similar 2000 cm3 of foreign material, including broken glass and porcelain, branches, buttons, parts of clothing and other material were found in the gastrointestinal tract, leading to a complete obstruction of the distal intestine and colon with resulting faecal vomiting. The other case was even more unusual as a hair fetishist had swallowed a thick strand of his own hair, 50 cm long, also resulting in mechanical obstruction of the distal intestine

Tunable dipolar magnetism in high-spin molecular clusters

We report on the Fe17 high-spin molecular cluster and show that this system is an exemplification of nanostructured dipolar magnetism. Each Fe17 molecule, with spin S=35/2 and axial anisotropy as small as D=-0.02K, is the magnetic unit that can be chemically arranged in different packing crystals whilst preserving both spin ground-state and anisotropy. For every configuration, molecular spins are correlated only by dipolar interactions. The ensuing interplay between dipolar energy and anisotropy gives rise to macroscopic behaviors ranging from superparamagnetism to long-range magnetic order at temperatures below 1K.Comment: Replaced with version accepted for publication in Physical Review Letter

Phenotypic integration of behavioural and physiological traits is related to variation in growth among stocks of Chinook salmon

The selection for a single organismal trait like growth in breeding programs of farmed aquaculture species can counterintuitively lead to lowered harvestable biomass. We outbred a domesticated aquaculture stock of Chinook salmon (Oncorhynchus tshawytscha (Walbaum in Artedi, 1792)) with seven wild stocks from British Columbia, Canada. We then examined how functionally related traits underlying energy management – diel variation in cortisol and foraging, social, and movement behaviours — predicted stock-level variation in growth during the freshwater life history stage, which is a performance metric under aquaculture selection. Outbreeding generated significant variation in diel cortisol secretion and behaviours across stocks, and these traits co-varied, suggesting tight integration despite hybridization. The coupling of nighttime cortisol exposure with the daytime behavioural phenotype was the strongest predictor of stock-level variation in body mass. Our results suggest that selection for an integrated phenotype rather than on a single mechanistic trait alone can generate the greatest effect on aquaculture fish growth under outbreeding practices. Furthermore, selecting for these traits at the stock level may increase efficiency of farming methods designed to consistently maximize fish performance on a large scale

Phenotypic integration of behavioural and physiological traits is related to variation in growth among stocks of Chinook salmon

The selection for a single organismal trait like growth in breeding programs of farmed aquaculture species can counter-intuitively lead to lowered harvestable biomass. We outbred a domesticated aquaculture stock of Chinook salmon (Oncorhynchus tshawytscha) with 7 wild stocks from British Columbia, Canada. We then examined how functionally related traits underlying energy management - diel variation in cortisol; foraging, social, and movement behaviours - predicted stock-level variation in growth during the freshwater life history stage, a performance metric under aquaculture selection. Outbreeding generated significant variation in diel cortisol secretion and behaviours across stocks, and these traits covaried, suggesting tight integration despite hybridization. The coupling of nighttime cortisol exposure with daytime behavioural phenotype was the strongest predictor of stock-level variation in body mass. Our results suggest selecting for an integrated phenotype rather than on single mechanistic traits alone can generate the greatest effect on aquaculture fish growth under outbreeding practices. Furthermore, selecting for these traits at the stock level may increase efficiency of farming methods designed to consistently maximize fish performance on a large scale

Practical Spectrophotometric Assay for the \u3cem\u3edapE\u3c/em\u3e-Encoded \u3cem\u3eN\u3c/em\u3e-Succinyl-L,L-Diaminopimelic Acid Desuccinylase, a Potential Antibiotic Target

A new enzymatic assay for the bacterial enzyme succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) is described. This assay employs N6-methyl-N2-succinyl-L,L-diaminopimelic acid (N6-methyl-L,L-SDAP) as the substrate with ninhydrin used to detect cleavage of the amide bond of the modified substrate, wherein N6-methylation enables selective detection of the primary amine enzymatic product. Molecular modeling supported preparation of the mono-N6-methylated-L,L-SDAP as an alternate substrate for the assay, given binding in the active site of DapE predicted to be comparable to the endogenous substrate. The alternate substrate for the assay, N6-methyl-L,L-SDAP, was synthesized from the tert-butyl ester of Boc-L-glutamic acid employing a Horner-Wadsworth-Emmons olefination followed by an enantioselective reduction employing Rh(I)(COD)(S,S)-Et-DuPHOS as the chiral catalyst. Validation of the new ninhydrin assay was demonstrated with known inhibitors of DapE from Haemophilus influenza (HiDapE) including captopril (IC50 = 3.4 [± 0.2] μM, 3-mercaptobenzoic acid (IC50 = 21.8 [±2.2] μM, phenylboronic acid (IC50 = 316 [± 23.6] μM, and 2-thiopheneboronic acid (IC50 = 111 [± 16] μM. Based on these data, this assay is simple and robust, and should be amenable to high-throughput screening, which is an important step forward as it opens the door to medicinal chemistry efforts toward the discovery of DapE inhibitors that can function as a new class of antibiotics