Stability of Breakwater Armor Units against Tsunami Attacks

The design of breakwater armour units against tsunami attacks has received little attention in the past because of the comparative low frequency of these events and the rarity of structures designed specifically to withstand them. However, field surveys of recent events, such as the 2011 Great Eastern Japan Earthquake Tsunami and the 2004 Indian Ocean Tsunami, have shown flaws in the design of protection structures. During these extreme events, many breakwaters suffered partial or catastrophic damage. Although it is to be expected that most normal structures fail due to such high order events, practicing engineers need to possess tools to design certain important breakwaters that should not fail even during level 2 events. Research into the design of critical structures that only partially fail (i.e., “resilient” or “tenacious” structures) during a very extreme level 2 tsunami event should be prioritized in the future, and in this sense the present paper proposes a formula that allows the estimation of armour unit damage depending on the tsunami wave height

Biochemical evidence for the tyrosine involvement in cationic intermediate stabilization in mouse β-carotene 15, 15'-monooxygenase

<p>Abstract</p> <p>Background</p> <p>β-carotene 15,15'-monooxygenase (BCMO1) catalyzes the crucial first step in vitamin A biosynthesis in animals. We wished to explore the possibility that a carbocation intermediate is formed during the cleavage reaction of BCMO1, as is seen for many isoprenoid biosynthesis enzymes, and to determine which residues in the substrate binding cleft are necessary for catalytic and substrate binding activity. To test this hypothesis, we replaced substrate cleft aromatic and acidic residues by site-directed mutagenesis. Enzymatic activity was measured <it>in vitro </it>using His-tag purified proteins and <it>in vivo </it>in a β-carotene-accumulating <it>E. coli </it>system.</p> <p>Results</p> <p>Our assays show that mutation of either Y235 or Y326 to leucine (no cation-π stabilization) significantly impairs the catalytic activity of the enzyme. Moreover, mutation of Y326 to glutamine (predicted to destabilize a putative carbocation) almost eliminates activity (9.3% of wt activity). However, replacement of these same tyrosines with phenylalanine or tryptophan does not significantly impair activity, indicating that aromaticity at these residues is crucial. Mutations of two other aromatic residues in the binding cleft of BCMO1, F51 and W454, to either another aromatic residue or to leucine do not influence the catalytic activity of the enzyme. Our <it>ab initio </it>model of BCMO1 with β-carotene mounted supports a mechanism involving cation-π stabilization by Y235 and Y326.</p> <p>Conclusions</p> <p>Our data are consistent with the formation of a substrate carbocation intermediate and cation-π stabilization of this intermediate by two aromatic residues in the substrate-binding cleft of BCMO1.</p

Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection.

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to Mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following Mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to Mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies

Supplementary Material for: Optimal use of serum leucine-rich alpha-2 glycoprotein as a biomarker for small bowel lesions of Crohn's disease

Introduction A large proportion of small bowel lesions in Crohn’s disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a Crohn’s disease activity index > 150 and active colonic lesions were excluded. Results A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP < 3 mg/l (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81), and 0.74 (0.54-0.84), respectively. The cut-off of 16 μg/ml of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00 while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 μg/ml. Discussion/Conclusion LRG can accurately detect and/or exclude the small bowel lesions by two cut-off values

Supplementary Material for: Optimal use of serum leucine-rich alpha-2 glycoprotein as a biomarker for small bowel lesions of Crohn's disease

Introduction A large proportion of small bowel lesions in Crohn’s disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a Crohn’s disease activity index > 150 and active colonic lesions were excluded. Results A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP < 3 mg/l (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81), and 0.74 (0.54-0.84), respectively. The cut-off of 16 μg/ml of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00 while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 μg/ml. Discussion/Conclusion LRG can accurately detect and/or exclude the small bowel lesions by two cut-off values

Supplementary Material for: Optimal use of serum leucine-rich alpha-2 glycoprotein as a biomarker for small bowel lesions of Crohn's disease

Introduction A large proportion of small bowel lesions in Crohn’s disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a Crohn’s disease activity index > 150 and active colonic lesions were excluded. Results A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP < 3 mg/l (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81), and 0.74 (0.54-0.84), respectively. The cut-off of 16 μg/ml of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00 while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 μg/ml. Discussion/Conclusion LRG can accurately detect and/or exclude the small bowel lesions by two cut-off values

Supplementary Material for: Optimal use of serum leucine-rich alpha-2 glycoprotein as a biomarker for small bowel lesions of Crohn's disease

Introduction A large proportion of small bowel lesions in Crohn’s disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a Crohn’s disease activity index > 150 and active colonic lesions were excluded. Results A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP < 3 mg/l (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81), and 0.74 (0.54-0.84), respectively. The cut-off of 16 μg/ml of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00 while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 μg/ml. Discussion/Conclusion LRG can accurately detect and/or exclude the small bowel lesions by two cut-off values

Supplementary Material for: Optimal use of serum leucine-rich alpha-2 glycoprotein as a biomarker for small bowel lesions of Crohn's disease

Introduction A large proportion of small bowel lesions in Crohn’s disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a Crohn’s disease activity index > 150 and active colonic lesions were excluded. Results A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP < 3 mg/l (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81), and 0.74 (0.54-0.84), respectively. The cut-off of 16 μg/ml of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00 while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 μg/ml. Discussion/Conclusion LRG can accurately detect and/or exclude the small bowel lesions by two cut-off values

Attractive noncovalent interactions in asymmetric catalysis: Links between enzymes and small molecule catalysts

Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions—particularly H-bonding—has emerged as an important approach in organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms responsible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts