Chemo-enzymatic hybrid process for production of monatin, a high intensity sweetener

Monatin, 4-hydroxy-4-(3-indolylmethyl)-glutamic acid, is a naturally occurring sweet amino acid isolated from the plant Sclerochiton ilicifolius, found in South Africa [1]. Monatin has two asymmetric centers at C2 and C4, the (2R,4R)-monatin isomer has been found to be the sweetest among its four stereoisomers. It is 2700 times sweeter than sugar and has a clean taste like sugar. Because of these properties, (2R,4R)-monatin has been expected as an new high-intensity sweetener [2]. However, industrial production process of (2R,4R)-monatin using inexpensive raw materials has not been established owing to the difficulty for optically specific synthesis. Here, we report a chemo-enzymatic hybrid process for production of (2R,4R)-monatin from l-tryptophan. In the steps of enzymatic reaction from l-tryptophan, l-amino acid deaminase and aldolase were used for production of 4-(Indole-3-ylmethyl)-4-hydroxy-2-oxoglutaric acid (IHOG) with pyruvic acid as co-substrate. The keto-form of (2R,4R)-monatin, (R)-IHOG, was specifically synthesized by using R-specific aldolase from Shingomonas sp. in the second reaction. In the next chemical reaction steps, (R)-IHOG was converted to the oxime form, reduced to (2R,4R) and (2S,4R)-monatin, and (2R,4R)-monatin salt was obtained from optical resolution by crystallization. By the combination of epimerization and crystallization, (2R,4R)-monatin was obtained specifically from the mixture of diastereomers. In this study, we established an efficient production process for (2R,4R)-monatin using both chemical and enzymatic reactions, and a large amount of (2R,4R)-monatin was prepared by the bench-scale production. Please click Additional Files below to see the full abstract

Token Economy–Based Hospital Bed Allocation to Mitigate Information Asymmetry: Proof-of-Concept Study Through Simulation Implementation

[Background:] Hospital bed management is an important resource allocation task in hospital management, but currently, it is a challenging task. However, acquiring an optimal solution is also difficult because intraorganizational information asymmetry exists. Signaling, as defined in the fields of economics, can be used to mitigate this problem. [Objective:] We aimed to develop an assignment process that is based on a token economy as signaling intermediary. [Methods:] We implemented a game-like simulation, representing token economy–based bed assignments, in which 3 players act as ward managers of 3 inpatient wards (1 each). As a preliminary evaluation, we recruited 9 nurse managers to play and then participate in a survey about qualitative perceptions for current and proposed methods (7-point Likert scale). We also asked them about preferred rewards for collected tokens. In addition, we quantitatively recorded participant pricing behavior. [Results:] Participants scored the token economy–method positively in staff satisfaction (3.89 points vs 2.67 points) and patient safety (4.38 points vs 3.50 points) compared to the current method, but they scored the proposed method negatively for managerial rivalry, staff employee development, and benefit for patients. The majority of participants (7 out of 9) listed human resources as the preferred reward for tokens. There were slight associations between workload information and pricing. [Conclusions:] Survey results indicate that the proposed method can improve staff satisfaction and patient safety by increasing the decision-making autonomy of staff but may also increase managerial rivalry, as expected from existing criticism for decentralized decision-making. Participant behavior indicated that token-based pricing can act as a signaling intermediary. Given responses related to rewards, a token system that is designed to incorporate human resource allocation is a promising method. Based on aforementioned discussion, we concluded that a token economy–based bed allocation system has the potential to be an optimal method by mitigating information asymmetry

Bezier Simplex Fitting: Describing Pareto Fronts of Simplicial Problems with Small Samples in Multi-objective Optimization

Multi-objective optimization problems require simultaneously optimizing two or more objective functions. Many studies have reported that the solution set of an M-objective optimization problem often forms an (M-1)-dimensional topological simplex (a curved line for M=2, a curved triangle for M=3, a curved tetrahedron for M=4, etc.). Since the dimensionality of the solution set increases as the number of objectives grows, an exponentially large sample size is needed to cover the solution set. To reduce the required sample size, this paper proposes a Bezier simplex model and its fitting algorithm. These techniques can exploit the simplex structure of the solution set and decompose a high-dimensional surface fitting task into a sequence of low-dimensional ones. An approximation theorem of Bezier simplices is proven. Numerical experiments with synthetic and real-world optimization problems demonstrate that the proposed method achieves an accurate approximation of high-dimensional solution sets with small samples. In practice, such an approximation will be conducted in the post-optimization process and enable a better trade-off analysis.Comment: To appear in AAAI 201

Optimizing Charge Switching in Membrane Lytic Peptides for Endosomal Release of Biomacromolecules.

Endocytic pathways are practical routes for the intracellular delivery of biomacromolecules. Along with this, effective strategies for endosomal cargo release into the cytosol are desired to achieve successful delivery. Focusing on compositional differences between the cell and endosomal membranes and the pH decrease within endosomes, we designed the lipid-sensitive and pH-responsive endosome-lytic peptide HAad. This peptide contains aminoadipic acid (Aad) residues, which serve as a safety catch for preferential permeabilization of endosomal membranes over cell membranes, and His-to-Ala substitutions enhance the endosomolytic activity. The ability of HAad to destabilize endosomal membranes was supported by model studies using large unilamellar vesicles (LUVs) and by increased intracellular delivery of biomacromolecules (including antibodies) into live cells. Cerebral ventricle injection of Cre recombinase with HAad led to Cre/loxP recombination in a mouse model, thus demonstrating potential applicability of HAad in vivo

Pembrolizumab-induced hypothyroidism caused reversible increased serum creatinine levels: a case report

Background The advent of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced malignancies. On the other hand, these drugs might cause immune-related adverse events (irAEs) including endocrinopathies and nephropathies. Thyroid dysfunction is one of the most common irAEs. For ICIs-induced nephropathies, most cases are due to tubulointerstitial nephritis, which might require steroid treatment. Here, we report a patient with non-small cell lung cancer treated with ICI who developed increased serum creatinine (s-Cr) levels due to ICIs-induced hypothyroidism. Case presentation A 57-year-old Asian man with refractory non-small cell lung cancer under ICIs therapy (pembrolizumab, an anti-programmed cell death-1 monoclonal antibody) developed increased s-Cr levels 5 months after the pembrolizumab initiation. His laboratory data, renal biopsy, and Gallium-67 scintigraphy findings denied pembrolizumab-induced tubulointerstitial nephritis. His renal function was correlated with thyroid function. Despite the increase of s-Cr levels, serum cystatin C levels were normal, which could be explained by the hypothyroidism. Levothyroxine treatment improved renal function as well as thyroid function. Then pembrolizumab was resumed, and both his thyroid and renal function remained normal level. Ultimately, we concluded that the increased s-Cr levels were caused by pembrolizumab-induced hypothyroidism. Conclusion All clinicians involved in ICI treatment need to recognize the possible increase in s-Cr levels caused by ICIs-induced hypothyroidism, and we propose monitoring serum cystatin C levels to differentiate ICIs-induced hypothyroidism from tubulointerstitial nephritis before invasive renal biopsies or steroid treatment, which are recommended by the prescribing information for pembrolizumab, are performed

CFD study of Jet Impingement Test erosion using Ansys Fluent® and OpenFOAM®

The initial aim of this study was to compare OpenFoam and Ansys Fluent in order to verify OpenFoam’s Lagrangian Library and erosion capabilities. However, it was found that previous versions of Fluent have been providing wrong results for the discrete phase and the differences with the latest version (Ansys Fluent 15) are shown. A Submerged Jet Impingement Test is an effective method for studying erosion created by solid particles entrained in a liquid. When considering low particle concentrations a Lagrangian modeling of the particulate phase is a reasonable approach. Proper linkage between OpenFOAM’s Lagrangian library and the solver pimpleFoam for incompressible transient flows allows two-phase simulations to be undertaken for comparison with Ansys Fluent with the aim of verifying OpenFoam’s accuracy. Steady state convergence for the fluid flow is first accomplished and the results are compared, confirming a good agreement between the two packages. A transient simulation was then set up and spherical particles incorporated into the fluid flow. An assessment of the two codes’ discrete phase models was carried out, focusing on the differences between impact angles and velocities yielded at the impingement plate’s surface employing a similar strategy to that outlined first by Hattori et al. (2008) and later by Gnanavelu et al. (2009, 2011). In the comparison of OpenFoam with the latest version of Fluent, the main differences between the injection models are highlighted and the coupling possibilities between phases are taken into consideration. Agreement between trends for both impact angles and velocities is satisfactory when the last version of the commercial package is considered and the average discrepancy between numerical values is very low, verifying OpenFoam’s Lagrangian library. Two different Jet Impingement Test configurations are also compared and the differences highlighted

The association between hypothyroidism and proteinuria in patients with chronic kidney disease: a cross-sectional study

Hypothyroidism is known to be correlated with kidney function and nephrotic range proteinuria. However, it is uncertain whether non-nephrotic proteinuria is associated with hypothyroidism. This study aimed to evaluate the association of proteinuria and hypothyroidism in chronic kidney disease (CKD) patients. We conducted a cross-sectional study composed of 421 CKD patients in a single hospital with measurements of 24-h urine protein excretion (UP) and thyroid function tests. Spearman correlation analysis revealed that 24-h Cr clearance (24hrCcr) was positively (r = 0.273, p < 0.001) and UP was negatively (r = - 0.207, p < 0.001) correlated with free triiodothyronine. Frequency distribution analysis stratified by CKD stage and UP for hypothyroidism revealed that the prevalence of hypothyroidism was higher among participants with higher CKD stage and nephrotic range proteinuria. Multivariate logistic regression analysis revealed that 24hrCcr and UP were significantly correlated with hypothyroidism (24hrCcr/10 mL/min decrease: odds ratio [OR], 1.29; 95% confidence interval [CI], 1.18-1.41; UP/1 g increase: OR, 1.10; 95% CI, 1.03-1.17). In addition, nephrotic range proteinuria, but not moderate UP (UP: 1.5-3.49 g/day), was significantly correlated with hypothyroidism compared to UP < 0.5 g/day. In summary, decreased kidney function and nephrotic range proteinuria, not non-nephrotic proteinuria, are independently associated with the hypothyroidism