Double Normalizing Flows: Flexible Bayesian Gaussian Process ODEs Learning

Recently, Gaussian processes have been utilized to model the vector field of continuous dynamical systems. Bayesian inference for such models \cite{hegde2022variational} has been extensively studied and has been applied in tasks such as time series prediction, providing uncertain estimates. However, previous Gaussian Process Ordinary Differential Equation (ODE) models may underperform on datasets with non-Gaussian process priors, as their constrained priors and mean-field posteriors may lack flexibility. To address this limitation, we incorporate normalizing flows to reparameterize the vector field of ODEs, resulting in a more flexible and expressive prior distribution. Additionally, due to the analytically tractable probability density functions of normalizing flows, we apply them to the posterior inference of GP ODEs, generating a non-Gaussian posterior. Through these dual applications of normalizing flows, our model improves accuracy and uncertainty estimates for Bayesian Gaussian Process ODEs. The effectiveness of our approach is demonstrated on simulated dynamical systems and real-world human motion data, including tasks such as time series prediction and missing data recovery. Experimental results indicate that our proposed method effectively captures model uncertainty while improving accuracy

Heterologous expression and characterization of a malathion-hydrolyzing carboxylesterase from a thermophilic bacterium, Alicyclobacillus tengchongensis

A carboxylesterase gene from thermophilic bacterium, Alicyclobacillus tengchongensis, was cloned and expressed in Escherichia coli BL21 (DE3). The gene coded for a 513 amino acid protein with a calculated molecular mass of 57.82 kDa. The deduced amino acid sequence had structural features highly conserved among serine hydrolases, including Ser204, Glu325, and His415 as a catalytic triad, as well as type-B carboxylesterase serine active site (FGGDPENITIGGQSAG) and type-B carboxylesterase signature 2 (EDCLYLNIWTP). The purified enzyme exhibited optimum activity with β-naphthyl acetate at 60 °C and pH 7 as well as stability at 25 °C and pH 7. One unit of the enzyme hydrolyzed 5 mg malathion l(−1) by 50 % within 25 min and 89 % within 100 min. The enzyme strongly degraded malathion and has a potential use for the detoxification of malathion residues

Dual drug delivery from hydrophobic and hydrophilic intraocular lenses: in-vitro and in-vivo studies

Posterior capsule opacification (PCO) still remains the most frequent long term complication after cataract surgery, while endophthalmitis is rare but severe and should be prevented at all cost. Intraocular lenses (IOLs) with different designs (eg. edge and body-haptics angle) and materials (acrylic hydrophobic and acrylic hydrophilic surfaces) have been studied to reduce PCO. For the prevention of endophthalmitis, intracameral injection followed or not by topical treatment with antibiotics and anti-inflammatories are usually prescribed. The objective of this work was to investigate the use of IOLs as controlled release platforms of two drugs, the antibiotic moxifloxacin (MXF) and the anti-inflammatory ketorolac (KTL) that could advantageously substitute the usual treatment. Two types of IOLs were chosen, hydrophobic and hydrophilic. Hydrophobic IOLs have shown better results in the prevention of PCO because they adhere better to the posterior capsular bag, while hydrophilic IOLs are advised in the case of patients with uveitis, glaucoma or diabetes. The IOLs were loaded with MXF + KTL and sterilized by high hydrostatic pressure. Both IOLs reduced the tendency for adhesion of LECs. In vivo tests were done to compare the concentration of the drugs in the aqueous humor obtained after eye drops administration and drug-loaded IOLs implantation. The developed IOLs were able to release MXF and KTL at therapeutic levels, in a sustained way, which contrasts with the eye drops prophylaxis. No PCO signs were detected and histological analyses demonstrated biocompatibility of these devices.publishe

Biochemical characterization of an acetylesterase from Bacillus subtilis and its application for 7-aminocephalosporanic acid deacetylation

Deacetyl-7-aminocephalosporanic acid (D-7-ACA), which could be converted from 7-aminocephalosporanic acid (7-ACA), is a crucial starting material that is used for synthesizing industrial semisynthetic β-lactam antibiotics. Enzymes involved in the conversion from 7-ACA to D-7-ACA present critical resources in the pharmaceutical industry. In the present study, a putative acetylesterase, EstSJ, identified from Bacillus subtilis KATMIRA1933, was first heterologously expressed in Escherichia coli BL21(DE3) cells and biochemically characterized. EstSJ belongs to carbohydrate esterase family 12 and is active on short-chain acyl esters from p-NPC2 to p-NPC6. Multiple sequence alignments showed that EstSJ was also an SGNH family esterase with a typical GDS(X) motif at its N-terminal end and a catalytic triad composed of Ser186-Asp354-His357. The purified EstSJ displayed the highest specific activity of 1,783.52 U mg–1 at 30°C and pH 8.0, and was stable within the pH range of 5.0–11.0. EstSJ can deacetylate the C3′ acetyl group of 7-ACA to generate D-7-ACA, and the deacetylation activity was 4.50 U mg–1. Based on the structural and molecular docking with 7-ACA, the catalytic active sites (Ser186-Asp354-His357) together with four substrate-binding residues (Asn259, Arg295, Thr355, and Leu356) of EstSJ are revealed. This study provided a promising 7-ACA deacetylase candidate that could be applied to produce D-7-ACA from 7-ACA in the pharmaceutical industry

Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics

Background: Lipids have critical functions in cellular energy storage, structure and signaling. Many individual lipid molecules have been associated with the evolution of prostate cancer; however, none of them has been approved to be used as a biomarker. The aim of this study is to identify lipid molecules from hundreds plasma apparent lipid species as biomarkers for diagnosis of prostate cancer. Methodology/Principal Findings: Using lipidomics, lipid profiling of 390 individual apparent lipid species was performed on 141 plasma samples from 105 patients with prostate cancer and 36 male controls. High throughput data generated from lipidomics were analyzed using bioinformatic and statistical methods. From 390 apparent lipid species, 35 species were demonstrated to have potential in differentiation of prostate cancer. Within the 35 species, 12 were identified as individual plasma lipid biomarkers for diagnosis of prostate cancer with a sensitivity above 80%, specificity above 50% and accuracy above 80%. Using top 15 of 35 potential biomarkers together increased predictive power dramatically in diagnosis of prostate cancer with a sensitivity of 93.6%, specificity of 90.1% and accuracy of 97.3%. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) demonstrated that patient and control populations were visually separated by identified lipid biomarkers. RandomForest and 10-fold cross validation analyses demonstrated that the identified lipid biomarkers were able to predict unknown populations accurately, and this was not influenced by patient's age and race. Three out of 13 lipid classes, phosphatidylethanolamine (PE), ether-linked phosphatidylethanolamine (ePE) and ether-linked phosphatidylcholine (ePC) could be considered as biomarkers in diagnosis of prostate cancer. Conclusions/Significance: Using lipidomics and bioinformatic and statistical methods, we have identified a few out of hundreds plasma apparent lipid molecular species as biomarkers for diagnosis of prostate cancer with a high sensitivity, specificity and accuracy

Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs

Silencing specificity is a critical issue in the therapeutic applications of siRNA, particularly in the treatment of single nucleotide polymorphism (SNP) diseases where discrimination against single nucleotide variation is demanded. However, no generally applicable guidelines are available for the design of such allele-specific siRNAs. In this paper, the issue was approached by using a reporter-based assay. With a panel of 20 siRNAs and 240 variously mismatched target reporters, we first demonstrated that the mismatches were discriminated in a position-dependent order, which was however independent of their sequence contexts using position 4th, 12th and 17th as examples. A general model was further built for mismatch discrimination at all positions using 230 additional reporter constructs specifically designed to contain mismatches distributed evenly along the target regions of different siRNAs. This model was successfully employed to design allele-specific siRNAs targeting disease-causing mutations of PIK3CA gene at two SNP sites. Furthermore, conformational distortion of siRNA-target duplex was observed to correlate with the compromise of gene silencing. In summary, these findings could dramatically simplify the design of allele-specific siRNAs and might also provide guide to increase the specificity of therapeutic siRNAs

The synthesis of alumina membrane with interconnected uniform pores from inactive spheres

In this work, the interlayer and top-layer of alumina membrane are synthesized on substrate by one-step sintering process, and the microstructure evolution and mass transfer characterization of top-layer synthesized from sub-micrometer spheres is fully investigated. It shows that the pores in top-layer of membrane are interconnected and uniform and their microstructure evolution can be controlled by adjusting the sintering temperature in a wide range. Kinetics analysis of the sintering behavior shows that the superior thermostability of spheres can eliminate the rapid uneven shrinkage of membrane and result in the uniform microstructures. In addition, it is found that the mass transfer among spheres with polycrystalline phases of and cannot occur unless these metastable phases transform to stable -Al2O3, which is favorable to sinter at the same temperature range with the interlayer. Moreover, the effect of phase composition on mass transfer is further put forward. Finally, solid/water mixture has been processed by the synthesized membrane and the excellent filter performance confirms the uniform pores.</p