Rule extraction in gene–disease relationship discovery

Background

Biomedical data available to researchers and clinicians have increased dramatically over the past years because of the exponential growth of knowledge in medical biology. It is difficult for curators to go through all of the unstructured documents so as to curate the information to the database. Associating genes with diseases is important because it is a fundamental challenge in human health with applications to understanding disease properties and developing new techniques for prevention, diagnosis and therapy.

Methods

Our study uses the automatic rule-learning approach to gene–disease relationship extraction. We first prepare the experimental corpus from MEDLINE and OMIM. A parser is applied to produce some grammatical information. We then learn all possible rules that discriminate relevant from irrelevant sentences. After that, we compute the scores of the learned rules in order to select rules of interest. As a result, a set of rules is generated.

Results

We produce the learned rules automatically from the 1000 positive and 1000 negative sentences. The test set includes 400 sentences composed of 200 positives and 200 negatives. Precision, recall and F-score served as our evaluation metrics. The results reveal that the maximal precision rate is 77.8% and the maximal recall rate is 63.5%. The maximal F-score is 66.9% where the precision rate is 70.6% and the recall rate is 63.5%.

Conclusions

We employ the rule-learning approach to extract gene–disease relationships. Our main contributions are to build rules automatically and to support a more complete set of rules than a manually generated one. The experiments show exhilarating results and some improving efforts will be made in the future.     

Laccase immobilization and insolubilization: from fundamentals to applications for the elimination of emerging contaminants in wastewater treatment

Over the last few decades many attempts have been made to use biocatalysts for the biotransformation of emerging contaminants in environmental matrices. Laccase, a multicopper oxidoreductase enzyme, has shown great potential in oxidizing a large number of phenolic and non-phenolic emerging contaminants. However, laccases and more broadly enzymes in their free form are biocatalysts whose applications in solution have many drawbacks rendering them currently unsuitable for large scale use. To circumvent these limitations, the enzyme can be immobilized onto carriers or entrapped within capsules; these two immobilization techniques have the disadvantage of generating a large mass of non-catalytic product. Insolubilization of the free enzymes as cross-linked enzymes (CLEAs) is found to yield a greater volume ratio of biocatalyst while improving the characteristics of the biocatalyst. Ultimately, novel techniques of enzymes insolubilization and stabilization are feasible with the combination of cross-linked enzyme aggregates (combi-CLEAs) and enzyme polymer engineered structures (EPESs) for the elimination of emerging micropollutants in wastewater. In this review, fundamental features of laccases are provided in order to elucidate their catalytic mechanism, followed by different chemical aspects of the immobilization and insolubilization techniques applicable to laccases. Finally, kinetic and reactor design effects for enzymes in relation with the potential applications of laccases as combi-CLEAs and EPESs for the biotransformation of micropollutants in wastewater treatment are discussed.     

濒危鱼类稀有白甲鱼沅江种群与西江种群形态度量学性状的差异性

分别以采自沅江水系142例和西江水系92例稀有白甲鱼标本为材料,采用差异系数法、方差分析法、判别分析法和主成分分析法,研究了稀有白甲鱼沅江种群、西江种群包括10个可数性状和31个比例性状等形态度量学性状的差异性.方差分析表明,2个种群之间共有6个可数性状和27个比例性状存在着显著性差异(P＜0.05).判别分析筛选出了9个对区分2个种群贡献较大的比例性状,并建立了2个种群的判别函数式.主成分分析显示,稀有白甲鱼种群鱼体沿背腹轴、头尾轴分别有16和6个比例性状表现出了明显的变化,在尾部有2个比例性状差异明显.可见2个种群之间形态度量学性状已显示了明显的分化.这可能是两个种群长期隔离,在不同水系生态环境中产生了适应性进化的结果.然而,差异系数的计算结果表明,两个种群之间形态度量学性状的差异尚未达到亚种分化的水平.     

A time for every season: soil aggregate turnover stimulates decomposition and reduces carbon loss in grasslands managed for bioenergy

A primary goal of many next‐generation bioenergy systems is to increase ecosystem services such as soil carbon (C) storage and nutrient retention. Evaluating whether bioenergy management systems are achieving these goals is challenging in part because these processes occur over long periods of time at varying spatial scales. Investigation of microbially mediated soil processes at the microbe scale may provide early insights into the mechanisms driving these long‐term ecosystem services. Furthermore, seasonal fluctuations in microbial activity are rarely considered when estimating whole ecosystem functioning, but are central to decomposition, soil structure, and realized C storage. Some studies have characterized extracellular enzyme activity within soil structures (aggregates); however, seasonal variation in decomposition at the microscale remains virtually unknown, particularly in managed ecosystems. As such, we hypothesize that temporal variation in aggregate turnover is a strong regulator of microbial activity, with important implications for decomposition and C and nitrogen (N) storage in bioenergy systems. We address variation in soil microbial extracellular enzyme activity spatially across soil aggregates and temporally across two growing seasons in three ecosystems managed for bioenergy feedstock production: Zea mays L. (corn) agroecosystem, fertilized and unfertilized reconstructed tallgrass prairie. We measured potential N‐acetyl‐glucosaminidase (NAG), β‐glucosidase (BG), β‐xylosidase (BX), and cellobiohydrolase (CB) enzyme activity. Aggregate turnover in prairie systems was driven by precipitation events and seasonal spikes in enzyme activity corresponded with aggregate turnover events. In corn monocultures, soil aggregates turned over early in the growing season, followed by increasing, albeit low, enzyme activity throughout the growing season. Independent of management system or sampling date, NAG activity was greatest in large macroaggregates (>2000 μm) and CB activity was greatest in microaggregates (<250 μm). High microbial activity coupled with greater aggregation in prairie bioenergy systems may reduce loss of soil organic matter through decomposition and increase soil C storage.     

Acid-induced aggregation propensity of nivolumab is dependent on the Fc

Nivolumab, an anti-programmed death (PD)1 IgG₄ antibody, has shown notable success as a cancer treatment. Here, we report that nivolumab was susceptible to aggregation during manufacturing, particularly in routine purification steps. Our experimental results showed that exposure to low pH caused aggregation of nivolumab, and the Fc was primarily responsible for an acid-induced unfolding phenomenon. To compare the intrinsic propensity of acid-induced aggregation for other IgGs subclasses, tocilizumab (IgG₁), panitumumab (IgG₂) and atezolizumab (aglyco-IgG₁) were also investigated. The accurate pH threshold of acid-induced aggregation for individual IgG Fc subclasses was identified and ranked as: IgG₁?1?2?4. This result was cross-validated by thermostability and conformation analysis. We also assessed the effect of several protein stabilizers on nivolumab, and found mannitol ameliorated the acid-induced aggregation of the molecule. Our results provide valuable insight into downstream manufacturing process development, especially for immune checkpoint modulating molecules with a human IgG₄ backbone.     

Fibrous Aggregates of Short Peptides Containing Two Distinct Aromatic Amino Acid Residues

The aim of the study was the assessment of the ability of short peptides to form aggregates under physiological conditions. The dipeptides studied were derived from different aromatic amino acids (heteroaromatic peptides). Tripeptides were obtained from two distinct aromatic amino acids and cysteine or methionine residue in the C‐terminal, N‐terminal, or central position. The ability of the peptides to form fibrous aggregates under physiological conditions was evaluated using three independent methods: the Congo Red assay, the Thioflavin T assay, and microscopic examinations using normal and polarized light. Materials potentially useful for regenerative medicine were selected based on their cytotoxicity to the endothelial cell line EA.hy 926 and physicochemical properties of films formed by peptides. The required parameters of biocompatibility were fulfilled by H?PheCysTrp?OH, H?PheCysTyr?OH, H?PheTyrMet?OH, and H?TrpTyr?OH.     

Modifying bio-catalytic properties of enzymes for efficient biocatalysis: a review from immobilization strategies viewpoint

Enzyme-based catalysis has become one of the most important disciplines in organic synthesis and plays a noteworthy role in the establishment of many chemical industries, e.g. fine chemicals, food or energy, textiles, agricultural, cosmeceutical, medicinal and pharmaceutical industries. However, pristine enzymes fail to demonstrate requisite functionalities for an industrial setting where extremely specific and stable catalysts are required. Immobilization enhances the catalytic stability and activity of enzymes and trims the overall cost burden of the enzyme. Therefore, it widely endeavours for proficient, sustainable, and environmentally responsive catalytic processes. Amongst several immobilization strategies, e.g. (1) supports-assisted, i.e. physical or covalent coupling and (2) supports-free techniques, i.e. cross-linked enzyme crystals (CLECs) or aggregates are the most promising ones and widely pursued for enzyme immobilization purposes. This perspective review focuses on up-to-date developments in the area of enzyme immobilization and presents their potentialities to upgrade and/or modify enzyme properties. Both types of immobilization strategies, i.e. supports-assisted and supports-free techniques are discussed with particular reference to CLECs or aggregates and protein-coated microcrystals. Also, several useful traits achieved after immobilization are also discussed in the second half of the review.     

Soil physical properties and carbon/nitrogen relationships in stable aggregates under legume and grass fallow

Short-season fallow with legumes and/or grasses can restore the soil organic C and nitrogen (N) and improve soil structure. In this study, we accessed the effects of 2-season legume and grass fallow on structural properties and C/N relationships in aggregates of a sandy loam soil. Two legumes (Calopogonium mucunoides and Centrosema pubescens), and two grasses (Guinea grass (Panicum maximum) and goose grass (Eleusine indica) were used. Results showed that Calopogonium and Centrosema increased soil total porosity and reduced soil bulk densities, while goose grass increased bulk density and reduced total porosity of the soils at 0–15 and 15–30?cm depths. Guinea grass significantly increased the saturated hydraulic conductivity (50.4?cm?h^?1) and water holding capacity of the soils. Aggregates, 4.75 to 0.5?mm were greater in Guinea grass and least in goose grass fallowed soils. Calopogonium increased macro-aggregates at 0–15?cm soils by 48%, and mean weight diameter (MWD) by 44%. Organic carbon in 0.5–0.25?mm and <0.25?mm aggregate sizes was higher in Guinea grass soils. Generally, grasses had 4-fold increases of C:N contents in dry aggregates. In conclusion, short-season fallow with Guinea grass, Calopogonium and Centrosema, increased soil C and N and protected them from losses in stable aggregates.     

Cross-linked enzyme aggregates of recombinant Candida antarctica lipase B for the efficient synthesis of olvanil,a nonpungent capsaicin analogue

Despite the proven therapeutic role of capsaicin in human health, its usage is still hampered by its high pungency. In this sense, nonpungent capsaicin analogues as olvanil are a feasible alternative to the unpleasant sensations produced by capsaicin while maintaining a similar pharmacological profile. Olvanil can be obtained by a lipase-catalyzed chemoenzymatic process. In the present work, recombinant Candida antarctica lipase B (CALB) was expressed in Pichia pastoris and subsequently immobilized by cross-linked enzyme aggregate (CLEA) methodology for the synthesis of olvanil. The CALB-CLEAs were obtained directly from the fermentation broth of P. pastoris without any purification step in order to assess the role of the contaminant proteins of the crude extract as co-feeders. The CALB-CLEAs were also bioimprinted to enhance the catalytic performance in olvanil synthesis. When CALB was precipitated with isopropanol, the obtained CALB-CLEAs exhibited the highest activity in the synthesis of olvanil, regardless of the glutaraldehyde concentration. The maximum product synthesis was found at 72 hr obtaining 6.8 g L⁻¹ of olvanil with a reaction yield of 16%. When CALB was bioimprinted with olvanil, the synthesis was enhanced 1.3 times, reaching 10.7 g L⁻¹ of olvanil at 72 hr of reaction with a reaction yield of 25%. Scanning electron microscopy images indicated different morphologies of the CLEAs depending on the precipitating agent and the template used for bioimprinting. Recombinant CALB-CLEAs obtained directly from the fermentation broth are a suitable alternative to commercial enzymatic preparations for the synthesis of olvanil in organic medium.     

Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment

Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges.