Serendipity and Vision: Two Methods for Discovery Comments on Nickles

Thomas Nickles challenges my thesis that innovative discoveries can be based on deliberately chosen problems and research strategies. He suggests that all significant innovation can be seen as such only in retrospect and that its generation must be serendipitous. Here I argue in response that significant innovations can and do often arise from self conscious critical appraisal of orthodox practice combined with regulated though speculative abductive argumentation to alternative explanatory schemata. Orthodox practice is not based upon monolithic systems of belief about the subject of inquiry. Rather major domains of scientific practice often are approached from different conceptualizations that provide grounds for critical dialectic and consilient empirical information. Abductive arguments that meet appropriate conditions of likelihood, probability and analogy are an important means of justifying allocating resources to innovative practices that have yet to produce products that can rival those of established orthodoxy.     

The Effect of Traffic Density on Lead Contents in Roadside Soils: An Analysis of Published Data

Data from eight published studies were combined to show that the influence of traffic density on Pb contents in roadside soils increases with proximity to the road.     

DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.     

Lysine Succinylation of VBS Contributes to Sclerotia Development and Aflatoxin Biosynthesis in Aspergillus flavus

Aspergillus flavus is a common saprophytic and pathogenic fungus, and its secondary metabolic pathways are one of the most highly characterized owing to its aflatoxin (AF) metabolite affecting global economic crops and human health. Different natural environments can cause significant variations in AF synthesis. Succinylation was recently identified as one of the most critical regulatory post-translational modifications affecting metabolic pathways. It is primarily reported in human cells and bacteria with few studies on fungi. Proteomic quantification of lysine succinylation (Ksuc) exploring its potential involvement in secondary metabolism regulation (including AF production) has not been performed under natural conditions in A. flavus. In this study, a quantification method was performed based on tandem mass tag labeling and antibody-based affinity enrichment of succinylated peptides via high accuracy nano-liquid chromatography with tandem mass spectrometry to explore the succinylation mechanism affecting the pathogenicity of naturally isolated A. flavus strains with varying toxin production. Altogether, 1240 Ksuc sites in 768 proteins were identified with 1103 sites in 685 proteins quantified. Comparing succinylated protein levels between high and low AF-producing A. flavus strains, bioinformatics analysis indicated that most succinylated proteins located in the AF biosynthetic pathway were downregulated, which directly affected AF synthesis. Versicolorin B synthase is a key catalytic enzyme for heterochrome B synthesis during AF synthesis. Site-directed mutagenesis and biochemical studies revealed that versicolorin B synthase succinylation is an important regulatory mechanism affecting sclerotia development and AF biosynthesis in A. flavus. In summary, our quantitative study of the lysine succinylome in high/low AF-producing strains revealed the role of Ksuc in regulating AF biosynthesis. We revealed novel insights into the metabolism of AF biosynthesis using naturally isolated A. flavus strains and identified a rich source of metabolism-related enzymes regulated by succinylation.     

Prediction of heavy-metal concentrations in mature plants by chemical analysis of seedlings

Five plant species were cultivated on a soil from the Neckar alluvial fan near Heidelberg (FRG) polluted by the emissions of a cement plant. Thallium, cadmium and lead concentrations in seedlings and mature plants were determined by atomic absorption analysis. AdditionallyBrassica napus L.napus was grown on soils containing 5 different concentrations of heavy metals, achieved by mixing two similar soils, from the same area but with different metal concentrations. Thallium and cadmium were shown to be taken up by roots whilst lead which was also absorbed, was deposited mainly on the plant surface. However during cultivation in the winter months, a remarkable deposit of lead via the roots was found. Thallium in the soil from a anthrorogen source was more available to plants than thallium of geological origin. During the lifetime of a plant concentrations of thallium and cadmium were always highest in the seedling. The decrease in metal concentration with maturity depended on the plant species and the element, but was not a function of the metal concentration in the soil.     

Decreased incidence of mycorrhizal root tips associated with soil heavy-metal enrichment

Mycorrhizal incidence was studied at two forested locations in south-central Virgina. At each location, one site with soil naturally enriched in copper, lead and zinc was designated as mineralized, and an adjacent site, with significantly lower levels of these metals, was used as a control. A total of 223 soil samples were collected during the summer of 1984 and assayed for active mycorrhizal tips. A reduced active mycorrhizal root tip count was found in those samples collected from the mineralized sites at both locations (P≤0.001).     

Effects of lead on hepatocyte ultrastructure in Carassius carassius (L.) var. auratus

Subcellular modifications in hepatocytes of Carassius carassius var. auratus subjected to 24 hr and 48 hr sublethal acute lead (5mg·1⁻¹) exposure were studied by electron microscopy. Cytological alterations were observed after 24 hr of treatment and became more evident after 48 hr. Lead induced an increase in nuclear heterochromatin and alterations in mitochondria, endoplasmic reticulum and Golgi complex ultrastructure. Glycogen granula decreased, and secondary lysosomes and lipid droplets increased. Furthermore, intracytoplasmic lumina with microvilli-bearing surfaces and numerous autophagic vacuola were observed after 48 hr of exposure.