Multiomic Metabolic Enrichment Network Analysis Reveals Metabolite–Protein Physical Interaction Subnetworks Altered in Cancer

Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce multiomic metabolic enrichment network analysis (MOMENTA), an integrative multiomic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.     

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.     

Limitations of Chromogranin A in clinical practice

Context: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. Methods: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. Results: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. Conclusion: Serum CgA is not helpful for the first-line diagnosis of NEN.     

一种目视激光显微镜

本文介绍一种目视激光显微镜。该装置采用白炽灯和激光做光源。通过调压器衬底亮度可以调整到零。由于激光的高亮度和强相干性,与普通显微镜相比,该显微镜具有景深长,分辨率高,层次丰富的特点。使用该显微镜时能实现镜象的假色彩编码,且镜象具有立体感。文中报导了该显微镜的原理和使用效果。     

A cladistic analysis of Nassauvia Comm. ex Juss. (Asteraceae, Mutisieae) and related genera

FREIRE, S. E., CRISCI, J. V. & KATINAS, L., 1993. A cladistic analysis of Nassauvia Comm. ex Juss. (Asteraceae, Mutisieae) and related genera. Nassauvia and the most closely related genera Calopappus and Triptilion from the southern Andes and Patagonia of South America, form a monophyletic group diagnosed by the following synapomorphies: cypsela trichomes single two-celled, cypsela testa with strengthened cells, pollen grains spheroidal to spheroidal-oblate, colpi membrane with sexine processes, pappus bristles two to six, and pappus deciduous. Furthermore, Nassauvia, Triptilion, and Calopappus form a group with two other Andean genera, Moscharia and Polyachyrus, diagnosed by occurrence of pseudocephalia and a reduction in the number of flowers to five, three or one. A cladistic analysis of the group was undertaken using 35 characters from morphology, anatomy, and palynology. The monophyletic terminal taxa were the 38 species of Nassauvia, the genus Triptilion, the monotypic genus Calopappus, the genus Polyachyrus, and the genus Moscharia. Character polarity was based on outgroup comparison using Cephalopappus. The analysis resulted in 223 equally parsimonious cladograms, each with 70 steps and a consistency index of 0.57. A successive weighting procedure was applied, resulting in 15 cladograms with a consistency index of 0.82. Results of the cladistic analysis support most of the current systematic classification of Nassauvia, with three exceptions: (1) Nassauvia (excluding Calopappus) is paraphyletic; (2) section Masligophorus appears to be a polyphyletic group (N. pygmaea does not cluster with the remaining species of the section); (3) section Panargyrum (without N. lagascae= section Caloptilium) appears to be a paraphyletic group. The capitula arranged in cymose conflorescences in Triptilion are regarded as a primitive condition which gave rise to all stages present in Nassauvia (conflorescence spicate, pseudocephalium, capitula solitary). The capitula arranged in pseudocephalia in Moscharia and Polyachyrus are regarded as a parallel development to the pseudocephalium found in Nassauvia. Nassauvia, subgenus Strongyloma appears as the most primitive taxon, with its spicate conflorescence, whereas section Masligophorus with its solitary capitulum is thought-derived. These results correspond well with cytological data where species of the subgenus Strongyloma have n= 11 and the species of section Masligophorus are tetraploids (n = 22).     

离乳大鼠假性性早熟模型的建立及对雌活性物质的应答

以雌激素含量明确的避孕药物作诱导剂观察了其对离乳Wistsar大鼠性成熟的影响,结果显示在给予避孕药后体重、乳腺、阴门、阴道上皮细胞、卵巢、子宫均发生类似人体假性性早熟变化,而肾上腺、脑垂体、甲状腺等与对照组比较均未见明显差异。     

Electron microscopy study of viral DNA packaging with lambda head mutants

In a previous study, various intermediates in λ DNA packaging were visualized after lysis of λ-infected cells with osmotic shock and sedimentation through a sucrose formalin cushion onto electron microscope grids. Along this line, a systematic screening for intermediates accumulated in all head mutants available was performed. λA^?-infected cells accumulate only empty spherical protein shells (petit λ) bound at an intermediate point along the DNA thread. In situ digestion experiments with restriction endonuclease EcoRI show that the petit λ-DNA complexes are formed at a fixed point on the DNA concatemer. In $\text{λNu1}{}^{\mathrm{?}}\text{-}\text{infected}$ cells, however, most petit λ was not bound to DNA. In Fec^? cells, which are defective in formation of concatemers but normal in head protein synthesis, most petit λ did not sediment onto the carbon film of the grid. In $\text{D}{}^{\mathrm{?}}$ mutant, petit λ, partially full heads and empty heads with released DNA were observed. λFI^?-infected cells also accumulate petit λ and partially full heads. The present studies suggest that protein pNu1 is required for complex formation between head precursors and DNA concatemers, $\text{p}\text{A}$ for the initiation of DNA packaging, $\text{p}\text{D}$ and $\text{p}\text{F}$I for the promotion of DNA packaging, and $\text{p}\text{D}$ for stabilization of head structures. The results obtained with other head mutants involved in formation of mature proheads and head completion confirm earlier results obtained by different techniques.     

Spatial distribution and sequential sampling of adults ofGonocephalum macleayi andPterohelaeus darlingensis in different cropping regimes

Counts of adults of the false wirewormsGonocephalum macleayi (Blackburn) andPterohelaeus darlingensis Carter in pitfall traps in burnt, mulched and sorghum treatments conformed to Taylor's power law. Within a species there were no significant differences in distributions of counts of either sex in any habitat butG. macleayi were more aggregated thanP. darlingensis (Taylor'sb 1.35 and 1.26, respectively). Relationships to determine sample sizes for fixed levels of precision and fixed-precision-level stop lines for sequential sampling are developed for each species using Taylor's parameters for combined data over all habitats.