Identification and Characterization of Metabolic Subtypes of Endometrial Cancer Using a Systems-Level Approach.

Endometrial cancer (EC) is the most common gynecological cancer worldwide. Understanding metabolic adaptation and its heterogeneity in tumor tissues may provide new insights and help in cancer diagnosis, prognosis, and treatment. In this study, we investigated metabolic alterations of EC to understand the variations in metabolism within tumor samples. Integration of transcriptomics data of EC (RNA-Seq) and the human genome-scale metabolic network was performed to identify the metabolic subtypes of EC and uncover the underlying dysregulated metabolic pathways and reporter metabolites in each subtype. The relationship between metabolic subtypes and clinical variables was explored. Further, we correlated the metabolic changes occurring at the transcriptome level with the genomic alterations. Based on metabolic profile, EC patients were stratified into two subtypes (metabolic subtype-1 and subtype-2) that significantly correlated to patient survival, tumor stages, mutation, and copy number variations. We observed the co-activation of the pentose phosphate pathway, one-carbon metabolism, and genes involved in controlling estrogen levels in metabolic subtype-2, which is linked to poor survival. PNMT and ERBB2 are also upregulated in metabolic subtype-2 samples and present on the same chromosome locus 17q12, which is amplified. PTEN and TP53 mutations show mutually exclusive behavior between subtypes and display a difference in survival. This work identifies metabolic subtypes with distinct characteristics at the transcriptome and genome levels, highlighting the metabolic heterogeneity within EC.

Modeling the Control of Meiotic Cell Divisions: Entry, Progression, and Exit.

Upon nitrogen starvation, Schizosaccharomyces pombe exit the mitotic cell cycle and become irreversibly committed to the completion of meiosis program. Meiotic cell divisions are coordinated with sporulation events to produce haploid spores. In the last few decades, experiments on fission yeast have revealed different molecular players involved in two meiotic cell divisions, meiosis I (MI) and meiosis II (MII). How the MI entry, MI-to-MII transition, and MII exit occur because of the dynamics of the regulatory network is not well understood. In this work, we developed a comprehensive mathematical model of the network that describes the temporal dynamics of meiotic progression. The model accounts for the phenotypes of several experimental data (single and multiple mutations). We demonstrate the control strategy involving multiple feedback loops to yield two successive division cycles. The differential regulation of anaphase-promoting complex/cyclosome (APC/C) coactivators and its inhibitors is crucial for the dynamics of both MI-to-MII transition and MII exit. This model generates mechanistic insights that help in further experiments and modeling.

Age, Disease, and Their Interaction Effects on Intrinsic Connectivity of Children and Adolescents in Autism Spectrum Disorder Using Functional Connectomics.

Brain connectivity analysis has provided crucial insights to pinpoint the differences between autistic and typically developing (TD) children during development. The aim of this study is to investigate the functional connectomics of autism spectrum disorder (ASD) versus TD and underpin the effects of development, disease, and their interactions on the observed atypical brain connectivity patterns. Resting-state functional magnetic resonance imaging (rs-fMRI) from the Autism Brain Imaging Data Exchange (ABIDE) data set, which is stratified into two cohorts: children (9-12 years) and adolescents (13-16 years), is used for the analysis. Differences in various graph theoretical network measures are calculated between ASD and TD in each group. Furthermore, two-factor analysis of variance test is used to study the effect of age, disease, and their interaction on the network measures and the network edges. Furthermore, the differences in connection strength between TD and ASD subjects are assessed using network-based statistics. The results showed that ASD exhibits increased functional integration at the expense of decreased functional segregation. In ASD adolescents, there is a significant decrease in modularity suggesting a less robust modular organization, and an increase in participation coefficient suggesting more random integration and widely distributed connection edges. Furthermore, there is significant hypoconnectivity observed in the adolescent group especially in the default mode network, while the children group shows both hyper- and hypoconnectivity. This study lends support to a model of global atypical connections and further identifies functional networks and areas that are independently affected by age, disease, and their interaction.

RETRACTED: The Anaphase-Promoting Complex/Cyclosome Is Essential for Entry into Meiotic M-Phase.

Vertebrate immature oocytes are arrested at prophase of meiosis I (MI). Hormonal stimulation breaks this prophase-I arrest and induces re-entry into MI. The mechanism underlying meiotic resumption remains largely elusive. Here, we demonstrate that the anaphase-promoting complex/cyclosome (APC/C) in complex with Cdh1 has an unexpected function in meiosis in that it is essential for meiotic resumption. We identify the catalytic subunit of protein phosphatase 6 (PP6c) as the critical substrate whose APC/C(Cdh1)-mediated destruction is a prerequisite for the re-entry of immature Xenopus laevis oocytes into MI. Preventing PP6c destruction impairs activating autophosphorylation of Aurora A, a cell-cycle kinase critical for meiotic translation. Restoring meiotic translation rescues the meiotic resumption defect of Cdh1-depleted oocytes. Thus, our studies discover that the essential function of the APC/C in triggering cell-cycle transitions is not limited to M-phase exit but also applies to entry into meiotic M-phase, and identify a crucial APC/C-PP6c-Aurora A axis in the resumption of female meiosis.