Tyrosine kinase inhibitor-induced hypothyroidism: mechanism and clinical implications.

INTRODUCTION: Since the first experimentally proven tyrosine kinase inhibitor (TKI) imatinib was introduced in the clinical setting, TKIs have attracted widespread attention because of their remarkable therapeutic effects and improvement of survival rates. TKIs are small-molecule, multi-target, anti-cancer agents that target different tyrosine kinases and block downstream signaling. ADVERSE REACTIONS AND CONCERNS: However, with in-depth research on TKI drugs, the adverse reactions-for example, thyroid dysfunction-have become a concern and thus have attracted the attention of numerous researchers. Thyroid dysfunction, especially hypothyroidism, that occurs in high incidence during TKI therapy has a close relationship with treatment efficacy, but the mechanism of TKI-induced thyroid dysfunction is obscure. DISCUSSION: This review discusses the epidemiology, possible mechanisms, and clinical significance of hypothyroidism in cancer patients treated with TKI.

Global Profiling of the Lysine Crotonylome in Different Pluripotent States.

Pluripotent stem cells (PSCs) can be expanded in vitro in different culture conditions, resulting in a spectrum of cell states with distinct properties. Understanding how PSCs transition from one state to another, ultimately leading to lineage-specific differentiation, is important for developmental biology and regenerative medicine. Although there is significant information regarding gene expression changes controlling these transitions, less is known about post-translational modifications of proteins. Protein crotonylation is a newly discovered post-translational modification where lysine residues are modified with a crotonyl group. Here, we employed affinity purification of crotonylated peptides and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to systematically profile protein crotonylation in mouse PSCs in different states including ground, metastable, and primed states, as well as metastable PSCs undergoing early pluripotency exit. We successfully identified 3628 high-confidence crotonylated sites in 1426 proteins. These crotonylated proteins are enriched for factors involved in functions/processes related to pluripotency such as RNA biogenesis, central carbon metabolism, and proteasome function. Moreover, we found that increasing the cellular levels of crotonyl-coenzyme A (crotonyl-CoA) through crotonic acid treatment promotes proteasome activity in metastable PSCs and delays their differentiation, consistent with previous observations showing that enhanced proteasome activity helps to sustain pluripotency. Our atlas of protein crotonylation will be valuable for further studies of pluripotency regulation and may also provide insights into the role of metabolism in other cell fate transitions.

Global crotonylome reveals CDYL-regulated RPA1 crotonylation in homologous recombination-mediated DNA repair.

Previously, we reported that chromodomain Y-like (CDYL) acts as a crotonyl-coenzyme A hydratase and negatively regulates histone crotonylation (Kcr). However, the global CDYL-regulated crotonylome remains unclear. Here, we report a large-scale proteomics analysis for protein Kcr. We identify 14,311 Kcr sites across 3734 proteins in HeLa cells, providing by far the largest crotonylome dataset. We show that depletion of CDYL alters crotonylome landscape affecting diverse cellular pathways. Specifically, CDYL negatively regulated Kcr of RPA1, and mutation of the Kcr sites of RPA1 impaired its interaction with single-stranded DNA and/or with components of resection machinery, supporting a key role of RPA1 Kcr in homologous recombination DNA repair. Together, our study indicates that protein crotonylation has important implication in various pathophysiological processes.

Quantitative ubiquitylomics approach for characterizing the dynamic change and extensive modulation of ubiquitylation in rice seed germination.

During seed germination, cells embark on extensive post-transcriptional and post-translational modifications (PTM), providing a perfect platform to study these events in embryo rebooting from relative quiescenct to highly active state. PR-619, a deubiquitylase inhibitor, delayed the rice seed germination and resulted in the accumulation of ubiquitylated proteins, which indicated the protein ubiquitylation is involved in this process. Using the K-Ɛ-GG antibody enrichment method integrated with high-resolution mass spectrometry, a list of 2576 lysine ubiquitylated (Kub) sites in 1171 proteins was compiled for rice embryos at 0, 12 and 24 h after imbibition (HAI). Of these, the abundance of 1419 Kub sites in 777 proteins changed significantly. Most of them substantially increased within the first 12 HAI, which is similar to the dynamic state previously observed for protein phosphorylation, implying that the first 12 HAI are essential for subsequent switch during rice seed germination. We also quantitatively analyzed the embryo proteome in these samples. Generally, a specific protein's abundance in the ubiquitylome was uncorrelated to that in the proteome. The differentially ubiquitinated proteins were greatly enriched in the categories of protein processing, DNA and RNA processing/regulation related, signaling, and transport. The DiGly footprint of the Kub sites was significantly reduced on K48, a linkage typically associated with proteasome-mediated degradation. These observations suggest ubiquitylation may modulate the protein function more than providing 26S degradation signals in the early stage of rice seed germination. Revealing this comprehensive ubiquitylome greatly increases our understanding of this critical PTM during seed germination.

Divergence and plasticity shape adaptive potential of the Pacific oyster.

The interplay between divergence and phenotypic plasticity is critical to our understanding of a species' adaptive potential under rapid climate changes. We investigated divergence and plasticity in natural populations of the Pacific oyster Crassostrea gigas with a congeneric oyster Crassostrea angulata from southern China used as an outgroup. Genome re-sequencing of 371 oysters revealed unexpected genetic divergence in a small area that coincided with phenotypic divergence in growth, physiology, heat tolerance and gene expression across environmental gradients. These findings suggest that selection and local adaptation are pervasive and, together with limited gene flow, influence population structure. Genes showing sequence differentiation between populations also diverged in transcriptional response to heat stress. Plasticity in gene expression is positively correlated with evolved divergence, indicating that plasticity is adaptive and favoured by organisms under dynamic environments. Divergence in heat tolerance-partly through acetylation-mediated energy depression-implies differentiation in adaptive potential. Trade-offs between growth and survival may play an important role in local adaptation of oysters and other marine invertebrates.

Quantitative Dynamics of Proteome, Acetylome, and Succinylome during Stem-Cell Differentiation into Hepatocyte-like Cells.

Stem-cell differentiation is a complex biological process controlled by a series of functional protein clusters and signaling transductions, especially metabolism-related pathways. Although previous studies have quantified the proteome and phosphoproteome for stem-cell differentiation, the investigation of acylation-mediated regulation is still absent. In this study, we quantitatively profiled the proteome, acetylome, and succinylome in pluripotent human embryonic stem cells (hESCs) and differentiated hepatocyte-like cells (HLCs). In total, 3843 proteins, 185 acetylation sites in 103 proteins, and 602 succinylation sites in 391 proteins were quantified. The quantitative proteome showed that in differentiated HLCs the TGF-ß, JAK-STAT, and RAS signaling pathways were activated, whereas ECM-related processes such as sulfates and leucine degradation were depressed. Interestingly, it was observed that the acetylation and succinylation were more intensive in hESCs, whereas protein processing in endoplasmic reticulum and the carbon metabolic pathways were especially highly succinylated. Because the metabolism patterns in pluripotent hESCs and the differentiated HLCs were different, we proposed that the dynamic acylations, especially succinylation, might regulate the Warburg-like effect and TCA cycle during differentiation. Taken together, we systematically profiled the protein and acylation levels of regulation in pluripotent hESCs and differentiated HLCs, and the results indicated the important roles of acylation in pluripotency maintenance and differentiation.

Dynamically tunable band stop filter enabled by the metal-graphene metamaterials.

Dynamically tunable band stop filter based on metal-graphene metamaterials is proposed and numerically investigated at mid-infrared frequencies. The proposed filter is constructed by unit cells with simple gold strips on the stack of monolayer graphene and the substrate of BaF2. A stable modulation depth up to -23.26 dB can be achieved. Due to the cooperative effect of the "bright-bright" elements, the amount of the gold strips in each unit cell determines the number of the stop-bands, providing a simple and flexible approach to develop multispectral devices. Further investigations illustrate that the location of the stop bands not only can be adjusted by varying the length of gold strips, but also can be dynamically controlled by tuning the Fermi energy level of graphene, and deep modulation is acquired through designing the carrier mobility. With the sensitivity as high as 2393 nm/RIU of the resonances to the varieties of surrounding medium, the structure is also enabled to be an index based sensor. The results will benefit the on plane or integrated micro-structure research with simple structure and flexible tunability, and can be applied in multi-band stop filters, sensors and other graphene-based multispectral devices.

Comparative Proteomic Analysis of Lysine Acetylation in Fish CIK Cells Infected with Aquareovirus.

Grass carp (Ctenopharyngodon idellus) is an important worldwide commercial freshwater culture species. However, grass carp reovirus (GCRV) causes serious hemorrhagic disease in fingerlings and yearlings of fishes. To understand the molecular pathogenesis of host cells during GCRV infection, intensive proteomic quantification analysis of lysine acetylation in Ctenopharyngodon idella kidney (CIK) cells was performed. Using dimethylation labeling-based quantitative proteomics, 832 acetylated proteins with 1391 lysine acetylation sites were identified in response to GCRV infection, among which 792 proteins with 1323 sites were quantifiable. Bioinformatics analysis showed that differentially expressed lysine acetylated proteins are involved in diverse cellular processes and associated with multifarious functions, suggesting that extensive intracellular activities were changed upon viral infection. In addition, extensive alterations on host-protein interactions at the lysine acetylation level were also detected. Further biological experiments showed that the histone deacetylases (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) could significantly suppress the GCRV replication. To our knowledge, this is the first to reveal the proteome-wide changes in host cell acetylome with aquatic virus infection. The results provided in this study laid a basis for further understanding the host response to aquareovirus infection in the post-translational modification aspect by regulating cell lysine acetylation conducive to viral replication.

Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis.

Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to ß-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.

Quantitative analyses of the global proteome and phosphoproteome reveal the different impacts of propofol and dexmedetomidine on HT22 cells.

Propofol and dexmedetomidine are both commonly used anaesthetics. Although they employ two different mechanisms to induce anaesthesia, both compounds influence the hippocampus and the HT22 cell line. HT22 cells are broadly used in neurobiological research. In this study, we assessed the effects of propofol and dexmedetomidine on signalling in HT22 cells. Using the SILAC (stable isotope labelling with amino acids in cell culture) labelling technique, IMAC (immobilized metal affinity chromatography) enrichment and high-resolution LC-MS/MS (liquid chromatography tandem mass spectrometry) analysis, we investigated the quantitative proteome and phosphoproteome in HT22 cells treated with propofol or dexmedetomidine. In total, 4,527 proteins and 6,824 phosphosites were quantified in cells treated with these two anaesthetics. With the assistance of intensive bioinformatics, the propofol and dexmedetomidine treatments were shown to induce distinct proteome and phosphoproteome profiles in HT22 cells. Consistent with our bioinformatics analysis, dexmedetomidine had a smaller effect than propofol on cell survival. These findings deepen our understanding of drug-induced anaesthesia.

Malonylome of the plant growth promoting rhizobacterium with potent biocontrol activity, Bacillus amyloliquefaciens FZB42.

The data presented in this article are related to the publication entitled "Malonylome analysis of rhizobacterium Bacillus amyloliquefaciens FZB42 reveals involvement of lysine malonylation in polyketide synthesis and plant-bacteria interactions"(doi:10.1016/j.jprot.2016.11.022) (B. Fan, Y. Li, L. Li et al.) [1]. This article presented the raw information of all malonyllysine sites identified by LC-MS/MS in the Bacillus amyloliquefaciens FZB42. Further, the functional features and conservation of the malonylated peptide/proteins were analyzed and made publicly available to enable critical or extended analyses.

Malonylome analysis of rhizobacterium Bacillus amyloliquefaciens FZB42 reveals involvement of lysine malonylation in polyketide synthesis and plant-bacteria interactions.

Using the combination of affinity enrichment and high-resolution LC-MS/MS analysis, we performed a large-scale lysine malonylation analysis in the model representative of Gram-positive plant growth-promoting rhizobacteria (PGPR), Bacillus amyloliquefaciens FZB42. Altogether, 809 malonyllysine sites in 382 proteins were identified. The bioinformatic analysis revealed that lysine malonylation occurs on the proteins involved in a variety of biological functions including central carbon metabolism, fatty acid biosynthesis and metabolism, NAD(P) binding and translation machinery. A group of proteins known to be implicated in rhizobacterium-plant interaction were also malonylated; especially, the enzymes responsible for antibiotic production including polyketide synthases (PKSs) and nonribosomal peptide synthases (NRPSs) were highly malonylated. Furthermore, our analysis showed malonylation occurred on proteins structure with higher surface accessibility and appeared to be conserved in many bacteria but not in archaea. The results provide us valuable insights into the potential roles of lysine malonylation in governing bacterial metabolism and cellular processes. BIOLOGICAL SIGNIFICANCE: Although in mammalian cells some important findings have been discovered that protein malonylation is related to basic metabolism and chronic disease, few studies have been performed on prokaryotic malonylome. In this study, we determined the malonylation profiles of Bacillus amyloliquefaciens FZB42, a model organism of Gram-positive plant growth-promoting rhizobacteria. FZB42 is known for the extensive investigations on its strong ability of producing antimicrobial polyketides and its potent activities of stimulating plant growth. Our analysis shows that malonylation is highly related to the polyketide synthases and the proteins involved bacterial interactions with plants. The results not only provide one of the first malonylomes for exploring the biochemical nature of bacterial proteins, but also shed light on the better understanding of bacterial antibiotic biosynthesis and plant-microbe interaction.

Studies on chemical constituents and anti-hepatoma effects of essential oil from Annona squamosa L. pericarps.

Annona squamosa L. fruit played great anti-neoplastic activities. Its pericarps were discarded as waste. In this study, essential oil extracted from A. squamosa L. pericarps (APEO) was obtained by hydrodistillation and analysed by GC-MS. Furthermore, the anti-hepatoma activities and the underlying mechanism of the oil were firstly described. A total of 59 compounds were identified by Gas chromatography-mass spectrometry (GC-MS). The major compound in the oil was (-)-spathulenol (32.51%). The APEO demonstrated anti-hepatoma activity against SMMC-7721 hepatoma cell line with IC50 lower than 55 µg/mL. At the same time, nucleus shrinkage or broken were found in cells incubated with APEO through fluorescent microscope. In addition, pro-apoptosis and cell cycle arrest effects were confirmed by flow cytometry analysis.

Aberrant Methylation of RASSF1A gene Contribute to the Risk of Renal Cell Carcinoma: a Meta-Analysis.

The aim of this study was to assess the diagnostic value of RASSF1A methylation in renal cell carcinoma. Systematically search were performed using the Pubmed, ProQest and Web of Science for all articles on the association between RASSF1A methylation and renal cell carcinoma before 15 April 2015. After the filtration, 13 studies involving 677 cases and 497 controls met our criteria. Our meta-analysis suggested that hypermethylation of RASSF1A gene was associated with the increased risk of RCC(OR:4.14, 95%CI:1.06-16.1). Stratified analyses showed a similar risk in qualitative detection method(OR:28.4, 95%CI:10.2-79.6), body fluid sample(OR:12.8, 95%CI:5.35-30.8), and American(OR:10.5, 95%CI:1.97-55.9). Our result identified that RASSF1A methylation had a strong potential in prediction the risk of Renal cell carcinoma.

[The effects of human cytomegalovirus infection on college students' neurobehaviors].

OBJECTIVE: To explore relevant between human cytomegalovirus (HCMV) infection and college students' neurobehaviors. METHODS: 87 college students were enlisted. They were tested with Bole. Neurobehavioral evaluation system (B. NES), and HCMV IgG antibody was detected after separation of serum. We analyzed the test results of B. NES by SPSS software. RESULTS: 76 college students were infected by HCMV in the past and 11 college students were not infected. The infected group scored 8.89 +/- 6.60 in depression aspect of emotion state test, while control group got 15.73 +/- 9.00. There was Significant difference between infection group and control (P < 0.05). There were no significant differences in other aspects of emotion states, study and memory, perception and mental movement (P > 0.05). CONCLUSION: HCMV infection is associated with depression status.