Lack of SNF1 induces localization of active Ras in mitochondria and triggers apoptosis in the yeast Saccharomyces cerevisiae.

Biochem Biophys Res Commun. 2019 Dec 11;:

Authors: Bonomelli B, Martegani E, Colombo S

Abstract
In previous papers we showed that activated Ras proteins are localized to the plasma membrane and in the nucleus in wild-type yeast cells growing exponentially on glucose, while an aberrant accumulation of activated Ras in mitochondria correlated to mitochondrial dysfunction, accumulation of ROS and regulated cell death. Here we show that also in a strain lacking Snf1, the homolog of the AMP-activated protein kinase (AMPK) in Saccharomyces cerevisiae, activated Ras proteins accumulate mainly in these organelles, suggesting an antiapoptotic role for this protein, beside its well-known function in glucose repression. Indeed, in this paper we show that Snf1 protects against apoptosis in Saccharomyces cerevisiae. In particular, following treatment with acetic acid, a well-known inducer of apoptosis in this microorganism, snf1Δ cells show a significant reduction in cell survival and a higher level of ROS when compared with wild-type cells. More importantly, untreated snf1Δ cells show a higher percentage of apoptotic cells compared with wild-type cells, which further increases upon treatment with acetic acid. In order to determine whether the role of Snf1 in regulated cell death is dependent on its catalytic activity, we characterized the Snf1-S214E strain, expressing a catalytically inactive form of Snf1. Data on active Ras proteins localization, cell survival, level of ROS and percentage of apoptotic cells are congruent and suggest that the antiapoptotic role of Snf1 is independent on its kinase activity.

PMID: 31837801 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/15

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"systems biology"

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"systems biology"

These pubmed results were generated on 2019/12/13

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21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/12

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"systems biology"

These pubmed results were generated on 2019/12/11

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19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/11

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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Understanding sheath blight resistance in rice: the road behind and the road ahead.

Plant Biotechnol J. 2019 Dec 07;:

Authors: Molla KA, Karmakar S, Molla J, Bajaj P, Varshney RK, Datta SK, Datta K

Abstract
Rice Sheath blight disease, caused by the basidiomycetous necrotrophy Rhizoctonia solani, became one of the major threats to the rice cultivation worldwide, especially after the adoption of high yielding varieties. The pathogen is challenging to manage because of its extensively broad host range and high genetic variability and also due to the inability to find any satisfactory level of natural resistance among the available rice germplasm. It is high time to find remedies to combat the pathogen for reducing rice yield losses and subsequently to minimize the threat to global food security. The development of genetic resistance is the only alternative means to avoid the use of hazardous chemical fungicides. This review mainly focuses on the effort of better understanding the host-pathogen relationship, finding the gene loci/markers imparting resistance response, and modifying the host genome through transgenic development. The latest development and trend in the R. solani- rice patho-system research with gap analysis is provided.

PMID: 31811745 [PubMed - as supplied by publisher]

Structure of Galactarate Dehydratase, a New Fold in an Enolase Involved in Bacterial Fitness after Antibiotic Treatment.

Protein Sci. 2019 Dec 06;:

Authors: Rosas-Lemus M, Minasov G, Shuvalova L, Wawrzak Z, Kiryukhina O, Mih N, Jaroszewski L, Palsson B, Godzik A, Satchell KJF

Abstract
Galactarate dehydratase (GarD) is the first enzyme in the galactarate/glucarate pathway and catalyzes the dehydration of galactarate to 3-keto-5-dehydroxygalactarate. This protein is known to increase colonization fitness of intestinal pathogens in antibiotic-treated mice and to promote bacterial survival during stress. The galactarate/glucarate pathway is widespread in bacteria, but not in humans, and thus could be a target to develop new inhibitors for use in combination therapy to combat antibiotic resistance. The structure of almost all the enzymes of the galactarate/glucarate pathway were solved previously, except for GarD, for which only the structure of the N-terminal domain was determined previously. Herein, we report the first crystal structure of full-length GarD solved using a seleno-methoionine derivative revealing a new protein fold. The protein consist of three domains, each presenting a novel twist as compared to their distant homologs. GarD in the crystal structure forms dimers and each monomer is divided into three domains. The N-terminal domain is comprised of a β-clip fold, connected to the second domain by a long unstructured linker. The second domain serves as a dimerization interface between two monomers. The C-terminal domain forms an unusual variant of a Rossmann fold with a crossover and is built around a seven-stranded parallel β-sheet supported by nine α-helices. A metal binding site in the C-terminal domain is occupied by Ca2+ . The activity of GarD was corroborated by the production of 3-keto-5-dehydroxyglucarate under reducing conditions and in the presence of iron. Thus, GarD is an unusual enolase with a novel protein fold never previously seen in this class of enzymes. This article is protected by copyright. All rights reserved.

PMID: 31811683 [PubMed - as supplied by publisher]

The Convergence of Cell-Based Surface Plasmon Resonance and Biomaterials: The Future of Quantifying Bio-molecular Interactions-A Review.

Ann Biomed Eng. 2019 Dec 06;:

Authors: Mamer SB, Page P, Murphy M, Wang J, Gallerne P, Ansari A, Imoukhuede PI

Abstract
Cell biology is driven by complex networks of biomolecular interactions. Characterizing the kinetic and thermodynamic properties of these interactions is crucial to understanding their role in different physiological processes. Surface plasmon resonance (SPR)-based approaches have become a key tool in quantifying biomolecular interactions, however conventional approaches require isolating the interacting components from the cellular system. Cell-based SPR approaches have recently emerged, promising to enable precise measurements of biomolecular interactions within their normal biological context. Two major approaches have been developed, offering their own advantages and limitations. These approaches currently lack a systematic exploration of 'best practices' like those existing for traditional SPR experiments. Toward this end, we describe the two major approaches, and identify the experimental parameters that require exploration, and discuss the experimental considerations constraining the optimization of each. In particular, we discuss the requirements of future biomaterial development needed to advance the cell-based SPR technique.

PMID: 31811474 [PubMed - as supplied by publisher]

Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer.

Cell Res. 2019 Dec 06;:

Authors: Teng S, Li YE, Yang M, Qi R, Huang Y, Wang Q, Zhang Y, Chen S, Li S, Lin K, Cao Y, Ji Q, Gu Q, Cheng Y, Chang Z, Guo W, Wang P, Garcia-Bassets I, Lu ZJ, Wang D

Abstract
Metastasis, the development of secondary malignant growths at a distance from a primary tumor, is the cause of death for 90% of cancer patients, but little is known about how metastatic cancer cells adapt to and colonize new tissue environments. Here, using clinical samples, patient-derived xenograft (PDX) samples, PDX cells, and primary/metastatic cell lines, we discovered that liver metastatic colorectal cancer (CRC) cells lose their colon-specific gene transcription program yet gain a liver-specific gene transcription program. We showed that this transcription reprogramming is driven by a reshaped epigenetic landscape of both typical enhancers and super-enhancers. Further, we identified that the liver-specific transcription factors FOXA2 and HNF1A can bind to the gained enhancers and activate the liver-specific gene transcription, thereby driving CRC liver metastasis. Importantly, similar transcription reprogramming can be observed in multiple cancer types. Our data suggest that reprogrammed tissue-specific transcription promotes metastasis and should be targeted therapeutically.

PMID: 31811277 [PubMed - as supplied by publisher]

Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target.

Exp Mol Med. 2019 Dec 06;51(12):147

Authors: Han S, Shin H, Lee JK, Liu Z, Rabadan R, Lee J, Shin J, Lee C, Yang H, Kim D, Kim SH, Kim J, Oh JW, Kong DS, Lee JI, Seol HJ, Choi JW, Kang HJ, Nam DH

Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.

PMID: 31811117 [PubMed - in process]

Inhibition of MDR1 overcomes resistance to brentuximab vedotin in Hodgkin lymphoma.

Clin Cancer Res. 2019 Dec 06;:

Authors: Chen R, Herrera AF, Hou J, Chen L, Wu J, Guo Y, Synold TW, Ngo VN, Puverel S, Mei M, Popplewell L, Yi S, Song JY, Tao S, Wu X, Chan WC, Forman S, Kwak LW, Rosen ST, Newman EM

Abstract
PURPOSE: In classical Hodgkin lymphoma (HL), the malignant Reed-Sternberg cells express the cell surface marker CD30. Brentuximab vedotin (BV) is an antibody-drug conjugate that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although BV elicits a high response rate (75%) in relapsed/refractory HL, most patients who respond to BV eventually develop resistance.
EXPERIMENTAL DESIGN: We developed two BV-resistant HL cell line models using a pulsatile approach and observed that resistance to BV is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase 1 trial combining BV and cyclosporine A (CsA) in patients with relapsed/refractory HL.
RESULTS: Here, we show that competitive inhibition of MDR1 restored sensitivity to BV in our BV-resistant cell lines by increasing intracellular MMAE levels, and potentiated BV activity in BV-resistant HL tumors in a human xenograft mouse model. In our phase 1 trial, the combination of BV and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to BV.
CONCLUSIONS: This study may provide a new therapeutic strategy to combat BV resistance in HL. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an antibody-drug conjugate in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to BV to confirm clinical activity in this population with unmet need.

PMID: 31811017 [PubMed - as supplied by publisher]

Ecofriendly laccases treatment to challenge micropollutants issue in municipal wastewaters.

Environ Pollut. 2019 Nov 12;:113579

Authors: Spina F, Gea M, Bicchi C, Cordero C, Schilirò T, Varese GC

Abstract
In this study, a multidisciplinary approach investigated the enzymatic degradation of micropollutants in real, not modified, municipal wastewaters of a plant located in Italy. Stir Bar Sorptive Extraction combined to Gas Chromatography-Mass Spectrometric detection (SBSE-GC-MS) was applied to profile targeted pollutants in wastewaters collected after the primary sedimentation (W1) and the final effluent (W2). Fifteen compounds were detected at ng/L - μg/L, including pesticides, personal care products (PCPs) and drugs. The most abundant micropollutants were bis(2-ethylhexyl) phthalate, diethyl phthalate and ketoprofen. Laccases of Trametes pubescens MUT 2400 were very active against all the target micropollutants: except few cases, their concentration was reduced more than 60%. Chemical analysis and environmental risk do not always come together. To verify whether the treated wastewaters can represent a stressor for the aquatic ecosystem, toxicity was also evaluated. Raphidocelis subcapitata and Lepidium sativum tests showed a clear ecotoxicity reduction, even though they did not evenly respond. Two in vitro tests (E-screen test and MELN assay) were used to evaluate the estrogenic activity. Treatments already operating in the plant (e.g. activated sludge) partially reduced the estradiol equivalent concentration, and it was almost negligible after the laccases treatment. The results of this study suggest that laccases of T. pubescens are promising biocatalysts for the micropollutants transformation in wastewaters and surface waters.

PMID: 31810716 [PubMed - as supplied by publisher]

A General Workflow for Characterization of Nernstian Dyes and Their Effects on Bacterial Physiology.

Biophys J. 2019 Nov 15;:

Authors: Mancini L, Terradot G, Tian T, Pu Y, Li Y, Lo CJ, Bai F, Pilizota T

Abstract
The electrical membrane potential (Vm) is one of the components of the electrochemical potential of protons across the biological membrane (proton motive force), which powers many vital cellular processes. Because Vm also plays a role in signal transduction, measuring it is of great interest. Over the years, a variety of techniques have been developed for the purpose. In bacteria, given their small size, Nernstian membrane voltage probes are arguably the favorite strategy, and their cytoplasmic accumulation depends on Vm according to the Nernst equation. However, a careful calibration of Nernstian probes that takes into account the tradeoffs between the ease with which the signal from the dye is observed and the dyes' interactions with cellular physiology is rarely performed. Here, we use a mathematical model to understand such tradeoffs and apply the results to assess the applicability of the Thioflavin T dye as a Vm sensor in Escherichia coli. We identify the conditions in which the dye turns from a Vm probe into an actuator and, based on the model and experimental results, propose a general workflow for the characterization of Nernstian dye candidates.

PMID: 31810660 [PubMed - as supplied by publisher]

The Biogenesis and Precise Control of RNA m6A Methylation.

Trends Genet. 2019 Dec 03;:

Authors: Huang H, Weng H, Chen J

Abstract
N6-Methyladenosine (m6A) is the most prevalent internal RNA modification in mRNA, and has been found to be highly conserved and hard-coded in mammals and other eukaryotic species. The importance of m6A for gene expression regulation and cell fate decisions has been well acknowledged in the past few years. However, it was only until recently that the mechanisms underlying the biogenesis and specificity of m6A modification in cells were uncovered. We review up-to-date knowledge on the biogenesis of the RNA m6A modification, including the cis-regulatory elements and trans-acting factors that determine general de novo m6A deposition and modulate cell type-specific m6A patterns, and we discuss the biological significance of such regulation.

PMID: 31810533 [PubMed - as supplied by publisher]

Advancing functional and translational microbiome research using meta-omics approaches.

Microbiome. 2019 Dec 06;7(1):154

Authors: Zhang X, Li L, Butcher J, Stintzi A, Figeys D

Abstract
The gut microbiome has emerged as an important factor affecting human health and disease. The recent development of -omics approaches, including phylogenetic marker-based microbiome profiling, shotgun metagenomics, metatranscriptomics, metaproteomics, and metabolomics, has enabled efficient characterization of microbial communities. These techniques can provide strain-level taxonomic resolution of the taxa present in microbiomes, assess the potential functions encoded by the microbial community and quantify the metabolic activities occurring within a complex microbiome. The application of these meta-omics approaches to clinical samples has identified microbial species, metabolic pathways, and metabolites that are associated with the development and treatment of human diseases. These findings have further facilitated microbiome-targeted drug discovery and efforts to improve human health management. Recent in vitro and in vivo investigations have uncovered the presence of extensive drug-microbiome interactions. These interactions have also been shown to be important contributors to the disparate patient responses to treatment that are often observed during disease therapy. Therefore, developing techniques or frameworks that enable rapid screening, detailed evaluation, and accurate prediction of drug/host-microbiome interactions is critically important in the modern era of microbiome research and precision medicine. Here we review the current status of meta-omics techniques, including integrative multi-omics approaches, for characterizing the microbiome's functionality in the context of health and disease. We also summarize and discuss new frameworks for applying meta-omics approaches and microbiome assays to study drug-microbiome interactions. Lastly, we discuss and exemplify strategies for implementing microbiome-based precision medicines using these meta-omics approaches and high throughput microbiome assays.

PMID: 31810497 [PubMed - in process]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/12/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.