Convergent Identification and Interrogation of Tumor-Intrinsic Factors that Modulate Cancer Immunity In Vivo.

Cell Syst. 2019 Feb 11;:

Authors: Codina A, Renauer PA, Wang G, Chow RD, Park JJ, Ye H, Zhang K, Dong MB, Gassaway B, Ye L, Errami Y, Shen L, Chang A, Jain D, Herbst RS, Bosenberg M, Rinehart J, Fan R, Chen S

Abstract
The genetic makeup of cancer cells directs oncogenesis and influences the tumor microenvironment. In this study, we massively profiled genes that functionally drive tumorigenesis using genome-scale in vivo CRISPR screens in hosts with different levels of immunocompetence. As a convergent hit from these screens, Prkar1a mutant cells are able to robustly outgrow as tumors in fully immunocompetent hosts. Functional interrogation showed that Prkar1a loss greatly altered the transcriptome and proteome involved in inflammatory and immune responses as well as extracellular protein production. Single-cell transcriptomic profiling and flow cytometry analysis mapped the tumor microenvironment of Prkar1a mutant tumors and revealed the transcriptomic alterations in host myeloid cells. Taken together, our data suggest that tumor-intrinsic mutations in Prkar1a lead to drastic alterations in the genetic program of cancer cells, thereby remodeling the tumor microenvironment.

PMID: 30797773 [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 2019/02/24

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.

Gene space completeness in complex plant genomes.

Curr Opin Plant Biol. 2019 Feb 20;48:9-17

Authors: Van Bel M, Bucchini F, Vandepoele K

Abstract
Genome annotations offer ample opportunities to study gene functions, biochemical and regulatory pathways, or quantitative trait loci in plants. Determining the quality and completeness of a genome annotation, and maintaining the balance between them, are major challenges, even for genomes of well-studied model organisms. In this review, we present a historical overview of the complexity in different plant genomes and discuss the hurdles and possible solutions in obtaining a complete and high-quality genome annotation. We illustrate there is no clear-cut answer to solve these challenges for different gene types, but provide tips on guiding the iterative process of generating a superior genome annotation, which is a moving target as our knowledge about plant genomics increases and additional data sources become available.

PMID: 30797187 [PubMed - as supplied by publisher]

Intestinal archaea inversely associated with childhood asthma.

J Allergy Clin Immunol. 2019 Feb 20;:

Authors: Barnett DJM, Mommers M, Penders J, Arts ICW, Thijs C

Abstract
BACKGROUND: Methanogenic archaea are a key part of the gut microbiota alongside bacteria. However there is comparatively little research on the role of archaea in health.
OBJECTIVE: As in-vitro and animal experiments have demonstrated immunological effects of archaea, we hypothesised that intestinal exposure to archaeal species would influence the risk of asthma and other allergic diseases. We present the first human study connecting gut archaea with childhood asthma.
METHODS: We performed a cross-sectional analysis nested within the Dutch KOALA Birth Cohort Study. DNA from two common intestinal archaeal species, Methanosphaera stadtmanae and Methanobrevibacter smithii, was quantified in faecal samples from 472 children at school age, using qPCR. Our primary outcome was parent-reported asthma at 6-10 years. Secondary outcomes were questionnaire-reported eczema, total serum IgE levels, sensitisation to aero- and food-allergens and lung function (FEV1/FVC). Associations between the presence/absence of each archaeal species and outcome were assessed with logistic or linear regression models, adjusted for potential confounders.
RESULTS: Presence of M. stadtmanae was significantly associated with a lower risk of asthma, adjusted OR 0.32 (0.08 - 0.98). In addition, asthma risk decreased monotonically across three categories of increasing M. stadtmanae abundance (adjusted p-for-trend = 0.035). We also observed a non-significant tendency for less eczema and IgE sensitisation amongst children with M. stadtmanae. M. smithii was not associated with any outcome.
CONCLUSION: Further longitudinal and experimental research is needed to explore whether archaea could be directly linked to asthma risk, or if archaeal abundance is indicative of other health-relevant variation in microbiota composition.

PMID: 30796982 [PubMed - as supplied by publisher]

Evolutionary design of regulatory control. II. Robust error-correcting feedback increases genetic and phenotypic variability.

J Theor Biol. 2019 Feb 20;:

Authors: Frank SA

Abstract
As systems become more robust against perturbations, they can compensate for greater sloppiness in the performance of their components. That robust compensation reduces the force of natural selection on the system's components, leading to component decay. The paradoxical coupling of robustness and decay predicts that robust systems evolve cheaper, lower performing components, which accumulate greater mutational genetic variability and which have greater phenotypic stochasticity in trait expression. Previous work noted the paradox of robustness. However, no general theory for the evolutionary dynamics of system robustness and component decay has been developed. This article takes a first step by linking engineering control theory with the genetic theory of evolutionary dynamics. Control theory emphasizes error-correcting feedback as the single greatest principle in robust system design. Linking control theory to evolution leads to a theory for the evolutionary dynamics of error-correcting feedback, a unifying approach for the evolutionary analysis of robust systems. This article shows how increasingly robust systems accumulate more genetic variability and greater stochasticity of expression in their components. The theory predicts different levels of variability between different regulatory control architectures and different levels of variability between different components within a particular regulatory control system. The theory also shows that increasing robustness reduces the frequency of system failures associated with disease and, simultaneously, causes a strong increase in the heritability of disease. Thus, robust error correction in biological regulatory control may partly explain the puzzlingly high heritability of disease and, more generally, the surprisingly high heritability of fitness.

PMID: 30796941 [PubMed - as supplied by publisher]

Chloroplasts use calcium signals to call for help under heat stress.

Plant Cell Physiol. 2019 Feb 22;:

Authors: Teige M

PMID: 30796458 [PubMed - as supplied by publisher]

Odorant ligands for the CO2 receptor in two Anopheles vectors of malaria.

Sci Rep. 2019 Feb 22;9(1):2549

Authors: Coutinho-Abreu IV, Sharma K, Cui L, Yan G, Ray A

Abstract
Exhaled CO2 is an important host-seeking cue for Anopheles mosquitoes, which is detected by a highly conserved heteromeric receptor consisting of three 7-transmembrane proteins Gr22, Gr23, and Gr24. The CO2 receptor neuron has been shown to also respond sensitively to a variety of odorants in Aedes aegypti. The detection of CO2 is important for upwind navigation and for enhancing the attraction to body heat as well as to skin odorants. The orthologs of the CO2 receptor proteins are present in malaria-transmitting mosquitoes like Anopheles coluzzii and Anopheles sinensis. Activators and inhibitors of the CO2-neuron were tested on the maxillary palps in these two species by single-sensillum electrophysiology. The electrophysiological testing of three prolonged-activator odorants identified originally in Aedes aegypti also showed varying ability to reduce the CO2-ellicited increase in spikes. These findings provide a foundation for comparing the functional conservation with the evolutionary conservation of an important class of odorant receptor. The identification of a suite of natural odorants that can be used to modify the CO2-detection pathway may also contribute to odor-blends that can alter the behavior of these disease transmitting mosquitoes.

PMID: 30796292 [PubMed - in process]

Novel RU486 (mifepristone) analogues with increased activity against Venezuelan Equine Encephalitis Virus but reduced progesterone receptor antagonistic activity.

Sci Rep. 2019 Feb 22;9(1):2634

Authors: DeBono A, Thomas DR, Lundberg L, Pinkham C, Cao Y, Graham JD, Clarke CL, Wagstaff KM, Shechter S, Kehn-Hall K, Jans DA

Abstract
There are currently no therapeutics to treat infection with the alphavirus Venezuelan equine encephalitis virus (VEEV), which causes flu-like symptoms leading to neurological symptoms in up to 14% of cases. Large outbreaks of VEEV can result in 10,000 s of human cases and mass equine death. We previously showed that mifepristone (RU486) has anti-VEEV activity (EC50 = 20 μM) and only limited cytotoxicity (CC50 > 100 μM), but a limitation in its use is its abortifacient activity resulting from its ability to antagonize the progesterone receptor (PR). Here we generate a suite of new mifepristone analogues with enhanced antiviral properties, succeeding in achieving >11-fold improvement in anti-VEEV activity with no detectable increase in toxicity. Importantly, we were able to derive a lead compound with an EC50 of 7.2 µM and no detectable PR antagonism activity. Finally, based on our SAR analysis we propose avenues for the further development of these analogues as safe and effective anti-VEEV agents.

PMID: 30796232 [PubMed - in process]

Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477.

Cell Death Dis. 2019 Feb 22;10(3):185

Authors: Mallick DJ, Soderquist RS, Bates D, Eastman A

Abstract
Targeting anti-apoptotic BCL2 family proteins has become an attractive therapeutic strategy for many cancers, and the BCL2-selective inhibitor ABT-199 (venetoclax) has obtained clinical success. However, MCL1 can promote drug resistance and overall cancer cell survival. Thus, there is a critical need to develop an effective drug that antagonizes MCL1. However, most putative MCL1 inhibitors have been misclassified as they fail to directly inhibit MCL1 in cells, but rather induce the pro-apoptotic protein NOXA. We have investigated three putative MCL1 inhibitors: MIM1, UMI-77, and A-1210477. All three compounds were developed in cell-free assays and then found to be cytotoxic, and hence assumed to directly target MCL1 in cells. Here, we investigated whether these compounds directly inhibit MCL1 or inhibit MCL1 indirectly through the induction of NOXA. Both MIM1- and UMI-77-induced NOXA through the unfolded protein response pathway, and sensitized leukemia cells to ABT-199; this cytotoxicity was dependent on NOXA suggesting that these compounds do not directly target MCL1. A-1210477 was the only compound that did not induce NOXA, but it still sensitized cells to ABT-199. A-1210477 induced accumulation of MCL1 protein consistent with it binding and preventing MCL1 degradation. However, at concentrations used in several prior studies, A-1210477 also induced cytochrome c release, caspase activation, and apoptosis in a BAX/BAK-independent manner. Furthermore, the release of cytochrome c occurred without loss of mitochondrial membrane potential. This apoptosis was extremely rapid, sometimes occurring within 0.5-1 h. Hence, we have identified a novel mechanism of apoptosis that circumvents the known mechanisms of cytochrome c release. It remains to be determined whether these unexpected mechanisms of action of putative BH3 mimetics will have therapeutic potential.

PMID: 30796196 [PubMed - in process]

De novo gene signature identification from single-cell RNA-seq with hierarchical Poisson factorization.

Mol Syst Biol. 2019 Feb 22;15(2):e8557

Authors: Levitin HM, Yuan J, Cheng YL, Ruiz FJ, Bush EC, Bruce JN, Canoll P, Iavarone A, Lasorella A, Blei DM, Sims PA

Abstract
Common approaches to gene signature discovery in single-cell RNA-sequencing (scRNA-seq) depend upon predefined structures like clusters or pseudo-temporal order, require prior normalization, or do not account for the sparsity of single-cell data. We present single-cell hierarchical Poisson factorization (scHPF), a Bayesian factorization method that adapts hierarchical Poisson factorization (Gopalan et al, 2015, Proceedings of the 31st Conference on Uncertainty in Artificial Intelligence, 326) for de novo discovery of both continuous and discrete expression patterns from scRNA-seq. scHPF does not require prior normalization and captures statistical properties of single-cell data better than other methods in benchmark datasets. Applied to scRNA-seq of the core and margin of a high-grade glioma, scHPF uncovers marked differences in the abundance of glioma subpopulations across tumor regions and regionally associated expression biases within glioma subpopulations. scHFP revealed an expression signature that was spatially biased toward the glioma-infiltrated margins and associated with inferior survival in glioblastoma.

PMID: 30796088 [PubMed - in process]

Unraveling the hidden universe of small proteins in bacterial genomes.

Mol Syst Biol. 2019 Feb 22;15(2):e8290

Authors: Miravet-Verde S, Ferrar T, Espadas-García G, Mazzolini R, Gharrab A, Sabido E, Serrano L, Lluch-Senar M

Abstract
Identification of small open reading frames (smORFs) encoding small proteins (≤ 100 amino acids; SEPs) is a challenge in the fields of genome annotation and protein discovery. Here, by combining a novel bioinformatics tool (RanSEPs) with "-omics" approaches, we were able to describe 109 bacterial small ORFomes. Predictions were first validated by performing an exhaustive search of SEPs present in Mycoplasma pneumoniae proteome via mass spectrometry, which illustrated the limitations of shotgun approaches. Then, RanSEPs predictions were validated and compared with other tools using proteomic datasets from different bacterial species and SEPs from the literature. We found that up to 16 ± 9% of proteins in an organism could be classified as SEPs. Integration of RanSEPs predictions with transcriptomics data showed that some annotated non-coding RNAs could in fact encode for SEPs. A functional study of SEPs highlighted an enrichment in the membrane, translation, metabolism, and nucleotide-binding categories. Additionally, 9.7% of the SEPs included a N-terminus predicted signal peptide. We envision RanSEPs as a tool to unmask the hidden universe of small bacterial proteins.

PMID: 30796087 [PubMed - in process]

The dual PI3K/mTOR-pathway inhibitor GDC-0084 achieves antitumor activity in PIK3CA-mutant breast cancer brain metastases.

Clin Cancer Res. 2019 Feb 22;:

Authors: Ippen FM, Alvarez-Breckenridge CA, Kuter BM, Fink AL, Bihun IV, Lastrapes M, Penson T, Schmidt SP, Wojtkiewicz GR, Ning J, Subramanian M, Giobbie-Hurder A, Martinez-Lage M, Carter SL, Cahill DP, Wakimoto H, Brastianos PK

Abstract
PURPOSE: Previous studies have shown that the PI3K/Akt/mTOR-pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR-inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.
EXPERIMENTAL DESIGN: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA-wildtype breast cancer cell lines and the isogenic pairs of PIK3CA-wildtype and -mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell cycle analysis and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and immunohistochemistry.
RESULTS: In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA-wildtype cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA-wildtype brain tumors.
CONCLUSIONS: The results of this study suggest that the brain-penetrant PI3K/mTOR-targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

PMID: 30796030 [PubMed - as supplied by publisher]

67 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 2019/02/23

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.

16 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 2019/02/21

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.

29 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 2019/02/20

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.

13 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 2019/02/19

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.

An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors.

Eur J Med Chem. 2019 Feb 10;167:269-290

Authors: Tiz DB, Skok Ž, Durcik M, Tomašič T, Mašič LP, Ilaš J, Zega A, Draskovits G, Révész T, Nyerges Á, Pál C, Cruz CD, Tammela P, Žigon D, Kikelj D, Zidar N

Abstract
ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC50 values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.

PMID: 30776691 [PubMed - as supplied by publisher]

Translating transcription: proteomics in chronic rhinosinusitis with nasal polyps reveals significant discordance with messenger RNA expression.

Int Forum Allergy Rhinol. 2019 Feb 18;:

Authors: Workman AD, Nocera AL, Mueller SK, Otu HH, Libermann TA, Bleier BS

Abstract
BACKGROUND: Much of the literature examining chronic rhinosinusitis with nasal polyps (CRSwNP) immunopathology has been predicated on messenger RNA (mRNA) analysis with the assumption that transcriptional changes would reflect end-effector protein expression. The purpose of this study was to test this hypothesis using matched transcriptomic and proteomic data sets.
METHODS: Matched tissue proteomic and transcriptomic arrays were quantified in CRSwNP polyp tissue and control inferior turbinate tissue (n = 10/group). Mucus samples were additionally collected in 6 subjects from each group. Proteins were grouped into functional categories by bioinformatics and differential expression analyses. Log-log regression and Pearson correlations were performed to determine the level of agreement between data sets.
RESULTS: Of the 1310 proteins examined, 393 were significantly differentially expressed in CRSwNP. On regression analysis, differences in protein expression were poorly predicted by differences in mRNA expression (R2 = 0.020, p < 0.05). Several genes canonically thought to be overexpressed in CRSwNP, including IL-5, IL-13, TSLP, CCL13, and CCL26, showed substantial increases in mRNA transcription, but had minimally or unchanged protein expression. Others, including IgE, periostin, CCL18, and CST1/2, were increased at both the transcriptomic and proteomic levels. Among differentially regulated proteins, tissue and mucus protein levels showed weak correlation (r = 0.26, p < 0.0001).
CONCLUSION: Proteomic analysis in CRSwNP has revealed novel disease-associated proteins and pathways, yet correlates poorly with transcriptomic data. The increasing availability of proteomic arrays opens the door to new potential explanatory mechanisms in CRSwNP and suggests that mRNA based studies should be validated with protein analysis.

PMID: 30775848 [PubMed - as supplied by publisher]

Recent advances in proximity-based labeling methods for interactome mapping.

F1000Res. 2019;8:

Authors: Trinkle-Mulcahy L

Abstract
Proximity-based labeling has emerged as a powerful complementary approach to classic affinity purification of multiprotein complexes in the mapping of protein-protein interactions. Ongoing optimization of enzyme tags and delivery methods has improved both temporal and spatial resolution, and the technique has been successfully employed in numerous small-scale (single complex mapping) and large-scale (network mapping) initiatives. When paired with quantitative proteomic approaches, the ability of these assays to provide snapshots of stable and transient interactions over time greatly facilitates the mapping of dynamic interactomes. Furthermore, recent innovations have extended biotin-based proximity labeling techniques such as BioID and APEX beyond classic protein-centric assays (tag a protein to label neighboring proteins) to include RNA-centric (tag an RNA species to label RNA-binding proteins) and DNA-centric (tag a gene locus to label associated protein complexes) assays.

PMID: 30774936 [PubMed - in process]

Efficient anticorrelated variance reduction for stochastic simulation of biochemical reactions.

IET Syst Biol. 2019 Feb;13(1):16-23

Authors: Thanh VH

Abstract
We investigate the computational challenge of improving the accuracy of the stochastic simulation estimation by inducing negative correlation through the anticorrelated variance reduction technique. A direct application of the technique to the stochastic simulation algorithm (SSA), employing the inverse transformation, is not efficient for simulating large networks because its computational cost is similar to the sum of independent simulation runs. We propose in this study a new algorithm that employs the propensity bounds of reactions, introduced recently in their rejection-based SSA, to correlate and synchronise the trajectories during the simulation. The selection of reaction firings by our approach is exact due to the rejection-based mechanism. In addition, by applying the anticorrelated variance technique to select reaction firings, our approach can induce substantial correlation between realisations, hence reducing the variance of the estimator. The computational advantage of our rejection-based approach in comparison with the traditional inverse transformation is that it only needs to maintain a single data structure storing propensity bounds of reactions, which is updated infrequently, hence achieving better performance.

PMID: 30774112 [PubMed - in process]