Characterization of physiological responses to 22 gene knockouts in Escherichia coli central carbon metabolism.

Metab Eng. 2016 May 19;

Authors: Long CP, Gonzalez JE, Sandoval NR, Antoniewicz MR

Abstract
Understanding the impact of gene knockouts on cellular physiology, and metabolism in particular, is centrally important to quantitative systems biology and metabolic engineering. Here, we present a comprehensive physiological characterization of wild-type Escherichia coli and 22 knockouts of enzymes in the upper part of central carbon metabolism, including the PTS system, glycolysis, pentose phosphate pathway and Entner-Doudoroff pathway. Our results reveal significant metabolic changes that are affected by specific gene knockouts. Analysis of collective trends and correlations in the data using principal component analysis (PCA) provide new, and sometimes surprising, insights into E. coli physiology. Additionally, by comparing the data-to-model predictions from constraint-based approaches such as FBA, MOMA and RELATCH we demonstrate the important role of less well-understood kinetic and regulatory effects in central carbon metabolism.

PMID: 27212692 [PubMed - as supplied by publisher]

Multi-Omics of Single Cells: Strategies and Applications.

Trends Biotechnol. 2016 May 19;

Authors: Bock C, Farlik M, Sheffield NC

Abstract
Most genome-wide assays provide averages across large numbers of cells, but recent technological advances promise to overcome this limitation. Pioneering single-cell assays are now available for genome, epigenome, transcriptome, proteome, and metabolome profiling. Here, we describe how these different dimensions can be combined into multi-omics assays that provide comprehensive profiles of the same cell.

PMID: 27212022 [PubMed - as supplied by publisher]

Characterizing Strain Variation in Engineered E. coli Using a Multi-Omics-Based Workflow.

Cell Syst. 2016 May 19;

Authors: Brunk E, George KW, Alonso-Gutierrez J, Thompson M, Baidoo E, Wang G, Petzold CJ, McCloskey D, Monk J, Yang L, O'Brien EJ, Batth TS, Martin HG, Feist A, Adams PD, Keasling JD, Palsson BO, Lee TS

Abstract
Understanding the complex interactions that occur between heterologous and native biochemical pathways represents a major challenge in metabolic engineering and synthetic biology. We present a workflow that integrates metabolomics, proteomics, and genome-scale models of Escherichia coli metabolism to study the effects of introducing a heterologous pathway into a microbial host. This workflow incorporates complementary approaches from computational systems biology, metabolic engineering, and synthetic biology; provides molecular insight into how the host organism microenvironment changes due to pathway engineering; and demonstrates how biological mechanisms underlying strain variation can be exploited as an engineering strategy to increase product yield. As a proof of concept, we present the analysis of eight engineered strains producing three biofuels: isopentenol, limonene, and bisabolene. Application of this workflow identified the roles of candidate genes, pathways, and biochemical reactions in observed experimental phenomena and facilitated the construction of a mutant strain with improved productivity. The contributed workflow is available as an open-source tool in the form of iPython notebooks.

PMID: 27211860 [PubMed - as supplied by publisher]

Systems toxicology-based assessment of the candidate modified risk tobacco product THS2.2 for the adhesion of monocytic cells to human coronary arterial endothelial cells.

Toxicology. 2016 Jan 2;339:73-86

Authors: Poussin C, Laurent A, Peitsch MC, Hoeng J, De Leon H

Abstract
Alterations of endothelial adhesive properties by cigarette smoke (CS) can progressively favor the development of atherosclerosis which may cause cardiovascular disorders. Modified risk tobacco products (MRTPs) are tobacco products developed to reduce smoking-related risks. A systems biology/toxicology approach combined with a functional in vitro adhesion assay was used to assess the impact of a candidate heat-not-burn technology-based MRTP, Tobacco Heating System (THS) 2.2, on the adhesion of monocytic cells to human coronary arterial endothelial cells (HCAECs) compared with a reference cigarette (3R4F). HCAECs were treated for 4h with conditioned media of human monocytic Mono Mac 6 (MM6) cells preincubated with low or high concentrations of aqueous extracts from THS2.2 aerosol or 3R4F smoke for 2h (indirect treatment), unconditioned media (direct treatment), or fresh aqueous aerosol/smoke extracts (fresh direct treatment). Functional and molecular investigations revealed that aqueous 3R4F smoke extract promoted the adhesion of MM6 cells to HCAECs via distinct direct and indirect concentration-dependent mechanisms. Using the same approach, we identified significantly reduced effects of aqueous THS2.2 aerosol extract on MM6 cell-HCAEC adhesion, and reduced molecular changes in endothelial and monocytic cells. Ten- and 20-fold increased concentrations of aqueous THS2.2 aerosol extract were necessary to elicit similar effects to those measured with 3R4F in both fresh direct and indirect exposure modalities, respectively. Our systems toxicology study demonstrated reduced effects of an aqueous aerosol extract from the candidate MRTP, THS2.2, using the adhesion of monocytic cells to human coronary endothelial cells as a surrogate pathophysiologically relevant event in atherogenesis.

PMID: 26655683 [PubMed - indexed for MEDLINE]

Network Modeling Reveals Cross Talk of MAP Kinases during Adaptation to Caspofungin Stress in Aspergillus fumigatus.

PLoS One. 2015;10(9):e0136932

Authors: Altwasser R, Baldin C, Weber J, Guthke R, Kniemeyer O, Brakhage AA, Linde J, Valiante V

Abstract
Mitogen activated protein kinases (MAPKs) are highly conserved in eukaryotic organisms. In pathogenic fungi, their activities were assigned to different physiological functions including drug adaptation and resistance. Aspergillus fumigatus is a human pathogenic fungus, which causes life-threatening invasive infections. Therapeutic options against invasive mycoses are still limited. One of the clinically used drugs is caspofungin, which specifically targets the fungal cell wall biosynthesis. A systems biology approach, based on comprehensive transcriptome data sets and mathematical modeling, was employed to infer a regulatory network and identify key interactions during adaptation to caspofungin stress in A. fumigatus. Mathematical modeling and experimental validations confirmed an intimate cross talk occurring between the cell wall-integrity and the high osmolarity-glycerol signaling pathways. Specifically, increased concentrations of caspofungin promoted activation of these signalings. Moreover, caspofungin affected the intracellular transport, which caused an additional osmotic stress that is independent of glucan inhibition. High concentrations of caspofungin reduced this osmotic stress, and thus decreased its toxic activity. Our results demonstrated that MAPK signaling pathways play a key role during caspofungin adaptation and are contributing to the paradoxical effect exerted by this drug.

PMID: 26356475 [PubMed - indexed for MEDLINE]

Clinical decision-making and secondary findings in systems medicine.

BMC Med Ethics. 2016;17(1):32

Authors: Fischer T, Brothers KB, Erdmann P, Langanke M

Abstract
BACKGROUND: Systems medicine is the name for an assemblage of scientific strategies and practices that include bioinformatics approaches to human biology (especially systems biology); "big data" statistical analysis; and medical informatics tools. Whereas personalized and precision medicine involve similar analytical methods applied to genomic and medical record data, systems medicine draws on these as well as other sources of data. Given this distinction, the clinical translation of systems medicine poses a number of important ethical and epistemological challenges for researchers working to generate systems medicine knowledge and clinicians working to apply it.
DISCUSSION: This article focuses on three key challenges: First, we will discuss the conflicts in decision-making that can arise when healthcare providers committed to principles of experimental medicine or evidence-based medicine encounter individualized recommendations derived from computer algorithms. We will explore in particular whether controlled experiments, such as comparative effectiveness trials, should mediate the translation of systems medicine, or if instead individualized findings generated through "big data" approaches can be applied directly in clinical decision-making. Second, we will examine the case of the Riyadh Intensive Care Program Mortality Prediction Algorithm, pejoratively referred to as the "death computer," to demonstrate the ethical challenges that can arise when big-data-driven scoring systems are applied in clinical contexts. We argue that the uncritical use of predictive clinical algorithms, including those envisioned for systems medicine, challenge basic understandings of the doctor-patient relationship. Third, we will build on the recent discourse on secondary findings in genomics and imaging to draw attention to the important implications of secondary findings derived from the joint analysis of data from diverse sources, including data recorded by patients in an attempt to realize their "quantified self." This paper examines possible ethical challenges that are likely to be raised as systems medicine to be translated into clinical medicine. These include the epistemological challenges for clinical decision-making, the use of scoring systems optimized by big data techniques and the risk that incidental and secondary findings will significantly increase. While some ethical implications remain still hypothetical we should use the opportunity to prospectively identify challenges to avoid making foreseeable mistakes when systems medicine inevitably arrives in routine care.

PMID: 27209083 [PubMed - as supplied by publisher]

Text mining, a race against time? An attempt to quantify possible variations in text corpora of medical publications throughout the years.

Comput Biol Med. 2016 Apr 20;73:173-185

Authors: Wagner M, Vicinus B, Muthra ST, Richards TA, Linder R, Frick VO, Groh A, Rubie C, Weichert F

Abstract
BACKGROUND: The continuous growth of medical sciences literature indicates the need for automated text analysis. Scientific writing which is neither unitary, transcending social situation nor defined by a timeless idea is subject to constant change as it develops in response to evolving knowledge, aims at different goals, and embodies different assumptions about nature and communication. The objective of this study was to evaluate whether publication dates should be considered when performing text mining.
METHODS: A search of PUBMED for combined references to chemokine identifiers and particular cancer related terms was conducted to detect changes over the past 36 years. Text analyses were performed using freeware available from the World Wide Web. TOEFL Scores of territories hosting institutional affiliations as well as various readability indices were investigated. Further assessment was conducted using Principal Component Analysis. Laboratory examination was performed to evaluate the quality of attempts to extract content from the examined linguistic features.
RESULTS: The PUBMED search yielded a total of 14,420 abstracts (3,190,219 words). The range of findings in laboratory experimentation were coherent with the variability of the results described in the analyzed body of literature. Increased concurrence of chemokine identifiers together with cancer related terms was found at the abstract and sentence level, whereas complexity of sentences remained fairly stable.
CONCLUSIONS: The findings of the present study indicate that concurrent references to chemokines and cancer increased over time whereas text complexity remained stable.

PMID: 27208610 [PubMed - as supplied by publisher]

Members of BTB gene family regulate negatively nitrate uptake and nitrogen use efficiency in Arabidopsis thaliana and Oryza sativa.

Plant Physiol. 2016 Apr 27;

Authors: Araus V, Vidal EA, Puelma T, Alamos S, Mieulet D, Guiderdoni E, Gutiérrez RA

Abstract
Development of crops with improved nitrogen use efficiency (NUE) is essential for sustainable agriculture. However, achieving this goal has proven difficult due to NUE is a complex trait encompassing physiological and developmental processes. We thought to tackle this problem by taking a systems biology approach to identify candidate target genes. First, we used a supervised machine-learning algorithm to predict a NUE gene network in Arabidopsis thaliana. Second, we identified BT2, a member of the Bric-a-Brac/Tramtrack/Broad (BTB) gene family, as the most central and connected gene in the NUE network. Third, we experimentally tested BT2 for a role in NUE. We found NUE decreased in plants overexpressing BT2 gene as compared to wild-type plants under limiting nitrate conditions. Additionally, NUE increased as compared to wild-type plants under low nitrate conditions in double mutant plants in bt2 and its closely related homolog bt1, indicating a functional redundancy of BT1 and BT2 for NUE. Expression of the nitrate transporter genes NRT2.1 and NRT2.4 increased in the bt1/bt2 double mutant as compared to wild-type plants, with a concomitant 65% increase in nitrate uptake under low nitrate conditions. Similar to Arabidopsis, we found that mutation of the BT1/BT2 ortholog gene in rice OsBT increased NUE by 20% as compared to wild-type rice plants under low nitrogen conditions. These results indicate BT gene family members act as conserved negative regulators of nitrate uptake genes and NUE in plants and highlight them as prime targets for future strategies to improve NUE in crops.

PMID: 27208309 [PubMed - as supplied by publisher]

It may Seem Inflammatory, but Some T Cells are Innately Healing to the Bone.

J Bone Miner Res. 2016 May 21;

Authors: Kalyan S

Abstract
Among the most significant developments to have taken place in osteology over the last few decades is an evolution from treating and viewing bone disorders primarily through an endocrine lens to instead seeing them as metabolic disorders that interface at the molecular and cellular level with the immune system. Osteoimmunology was officially born in response to accumulating evidence that the immune system is integrally involved in bone remodelling, but much of the early work focused on the role of conventional αβ T cells in driving bone loss. There is, however, emerging data indicating that innate lymphocytes, in particular γδ T cells, may in fact be important for bone regeneration. We first observed that bisphosphonate-associated osteonecrosis of the jaw (ONJ), a rare but serious adverse drug effect characterized by non-healing necrotic bone tissue of the mandible or maxilla, was linked to a deficiency in a subset of γδ T cells found in human peripheral blood. Patients who developed ONJ while on bisphosphonate therapy not only lacked the main subset of circulating γδ T cells, but they also all had underlying conditions that compromised their immune integrity. A number of recent studies have unraveled the role of γδ T cells (and lymphocytes sharing their characteristics) in bone regeneration - particularly for fracture healing. These findings seem to contradict the prevailing view of such "inflammatory" T cells as being bone degenerative rather than restorative. This viewpoint melds together the emerging evidence of these so-called inflammatory T cells in bone remodeling and healing - showing that they are not in fact "all bad to the bone". This article is protected by copyright. All rights reserved.

PMID: 27207251 [PubMed - as supplied by publisher]

Strategies for new and improved vaccines against ticks and tick-borne diseases.

Parasite Immunol. 2016 May 20;

Authors: de la Fuente J, Kopáček P, Lew-Tabor A, Maritz-Olivier C

Abstract
Ticks infest a variety of animal species and transmit pathogens causing disease in both humans and animals worldwide. Tick-host-pathogen interactions have evolved through dynamic processes that accommodated the genetic traits of the hosts, pathogens transmitted and the vector tick species that mediate their development and survival. New approaches for tick control are dependent on defining molecular interactions between hosts, ticks and pathogens to allow for discovery of key molecules that could be tested in vaccines or new generation therapeutics for intervention of tick-pathogen cycles. Currently, tick vaccines constitute an effective and environmentally sound approach for the control of ticks and the transmission of the associated tick-borne diseases. New candidate protective antigens will most likely be identified by focusing on proteins with relevant biological function in the feeding, reproduction, development, immune response, subversion of host immunity of the tick vector and/or molecules vital for pathogen infection and transmission. This review addresses different approaches and strategies used for the discovery of protective antigens, including focusing on relevant tick biological functions and proteins, reverse genetics, vaccinomics and tick protein evolution and interactomics. New and improved tick vaccines will most likely contain multiple antigens to control tick infestations and pathogen infection and transmission. This article is protected by copyright. All rights reserved.

PMID: 27203187 [PubMed - as supplied by publisher]

The Obama Administration's Cancer Moonshot: A Call for Proteomics.

Clin Cancer Res. 2016 May 19;

Authors: Conrads TP, Petricoin EF

Abstract
The Cancer Moonshot Program has been launched and represents a potentially paradigm-shifting initiative with the goal to implement a focused national effort to double the rate of progress against cancer. The placement of precision medicine, immunotherapy, genomics, and combination therapies was placed at the central nexus of this initiative. While we are extremely enthusiastic about the goals of the program, it is time we meet this revolutionary project with equally bold and cutting-edge ideas: its time we move firmly into the post-genome era and provide the necessary resources to propel and seize on innovative recent gains in the field of proteomics required for it to stand on equal footing in this narrative as a combined, synergistic engine for molecular profiling. After all, while the genome is the information archive, it is the proteins that actually do the work of the cell and represent the structural cellular machinery. It is the proteins that comprise most of the biomarkers that are measured to detect cancers, constitute the antigens that drive immune response and inter and itntracellular communications, and it is the proteins that are the drug targets for nearly every targeted therapy that is being evaluated in cancer trials today. We believe that a combined systems biology view of the tumor microenvironment that orients cancer studies back to the functional proteome, phosphoproteome and biochemistry of the cell will be essential to deliver on the promise of the Cancer Moonshot program.

PMID: 27199492 [PubMed - as supplied by publisher]

Reconstruction of gene regulatory networks reveals chromatin remodelers and key transcription factors in tumorigenesis.

Genome Med. 2016;8(1):57

Authors: Malysheva V, Mendoza-Parra MA, Saleem MA, Gronemeyer H

Abstract
BACKGROUND: Alterations in genetic and epigenetic landscapes are known to contribute to the development of different types of cancer. However, the mechanistic links between transcription factors and the epigenome which coordinate the deregulation of gene networks during cell transformation are largely unknown.
METHODS: We used an isogenic model of stepwise tumorigenic transformation of human primary cells to monitor the progressive deregulation of gene networks upon immortalization and oncogene-induced transformation. We applied a systems biology approach by combining transcriptome and epigenome data for each step during transformation and integrated transcription factor-target gene associations in order to reconstruct the gene regulatory networks that are at the basis of the transformation process.
RESULTS: We identified 142 transcription factors and 24 chromatin remodelers/modifiers (CRMs) which are preferentially associated with specific co-expression pathways that originate from deregulated gene programming during tumorigenesis. These transcription factors are involved in the regulation of divers processes, including cell differentiation, the immune response, and the establishment/modification of the epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed patterns that distinguish groups of genes which are not only co-regulated but also functionally related. Decortication of transcription factor targets enabled us to define potential key regulators of cell transformation which are engaged in RNA metabolism and chromatin remodeling.
CONCLUSIONS: We reconstructed gene regulatory networks that reveal the alterations occurring during human cellular tumorigenesis. Using these networks we predicted and validated several transcription factors as key players for the establishment of tumorigenic traits of transformed cells. Our study suggests a direct implication of CRMs in oncogene-induced tumorigenesis and identifies new CRMs involved in this process. This is the first comprehensive view of the gene regulatory network that is altered during the process of stepwise human cellular tumorigenesis in a virtually isogenic system.

PMID: 27198694 [PubMed - in process]

Simple biophysics underpins collective conformations of the intrinsically disordered proteins of the Nuclear Pore Complex.

Elife. 2016;5

Authors: Vovk A, Gu C, Opferman MG, Kapinos LE, Lim RY, Coalson RD, Jasnow D, Zilman A

Abstract
Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function.

PMID: 27198189 [PubMed - in process]

Metabolomics in cardiovascular diseases.

J Pharm Biomed Anal. 2015 Sep 10;113:121-36

Authors: Kordalewska M, Markuszewski MJ

Abstract
Cardiovascular diseases (CVDs) are the main cause of death globally. There is a need for the development of specific diagnostic methods, more effective therapeutic procedures as well as drugs, which can decrease the risk of deaths in the course of CVDs. For this reason, better understanding and explanation of molecular pathomechanisms of CVDs are essential. Metabolomics is focused on analysis of metabolites, small molecules which reflect the state of an organism in a certain point of time. Application of metabolomics approach in the investigation of molecular processes responsible for CVDs development may provide valuable information. In this article we overviewed recent reports employing application of untargeted and targeted metabolomic analyses in particular CVDs. Moreover, we focused on applications of various analytical platforms and metabolomics approaches which may contribute to the explanation of the pathomechanisms of different cardiovascular diseases.

PMID: 25958299 [PubMed - indexed for MEDLINE]

Metabolomics for laboratory diagnostics.

J Pharm Biomed Anal. 2015 Sep 10;113:108-20

Authors: Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R

Abstract
Metabolomics is an emerging approach in a systems biology field. Due to continuous development in advanced analytical techniques and in bioinformatics, metabolomics has been extensively applied as a novel, holistic diagnostic tool in clinical and biomedical studies. Metabolome's measurement, as a chemical reflection of a current phenotype of a particular biological system, is nowadays frequently implemented to understand pathophysiological processes involved in disease progression as well as to search for new diagnostic or prognostic biomarkers of various organism's disorders. In this review, we discussed the research strategies and analytical platforms commonly applied in the metabolomics studies. The applications of the metabolomics in laboratory diagnostics in the last 5 years were also reviewed according to the type of biological sample used in the metabolome's analysis. We also discussed some limitations and further improvements which should be considered taking in mind potential applications of metabolomic research and practice.

PMID: 25577715 [PubMed - indexed for MEDLINE]

Genetic Approaches to Study Plant Responses to Environmental Stresses: An Overview.

Biology (Basel). 2016;5(2)

Authors: Moustafa K, Cross JM

Abstract
The assessment of gene expression levels is an important step toward elucidating gene functions temporally and spatially. Decades ago, typical studies were focusing on a few genes individually, whereas now researchers are able to examine whole genomes at once. The upgrade of throughput levels aided the introduction of systems biology approaches whereby cell functional networks can be scrutinized in their entireties to unravel potential functional interacting components. The birth of systems biology goes hand-in-hand with huge technological advancements and enables a fairly rapid detection of all transcripts in studied biological samples. Even so, earlier technologies that were restricted to probing single genes or a subset of genes still have their place in research laboratories. The objective here is to highlight key approaches used in gene expression analysis in plant responses to environmental stresses, or, more generally, any other condition of interest. Northern blots, RNase protection assays, and qPCR are described for their targeted detection of one or a few transcripts at a once. Differential display and serial analysis of gene expression represent non-targeted methods to evaluate expression changes of a significant number of gene transcripts. Finally, microarrays and RNA-seq (next-generation sequencing) contribute to the ultimate goal of identifying and quantifying all transcripts in a cell under conditions or stages of study. Recent examples of applications as well as principles, advantages, and drawbacks of each method are contrasted. We also suggest replacing the term "Next-Generation Sequencing (NGS)" with another less confusing synonym such as "RNA-seq", "high throughput sequencing", or "massively parallel sequencing" to avoid confusion with any future sequencing technologies.

PMID: 27196939 [PubMed - as supplied by publisher]

Revealing oxidative damage to enzymes of carbohydrate metabolism in yeast: An integration of 2D DIGE, quantitative proteomics and bioinformatics.

Proteomics. 2016 May 19;

Authors: Boone C, Grove R, Adamcova D, Braga C, Adamec J

Abstract
Clinical usage of lidocaine, a pro-oxidant has been linked with severe, mostly neurological complications. The mechanism(s) causing these complications is independent of the blockade of voltage gated sodium channels. The budding yeast S. cerevisiae lacks voltage gated sodium channels, thus provides an ideal system to investigate lidocaine induced protein and pathway alterations. Whole proteome alterations leading to these complications have not been identified. To address this S. cerevisiae was grown to stationary phase and exposed to an LC50 dose of lidocaine. The differential proteomes of lidocaine treatment and control were resolved six hours post exposure using 2D DIGE. Amine reactive dyes and carbonyl reactive dyes were used to assess protein abundance and protein oxidation, respectively. Quantitative analysis of these dyes ( ≥ 1.5-fold alteration, p ≤ 0.05 ) revealed a total of 33 proteoforms identified by mass spectrometry differing in abundance and/or oxidation upon lidocaine exposure. Network analysis showed enrichment of apoptotic proteins and cell wall maintenance proteins; while the abundance of proteins central to carbohydrate metabolism, such as triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase, and redox proteins superoxide dismutase and peroxiredoxin were significantly decreased. Enzymes of carbohydrate metabolism, such as phosphoglycerate kinase and enolase, the TCA cycle enzyme aconitase, and multiple ATP synthase subunits were found to be oxidatively modified. Also, the activity of aconitase was found to be decreased. Overall these data suggest that toxic doses of lidocaine induce significant disruption of glycolytic pathways, energy production, and redox balance potentially leading to cell malfunction and death. This article is protected by copyright. All rights reserved.

PMID: 27193513 [PubMed - as supplied by publisher]

Peptide-based systems analysis of inflammation induced myeloid-derived suppressor cells reveals diverse signaling pathways.

Proteomics. 2016 May 19;

Authors: Choksawangkarn W, Graham LM, Burke M, Lee SB, Ostrand-Rosenberg S, Fenselau C, Edwards NJ

Abstract
A better understanding of molecular signaling between myeloid-derived suppressor cells (MDSC), tumor cells, T-cells, and inflammatory mediators is expected to contribute to more effective cancer immunotherapies. We focus on plasma membrane associated proteins, which are critical in signaling and intercellular communication, and investigate changes in their abundance in MDSC of tumor-bearing mice subject to heightened versus basal inflammatory conditions. Using spectral counting, we observed statistically significant differential abundances for thirty-five proteins associated with the plasma membrane, most notably the pro-inflammatory proteins S100A8 and S100A9 which induce MDSC and promote their migration. We also tested whether the peptides associated with canonical pathways showed a statistically significant increase or decrease subject to heightened versus basal inflammatory conditions. Collectively, these studies used bottom-up proteomic analysis to identify plasma membrane associated pro-inflammatory molecules and pathways that drive MDSC accumulation, migration, and suppressive potency. This article is protected by copyright. All rights reserved.

PMID: 27193397 [PubMed - as supplied by publisher]

Minimum network constraint on reverse engineering to develop biological regulatory networks.

J Theor Biol. 2015 Sep 7;380:9-15

Authors: Shao B, Wu J, Tian B, Ouyang Q

Abstract
Reconstructing the topological structure of biological regulatory networks from microarray expression data or data of protein expression profiles is one of major tasks in systems biology. In recent years, various mathematical methods have been developed to meet this task. Here, based on our previously reported reverse engineering method, we propose a new constraint, i.e., the minimum network constraint, to facilitate the reconstruction of biological networks. Three well studied regulatory networks (the budding yeast cell cycle network, the fission yeast cell cycle network, and the SOS network of Escherichia coli) were used as the test sets to verify the performance of this method. Numerical results show that the biological networks prefer to use the minimal networks to fulfill their functional tasks, making it possible to apply minimal network criteria in the network reconstruction process. Two scenarios were considered in the reconstruction process: generating data using different initial conditions; and generating data from knock out and over-expression experiments. In both cases, network structures are revealed faithfully in a few steps using our approach.

PMID: 25981630 [PubMed - indexed for MEDLINE]

The fetal brain transcriptome and neonatal behavioral phenotype in the Ts1Cje mouse model of Down syndrome.

Am J Med Genet A. 2015 Sep;167A(9):1993-2008

Authors: Guedj F, Pennings JL, Ferres MA, Graham LC, Wick HC, Miczek KA, Slonim DK, Bianchi DW

Abstract
Human fetuses with Down syndrome demonstrate abnormal brain growth and reduced neurogenesis. Despite the prenatal onset of the phenotype, most therapeutic trials have been conducted in adults. Here, we present evidence for fetal brain molecular and neonatal behavioral alterations in the Ts1Cje mouse model of Down syndrome. Embryonic day 15.5 brain hemisphere RNA from Ts1Cje embryos (n = 5) and wild type littermates (n = 5) was processed and hybridized to mouse gene 1.0 ST arrays. Bioinformatic analyses were implemented to identify differential gene and pathway regulation during Ts1Cje fetal brain development. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate behavioral deficits in Ts1Cje pups (n = 29) versus WT littermates (n = 64) at postnatal days 3-21. Ts1Cje fetal brains displayed more differentially regulated genes (n = 71) than adult (n = 31) when compared to their age-matched euploid brains. Ts1Cje embryonic brains showed up-regulation of cell cycle markers and down-regulation of the solute-carrier amino acid transporters. Several cellular processes were dysregulated at both stages, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling, and oxidoreductase activity. In addition, early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization, and the homing tests were observed. The Ts1Cje mouse model exhibits abnormal gene expression during fetal brain development, and significant neonatal behavioral deficits in the pre-weaning period. In combination with human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition.

PMID: 25975229 [PubMed - indexed for MEDLINE]