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Introduction
Current institution
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May 2013 - July 2015
June 2013 - present
November 2003 - June 2013
Publications
Publications (72)
Background
Diffuse hemispheric glioma, H3 G34-mutant, is a pediatric-type high-grade glioma with limited treatment options and a poor prognosis. RNA-modifying enzymes, including METTL3, are critical for the initiation and maintenance of various cancers, including brain tumors. We previously presented STM2457, a first-in-class RNA-modifying enzyme i...
Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and...
Receptor-ligand interactions govern a wide array of biological pathways, facilitating a cell’s ability to interrogate and integrate information from the extracellular space. Here, using an unbiased genome-wide knockout screen, we identify heparan sulfate proteoglycans (HSPGs) as a major component in the organizational mechanism of cell surface glyc...
Despite technological advances in the proteomics field, sample preparation still represents the main bottleneck in mass spectrometry (MS) analysis. Bead-based protein aggregation techniques have recently emerged as an efficient, reproducible, and high-throughput alternative for protein extraction and digestion. Here, a refined paramagnetic bead–bas...
Xeroderma pigmentosum (XP) is characterized by defective repair of ultraviolet-radiation (UVR)-induced DNA damage. Patients have UVR hypersensitivity and increased skin cancer risk. Effective photoprotection has reduced childhood cancer-related deaths, but revealed adolescence-onset neurodegeneration, arising through unknown mechanisms. Here, we in...
Purpose
Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored.
Experimental Design
We challenged 112 cell models recapitulating the genomic landscape of m...
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage, and repair processes that have arisen in each patient’s cancer. We performed mutational signature analyses on 12,222 whole-genome–sequenced tumor-normal matched pairs from patients recruited via the UK National Health...
PARP inhibitors (PARPi) are approved drugs for platinum-sensitive, high-grade serous ovarian cancer (HGSOC) and for breast, prostate, and pancreatic cancers (PaC) harboring genetic alterations impairing homologous recombination repair (HRR). Detection of nuclear RAD51 foci in tumor cells is a marker of HRR functionality, and we previously establish...
Despite the conventional view that a truly random V(D)J recombination process should generate a highly diverse immune repertoire, emerging reports suggest that there is a certain bias toward the generation of shared/public immune receptor chains. These studies were performed in viral diseases where public T cell receptors (TCR) appear to confer bet...
The N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A writer METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but its true therapeutic importance is still unknown5–7. Here we present the identification and...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods to 3,107 whole-genome-sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight inte...
Sequencing studies of diffuse large B cell lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limit...
"Mutational signatures" are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole-genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-yr-old male with xeroderma pigmentosum developed metastatic angiosarcoma that was u...
Despite technological advances, two-dimensional electrophoresis (2DE) of biological fluids, such as vitreous, remains a major challenge. In this study, artificial neural network was applied to optimize the recovery of vitreous proteins and its detection by 2DE analysis through the combination of several solubilizing agents (CHAPS, Genapol, DTT, IPG...
Sequencing studies of Diffuse Large B Cell Lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limit...
We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 in...
FLT3 internal tandem duplication (FLT3ITD) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific and validated therapeut...
Key Points
FLT3ITD TK inhibition impairs glycolysis and glucose utilization without equally affecting glutamine metabolism. Combined targeting of FLT3 TK activity and glutamine metabolism decreases FLT3ITD mutant cells leukemogenic potential in vitro and in vivo.
[This corrects the article DOI: 10.1099/mic.0.000477.].
Multiple interacting factors affect the performance of engineered biological systems in synthetic biology projects. The complexity of these biological systems means that experimental design should often be treated as a multiparametric optimization problem. However, the available methodologies are either impractical, due to a combinatorial explosion...
Multiple interacting factors affect the performance of engineered biological systems in synthetic biology projects. The complexity of these biological systems means that experimental design should often be treated as a multiparametric optimization problem. However, the available methodologies are either impractical, due to a combinatorial explosion...
The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a cl...
Fatty acids (FAs) are proxies for nutritional health & disease. To date, EPIC is the largest study of 46k FA profiles derived from plasma phospholipids. This preliminary complete-case analysis of FAs reveals states with distinct mixtures of selected FAs. The result is a stratified landscape appropriate for detailed metadata analysis. This work is a...
Membrane proteins are important drug targets in many human diseases and gathering structural information regarding these proteins encourages the pharmaceutical industry to develop new molecules using structure-based drug design studies. Specifically, membrane-bound catechol-O-methyltransferase (MBCOMT) is an integral membrane protein that catalyzes...
Argyris Zardilis(1,2,5), João Dias(3,4), Animesh Acharjee(5), and James Smith(1,4,5)
A.Zardilis@sms.ed.ac.uk, James.Smith@mrc-hnr.cam.ac.uk
1 Cambridge Computational Biology Institute, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, U.K. 2 SynthSys, C.H. Waddington Building, University of Edinburgh, U.K. 3 Cambr...
Stochastic reaction-centric views are suitable for exploring hybrid minimal mechanism-statistical models of fatty acid and lipid metabolism, the basis of de novo lipogenesis. In this work, we demonstrate a reduced model for the core fatty acid synthesis and elongation process with a regulatory mechanism. This allows us to explore fatty acid profile...
In this paper, we implemented a model-based optimization platform for fast development of Pichia pastoris cultures employing batch-to-batch control and hybrid semi-parametric modeling. We illustrate the methodology with a P. pastoris GS115 strain expressing a single-chain antibody fragment (scFv) by determining the optimal time profiles of temperat...
In this work, we present a dynamic metabolic model that describes the uptake of complex mixtures of volatile fatty acids (VFA) and respective conversion into PHA by mixed microbial cultures (MMC). This model builds upon a previously published flux balance analysis model [1] that identified the minimization of TCA cycle activity as the key metabolic...
In this study we developed a segregated flux balance analysis (FBA) method to calculate metabolic flux distributions of the individual populations present in a mixed microbial culture (MMC). Population specific flux data constraints were derived from the raw data typically obtained by the Fluorescence in situ hybridization (FISH) and microautoradio...
Background
Novel analytical tools, which shorten the long and costly development cycles of biopharmaceuticals are essential. Metabolic flux analysis (MFA) shows great promise in improving our understanding of the metabolism of cell factories in bioreactors, but currently only provides information post-process using conventional off-line methods. MF...
This work describes a method for on-line monitoring of biomass production, acetate consumption and intracellular polyhydroxybutyrate (PHB) storage by mixed microbial cultures (MMC). The method is based on reliable and easily available on-line measurements, namely pH, dissolved oxygen, dissolved carbon dioxide, on-line respirometry and on-line titri...
Phenomenological models and hybrid phenomenological-chemometric models were developed to predict natural organic matter (NOM) removal based on the real water treatment data from the city of Minneapolis over a 3 year period. The analysis of the modeling results showed that the phenomenological model was able to capture the major variations of NOM re...
A neural network based methodology for the modelling of a sequencing batch reactor (SBR) for producing Polyhydroxybutyrate (PHB) with Mixed Microbial Cultures (MMC) is proposed. The advantages of applying MMC for more effective production of PHB have already been documented and mechanistic models were developed, however, the lack of good understand...
In this chapter we explore the basic tools for the design of bioprocess monitoring, optimization, and control algorithms that incorporate a priori knowledge of metabolic networks. The main advantage is that this ultimately enables the targeting of intracellular control variables such as metabolic reactions or metabolic pathways directly linked with...
Fermented agro-industrial wastes are potential low cost substrates for polyhydroxyalkanoates (PHA) production by mixed microbial cultures (MMC). The use of complex substrates has however profound implications in the PHA metabolism. In this paper we investigate PHA accumulation using a lumped metabolic model that describes PHA storage from arbitrary...
In this study, fed-batch cultures of a Pichia pastoris strain constitutively expressing a single chain antibody fragment (scFv) under the control of the glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter were performed in a pilot 50 L bioreactor. Due to the very high cell density achieved within the first 75 h, typically between 140 and 160 g-...
The aim of this work was to optimize the temperature, pH and stirring rate of the production of human soluble catechol-O-methyltransferase (hSCOMT) in a batch Escherichia coli culture process. A central composite design (CCD) was firstly employed to design the experimental assays used in the evaluation of these operational parameters on the hSCOMT...
BHK metabolic network. Biochemical reactions/pathways, enzymes and biomass composition considered in the metabolic model of BHK cells.
BHK elementary modes. List of elementary modes obtained from the BHK metabolic network (Additional File 1). Elementary modes are represented in reduced form in terms of extracellular metabolites.
Envirome factors regression coefficients. List of PLP regression coefficients and the respective confidence intervals resulting from the bootstrapping analysis.
Elementary flux modes (EFM) are unique and non-decomposable sets of metabolic reactions able to operate coherently in steady-state. A metabolic network has in general a very high number of EFM reflecting the typical functional redundancy of biological systems. However, most of these EFM are either thermodynamically unfeasible or inactive at pre-set...
BHK elementary modes. List of elementary modes obtained from the BHK metabolic network (additional file 2). Elementary modes are represented in reduced form in terms of extracellular metabolites.
BHK metabolic network. Biochemical reactions/pathways, enzymes and biomass composition considered in the metabolic model of BHK cells
While functional genomics, focused on gene functions and gene-gene interactions, has become a very active field of research in molecular biology, equivalent methodologies embracing the environment and gene-environment interactions are relatively less developed. Understanding the function of environmental factors is, however, of paramount importance...
Biodiesel was produced by transesterification of soybean oil with methanol using poly(vinyl alcohol) membranes as solid base catalysts. The membranes were prepared dispersing hydrotalcite in the polymer solution. The reactions were carried out at 60 °C in a three-necked batch reactor using all the catalysts in the form of pellets. The effect of the...
The main objective of the present study was to investigate the use of in situ 2D fluorometry for monitoring key bioprocess variables in mammalian cell cultures, namely the concentration of viable cells and the concentration of recombinant proteins. All studies were conducted using a recombinant Baby Hamster Kidney (BHK) cell line expressing a fusio...
In this work, an algorithm for on-line adaptive metabolic flux analysis (MFA) is proposed and applied to polyhydroxybutyrate (PHB) production by mixed microbial cultures (MMC). In this process, population dynamics constitutes an important source of perturbation to MFA calculations because some stoichiometric and energetic parameters of the underlyi...
This paper presents a metabolic model describing the production of polyhydroxyalkanoate (PHA) copolymers in mixed microbial cultures, using mixtures of acetic and propionic acid as carbon source material. Material and energetic balances were established on the basis of previously elucidated metabolic pathways. Equations were derived for the theoret...
Systems biology is an integrative science that aims at the global characterization of biological systems. Huge amounts of data regarding gene expression, proteins activity and metabolite concentrations are collected by designing systematic genetic or environmental perturbations. Then the challenge is to integrate such data in a global model in orde...
In this work we study the optimization of a polyhydroxyalkanoates (PHA) production process by mixed cultures based on a detailed hybrid metabolic model. The metabolic network under consideration was first decomposed into its fundamental pathways using the elementary flux modes (EFM) technique. Then, a dynamical hybrid semi-parametric model was form...
A model-based algorithm is presented for the on-line monitoring of the oxidative phosphorylation efficiency and intracellular metabolic fluxes in mixed microbial cultures producing Polyhydroxybutyrate (PHB). The method assumes the knowledge of the metabolic reactions and the respective material and energetic balances. The on-line availability of di...
Numerous bacteria have been found to exhibit the capacity for intracellular polyhydroxyalkanoates (PHA) accumulation. Current methods for PHA production at the industrial scale are based on their synthesis from microbial isolates in either their wild form or by recombinant strains. High production costs are associated with these methods; thus, atte...
Mixed cultures submitted to acetate "feast" and "famine" cycles are able to store intracellularly high quantities of polyhydroxybutyrate (PHB). It was demonstrated in a previous study that the intracellular PHB content can be increased up to 78.5% (g HB/gVSS) of cell dry weight in a sequencing batch reactor (SBR) with optimised operating conditions...
