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DTSTART:20000101T000000
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BEGIN:VEVENT
UID:pretalx-isgsb2024-VNL3AN@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240909T184000
DTEND;TZID=SAST:20240909T194000
DESCRIPTION:The history of Biology abounds in discoveries where the integra
 l of precise theory and precise experimentation\, the trade mark of the IS
 GSB\, has made the difference. These discoveries include no less than the 
 structure of DNA and the mechanisms underlying biological free-energy tran
 sduction and the multiplicity of oncogenes.  This opening lecture of the 2
 024 International Study Group on Systems Biology (ISGSB) will sketch the e
 ssence and history of ISGSB/BTK.  The essence will be identified as ISGSB
 ’s intensive and informal discussions of controversial issues in biology
 .  The latter will be described not in terms of numbers\, but in terms of 
 leaps in (my) understanding\, produced by ISGSB’s core methodologies.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:ISGSB: Past (solutions) and future (problems) - Hans V. Westerhoff
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/VNL3AN/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-W8CVDQ@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T090000
DTEND;TZID=SAST:20240910T093000
DESCRIPTION:NAD is a vital coenzyme participating in a multitude of metabol
 ic reactions. Moreover\, it serves as a signaling molecule to mediate fund
 amental cellular processes including DNA repair\, cell cycle progression\,
  transcriptional\, epigenetic and metabolic regulation. In these processes
 \, NAD is cleaved to liberate nicotinamide\, and the ADP-ribosyl moiety is
  used to perform protein or nucleic acid modifications or to generate mess
 enger molecules. To maintain cellular NAD levels\, the released nicotinami
 de is recycled into NAD synthesis through the salvage pathway.\nHere\, we 
 aimed to understand the potential interaction between different subcellula
 r NAD pools with a main interest in mitochondria. These organelles represe
 nt a major pool with the highest concentration of the dinucleotide. Follow
 ing targeted overexpression of an NAD consumer in a variety of subcellular
  compartments we measured NAD turnover using stable isotope-labeled precur
 sors. Remarkably\, turnover was hardly affected by the induced increase of
  NAD-consuming activity\, irrespective of its subcellular expression. Acco
 rdingly\, no upregulation of NAD synthesis was observed and therefore\, NA
 D levels were chronically decreased to limit NAD consumption to the origin
 al value. We hypothesize that these observations might provide a mechanist
 ic background for age-dependent cellular NAD decline.\nThe mitochondrial N
 AD pool is known to have a certain degree of autonomy\, and this has been 
 linked to the mitochondrial localization of NMNAT3\, an enzyme catalyzing 
 the reversible\, final step of NAD formation from NMN and ATP. However\, N
 MNAT3 is dispensable in mice\, and the recent identification of SLC25A51\,
  or MCART1\, as a mitochondrial NAD+ transporter\, seems to finally have s
 ettled the question regarding the establishment and maintenance of the mit
 ochondrial NAD pool in mammals. Based on a large set of experiments includ
 ing genetically modified cell lines\, we propose a key role of NMNAT3 in t
 he mechanism how mitochondria maintain a balanced NAD pool. We posit that 
 the reversible cleavage of imported NAD into NMN and ATP establishes an eq
 uilibrium between NAD and NMN (and ATP) that can be shifted to either side
  upon demand. For example\, high cytosolic NAD increases mitochondrial upt
 ake and subsequent cleavage of NAD\, whereas high NAD consumption activity
  would favor NAD synthesis. This mechanism would establish a buffer to com
 pensate fluctuations in mitochondrial NAD concentrations. Moreover\, in co
 ncert with reversible NAD exchange through SLC25A51\, this buffer would be
  functional for NAD pools in other subcellular locations. Indeed\, we demo
 nstrate that the mitochondrial NAD pool is “tapped” when the NAD consu
 mer is overexpressed outside mitochondria. We conclude that subcellular NA
 D pools are interconnected with a major role of mitochondria in maintainin
 g the cellular homeostasis of this coenzyme.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Dynamics and interconnectivity of subcellular NAD pools - Mathias Z
 iegler
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/W8CVDQ/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-TGNUAP@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T093000
DTEND;TZID=SAST:20240910T100000
DESCRIPTION:Lactococcus cremoris is a lactic acid bacterium that is used in
  dairy applications such as a strarter for cheese production\, where lacta
 te acidifies the milk as the key product produced from sugars. The central
  metabolism of L. cremoris has been studied intensively as a model system\
 , in particular because of its interesting metabolic switching behaviour: 
 Under sugar excess - or more precisely\, high glycolytic flux conditions -
  lactate is produced by homolactic fermentation. However\, when glucose is
  limited (e.g. in a glucose limited chemostat)\, or in the presence of a 
 “slow” sugar\, mixed acid fermentation occurs with formate\, acetate a
 nd ethanol as products.\n\n \n\nSince enzyme concentrations hardly vary in
  the chemostat when the switch occurs\, metabolic regulation is believed t
 o underlie the shift. However\, a satisfying and unifying explanation of t
 he switch\, and how glycolysis is regulated in this bacterium remains elus
 ive\, despite a number of kinetic models in the literature. We revisited t
 hese models and designed a kinetic model of glycolysis with a focus on gro
 wth-associated ATP supply and demand\, phosphate homeostasis and enzyme ki
 netics that captures the most important regulatory mechanisms known from l
 iterature. Our model reproduces the metabolic shift and is able to reprodu
 ce and explain many different experimental results regarding to the contro
 l and regulation of the glycolytic flux and its branches.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:A growth-embedded kinetic model of glycolysis of Lactococcus cremor
 is explains effects of growth conditions and genetic perturbations - Luis 
 Salinas
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/TGNUAP/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-K3SCHR@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T100000
DTEND;TZID=SAST:20240910T103000
DESCRIPTION:The acetylation of lysine residues in histones are an important
  regulatory mechanism. But still relatively little is known about the dyna
 mics of histone acetylation and their dependency on metabolic processes. W
 e therefore developed a stable isotope labelling approach based on ^13^C-g
 lucose that allows the quantitative analysis of histone acetylation dynami
 cs in human cell lines. The substrate for histone acetylation is acetyl-Co
 A which first needs to be synthesized from ^13^C-glucose causing a delay i
 n the label incorporation of histone-acetyl-lysins. To correctly determine
  histone-acetylation dynamics we therefore simultaneously extracted protei
 ns and metabolites and measured the time-dependent incorporation of ^13^C 
 into both acetyl-CoA and acetylated histone peptides. We than used an ODE 
 based modelling approach to calculate the correct histone acetylation and 
 deacetylation rates. We show that without correction alterations in metabo
 lic fluxes would erroneously be interpreted as changes in histone acetylat
 ion dynamics while our approach allows to discriminate between both proces
 ses.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Modelling based integrated analysis of histone acetylation dynamics
  and glycolytic fluxes - Ines Heiland
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/K3SCHR/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-QRVUM8@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T110000
DTEND;TZID=SAST:20240910T113000
DESCRIPTION:Cell growth relies on anabolism synthesizing precursors for mac
 romolecule biosynthesis from nutrients and from energy equivalents (synthe
 sized from nutrients by catabolism). Since anabolism involves catabolic pa
 thways – i.e. anabolic precursors (e.g. pyruvate) are intermediates of c
 atabolism – catabolism and anabolism are severely intertwined and not re
 adily disentangled. The fact that energy equivalents are then also synthes
 ized by anabolism (e.g. pyruvate synthesis from glucose yields 2 ATP and 2
  NADH) obscures the exact contribution of energy supply by catabolism for 
 cell growth. For instance\, how much of the ATP needed to make 1 gram biom
 ass is actually supplied by catabolism? When is catabolism providing NAD(P
 )H in addition to ATP for anabolism? Since genome-scale stoichiometric mod
 els (GSSMs) study catabolism and anabolism as entangled processes\, we nee
 d to develop a method first for separating catabolism and anabolism.<br>\n
 To address this\, we developed a computational method\, which is general\,
  unbiased and enables us to understand the role of catabolism across diver
 se microbes. For this contribution\, we analysed GSMMs of seven microbial 
 species across 50 growth conditions\, utilizing various organic and inorga
 nic carbon\, electron\, and nitrogen sources. We found that the amount of 
 ATP produced in anabolism varies from none at all to all\, and that redox 
 cofactors\, such as NAD(P)H\, are exchanged between catabolism and anaboli
 sm in certain cases.<br>\nGiven these results\, we reasoned that catabolis
 m is “driven” (determined) by anabolism. Accordingly\, we expect that 
 the stoichiometry of the net anabolic reaction can be determined prior to 
 that of the catabolic reactions and its energy need (ATP and/or NAD(P)H) s
 ubsequently dictates the net stoichiometry of the catabolic reaction. Ther
 efore\, we aimed to identify the factors that determine the amount of ATP 
 produced during anabolism. Typically\, donating electrons to a terminal el
 ectron acceptor yields ATP. Accordingly\, the presence of an electron acce
 ptor in the anabolic overall reaction correlates positively with the fract
 ion of ATP produced in anabolism. The need for reduced redox cofactors in 
 anabolism depends on the electron balance within this process. Anabolism c
 onverts a carbon substrate into biomass and potentially also into carbon-c
 ontaining byproducts\, with the electron balance of these components dicta
 ting the use of electron acceptors or donors. If an electron donor supplie
 d by catabolism and an external electron acceptor cannot exchange electron
 s\, both are consumed in anabolism. The energy carriers that are consumed 
 in anabolism\, must be supplied by catabolism using the same carbon and/or
  energy source.<br>\nTo conclude\, the fraction of energy supplied by cata
 bolism for cell growth varies depending on the nature of the involved ener
 gy sources and is determined by the pathway stoichiometry of anabolism.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:The pathway stoichiometry of anabolism determines the role of catab
 olism - Maaike Remeijer
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/QRVUM8/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-87VSTJ@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T113000
DTEND;TZID=SAST:20240910T120000
DESCRIPTION:Abstract Established genome-scale modelling methods primarily p
 redict reaction fluxes while established high-throughput experimental tech
 nologies primarily measure molecular species concentrations. This paradoxi
 cal situation has arisen because of the problem to implement the nonlinear
  constraints that represent reaction kinetic rate equations without recour
 se to convenient yet inaccurate approximations. We present a mathematicall
 y elegant and computationally tractable solution to this problem. First we
  introduce a mathematical reformulation of established knowledge on metabo
 lic reactions and reaction kinetics in matrix vector notation. Then we int
 roduce variational kinetics\, a novel approach to satisfy steady-state rea
 ction kinetics at genome scale using novel mathematical and numerical opti
 misation techniques. We illustrate how this approach may be used to simult
 aneously optimise over the set of steady-state reaction fluxes\, thermodyn
 amically feasible kinetic parameters and kinetically feasible elementary a
 nd phenomenological rate laws\, with solution times competitive with linea
 r optimisation.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Variational kinetics: a variational formulation of reaction kinetic
 s - Ronan M.T. Fleming
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/87VSTJ/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-3XNVS3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T120000
DTEND;TZID=SAST:20240910T123000
DESCRIPTION:The dry mass in the cytosol of a bacterial cell is composed of 
 molecules of diverse sizes\, spanning from tiny metabolites to large ribos
 omes. The dry mass density determines the diffusion of macro- and small-me
 tabolites and also the catalytic efficiency of enzymes\, and thereby deter
 mines the reaction fluxes. As a bacterial cell is optimized for fast growt
 h\, it must strike a balance between competing factors such as the density
  and distribution of the constituent molecules of the dry mass when alloca
 ting resources for their synthesis. Here we simulate a model cell to inves
 tigate how bacterial cells optimize their cytosolic density\, accounting f
 or the effects of molecular crowding on metabolic reactions. Our simplifie
 d model classifies molecular interactions into two groups: ribosomal react
 ions involving larger ribosomes and tRNAs\, and metabolic reactions involv
 ing smaller globular enzymes and metabolites. We find that while higher de
 nsity enhances encounter rates for metabolic reactions involving small mol
 ecules\, lower density is preferred for ribosomal reactions involving larg
 er molecules to facilitate better diffusion. Notably\, our model predicts 
 that large deviations from the optimal density lead to small reductions in
  growth rate. Moreover\, our model's predictions of optimal density across
  different growth rates are consistent with the trends observed in experim
 ents\, such as the cytosolic density in E. coli cells cultured in both min
 imal and rich media. In sum\, the cytosolic density of bacterial cells is 
 governed by an optimality principle that aims at maximizing cellular effic
 iency.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Natural selection for the optimal cytosolic density of a bacterial 
 cell - Tin Yau Pang
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/3XNVS3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-BRKPSX@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T140000
DTEND;TZID=SAST:20240910T143000
DESCRIPTION:Metabolic networks need to meet more requirements than single e
 nzymes\, in order to be functional.  Aware of the heterogeneity of (tumor)
  cell populations\, we went after this principle and engaged in network ba
 sed drug design.  We thought that by identifying the metabolic potential o
 f individual cells\, we could identify which targets could be used to most
  effectively incapacitate most individuals of a tumor cell population.\nWe
  projected mRNA sequence counts obtained for >3000 cells out of a growing 
 tumor-cell population onto the genome-wide metabolic map after converting 
 the numbers to Vmax’s.  We used Flux Balance Analysis to predict the pat
 hways the individual cells could be using and thereby their vulnerabilitie
 s to potential metabolic drugs.  That is at least what we thought we would
  do. \nMuch to our surprise however\, none of the cells was predicted to b
 e able to grow.\nWe then considered whether this could be due to the cells
  being social metabolically\, i.e. massively exchanging metabolites\, with
  some cells taking care of the upper part of glycolysis\, others the TCA c
 ycle\, yet others the lower part of glycolysis.  This was a nice and socia
 l idea\, but apparently not realistic:  subdividing the cells into subpopu
 lations and offering metabolites synthesized by one subpopulation as subst
 rates to the others\, did not lead to growth of either subpopulation.\nIn 
 this presentation we shall discuss what explanation of the growth in the a
 bsence of mRNA for the metabolic pathways\, we did come up with.\nAnd\, we
  discuss how the actual resulting model did identify cholesterol and aspar
 agine synthesis pathways as relevant\, though complex\, drug targets.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:The metabolic riddle of single cell transcriptomics: how mRNAs do n
 ot suffice - Hans V. Westerhoff
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/BRKPSX/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-GEYC7D@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T143000
DTEND;TZID=SAST:20240910T150000
DESCRIPTION:<i>In silico</i> tools such as genome-scale metabolic models ha
 ve shown to be powerful for metabolic engineering of microorganisms. <i>Sa
 ccharomyces pastorianus</i> is a complex aneuploid hybrid between the meso
 philic <i>Saccharomyces cerevisiae</i> and the cold-tolerant <i>Saccharomy
 ces eubayanus</i>. This species is of biotechnological importance because 
 it is the primary yeast used in lager beer fermentation and is also a key 
 model for studying the evolution of hybrid genomes\, including expression 
 pattern of ortholog genes\, composition of protein complexes\, and phenoty
 pic plasticity. Here\, we created the iSP_1513 GSMM for <i>S. pastorianus<
 /i> CBS1513 to allow top-down computational approaches to predict the evol
 ution of metabolic pathways and to aid strain optimization in production p
 rocesses. The iSP_1513 comprises 4\,062 reactions\, 1\,808 alleles\, and 2
 \,747 metabolites\, and takes into account the functional redundancy in th
 e gene-protein-reaction rule caused by the presence of orthologous genes. 
 Moreover\, a universal algorithm to constrain GSMM reactions using transcr
 iptome data was developed as a python library and enabled the integration 
 of temperature as parameter. Essentiality data sets\, growth data on vario
 us carbohydrates and volatile metabolites secretion were used to validate 
 the model and showed the potential of media engineering to improve specifi
 c flavor compounds. The iSP_1513 also highlighted the different contributi
 ons of the parental sub-genomes to the oxidative and non-oxidative parts o
 f the pentose phosphate pathway. Overall\, the iSP_1513 GSMM represent an 
 important step toward understanding the metabolic capabilities\, evolution
 ary trajectories\, and adaptation potential of <i>S. pastorianus</i> in di
 fferent industrial settings.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Development of a genome-scale model for the lager yeast S. pastoria
 nus to understand metabolic pathways evolution in industrial settings - So
 ukaina Timouma
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/GEYC7D/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-37K9UL@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T150000
DTEND;TZID=SAST:20240910T153000
DESCRIPTION:Peroxiredoxins (Prxs) play central roles in the detoxification 
 of reactive oxygen species. These proteins exist in multiple oligomeric fo
 rms\, depending on their state of oxidation/reduction. The most common of 
 these states are dimers and decamers\, with decamers predominating under r
 educed conditions. Prxs have been modelled across multiple organisms using
  a variety of kinetic methods. However\, their dimer-to-decamer transition
  has been underappreciated in these studies despite the 100-fold differenc
 e in activity between dimers and decamers. This is due to the lack of avai
 lable kinetics and theoretical framework for modelling this process. Using
  published isothermal titration calorimetry data\, we were able to obtain 
 association and dissociation rate constants for the dimer-decamer transiti
 on of human PRDX1. We developed an approach that greatly reduces the numbe
 r of reactions and species needed to model the peroxiredoxin decamer oxida
 tion cycle. Using these data\, we simulated horse radish peroxidase compet
 ition and NADPH-oxidation linked assays and found that the dimer-decamer t
 ransition had an inhibition-like effect on peroxidase activity. Further\, 
 we incorporated this dimer-decamer topology and kinetics into a published 
 and validated in vivo model of PRDX2 in the erythrocyte and found that it 
 almost perfectly reconciled experimental and simulated responses of PRDX2 
 oxidation state to hydrogen peroxide insult. This allowed us to mechanisti
 cally resolve a discrepancy between experimental data and kinetic simulati
 ons by showing that reduced Prx sites can be sequestered in a less active 
 dimeric form\, thus obviating the need to postulate an "inhibited" form of
  Prx as had been done in earlier models. Additionally\, we have demonstrat
 ed that Prx decamer dissociation occurs within a time-frame relevant to pe
 roxidase assays and other oxidation experiments and needs to be considered
  when working with Prx in a laboratory. Using computational modelling\, we
  were able to to combine and organise different types of experimental data
  into a single framework to better understand the dynamics of these import
 ant antioxidant proteins.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Effect of oligomerisation on enzyme kinetics: the case of peroxired
 oxin - Johann Rohwer
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/37K9UL/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-VLJP8C@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T160000
DTEND;TZID=SAST:20240910T163000
DESCRIPTION:One of the goals of bottom-up systems biology is to generate hi
 gh-quality predictive models that enhance our understanding of cellular be
 haviour. For mathematical models of metabolism to accurately simulate expe
 rimental data\, the conditions under which enzyme parameter values are obt
 ained should closely resemble the actual in vivo environment. Traditionall
 y\, this alignment is often lacking\, as many enzyme kinetic studies are c
 onducted under optimal conditions for the enzyme\, which may significantly
  differ from the enzyme’s native conditions. A frequently overlooked asp
 ect of the intracellular environment is macromolecular crowding—the infl
 uence\, through the excluded volume effect\, of large quantities of differ
 ent macromolecules occupying the cell.\nTo better understand how the compl
 ex heterogeneous environment of the cell influences enzyme kinetics\, we e
 xposed kinetic assays of various enzymes in the glycolytic pathway of Sacc
 haromyces cerevisiae to inert synthetic polymers of different shapes and s
 izes at two concentrations\, thus mimicking in vivo crowded conditions. Ki
 netic data were acquired from spectrophotometric assays with microtitre pl
 ates or from Nuclear Magnetic Resonance (NMR) spectroscopy time courses. E
 nzyme kinetic parameters were estimated by fitting initial rate kinetics a
 nd NMR time-course data to kinetic models based on rate equations for each
  enzyme.\nThe presence of synthetic polymers (Dextran70\, Ficoll70\, and P
 EG35) influenced the Vmax and KM-values for different enzymes to varying e
 xtents. In some cases\, significant changes in kinetic parameters were obs
 erved in crowded solutions relative to baseline uncrowded solutions\; for 
 instance\, high concentrations of crowding agents decreased the Vmax value
 s of numerous enzymes. The changes in kinetic parameters depended on the s
 ize and shape of the crowding agent used. Current work focuses on determin
 ing the effect of these parameter changes on the kinetic behaviour of the 
 entire pathway network\, allowing us to assess the broader impact of macro
 molecular crowding on the network and its emergent properties under crowde
 d versus dilute conditions.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Investigating Enzyme Kinetics under Crowded Conditions in Saccharom
 yces cerevisiae - Kamogelo Matenchi
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/VLJP8C/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-MDMYNY@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T163000
DTEND;TZID=SAST:20240910T170000
DESCRIPTION:Cellular constraints and limited resources govern the metabolic
  strategies of cells to adapt to environmental conditions. Under excess gl
 ucose conditions\, many yeasts switch from high-yield respiratory metaboli
 sm to low-yield fermentation\, a phenomenon called the Crabtree effect in 
 yeast\, or the Warburg effect in mammalian cells. Which constraints cause 
 this effect is still under debate.\nHere we study the Crabtree-negative\, 
 fully respiratory yeast Pichia kluyveri and compare it to the Crabtree-pos
 itive yeast Saccharomyces cerevisiae from a resource allocation perspectiv
 e. By integrating quantitative physiology and proteomics into genome-scale
  proteome-constrained models\, we find that the Crabtree effect is determi
 ned by the composition of the electron transport chain and is rather sensi
 tive to (often poorly characterized) catalytic constants of mitochondrial 
 enzymes and complexes. This suggests that the “proteome efficiency” - 
 a concept in need of a proper definition that will be addressed - of respi
 ration versus fermentation varies between species. This variation likely r
 eflects evolutionary and ecological history and remains to be explained. \
 nThis study advances our understanding of the role of proteome constraints
  and proteome efficiency in governing cellular metabolism of yeasts\, and 
 that of eukaryotic cells at large.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Proteome efficiency of respiration versus fermentation determines o
 ptimal metabolic strategies and varies across yeast species - Bas Teusink
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/MDMYNY/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-X8QVWH@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240910T170000
DTEND;TZID=SAST:20240910T173000
DESCRIPTION:In many cells\, thiol-based redox systems are primarily respons
 ible for hydrogen peroxide reduction but also trigger signalling cascades 
 leading to the induction of oxidant-specific transcriptional programs by r
 edox-sensitive transcription factors. Cells lacking these transcription fa
 ctors are extremely sensitive to oxidative stress\, but their constitutive
  activation is also detrimental. However\, the quantitative relationship b
 etween these oxidative inputs and transcriptional outputs has remained obs
 cure because we lacked tools to quantify the dynamics of redox signals. Us
 ing the fission yeast Pap1 transcription factor pathway as a model\, we sh
 ow how hydrogen peroxide and tert-butyl hydroperoxide triggered quantifiab
 ly distinct Pap1 activation profiles and transcriptional responses. Based 
 on these findings\, we propose that different oxidants and oxidant concent
 rations modulate the Pap1 dynamic profile\, leading to specific transcript
 ional responses. We further show how the effect of combination and pre-exp
 osure stresses on Pap1 activation dynamics can be quantified using this ap
 proach. Our work advances the concept that redox signalling dynamics are a
  key aspect of the oxidative stress response.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Quantifying signaling by a redox-regulated transcription factor - C
 he Pillay
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/X8QVWH/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-ZJZXRY@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T090000
DTEND;TZID=SAST:20240911T093000
DESCRIPTION:Christoff Odendaal1$\, Ligia Akemi Kiyuna1$\, Madhulika Singh2$
 \, Albert Gerding1\,3\, Miriam Langelaar-Makkinje1\, Marianne van der Zwaa
 g4\, Asmara Drachman2\, Vladimíra Cetkovská2\, Gaby Liem Foeng Kioen2\, 
 Anne-Claire M.F. Martines1\, Nicolette C. A. Huijkman1\, Hein Schepers4\, 
 Bart van de Sluis1\, Dirk-Jan Reijngoud1\,  Ody C.M. Sibon4\, Amy C. Harms
 2\, Thomas Hankemeier2\, Barbara M. Bakker1\n  \n1Laboratory of Pediatrics
 \, 3Departments of Laboratory Medicine and 4Biomedical Sciences of Cells a
 nd Systems\, University of Groningen\, UMCG\, The Netherlands\n\n2Division
  of Analytical Biosciences\, Leiden Academic Centre for Drug Research\, Le
 iden University\, The Netherlands.\n\n$ These authors contributed equally 
 \n\n\nCoenzyme A (CoA) is a vital cofactor that is involved in 8-10% of al
 l metabolic reactions in human cells. In so-called ‘CoA Sequestration\, 
 Toxicity\, and Redistribution’ (CASTOR) diseases\, specific enzyme defic
 iencies lead to the accumulation of a corresponding CoA ester that is not 
 efficiently metabolised. Common symptoms include acidosis\, hypoglycaemia 
 and hyperammonaemia. It has been proposed that a depletion of free\, non-e
 sterified CoA (CoASH) is underlying these symptoms\, but there is limited 
 direct evidence for this hypothesis. Here\, we focus on medium-chain acyl-
 CoA dehydrogenase deficiency (MCADD)\, the most prevalent fatty-acid oxida
 tion (mFAO) disorder\, in which patients accumulate medium-chain acylcarni
 tine esters. The aim of this study is to investigate if the loss of MCAD l
 eads to the accumulation of medium-chain acyl-CoA esters\, sequestration o
 f CoASH\, and remodelling of CoA metabolism.  \nIn agreement with the CAST
 OR hypothesis\, kinetic computational simulations of the mFAO pathway pred
 icted elevated medium-chain C8-acyl-CoA levels and reduced CoASH and short
 -chain acyl-CoA esters in MCAD knockout (-KO) versus wild-type (WT) hepato
 cytes. Remarkably\, the model predictions were replicated experimentally i
 n MCAD-KO HepG2 cells. Moreover\, long-chain acyl-CoA esters\, upstream of
  the deficient enzyme\, were also reduced in both the MCAD-KO computationa
 l model as well as in MCAD-KO HepG2 cells. According to the model\, this m
 ay point to a limitation imposed by reduced CoASH\, as the generation of n
 ew long-chain acyl-CoA esters and their entry into the mFAO pathway also r
 equire CoASH. Incorporation of 13C315N1- labelled pantothenate (vitamine B
 5\, the precursor of CoA) showed no difference in the CoA biosynthesis rat
 e between MCAD-KO and WT HepG2 cells. In MCAD-KO mice exposed to severe en
 ergetic stress (14h overnight fasting at room temperature followed by 4h f
 asting at 4°C)\, however\, the total CoA concentration (free plus esterif
 ied) was increased. This was accompanied by the upregulation of genes invo
 lved in CoA biosynthesis (pantothenate kinases) and CoA release (carnitine
  acyltransferases and acyl-CoA thioesterases (ACOTs)). Computational simul
 ations showed that the combined effect of elevated CoA and ACOT activity i
 s an effective way to increase free CoASH\, while relieving the excessive 
 accumulation of C8-acyl-CoA.  \nTo our knowledge\, these results represent
  the first experimental evidence of the CASTOR mechanism in MCADD. Further
 more\, using in vivo and computational models of MCADD\, this study provid
 es insights into a potential compensatory remodelling of CoA metabolism\, 
 activated under catabolic stress.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Reduced free coenzyme A availability in medium-chain acyl-CoA dehyd
 rogenase deficiency - Barbara M. Bakker
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/ZJZXRY/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-YVMXXP@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T093000
DTEND;TZID=SAST:20240911T100000
DESCRIPTION:Head and neck squamous cell carcinoma (HNSCC)\, the most common
  form of head and neck cancer\, is diagnosed in almost 900 000 patients an
 nually with a mortality rate of approximately 40% within 5 years of diagno
 sis. Early diagnosis and effective treatment strategies with limited toxic
 ity are urgently awaited. Alterations in cellular metabolism is one of the
  hallmarks of cancer and could reveal potential diagnostic options and/or 
 therapeutic targets. We have found that HNSCC cells exhibit a remarkable a
 erobic fermentation\, which we termed the ‘super-Warburg effect’. This
  means that their lactate production was >2.0 times higher than their gluc
 ose consumption\, while the full fermentation of one molecule of glucose c
 an maximally yield two lactate molecules. \n\nTo study the possible origin
  of this surplus lactate in a systemic context\, we used proteomics from H
 NSCC cell lines to make context-specific HNSCC models from an existing gen
 ome-scale reconstruction of human metabolism (Human1). Flux balance analys
 is and flux variability analysis revealed anaplerotic amino acids – in a
 ddition to glucose – as likely sources of extra carbon. These amino acid
 s enter the Krebs cycle and exit again\, for instance as malate\, to be de
 carboxylated to pyruvate\, and subsequently to lactate. Our model analysis
  showed glutamine to be by far the most abundant source of extra carbon\, 
 and also showed it to be an obligatory substrate for the cells to grow the
  at the measured rate with the substrates available in the medium\, while 
 maintaining super Warburg lactate production. Malic enzyme 1 (ME1) and ser
 ine dehydratase (SDH) were indicated as important nodes in this conversion
 .\n\nSurprisingly\, cultured cells did not take up glutamine from the medi
 um as measured by nuclear magnetic resonance spectroscopy. This could be d
 ue to the uptake fluxes simply being undetectably low. One factor causing 
 this might be the availability of alternative amino acid sources. A promin
 ent candidate is the medium component\, foetal calf serum (FCS)\, which co
 ntains proteins. It has been shown previously that some cancers can take u
 p proteins by macropinocytosis and convert it into lactate. \n\nWe adjuste
 d our model to test the hypothesis that albumin – comprising about two-t
 hirds of FCS protein – could reduce the required glutamine uptake to exp
 lain the lack of a detectable glutamine uptake flux in the data. However\,
  the amount of albumin approximated to be present in a growth medium conta
 ining 5% of FCS is very low and millimolar changes in glutamine were still
  necessary to account for the growth rate and lactate production in our si
 mulation. We will further investigate the dependency of the cells on prote
 ins in the medium\, and analyse possible flux distributions at low uptake 
 of glutamine. We will also manipulate the genes for ME1 and SDH test their
  importance in the production of lactate from glutamine.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Investigating the origin of super Warburg metabolism in head and ne
 ck cancer - Christoff Odendaal
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/YVMXXP/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-EHDT8Q@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T100000
DTEND;TZID=SAST:20240911T103000
DESCRIPTION:Adrenal steroids\, which include corticosteroids (glucocorticoi
 ds like cortisol and mineralocorticoids like aldosterone)\, and adrenal an
 drogens such as androstenedione (A4)\, play an important role in regulatin
 g electrolyte and water levels in the kidneys. Originally thought of havin
 g marginal biological significance\, the 11-oxygenated androgens are incre
 asingly recognized as potent steroids with significant roles in human heal
 th and disease\, particularly in disorders associated with androgen excess
  or androgen dependence such as polycystic ovary syndrome\, congenital adr
 enal hyperplasia and castration-resistant prostate cancer.\nWe constructed
  a detailed mathematical model for the interconversion of the oxygenated a
 ndrogens (11-hydroxyandrostenedione\, 11OHA4\; 11-ketoandrostenedione\, 11
 KA4\; 11-ketotestoterone\, 11KT\; 11-hydroxytestosterone\, 11OHT) based on
  in vitro kinetics of the individual enzymes (11-hydroxysteroid dehydrogen
 ase type 2\, HSD11B2\; aldo-keto reductase type 1C3\, AKR1C3\; 11-hydroxys
 teroid dehydrogenase type 1\, HSD11B1\; and 17-hydroxysteroid dehydrogenas
 e type 2\, HSD17B2) and validated the model with experimental data for rec
 onstituted systems with varying enzyme levels at the cellular level\, and 
 with inhibitor titrations of HSD11B1 in adipose tissue using the Astra-Zen
 ica drug  AZD4017. \nWe subsequently used the model to analyze clinical da
 ta of Chronic Kidney Disease (CKD)\, and PolyCystic Ovary Syndrome (PCOS) 
 patients\, in terms of relative expression levels of the four enzymes\, ba
 sed on plasma concentrations of the oxygenated steroids. For the CKD patie
 nts the different disease states could be described by varying HSD11B2 whi
 le keeping the other enzymes at the healthy control group values. Interest
 ingly the estimated HSD11B2 levels correlated proportionally to the indepe
 ndent clinically measured eGFR  values (estimated Glomerular Filtration Ra
 te)\, normally used for evaluation of kidney function. The PCOS clinical d
 ata could be well described by adapting the AKR1C3 expression (together wi
 th a smaller adjustment of HSD17B2\, and the implicit total androgen level
 s). Model simulations showed that an inhibition of AKR1C3 could bring the 
 oxygenated androgens back to wild type levels.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Modeling 11-oxygenated androgen levels in chronic kidney disease an
 d in polycystic ovary syndrome patients - Jacky Snoep
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/EHDT8Q/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-RFKVAN@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T110000
DTEND;TZID=SAST:20240911T113000
DESCRIPTION:Patients with severe malaria can experience parasitemia levels 
 exceeding 10%\, while also suffering from symptoms such as fever\, anemia 
 and renal impairment. The symptoms can be attributed to the disease as wel
 l as the immune response to disease. Indicative of a poor prognosis\, some
  patients also present with hyperlactatemia and hypoglycemia\, attributed 
 to changes to the host metabolism during infection as well as an increase 
 in glycolytic flux through the parasite.  \n \nTo investigate the effects 
 of disease and parasite metabolism on disease manifestation and metabolic 
 abnormalities a multi-scale model was developed. The model linked two exis
 ting models: 1) a within-host disease model that incorporates the immune r
 esponse and\, 2) a whole-body glucose metabolism model that includes paras
 ite metabolism. The models were linked in two steps. The top-down linking 
 of the models used comparable variables and mapped the red blood cell (RBC
 ) populations from the disease model to the metabolic model. The bottom-up
  linking mapped the parasite ATP production rate to biomass formation in t
 he disease model. A Monte-Carlo simulation was performed and model predict
 ions were compared to clinical data from literature. \n \nSensitivity anal
 ysis on the linked model suggested that processes that affect the disease 
 and immune response have the largest effects on parasitemia and hematocrit
 \, while parasite glycolysis and the total number of RBCs have the largest
  effects on blood lactate and glucose levels. Additionally\, the model als
 o suggested that the innate immune response\, and more specifically innate
  immune cell longevity\, has a greater effect on disease outcome than the 
 adaptive immune response.  \n \nSeven treatments were added to the model t
 argeting specific processes. Two treatments affect the disease directly by
  blocking the invasion of healthy RBCs and by reducing the number of meroz
 oites released per bursting iRBC. Two treatments enhance the innate immune
  response\, one by increasing its efficiency and one by increasing its pro
 duction. The last three treatments all targeted parasite glycolysis by inh
 ibiting the glucose transporter\, hexokinase or phosphofructokinase. \n \n
 Comparison of the treatment effects indicated that targeting the prolifera
 tion of merozoites within the infected RBC is most efficient\, while glyco
 lytic inhibitors\, although less effective against disease itself\, led to
  the best treatment of hyperlactatemia and hypoglycemia.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Uncovering the effects of disease\, parasite metabolism and treatme
 nts on disease manifestation and metabolic abnormalities in a malaria infe
 cted host. - Shadé Horn
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/RFKVAN/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-KWE97E@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T113000
DTEND;TZID=SAST:20240911T120000
DESCRIPTION:Infections caused by common human pathogenic fungi result in ov
 er 1.5 million deaths worldwide every year. The main source of this proble
 m is the increasing emergence of species resistant to widely used antifung
 al agents. They emerge due to selection events induced by the over-use of 
 these agents in agriculture and medicine. This issue could be tackled by t
 argeting mechanisms important for fungal pathogenicity and survival. The r
 egulation of carbon metabolic pathways is crucial to adapting cellular pro
 cesses\, like energy production and cellular component synthesis\, to chan
 ging environmental conditions for fungal cells.\n\nOne of the most prevale
 nt human pathogenic fungi is the airborne saprophytic fungus Aspergillus f
 umigatus. This pathogen can cause infections in the lower respiratory trac
 t\, lungs\, sinuses and skin. Aspergillus fumigatus uses a complex signall
 ing network system to make changes in carbon metabolic processes when expo
 sed to osmotic or cell wall stress. These pathways are key to infecting th
 e host and surviving in the human organism. Many existing antifungal drugs
 \, like azoles and echinocandins\, target biomolecules in these pathways. 
 However\, the problem of increasing A. fumigatus resistance to the availab
 le drugs is causing a surge of deaths among immunodeficient patients with 
 invasive aspergillosis.\n\nKnowledge about the networks that regulate core
  cellular processes in A. fumigatus can be used to look for new fungicide 
 targets and help reduce the problem of antifungal drug resistance. Here\, 
 we designed two Boolean models that show how carbon metabolism signalling 
 pathways respond to osmotic and cell wall stress in A. fumigatus. Then\, w
 e used these models to identify new antifungal drug targets in these netwo
 rks. Our results suggest that osmotic and cell wall stress both induce the
  synthesis of carbon-based cell wall components in order to defend against
  stressors. Moreover\, we show how these processes can be disrupted by tar
 geting the RlmA transcription factor under cell wall stress and the SskB k
 inase under osmotic stress. Our models show that targetting RlmA of the ce
 ll wall integrity pathway is a way to inhibit 1\,3-beta-D glucan synthase 
 and increase echinocandin drug effectiveness\, while targetting SskB of th
 e HOG pathway is a possible way to inhibit fungal cell wall component synt
 hesis.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Boolean modelling of carbon metabolic signalling to identify new an
 tifungal drug targets in Aspergillus fumigatus - Jean-Marc Schwartz
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/KWE97E/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-CBYFN9@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T120000
DTEND;TZID=SAST:20240911T123000
DESCRIPTION:Parasite growth and metabolism are crucial areas of study in pa
 rasitology\, particularly concerning the development of effective treatmen
 ts. We focused on the model protozoan parasite Plasmodium falciparum\, the
  causative agent of malaria\, known for its high metabolic activity and re
 liance on glycolysis for ATP production. This study investigates the impac
 t of Spinosad\, a natural insecticide derived from Saccharopolyspora spino
 sa\, on parasite growth\, glycolytic flux\, and ATP levels. Spinosad has b
 een primarily used against insect pests\, but its effects on parasites\, e
 specially protozoans\, are less understood. This research aims to elucidat
 e the biochemical and physiological responses of P. falciparum to Spinosad
  treatment. \nCompared to untreated controls parasites treated with Spinos
 ad showed a marked decrease in specific growth rate\, and in glucose conve
 rsion to lactate. The decrease in glycolytic flux suggests that Spinosad m
 ight target glycolytic enzymes or regulatory mechanisms within the parasit
 e. To further understand the mechanism underlying these observations\, we 
 conducted kinetic assays for the glycolytic enzymes\, in Spinosad-treated 
 parasites. Preliminary data suggest a direct inhibitory effect of Spinosad
  on phosphofructokinase and to a lesser extent glucose-isomerase activity\
 , while none of the other glycolytic enzymes were affected. PFK in yeast a
 nd in red blood cells were not inhibited by Spinosad indicated some specif
 icity of the inhibitor for Plasmodium glycolysis. A dose dependent inhibit
 ion of PFK by Spinosad indicated a high flux control by the enzyme and con
 firmed the mechanism of Spinosad inhibition of glycolysis.\nIn conclusion\
 , Spinosad disrupted glycolytic metabolism\, leading to decreased ATP prod
 uction and impaired parasite growth. These findings highlight the potentia
 l of Spinosad as a novel antimalarial agent and underscore the importance 
 of targeting parasite metabolism in the development of new therapeutic str
 ategies. Further studies are warranted to fully elucidate the molecular ta
 rgets of Spinosad in P. falciparum and to evaluate its efficacy in vivo. T
 his research contributes to the broader understanding of how metabolic int
 erventions can be leveraged to combat parasitic diseases.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:An insecticide with antimalarial activity: Spinosad inhibits glucos
 e metabolism in P. falciparum - Tagwin Frantz
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/CBYFN9/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-WYYXQ3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T141500
DTEND;TZID=SAST:20240911T142000
DESCRIPTION:In 2022\, the ELIXIR Systems Biology community was established 
 within the broader ELIXIR infrastructure to represent and advocate for sys
 tems biology within European scientific infrastructures. While ELIXIR focu
 ses on improving the infrastructure for "data for life\," the Systems Biol
 ogy Community is dedicated to "models for life." Over the past couple of y
 ears\, community-led activities have begun to yield tangible results.\nOne
  such results is the publication of a revised whitepaper in June 2024\, wh
 ich outlines the major short- and long-term infrastructural challenges in 
 systems biology. These challenges include identifying and overcoming barri
 ers to the broader adoption of systems biology\, making data more model-fr
 iendly\, ensuring the interoperability of systems biology resources\, and 
 enhancing education and training.\nThe first Systems Biology implementatio
 n study has initiated efforts to address some of these challenges. This in
 cludes preparing a whitepaper on FAIR PBPK modeling\, the integration of t
 wo existing systems biology ontologies (EDAM and SBO)\, annotating (a set 
 of ) systems biology tools in the bio.tools repository\, and planning a co
 mprehensive analysis of the interoperability of these tools to be conducte
 d later in 2024.\nA second implementation study is currently being prepare
 d\, focusing on how AI can enhance various aspects of systems biology. Des
 pite these positive steps over the past two years\, many challenges remain
 . The success of these endeavors will be greatly enhanced by a larger and 
 more engaged community. We invite you to join us in our efforts: https://e
 lixir-europe.org/communities/systems-biology.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P1: ELIXIR Systems biology community: update two years after establ
 ishment - Anže Županič
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/WYYXQ3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-TWG7UX@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T142000
DTEND;TZID=SAST:20240911T142500
DESCRIPTION:Constraint-based modelling and genome scale models (GSM's) are 
 ubiquitous in Systems Biology with applications ranging from agriculture t
 o human health ([1](#references)). Fundamental to this methodology is the 
 ability to create and exchange models\, a process facilitated through the 
 use of the Systems Biology Markup Language (SBML) ([2](#references)) and i
 ts Flux Balance Constraints Package (FBC) extension.\n\nReleased in Septem
 ber 2015\, FBC version 2 has become the *de facto* standard for encoding G
 SM's and is widely used in model repositories (BioModels\, BiGG)\, softwar
 e (e.g. COBRAPy\, CBMPy) and curation pipelines (MEMOTE\, FROG). It extend
 s SBML by adding the components necessary for building typical GSM\, inclu
 ding a linear objective function\, reaction flux bounds and gene-protein-r
 eaction associations ([3](#references)). However\, more recent model types
 \, such as community and macromolecular expression (ME) models\, could not
  be fully encoded in FBC version 2. \n\nTo address these shortcomings a wo
 rking group\, including members of both the SBML and constraint-based mode
 lling community\, have been working towards a new version of FBC. Recently
  finalised\, the FBC version 3 specification ([4](#references)) builds on 
 FBC version 2 by allowing the definition of:\n\n- objective functions with
  mixed quadratic and linear terms\, that allows the definition of QP based
  models\,\n- user-defined (UD) constraints that are not defined as part of
  the stoichiometric matrix\,\n- UD constraints can contain quadratic terms
  that allow the definition of quadratic constraint (QC) models\,\n- UD con
 straint can also contain "artificial" variables that are defined as non-co
 nstant parameters\,\n- species that have chemical formulas with generic te
 rms (e.g. R\, X) and non-integer charges\,\n- KeyValuePairs\, a simple\, f
 lexible annotation type that supplements the existing SBML annotations.\n\
 nThe FAIR (**f**indable\, **a**ccessible\, **i**nteroperable\, **r**eusabl
 e) data principles form the basis of data management practices that are fo
 cussed on the reuse of research data ([5](#references)). In this context m
 odels are also considered research data that should be reusable by yoursel
 f and others thus enabling good and reproducible research practices. While
  much of the focus on FAIR data is on the findability and accessibility\, 
 SBML provides a structured data format with built-in support for metadata 
 that is primarily focussed on interoperability. The FBC 3 *KeyValuePair* a
 nnotations introduce support for less metadata that allows for a wider ran
 ge of information to be stored as model annotation\, and documentation\, p
 otentially leading to enhanced model reusability.\n\n### References\n1. ht
 tps://doi.org/10.1038/s41579-019-0264-8\n2. https://doi.org/10.15252/msb.2
 0199110\n3. https://doi.org/10.1515/jib-2017-0082\n4. https://github.com/s
 bmlteam/sbml-specifications/blob/develop/sbml-level-3/version-1/fbc/spec/s
 bml-fbc-version-3-release-1.pdf\n5. https://doi.org/10.1038%2Fsdata.2016.1
 8
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P2: Building constraint-based models with SBML FBC Version 3 - new 
 and improved\, but is it FAIR? - Brett G. Olivier
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/TWG7UX/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-XQPKJ7@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T142500
DTEND;TZID=SAST:20240911T143000
DESCRIPTION:LabNexus – An open-source enzyme kinetics data automation web
  application based on FAIR principles and STRENDA guidelines.\nAuthors: C.
 E. de Beer and J.M. Rohwer\nIn response to the reproducibility crisis in e
 nzymology and the principles of FAIR (Findable\, Accessible\, Interoperabl
 e\, and Reusable) data\, we present LabNexus\, a novel and user-friendly p
 latform for standardizing procedures related to the collection\, processin
 g\, and storage of both data and metadata with respect to enzyme kinetics 
 experiments.\nLabNexus features a fully integrated web interface that auto
 mates the corroboration of raw experimental data with corresponding metada
 ta with minimal user input. This includes integrated search tools for cros
 s-referencing external databases such as PubChem\, ChEBI\, and UniProt\, a
 nd efficient data processing capabilities. The platform utilizes the Enzym
 e Markup Language (EnzymeML)\, a derivative of SBML\, to package data and 
 metadata in adherence to STRENDA guidelines. Users can submit various type
 s of data\, including EnzymeML documents and raw spectrophotometric data\,
  both of which can be read into the  platform with minimal user interventi
 on.\nLabNexus is designed to be accessible to all enzyme kinetics research
 ers\, regardless of their programming literacy\, ensuring a broader adhere
 nce to FAIR principles in published literature. Users can view their submi
 tted data for validation purposes\, ensuring accuracy and consistency in t
 heir experimental results. The platform's modular design facilitates the e
 xpansion of supported spectrophotometric models and output formats. Users 
 can output their virtual documents (referred to as workspaces) in various 
 formats\, including EnzymeML\, YAML\, or Markdown\, enhancing the flexibil
 ity and utility of the data management ecosystem.\nOptionally\, LabNexus o
 ffers automated synchronization of spectrophotometric instrument output fi
 les to the server via a companion application on the instrument host machi
 ne\, adding redundancy to experiments. \nThe platform supports operation i
 n both closed and open networks\, incorporating network security protocols
  to safeguard data. In an open network configuration\, automated synchroni
 zation allows users to access\, view\, edit\, and annotate their data from
  anywhere in the world via an internet connection.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P3: LabNexus – An open-source enzyme kinetics data automation web
  application based on FAIR principles and STRENDA guidelines. - Coenraad d
 e Beer
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/XQPKJ7/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-BT7LX9@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T143000
DTEND;TZID=SAST:20240911T143500
DESCRIPTION:Systems biology is largely becoming transformed by the fourth i
 ndustrial revolution\; the integration of artificial intelligence and mach
 ine-learning within scientific research practice. Parameter estimation wit
 hin enzyme kinetics entails determining the values of the parameters in a 
 kinetic model that best fit the experimental data. However\, experimentall
 y\, this process can be laborious\, prone to error\, and expensive. Theref
 ore\, a machine-learning system approach might provide some benefits.\n\nW
 e here address these challenges by implementing the use of Neural Differen
 tial Equations (NDEs) for modeling experimental enzymatic time series data
 \, using the phosphoglycerate mutase (PGM) and enolase enzymes in the glyc
 olytic pathway as an example model system. NDEs combine deep learning with
  differential equations by modeling the change of a neural network’s unk
 nown position repeatedly over time. This allows the handling of convoluted
 \, irregular and time-dependent time series data. This research utilized 5
 2 experimental time-series datasets from our own laboratory. Validation of
  the NDE models is performed through classic machine learning procedures i
 n order to test integrity and reliability. This includes a 20/80 test/trai
 n dataset split\, to evaluate model performance\, cross validation using k
 -fold cross validation methods as well as comparisons to established basel
 ine models.\n\nNDEs present numerous advantages in comparison to tradition
 al Bayesian parameter estimation techniques. These include greater efficie
 ncy\, enhanced scalability for handling large and complex datasets and the
  ability to accurately represent and capture underlying processes of dynam
 ical systems in a continuous manner.\n\nThis research utilizes the applica
 tion of Catalax\, a JAX-based framework developed by Jan Range at the Univ
 ersity of Stuttgart\, Germany\, which supports simulation and parameter in
 ference through Bayesian parameter estimation. Catalax leverages Markov Ch
 ain Monte Carlo (MCMC) sampling to infer posterior distributions of model 
 parameters with the inclusion of the training framework for the NDEs.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P4: The Application of Neural Differential Equations to Enzyme-Kine
 tic Time Series - Danica Aimee Heusdens
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/BT7LX9/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-AFLBTH@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T143500
DTEND;TZID=SAST:20240911T144000
DESCRIPTION:Many experimental procedures in biochemical laboratory practice
  are repetitive\, time-consuming\, and prone to human error due to manual 
 processing. One procedure is the spectrophotometric assay for analysing en
 zymatic activity using microtiter plates. Currently\, transferring experim
 ental data from the instrument to the analysis platform requires manual co
 pying and pasting. Recently\, a specialized markup language EnzymeML and t
 he associated PyEnzyme software were created to automate parts of this wor
 kflow\, specifically fitting models to experimental data and transferring 
 kinetic parameters to databases. However\, the programming of the experime
 ntal protocol and the transfer of metadata have not yet been automated. Mo
 reover\, in enzymology research\, scientists are frequently facing reprodu
 cibility issues\, mainly because crucial metadata are not reported. These 
 can include the precise reaction conditions\, comprehensive experimental r
 esults\, and procedures used for data analysis. Therefore\, the aim of thi
 s study was to implement and test tools and interfaces to automate aspects
  of the experimental workflow and associated data management. These interf
 aces will assist in enabling data to be Findable\, Accessible\, Interopera
 ble and Reusable (FAIR). The tools are tested in the laboratory by perform
 ing enzymatic assays using an OT2 liquid handler to characterize the bi-fu
 nctional enzyme complex consisting of phosphopantothenoylcysteine syntheta
 se and phophopantothenoylcysteiene decarboxylase (CoaBC)\, the second and 
 third enzymes in the coenzyme A biosynthesis pathway. In Staphylococcus au
 reus\, CoaBC has not yet been kinetically characterised\; this process is 
 extremely challenging due to the complexity of the enzyme system\, as it i
 nvolves multiple substrates\, products and sequential reactions. To mitiga
 te this\, we aim to link the activity of CoaBC to the activity of the four
 th enzyme CoaD\, which is responsible for catalysing the conversion of 4
 ’-phosphopantetheine to dephospho-Coenzyme A with the release of pyropho
 sphate. The kinetics of the first step catalysed by CoaBC and the kinetics
  of CoaD were investigated by measuring the production of pyrophosphate in
  an enzyme-linked assay. During the second step of the reaction catalysed 
 by CoaBC\, CO2 is released\, which cannot be measured spectrophotometrical
 ly. Therefore\, we aim to perform kinetic assays either with CoaBC on its 
 own\, or by combining both enzymes CoaBC and CoaD. In the case where we co
 mbine both enzymes\, we expect the rate to be twice as fast\, since two py
 rophosphate molecules are released compared to the case with only CoaBC wh
 ere only one pyrophosphate is released. Lastly\, we construct a kinetic mo
 del using PySCeS\, where datasets with CoaBC and CoaD and datasets without
  CoaD are combined and the kinetic parameters for previously obtained for 
 the first step of CoaBC and CoaD are included\, to fit the kinetic paramet
 er values for the second step catalysed by CoaBC.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P5: The FAIR kinetic characterization of CoaBC from Staphylococcus 
 aureus - Francel Wessels
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/AFLBTH/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-PJ7CZ3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T144000
DTEND;TZID=SAST:20240911T144500
DESCRIPTION:Microbiota plasticity\, the ability of microbial communities to
  adapt to changing environments\, is crucial for understanding gut health.
  We develop a spatiotemporal model to simulate small intestinal microbiota
  and their interactions with host cells. We begin by constructing a commun
 ity model of various microbial species using metabolic reconstructions and
  Flux Balance Analysis (FBA). By optimizing community growth\, we investig
 ate species interactions\, applying L2-regularization and alternative obje
 ctive formulations. The next phase incorporates enterocytes into the micro
 bial community model. Utilizing metabolic reconstructions of *S. thermophi
 lus*\, *F. prausnitzii*\, *B. caccae*\, and *E. rectale*\, we simulate int
 eractions under conditions resembling an average Western diet. Our finding
 s highlight significant interactions\, including cross-feeding and competi
 tion among species. Finally\, we expand the model into a spatiotemporal fr
 amework\, simulating microbial dynamics along the small intestine. These s
 imulations reveal how species abundance varies with distance and time\, in
 fluenced by community composition and medium conditions.\nDespite challeng
 es in parameterization and validation\, our model offers insights into the
  plasticity of small intestinal microbiota and their interactions with ent
 erocytes\, enhancing our understanding of gut microbiome dynamics.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P6: Spatiotemporal Metabolic Modeling of Intestinal Epithelial Cell
 s and Microbial Communities - Natal van Riel
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/PJ7CZ3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-RXEDD7@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T144500
DTEND;TZID=SAST:20240911T145000
DESCRIPTION:Large collaborative projects need to share data during and afte
 r\, within and beyond the consortium. FAIRDOM-SEEK (https://fairdomseek.or
 g/) is an open-source software for storing\, cataloguing\, sharing and reu
 sing research outcomes designed to support the principles of FAIR (Findabl
 e\, Accessible\, Interoperable\, and Reusable) research data management. O
 riginally developed for the needs of systems biology of microorganisms\, S
 EEK is used in numerous projects of systems biology\, systems medicine\, a
 nd related domains. All data types can be handled and the use of files or 
 references to files is possible. Users can change the visibility of files 
 and references\, making it a platform for projects and data publication. I
 ts properties make it an interoperability resource for combining different
  tools for scientific work and subsequent publication of the outcomes.\nTh
 e systems medicine approach to quantification and characterization of larg
 e complex systems involves integration of multipledata types (e.g. genomic
 s\, proteomics\, metabolomics\, phenomics\, images\, patient related data\
 , etc.)\, stored in several specialized systems used within one project.  
  \nLiSyM-Cancer for example\, uses REDCap (https://www.project-redcap.org/
 ) as a clinical data system that manages information about patients and sa
 mples\; openBIS (https://openbis.ch/) as primary system for experimental r
 aw data and its metadata\; Nextcloud (https://nextcloud.com/) for short-te
 rm raw data exchange\; and OMERO for microscopic images. The harmonisation
  and integration of (meta)data between these platforms is mandatory to mak
 e the data comparable and publishable in open data repositories.\nHere\, w
 e describe our experience in combining multiple open-source data repositor
 y systems for the benefit of large collaborative projects.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P7: FAIR data management for collaborative Systems Medicine project
 s : from Instruments to Publication - Olga Krebs
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/RXEDD7/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-MAFVSY@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T145000
DTEND;TZID=SAST:20240911T145500
DESCRIPTION:In physical chemistry\, Gibbs free energies and chemical potent
 ials (not energies) are the descriptors for the energetics of compounds an
 d processes.  They integrate energy\, entropy and volume-work.  Changes in
  Gibbs energy and between chemical potentials equal the useful work at con
 stant temperature and pressure.  However\, this systematics requires one t
 o be explicit about the protonation\, Mg-complexation and hydration states
  of the molecules\, and to correct of activity coefficients differing from
  1.  Moreover the standard chemical potentials are defined for biologicall
 y irrelevant situations such as pH=pMg=0\, concentrations of 1 Molar\, hyd
 rogen gas at 1 atmosphere and crystalline phosphorous.  In addition\, one 
 must monitor the number of protons and Mg ions liberated or consumed by th
 e reaction.  Rather than a single ATP synthesis reaction\, this methodolog
 y requires describing some 20 reaction variants\, explicating the various 
 protonation\, Mg-complexation and hydration states of the three molecules 
 involved.  Indeed\, multiple literature studies have presented highly comp
 lex ways of calculating the standard Gibbs energy of this highly important
  reaction\, which then typically differed by 17 kJ/mol from its actual wor
 k potential.\nWe here present new ‘metabolic’ energies and potentials.
   These should replace the Gibbs free energy and the chemical potential fo
 r life processes and metabolites under in-vivo like conditions.  We also p
 resent a new ‘Thermotable’\, which contains the standard metabolic pot
 entials for up to a thousand metabolites of interest to systems biology.  
 The Thermotable enables the direct computation of standard (i.e.\, concent
 ration-independent) reaction energies by simple subtraction.  These are im
 mediately relevant for the in vivo reference conditions of pH=7\, pMg=3\, 
 ionic strength 0.15 M\, and T=310 K\, and concentrations of 1 mM.  There i
 s no need for correcting concentrations to activities.  The new standard r
 eaction energies are very good approximations towards the actual reaction 
 energies\, for when concentrations are unknown (yet on the order of 1 mM r
 ather than 1 M).\nThe metabolic potentials given in the Thermotable are mu
 ch better descriptors of the energetic potential of biochemicals than the 
 chemical potentials were\, because they are taken relative to a growth med
 ium of biological significance\, i.e.\, 1 mM of (total) bicarbonate\, ammo
 nium\, phosphate\, and sulfate\, as well as liquid water\, H+ at pH7\, and
  Mg2+ at pMg3.  This will be illustrated by plotting the metabolic energy 
 landscape for travelling down major metabolic pathways.  Whilst the maps o
 f chemical potentials were rugged and irregular\, the magnitudes of the po
 tentials are realistic (in terms of numbers of ATP energies) and the new m
 aps are smoothly down-hill except for steps up of about 50 kJ/mol where AT
 P energy is invested  (and down where ATP is made).  With the new metaboli
 c energies\, the calculation of free energy differences and equilibrium co
 nstants becomes facile\, omitting the many usual points of confusion in ca
 lculating from standard chemical potentials.\nThe new thermodynamics will 
 be useful for turning metabolic network maps into metabolic energy landsca
 pes and for warning against perpetua mobilia proposed by Flux Balance Anal
 ysis.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P8: Metabolic energies: how metabolites can really work for life - 
 Hans V. Westerhoff
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/MAFVSY/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-BRR8M3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T145500
DTEND;TZID=SAST:20240911T150000
DESCRIPTION:Low hydrogen peroxide concentrations are essential for eukaryot
 ic cell physiology\, but high concentrations trigger an antioxidant respon
 se. The redox-dependent activation of specific transcription factors is a 
 critical feature of this response. Deleting these transcription factors in
 creases the sensitivity of cells to hydrogen peroxide stress\, but their c
 onstitutive activation is also harmful. Curiously\, many redox transcripti
 on factors require multiple oxidation events for full activation. E. coli 
 OxyR needs four events\, mammalian Nrf2-Keap1 requires three\, Yap1 in bak
 er’s yeast needs three to four\, and Pap1 in S. pombe requires at least 
 two oxidation events. We investigated the purpose of these multiple oxidat
 ion events using computational modelling of a basic system and the fission
  yeast Pap1 system.  Our results demonstrated that multiple oxidation step
 s increased the system’s ability to attenuate signal activation at low h
 ydrogen peroxide concentrations and amplify it at higher peroxide concentr
 ations. This high-pass filtering property\, in part\, explains how eukaryo
 tic cells can tolerate low hydrogen peroxide levels without triggering an 
 adaptive response.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P9: Multiple Oxidation Events Drive Signal Attenuation and Amplific
 ation in the Tpx1-Pap1 Pathway for Hydrogen Peroxide Concentration Gradien
 ts - Limpho Parkies
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/BRR8M3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-W3LA87@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T150000
DTEND;TZID=SAST:20240911T150500
DESCRIPTION:Metabolic rewiring is observed in almost all cancer types and i
 s considered one of the hallmarks of cancer. The Warburg effect\, also nam
 ed aerobic glycolysis\, is characterised by an increased conversion of glu
 cose to lactate and was first observed by Otto Warburg in the 1920s. Studi
 es have shown a correlation between aerobic glycolysis and metastatic prop
 erties of cancer. The cancer-specific metabolic rewiring raises the questi
 on of whether the flux control distribution over the glycolytic pathway ha
 s changed compared to normal cells\, and whether such a redistribution cou
 ld be exploited for drug target identification. Work by Shestov et al. (20
 16) highlighted glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a good
  glycolytic target to perturb aerobic glycolysis in cancer. In a combined 
 experimental and modelling approach we investigated aerobic glycolysis in 
 the MDA-mb-231 cell line - a highly invasive and hormone-independent breas
 t cancer cell line\, to study the flux control distribution\, particularly
  the control by GAPDH.\n\nFor the construction of a detailed mathematical 
 model for the glycolytic pathway\, we kinetically characterised all 12 gly
 colytic enzymes. Kinetic parameters were obtained by performing a global f
 it on the enzyme’s initial rate kinetics using the corresponding rate eq
 uations. A set of ordinary differential equations was defined with paramet
 erised rate equations based on the kinetic data. The model was successfull
 y tested in its capacity to predict intermediate dynamics upon a pulse of 
 14C labelled glucose to cell free extracts and in its prediction of the ef
 fect of inhibition of GAPDH by iodoacetic acid. \nSubsequently\, the gluco
 se transporter was characterised\, and we are busy integrating the transpo
 rter kinetics with the glycolytic enzymes to simulate glucose metabolism i
 n intact cells. \n\nInhibitor titrations of intact cells revealed that the
  flux control coefficient of GAPDH is very low\, Kouril et al. (2023)\, ma
 king the enzyme a poor therapeutic target in this highly invasive breast c
 ancer cell line. We are currently investigating whether the high flux cont
 rol observed by Shestov is cell line dependent\, by analysing more sensiti
 ve cell lines. Once the intact cell model has been validated\, we will app
 ly MCA for drug target identification. \n\nShestov\, A.A.\, Liu\, X.\, Ser
 \, Z.\, Cluntun\, A.A.\, Hung\, Y.P.\, Huang\, L.\, Kim\, D.\, Le\, A.\, Y
 ellen\, G.\, Albeck\, J.G. and Locasale\, J.W.\, 2014. Quantitative determ
 inants of aerobic glycolysis identify flux through the enzyme GAPDH as a l
 imiting step. elife\, 3\, p.e03342.\n\nKouril\, T.\, October\, C.\, Holloc
 ks\, S.\, Odendaal\, C.\, van Niekerk\, D.D. and Snoep\, J.L.\, 2023. Inhi
 bitor titrations reveal low control of glyceraldehyde 3-phosphate dehydrog
 enase and high control of hexokinase on glycolytic flux in an aggressive t
 riple-negative breast cancer cell line. Biosystems\, 231\, p.104969.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P10: Drug target identification in glycolysis of highly invasive\, 
 triple-negative breast cancer cell line - Craig October
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/W3LA87/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-MBELTC@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T150500
DTEND;TZID=SAST:20240911T151000
DESCRIPTION:Type 2 diabetes (T2D) is a metabolic disease that negatively im
 pacts the health of many individuals worldwide. It accounts for roughly 95
 % of diabetes cases and was found to be responsible for 6.7 million diabet
 es related deaths in 2021\, with approximately 536.6 million people suffer
 ing from this disease globally. Despite the advancements that have been ma
 de in our understanding of T2D\, the molecular mechanisms underlying this 
 disease remain poorly understood. Therefore\, it is necessary to investiga
 te the cellular mechanisms underlying conditions such as insulin resistanc
 e and T2D to understand the extent of the metabolic dysfunction. There are
  three main tissues implicated in T2D\; skeletal muscle\, adipocytes and t
 he liver. Among these\, skeletal muscle is responsible for 75% of insulin-
 dependent glucose uptake and is therefore important for maintaining glucos
 e homeostasis. \nCore mathematical models were constructed for the insulin
  signalling pathway\, glucose transport and glucose metabolism to simulate
  insulin dependent glucose metabolism in control C2C12 skeletal muscle cel
 ls\, and in insulin insensitive cells. The model parameters were fitted to
  experimental data for dose and time dependent data for insulin addition a
 nd removal. Analysis of the individual models and their interactions will 
 reveal the effected points leading to insulin insensitivity. Although the 
 mouse cell model might not accurately reflect the T2D disease state in pat
 ients\, the concept to analyse the point(s) of interference is still appli
 cable.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P11: Analysis of insulin sensitivity in C2C12 skeletal muscle cells
  - Klarissa Shaw
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/MBELTC/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-QA7TLS@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T151000
DTEND;TZID=SAST:20240911T151500
DESCRIPTION:Diabetes is a growing global epidemic currently affecting 537 m
 illion adults worldwide\, with 90% of these cases attributed to type 2 dia
 betes mellitus. Individuals with diabetes suffer from glucose intolerance\
 , hyperinsulinaemia and hyperglycaemia. Additionally\, target tissues and 
 organs of insulin have a diminished response to insulin\, known as insulin
  resistance\, which results in the dysregulation of insulin signalling. Pr
 olonged insulin resistance\, in turn\, leads to pancreatic β cell dysfunc
 tion leading to decreased insulin production and ultimately the cessation 
 of insulin secretion. Several target tissues and organs are implicated in 
 type 2 diabetes mellitus namely the liver\, brain\, skeletal muscle and ad
 ipose tissue. Skeletal muscle cells are primarily responsible for insulin-
 dependent glucose uptake and homeostasis. Ergo\, in vitro models of skelet
 al muscle cells often are utilised in studies examining insulin signalling
  and glucose uptake. In the highly complex insulin signalling pathway\, pr
 otein kinase B more commonly known as Akt\, plays an essential role where 
 its dysregulation has been implicated in several deceases.  Specifically\,
  the overactivation of Akt can result in tumour growth\, whereas metabolic
  conditions such as insulin resistance can occur when Akt phosphorylation 
 is impaired. Thus\, inhibitors of this enzyme are of interest as a tool fo
 r research into Akt phosphorylation and insulin signalling.\nRecently\, ou
 r group has developed a kinetic mechanistic model to describe the dynamics
  of insulin signalling\, glucose uptake and its metabolism in C2C12 mouse 
 skeletal muscle. The activities of these modules were analysed dose- and t
 ime-dependently upon induction with insulin. This model serves as the refe
 rence state to further study mechanisms leading to insulin resistance as a
  function of known agents causing type 2 diabetes mellitus. \nAccordingly\
 , the effect of Akt inhibition on insulin signalling\, glucose uptake and 
 glycolytic flux was investigated in C2C12 mouse skeletal muscle myotubes. 
 The current phase II trial Akt allosteric inhibitor\, MK-2206\, was utilis
 ed. The inhibitory effect of MK-2206 on Akt phosphorylation was analysed u
 sing our group’s minimal mathematical model. As before\, 100 nM insulin 
 stimulation of untreated cells increased Akt Ser473 and Thr308 phosphoryla
 tion dose- and time-dependently. Treatment with MK-2206 decreased the dose
 -dependent increase of Akt phosphorylation of both Ser473 and Thr308 regul
 atory sites after stimulation with 100 nM insulin. In addition\, MK-2206 t
 reatment delayed the time dynamics of insulin-induced Akt phosphorylation.
  Model simulations were able to describe the delay and decrease of Akt pho
 sphorylation that was observed experimentally. In control cells\, stimulat
 ion with 100 nM insulin increased glucose uptake rate and lactate producti
 on rate by 2-fold and 1.9-fold\, respectively. MK-2206 treatment did not a
 ffect the basal rate of glucose uptake or lactate production\, but a stron
 g decrease of insulin stimulation of glucose metabolism was observed in MK
 -2206 treated cells.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P12: Quantitative analysis of Akt inhibition: Insulin signalling an
 d metabolic response in C2C12 skeletal muscle cells. - Nicole Pestana
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/QA7TLS/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-BGFYP9@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240911T151500
DTEND;TZID=SAST:20240911T152000
DESCRIPTION:Metabolic alterations are associated with many especially age r
 elated diseases and they are caused by changes in the expression of the co
 rresponding enzymes. Although analysis of gene expression data has become 
 a standard approach\, predicting large scale metabolic alterations is stil
 l challenging. Here\, we present a mathematical framework GEMCAT\, Gene Ex
 pression-based Metabolite Centrality Analysis Tool\, that is based on the 
 centrality of nodes in a directed graph. Through integration of differenti
 al expression data from either transcriptomics or proteomics we can predic
 t metabolic alterations for a large set of metabolites but avoid artificia
 l biomass or energy constraints required for other genome-scale modelling 
 approaches. We demonstrate the predictive efficacy of GEMCAT using two dis
 tinct datasets: one involving RNA sequencing data and metabolomics from a 
 human cell line featuring a deleted mitochondrial NAD-transporter\, and an
 other comprising proteomics and metabolomics data from patients afflicted 
 with inflammatory bowel disease. We furthermore extended our approach to t
 race the experimentally confirmed metabolic alterations back to the expres
 sion changes enabling network based multi-omics integration.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:P13: GEMCAT – An algorithm for the prediction of metabolic altera
 tions at genome-scale - Ines Heiland
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/BGFYP9/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-JKB8SA@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T090000
DTEND;TZID=SAST:20240912T093000
DESCRIPTION:Three components of sustainability (environmental\, economic an
 d societal) of various bioprocesses become increasingly important. Neglect
 ing the sustainability issues may cause adverse environmental and societal
  problems proportional to the production volumes. Governmental bodies are 
 expected to pay more attention to environmental and societal parameters of
  industry in near future.\nSustainable metabolic engineering (SME) is defi
 ned by Stalidzans and Dace (2021) as optimization of metabolism where econ
 omic\, environmental and societal sustainability parameters of all incomin
 g and outgoing fluxes and produced biomass of the applied organisms are co
 nsidered. \nConstraint-based stoichiometric modelling framework can be ada
 pted for the calculation of the integrated sustainability score (ISS) that
  consists of weighed economic (Econ)\, environmental (Env) and social (Soc
 ) components. ISS= Wecon*Econ + Wenv*Env + Wsoc*Soc. \nThe calculations ar
 e carried out introducing economic and environmental sustainability indica
 tor vectors for all exchange metabolites that have to be multiplied by the
  metabolic flux vector of all exchange fluxes accounting for the contribut
 ion of each exchange metabolite. The economic indicator vector (Econ) cont
 ains prices of substrates\, products and by-products. The environmental ve
 ctor (Env) contains characteristics of environmental impact parameters of 
 substrates\, products\, by-products and biomass. The value of the social c
 omponent (Soc) is calculated for the whole design of the organism (does no
 t depend directly on the values of exchange fluxes). Social component take
 s into account characteristics like health and safety risks\, newly create
 d working places (depend on the estimated financial turnover)\, social acc
 eptance of genetic engineering methods and others.\nGrowth-coupled product
 ion approach where the production of the target metabolite is coupled with
  the production of biomass has been selected as an option to implement SME
 . In case of SME the biomass production is coupled with the ISS that can b
 e introduced as an objective function. An important side-effect of growth-
 coupling is the reduction of exchange flux variability that reduces also t
 he variability of ISS.\nOptGene tool is adapted for the implementation of 
 ISS and applied for deletion-based design development. Sustainable designs
  of E.coli and some other organisms are proposed and compared indicating a
 dvantages and disadvantages of designs for production of particular metabo
 lites pointing at some patterns in sustainability analysis. We have observ
 ed that the environmental and societal sustainability components can be im
 proved without harming the economic parameters of target metabolite produc
 tion. \nCurrently SME can be used as a tool for preliminary selection of a
 ppropriate organisms and designs to study them in more detail. Further dev
 elopment of SME approach depends on the availability of suitable data for 
 environmental assessment of metabolite production and consumption impact o
 n the environment.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Sustainable metabolic engineering approach in strain development - 
 Egils Stalidzans
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/JKB8SA/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-XDTRC3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T093000
DTEND;TZID=SAST:20240912T100000
DESCRIPTION:An integrated systems toxicological approach was taken to ident
 ify physiologically relevant biomarkers of perfluorooctane sulfonate (PFOS
 ) toxicity in fish. PFOS is a ubiquitous pollutant in global aquatic ecosy
 stems with increasing concern for its toxicity to aquatic wildlife. An in 
 silico stoichiometric metabolism model of zebrafish was used to integrate 
 available metabolomics and transcriptomics datasets from in vivo toxicolog
 ical studies with 5 days post fertilized embryo-larval zebrafish. The expe
 rimentally derived omics datasets were used as constraints to parameterize
  the in silico zebrafish model. In silico simulations using flux balance a
 nalysis (FBA) showed prominent effects of PFOS exposure on the carnitine s
 huttle and fatty acid oxidation. Further analysis of impacted metabolites 
 indicated carnitine to be the most highly represented cofactor metabolite.
  Taken together\, our results showed dyslipidemia effects under PFOS expos
 ure and uniquely identified carnitine as a candidate metabolite biomarker.
  Subsequently\, verification of this prediction was sought through an in v
 ivo environmental monitoring study which showed carnitine to be a modal bi
 omarker of PFOS exposure in wild-caught fish and marine mammals sampled fr
 om the northern Gulf of Mexico. Therefore\, we highlight the efficacy of F
 BA to integrate multi-omics datasets to study the properties of large-scal
 e metabolic networks and identify biomarkers of exposure and likely advers
 e effects.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:In silico Biomarker Discovery and In vivo Verification Using a Zebr
 afish (Danio rerio) Genome-Scale Metabolic Model - David Hala
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/XDTRC3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-VKNQA7@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T100000
DTEND;TZID=SAST:20240912T103000
DESCRIPTION:Chinese Hamster Ovary (CHO) cells are cell factories for a vari
 ety of pharmaceutical outputs\, namely monoclonal antibody production and 
 biotherapeutics. Having been utilised for the synthesis of biological comp
 ounds for over a century\, CHO cells facilitate a wide range of post-trans
 lational modifications\, including glycosylation\, making them a popular c
 hoice for human drug development. Furthermore\, CHO cells can tolerate shi
 fts in their culture conditions\, such as pH\, oxygen levels\, temperature
  and cell density. These characteristics can be predicted and explained us
 ing constraint-based modelling\, which through the integration of ‘omics
  data\, invites the simulation of changing environmental conditions favour
 ing improved productivity.\nHere\, the recently published iCHO2441 genome-
 scale model (GEM) (Strain et al\, 2023) has been modified to closely match
  a specific cell line used for production by FUJIFILM Diosynth Biotechnolo
 gies (FDB)\, as part of our industry partnership. A wealth of time-course 
 ‘omics data (transcriptomics\, proteomics and metabolomics) has been gen
 erated to enable constraint-based modelling and provide opportunities for 
 creative model inputs and validations. Initial work has seen the flux samp
 ling of models constrained using transcriptomics data to represent specifi
 c time points over a two-week culture period. Flux sampling for bioenginee
 ring is a novel approach\, and here we have used it in conjunction with bo
 th unsupervised and supervised methods to identify metabolic signatures of
  low- and high-producing cell lines. Results from this analysis suggested 
 a range of metabolic subsystems associated with high productivity\, includ
 ing bile\, eicosanoid and steroid metabolism\, fatty acid metabolism and v
 itamin metabolism\, amongst others. Furthermore\, we have used these model
 s as a framework for media simulations\, to validate predictions against e
 xperimental metabolite uptake rates\, production rates and growth measurem
 ents. From here we have been able to begin predicting media supplements wh
 ich could favour high productivity. \nResults generated here could have ex
 citing implications for bioengineering\, expanding our knowledge of CHO ce
 ll metabolism and pathways underlying recombinant protein production. In a
 ddition\, we are developing a workflow involving more unconventional ‘om
 ics constraints and the interpretation of complex flux sampling results. T
 his project could be translated to other bioengineering systems and our si
 mulations aim to maximise the efficiency\, cost-effectiveness and predicti
 ve potential of sample-specific constraint-based models. \n\nStrain\, B. e
 t al. (2023) ‘How reliable are Chinese hamster ovary (CHO) cell genome-s
 cale metabolic models?’\, Biotechnology and Bioengineering [Preprint]. A
 vailable at: https://doi.org/10.1002/bit.28366.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Constraint-based modelling of CHO cells to propose high productivit
 y metabolic signatures - Kate Meeson
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/VKNQA7/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-7TVDMB@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T110000
DTEND;TZID=SAST:20240912T113000
DESCRIPTION:Genetically encoded redox sensors\, such as the Hyper and roGFP
  sensor families\, are powerful tools for enumerating the real-time dynami
 cs of hydrogen peroxide in cells. In typical experiments\, a dynamic profi
 le of sensor oxidation and reduction is obtained following an external hyd
 rogen peroxide perturbation. Using these profiles to characterise the quan
 titative relationship between the hydrogen peroxide concentration and sens
 or outputs is challenging as non-linearity in sensor responses to hydrogen
  peroxide may not be evident. Further\, it is unclear how different sensor
 s could be compared. We tested whether these profiles could be characteris
 ed by the area under the curve (AUC)\, signal amplitude\, signal time and 
 signal duration parameters. In baker’s yeast\, the Hyper7 AUC and amplit
 ude showed a strong linear correlation (r>0.9) to a wide range of hydrogen
  peroxide concentrations (1-1000 μM). These responses were higher than ro
 GFP2-Tsa2ΔCR parameters at hydrogen peroxide concentrations greater than 
 100 μM. By contrast\, the roGFP2-Tsa2ΔCR AUC and amplitude plots present
 ed distinct linear correlation equations for lower (<100 μM) and higher h
 ydrogen peroxide (>100 μM) concentrations establishing that this sensor
 ’s output is range specific. The signal time and duration for Hyper7 wer
 e lower than roGFP2-Tsa2ΔCR at higher hydrogen peroxide concentrations (>
 100 μM)\, showing that its activation/deactivation cycle was faster. By c
 ontrast\, in the fission yeast\, the AUC and amplitude for Hyper7 and roGF
 P2-Tpx1.C169S both showed distinct linear correlations for lower (<50 μM)
  and higher (>50 μM) concentrations\, and the signal time and duration we
 re constant in this background. These results show that any purported corr
 elation between hydrogen peroxide input and sensor output depends on the s
 ensor\, cell type and the hydrogen peroxide concentration range chosen. In
  summary\, this method facilitates the characterisation signalling data ge
 nerated by redox sensors.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Quantifying the signalling profiles of genetically encoded redox se
 nsors - Diane Lind
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/7TVDMB/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-GX7NBM@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T113000
DTEND;TZID=SAST:20240912T120000
DESCRIPTION:Climate change is galvanising plant science and agricultural re
 search to develop stress resilient crops\, highlighting the importance of 
 a holistic understanding of the complex signalling responses and growth tr
 adeoffs in plants under various stresses (biotic and abiotic). Knowledge o
 n these molecular interactions and processes is scattered across various s
 ources\, in diverse formats and levels of detail\, and thus not easily acc
 essible for downstream analysis and modelling. Knowledge graphs provide a 
 powerful and flexible platform for integrating information from diverse da
 tasets with complex relationships. Stress Knowledge Map ([SKM](https://skm
 .nib.si/)) is a knowledge graph resource that integrates previously disper
 sed information on molecular interactions in _A. thaliana_ and _S. tuberos
 um_ into a single entrypoint for plant stress response investigations. The
  knowledge graph implementation of SKM\, together with our library of anal
 ysis tools ([SKM-tools](https://github.com/NIB-SI/skm-tools)) allows for t
 he systematic generation of context specific formulations\, providing a mu
 lti-purpose platform for complex analyses to gain new insights behind expe
 rimental observations\, as well as the development of systems biology mode
 ls. Given the frequently missing kinetics for such models\, a Boolean grap
 h formulation circumvents the need for exhaustive mechanistic details. Tog
 ether with our Python package for Boolean and semi-quantitative modelling 
 ([BoolDog](https://nib-si.github.io/BoolDoG/))\, we are exploring signalli
 ng dynamics underlying plant responses to stress\, with the long term aim 
 of developing a digital twin. We will describe the development and feature
 s of SKM\, showcase examples of system-wide data contextualisation and hyp
 othesis generation\, and our forays into systematically generating a basis
  for a molecular digital twin in plants.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Stress Knowledge Map for network analysis and dynamical modelling o
 f plant stress signalling - Carissa Bleker
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/GX7NBM/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-GVSHXS@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240912T120000
DTEND;TZID=SAST:20240912T123000
DESCRIPTION:Metabolic reconstruction is a challenging and time-consuming pr
 ocess\, often resulting in slow progress in developing new reactions. An o
 pen-source and accessible interactive interface that allows users to test 
 their curated reactions quickly and accurately can significantly improve e
 fficiency.\n\nWe present **Reconstructor**\, a manual and AI-enabled recon
 struction interface that allows researchers to analyze curated reactions a
 nd generate predicted reactions. Reconstructor accurately provides mass an
 d charge balance information related to curated reactions\, offers detaile
 d information on metabolites\, and generates atom mapping of the reaction.
  Reconstructor features a GPT-enabled prediction function where users can 
 input a gene and receive predicted reactions. This predictive capability h
 as been demonstrated to be somewhat accurate in certain types of metabolis
 m when compared to known reactions in a reliable database.\n\nReconstructo
 r allows various input types for metabolites from reference databases such
  as VMH\, ChEBI\, SwissLipids\, and MetaNetX formats. It also includes a d
 rawing function using ChemDoodle\, with standardisation performed using RD
 Kit. Reactions are created by verifying metabolites\, generating RXN files
 \, and performing atom mapping via Reaction Decoder. Mass and charge balan
 ce are checked and detailed molecular information\, including formula and 
 atom counts\, is provided.\n\nUsers can save their curated reactions\, nam
 e them (and optionally add them to a group) for easy access\, and edit the
 m through the interface. \n\nReconstructor supports integration with metab
 olic databases like VMH. As a test of this integration\, we used a copy of
  the VMH database and have successfully integrated the interface with it\,
  ensuring smooth operation. The integration process includes validation to
  avoid duplicates\, preparation of reaction data\, submission to the datab
 ase\, and confirmation to the user. This integration ensures up-to-date da
 tasets and facilitates efficient data management across platforms.\n\n**Av
 ailability and Implementation:** The interface is available at [http://rec
 onstructor.humanmetabolism.org/](http://reconstructor.humanmetabolism.org/
 ) and the source code can be found at [https://github.com/opencobra/recons
 tructor](https://github.com/opencobra/reconstructor).
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Reconstructor: An Interactive Interface for Efficient Metabolic Rec
 onstruction and Analysis - Saleh Alwer
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/GVSHXS/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-FR3CD3@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T090000
DTEND;TZID=SAST:20240913T093000
DESCRIPTION:Synaptic transmission is the main process providing cross-conne
 cting activity among neurons in the central nervous system (CNS). It is co
 mmonly accepted that a synaptic contact consists of the complex of pre- an
 d post-synaptic membranes contacting with astrocytes. The transmission is 
 accomplished through several steps. Initially\, neuromediators stored in p
 re-synaptic vesicles release into a synaptic cleft. Then they diffuse to p
 ost-synaptic membrane where neuromediators bind to specific receptors caus
 e their activation. Finally\, in the most cases except acetylcholine the m
 ediators will be removed from the cleft either by convectional diffusion o
 r by re-uptake. There is much experimental evidence indicating a structura
 l ordering of both vesicles with pre-synaptic contacts and receptor locali
 zation. In particular\, the number and eventual position of glycine recept
 ors (GlyRs) on a post-synaptic membrane are defined by the structural data
  of the GlyR-gephyrin complex. In this case the membrane cluster of GlyR c
 an have central\, divided and rear localizations. In the present study\, t
 he 3D mathematical model of a neuronal bouton with a cluster localization 
 of glycine receptors (GlyRs) on the post-synaptic membrane was developed. 
 GlyR provides a transmembrane current of Cl- mediating a hyperpolarization
  of neuronal membranes. The forming of inhibitory postsynaptic potential (
 IPSP) and an electro-diffusion of chloride ions were evaluated by applying
  the boundary problems for a Poisson’s equation and a non-steady-state d
 iffusion equation\, respectively. The local changes ion concentration near
  the post-synaptic membrane\, mediated by GlyRs activation\, can raise up 
 to 80–110% from the initial level. It is remarkable that the central spa
 tial localization of GlyRs in the cluster had a considerable difference bo
 th in the chloride ion concentration changes (6%) and IPSP (17%) compared 
 to the divided or rear localization. Thus\, a spatial polymorphism of the 
 post-synaptic density of GlyRs is important to form a physiological respon
 se to a neuromediator release.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Micro diversity of sub-cell structures determines the activity of a
  synaptic bouton in neurons - Yaroslav R. Nartsissov
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/FR3CD3/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-TZC7FG@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T093000
DTEND;TZID=SAST:20240913T100000
DESCRIPTION:The aim of the study was to investigate the effect of dietary r
 estriction on the development of insulin resistance\, an established precu
 rsor to Type 2 Diabetes. This was investigated in conjunction with the eff
 ects of both age and diet in a mouse model. The mice were separated into 1
 6 cohorts according to the implementation of dietary restriction or unrest
 ricted access to food (DR or AL\, respectively)\, being fed either a high-
 fat (HF) or a low fat (LF) diet\, as well as the age at which the Oral Glu
 cose Tolerance Test (OGTT) was performed (4\, 9\, 15\, or 21 months of age
 ). The OGTT was performed using a glucose bolus consisting of both unlabel
 led (natural) glucose as well as deuterium labelled glucose ([6\,6-<sup>2<
 /sup>H<sub>2</sub>]-glucose). Blood plasma glucose and insulin concentrati
 ons were measured for a 2-hour interval following administration of the gl
 ucose bolus. A mathematical model consisting of 2 compartments\, the Gastr
 ointestinal (GI) and Plasma compartments was used to mathematically model 
 the appearance and disappearance of glucose in the blood plasma. This was 
 achieved using mass action kinetics to describe the transport of glucose f
 rom the GI compartment into the blood plasma compartment\, as well as its 
 subsequent removal. The contribution of the liver to plasma glucose concen
 trations was also included as the endogenous glucose production (EGP). Pla
 sma glucose concentrations were then described as functions of time and fi
 t to the OGTT time course data. The parameters obtained from these fitted 
 functions were then used in conjunction with the measured plasma insulin c
 oncentrations to calculate Peripheral and Liver specific insulin sensitivi
 ty indices (IS<sub>P</sub> and IS<sub>L</sub>\, respectively). The IS<sub>
 P</sub> is calculated using the quotient of the rate of elimination of lab
 elled glucose from the plasma compartment as well as the average insulin c
 oncentration throughout the OGTT. In this way\, lowered insulin concentrat
 ions in conjunction with elevated rates of glucose elimination indicate el
 evated sensitivity to insulin. The calculated IS<sub>P</sub> showed DR str
 ongly increased sensitivity\, with advanced age and a HF diet only dampeni
 ng this effect but not preventing it. The IS<sub>L</sub> is calculated usi
 ng the average measured plasma insulin concentrations and the average calc
 ulated EGP during the time course. Consequently\, reduced EGP in conjuncti
 on with reduced plasma insulin concentrations indicate an elevated respons
 e of the liver to insulin and subsequently a high IS<sub>L</sub>. The calc
 ulated IS<sub>L</sub> showed DR strongly elevated sensitivity independent 
 of both advanced age and diet. This study highlights the substantial impro
 vement in insulin sensitivity caused by DR\, its subsequent reduction in i
 nsulin resistance and lowered risk of developing Type 2 Diabetes\, as well
  as the differential effect DR has on both peripheral and hepatic insulin 
 sensitivity.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Long term dietary restriction has a strong and positive effect on b
 oth hepatic and peripheral insulin sensitivity\, irrespective of diet - Jo
 el Fisher
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/TZC7FG/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-8Z7MEU@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T100000
DTEND;TZID=SAST:20240913T103000
DESCRIPTION:One of the hallmarks of cancer is a deregulated energy metaboli
 sm. A well-known characteristic is the Warburg effect describing an increa
 sed glucose uptake and lactate release of the cells\, identified first 100
  years ago by Otto Warburg. In recent years\, more global changes in the m
 etabolism of cancer cells have been described\, in particular in biosynthe
 tic pathways\, e.g. the amino acid and nucleotide metabolism. Also\, the i
 mpact of oncogenes\, e.g. MYC family members\, on metabolic processes has 
 been studied in great detail.\n\nA powerful tool to study metabolic change
 s in cancer cells are computational models. These often are either relativ
 ely small-scale ordinary differential equation models (ODEs) or genome-sca
 le metabolic stoichiometric models (GEMs). While ODE models give detailed 
 insights on the pathways kinetic behavior\, they include a limited number 
 of metabolites and often neglect the multitude of connections to neighbori
 ng pathways. GEMs on the other hand usually focus on the stoichiometry of 
 the reactions and the steady state flux distribution\, but aim to include 
 all known metabolic processes.\n\nIn our work\, we developed a detailed OD
 E model of the energy metabolism of a childhood cancer and analyzed the in
 fluence of the high-risk oncogene MYCN. Moreover\, we aim to embed detaile
 d kinetic models of the energy metabolism into large-scale GEMs. Therefore
 \, we applied an algorithmic reduction of a GEM to derive stoichiometrical
 ly correct rates for the withdrawal and import of biosynthetic precursors 
 of an ODE model during growth.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Modeling the metabolism of cancer cells: analyzing the effect of on
 cogenes and growth - Mareike Simon
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/8Z7MEU/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-KFBFWA@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T110000
DTEND;TZID=SAST:20240913T113000
DESCRIPTION:Objective: The objective of this study was to investigate how d
 ifferent weight-loss interventions result in metabolic changes\, at differ
 ent time scales.\nMethods: Mathematical models (differential equations) of
  energy metabolism were used to study weight loss trajectories and changes
  in postprandial dynamics in response to diet restriction\, Roux-en-Y gast
 ric bypass (RYGB) surgery and semaglutide (Ozempic\, Wegovy) interventions
 . Personalized models and Virtual Patients were created and analyzed.\nRes
 ults and Conclusions: Model for long-term obesity-driven development and p
 rogression of diabetes based on the 'twin cycle hypothesis' (liver cycle\,
  pancreas cycle) expanded with inflammation contributing to glucolipotoxic
 ity. The model identifies a window of opportunity for remission through we
 ight loss. \nRYGB surgery increases glucagon-like peptide 1 (GLP-1) and im
 proves glucose levels\, but also increases (postprandial) insulin. Strikin
 gly\, postprandial hypoglycemia is a common problem after RYGB. Model traj
 ectory simulations suggest that interplay between changed anatomy\, GLP-1 
 kinetics and changes in insulin sensitivity may explain the emergence of p
 ost-bariatric hypoglycemia months or years after surgery.\nBoth RYGB surge
 ry and GLP-1 receptor agonism interventions weaken the appetite feedback c
 ontrol circuit that regulates body weight. Treatment with semaglutide not 
 only lowers body weight\, but also glucose levels\, an effect that warrant
 s further investigation for non-diabetic individuals.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:Weight loss and metabolic changes in response to diet restriction a
 nd bariatric surgery - Natal van Riel
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/KFBFWA/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-LYXTYY@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T113000
DTEND;TZID=SAST:20240913T120000
DESCRIPTION:The persistence of endemic malaria infections and the increasin
 g occurrence of antimalarial resistance necessitates the search for treatm
 ent strategies to combat and ultimately eradicate the disease. When consid
 ering treatment regimens\, it also becomes important to consider the speci
 fic stages of the parasite life cycle that are affected by treatments. Of 
 interest are the distinct within-host asexual and sexual stages which are 
 associated with disease symptoms and transmission respectively. Ideally on
 e should aim to target both stages to treat an ill patient and to prevent 
 the further spread of the disease.\n\nIn this study\, we investigated the 
 use of monotherapies and dual therapy antimalarial treatment regimens by u
 sing published disease\, pharmacokinetic and pharmacodynamic data and mode
 ls. First\, we constructed linked PKPD-disease models that contain a newly
  developed gametocyte description to account for observed time delays betw
 een parasite forms in clinical trial data. Candidate models were validated
  using clinical data to assess their ability to predict treatment outcomes
  in vivo\, which was used to identify the most appropriate model for furth
 er analysis. \n\nOur research also delved into the potential of a novel tr
 eatment approach. We evaluated disease outcomes in the model using a CDC-r
 ecommended administration of artesunate\, used to treat severe P. falcipar
 um malaria. We also explored the use of artemisinin-free combination thera
 py. This approach involved the repurposing of tafenoquine (a gametocytocid
 al) to target sexual forms\, in combination with lumefantrine (a blood sch
 izonticidal) to target asexual forms. Our model construction\, validation\
 , and analysis results will be presented.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:In silico analysis of Plasmodium falciparum malaria treatment targe
 ting asexual and sexual parasite forms. - Tasmin Summerton
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/LYXTYY/
END:VEVENT
BEGIN:VEVENT
UID:pretalx-isgsb2024-QHZRG9@isgsb2024.sun.ac.za:4443
DTSTART;TZID=SAST:20240913T120000
DTEND;TZID=SAST:20240913T123000
DESCRIPTION:Energy metabolism is essential for all living cells\, particula
 rly during periods of rapid growth or stress.\nCancer cells\, activated im
 mune cells\, and yeasts predominantly rely on aerobic glucose fermentation
  to\ngenerate ATP. This phenomenon is termed the ”Warburg effect” in c
 ancer cells and the ”Crabtree effect”\nin yeast cells [1]. Recently\, 
 several mathematical models have been proposed to theoretically explain th
 e\nWarburg effect.\n\nBeyond glucose\, glutamine is an important substrate
  for eukaryotic cells\, playing significant role not\nonly in biosynthesis
  but also in energy metabolism. In this study\, we develop a minimal const
 raint-based\nstoichiometric model to explain the Warburg effect\, incorpor
 ating the experimentally observed utilization\nof glutamine (the WarburQ e
 ffect) [2]. Our model considers both glucose and glutamine respiration\, a
 s\nwell as the fermentation of these metabolites. By accounting for enzyme
  masses when calculating the\nATP production rates\, our resource allocati
 on model reflects the costs associated with different pathways.\n\nOur res
 ults indicate that glucose fermentation is a superior energy-generating pa
 thway in human\ncancer cells. However\, the characteristics of yeast homol
 ogues diminish this advantage or lead to the\nsituation when glucose respi
 ration is more effective. The latter observation is consistent with the be
 havior of the fungal pathogen *Candida albicans*\, which is known to be a 
 Crabtree-negative yeast. Our results also demonstrate that glutamine serve
 s as a valuable energy source under glucose-limited conditions\, in additi
 on to its role as a carbon and nitrogen source in eukaryotic cells. Moreov
 er\, the results effectively explain the observed simultaneous uptake of g
 lucose and glutamine.\n\n## References\n[1] Noureddine Hammad *et al.* “
 The Crabtree and Warburg effects: Do metabolite-induced regulations partic
 ipate in their induction?” In: *Biochimica et Biophysica Acta (BBA)-Bioe
 nergetics* 1857.8\n(2016)\, pp. 1139–1146.\n\n[2] Jing Fan *et al.* “G
 lutamine-driven oxidative phosphorylation is a major ATP source in transfo
 rmed\nmammalian cells in both normoxia and hypoxia”. In: *Molecular Syst
 ems Biology* 9.1 (2013)\, pp. 1–11.
DTSTAMP:20260307T213051Z
LOCATION:Omega
SUMMARY:A minimal model of the WarburQ effect elucidates energy metabolism 
 of cancer and fungal cells - Wassili Dimitriew
URL:https://isgsb2024.sun.ac.za:4443/isgsb2024/talk/QHZRG9/
END:VEVENT
END:VCALENDAR