Targeting host glycolysis as a strategy for antimalarial development

Glycolysis controls cellular energy, redox balance, and biosynthesis. Antiglycolytic therapies are under investigation for treatment of obesity, cancer, aging, autoimmunity, and microbial diseases. Interrupting glycolysis is highly valued as a therapeutic strategy, because glycolytic disruption is generally tolerated in mammals. Unfortunately, anemia is a known dose-limiting side effect of these inhibitors and presents a major caveat to development of antiglycolytic therapies. We developed specific inhibitors of enolase - a critical enzyme in glycolysis - and validated their metabolic and cellular effects on human erythrocytes. Enolase inhibition increases erythrocyte susceptibility to oxidative damage and induces rapid and premature erythrocyte senescence, rather than direct hemolysis. We apply our model of red cell toxicity to address questions regarding erythrocyte glycolytic disruption in the context o

Counting valence quarks at RHIC and LHC

We consider the Nuclear Modification Ratios in heavy ion collisions, R_CP and R_AA, in the region of intermediate transverse momentum, and study the dependency upon the constituent quark composition of the observed hadron. Adopting a two component recombination/fragmentation model, validated by experimental information from STAR and PHENIX, we show that a clear distinction is predicted for the f0(980) between the assumptions of $s\bar s$ or diquark-antidiquark content.Comment: 14 pages, 11 eps figures, added figures and minor corrections, to appear in Phys. Lett.

Structure-guided microbial targeting of antistaphylococcal prodrugs

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs i

X-ray imaging with gaseous detectors using the VMM3a and the SRS

The integration of the VMM3a Application-Specific Integrated Circuit (ASIC) into RD51's Scalable Readout System (SRS) provides a versatile tool for the readout of Micro-Pattern Gaseous Detectors (MPGDs). With its self-triggered high-rate readout, its analogue part that allows to get information on the deposited energy in the detector, and its so-called neighbouring-logic that allows to recover information on the charge distribution, this new system has features of particular interest for digital X-ray imaging. In the present article, we want to emphasise the capabilities of VMM3a/SRS by presenting results of X-ray imaging studies. We will highlight the advantages on the energy and the spatial resolution provided by the neighbouring-logic. In the first part, we focus on spatial resolution studies. We show how segmented readout structures introduce a repeating pattern in the distribution of the reconstructed positions (using the centre-of-gravity method) and how this behaviour can be mitigated with the neighbouring-logic. As part of these studies, we explore as well an alternative position reconstruction algorithm. In the second part of the article, we present the energy resolution studies.Peer reviewe

Prodrugs of a 1-Hydroxy-2-Oxopiperidin-3-Yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation

Whole-genome and multisector exome sequencing of primary and post-treatment glioblastoma reveals patterns of tumor evolution

Glioblastoma (GBM) is a prototypical heterogeneous brain tumor refractory to conventional therapy. A small residual population of cells escapes surgery and chemoradiation, resulting in a typically fatal tumor recurrence ~7 mo after diagnosis. Understanding the molecular architecture of this residual population is critical for the development of successful therapies. We used whole-genome sequencing and whole-exome sequencing of multiple sectors from primary and paired recurrent GBM tumors to reconstruct the genomic profile of residual, therapy resistant tumor initiating cells. We found that genetic alteration of the p53 pathway is a primary molecular event predictive of a high number of subclonal mutations in glioblastoma. The genomic road leading to recurrence is highly idiosyncratic but can be broadly classified into linear recurrences that share extensive genetic similarity with the primary tumor and can be directly traced to one of its specific sectors, and divergent recurrences that share few genetic alterations with the primary tumor and originate from cells that branched off early during tumorigenesis. Our study provides mechanistic insights into how genetic alterations in primary tumors impact the ensuing evolution of tumor cells and the emergence of subclonal heterogeneity

Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine.

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a potentially targetable vulnerability. Homozygous MTAP-deleted cell lines in culture show elevation of MTAP\u27s substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit protein arginine methyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibition. While this concept has been extensively corroborated in vitro, the clinical relevance relies on exhibiting significant MTA accumulation in human glioblastoma. In this work, using comprehensive metabolomic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of extracellular MTA. We further demonstrate that homozygous MTAP-deleted primary glioblastoma tumors do not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma. These findings highlight metabolic discrepancies between in vitro models and primary human tumors that must be considered when developing strategies for precision therapies targeting glioblastoma with homozygous MTAP deletion

The QCD confinement transition: hadron formation

We review the foundations and the applications of the statistical and the quark recombination model as hadronization models.Comment: 45 pages, 16 figures, accepted for publication in Landolt-Boernstein Volume 1-23

Timing performance of a Micro-Channel-Plate Photomultiplier Tube

The spatial dependence of the timing performance of the R3809U-50 Micro-Channel-Plate PMT (MCP-PMT) by Hamamatsu was studied in high energy muon beams. Particle position information is provided by a GEM tracker telescope, while timing is measured relative to a second MCP-PMT, identical in construction. In the inner part of the circular active area (radius r5.5 mm) the time resolution of the two MCP-PMTs combined is better than 10 ps. The signal amplitude decreases in the outer region due to less light reaching the photocathode, resulting in a worse time resolution. The observed radial dependence is in quantitative agreement with a dedicated simulation. With this characterization, the suitability of MCP-PMTs as t0 reference detectors has been validated.Peer reviewe