Microenvironmental cooperation promotes early spread and bistability of a Warburg-like phenotype

We introduce an in silico model for the initial spread of an aberrant phenotype with Warburg-like overflow metabolism within a healthy homeostatic tissue in contact with a nutrient reservoir (the blood), aimed at characterizing the role of the microenvironment for aberrant growth. Accounting for cellular metabolic activity, competition for nutrients, spatial diffusion and their feedbacks on aberrant replication and death rates, we obtain a phase portrait where distinct asymptotic whole-tissue states are found upon varying the tissue-blood turnover rate and the level of blood-borne primary nutrient. Over a broad range of parameters, the spreading dynamics is bistable as random fluctuations can impact the final state of the tissue. Such a behaviour turns out to be linked to the re-cycling of overflow products by non-aberrant cells. Quantitative insight on the overall emerging picture is provided by a spatially homogeneous version of the model

Optimally designed quantum transport across disordered networks

We establish a general mechanism for highly efficient quantum transport through finite, disordered 3D networks. It relies on the interplay of disorder with centro-symmetry and a dominant doublet spectral structure, and can be controlled by proper tuning of only coarse-grained quantities. Photosynthetic light harvesting complexes are discussed as potential biological incarnations of this design principle.Comment: 7 pages (incl. 2 pages of suppl. mat.), 3 figure

Inclusion of maintenance energy improves the intracellular flux predictions of CHO

Chinese hamster ovary (CHO) cells are the leading platform for the production of biopharmaceuticals with human-like glycosylation. The standard practice for cell line generation relies on trial and error approaches such as adaptive evolution and high-throughput screening, which typically take several months. Metabolic modeling could aid in designing better producer cell lines and thus shorten development times. The genome-scale metabolic model (GSMM) of CHO can accurately predict growth rates. However, in order to predict rational engineering strategies it also needs to accurately predict intracellular fluxes. In this work we evaluated the agreement between the fluxes predicted by parsimonious flux balance analysis (pFBA) using the CHO GSMM and a wide range of 13C metabolic flux data from literature. While glycolytic fluxes were predicted relatively well, the fluxes of tricarboxylic acid (TCA) cycle were vastly underestimated due to too low energy demand. Inclusion of computationally estimated maintenance energy significantly improved the overall accuracy of intracellular flux predictions. Maintenance energy was therefore determined experimentally by running continuous cultures at different growth rates and evaluating their respective energy consumption. The experimentally and computationally determined maintenance energy were in good agreement. Additionally, we compared alternative objective functions (minimization of uptake rates of seven nonessential metabolites) to the biomass objective. While the predictions of the uptake rates were quite inaccurate for most objectives, the predictions of the intracellular fluxes were comparable to the biomass objective function.COMET center acib: Next Generation Bioproduction, which is funded by BMK, BMDW, SFG, Standortagentur Tirol, Government of Lower Austria and Vienna Business Agency in the framework of COMET - Competence Centers for Excellent Technologies. The COMET-Funding Program is managed by the Austrian Research Promotion Agency FFG; D.S., J.S., M.W., M.H., D. E.R. This work has also been supported by the PhD program BioToP of the Austrian Science Fund (FWF Project W1224)info:eu-repo/semantics/publishedVersio

Benchmarking solutions to the T-cell receptor epitope prediction problem: IMMREP22 workshop report

Many different solutions to predicting the cognate epitope target of a T-cell receptor (TCR) have been proposed. However several questions on the advantages and disadvantages of these different approaches remain unresolved, as most methods have only been evaluated within the context of their initial publications and data sets. Here, we report the findings of the first public TCR-epitope prediction benchmark performed on 23 prediction models in the context of the ImmRep 2022 TCR-epitope specificity workshop. This benchmark revealed that the use of paired-chain alpha-beta, as well as CDR1/2 or V/J information, when available, improves classification obtained with CDR3 data, independent of the underlying approach. In addition, we found that straight-forward distance-based approaches can achieve a respectable performance when compared to more complex machine-learning models. Finally, we highlight the need for a truly independent follow-up benchmark and provide recommendations for the design of such a next benchmark

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

SiPM-matrix readout of two-phase argon detectors using electroluminescence in the visible and near infrared range

Proportional electroluminescence (EL) in noble gases is used in two-phase detectors for dark matter searches to record (in the gas phase) the ionization signal induced by particle scattering in the liquid phase. The “standard” EL mechanism is considered to be due to noble gas excimer emission in the vacuum ultraviolet (VUV). In addition, there are two alternative mechanisms, producing light in the visible and near infrared (NIR) ranges. The first is due to bremsstrahlung of electrons scattered on neutral atoms (“neutral bremsstrahlung”, NBrS). The second, responsible for electron avalanche scintillation in the NIR at higher electric fields, is due to transitions between excited atomic states. In this work, we have for the first time demonstrated two alternative techniques of the optical readout of two-phase argon detectors, in the visible and NIR range, using a silicon photomultiplier matrix and electroluminescence due to either neutral bremsstrahlung or avalanche scintillation. The amplitude yield and position resolution were measured for these readout techniques, which allowed to assess the detection threshold for electron and nuclear recoils in two-phase argon detectors for dark matter searches. To the best of our knowledge, this is the first practical application of the NBrS effect in detection science

Design and construction of a new detector to measure ultra-low radioactive-isotope contamination of argon

Large liquid argon detectors offer one of the best avenues for the detection of galactic weakly interacting massive particles (WIMPs) via their scattering on atomic nuclei. The liquid argon target allows exquisite discrimination between nuclear and electron recoil signals via pulse-shape discrimination of the scintillation signals. Atmospheric argon (AAr), however, has a naturally occurring radioactive isotope, 39Ar, a β emitter of cosmogenic origin. For large detectors, the atmospheric 39Ar activity poses pile-up concerns. The use of argon extracted from underground wells, deprived of 39Ar, is key to the physics potential of these experiments. The DarkSide-20k dark matter search experiment will operate a dual-phase time projection chamber with 50 tonnes of radio-pure underground argon (UAr), that was shown to be depleted of 39Ar with respect to AAr by a factor larger than 1400. Assessing the 39Ar content of the UAr during extraction is crucial for the success of DarkSide-20k, as well as for future experiments of the Global Argon Dark Matter Collaboration (GADMC). This will be carried out by the DArT in ArDM experiment, a small chamber made with extremely radio-pure materials that will be placed at the centre of the ArDM detector, in the Canfranc Underground Laboratory (LSC) in Spain. The ArDM LAr volume acts as an active veto for background radioactivity, mostly γ-rays from the ArDM detector materials and the surrounding rock. This article describes the DArT in ArDM project, including the chamber design and construction, and reviews the background required to achieve the expected performance of the detector