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In this work, we report on the synthesis, in-depth crystal structure studies as well as optical and magnetic properties of newly synthesized heterometallic quaternary selenides of the Eu+2Ln+3Cu+1Se3 composition. Crystal structures of the obtained compounds were refined by the derivative difference minimization (DDM) method from the powder X-ray diffraction data. The structures are found to belong to orthorhombic space groups Pnma (structure type Ba2MnS3 for EuLaCuSe3 and structure type Eu2CuS3 for EuLnCuSe3, where Ln = Sm, Gd, Tb, Dy, Ho and Y) and Cmcm (structure type KZrCuS3 for EuLnCuSe3, where Ln = Tm, Yb and Lu). Space groups Pnma and Cmcm were delimited based on the tolerance factor t’, and vibrational spectroscopy additionally confirmed the formation of three structural types. With a decrease in the ionic radius of Ln3+ in the reported structures, the distortion of the (LnCuSe3) layers decreases, and a gradual formation of the more symmetric structure occurs in the sequence Ba2MnS3 → Eu2CuS3 → KZrCuS3. According to magnetic studies, compounds EuLnCuSe3 (Ln = Tb, Dy, Ho and Tm) each exhibit ferrimagnetic properties with transition temperatures ranging from 4.7 to 6.3 K. A negative magnetization effect is observed for compound EuHoCuSe3 at temperatures below 4.8 K. The magnetic properties of the discussed selenides and isostructural sulfides were compared. The direct optical band gaps for EuLnCuSe3, subtracted from the corresponding diffuse reflectance spectra, were found to be 1.87–2.09 eV. Deviation between experimental and calculated band gaps is ascribed to lower d states of Eu2+ in the crystal field of EuLnCuSe3, while anomalous narrowing of the band gap of EuYbCuSe3 is explained by the low-lying charge-transfer state. Ab initio calculations of the crystal structures, elastic properties and phonon spectra of the reported compounds were performed.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide, constituting around 30-40% of all cases. Almost 60% of patients develop relapse of refractory DLBCL. Among the reasons for the therapy failure, tumour microenvironment (TME) components could be involved, including tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (TANs), cancer-associated fibroblasts (CAFs), and different subtypes of cytotoxic CD8+ cells and T regulatory cells, which show complex interactions with tumour cells. Understanding of the TME can provide new therapeutic options for patients with DLBCL and improve their prognosis and overall survival. This review provides essentials of the latest understanding of tumour microenvironment elements and discusses their role in tumour progression and immune suppression mechanisms which result in poor prognosis for patients with DLBCL. In addition, we point out important markers for the diagnostic purposes and highlight novel therapeutic targets., Competing Interests: The authors declare no conflicts of interest.

Summary: Kinetic models of metabolism are crucial to understand the inner workings of cell metabolism. By taking into account enzyme regulation, detailed kinetic models can provide accurate predictions of metabolic fluxes. Comprehensive consideration of kinetic regulation requires highly parameterized non-linear models, which are challenging to build and fit using available modelling tools. Here, we present a computational package implementing the GRASP framework for building detailed kinetic models of cellular metabolism. By defining the mechanisms of enzyme regulation and a reference state described by reaction fluxes and their corresponding Gibbs free energy ranges, GRASP can efficiently sample an arbitrarily large population of thermodynamically feasible kinetic models. If additional experimental data are available (fluxes, enzyme and metabolite concentrations), these can be integrated to generate models that closely reproduce these observations using an approximate Bayesian computation fitting framework. Within the same framework, model selection tasks can be readily performed., Availability and Implementation: GRASP is implemented as an open-source package in the MATLAB environment. The software runs in Windows, macOS and Linux, is documented (graspk.readthedocs.io) and unit-tested. GRASP is freely available at github.com/biosustain/GRASP., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2022. Published by Oxford University Press.)

Pseudomonas putida is evolutionarily endowed with features relevant for bioproduction, especially under harsh operating conditions. The rich metabolic versatility of this species, however, comes at the price of limited formation of acetyl-coenzyme A (CoA) from sugar substrates. Since acetyl-CoA is a key metabolic precursor for a number of added-value products, in this work we deployed an in silico-guided rewiring program of central carbon metabolism for upgrading P. putida as a host for acetyl-CoA-dependent bioproduction. An updated kinetic model, integrating fluxomics and metabolomics datasets in addition to manually-curated information of enzyme mechanisms, identified targets that would lead to increased acetyl-CoA levels. Based on these predictions, a set of plasmids based on clustered regularly interspaced short palindromic repeats (CRISPR) and dead CRISPR-associated protein 9 (dCas9) was constructed to silence genes by CRISPR interference (CRISPRi). Dynamic reduction of gene expression of two key targets (gltA, encoding citrate synthase, and the essential accA gene, encoding subunit A of the acetyl-CoA carboxylase complex) mediated an 8-fold increase in the acetyl-CoA content of rewired P. putida. Poly(3-hydroxybutyrate) (PHB) was adopted as a proxy of acetyl-CoA availability, and two synthetic pathways were engineered for biopolymer accumulation. By including cell morphology as an extra target for the CRISPRi approach, fully rewired P. putida strains programmed for PHB accumulation had a 5-fold increase in PHB titers in bioreactor cultures using glucose. Thus, the strategy described herein allowed for rationally redirecting metabolic fluxes in P. putida from central metabolism towards product biosynthesis-especially relevant when deletion of essential pathways is not an option., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic networks are regulated to ensure the dynamic adaptation of biochemical reaction fluxes to maintain cell homeostasis and optimal metabolic fitness in response to endogenous and exogenous perturbations. To this end, metabolism is tightly controlled by dynamic and intricate regulatory mechanisms involving allostery, enzyme abundance and post-translational modifications. The study of the molecular entities involved in these complex mechanisms has been boosted by the advent of high-throughput technologies. The so-called omics enable the quantification of the different molecular entities at different system layers, connecting the genotype with the phenotype. Therefore, the study of the overall behavior of a metabolic network and the omics data integration and analysis must be approached from a holistic perspective. Due to the close relationship between metabolism and cellular phenotype, metabolic modelling has emerged as a valuable tool to decipher the underlying mechanisms governing cell phenotype. Constraint-based modelling and kinetic modelling are among the most widely used methods to study cell metabolism at different scales, ranging from cells to tissues and organisms. These approaches enable integrating metabolomic data, among others, to enhance model predictive capabilities. In this review, we describe the current state of the art in metabolic modelling and discuss future perspectives and current challenges in the field.

Adaptive laboratory evolution is an important tool to evolve organisms to increased tolerance towards different physical and chemical stress. It is applied to study the evolution of antibiotic resistance as well as genetic mechanisms underlying improvements in production strains. Adaptive evolution experiments can be automated in a high-throughput fashion. However, the characterization of the resulting lineages can become a time consuming task, when the performance of each lineage is evaluated individually. Here, we present a novel method for the markerless insertion of randomized genetic barcodes into the genome of Escherichia coli using a novel dual-auxotrophic selection approach. The barcoded E. coli library allows multiplexed phenotyping of evolved strains in pooled competition experiments. We use the barcoded library in an adaptive evolution experiment; evolving resistance towards three common antibiotics. Comparing this multiplexed phenotyping with conventional susceptibility testing and growth-rate measurements we can show a significant positive correlation between the two approaches. Use of barcoded bacterial strain libraries for individual adaptive evolution experiments drastically reduces the workload of characterizing the resulting phenotypes and enables prioritization of lineages for in-depth characterization. In addition, barcoded clones open up new ways to profile community dynamics or to track lineages in vivo or situ.

The vestibular system receives a permanent influence from gravity and reflexively controls equilibrium. If we assume gravity has remained constant during the species' evolution, will its sensory system adapt to abrupt loss of that force? We address this question in the land snail Helix lucorum exposed to 30 days of near weightlessness aboard the Bion-M1 satellite, and studied geotactic behavior of postflight snails, differential gene expressions in statocyst transcriptome, and electrophysiological responses of mechanoreceptors to applied tilts. Each approach revealed plastic changes in the snail's vestibular system assumed in response to spaceflight. Absence of light during the mission also affected statocyst physiology, as revealed by comparison to dark-conditioned control groups. Readaptation to normal tilt responses occurred at ~20 h following return to Earth. Despite the permanence of gravity, the snail responded in a compensatory manner to its loss and readapted once gravity was restored.