As interest in sustainability grows, many researchers raise questions about changing scientific practices. To enable effective change, we reconceptualize sustainability as an approach that optimizes the efficiency of procedures, thereby benefiting scientists and minimizing environmental footprints. Since the implementation of sustainable approaches can be challenging, we describe the 6R concept as a framework to arrive at actionable steps.
Ewing sarcoma (ES) is a highly aggressive pediatric tumor driven by the EWS/FLi1 transcription factor, influencing epithelial–mesenchymal transition (EMT). EMT stabilizes a hybrid cell state, boosting metastatic potential and drug resistance. Nevertheless, the mechanisms underlying this ES phenotype remain elusive. Through a computational model, we predicted ZEB2, miR-200, and miR-145 circuits responsible for maintaining hybrid states in ES.
Ewing sarcoma (ES) is a highly aggressive pediatric tumor driven by the RNA-binding protein EWS (EWS)/friend leukemia integration 1 transcription factor (FLI1) chimeric transcription factor, which is involved in epithelial–mesenchymal transition (EMT). EMT stabilizes a hybrid cell state, boosting metastatic potential and drug resistance. Nevertheless, the mechanisms underlying the maintenance of this hybrid phenotype in ES remain elusive. Our study proposes a logical EMT model for ES, highlighting zinc finger E-box-binding homeobox 2 (ZEB2), miR-145, and miR-200 circuits that maintain hybrid states. The model aligns with experimental findings and reveals a previously unknown circuit supporting the mesenchymal phenotype. These insights emphasize the role of ZEB2 in the maintenance of the hybrid state in ES.
Grimontia hollisae collagenase (Ghcol) consists of 767 amino acid residues with a single catalytic domain containing the zinc-binding motif H492EYVH496. The crystal structure of Ghcol in complex with its substrate (Gly-Pro-hydroxyproline-Gly-Pro-hydroxyproline) and site-directed mutagenesis of active-site Tyr residues revealed the catalytic mechanism: Glu493 functions as an acid and base catalyst while Tyr564 stabilizes the tetrahedral complex in the transition state.
Grimontia hollisae collagenase (Ghcol) exhibits high collagen-degrading activity. To explore its catalytic mechanism, its substrate (Gly-Pro-Hyp-Gly-Pro-Hyp, GPOGPO)-complexed crystal structure was determined at 2.0 Å resolution. A water molecule was observed near the active-site zinc ion. Since this water was not observed in the product (GPO)-complexed Ghcol, it was hypothesized that the GPOGPO-complexed Ghcol structure reflects a Michaelis complex, providing a structural basis for understanding the catalytic mechanism. Analyses of the active-site geometry and site-directed mutagenesis of the active-site tyrosine residues revealed that Glu493 and Tyr564 were essential for catalysis, suggesting that Glu493 functions as an acid and base catalyst while Tyr564 stabilizes the tetrahedral complex in the transition state. These results shed light on the catalytic mechanism of bacterial collagenase.
Cover illustration By optimising the efficiency of experimental procedures, we can minimise the lab’s environmental footprint, making research more sustainable. Read more in Penndorf and Jabs ‘A new approach to making scientific research more efficient ’ rethinking sustainability’ in this issue.
In this review, we summarize the recent advances in our understanding of how local and systemic sources of TNF contribute to its antitumor and tumor-promoting properties. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity- and cancer-associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis.
Tumor necrosis factor (TNF)-α is a highly conserved proinflammatory cytokine with important functions in immunity, tissue repair, and cellular homeostasis. Due to the simplicity of the Drosophila TNF-TNF receptor (TNFR) system and a broad genetic toolbox, the fly has played a pivotal role in deciphering the mechanisms underlying TNF-mediated physiological and pathological functions. In this review, we summarize the recent advances in our understanding of how local and systemic sources of Egr/TNF contribute to its antitumor and tumor-promoting properties, and its emerging functions in adaptive growth responses, sleep regulation, and adult tissue homeostasis. The recent annotation of TNF as an adipokine and its indisputable contribution to obesity- and cancer-associated metabolic diseases have provoked a new area of research focusing on its dual function in regulating immunity and energy homeostasis. Here, we discuss the role of TNFR signaling in coupling immune and metabolic processes and how this might be relevant in the adaption of host to environmental stresses, or, in the case of obesity, promote metabolic derangements and disease.
This review highlights the established and emerging roles of the SRPK, CLK, and DYRK kinase families in development. Kinase functions elucidated in biochemical and genetic studies inform the underlying mechanisms of human development, whereby kinase-associated phenotypes arising from developmental models can parallel features of human development disorders.
Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub-family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co-ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.
In this study, the role of STAP-2 in B cell functions was analyzed. BCR-mediated B cell activation was enhanced in STAP-2 KO mice by inhibiting recruitment of Csk to Lyn. In accordance with the results, antibody production was significantly higher in STAP-2 KO mice compared with WT mice. Therefore, STAP-2 is important for the regulation of BCR signaling in B cells.
Although signal-transducing adaptor protein-2 (STAP-2) acts in certain immune responses, its role in B cell receptor (BCR)-mediated signals remains unknown. In this study, we have revealed that BCR-mediated signals, cytokine production and antibody production were increased in STAP-2 knockout (KO) mice compared with wild-type (WT) mice. Phosphorylation of tyrosine-protein kinase LYN Y508 was reduced in STAP-2 KO B cells after BCR stimulation. Mechanistic analysis revealed that STAP-2 directly binds to LYN, dependently of STAP-2 Y250 phosphorylation by LYN. Furthermore, phosphorylation of STAP-2 enhanced interactions between LYN and tyrosine-protein kinase CSK, resulting in enhanced CSK-mediated LYN Y508 phosphorylation. These results suggest that STAP-2 is crucial for controlling BCR-mediated signals and antibody production by enhanced CSK-mediated feedback regulation of LYN.
This work rectifies the previous view that eukaryotic inositol lipids may derive from archaea that used such lipids together with membrane traffic proteins to engulf an aerobic bacterium, which became the mitochondrion. Eukaryotic biosynthesis of inositol lipids is of bacterial origin, as exemplified by the phylogeny of D-myo-inositol 3-phosphate synthase (MIPS), the initial enzyme of the biosynthetic pathway.
The merger of two very different microbes, an anaerobic archaeon and an aerobic bacterium, led to the birth of eukaryotic cells. Current models hypothesize that an archaeon engulfed bacteria through external protrusions that then fused together forming the membrane organelles of eukaryotic cells, including mitochondria. Images of cultivated Lokiarchaea sustain this concept, first proposed in the inside-out model which assumes that the membrane traffic system of archaea drove the merging with bacterial cells through membrane expansions containing inositol lipids, considered to have evolved first in archaea. This assumption has been evaluated here in detail. The data indicate that inositol lipids first emerged in bacteria, not in archaea. The implications of this finding for the models of eukaryogenesis are discussed.
Hybrid RNA–DNA triplexes belong to two different motifs: Parallel pyrimidine or antiparallel purine. Their formation at engineered Escherichia coli promoters produced transcription modulation with enhancing or inhibiting effects, depending on triplex geometry. These modular synthetic biology units were used to build molecular gates XOR and XNOR and a threshold gate.
In recent years, increasing numbers of noncoding RNA molecules were identified as possible components of endogenous DNA–RNA hybrid triplexes involved in gene regulation. Triplexes are potentially involved in complex molecular signaling networks that, if understood, would allow the engineering of biological computing components. Here, by making use of the enhancing and inhibiting effects of such triplexes, we demonstrate in vitro the construction of triplex-based molecular gates: ‘exclusive OR’ (XOR), ‘exclusive NOT-OR’ (XNOR), and a threshold gate, via transcription of a fluorogenic RNA aptamer. Precise modulation was displayed by the biomolecular-integrated systems over a wide interval of transcriptional outputs, ranging from drastic inhibition to significant enhancement. The present contribution represents a first example of molecular gates developed using DNA–RNA triplex nanostructures.
This review focuses on the importance of sumoylation and SUMO-dependent ubiquitination in the relocalization/targeting of different types of DNA damage, stalled replication forks, telomeres and both activated and repressed genes to the nuclear periphery. The enrichment of proteasome at the nuclear envelope and association of SUMO proteases with nuclear pore complexes facilitate DNA repair pathway choice and optimal transcription regulation.
Abstract
Two related post-translational modifications, the covalent linkage of Ubiquitin and the Small Ubiquitin-related MOdifier (SUMO) to lysine residues, play key roles in the regulation of both DNA repair pathway choice and transcription. Whereas ubiquitination is generally associated with protein degradation, the impact of sumoylation has been more mysterious. Sumoylation effects are largely mediated by the subnuclear localization of its targets, particularly in response to DNA damage. This is governed in part by the concentration of SUMO protease at nuclear pores (1,2). We review here the roles of sumoylation in determining subnuclear locus positioning relative to the nuclear envelope and the nuclear envelope to facilitate repair and to regulate transcription.