Many postdocs work as leaders later in their career. But how do postdocs acquire the skills to become leaders? Postdocs from the international Marie Skłodowska-Curie leadership program (LEAD) at the University of Copenha...Many postdocs work as leaders later in their career. But how do postdocs acquire the skills to become leaders? Postdocs from the international Marie Skłodowska-Curie leadership program (LEAD) at the University of Copenhagen postulate that supervision should be seen as an opportunity for training leadership skills. However, although every postdoc will supervise a student sooner or later, too many might find it a burden, which can lead to poor supervision and frustration. To help peers overcome problems in supervision, LEAD postdocs provide concrete tips for supervisors regarding planning, expectations alignment, and trust building. These tips can help supervisors establish a healthy, professional student-supervisor relationship that fosters the students' independence and ultimately leads to good science. Furthermore, the authors point out that the tasks related to supervision translate into leadership skills, such as delegation, decision-making, and relationship building. Hence, by focusing on becoming good supervisors, postdocs can prepare themselves for future leadership positions and provide a fruitful professional environment for students.
Bifidobacterium bifidum, a predominant colonizer of the infant gut, utilizes lacto-N-biose I (LNB), a prominent component of human milk oligosaccharides (HMOs), through a dedicated metabolic pathway. Among a diverse set...Bifidobacterium bifidum, a predominant colonizer of the infant gut, utilizes lacto-N-biose I (LNB), a prominent component of human milk oligosaccharides (HMOs), through a dedicated metabolic pathway. Among a diverse set of extracellular glycosidases involved in HMO degradation, lacto-N-biosidase (LnbB) plays a pivotal role by releasing LNB. We investigated the structure and function of the carbohydrate-binding module family 32 (CBM32) domain located at the C-terminus of the glycoside hydrolase family 20 catalytic domain in LnbB. Isothermal titration calorimetry showed that CBM32 binds LNB with a dissociation constant (K) of 98 μm. The crystal structure of the CBM32 complexed with LNB reveals the molecular basis for its specific recognition. Impact statement Bifidobacteria are beneficial gut microbes, and infant-associated strains establish symbiosis by degrading human milk oligosaccharides. This study uncovers the molecular mechanism by which Bifidobacterium bifidum captures lacto-N-biose I, a key disaccharide, functioning as a cross-feeder that promotes the growth of other bifidobacteria and supports the infant gut ecosystem.
Phosphoinositides, a versatile class of phosphorylated phosphatidylinositols, are emerging as central orchestrators of cellular stress responses. Beyond defining the organization and identity of endomembranes, these dyna...Phosphoinositides, a versatile class of phosphorylated phosphatidylinositols, are emerging as central orchestrators of cellular stress responses. Beyond defining the organization and identity of endomembranes, these dynamic lipids act as highly adaptable signaling hubs that integrate diverse stress cues, from nutrient deprivation and mechanical strain to osmotic imbalance and DNA damage. Across evolution-from unicellular organisms to mammals-they drive conserved adaptation programs, including vacuolar remodeling, endosomal trafficking, and autophagosome biogenesis, through a finely tuned metabolism governed by an intricate network of kinases, phosphatases, and regulatory partners. Recent advances uncover how compartment-specific regulation, enzymatic diversity, and organelle crosstalk converge on phosphoinositide signaling, revealing these lipids as not only molecular adaptors but also promising therapeutic entry points in diseases marked by defective stress resolution. This review synthesizes emerging insights into the multifaceted roles of phosphoinositides in mobilizing membranes under stress, with a focus on mechanistic principles and recent research.
Human BRCA2 protects the DNA when replication forks stall, whereas MRE11-RAD50 and DNA2-WRN process or partially degrade these substrates. When mutated, these genes result in distinct genetic instabilities and cancers, a...Human BRCA2 protects the DNA when replication forks stall, whereas MRE11-RAD50 and DNA2-WRN process or partially degrade these substrates. When mutated, these genes result in distinct genetic instabilities and cancers, arguing they have unique, not redundant, functions. Escherichia coli encodes functional homologs of MRE11-RAD50 (SbcC-SbcD), DNA2-WRN (RecJ-RecQ), and BRCA2 (RecF). Here, we use 2-dimensional gels, pulse-labelling, and replication-profiling analysis to show the bacterial homologs act at distinct substrates and loci on the chromosome. Whereas RecF and RecJ-RecQ protect and process DNA at arrested replication forks to facilitate repair, RecBCD and SbcC-SbcD protect and process DNA at sites where forks converge. Comparing the assays used in E. coli to human cells, we consider whether these cellular roles may be functionally conserved. Impact statement BRCA2, MRE11-RAD50, and WRN-DNA2 encode human proteins that process replication forks and result in distinct genetic instabilities and cancers when mutated. Here, we show their bacterial homologs act on unique replication fork substrates-those at DNA damage sites or as replication completes, and discuss their possible functional conservation in humans.
Rising atmospheric CO negatively affects plant iron (Fe) content, yet the underlying mechanisms remain poorly understood. Here, we identified More Iron under elevated CO (MIC) as a new player involved in Fe homeostasis u...Rising atmospheric CO negatively affects plant iron (Fe) content, yet the underlying mechanisms remain poorly understood. Here, we identified More Iron under elevated CO (MIC) as a new player involved in Fe homeostasis under elevated CO in Arabidopsis thaliana. MIC is a previously uncharacterized transmembrane protein which we found predominantly localized to the Golgi apparatus. Loss of MIC function results in increased Fe content under elevated CO, effectively mitigating the Fe decline observed in plants. MIC protein abundance is reduced in roots under elevated CO, suggesting post-transcriptional regulation of protein stability. This work identifies MIC as a novel component in the plant response to elevated CO, with potential implications for improving the nutritional quality of crops under climate change.
Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy characterized by dedifferentiation and radioiodine refractoriness. We investigated whether EZH2-mediated H3K27me3 deposition represses thyroid differen...Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy characterized by dedifferentiation and radioiodine refractoriness. We investigated whether EZH2-mediated H3K27me3 deposition represses thyroid differentiation genes (TDGs) in ATC cells. Online ChIP-seq analyses and CUT&RUN confirmed EZH2/H3K27me3 enrichment at key TDGs (SLC5A5, NKX2-1, TSHR, FOXE1, TPO). Pharmacological inhibition of EZH2 with EPZ6438 reactivated TDG expression in RAS and BRAF-mutated ATC cell lines and partially restored iodide uptake. Co-treatment with the MEK1/2 inhibitor U0126 further enhanced TDG expression, consistent with MAPK-dependent regulation of EZH2. These findings reveal EZH2 as a mediator of ATC dedifferentiation and highlight its inhibition as a potential strategy to restore thyroid function and sensitize tumors to radioiodine. Impact statement This study reveals how EZH2-driven epigenetic remodeling controls thyroid cell dedifferentiation and loss of iodide uptake in anaplastic thyroid cancer. Our findings provide new mechanistic insights and highlight an FDA-approved drug with repurposing potential, advancing both anaplastic thyroid cancer biology research and therapeutic perspectives.
In plants and algae, photosynthesis is driven by the absorption of sunlight energy by networks of pigments housed within light-harvesting proteins. Special photosynthetic complexes can intercept the low-energy photons co...In plants and algae, photosynthesis is driven by the absorption of sunlight energy by networks of pigments housed within light-harvesting proteins. Special photosynthetic complexes can intercept the low-energy photons corresponding to the far-red spectrum of the photosynthetically active radiation. These so-called red chlorophyll forms are found in multiple lineages of the Viridiplantae clade, are formed upon a change in spatial organization of chromophores within specific subunits of the photosystem I supercomplex, and can be detected by their unique red-shifted fluorescence emission signatures. Red forms enabled phototrophs to colonize light-limited ecological niches, especially where far-red radiation is enriched by leaf shading. The protein environment plays a key role in determining the occurrence of red forms, promoting strong excitonic interactions among chlorophyll a molecules and facilitating their excitation by low-energy photons. In this review, we present a comprehensive account of the evolutionary diversity of long-wavelength-driven photosynthesis in eukaryotes, and detail the biophysical and structural determinants of this phenomenon. Finally, we discuss how this knowledge can be applied in biotechnology to engineer crop canopies with broadened light absorption and higher yield potential.
Colorectal cancer (CRC) presents significant therapeutic challenges, particularly due to the development of resistance to standard chemotherapeutic agents such as irinotecan. In this study, we aimed to investigate the mo...Colorectal cancer (CRC) presents significant therapeutic challenges, particularly due to the development of resistance to standard chemotherapeutic agents such as irinotecan. In this study, we aimed to investigate the molecular and phenotypic mechanisms underlying irinotecan resistance in CRC using the LIM1215 cell line model. Transcriptomic analysis demonstrated that drug withdrawal induced major transcriptional reprogramming, characterized by downregulation of ABC transporters (ABCB1 and ABCG2), extracellular matrix-related genes, and markers of epithelial-to-mesenchymal transition (EMT), alongside reactivation of cell cycle pathways. Drug screening further indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug-resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors. Supplementation with the efflux inhibitor Elacridar partially restored drug sensitivity in resistant cells, emphasizing the role of transporter-mediated efflux in maintaining resistance.
Lentiviral vectors are powerful tools for long-term expression of large genes in the mammalian brain, but the palette of lentiviral tools available for targeting specific cell subpopulations is restricted. We describe a...Lentiviral vectors are powerful tools for long-term expression of large genes in the mammalian brain, but the palette of lentiviral tools available for targeting specific cell subpopulations is restricted. We describe a lentiviral vector for neuronal subtype-specific expression in Cre mouse lines. Combining a Cre-dependent flip excision switch with a GFP and a 2A self-cleaving peptide, it enables identification of living neurons expressing a gene of interest using fluorescence. We validated this vector by targeting neocortical interneuron types and midbrain dopaminergic neurons. Gene expression occurred exclusively in Cre-expressing neurons without altering their basic electrophysiological properties. This system has been designed to be flexible and easy to modify in order to target expression of any gene of interest in any cell subtype.
The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is a central regulator of B cell biology, influencing survival, proliferation, metabolism, and immune responses. This Review explores how in bot...The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is a central regulator of B cell biology, influencing survival, proliferation, metabolism, and immune responses. This Review explores how in both normal and malignant B cells, signaling operates within a finely tuned "comfort zone", where appropriate levels support cell growth and survival. This comfort zone is dynamically modulated by the developmental stage, costimulatory signals, and the duration, magnitude, and subcellular localization of signaling events. In chronic lymphocytic leukemia, aberrant PI3K/AKT activation drives disease progression and resistance to therapy. Notably, deviations from the comfort zone-whether through excessive hyperactivation or insufficient signaling-can trigger cell death, presenting therapeutic opportunities. Signaling thresholds influence normal B cell development and chronic lymphocytic leukemia pathogenesis, including mechanisms of immune escape and Richter's transformation, an aggressive progression from chronic lymphocytic leukemia. Therapeutic strategies targeting PI3K/AKT are evaluated, with a focus on challenges such as toxicity. By understanding the nuanced modulation of the signaling comfort zone, we can refine therapies to selectively eliminate leukemic cells while preserving normal B cell function, offering new hope for improved treatment outcomes.
DNA copy number changes are the most frequent genomic alterations in cancer cells. Here, we demonstrate that Rad27/FEN1, a structure-specific nuclease in budding yeast, plays a crucial role in maintaining the stability o...DNA copy number changes are the most frequent genomic alterations in cancer cells. Here, we demonstrate that Rad27/FEN1, a structure-specific nuclease in budding yeast, plays a crucial role in maintaining the stability of the ribosomal DNA (rDNA) repeats. Severe rDNA instability is observed in the rad27∆ mutant, independently of Fob1-mediated DNA replication fork arrest and DNA double-strand break (DSB) formation in the rDNA. The rad27Δ mutant accumulates Okazaki fragments in the rDNA region, without inducing the formation of detectable DSBs. Similar rDNA instability is observed in DNA ligase-deficient cells. Furthermore, Exonuclease 1 and PCNA partially compensate for the loss of Rad27 in rDNA stabilization. These findings highlight the importance of proper Okazaki fragment maturation in the maintenance of rDNA stability.
Most mitochondrial proteins are synthesized in the cytosol and imported into the organelle. Here, we describe a novel Import and de-Quenching Competition (IQ-compete) assay which monitors the import efficiency of model p...Most mitochondrial proteins are synthesized in the cytosol and imported into the organelle. Here, we describe a novel Import and de-Quenching Competition (IQ-compete) assay which monitors the import efficiency of model proteins by fluorescence in living cells. For this method, the sequence of the tobacco etch virus (TEV) protease is fused to a mitochondrial precursor and coexpressed with a cytosolic reporter which becomes fluorescent upon TEV cleavage. Thus, inefficient import of the fusion protein leads to a fluorescent signal. With the IQ-compete assay, the import efficiency of proteins can be reliably analyzed in fluorescence readers, by flow cytometry, by microscopy, and by western blotting. We are convinced that the IQ-compete assay will be a powerful strategy for many different applications. Impact statement This article describes a novel method to monitor the mitochondrial import efficiency for a given protein in living yeast cells. With this IQ-compete assay, protein import efficiencies can be quantified by fluorescent microscopy, flow cytometry, fluorescence spectrometry or western blotting.
CRISPR-Cas systems provide adaptive immunity to bacteria by recognizing and destroying foreign genetic elements. The type I-E CRISPR-Cas system utilizes a multi-subunit Cascade complex to detect target DNA and recruit th...CRISPR-Cas systems provide adaptive immunity to bacteria by recognizing and destroying foreign genetic elements. The type I-E CRISPR-Cas system utilizes a multi-subunit Cascade complex to detect target DNA and recruit the Cas3 nuclease for degradation. To overcome this defense, bacteriophages have evolved anti-CRISPR (Acr) proteins that inhibit various steps of the CRISPR interference pathway. Here, we determined the crystal structure of AcrIE8.1, an uncharacterized Acr, revealing it binds to Cas11, a Cascade subunit, to disrupt function. AcrIE8.1 has a compact fold with a defined Cas11-binding interface, suggesting a unique inhibitory mechanism among AcrIE proteins. These findings highlight Cas11 as a critical target for Acr-mediated immune evasion. Impact statement Through a combination of structural and biochemical analyses, we demonstrate that AcrIE8.1 directly binds to the Cas11 subunit of the Cascade complex to inhibit the CRISPR-Cas system. This represents a novel inhibitory strategy not previously observed among AcrIE proteins.
The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated...The fibroblast growth factor (FGF) family and the FGF receptors are ubiquitously expressed and regulate a plethora of cell signaling cascades during development, tissue and cell homeostasis, and metabolism. Dysregulated FGF signaling is associated with cancer and several genetic and metabolic disorders. As FGF signaling regulates all the key metabolic processes to maintain whole-body homeostasis, there is an increasing focus on engineering FGFs as potential treatments for dysregulated metabolism. Within cancer, reprogramming of energy metabolism is a crucial step leading to tumorigenesis, metastasis formation, and resistance to therapy. FGF signaling dysregulation in cancer enables uncontrolled proliferation and survival and promotes therapy resistance and metastasis. However, the role of FGF signaling within cancer metabolism is not well understood. A better understanding of how FGF signaling affects the rewiring of cancer metabolism as well as tumorigenesis would provide novel avenues for discovering potential drug targets and biomarkers. Here, we discuss the role of paracrine, endocrine, and intracellular FGFs within metabolism as well as the current understanding of how FGF signaling contributes to rewired cancer metabolism.
Inositol phosphates (InsPs) are intracellular signaling molecules that are essential for life. Inositol pyrophosphates, a subset of inositol phosphates, are the end products of inositol phosphate metabolism. In mammalian...Inositol phosphates (InsPs) are intracellular signaling molecules that are essential for life. Inositol pyrophosphates, a subset of inositol phosphates, are the end products of inositol phosphate metabolism. In mammalian cells, up to 90% of inositol pyrophosphates are 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5PP-InsP), which is generated by inositol hexakisphosphate kinases (IP6Ks). 5PP-InsP can be further phosphorylated by diphosphoinositol pentakisphosphate kinases (PPIP5Ks) to generate 1,5-bisdiphosphoinositol 2,3,4,6-tetrakisphosphate (InsP). Unlike freely diffusible molecules, 5PP-InsP and InsP act locally at the sites where they are synthesized. Thus, individual IP6K and PPIP5K enzymes perform specific functions. Preclinical and clinical studies suggest that these molecules contribute to early life development, but mediate age-related diseases beyond adulthood. In this review, we summarize the functions and mechanisms of action of every individual IP6K and PPIP5K in both physiological processes and diseases and discuss the potential applications of these inositol pyrophosphate kinases as druggable targets for disease treatment.
To mark the 10th anniversary of International Day of Women and Girls in Science on 11th February 2025, FEBS Letters opened a writing contest on the topic of female role models in science. We invited entrants not only to...To mark the 10th anniversary of International Day of Women and Girls in Science on 11th February 2025, FEBS Letters opened a writing contest on the topic of female role models in science. We invited entrants not only to reflect on the careers of prominent academics, but also to share stories about the supervisors, colleagues, and other women who have inspired their own research journeys. Here, we present one of two runners-up, an essay by physicist Cara Giovanetti (UC Berkeley and Lawrence Berkeley National Lab), which maps out the challenges faced by women in physical science in an antagonistic political climate through conversations with mentors and colleagues.
To mark the 10th anniversary of the International Day of Women and Girls, FEBS Letters opened a writing contest on the topic of female role models in science. Here, we present a runner-up, an essay by Mahaiwon Shadang (A...To mark the 10th anniversary of the International Day of Women and Girls, FEBS Letters opened a writing contest on the topic of female role models in science. Here, we present a runner-up, an essay by Mahaiwon Shadang (All India Institute of Medical Sciences) celebrating her circle of colleagues who have built a supportive and nurturing academic environment through peer mentorship.
Tropomodulin-1 (TMOD1) is a key regulator of actin filament dynamics that functions as an actin-binding protein. It specifically caps the slow-growing (pointed) ends of actin filaments, and the interaction is further sta...Tropomodulin-1 (TMOD1) is a key regulator of actin filament dynamics that functions as an actin-binding protein. It specifically caps the slow-growing (pointed) ends of actin filaments, and the interaction is further stabilized by tropomyosin (TPM). By modulating actin monomer polymerization and depolymerization, TMOD1 critically controls filament length, thereby maintaining both the stability and plasticity of actin-based structures. Emerging evidence has highlighted the participation of TMOD1 in diverse cellular processes, such as cytoskeletal organization, neurite outgrowth, cell motility, and cancer progression. This review summarizes recent advances in TMOD1 research and offers a comprehensive overview of its multifaceted biological roles and implications for future studies.
Comprehensive understanding of phosphoinositide signaling requires both spatiotemporal visualization and precise quantitative analysis of individual lipid species. Phosphoinositides, a family of phosphorylated derivative...Comprehensive understanding of phosphoinositide signaling requires both spatiotemporal visualization and precise quantitative analysis of individual lipid species. Phosphoinositides, a family of phosphorylated derivatives of phosphatidylinositol (PI), are structurally diverse lipid messengers that orchestrate a wide range of cellular functions, including membrane trafficking, cytoskeletal dynamics, and signal transduction. Due to their dynamic metabolism and compartment-specific localization, their analysis demands complementary strategies that integrate live-cell imaging with molecular quantification. In this review, we first summarize the development and application of fluorescence-based probes designed to monitor the distribution and dynamics of phosphoinositides in living cells, highlighting their specificity, targeting mechanisms, and limitations. We then provide an overview of recent advances in mass spectrometry-based methodologies that enable high-sensitivity, isomer-resolved quantification of phosphoinositides in biological specimens, including improvements in lipid extraction, derivatization, and chromatographic separation. Together, these dual approaches offer synergistic insights into the biochemical and cellular regulation of phosphoinositide signaling.