ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons.

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease leading to motor neuron loss. Currently mutations in > 40 genes have been linked to ALS, but the contribution of many genes and genetic mutations to the ALS pathogenic process remains poorly understood. Therefore, we first performed comparative interactome analyses of five recently discovered ALS-associated proteins (C21ORF2, KIF5A, NEK1, TBK1, and TUBA4A) which highlighted many novel binding partners, and both unique and shared interactors.

Deciphering lineage specification during early embryogenesis in mouse gastruloids using multilayered proteomics.

Gastrulation is a critical stage in embryonic development during which the germ layers are established. Advances in sequencing technologies led to the identification of gene regulatory programs that control the emergence of the germ layers and their derivatives. However, proteome-based studies of early mammalian development are scarce.

Mitochondrial HO release does not directly cause damage to chromosomal DNA.

Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of HO released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach.

Targeted perturbation of signaling-driven condensates.

Biomolecular condensates have emerged as a major organizational principle in the cell. However, the formation, maintenance, and dissolution of condensates are still poorly understood. Transcriptional machinery partitions into biomolecular condensates at key cell identity genes to activate these.

FOXO transcription factors as mediators of stress adaptation.

The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels.

Oxygen-consumption based quantification of chemogenetic HO production in live human cells.

Reactive Oxygen Species (ROS) in the form of HO can act both as physiological signaling molecules as well as damaging agents, depending on their concentration and localization. The downstream biological effects of HO were often studied making use of exogenously added HO, generally as a bolus and at supraphysiological levels. But this does not mimic the continuous, low levels of intracellular HO production by for instance mitochondrial respiration.

Pyruvate metabolism controls chromatin remodeling during CD4 T cell activation.

Upon antigen-specific T cell receptor (TCR) engagement, human CD4 T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation.

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis.

Hyperplasia of epidermal keratinocytes that depend on glycolysis is a new hallmark of psoriasis pathogenesis. Our previous studies demonstrated that PSORI-CM02 could halt the pathological progression of psoriasis by targeting inflammatory response and angiogenesis, but its effect(s) and mechanism(s) on proliferating keratinocytes remained unclear. In this study, we aim to identify components of PSORI-CM02 that are absorbed into the blood and to determine the effect(s) of PSORI-CM02 on keratinocyte proliferation and its molecular mechanism(s).

Metabolic profiling of colorectal cancer organoids: A comparison between high-resolution magic angle spinning magnetic resonance spectroscopy and solution nuclear magnetic resonance spectroscopy of polar extracts.

Patient-derived cancer cells cultured in vitro are a cornerstone of cancer metabolism research. More recently, the introduction of organoids has provided the research community with a more versatile model system. Physiological structure and organization of the cell source tissue are maintained in organoids, representing a closer link to in vivo tumor models.

Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRAS glycolytic colorectal tumors.

Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure.

Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice.

Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as effective treatments for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (mBC). Dedicated research efforts have been undertaken to find predictive biomarkers of response or resistance to these therapies although no molecular biomarkers for mBC have reached the clinic so far. This review aims to summarize and evaluate the performance of biomarkers in predicting progression-free survival in phase II and III clinical trials of CDK4/6 inhibitors in HR+/HER2- mBC.

The Contribution of Evolutionary Game Theory to Understanding and Treating Cancer.

Evolutionary game theory mathematically conceptualizes and analyzes biological interactions where one's fitness not only depends on one's own traits, but also on the traits of others. Typically, the individuals are not overtly rational and do not select, but rather inherit their traits. Cancer can be framed as such an evolutionary game, as it is composed of cells of heterogeneous types undergoing frequency-dependent selection.

Global analysis of protein arginine methylation.

Quantitative information about the levels and dynamics of post-translational modifications (PTMs) is critical for an understanding of cellular functions. Protein arginine methylation (ArgMet) is an important subclass of PTMs and is involved in a plethora of (patho)physiological processes. However, because of the lack of methods for global analysis of ArgMet, the link between ArgMet levels, dynamics, and (patho)physiology remains largely unknown.

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes.

Calpain-2 regulates hypoxia/HIF-induced plasticity toward amoeboid cancer cell migration and metastasis.

Hypoxia, through hypoxia inducible factor (HIF), drives cancer cell invasion and metastatic progression in various cancer types. In epithelial cancer, hypoxia induces the transition to amoeboid cancer cell dissemination, yet the molecular mechanisms, relevance for metastasis, and effective intervention to combat hypoxia-induced amoeboid reprogramming remain unclear. Here, we identify calpain-2 as a key regulator and anti-metastasis target of hypoxia-induced transition from collective to amoeboid dissemination of breast and head and neck (HN) carcinoma cells.

FOXOs: masters of the equilibrium.

Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan.

Berkchaetoazaphilone B has antimicrobial activity and affects energy metabolism.

Antimicrobial resistance has become one of the major threats to human health. Therefore, there is a strong need for novel antimicrobials with new mechanisms of action. The kingdom of fungi is an excellent source of antimicrobials for this purpose because it encompasses countless fungal species that harbor unusual metabolic pathways.

Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function.

Transcription factors harbor defined regulatory intrinsically disordered regions (IDRs), which raises the question of how they mediate binding to structured co-regulators and modulate their activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation.

DNA damage and oxidant stress activate p53 through differential upstream signaling pathways.

Stabilization and activation of the p53 tumor suppressor are triggered in response to various cellular stresses, including DNA damaging agents and elevated Reactive Oxygen Species (ROS) like HO. When cells are exposed to exogenously added HO, ATR/CHK1 and ATM/CHK2 dependent DNA damage signaling is switched on, suggesting that HO induces both single and double strand breaks. These collective observations have resulted in the widely accepted model that oxidizing conditions lead to DNA damage that subsequently mediates a p53-dependent response like cell cycle arrest and apoptosis.

The Human 2-Cys Peroxiredoxins form Widespread, Cysteine-Dependent- and Isoform-Specific Protein-Protein Interactions.

Redox signaling is controlled by the reversible oxidation of cysteine thiols, a post-translational modification triggered by HO acting as a second messenger. However, HO actually reacts poorly with most cysteine thiols and it is not clear how HO discriminates between cysteines to trigger appropriate signaling cascades in the presence of dedicated HO scavengers like peroxiredoxins (PRDXs). It was recently suggested that peroxiredoxins act as peroxidases and facilitate HO-dependent oxidation of redox-regulated proteins via disulfide exchange reactions.

Protocol to profile the bioenergetics of organoids using Seahorse.

Addressing bioenergetics is key to evaluate the impact of metabolism on the regulation of biological processes and its alteration in disease. Organoids are grown self-organizing structures derived from healthy and diseased tissue that recapitulate with high fidelity the tissue of origin. Bioenergetics is commonly analyzed by Seahorse XF analysis.

Implication of miR-126 and miR-139-5p in Plasmacytoid Dendritic Cell Dysregulation in Systemic Sclerosis.

Compelling evidence shows the involvement of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc) pathogenesis. This study investigated whether microRNAs (miRNAs) are involved in the dysregulation of pDCs in SSc patients already at early stages. RNA from circulating pDCs was isolated from two independent cohorts of SSc patients with different disease phenotypes, and individuals with Raynaud's phenomenon, for microRNA profiling and RNA-sequencing analysis.