bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024‒06‒23
nineteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Standardized Workflow for Mass-Spectrometry-Based Single-Cell Proteomics Data Processing and Analysis Using the scp Package.
  2. µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics.
  3. Machine learning prediction of prime editing efficiency across diverse chromatin contexts.
  4. Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
  5. The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.
  6. Label-Free Sample Preparation for Single-Cell Proteomics.
  7. OneSC: A computational platform for recapitulating cell state transitions.
  8. Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome.
  9. Single-Cell Proteomics Analysis with Tecan Uno and SCREEN Workflow.
  10. Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.
  11. Molecular causality in the advent of foundation models.
  12. Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.
  13. Bioinformatics Pipeline for Processing Single-Cell Data.
  14. Crosstalk of growth factor receptors at plasma membrane clathrin-coated sites.
  15. A stochastic vs deterministic perspective on the timing of cellular events.
  16. The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
  17. Disruption of DLL4/NOTCH1 Causes Dysregulated PPARγ/AKT Signaling in Pulmonary Arterial Hypertension.
  18. Insulin and leptin oscillations license food-entrained browning and metabolic flexibility.
  19. Food perception induces fast fragmentation of hepatic mitochondria.
  1. Methods Mol Biol. 2024 ;2817 177-220
    Standardized Workflow for Mass-Spectrometry-Based Single-Cell Proteomics Data Processing and Analysis Using the scp Package.
    Samuel Grégoire, Christophe Vanderaa, Sébastien Pyr Dit Ruys, Christopher Kune, Gabriel Mazzucchelli, Didier Vertommen, Laurent Gatto.
      Mass-spectrometry (MS)-based single-cell proteomics (SCP) explores cellular heterogeneity by focusing on the functional effectors of the cells-proteins. However, extracting meaningful biological information from MS data is far from trivial, especially with single cells. Currently, data analysis workflows are substantially different from one research team to another. Moreover, it is difficult to evaluate pipelines as ground truths are missing. Our team has developed the R/Bioconductor package called scp to provide a standardized framework for SCP data analysis. It relies on the widely used QFeatures and SingleCellExperiment data structures. In addition, we used a design containing cell lines mixed in known proportions to generate controlled variability for data analysis benchmarking. In this chapter, we provide a flexible data analysis protocol for SCP data using the scp package together with comprehensive explanations at each step of the processing. Our main steps are quality control on the feature and cell level, aggregation of the raw data into peptides and proteins, normalization, and batch correction. We validate our workflow using our ground truth data set. We illustrate how to use this modular, standardized framework and highlight some crucial steps.
    Keywords:  Bioconductor; Data processing; Mass spectrometry; Quantitative data analysis; R; Single-cell proteomics
    DOI:  https://doi.org/10.1007/978-1-0716-3934-4_14
  2. Mol Syst Biol. 2024 Jun 21.
    µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics.
    Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier.
      Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos ('microPhos'), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in <8 h total processing time. By greatly minimizing transfer steps and liquid volumes, we demonstrate increased sensitivity, >90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.
    Keywords:  Drug Response; Mass Spectrometry; Phosphoproteomics; Sample Preparation; Signaling
    DOI:  https://doi.org/10.1038/s44320-024-00050-9
  3. Nat Biotechnol. 2024 Jun 21.
    Machine learning prediction of prime editing efficiency across diverse chromatin contexts.
    Nicolas Mathis, Ahmed Allam, András Tálas, Lucas Kissling, Elena Benvenuto, Lukas Schmidheini, Ruben Schep, Tanav Damodharan, Zsolt Balázs, Sharan Janjuha, Eleonora I Ioannidi, Desirée Böck, Bas van Steensel, Michael Krauthammer, Gerald Schwank.
      The success of prime editing depends on the prime editing guide RNA (pegRNA) design and target locus. Here, we developed machine learning models that reliably predict prime editing efficiency. PRIDICT2.0 assesses the performance of pegRNAs for all edit types up to 15 bp in length in mismatch repair-deficient and mismatch repair-proficient cell lines and in vivo in primary cells. With ePRIDICT, we further developed a model that quantifies how local chromatin environments impact prime editing rates.
    DOI:  https://doi.org/10.1038/s41587-024-02268-2
  4. Nat Commun. 2024 Jun 17. 15(1): 5144
    Low potassium activation of proximal mTOR/AKT signaling is mediated by Kir4.2.
    Yahua Zhang, Fabian Bock, Mohammed Ferdaus, Juan Pablo Arroyo, Kristie L Rose, Purvi Patel, Jerod S Denton, Eric Delpire, Alan M Weinstein, Ming-Zhi Zhang, Raymond C Harris, Andrew S Terker.
      The renal epithelium is sensitive to changes in blood potassium (K+). We identify the basolateral K+ channel, Kir4.2, as a mediator of the proximal tubule response to K+ deficiency. Mice lacking Kir4.2 have a compensated baseline phenotype whereby they increase their distal transport burden to maintain homeostasis. Upon dietary K+ depletion, knockout animals decompensate as evidenced by increased urinary K+ excretion and development of a proximal renal tubular acidosis. Potassium wasting is not proximal in origin but is caused by higher ENaC activity and depends upon increased distal sodium delivery. Three-dimensional imaging reveals Kir4.2 knockouts fail to undergo proximal tubule expansion, while the distal convoluted tubule response is exaggerated. AKT signaling mediates the dietary K+ response, which is blunted in Kir4.2 knockouts. Lastly, we demonstrate in isolated tubules that AKT phosphorylation in response to low K+ depends upon mTORC2 activation by secondary changes in Cl- transport. Data support a proximal role for cell Cl- which, as it does along the distal nephron, responds to K+ changes to activate kinase signaling.
    DOI:  https://doi.org/10.1038/s41467-024-49562-w
  5. Hum Mol Genet. 2024 Jun 17. pii: ddae100. [Epub ahead of print]
    The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.
    Patricia G Wilson, Lina Abdelmoti, Tianyan Gao, Emilia Galperin.
      The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a "gatekeeper" in controlling the selection of downstream effectors within the EGFR signaling network.
    Keywords:  AKT; EGFR; ERK1/2; Noonan-like syndrome with loose anagen hair (NSLH); PAK; Shoc2; scaffold protein
    DOI:  https://doi.org/10.1093/hmg/ddae100
  6. Methods Mol Biol. 2024 ;2817 1-7
    Label-Free Sample Preparation for Single-Cell Proteomics.
    David Hartlmayr, Claudia Ctortecka, Rupert Mayer, Karl Mechtler, Anjali Seth.
      In recent years, single-cell proteomics (SCP) has become a valuable addition to other single-cell omics technologies for studying cellular heterogeneity. The amount of protein in a single cell is very limited, and in contrast to sequencing techniques, there are currently no means for protein amplification. Therefore, most single-cell proteomics approaches aim to maximize sample preparation efficiency while minimizing peptide loss. By reducing processing volumes to sub-microliters and avoiding manual transfer steps that could lead to peptide loss, peptide recovery, and the robustness of SCP workflows have been significantly improved. In this chapter, we describe a protocol for label-free SCP sample preparation using the cellenONE® platform and the proteoCHIP LF 48 substrate prior to analysis with high-performance liquid chromatography-mass spectrometry.
    Keywords:  Automation; Label-free; Single-cell proteomics; Sub-μL sample preparation; cellenONE®; proteoCHIP LF 48
    DOI:  https://doi.org/10.1007/978-1-0716-3934-4_1
  7. bioRxiv. 2024 Jun 03. pii: 2024.05.31.596831. [Epub ahead of print]
    OneSC: A computational platform for recapitulating cell state transitions.
    Da Peng, Patrick Cahan.
      Computational modelling of cell state transitions has been a great interest of many in the field of developmental biology, cancer biology and cell fate engineering because it enables performing perturbation experiments in silico more rapidly and cheaply than could be achieved in a wet lab. Recent advancements in single-cell RNA sequencing (scRNA-seq) allow the capture of high- resolution snapshots of cell states as they transition along temporal trajectories. Using these high-throughput datasets, we can train computational models to generate in silico 'synthetic' cells that faithfully mimic the temporal trajectories. Here we present OneSC, a platform that can simulate synthetic cells across developmental trajectories using systems of stochastic differential equations govern by a core transcription factors (TFs) regulatory network. Different from the current network inference methods, OneSC prioritizes on generating Boolean network that produces faithful cell state transitions and steady cell states that mimic real biological systems. Applying OneSC to real data, we inferred a core TF network using a mouse myeloid progenitor scRNA-seq dataset and showed that the dynamical simulations of that network generate synthetic single-cell expression profiles that faithfully recapitulate the four myeloid differentiation trajectories going into differentiated cell states (erythrocytes, megakaryocytes, granulocytes and monocytes). Finally, through the in-silico perturbations of the mouse myeloid progenitor core network, we showed that OneSC can accurately predict cell fate decision biases of TF perturbations that closely match with previous experimental observations.
    DOI:  https://doi.org/10.1101/2024.05.31.596831
  8. bioRxiv. 2024 Jun 06. pii: 2024.06.04.597443. [Epub ahead of print]
    Human TSC2 Mutant Cells Exhibit Aberrations in Early Neurodevelopment Accompanied by Changes in the DNA Methylome.
    Mary-Bronwen L Chalkley, Lindsey N Guerin, Tenhir Iyer, Samantha Mallahan, Sydney Nelson, Mustafa Sahin, Emily Hodges, Kevin C Ess, Rebecca A Ihrie.
      Tuberous Sclerosis Complex (TSC) is a debilitating developmental disorder characterized by a variety of clinical manifestations. While benign tumors in the heart, lungs, kidney, and brain are all hallmarks of the disease, the most severe symptoms of TSC are often neurological, including seizures, autism, psychiatric disorders, and intellectual disabilities. TSC is caused by loss of function mutations in the TSC1 or TSC2 genes and consequent dysregulation of signaling via mechanistic Target of Rapamycin Complex 1 (mTORC1). While TSC neurological phenotypes are well-documented, it is not yet known how early in neural development TSC1/2 -mutant cells diverge from the typical developmental trajectory. Another outstanding question is the contribution of homozygous-mutant cells to disease phenotypes and whether such phenotypes are also seen in the heterozygous-mutant populations that comprise the vast majority of cells in patients. Using TSC patient-derived isogenic induced pluripotent stem cells (iPSCs) with defined genetic changes, we observed aberrant early neurodevelopment in vitro , including misexpression of key proteins associated with lineage commitment and premature electrical activity. These alterations in differentiation were coincident with hundreds of differentially methylated DNA regions, including loci associated with key genes in neurodevelopment. Collectively, these data suggest that mutation or loss of TSC2 affects gene regulation and expression at earlier timepoints than previously appreciated, with implications for whether and how prenatal treatment should be pursued.
    DOI:  https://doi.org/10.1101/2024.06.04.597443
  9. Methods Mol Biol. 2024 ;2817 157-175
    Single-Cell Proteomics Analysis with Tecan Uno and SCREEN Workflow.
    Michael Lewandowski, Shad Morton, Matthew Blake, Erica Squires, Rushdy Ahmad, David R Walt, Bogdan Budnik.
      With advances in sample preparation, small-volume liquid dispensing technologies, high-resolution MS/MS instrumentation, and data acquisition methodologies, it has become increasingly possible to confidently investigate the heterogeneous proteome found within individual cells. In this chapter, we present an automated high-throughput sample preparation workflow based on the Tecan Uno instrument for quantitative single-cell mass spectrometry-based proteomics. Cells are analyzed by the Single-Cell Proteome Analysis platform (SCREEN), which was introduced earlier and provides deeper proteome coverage across single cells.
    Keywords:  Automation; High-throughput sample preparation; SCREEN method; Tecan Uno
    DOI:  https://doi.org/10.1007/978-1-0716-3934-4_13
  10. Nature. 2024 Jun 12.
    Endoplasmic reticulum-plasma membrane contact gradients direct cell migration.
    Bo Gong, Jake D Johnston, Alexander Thiemicke, Alex de Marco, Tobias Meyer.
      Directed cell migration is driven by the front-back polarization of intracellular signalling1-3. Receptor tyrosine kinases and other inputs activate local signals that trigger membrane protrusions at the front2,4-6. Equally important is a long-range inhibitory mechanism that suppresses signalling at the back to prevent the formation of multiple fronts7-9. However, the identity of this mechanism is unknown. Here we report that endoplasmic reticulum-plasma membrane (ER-PM) contact sites are polarized in single and collectively migrating cells. The increased density of these ER-PM contacts at the back provides the ER-resident PTP1B phosphatase more access to PM substrates, which confines receptor signalling to the front and directs cell migration. Polarization of the ER-PM contacts is due to microtubule-regulated polarization of the ER, with more RTN4-rich curved ER at the front and more CLIMP63-rich flattened ER at the back. The resulting ER curvature gradient leads to small and unstable ER-PM contacts only at the front. These contacts flow backwards and grow to large and stable contacts at the back to form the front-back ER-PM contact gradient. Together, our study suggests that the structural polarity mediated by ER-PM contact gradients polarizes cell signalling, directs cell migration and prolongs cell migration.
    DOI:  https://doi.org/10.1038/s41586-024-07527-5
  11. Mol Syst Biol. 2024 Jun 18.
    Molecular causality in the advent of foundation models.
    Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez.
      Correlation is not causation: this simple and uncontroversial statement has far-reaching implications. Defining and applying causality in biomedical research has posed significant challenges to the scientific community. In this perspective, we attempt to connect the partly disparate fields of systems biology, causal reasoning, and machine learning to inform future approaches in the field of systems biology and molecular medicine.
    Keywords:  Causality; Foundation Models; Inductive Bias; Latent Spaces; Systems Biology
    DOI:  https://doi.org/10.1038/s44320-024-00041-w
  12. Nat Methods. 2024 Jun 18.
    Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.
    Dominik J Otto, Cailin Jordan, Brennan Dury, Christine Dien, Manu Setty.
      Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive diverse biological processes. Here, we present Mellon, an algorithm for estimation of cell-state densities from high-dimensional representations of single-cell data. We demonstrate Mellon's efficacy by dissecting the density landscape of differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. We present evidence implicating enhancer priming and the activation of master regulators in emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during developmental processes. Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide insights into mechanisms guiding biological trajectories.
    DOI:  https://doi.org/10.1038/s41592-024-02302-w
  13. Methods Mol Biol. 2024 ;2817 221-239
    Bioinformatics Pipeline for Processing Single-Cell Data.
    Arthur Declercq, Nina Demeulemeester, Ralf Gabriels, Robbin Bouwmeester, Sven Degroeve, Lennart Martens.
      Single-cell proteomics can offer valuable insights into dynamic cellular interactions, but identifying proteins at this level is challenging due to their low abundance. In this chapter, we present a state-of-the-art bioinformatics pipeline for single-cell proteomics that combines the search engine Sage (via SearchGUI), identification rescoring with MS2Rescore, quantification through FlashLFQ, and differential expression analysis using MSqRob2. MS2Rescore leverages LC-MS/MS behavior predictors, such as MS2PIP and DeepLC, to recalibrate scores with Percolator or mokapot. Combining these tools into a unified pipeline, this approach improves the detection of low-abundance peptides, resulting in increased identifications while maintaining stringent FDR thresholds.
    Keywords:  Bioinformatics; DeepLC; MS2PIP; MS2Rescore; Machine learning; Single-cell proteomics
    DOI:  https://doi.org/10.1007/978-1-0716-3934-4_15
  14. bioRxiv. 2024 May 18. pii: 2024.05.16.594559. [Epub ahead of print]
    Crosstalk of growth factor receptors at plasma membrane clathrin-coated sites.
    Marco A Alfonzo-Méndez, Marie-Paule Strub, Justin W Taraska.
      Cellular communication is regulated at the plasma membrane by the interactions of receptor, adhesion, signaling, exocytic, and endocytic proteins. Yet, the composition and control of these nanoscale complexes in response to external cues remain unclear. Here, we use high-resolution and high-throughput fluorescence imaging to map the localization of growth factor receptors and related proteins at single clathrin-coated structures across the plasma membrane of human squamous HSC3 cells. We find distinct protein signatures between control cells and cells stimulated with ligands. Clathrin sites at the plasma membrane are preloaded with some receptors but not others. Stimulation with epidermal growth factor induces a capture and concentration of epidermal growth factor-, fibroblast growth factor-, and low-density lipoprotein-receptors (EGFR, FGFR, and LDLR). Regulatory proteins including ubiquitin ligase Cbl, the scaffold Grb2, and the mechanoenzyme dynamin2 are also recruited. Disrupting FGFR or EGFR individually with drugs prevents the recruitment of both EGFR and FGFR. Our data reveals novel crosstalk between multiple unrelated receptors and regulatory factors at clathrin-coated sites in response to stimulation by a single growth factor, EGF. This behavior integrates growth factor signaling and allows for complex responses to extracellular cues and drugs at the plasma membrane of human cells.Significance: Classically, receptor pathways including epidermal growth factor receptor and fibroblast growth factor receptor were thought of as independent systems. Yet, the plasma membrane is a complex environment where proteins interact, cluster, signal, and associate with organelles. For example, after EGF activation, EGFR is captured at sites on the inner plasma membrane coated with the protein clathrin. This causes clathrin to grow flat across the adherent membrane. Here, we observe co-capture along with EGFR of the related receptor FGFR and unrelated LDLR by clathrin after EGF stimulation. This is specific as other receptors are unaffected. Thus, separate but specific receptor systems co-assemble and signal to each other at nanoscale zones on the plasma membrane organized by clathrin. This provides new avenues for treating diseases like cancer.
    DOI:  https://doi.org/10.1101/2024.05.16.594559
  15. Nat Commun. 2024 Jun 20. 15(1): 5286
    A stochastic vs deterministic perspective on the timing of cellular events.
    Lucy Ham, Megan A Coomer, Kaan Öcal, Ramon Grima, Michael P H Stumpf.
      Cells are the fundamental units of life, and like all life forms, they change over time. Changes in cell state are driven by molecular processes; of these many are initiated when molecule numbers reach and exceed specific thresholds, a characteristic that can be described as "digital cellular logic". Here we show how molecular and cellular noise profoundly influence the time to cross a critical threshold-the first-passage time-and map out scenarios in which stochastic dynamics result in shorter or longer average first-passage times compared to noise-less dynamics. We illustrate the dependence of the mean first-passage time on noise for a set of exemplar models of gene expression, auto-regulatory feedback control, and enzyme-mediated catalysis. Our theory provides intuitive insight into the origin of these effects and underscores two important insights: (i) deterministic predictions for cellular event timing can be highly inaccurate when molecule numbers are within the range known for many cells; (ii) molecular noise can significantly shift mean first-passage times, particularly within auto-regulatory genetic feedback circuits.
    DOI:  https://doi.org/10.1038/s41467-024-49624-z
  16. J Clin Invest. 2024 Jun 18. pii: e170550. [Epub ahead of print]
    The Alzheimer's disease-linked protease BACE2 cleaves VEGFR3 and modulates its signaling.
    Andree Schmidt, Brian Hrupka, Frauke van Bebber, Sanjay Sunil Kumar, Xiao Feng, Sarah K Tschirner, Marlene Aßfalg, Stephan A Müller, Laura Sophie Hilger, Laura I Hofmann, Martina Pigoni, Georg Jocher, Iryna Voytyuk, Emily L Self, Mana Ito, Kana Hyakkoku, Akimasa Yoshimura, Naotaka Horiguchi, Regina Feederle, Bart De Strooper, Stefan Schulte-Merker, Eckhard Lammert, Dieder Moechars, Bettina Schmid, Stefan F Lichtenthaler.
      The β-secretase BACE1 is a central drug target for Alzheimer's disease. Clinically tested, BACE1-directed inhibitors also block the homologous protease BACE2. Yet, little is known about physiological BACE2 substrates and functions in vivo. Here, we identify BACE2 as the protease shedding the lymphangiogenic vascular endothelial growth factor receptor 3 (VEGFR3). Inactivation of BACE2, but not BACE1, inhibited shedding of VEGFR3 from primary human lymphatic endothelial cells (LECs) and reduced release of the shed, soluble VEGFR3 (sVEGFR3) ectodomain into the blood of mice, non-human primates and humans. Functionally, BACE2 inactivation increased full-length VEGFR3 and enhanced VEGFR3 signaling in LECs and also in vivo in zebrafish, where enhanced migration of LECs was observed. Thus, this study identifies BACE2 as a modulator of lymphangiogenic VEGFR3 signaling and demonstrates the utility of sVEGFR3 as a pharmacodynamic plasma marker for BACE2 activity in vivo, a prerequisite for developing BACE1-selective inhibitors for a safer prevention of Alzheimer's disease.
    Keywords:  Aging; Alzheimer disease; Drug therapy
    DOI:  https://doi.org/10.1172/JCI170550
  17. bioRxiv. 2024 Feb 02. pii: 2024.01.31.578230. [Epub ahead of print]
    Disruption of DLL4/NOTCH1 Causes Dysregulated PPARγ/AKT Signaling in Pulmonary Arterial Hypertension.
    Keytam S Awad, Shuibang Wang, Edward J Dougherty, Ali Keshavarz, Cumhur Y Demirkale, Zu Xi Yu, Latonia Miller, Jason M Elinoff, Robert L Danner.
      Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, activates NOTCH1 signaling and plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in PAECs activated AKT and decreased DLL4 expression. DLL4 loss was also seen in lungs of patients with IPAH and HPAH. Over-expression of DLL4 in PAECs induced BMPR2 promoter activity and exogenous DLL4 increased BMPR2 mRNA through NOTCH1 activation. Furthermore, DLL4/NOTCH1 signaling blocked AKT activation, decreased proliferation and reversed EndoMT in BMPR2 - silenced PAECs and ECs from IPAH patients. PPARγ, suppressed by BMPR2 loss, was induced and activated by DLL4/NOTCH1 signaling in both BMPR2 -silenced and IPAH PAECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Finally, leniolisib, a well-tolerated oral PI3K8/AKT inhibitor, decreased cell proliferation, induced apoptosis and reversed markers of EndoMT in BMPR2 -silenced PAECs. Restoring DLL4/NOTCH1/PPARγ signaling and/or suppressing AKT activation may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.
    DOI:  https://doi.org/10.1101/2024.01.31.578230
  18. Cell Rep. 2024 Jun 19. pii: S2211-1247(24)00718-6. [Epub ahead of print]43(7): 114390
    Insulin and leptin oscillations license food-entrained browning and metabolic flexibility.
    Pamela Mattar, Andressa Reginato, Christian Lavados, Debajyoti Das, Manu Kalyani, Nuria Martinez-Lopez, Mridul Sharma, Grethe Skovbjerg, Jacob Lercke Skytte, Urmas Roostalu, Rajasekaran Subbarayan, Elodie Picarda, Xingxing Zang, Jinghang Zhang, Chandan Guha, Gary Schwartz, Prashant Rajbhandari, Rajat Singh.
      Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.
    Keywords:  CP: Metabolism; ILC2; browning; circadian; insulin; intermittent fasting; leptin; oscillations; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2024.114390
  19. Trends Endocrinol Metab. 2024 Jun 18. pii: S1043-2760(24)00162-0. [Epub ahead of print]
    Food perception induces fast fragmentation of hepatic mitochondria.
    Arnaud Chevrollier, Jérome Boursier, Valérie Desquiret-Dumas.
      Henschke et al. have recently shown that sensory food perception in mice integrated at the hypothalamus would be sufficient to suppress hepatic glucose production in a rapid mechanism involving a newly described AKT-dependent kinase pathway that engages mitochondrial fission dynamics. Exploiting this pathway could guide strategies to treat type 2 diabetes.
    Keywords:  AKT kinase; diabetes mellitus; fission; liver mitochondria
    DOI:  https://doi.org/10.1016/j.tem.2024.06.002
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