Stages Of Differentiation Research Articles

ScPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases.

Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation.

Weighted Gene Co-Expression Network Based on Transcriptomics: Unravelling the Differentiation Dynamics of 3T3-L1 Preadipocytes and the Regulatory Mechanism of Protopanaxatriol

The intricate regulatory mechanisms governing adipocyte differentiation are pivotal in elucidating the complex pathophysiology underlying obesity. This study aims to explore the dynamic changes in gene expression during the differentiation of 3T3-L1 adipocytes using transcriptomics methods. Protopanaxatriol (PPT) significantly inhibited adipocyte differentiation. To uncover the molecular mechanisms, we conducted an extensive transcriptomic analysis of adipocytes throughout various differentiation stages, comparing gene expression profiles before and after PPT treatment. The construction of 16 co-expression modules was achieved using weighted gene co-expression network analysis (WGCNA). The 838 differentially expressed genes in the blue module were highly correlated with PPT treatment. Further analysis revealed that PIKfyve, STAT3, JAK1, CTTN, TYK2, JAK3, STAT2, STAT5b, SOCS3, and IRF9 were core genes closely associated with adipocyte differentiation. This discovery underscores the potential pivotal function of these ten genes in regulating adipocyte differentiation. This study elucidated that PPT, an active ingredient in ginseng, could reduce lipid accumulation by inhibiting the differentiation of adipocyte precursors through the negative regulation of genes such as PIKfyve, STAT3, and JAK1. Finally, molecular docking identified potential binding sites for PPT on PIKfyve and JAK1. This study provides potential drug targets for preventing obesity and related metabolic diseases.

In vitro bioprinted 3D model enhancing osteoblast-to-osteocyte differentiation

In vitrobone models are pivotal for understanding tissue behavior and cellular responses, particularly in unravelling certain pathologies' mechanisms and assessing the impact of new therapeutic interventions. A desirablein vitrobone model should incorporate primary human cells within a 3D environment that mimics the mechanical properties characteristics of osteoid and faithfully replicate all stages of osteogenic differentiation from osteoblasts to osteocytes. However, to date, no bio-printed model using primary osteoblasts has demonstrated the expression of osteocytic protein markers. This study aimed to develop bio-printedin vitromodel that accurately captures the differentiation process of human primary osteoblasts into osteocytes. Given the considerable impact of hydrogel stiffness and relaxation behavior on osteoblast activity, we employed three distinct cross-linking solutions to fabricate hydrogels. These hydrogels were designed to exhibit either similar elastic behavior with different elastic moduli, or similar elastic moduli with varying relaxation behavior. These hydrogels, composed of gelatin (5% w/v), alginate (1%w/v) and fibrinogen (2%w/v), were designed to be compatible with micro-extrusion bioprinting and proliferative. The modulation of their biomechanical properties, including stiffness and viscoelastic behavior, was achieved by applying various concentrations of cross-linkers targeting both gelatin covalent bonding (transglutaminase) and alginate chains' ionic cross-linking (calcium). Among the conditions tested, the hydrogel with a low elastic modulus of 8 kPa and a viscoelastic behavior over time exhibited promising outcomes regarding osteoblast-to-osteocyte differentiation. The cessation of cell proliferation coincided with a significant increase in alkaline phosphatase activity, the development of dendrites, and the expression of the osteocyte marker PHEX. Within this hydrogel, cells actively influenced their environment, as evidenced by hydrogel contraction and the secretion of collagen I. This bio-printed model, demonstrating primary human osteoblasts expressing an osteocyte-specific protein, marks a significant achievement. We envision its substantial utility in advancing research on bone pathologies, including osteoporosis and bone tumors.

Multi-center study on the application potential of Siaα-2,6Gal in early and differential diagnosis of lung cancer.

This study aimed to investigate the application potential of the abnormal glycan structure Siaα-2,6Gal in the early and differential diagnosis of lung cancer. Clinical data and serum samples from 730 patients and 120 healthy individuals participating in clinical trials on Siaα-2,6Gal were collected at three medical centers between January 2022 and June 2023. The levels of Siaα-2,6Gal, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (ProGRP) in serum were measured. The application potentials of these markers in the early and differential diagnosis, classification, and staging of lung cancer were explored. (1) Serum Siaα-2,6Gal levels in the lung cancer group were 2,606 (1,970-3,458) U/mL, significantly higher than those in the benign lung disease, miscellaneous malignant tumor, miscellaneous benign disease, and healthy individual groups at 1,359 (950-1,528), 1,252 (903-1,532), 1,196 (850-1,490), and 1,210 (1,100-1,287) U/mL (P < 0.0001). (2) Serum Siaα-2,6Gal levels in the early-stage lung cancer (stages 0-II) group were 2,576 (1,929-3,338) U/mL, significantly higher than those in the benign pulmonary nodule group at 1,419 (1,105-1,820) U/mL (P < 0.0001). (3) Receiver operating characteristic curves showed that Siaα-2,6Gal had a high diagnostic efficiency for lung cancer (area under the curve (AUC) = 0.9217), significantly superior to CEA, CYFRA21-1, SCC, NSE, and ProGRP (AUCs of 0.6618, 0.6605, 0.5783, 0.5985, and 0.6381). Siaα-2,6Gal is a promising biomarker for lung cancer diagnosis and may offer superior differential diagnosis of early-stage lung cancer from benign pulmonary nodules compared to traditional tumor markers.

A chopper amplifier with adaptive biasing OTA for biomedical applications, featuring high gain and CMRR.

This paper presents a design of fully differential chopper amplifier employing the flipped voltage follower (FVF) adaptive biasing technique, focusing on its potential use in biopotential recording applications. The suggested architectural OTA incorporates self-cascoded current mirrors (SCCMs) as the active load to achieve a substantial output swing. The FVFs based adaptive biasing approach for the differential input stage boosts extra current and enhances gain and dynamic characteristics. The chopper amplifier attains a common mode rejection ratio (CMRR) of more than 100 dB through the strategic utilization of chopper modulators and pseudo-resistors. Additionally, this device exhibits characteristics such as accurate and stable gain, high input impedance, and a compact physical footprint. The present study also includes a comparison between the suggested structure and the bio-potential amplifiers discussed in the existing literature. This comparison is based on key metrics such as gain, input referred noise (IRN), CMRR, and input impedance (Zin). The proposed structure yielded a gain of 63.72 dB, an IRN of 0.07nVrms, a CMRR of 127.97 dB and a Zin of 1.54 GΩ. The bio-potential chopper amplifier under consideration was constructed and simulations were performed by utilizing the Cadence Virtuoso Spectre simulator tool at 180 nm CMOS technology node.

The role of polyreactive memory B cells in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), the production of autoantibodies is a crucial characteristic, and B cells play a significant role in its pathogenesis. B cells are the immune cells most associated with the genetic predispositions of SLE, and recent clinical studies showing that anti-CD19 CAR-T cell therapy induces drug-free remission have underscored the importance of B cells in SLE. Meanwhile, various B cell subsets exist across different stages of differentiation, from naive B cells to plasma-cells, and identifying the important subpopulations within SLE remains a critical future challenge. Years of B cell repertoire analyses have revealed the importance of polyreactive B cell receptors (BCRs) and autoantibodies that react to a various self-antigens and microbial antigens. Particularly, memory B cells with polyreactive BCRs, which play a crucial role in biological defense during the fetal stage, are characteristically differentiated in SLE. Type I interferon-mediated expression of CXCL13 and IL21 in CD4+ T cells is associated with the development of polyreactive memory B cells. The expansion of the polyreactive B cell repertoire, vital for defending against infections such as viruses, may exert an intrinsic function in SLE.

Design and optimisation of a two-stage amplifier based on a differential input stage and a common-source amplifier

Abstract. Since the emergence of integrated circuits, through the circuit structure, the production process of continuous iterative updating, so that its used in various types of electronic equipment more and more widely. Currently, operational amplifier circuits play an extremely important role in signal processing and communication systems. Amplifiers have different characteristics depending on the needs of different electronic devices. This thesis addresses the optimisation and design of the characteristics of the two-stages amplifier. Firstly, several classical amplifier structures are analysed. Select the appropriate structure and combine it into a two-stages amplifier. Simulation is carried out on cadence software and later the simulation results are analysed before parameter optimisation. On this basis, a two-stages amplifier based on a PMOS differential input stage with a common-source amplifier has been designed. It also improves the amplifier's gain, frequency range, gain bandwidth, and other performance metrics. Using PMOS self-bias circuit to improve power supply stability. Finally, based on the development hotspots of integrated circuits, the possibility of circuit optimization was analyzed. Discussions were conducted on negative feedback circuits, phase compensation methods, and other aspects.

Dental Pulp Stem Cell Conditioned Medium Enhance Osteoblastic Differentiation and Bone Regeneration.

Cell-free approaches, utilizing mesenchymal stem cell secretome, have promising prospects in various fields of regenerative medicine. In this study, we examined in vitro and in vivo the potential of dental pulp stem cell-conditioned medium (DPSC-CM) for bone regeneration. The secretome of undifferentiated stem cells from dental pulp were collected, and the effects of this DPSC-CM were assessed for osteodifferentiation of osteoblast-like cells (MG-63) and osteoblasts deriving from DPSC. Cell proliferation, alkaline phosphatase (ALP) activity, gene expression of Runt-related transcription factor 2 (Runx2), Bone Sialoprotein (BSP), Osteocalcin (OCN), and extracellular matrix mineralization were evaluated. The rat caudal vertebrae critical size defect model was to investigate the effect of DPSC-CM in vivo. Results showed that DPSC-CM induced cell growth, and increased ALP activity and the expression of key marker genes at an early stage of osteoblastic differentiation compared to control. A rat bone defect model was used to illustrate the effect of DPSC-CM in vivo. The bone density within the defects were improved using conditioned medium, even though there was no significant difference between the control and DPSC-CM groups. The analysis of DPSC-CM by human growth factor antibody array revealed the presence of several factors involved in osteogenesis. Taken together, these findings indicate that DPSC-CM is a promising therapeutic candidate for bone regenerative therapy, accelerating the maturation of osteoblastic cells. And even though safety and efficiency of DPSC-CM have to be confirmed in preclinical studies, these results represent a first step toward clinical application.

Recruitment of homodimeric proneural factors by conserved CAT-CAT E-boxes drives major epigenetic reconfiguration in cortical neurogenesis.

Proneural factors of the basic helix-loop-helix family coordinate neurogenesis and neurodifferentiation. Among them, NEUROG2 and NEUROD2 subsequently act to specify neurons of the glutamatergic lineage. Disruption of these factors, their target genes and binding DNA motifs has been linked to various neuropsychiatric disorders. Proneural factors bind to specific DNA motifs called E-boxes (hexanucleotides of the form CANNTG, composed of two CAN half sites on opposed strands). While corticogenesis heavily relies on E-box activity, the collaboration of proneural factors on different E-box types and their chromatin remodeling mechanisms remain largely unknown. Here, we conducted a comprehensive analysis using chromatin immunoprecipitation followed bysequencing (ChIP-seq) data for NEUROG2 and NEUROD2, along with time-matched single-cell RNA-seq, ATAC-seq and DNA methylation data from the developing mouse cortex. Our findings show that these factors are highly enriched in transiently active genomic regions during intermediate stages of neuronal differentiation. Although they primarily bind CAG-containing E-boxes, their binding in dynamic regions is notably enriched in CAT-CAT E-boxes (i.e. CATATG, denoted as 5'3' half sites for dimers), which undergo significant DNA demethylation and exhibit the highest levels of evolutionary constraint. Aided by HT-SELEX data reanalysis, structural modeling and DNA footprinting, we propose that these proneural factors exert maximal chromatin remodeling influence during intermediate stages of neurogenesis by binding as homodimers to CAT-CAT motifs. This study provides an in-depth integrative analysis of the dynamic regulation of E-boxes during neuronal development, enhancing our understanding of the mechanisms underlying the binding specificity of critical proneural factors.

Single-cell sequencing applications in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of malignancies with poor prognosis. AML result from the proliferation of immature myeloid cells blocked at a variable stage of differentiation. Beyond inter-patient heterogeneity, AMLs are characterized by genetic and phenotypic intra-patient heterogeneity. Despite major advances in deciphering AML biology with bulk sequencing studies, pivotal questions remain unanswered. Analyses at the single-cell level could thus transform our understanding of these neoplasms. We review recent progresses in single-cell sequencing technologies from cell processing to bioinformatic pipelines. We next discuss how single-cell applications have helped understand the genetic and functional intra-leukemic heterogeneity, emphasizing aspects related to leukemic stem cells, clonal evolution and measurable residual disease (MRD) monitoring. We finally delineate how single-cell technologies could be implemented in routine clinical practice to improve patient management.

Erythrocytic α-Synuclein in Parkinson’s Disease and Progressive Supranuclear Palsy—A Pilot Study

Background/Objectives: The current research examines the accuracy of α-synuclein in RBCs as a diagnostic biomarker for PD and PSP, despite their distinct molecular etiologies. Methods: We used ELISA to measure total, oligomeric, and p129-α-synuclein levels in erythrocytes from 8 PSP patients, 19 PD patients, and 18 healthy controls (HCs). The classification performances of RBC α-synuclein levels were investigated by receiver operator characteristic (ROC) curve. We also evaluated a possible correlation between RBC α-synuclein level and the biological and clinical features of our cohorts. Results: RBC total α-synuclein was higher in PSP patients compared to both PD patients and HCs, achieving good classification performance (AUC: 0.853) in distinguishing PSP patients from PD patients, with a sensitivity of 100% and a specificity of 70.6%; moreover, the levels of this biomarker positively correlated with disease severity in PSP group. Regarding oligomeric α-synuclein and p129-α-synuclein, the latter was slightly increased in RBCs from PSP patients compared to HCs, but no correlations were detected. Conclusions: Although these findings need to be confirmed in larger studies, our pilot work suggests that RBC total α-synuclein may represent a potential molecular biomarker for the differential diagnosis and clinical staging of PSP.

Kynurenine’s Effect on the Different Stages of Osteoblastic Differentiation

This study focuses on the dynamics of age-related changes in osteoblasts’ matrix production, with a specific focus on the involvement of the aryl hydrocarbon receptor (AhR). The AhR is activated by kynurenine, a metabolite of the amino acid tryptophan that tends to increase with age. Kynurenine has been known to impair osteoblasts’ bone formation ability, however, the point at which this occurs is unknown. The study utilizes a 21-day differentiation process of mesenchymal stem cells. “Window experiments” that vary the intervals of kynurenine treatment to explore its impact at different stages of osteoblast development were utilized. The experimental setup involves four distinct conditions: a control group with a vehicle, a group treated with kynurenine, a group with an AhR antagonist (BAY), and a group treated with both kynurenine and BAY. The AhR antagonist, specifically BAY2416964, serves to investigate whether any observed effects of kynurenine are mediated through AhR signaling. Results, analyzed through alizarin red staining, demonstrate a notable negative impact of kynurenine on matrix production, particularly in the middle stages of osteoblast differentiation. The study further employs crystal violet staining to confirm the presence of cells in the experimental wells, providing assurance of the reliability of the alizarin staining procedure. Importantly, this staining procedure also suggests that the effects of kynurenine on mineralized matrix production are largely independent of any potential impacts on cell viability.

Kynurenine’s Effect on the Different Stages of Osteoblastic Differentiation

This study focuses on the dynamics of age-related changes in osteoblasts’ matrix production, with a specific focus on the involvement of the aryl hydrocarbon receptor (AhR). The AhR is activated by kynurenine, a metabolite of the amino acid tryptophan that tends to increase with age. Kynurenine has been known to impair osteoblasts’ bone formation ability, however, the point at which this occurs is unknown. The study utilizes a 21-day differentiation process of mesenchymal stem cells. “Window experiments” that vary the intervals of kynurenine treatment to explore its impact at different stages of osteoblast development were utilized. The experimental setup involves four distinct conditions: a control group with a vehicle, a group treated with kynurenine, a group with an AhR antagonist (BAY), and a group treated with both kynurenine and BAY. The AhR antagonist, specifically BAY2416964, serves to investigate whether any observed effects of kynurenine are mediated through AhR signaling. Results, analyzed through alizarin red staining, demonstrate a notable negative impact of kynurenine on matrix production, particularly in the middle stages of osteoblast differentiation. The study further employs crystal violet staining to confirm the presence of cells in the experimental wells, provid-ing assurance of the reliability of the alizarin staining procedure. Importantly, this staining procedure also suggests that the effects of kynurenine on mineralized matrix production are largely independent of any potential impacts on cell viability.

Integrative analyses of genetic mechanisms responsible for bone-fat imbalance in osteoporosis.

Osteoporosis manifests through adipocyte accrual and osteoblast diminution within bone marrow. However, the precise mechanisms driving the shift from osteogenesis to adipogenesis in bone marrow mesenchymal stem cells (BMSCs) remain largely undefined. In this study, we harnessed the power of bioinformatic tools to analyze gene expression patterns of BMSCs during adipogenic differentiation and osteoporosis using the data from Gene Expression Omnibus (GEO) repositories (GSE113253 and GSE35956), complemented by in vitro and in vivo experiments to validate the findings. Five distinct expression profiles of differentially expressed genes across the adipogenic timeline were identified. The initial phase is marked by ribosome biogenesis and rRNA processing, which is followed by the metabolism of organic acids and processing of inorganic ions. In contrast, the terminal phase is characterized by lipid transport, accumulation, and metabolism, alongside inorganic cation metabolism, thereby underscoring unique transcriptional signatures during the early and late stages of adipogenic differentiation. In BMSCs derived from osteoporotic samples, there is a notable decline in cellular proliferation and a diminished osteogenic capacity. Critically, the genes common to both adipogenesis and osteoporosis in BMSCs are predominantly involved in the negative regulation of Wnt signaling and cellular proliferation. Key genes including SOCS1, MYC, CEBPB, FYN, AXIN2, and RXRA are identified and show downregulation in BMSCs from aged mice. Subsequent in vitro experiments have validated the regulatory influence of RXRA on both adipogenic and osteogenic differentiations of BMSCs, highlighting its crucial role as a central modulator in bone formation and the pathophysiology of osteoporosis.

Single and Combinatorial Effects of Metformin and Thymoquinone in Diffuse Large B Cell Lymphoma Cells.

Diffuse large B cell lymphoma (DLBCL) is classified into Germinal Center B-cell (GCB) and activated B-cell (ABC) subgroups originating from different stages of lymphoid differentiation. Cell of origin dictates the behavior and therapeutic response of DLBCL. This study aimed to evaluate single and combinatorial effects of metformin and thymoquinone (TQ) in two DLBCL cell lines belonging to GCB and ABC subtypes. Metformin and TQ caused dose-dependent responses in both ABC and GCB DLBCL subtypes. Metformin had a greater impact on the ABC subtype while TQ demonstrated more pronounced effects on the GCB subtype. Synergistic effects were observed in the DHL4 (GCB subtype) but not in the HBL1 (ABC subtype) cell line. This is the first study to compare the effects of metformin and TQ in ABC versus GCB subtype of DLBCL. It brings valuable results that could be utilized in further research aimed at reshaping treatments for subtype-specific lymphomas.

Pan-ErbB inhibition impairs cognition via disrupting myelination and aerobic glycolysis in oligodendrocytes

White matter (WM) abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling, which is essential for peripheral myelination, has been genetically associated with schizophrenia and WM lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used an in vivo pan-ErbB inhibition strategy and demonstrated the functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulated ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the myelinating capacity of newly formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, ErbB inhibition attenuates K-Ras activities, leading to the reduced expression of lactate dehydrogenase A that promotes aerobic glycolysis in mature oligodendrocytes. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings emphasize the indispensable roles of ErbB signaling in WM integrity and function and provide insights into the multifaceted contributions of WM abnormalities to cognitive impairment.

Integrating machine learning and single-cell transcriptomic analysis to identify potential biomarkers and analyze immune features of ischemic stroke

This study employs machine learning and single-cell transcriptome sequencing (scRNA-seq) analysis to unearth novel biomarkers and delineate the immune characteristics of ischemic stroke (IS), thereby contributing fresh insights into IS treatment strategies.Our research leverages gene expression data sourced from the GEO database. We undertake weighted gene co-expression network analysis (WGCNA) to filter pertinent genes and subsequently employ machine learning algorithms for the identification of feature genes. Concurrently, we rigorously execute quality control measures, dimensionality reduction techniques, and cell annotation on the scRNA-seq data to pinpoint differentially expressed genes (DEGs). The identification of core genes, denoted as Hub genes, among the feature genes and DEGs, is achieved through meticulous overlapping analysis. We illuminate the immune characteristics of these Hub genes using a suite of analytical tools, encompassing CIBERSORT, MCPcounter, and pseudotemporal analysis, all based on immune cell annotations and single-cell transcriptome data.Subsequently, we harness the CMap database to prognosticate potential therapeutic drugs and scrutinize their associations with the identified Hub genes. Our findings unveil robust linkages between three pivotal Hub genes—namely, RNF13, VASP, and CD163—and specific immune cell types such as T cells and neutrophils. These Hub genes predominantly manifest in macrophages and microglial cells within the scRNA-seq immune cell population, exhibiting variances across different stages of cellular differentiation. In conclusion, this study unearths highly pertinent biomarkers for IS diagnosis and elucidates IS-induced immune infiltration characteristics, thus providing a firm foundation for a comprehensive exploration of potential immune mechanisms and the identification of novel therapeutic targets for IS.

JK-1, a useful erythroleukemic cell line model to study a controlled erythroid differentiation from progenitors to terminal erythropoiesis

New hematopoietic cell models have recently emerged through immortalization of CD34 cells to study and understand various molecular mechanisms of erythropoiesis. Here, we characterize the JK-1 CML-derived cell line, previously shown to spontaneously differentiate without cytokines. Using an epigenetic differentiation inhibitor that keeps JK-1 in an early differentiation phase, we characterized 2 progenitor stages: BFU-E JK-1 and CFU-E JK-1 with CD34+/CD36− and CD34−/CD36 + phenotypes respectively. Then, using the PFI-1 inducer known to synchronously control the terminal differentiation of JK-1 cells, 5 precursor stages were obtained (ProE, Baso1-2, PolyC, OrthoC) and characterized via cell morphology, CD49a and Band3 markers. Enlarged phenotyping was carried out for the earlier phase, and expression kinetics of membrane proteins such as RhAG, RhD/CE, CD47, DARC and CD44 were performed on each stage of the terminal phase. Furthermore, since JK-1 offers the unique property of covering a broad spectrum of differentiation stages, we explored deeper the GATA2/GATA1 and the non-erythroid/erythroid spectrin ‘switching’. The possibility of obtaining large quantities of JK-1 cells at each stage of differentiation, as shown in this study, as well as the potential to genetically modify these cells, via CrisprCas9, makes their use of considerable interest for studying pathologies occurring during erythropoiesis.

Potential Chronological Disturbance of the D’Orbigny Angrite Inferred from Discordant 26Al Ages

Angrites originate from the early-formed differentiated angrite parent body. The pristine volcanic angrite D’Orbigny is devoid of brecciation, shock effects, or any evidence of secondary processes and is thus key for studying the early stages of planetary accretion and differentiation. However, chronometers used to establish the formation chronology of angrites (including D’Orbigny) yield discordant ages, either (i) suggesting that secondary processes could have disturbed the apparent formation ages or (ii) being taken as evidence of heterogeneous distribution of 26Al in the early solar system. Yet spinel is minimally susceptible to secondary parent body processes and therefore a reliable target for establishing precise 26Al–26Mg ages. Here, we present the first in situ 26Al–26Mg analyses of spinel and plagioclase in D’Orbigny. Individual mineral assemblages provide distinct ages: olivine–spinel shows a well-defined isochron with an initial Al ratio ([26Al/27Al]i) of (5.39 ± 0.85) × 10−6, indicating formation at 2.35 +0.25−0.22 Myr after the formation of calcium–aluminum-rich inclusions (CAIs), whereas plagioclase–olivine defines an isochron with [26Al/27Al]i = (7.46 ± 1.87) × 10−7, implying formation at 4.40 +0.44−0.38 Myr after CAIs, consistent with previous MC-ICP-MS studies. This temporal gap can be attributed to secondary processes such as metamorphic or impact-generated diffusion. Thus, D’Orbigny and other angrites do not represent an immaculate anchor for chronometric comparison. This complexity should be considered in future studies, especially when using D’Orbigny as an anchor to discuss the chronology of the early solar system.

A transcriptomic hourglass in brown algae.

Complex multicellularity has emerged independently across a few eukaryotic lineages and is often associated with the rise of elaborate, tightly coordinated developmental processes1,2. How multicellularity and development are interconnected in evolution is a major question in biology. The hourglass model of embryonic evolution depicts how developmental processes are conserved during evolution, and predicts morphological and molecular divergence in early and late embryogenesis, bridged by a conserved mid-embryonic (phylotypic) period linked to the formation of the basic body plan3,4. Initially found in animal embryos5-8, molecular hourglass patterns have recently been proposed for land plants and fungi9,10. However, whether the hourglass pattern is an intrinsic feature of all complex multicellular eukaryotes remains unknown. Here we tested the presence of a molecular hourglass in the brown algae, a eukaryotic lineage that has evolved multicellularity independently from animals, fungi and plants1,11,12. By exploring transcriptome evolution patterns of brown algae with distinct morphological complexities, we uncovered an hourglass pattern during embryogenesis in morphologically complex species. Filamentous algae without canonical embryogenesis display transcriptome conservation in multicellular stages of the life cycle, whereas unicellular stages are more rapidly evolving. Our findings suggest that transcriptome conservation in brown algae is associated with cell differentiation stages, but is not necessarily linked to embryogenesis. Together with previous work in animals, plants and fungi, we provide further evidence for the generality of a developmental hourglass pattern across complex multicellular eukaryotes.