Long non-coding RNA fine-tunes bone homeostasis and repair by orchestrating cellular crosstalk and β-catenin-OPG/Jagged1 pathway.

The IncRNA was initially believed to be dispensable for physiology due to the lack of observable phenotypes in knockout (KO) mice. However, our study challenges this conclusion. We found that both KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis.

Selective Targeting of a Defined Subpopulation of Corticospinal Neurons using a Novel Klhl14-Cre Mouse Line Enables Molecular and Anatomical Investigations through Development into Maturity.

The corticospinal tract (CST) facilitates skilled, precise movements, which necessitates that subcerebral projection neurons (SCPN) establish segmentally specific connectivity with brainstem and spinal circuits. Developmental molecular delineation enables prospective identification of corticospinal neurons (CSN) projecting to thoraco-lumbar spinal segments; however, it remains unclear whether other SCPN subpopulations in developing sensorimotor cortex can be prospectively identified in this manner. Such molecular tools could enable investigations of SCPN circuitry with precision and specificity.

Combination of deep learning reconstruction and quantification for dynamic contrast-enhanced (DCE) MRI.

Dynamic contrast-enhanced (DCE) MRI is an important imaging tool for evaluating tumor vascularity that can lead to improved characterization of tumor extent and heterogeneity, and for early assessment of treatment response. However, clinical adoption of quantitative DCE-MRI remains limited due to challenges in acquisition and quantification performance, and lack of automated tools. This study presents an end-to-end deep learning pipeline that exploits a novel deep reconstruction network called DCE-Movienet with a previously developed deep quantification network called DCE-Qnet for fast and quantitative DCE-MRI.

At-RS31 orchestrates hierarchical cross-regulation of splicing factors and integrates alternative splicing with TOR-ABA pathways.

Alternative splicing is essential for plants, enabling a single gene to produce multiple transcript variants to boost functional diversity and fine-tune responses to environmental and developmental cues. At-RS31, a plant-specific splicing factor in the Serine/Arginine (SR)-rich protein family, responds to light and the Target of Rapamycin (TOR) signaling pathway, yet its downstream targets and regulatory impact remain unknown.To identify At-RS31 targets, we applied individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) and RNAcompete assays.

Conserved roles of engrailed: patterning tissues and specifying cell types.

More than 40 years ago, studies of the Drosophila engrailed and Hox genes led to major discoveries that shaped the history of developmental biology. We learned that these genes define the state of determination of cells that populate particular spatially defined regions: the identity of segmental domains by Hox genes, and the identity of posterior developmental compartments by engrailed. Hence, the boundaries that delimit spatial domains depend on engrailed.

Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.

Ageing is associated with a decline in the number and fitness of adult stem cells. Ageing-associated loss of stemness is posited to suppress tumorigenesis, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered mouse models and primary cells to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin.

The Serine Protease DPP9 and the Redox Sensor KEAP1 Form a Mutually Inhibitory Complex.

Synthetic inhibitors of the serine protease DPP9 activate the related NLRP1 and CARD8 inflammasomes and stimulate powerful innate immune responses. Thus, it seems plausible that a biomolecule similarly inhibits DPP9 and triggers inflammasome activation during infection, but one has not yet been discovered. Here, we wanted to identify and characterize DPP9-binding proteins to potentially uncover physiologically relevant mechanisms that control DPP9's activity.

Pretargeted alpha therapy in MUC16-positive high-grade serous ovarian cancer.

Background: Peritoneal metastasis with micrometastatic cell clusters is a common feature of advanced ovarian cancer. Targeted alpha therapy (TAT) is an attractive approach for treating micrometastatic diseases as alpha particles release enormous amounts of energy within a short distance. A pretargeting approach - leveraging the inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and trans-cyclooctene (TCO) - can minimize off-target toxicity related to TAT, often associated with full-length antibodies.

Meiotic DNA break resection and recombination rely on chromatin remodeler Fun30.

DNA double-strand breaks (DSBs) are nucleolytically processed to generate single-stranded DNA for homologous recombination. In Saccharomyces cerevisiae meiosis, this resection involves nicking by the Mre11-Rad50-Xrs2 complex (MRX), then exonucleolytic digestion by Exo1. Chromatin remodeling at meiotic DSBs is thought necessary for resection, but the remodeling enzyme was unknown.

Fungal symbiont transmitted by free-living mice promotes type 2 immunity.

The gut mycobiota is crucial for intestinal homeostasis and immune function. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome.

Cellular signatures in human blood track bone mineral density in postmenopausal women.

Osteoclasts are the sole bone-resorbing cells and are formed by the fusion of osteoclast precursor cells (OCPs) derived from myeloid lineage cells. Animal studies reveal that circulating OCPs (cOCPs) in blood travel to bone and fuse with bone-resident osteoclasts. However, the characteristics of human cOCPs and their association with bone diseases remain elusive.

ACK1 and BRK non-receptor tyrosine kinase deficiencies are associated with familial systemic lupus and involved in efferocytosis.

Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) and . Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model.

The Lipid Droplet Protein DHRS3 Is a Regulator of Melanoma Cell State.

Lipid droplets are fat storage organelles composed of a protein envelope and lipid-rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role.

Progressive plasticity during colorectal cancer metastasis.

As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition.

Postsynaptic BMP signaling regulates myonuclear properties in Drosophila larval muscles.

The syncytial mammalian muscle fiber contains a heterogeneous population of (myo)nuclei. At the neuromuscular junction (NMJ), myonuclei have specialized positioning and gene expression. However, it remains unclear how myonuclei are recruited and what regulates myonuclear output at the NMJ.

An increase in reactive oxygen species underlies neonatal cerebellum repair.

The neonatal mouse cerebellum shows remarkable regenerative potential upon injury at birth, wherein a subset of Nestin-expressing progenitors (NEPs) undergoes adaptive reprogramming to replenish granule cell progenitors that die. Here, we investigate how the microenvironment of the injured cerebellum changes upon injury and contributes to the regenerative potential of normally gliogenic-NEPs and their adaptive reprogramming. Single cell transcriptomic and bulk chromatin accessibility analyses of the NEPs from injured neonatal cerebella compared to controls show a temporary increase in cellular processes involved in responding to reactive oxygen species (ROS), a known damage-associated molecular pattern.

Reconstructing the sequence specificities of RNA-binding proteins across eukaryotes.

RNA-binding proteins (RBPs) are key regulators of gene expression. Here, we introduce EuPRI (Eukaryotic Protein-RNA Interactions) - a freely available resource of RNA motifs for 34,736 RBPs from 690 eukaryotes. EuPRI includes binding data for 504 RBPs, including newly collected RNAcompete data for 174 RBPs, along with thousands of reconstructed motifs.

Chronic interferon-stimulated gene transcription promotes oncogene-induced breast cancer.

The MRE11 complex (comprising MRE11, RAD50, and NBS1) is integral to the maintenance of genome stability. We previously showed that a hypomorphic mutant mouse strain ( ) was highly susceptible to oncogene-induced breast cancer. Here we used a mammary organoid system to examine which MRE11-dependent responses are tumor-suppressive.

Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8 T cells. However, the mechanisms that govern this immunometabolic axis remain unexplored.

Mechanisms of epigenomic and functional convergence between glucocorticoid- and IL4-driven macrophage programming.

Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2). Glucocorticoids (GC), widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics that M2 and M2 transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets.

Parallel genome-scale CRISPR-Cas9 screens uncouple human pluripotent stem cell identity versus fitness.

Pluripotent stem cells have remarkable self-renewal capacity: the ability to proliferate indefinitely while maintaining the pluripotent identity essential for their ability to differentiate into almost any cell type in the body. To investigate the interplay between these two aspects of self-renewal, we perform four parallel genome-scale CRISPR-Cas9 loss-of-function screens interrogating stem cell fitness in hPSCs and the dissolution of primed pluripotent identity during early differentiation. These screens distinguish genes with distinct roles in pluripotency regulation, including mitochondrial and metabolism regulators crucial for stem cell fitness, and chromatin regulators that control pluripotent identity during early differentiation.

Evolution of promoter-proximal pausing enabled a new layer of transcription control.

Promoter-proximal pausing of RNA polymerase II (Pol II) is a key regulatory step during transcription. Despite the central role of pausing in gene regulation, we do not understand the evolutionary processes that led to the emergence of Pol II pausing or its transition to a rate-limiting step actively controlled by transcription factors. Here we analyzed transcription in species across the tree of life.