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Any person that has broken a bone can attest to the existence of sensory innervation of the skeleton. Beyond afferent functions, sensory neurons have been implicated in the orchestration of bone repair via the release of neuroregulatory signals. Yet, these neurosecretory effects have principally been deciphered through loss‐of‐function studies. Indeed, the potential therapeutic benefit of boosting nerve‐to‐bone interactions remains cursorily studied. Here, using a mouse calvarial bone defect model, pharmacologic activation of TrkA with a small molecule partial agonist induced bone‐associated nerve ingrowth and significantly improved calvarial bone healing. Single‐cell RNA sequencing analysis of cells from the defect site revealed shifts in cluster proportions, with enrichment of immune cell populations in TrkA agonist‐treated mice. Within the skeletal cell lineage, TrkA agonism enhanced osteoblast differentiation while suppressing fibroblastic differentiation. Pathway analysis showed increased Hedgehog signaling activity, and interactome analyses between trigeminal ganglia sensory neurons and skeletal cells implicated Hedgehog signaling. The pro‐regenerative effects of TrkA agonism were abolished in conditional knockout mice lacking Smoothened (Smo) in PDGFRα+ skeletal progenitor cells. In summary, boosting sensory nerve signaling enhances membranous bone repair after injury, at least in part via Hedgehog pathway activation in osteoprogenitor cells. Boosting sensory nerve activity via TrkA agonism strongly accelerates calvarial bone repair in adult mice. Furthermore, single‐cell RNA sequencing and neuron–bone interactome analyses identify these sensory neurons as a direct neural source of Hedgehog pathway ligands. Consequently, these ligands drive osteoblast differentiation of skeletal progenitors, enhancing local tissue healing through Smoothened‐dependent signaling.

Abstract Platelet-derived growth factor receptor α (PDGFRα) is often considered as a general marker of mesenchymal cells and fibroblasts, but also shows expression in a portion of osteoprogenitor cells. Within the skeleton, Pdgfrα+ mesenchymal cells have been identified in bone marrow and periosteum of long bones, where they play a crucial role in participating in fracture repair. A similar examination of Pdgfrα+ cells in calvarial bone healing has not been examined. Here, we utilize Pdgfrα-CreERTM;mT/mG reporter animals to examine the contribution of Pdgfrα+ mesenchymal cells to calvarial bone repair through histology and single-cell RNA sequencing (scRNA-Seq). Results showed that Pdgfrα+ mesenchymal cells are present in several cell clusters by scRNA-Seq, and by histology a dramatic increase in Pdgfrα+ cells populated the defect site at early timepoints to give rise to healed bone tissue overtime. Notably, diphtheria toxin-mediated ablation of Pdgfrα reporter+ cells resulted in significantly impaired calvarial bone healing. Our findings suggest that Pdgfrα-expressing cells within the calvarial niche play a critical role in the process of calvarial bone repair. Graphical Abstract Graphical Abstract

It is well-established that activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) stimulated by neurotransmitters is a key mechanism underlying neuromodulation. Much less is known about how G-protein regulation after receptor-mediated activation contributes to neuromodulation. Recent evidence indicates that the neuronal protein GINIP shapes GPCR inhibitory neuromodulation via a unique mechanism of G-protein regulation that controls neurological processes like pain and seizure susceptibility. However, the molecular basis of this mechanism remains ill-defined because the structural determinants of GINIP responsible for binding Gαi subunits and regulating G-protein signaling are not known. Here, we combined hydrogen-deuterium exchange mass-spectrometry, protein folding predictions, bioluminescence resonance energy transfer assays, and biochemical experiments to identify the first loop of the PHD domain of GINIP as an obligatory requirement for Gαi binding. Surprisingly, our results support a model in which GINIP undergoes a long-range conformational change to accommodate Gαi binding to this loop. Using cell-based assays, we demonstrate that specific amino acids in the first loop of the PHD domain are essential for the regulation of Gαi-GTP and free Gβγ signaling upon neurotransmitter GPCR stimulation. In summary, these findings shed light onto the molecular basis for a post-receptor mechanism of G-protein regulation that fine-tunes inhibitory neuromodulation.

Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA-mediated sponge regulatory network that affects the expression of many protein-coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12.4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization-dependent function. Our findings not only suggest an important role of lncRNA-mediated sponge regulation in cancer, but also underscore the critical influence of cytoplasmic localization on the efficacy of a sponge lncRNA. Long non-coding RNAs (lncRNA; >200 base pair nucleic acids with little protein-coding capacity) are emerging as potentially important regulators of oncogenesis. Here the authors show tumour suppressive lncRNA sponge function for the protein products of prostate cancer driver genes.

Background Estriol (E 3 ) is a steroid hormone formed only during pregnancy in primates including humans. Although E 3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E 3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E 3 on fetal development using mouse as a model system. Results We administered E 3 to pregnant mice, exposing the fetus to E 3 . Adult females exposed to E 3 in utero (E 3 -mice) had increased fertility and superior pregnancy outcomes. Female and male E 3 -mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E 3 -mice were distinct from controls. E 3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E 3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation. Conclusions We identify an unexpected functional role for E 3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency.

Steady-state gene expression across the cell cycle has been studied extensively. However, transcriptional gene regulation and the dynamics of histone modification at different cell-cycle stages are largely unknown. By applying a combination of global nuclear run-on sequencing (GRO-seq), RNA sequencing (RNA-seq), and histone-modification Chip sequencing (ChIP-seq), we depicted a comprehensive transcriptional landscape at the G0/G1, G1/S, and M phases of breast cancer MCF-7 cells. Importantly, GRO-seq and RNA-seq analysis identified different cell-cycle–regulated genes, suggesting a lag between transcription and steady-state expression during the cell cycle. Interestingly, we identified genes actively transcribed at early M phase that are longer in length and have low expression and are accompanied by a global increase in active histone 3 lysine 4 methylation (H3K4me2) and histone 3 lysine 27 acetylation (H3K27ac) modifications. In addition, we identified 2,440 cell-cycle–regulated enhancer RNAs (eRNAs) that are strongly associated with differential active transcription but not with stable expression levels across the cell cycle. Motif analysis of dynamic eRNAs predicted Kruppel-like factor 4 (KLF4) as a key regulator of G1/S transition, and this identification was validated experimentally. Taken together, our combined analysis characterized the transcriptional and histone-modification profile of the human cell cycle and identified dynamic transcriptional signatures across the cell cycle.

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2 -induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5 , oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3 . Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities. The transition from normal esophageal tissue to squamous carcinoma is characterized by an altered SOX2 cistrome. This transcriptional reprogramming activates endogenous retroviruses and double-stranded RNA expression, creating a dependency on the RNA editing enzyme ADAR1.

This work develops a novel ice detection framework specifically suitable for rotorcraft using computational aeroacoustics and Bayesian neural networks. In an offline phase of the work, the acoustic signature of glaze and rime ice shapes on an oscillating wing are computed. In addition, the aerodynamic performance indicators corresponding to the ice shapes are also monitored. These performance indicators include the lift, drag, and moment coefficients. A Bayesian neural network is subsequently trained using projected Stein variational gradient descent to create a mapping from the acoustic signature generated by the iced wings to predict their performance indicators along with quantified uncertainty that is highly important for time- and safety-critical decision-making scenarios. While the training is carried out fully offline, usage of the Bayesian neural network to make predictions can be conducted rapidly online allowing for an ice detection system that can be used in real time and in-flight.

Importance As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. Objective To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. Design Cross-sectional study between 2008 and 2017. Setting Los Angeles County. Participants All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III–IV and unstaged cases. Exposure Sociodemographic factors. Main outcome(s) Geographic “hotspots” or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. Results 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify “high-risk” neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. Conclusion and relevance Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

By integrating the expression profiles of long noncoding RNAs (lncRNAs) with clinical outcome and somatic copy-number alteration, the authors identified new lncRNAs that are associated with certain cancer subtypes and clinical prognoses. Experimental validation of the prostate cancer cell growth dependence of two new lncRNAs demonstrates the power of this approach for discovering disease-related lncRNAs. Despite growing appreciation of the importance of long noncoding RNAs (lncRNAs) in normal physiology and disease, our knowledge of cancer-related lncRNAs remains limited. By repurposing microarray probes, we constructed expression profiles of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy-number alterations, we identified lncRNAs that are associated with cancer subtypes and clinical prognosis and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two newly identified lncRNAs. Our analysis provides a resource of clinically relevant lncRNAs for the development of lncRNA biomarkers and the identification of lncRNA therapeutic targets. It also demonstrates the power of integrating publically available genomic data sets and clinical information for discovering disease-associated lncRNAs.