Mitophagy Promotes Hair Regeneration by Activating Glutathione Metabolism.

Mitophagy maintains tissue homeostasis by self-eliminating defective mitochondria through autophagy. How mitophagy regulates stem cell activity during hair regeneration remains unclear. Here, we found that mitophagy promotes the proliferation of hair germ (HG) cells by regulating glutathione (GSH) metabolism. First, single-cell RNA sequencing, mitochondrial probe, transmission electron microscopy, and immunofluorescence staining showed stronger mitochondrial activity and increased mitophagy-related gene especially Prohibitin 2 (Phb2) expression at early-anagen HG compared to the telogen HG. Mitochondrial inner membrane receptor protein PHB2 binds to LC3 to initiate mitophagy. Second, molecular docking and functional studies revealed that PHB2-LC3 activates mitophagy to eliminate the damaged mitochondria in HG. RNA-seq, single-cell metabolism, immunofluorescence staining, and functional validation discovered that LC3 promotes GSH metabolism to supply energy for promoting HG proliferation. Third, transcriptomics analysis and immunofluorescence staining indicated that mitophagy was down-regulated in the aged compared to young-mouse HG. Activating mitophagy and GSH pathways through small-molecule administration can reactivate HG cell proliferation followed by hair regeneration in aged hair follicles. Our findings open up a new avenue for exploring autophagy that promotes hair regeneration and emphasizes the role of the self-elimination effect of mitophagy in controlling the proliferation of HG cells by regulating GSH metabolism.

Early intervention in Hirschsprung's disease: effects on enterocolitis and surgical outcomes.

BACKGROUND: The timing of surgical intervention for Hirschsprung's disease (HSCR) has been a topic of continued discussion. The objective of this study was to evaluate the significance of age at surgery in the management of HSCR by conducting a comparative analysis of the correlation between surgical age and midterm outcomes. METHODS: We conducted a retrospective analysis of children with HSCR who underwent one-stage laparoscopic assisted pull-through surgery with modified Swenson technology at our hospital between 2015 and 2019. The study population was stratified into two groups based on surgical age: patients who underwent surgery within a period of less than 3 months and those who underwent surgery between 3 and 12 months. The basic conditions, complications at 3-7 years after surgery, anal function (Rintala scale) and quality of life (PedsQLTM4.0) were compared between the groups. RESULTS: A total of 235 children (196 males and 39 females) were included in the study. No statistically significant differences in postoperative bowel function (P = 0.968) or quality of life (P = 0.32) were found between the two groups. However, there was a significant reduction in the incidence of Hirschsprung-associated enterocolitis (HAEC) among individuals under the age of three months prior to undergoing surgical intervention (69.1%) compared to the incidence observed postsurgery (30.9%). This difference was statistically significant (P < 0.001). CONCLUSION: In the current study, the age at which surgery was performed did not exhibit a discernible inclination towards influencing mid-term anal function or quality of life. Early surgical intervention can effectively diminish the occurrence of HAEC, minimize the extent of bowel resection, and expedite the duration of the surgical procedure.

The mechano-chemical circuit in fibroblasts and dendritic cells drives basal cell proliferation in psoriasis.

Psoriasis is an intractable immune-mediated disorder that disrupts the skin barrier. While studies have dissected the mechanism by which immune cells directly regulate epidermal cell proliferation, the involvement of dermal fibroblasts in the progression of psoriasis remains unclear. Here, we identified that signals from dendritic cells (DCs) that migrate to the dermal-epidermal junction region enhance dermal stiffness by increasing extracellular matrix (ECM) expression, which further promotes basal epidermal cell hyperproliferation. We analyzed cell-cell interactions and observed stronger interactions between DCs and fibroblasts than between DCs and epidermal cells. Using single-cell RNA (scRNA) sequencing, spatial transcriptomics, immunostaining, and stiffness measurement, we found that DC-secreted LGALS9 can be received by CD44+ dermal fibroblasts, leading to increased ECM expression that creates a stiffer dermal environment. By employing mouse psoriasis and skin organoid models, we discovered a mechano-chemical signaling pathway that originates from DCs, extends to dermal fibroblasts, and ultimately enhances basal cell proliferation in psoriatic skin.

The neurotransmitter calcitonin gene-related peptide shapes an immunosuppressive microenvironment in medullary thyroid cancer.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.

The biochemical characterization of a TatD nuclease from Thermus thermophilus.

Nucleases play pivotal roles in DNA repair and apoptosis. Moreover, they have various applications in biotechnology and industry. Among nucleases, TatD has been characterized as an exonuclease with various biological functions in different organisms. Here, we biochemically characterized the potential TatD nuclease from Thermus thermophilus. The tatD gene from T. thermophilus was cloned, then the recombinant TatD nuclease was expressed and purified. Our results revealed that the TthTatD nuclease could degrade both single-stranded and double-stranded DNA, and its activity is dependent on the divalent metal ions Mg2+ and Mn2+. Remarkably, the activity of TthTatD nuclease is highest at 37 °C and decreases with increasing temperature. TthTatD is not a thermostable enzyme, even though it is from a thermophilic bacterium. Based on the sequence similarity and molecular docking of the DNA substrate into the modeled TthTatD structure, several key conserved residues were identified and their roles were confirmed by analyzing the enzymatic activities of the site-directed mutants. The residues E86 and H149 play key roles in binding metal ions, residues R124/K126 and K211/R212 had a critical role in binding DNA substrate. Our results confirm the enzymatic properties of TthTatD and provide a primary basis for its possible application in biotechnology.

Mechanisms and applications of the regenerative capacity of platelets-based therapy in knee osteoarthritis.

Osteoarthritis (OA) is the most prevalent joint disease in the elderly population and its substantial morbidity and disability impose a heavy economic burden on patients and society. Knee osteoarthritis (KOA) is the most common subtype of OA, which is characterized by damage to progressive articular cartilage, synovitis, and subchondral bone sclerosis. Most current treatments for OA are palliative, primarily aim at symptom management, and do not prevent the progression of the disease or restore degraded cartilage. The activation of α-granules in platelets releases various growth factors that are involved in multiple stages of tissue repair, suggesting potential for disease modification. In recent years, platelet-based therapies, such as platelet-rich plasma, platelet-rich fibrin, and platelet lysates, have emerged as promising regenerative treatments for KOA, but their related effects and mechanisms are still unclear. Therefore, this review aims to summarize the biological characteristics and functions of platelets, classify the products of platelet-based therapy and related preparation methods. Moreover, we summarize the basic research of platelet-based regeneration strategies for KOA and discuss the cellular effects and molecular mechanisms. Further, we describe the general clinical application of platelet-based therapy in the treatment of KOA and the results of the meta-analysis of randomized controlled trials.

The Potential Value of Mean Platelet Volume and Platelet Distribution Width as Inflammatory Indicators in Surgical Necrotizing Enterocolitis.

Background: This study aims to investigate the potential significance of mean platelet volume (MPV) and platelet distribution width (PDW) in predicting surgical neonatal necrotizing enterocolitis (NEC) and establish the correlation between MPV/PDW levels and the severity/prognosis of NEC. Methods: A retrospective study was conducted on a cohort of 372 patients diagnosed with NEC. The patients were categorized into two groups based on whether they underwent surgical therapy. Univariate /multivariate analysis were employed to compare the MPV and PDW between the two groups. Moreover, patients in surgical group were categorized into multiple subgroups based on intraoperative findings and postoperative prognosis, and the levels of MPV and PDW were compared among these subgroups. Results: Of the 372 patients, the operative group exhibited significantly higher levels of MPV and PDW than the nonoperative group (P < 0.05). Logistic regression analysis revealed that MPV (OR = 4.895, P < 0.001) and PDW (OR = 1.476, P < 0.001) independently associated with surgical NEC. The analysis of the receiver operating characteristic (ROC) curve revealed that the area under the curve (AUC) was 0.706 for MPV alone, with a cut-off value of 11.8 fL. Similarly, the AUC was 0.728 for PDW alone, with a cut-off value of 16%. However, when MPV and PDW were combined, the AUC increased to 0.906 for predicting surgical NEC. In accordance with the intraoperative findings, the levels of MPV and PDW were found to be higher in the large area necrosis group than in the partial or mild necrosis group (P < 0.01). Furthermore, the MPV and PDW values in the death group were significantly greater than those in the survival group (P =0.040, P =0.008). Conclusion: MPV and PDW may serve as potentially valuable indicators for determining the need for surgical intervention and predicting the prognosis of patients with NEC.

Regulating the Distribution and Accumulation of Charged Molecules by Progressive Electroporation for Improved Intracellular Delivery.

The cell membrane separates the intracellular compartment from the extracellular environment, constraining exogenous molecules to enter the cell. Conventional electroporation typically employs high-voltage and short-duration pulses to facilitate the transmembrane transport of molecules impermeable to the membrane under natural conditions by creating temporary hydrophilic pores on the membrane. Electroporation not only enables the entry of exogenous molecules but also directs the intracellular distribution of the electric field. Recent advancements have markedly enhanced the efficiency of intracellular molecule delivery, achieved through the utilization of microstructures, microelectrodes, and surface modifications. However, little attention is paid to regulating the motion of molecules during and after passing through the membrane to improve delivery efficiency, resulting in an unsatisfactory delivery efficiency and high dose demand. Here, we proposed the strategy of regulating the motion of charged molecules during the delivery process by progressive electroporation (PEP), utilizing modulated electric fields. Efficient delivery of charged molecules with an expanded distribution and increased accumulation by PEP was demonstrated through numerical simulations and experimental results. The dose demand can be reduced by 10-40% depending on the size and charge of the molecules. We confirmed the safety of PEP for intracellular delivery in both short and long terms through cytotoxicity assays and transcriptome analysis. Overall, this work not only reveals the mechanism and effectiveness of PEP-enhanced intracellular delivery of charged molecules but also suggests the potential integration of field manipulation of molecular motion with surface modification techniques for biomedical applications such as cell engineering and sensitive cellular monitoring.

Energy competition remodels the metabolic glucose landscape of psoriatic epidermal cells.

Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin. Methods: Bulk- and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models. Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin. Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.

Raddeanin A Protects the BRB Through Inhibiting Inflammation and Apoptosis in the Retina of Alzheimer's Disease.

Neuroinflammation and endothelial cell apoptosis are prominent features of blood-brain barrier (BBB) disruption, which have been described in Alzheimer's disease (AD) and can predict cognitive decline. Recent reports revealed vascular ß-amyloid (Aß) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer's disease by targeting ß-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aß-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/ß-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.

Enhancing strategies of photosynthetic hydrogen production from microalgae: Differences in hydrogen production between prokaryotic and eukaryotic algae.

Hydrogen production through the metabolic bypass of microalgae photosynthesis is an environmentally friendly method. This review examines the genetic differences in hydrogen production between prokaryotic and eukaryotic microalgae. Additionally, the pathways for enhancing microalgae-based photosynthetic hydrogen generation are summarized. The main strategies for enhancing microalgal hydrogen production involve inhibiting the oxygen-generating process of photosynthesis and promoting the oxygen tolerance of hydrogenase. Future research is needed to explore the regulation of physiological metabolism through quorum sensing in microalgae to enhance photosynthetic hydrogen production. Moreover, effective evaluation of carbon emissions and sequestration across the entire photosynthetic hydrogen production process is crucial for determining the sustainability of microalgae-based production approaches through comprehensive lifecycle assessment. This review elucidates the prospects and challenges associated with photosynthetic hydrogen production by microalgae.

Platelet-to-lymphocyte ratios as a haematological marker of synovitis in rheumatoid arthritis with normal acute phase reactant level.

BACKGROUND: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients. METHODS: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated. RESULTS: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%). CONCLUSIONS: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.

Stellate ganglion block for visceral pain in elderly patients undergoing video-assisted thoracoscopic lung cancer surgery: a randomized, controlled trial.

BACKGROUND: Visceral pain occurs commonly following thoracic surgery, but an effective method to relieve visceral pain in thoracic surgery remains controversial. We test the effect of stellate ganglion blocks (SGB) on perioperative visceral pain following video-assisted thoracoscopic surgery (VATS). METHODS: A prospective, randomized, controlled trial enrolled 77 elderly patients undergoing VATS. Patients were randomized to SGB followed by modified intercostal nerve block (Group S, n=37); or modified intercostal nerve block only (Group C, n=40). Remifentanil 0.02-0.2 µg·kg-1·min-1 was titrated to keep pain threshold index values between 40-65 and maintain mean arterial pressure or heart rate values around 20% of baseline values. Patient-controlled intravenous analgesia with sufentanil was used in the postoperative period. The co-primary outcomes were the perioperative cumulative opioid consumption and pain scores on movement at 24 h after surgery. RESULTS: Compared with control group, SGB greatly reduced the intraoperative remifentanil consumption[300.00(235.00-450.00)µg versus 710.00(500.00-915.00)µg; P<0.01], with no difference in cumulative sufentanil consumption to 48h post-surgery. There was a statistically significant difference in pain scores on movement at 24h between groups [4.00(3.00-4.00) versus 4.00(3.25-5.00); P=0.01]. Further exploratory analyses showed significant difference for intra-chest pain on movement at 24h [3.00(2.00-3.00) versus 3.00(2.25-4.00); P=0.01]. No significant difference was observed in nausea/vomiting, time to pass flatus and postoperative length of stay. CONCLUSION: Preoperative stellate ganglion blocks for elderly patients could effectively blunt intraoperative visceral stress and reduce postoperative visceral pain extending 24 h after VATS. This initial finding deserve further investigation.

Comparison of the connectivity of the posterior intralaminar thalamic nucleus and peripeduncular nucleus in rats and mice.

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Cre-dependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP.

Crosstalk between endothelial cells and dermal papilla entails hair regeneration and angiogenesis during aging.

INTRODUCTION: Tissues maintain their function through interaction with microenvironment. During aging, both hair follicles and blood vessels (BV) in skin undergo degenerative changes. However, it is elusive whether the changes are due to intrinsic aging changes in hair follicles or blood vessels respectively, or their interactions. OBJECTIVE: To explore how hair follicles and blood vessels interact to regulate angiogenesis and hair regeneration during aging. METHODS: Single-cell RNA-sequencing (scRNA-seq) analyses were used to identify the declined ability of dermal papilla (DP) and endothelial cells (ECs) during aging. CellChat and CellCall were performed to investigate interaction between DP and ECs. Single-cell metabolism (scMetabolism) analysis and iPATH were applied to analyze downstream metabolites in DP and ECs. Hair-plucking model and mouse cell organoid model were used for functional studies. RESULTS: During aging, distance and interaction between DP and ECs are decreased. DP interacts with ECs, with decreased EDN1-EDNRA signaling from ECs to DP and CTF1-IL6ST signaling from DP to ECs during aging. ECs-secreted EDN1 binds to DP-expressed EDNRA which enhances Taurine (TA) metabolism to promote hair regeneration. DP-emitted CTF1 binds to ECs-expressed IL6ST which activates alpha-linolenic acid (ALA) metabolism to promote angiogenesis. Activated EDN1-EDNRA-TA signaling promotes hair regeneration in aged mouse skin and in organoid cultures, and increased CTF1-IL6ST-ALA signaling also promotes angiogenesis in aged mouse skin and organoid cultures. CONCLUSIONS: Our finding reveals reciprocal interactions between ECs and DP. ECs releases EDN1 sensed by DP to activate TA metabolism which induces hair regeneration, while DP emits CTF1 signal received by ECs to enhance ALA metabolism which promotes angiogenesis. Our study provides new insights into mutualistic cellular crosstalk between hair follicles and blood vessels, and identifies novel signaling contributing to the interactions of hair follicles and blood vessels in normal and aged skin.

Demonstration of Acoustic Higher-Order Topological Stiefel-Whitney Semimetal.

The higher-order topological phases have attracted intense attention in the past years, which reveals various intriguing topological properties. Meanwhile, the enrichment of group symmetries with projective symmetry algebras redefines the fundamentals of topological matter and makes Stiefel-Whitney (SW) classes in classical wave systems possible. Here, we report the experimental realization of higher-order topological nodal loop semimetal in an acoustic system and obtain the inherent SW topological invariants. In stark contrast to higher-order topological semimetals relating to complex vector bundles, the hinge and surface states in the SW topological phase are protected by two distinctive SW topological charges relevant to real vector bundles. Our findings push forward the studies of SW class topology in classical wave systems, which also show possibilities in robust high-Q-resonance-based sensing and energy harvesting.

Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study.

BACKGROUND: Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. AIM: To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD. METHODS: Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE. CONCLUSION: HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

YAP1-induced RBM24 promotes the tumorigenesis of triple-negative breast cancer through the ß-catenin pathway.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and refractory to current treatments. RBM24 is an RNA-binding protein and shows the ability to regulate tumor progression in multiple cancer types. However, its role in TNBC is still unclear. In this study, we analyzed publicly available profiling data from TNBC tissues and cells. Loss- and gain-of-function experiments were performed to determine the function of RBM24 in TNBC cells. The mechanism for RBM24 action in TNBC was investigated. RBM24 was deregulated in TNBC tissues and TNBC cells with depletion of SIPA1, YAP1, or ARID1A, three key regulators of TNBC. Compared to MCF10A breast epithelial cells, TNBC cells had higher levels of RBM24. Knockdown of RBM24 inhibited TNBC cell proliferation, colony formation, and tumorigenesis, while overexpression of RBM24 promoted aggressive phenotype in TNBC cells. YAP1 overexpression induced the expression of RBM24 and the RBM24 promoter-driven luciferase reporter. YAP1 was enriched at the promoter region of RBM24. Overexpression of RBM24 increased ß-catenin-dependent transcriptional activity. Most importantly, knockdown of CTNNB1 rescued RBM24 aggressive phenotype in TNBC cells. Collectively, the YAP1/RBM24/ß-catenin axis plays a critical role in driving TNBC progression. RBM24 may represent a novel therapeutic target for TNBC treatment.

DNA nanomachines reveal an adaptive energy mode in confinement-induced amoeboid migration powered by polarized mitochondrial distribution.

Energy metabolism is highly interdependent with adaptive cell migration in vivo. Mechanical confinement is a critical physical cue that induces switchable migration modes of the mesenchymal-to-amoeboid transition (MAT). However, the energy states in distinct migration modes, especially amoeboid-like stable bleb (A2) movement, remain unclear. In this report, we developed multivalent DNA framework-based nanomachines to explore strategical mitochondrial trafficking and differential ATP levels during cell migration in mechanically heterogeneous microenvironments. Through single-particle tracking and metabolomic analysis, we revealed that fast A2-moving cells driven by biomimetic confinement recruited back-end positioning of mitochondria for powering highly polarized cytoskeletal networks, preferentially adopting an energy-saving mode compared with a mesenchymal mode of cell migration. We present a versatile DNA nanotool for cellular energy exploration and highlight that adaptive energy strategies coordinately support switchable migration modes for facilitating efficient metastatic escape, offering a unique perspective for therapeutic interventions in cancer metastasis.

Modulation of plasmacytoid dendritic cell and CD4+ T cell differentiation accompanied by upregulation of the cholinergic anti-inflammatory pathway induced by enterovirus 71.

Enterovirus 71 (EV71) is a neurotropic enterovirus associated with hand, foot, and mouth disease (HFMD) fatalities. In this study, we investigated the impact of EV71 on plasmacytoid dendritic cells (pDCs) and CD4+ T cells. The results showed that pDCs were promptly activated, secreting interferon (IFN)-α and inducing CD4+ T cell proliferation and differentiation during early EV71 infection. This initiated adaptive immune responses and promoted proinflammatory cytokine production by CD4+ T cells. Over time, viral nucleic acids and proteins were synthesized in pDCs and CD4+ T cells. Concurrently, the cholinergic anti-inflammatory pathway (CAP) was activated, exhibiting an anti-inflammatory role. With constant viral stimulation, pDCs and CD4+ T cells showed reduced differentiation and cytokine secretion. Defects in pDCs were identified as a key factor in CD4+ T cell tolerance. CAP had a more significant regulatory effect on CD4+ T cells than on pDCs and was capable of inhibiting inflammation in these cells.