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"Fang, S."
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Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.
New vessel formation relies on a tightly controlled switch in endothelial biology from proliferating to specializing phenotypes. Here, Fang et al. elucidate the molecular mechanisms of this switch and show that the arterial shear activates a Notch-Cx37-p27 axis promoting endothelial cell cycle arrest and enabling arterial gene expression.
Journal Article
Magnetic resonance spectroscopy of an atomically thin material using a single-spin qubit
Two-dimensional (2D) materials offer a promising platform for exploring condensed matter phenomena and developing technological applications. However, the reduction of material dimensions to the atomic scale poses a challenge for traditional measurement and interfacing techniques that typically couple to macroscopic observables. We demonstrate a method for probing the properties of 2D materials via nanometer-scale nuclear quadrupole resonance (NQR) spectroscopy using individual atomlike impurities in diamond. Coherent manipulation of shallow nitrogen-vacancy (NV) color centers enables the probing of nanoscale ensembles down to approximately 30 nuclear spins in atomically thin hexagonal boron nitride (h-BN). The characterization of low-dimensional nanoscale materials could enable the development of new quantum hybrid systems, combining atomlike systems coherently coupled with individual atoms in 2D materials.
Journal Article
Hierarchically buckled sheath-core fibers for superelastic electronics, sensors, and muscles
Superelastic conducting fibers with improved properties and functionalities are needed for diverse applications. Here we report the fabrication of highly stretchable (up to 1320%) sheath-core conducting fibers created by wrapping carbon nanotube sheets oriented in the fiber direction on stretched rubber fiber cores. The resulting structure exhibited distinct short- and long-period sheath buckling that occurred reversibly out of phase in the axial and belt directions, enabling a resistance change of less than 5% for a 1000% stretch. By including other rubber and carbon nanotube sheath layers, we demonstrated strain sensors generating an 860% capacitance change and electrically powered torsional muscles operating reversibly by a coupled tension-to-torsion actuation mechanism. Using theory, we quantitatively explain the complementary effects of an increase in muscle length and a large positive Poisson's ratio on torsional actuation and electronic properties.
Journal Article
Sahel Droughts Induced by Large Volcanic Eruptions Over the Last Millennium in PMIP4/Past1000 Simulations
This work provides evidence of the influence of large volcanic eruptions on Sahel rainfall relying on PMIP4/past1000 multi‐model simulations, covering the last millennium. A classification of volcanic eruptions in the last millennium according to the meridional symmetry of the associated radiative forcing reveals different mechanisms of the West African Monsoon response at inter‐annual timescale. In all cases, these simulated changes result in Sahel drying up to 2 years after an eruption. Besides, we add evidence of a role of varying volcanic activity across the past millennium in the Sahel precipitation variability at multi‐decadal to secular timescales. Plain Language Summary Relying on climate simulations of the past millennium, this work shows that the largest volcanic eruptions documented induce different mechanisms in the West African Monsoon response depending on whether the eruption occurs at extra‐tropical or tropical latitudes. In both cases, such volcanic impacts can induce droughts the two following rainy seasons in the West African Sahel region. Moreover, we show first evidence of an influence of the frequency of volcanic eruptions on the Sahel precipitation regime over decades to centuries across the past millennium. Key Points Climate model simulations of the past millennium show Sahel drought in response to large volcanic eruptions up to the following 2 years The mechanisms leading to the Sahel drying are different if it responds to extra‐tropical or tropical eruptions The increasing frequency of eruptions throughout the past millennium modulates Sahel precipitation variability on multi‐decadal timescales
Journal Article
The Moderating Role of Health Literacy and Health Promoting Behavior in the Relationship Among Health Anxiety, Emotional Regulation, and Cyberchondria
People are increasingly turning to the internet to find answers to their health concerns in an era where there is a wealth of online health information, which frequently causes increased health anxiety and the phenomenon known as cyberchondria. The objectives of this study were to examine the moderating role of health literacy and health promotion behavior and the mediating role of emotional regulation between health anxiety and cyberchondria among the Pakistani population.
The study used a self-administered questionnaire to collect and examine health anxiety, emotional regulation, health literacy, health promotion behavior, and cyberchondria in 755 residents. A moderated mediation model of Hayes PROCESS was used to examine this hypothesis.
The findings unveiled the average score of the participants on the study variables, as well as their categorization into low, moderate, and high categories. On scale of Health Anxiety participant scores (32% vs 53% vs 15%), Emotional Regulation (25% vs 46% vs 29%), Cyberchondria (18% vs 41% vs 41%), Health Literacy (56% vs 29% vs 15%), and Health promotion Behavior (49% vs 28% vs 23%). Moreover, result revealed that emotional regulation mediates the significant positive association between health anxiety and cyberchondria (β=0.25**p<0.001). Furthermore, health literacy moderates the negative association health anxiety and emotional regulation (β=-0.42*p<0.031), and health promotion behavior also negatively moderate the relationship between emotional regulation and cyberchondria (β=-0.27*p<0.22).
Based on the findings, it is recommended that health policymakers consider comprehensive national initiatives that focus on educational planning. These initiatives should boost health literacy levels and promote health-related behavior. Additionally, there is urgent need for strict measures to be put in place for monitoring online platforms and websites that spread inaccurate or false health-related information.
Journal Article
Phosphorylation of Arl4A/D promotes their binding by the HYPK chaperone for their stable recruitment to the plasma membrane
The Arl4 small GTPases participate in a variety of cellular events, including cytoskeleton remodeling, vesicle trafficking, cell migration, and neuronal development. Whereas small GTPases are typically regulated by their GTPase cycle, Arl4 proteins have been found to act independent of this canonical regulatory mechanism. Here, we show that Arl4A and Arl4D (Arl4A/D) are unstable due to proteasomal degradation, but stimulation of cells by fibronectin (FN) inhibits this degradation to promote Arl4A/D stability. Proteomic analysis reveals that FN stimulation induces phosphorylation at S143 of Arl4A and at S144 of Arl4D. We identify Pak1 as the responsible kinase for these phosphorylations. Moreover, these phosphorylations promote the chaperone protein HYPK to bind Arl4A/D, which stabilizes their recruitment to the plasma membrane to promote cell migration. These findings not only advance a major mechanistic understanding of how Arl4 proteins act in cell migration but also achieve a fundamental understanding of how these small GTPases are modulated by revealing that protein stability, rather than the GTPase cycle, acts as a key regulatory mechanism.
Journal Article
Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis
Slug (
SNAI2
), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.
Slug supports heart development and tumor metastasis, but its role in blood vessel formation is less clear. Here the authors show that endothelial cell-expressed Slug regulates both physiologic and pathological angiogenesis, at least in part through the modulation of Notch signalling.
Journal Article
Endosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Ligand-induced epidermal growth factor receptor (EGFR) endocytosis followed by endosomal EGFR signaling and lysosomal degradation plays important roles in controlling multiple biological processes. ADP-ribosylation factor (Arf)-like protein 4 A (Arl4A) functions at the plasma membrane to mediate cytoskeletal remodeling and cell migration, whereas its localization at endosomal compartments remains functionally unknown. Here, we report that Arl4A attenuates EGFR degradation by binding to the endosomal sorting complex required for transport (ESCRT)-II component VPS36. Arl4A plays a role in prolonging the duration of EGFR ubiquitinylation and deterring endocytosed EGFR transport from endosomes to lysosomes under EGF stimulation. Mechanistically, the Arl4A-VPS36 direct interaction stabilizes VPS36 and ESCRT-III association, affecting subsequent recruitment of deubiquitinating-enzyme USP8 by CHMP2A. Impaired Arl4A-VPS36 interaction enhances EGFR degradation and clearance of EGFR ubiquitinylation. Together, we discover that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
Endosomal EGFR signaling and lysosomal degradation play important roles in controlling numerous biological processes. Here, the authors show that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
Journal Article