The human
ether-á-go-go-related
gene (hERG) encodes the pore-forming subunit (Kv11.1), conducting a rapidly delayed rectifier K
+
current (
I
Kr
). Reduction of
I
Kr
in pathological cardiac ...hypertrophy (pCH) contributes to increased susceptibility to arrhythmias. However, practical approaches to prevent
I
Kr
deficiency are lacking. Our study investigated the involvement of ubiquitin ligase Nedd4-2-dependent ubiquitination in
I
Kr
reduction and sought an intervening approach in pCH. Angiotensin II (Ang II) induced a pCH phenotype in guinea pig, accompanied by increased incidences of sudden death and higher susceptibility to arrhythmias. Patch-clamp recordings revealed a significant
I
Kr
reduction in pCH cardiomyocytes. Kv11.1 protein expression was decreased whereas its mRNA level did not change. In addition, Nedd4-2 protein expression was increased in pCH, accompanied by an enhanced Nedd4-2 and Kv11.1 binding detected by immunoprecipitation analysis. Cardiac-specific overexpression of inactive form of Nedd4-2 shortened the prolonged QT interval, reversed
I
Kr
reduction, and decreased susceptibility to arrhythmias. A synthesized peptide containing the PY motif in Kv11.1 C-terminus binding to Nedd4-2 and a cell-penetrating sequence antagonized Nedd4-2-dependent degradation of the channel and increased the surface abundance and function of hERG channel in HEK cells. In addition,
in vivo
administration of the PY peptide shortened QT interval and action potential duration, and enhanced
I
Kr
in pCH. We conclude that Nedd4-2-dependent ubiquitination is critically involved in
I
Kr
deficiency in pCH. Pharmacological suppression of Nedd4-2 represents a novel approach for antiarrhythmic therapy in pCH.
Biomedical alloys are paramount materials in biomedical applications, particularly in crafting biological artificial replacements. In traditional biomedical alloys, a significant challenge is ...simultaneously achieving an ultra‐low Young's modulus, excellent biocompatibility, and acceptable ductility. A multi‐component body‐centered cubic (BCC) biomedical high‐entropy alloy (Bio‐HEA), which is composed of non‐toxic elements, is noteworthy for its outstanding biocompatibility and compositional tuning capabilities. Nevertheless, the aforementioned challenges still remain. Here, a method to achieve a single phase with the lowest Young's modulus among the constituent phases by precisely tuning the stability of the BCC phase in the Bio‐HEA, is proposed. The subtle tuning of the BCC phase stability also enables the induction of stress‐induced martensite transformation with extremely low trigger stress. The transformation‐induced plasticity and work hardening capacity are achieved via the stress‐induced martensite transformation. Additionally, the hierarchical stress‐induced martensite twin structure and crystalline‐to‐amorphous phase transformation provide robust toughening mechanisms in the Bio‐HEA. The cytotoxicity test confirms that this Bio‐HEA exhibits excellent biocompatibility without cytotoxicity. In conclusion, this study provides new insights into the development of biomedical alloys with a combination of ultra‐low Young's modulus, excellent biocompatibility, and decent ductility.
Simultaneously achieving an ultra‐low Young's modulus, an excellent biocompatibility, and an acceptable ductility possess significant challenges in traditional biomedical alloys. This work presents a generic solution to an ever‐lasting challenge in metal materials design: i.e., achieving low Young's modulus analogous to the human bone while maintaining commendable tensile ductility as well as excellent biocompatibility in a biomedical high‐entropy alloy (Bio‐HEA).
The design of metal matrix composites predominantly focusses on synergistically integrating the intrinsic properties of matrix and reinforcing phase aiming to achieve outstanding strength and ...ductility simultaneously. In metal matrix composites, the reinforcing phase invariably faces challenges such as agglomeration and non-uniform distribution, resulting in a significant reduction in mechanical properties. Here, we propose a method to overcome this barrier through an in-situ alloying of laser powder bed fusion i.e., redistributing the reinforcing phase (Cr2B boride) in medium entropy alloy matrix (CoCrNi). The in-situ alloying can be achieved by a mixture of CoCrNi powders and B4C particles. After remelting, a nano-sized core-shell structure is developed by establishing “soft core” of CoCrNi matrix embedded with “hard shell” of Cr2B boride. Such nano-sized core-shell structure mainly contributes to a yield strength (867 ± 1.6 MPa), a high tensile strength (1200 ± 13 MPa) and a decent ductility (17 ± 0.5%) of the CoCrNi/Cr2B composite due to the load bearing strengthening and hetero-deformation induced hardening. Additionally, the crack propagation can be suppressed by the CoCrNi matrix/Cr2B interface. The insights provide a new design strategy of in-situ formation of the nano-sized core-shell structure to develop the metal matrix composites with high strength and ductility.
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The slowly activating delayed rectifier K+ current (IKs) is one of the main repolarizing currents in the human heart. Evidence has shown that angiotensin II (Ang II) regulates IKs through the protein ...kinase C (PKC) pathway, but the related results are controversial. This study was designed to identify PKC isoenzymes involved in the regulation of IKs by Ang II and the underlying molecular mechanism. The whole-cell patch-clamp technique was used to record IKs in isolated guinea pig ventricular cardiomyocytes and in human embryonic kidney (HEK) 293 cells co-transfected with human KCNQ1/KCNE1 genes and Ang II type 1 receptor genes. Ang II inhibited IKs in a concentration-dependent manner in native cardiomyocytes. A broad PKC inhibitor Gö6983 (not inhibiting PKCε) and a selective cPKC inhibitor Gö6976 did not affect the inhibitory action of Ang II. In contrast, the inhibition was significantly attenuated by PKCε-selective peptide inhibitor εV1–2. However, direct activation of PKC by phorbol 12-myristate 13-acetate (PMA) increased the cloned human IKs in HEK293 cells. Similarly, the cPKC peptide activator significantly enhanced the current. In contrast, the PKCε peptide activator inhibited the current. Further evidence showed that PKCε knockdown by siRNA antagonized the Ang II-induced inhibition on KCNQ1/KCNE1 current, whereas knockdown of cPKCs (PKCα and PKCβ) attenuated the potentiation of the current by PMA. Moreover, deletion of four putative phosphorylation sites in the C-terminus of KCNQ1 abolished the action of PMA. Mutation of two putative phosphorylation sites in the N-terminus of KCNQ1 and one site in KCNE1 (S102) blocked the inhibition of Ang II. Our results demonstrate that PKCε isoenzyme mediates the inhibitory action of Ang II on IKs and by phosphorylating distinct sites in KCNQ1/KCNE1, cPKC and PKCε isoenzymes produce the contrary regulatory effects on the channel. These findings have provided new insight into the molecular mechanism underlying the modulation of the KCNQ1/KCNE1 channel.
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•PKCε isoenzyme mediates the inhibitory action of angiotensin (Ang) II on IKs.•cPKC and PKCε isoenzymes produce the opposite regulatory effects on IKs.•cPKC and PKCε isoenzymes modulate the KCNQ1/KCNE1 channel by phosphorylating different sites.
Slow delayed rectifier potassium current (I
) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of ...I
and its involvement in age-dependent arrhythmogenesis.
The purpose of this study was to investigate age-related alteration of the I
response to β-adrenergic receptor (βAR) activation.
Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K
currents. Optical mapping of membrane potential was performed in ex vivo heart.
There was no difference in I
density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to I
potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on I
in a concentration-dependent manner in old guinea pig hearts. The β
AR antagonist, but not β
AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned I
channel and β
AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, Gβγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of I
by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias.
βAR activation acutely induces an inhibitory I
response in aging guinea pig hearts through β
AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.
Despite achieving notable strength and wear resistance in precipitation-strengthened Cantor high-entropy alloy (HEA), the inherent brittleness of precipitates leads to a loss of ductility. In this ...study, we propose a novel approach to address this issue by introducing nanosized M23C6-combined with Cr2N, termed dual-nanoprecipitation, and heterogeneous structure in a C and N co-doped interstitial HEA (iHEA). The abundant nanoscale M23C6 and Cr2N particles serve not only as reinforcing agents to enhance strength and wear resistance but also hinder the recrystallization process, resulting in a heterogeneous structure containing recrystallized and non-recrystallized zones. This heterogeneity triggers additional strengthening and strain hardening mechanisms, thereby enhancing the deformability of iHEA. Furthermore, the heterogeneous structure effectively mitigates strain localization on the sliding surface during wear, thus improving tribological properties. By overcoming the challenge of poor ductility while maintaining exceptional strength and wear resistance, the dual-nanoprecipitation-induced heterogeneous structure offers promising avenues for the development of alloys with superior strength-ductility synergy and wear resistance.
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Hybrid quantum systems are essential for the realization of distributed quantum networks. In particular, piezo-mechanics operating at typical superconducting qubit frequencies features low thermal ...excitations, and offers an appealing platform to bridge superconducting quantum processors and optical telecommunication channels. However, integrating superconducting and optomechanical elements at cryogenic temperatures with sufficiently strong interactions remains a tremendous challenge. Here, we report an integrated superconducting cavity piezo-optomechanical platform where 10 GHz phonons are resonantly coupled with photons in a superconducting cavity and a nanophotonic cavity at the same time. Taking advantage of the large piezo-mechanical cooperativity (C
~7) and the enhanced optomechanical coupling boosted by a pulsed optical pump, we demonstrate coherent interactions at cryogenic temperatures via the observation of efficient microwave-optical photon conversion. This hybrid interface makes a substantial step towards quantum communication at large scale, as well as novel explorations in microwave-optical photon entanglement and quantum sensing mediated by gigahertz phonons.
Superconducting cavity electro-optics presents a promising route to coherently convert microwave and optical photons and distribute quantum entanglement between superconducting circuits over ...long-distance. Strong Pockels nonlinearity and high-performance optical cavity are the prerequisites for high conversion efficiency. Thin-film lithium niobate (TFLN) offers these desired characteristics. Despite significant recent progresses, only unidirectional conversion with efficiencies on the order of 10
has been realized. In this article, we demonstrate the bidirectional electro-optic conversion in TFLN-superconductor hybrid system, with conversion efficiency improved by more than three orders of magnitude. Our air-clad device architecture boosts the sustainable intracavity pump power at cryogenic temperatures by suppressing the prominent photorefractive effect that limits cryogenic performance of TFLN, and reaches an efficiency of 1.02% (internal efficiency of 15.2%). This work firmly establishes the TFLN-superconductor hybrid EO system as a highly competitive transduction platform for future quantum network applications.
Single-photon counters are single-pixel binary devices that click upon the absorption of a photon but obscure its spectral information, whereas resolving the color of detected photons has been in ...critical demand for frontier astronomical observation, spectroscopic imaging and wavelength division multiplexed quantum communications. Current implementations of single-photon spectrometers either consist of bulky wavelength-scanning components or have limited detection channels, preventing parallel detection of broadband single photons with high spectral resolutions. Here, we present the first broadband chip-scale single-photon spectrometer covering both visible and infrared wavebands spanning from 600 nm to 2000 nm. The spectrometer integrates an on-chip dispersive echelle grating with a single-element propagating superconducting nanowire detector of ultraslow-velocity for mapping the dispersed photons with high spatial resolutions. The demonstrated on-chip single-photon spectrometer features small device footprint, high robustness with no moving parts and meanwhile offers more than 200 equivalent wavelength detection channels with further scalability.
Breast cancer (BC) continues to plague millions of people worldwide. MicroRNAs have been observed to be closely associated with many cancers and may serve as promising biomarkers for the diagnosis of ...BC. BC tissue samples were collected from 26 patients, and qRT-PCR and western blotting were performed to evaluate the levels of miR-543 and VCAN. The action of miR-543 and VCAN was determined using CCK-8, BrdU, wound healing, and transwell invasion assays. Luciferase and RNA pull-down assays were used to assess whether miR-543 bound to VCAN. We found that miR-543 inhibited BC cell viability, proliferation, migration, and invasion by repressing the expression of VCAN. VCAN was upregulated in BC tissues and exerted beneficial effects on the development process of BC. Our results highlighted that the miR-543/VCAN axis is a promising diagnostic and prognostic biomarker in clinical applications.
•MiR-543 and VCAN can be key players in BC.•MiR-543 suppressed BC cell malignancy.•VCAN was a target gene of miR-543.•The low expression of VCAN blocked BC cell malignancy caused by miR-543 inhibitor.
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