ACE2 Receptor-Targeted Inhaled Nanoemulsions Inhibit SARS-CoV-2 and Attenuate Inflammatory Responses.

Three kinds of coronaviruses are highly pathogenic to humans, and two of them mainly infect humans through Angiotensin-converting enzyme 2 （ACE2）receptors. Therefore, specifically blocking ACE2 binding at the interface with the receptor-binding domain is promising to achieve both preventive and therapeutic effects of coronaviruses. Alternatively, drug-targeted delivery based on ACE2 receptors can further improve the efficacy and safety of inhalation drugs. Here, these two approaches are innovatively combined by designing a nanoemulsion (NE) drug delivery system (termed NE-AYQ) for inhalation that targets binding to ACE2 receptors. This inhalation-delivered remdesivir nanoemulsion (termed RDSV-NE-AYQ) effectively inhibits the infection of target cells by both wild-type and mutant viruses. The RDSV-NE-AYQ strongly inhibits Severe acute respiratory syndrome coronavirus 2 at two dimensions: they not only block the binding of the virus to host cells at the cell surface but also restrict virus replication intracellularly. Furthermore, in the mouse model of acute lung injury, the inhaled drug delivery system loaded with anti-inflammatory drugs (TPCA-1-NE-AYQ) can significantly alleviate the lung tissue injury of mice. This smart combination provides a new choice for dealing with possible emergencies in the future and for the rapid development of inhaled drugs for the treatment of respiratory diseases.

Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation.

In recent years, live-cell-based drug delivery systems have gained considerable attention. However, shear stress, which accompanies blood flow, may cause cell death and weaken the delivery performance. In this study, we found that reducing cholesterol in macrophage plasma membranes enhanced their tumor targeting ability by more than 2-fold. Our study demonstrates that the reduced cholesterol level deactivated the mammalian target of rapamycin (mTOR) and consequently promoted the nuclear translocation of transcription factor EB (TFEB), which in turn enhanced the expression of superoxide dismutase (SOD) to reduce reactive oxygen species (ROS) induced by shear stress. A proof-of-concept system using low cholesterol macrophages attached to MXene (e.g., l-RX) was fabricated. In a melanoma mouse model, l-RX and laser irradiation treatments eliminated tumors with no recurrences observed in mice. Therefore, cholesterol reduction is a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.

Pushing Optical Virus Detection to a Single Particle through a High-Q Quasi-bound State in the Continuum in an All-dielectric Metasurface.

Bound states in the continuum (BICs) have emerged as a powerful platform for boosting light-matter interactions because they provide an alternative way of realizing optical resonances with ultrahigh quality factors, accompanied by extreme field confinement. In this work, we realized an optical biosensor by harnessing a quasi-BIC (qBIC) supported by an all-dielectric metasurface with broken symmetry, whose unit cell is composed of a silicon cuboid with two asymmetric air holes. Thanks to the excellent field confinement within the air gap of a metasurface enabled by such a high-Q qBIC, the figure of merit (FOM) of the biosensor is up to 2136.35 RIU-1. Futhermore, we demonstrated that such a high-Q metasurface can push the detection limit to a few virus particles. Our results may find exciting applications in extreme biochemical sensing like COVID-19 with ultralow concentrations.

The impact of antiplatelet therapy on the descending thoracic aorta fate and long-term prognosis of extensive repaired type A aortic dissection.

OBJECTIVES: To evaluate the impact of antiplatelet therapy on the long-term descending thoracic aorta (DTA) fate and prognosis of extensive repaired type A aortic dissection (TAAD). METHODS: 1147 eligible TAAD patients from January 2010 to December 2019 were stratified into non-antiplatelet (n = 754) and antiplatelet groups (n = 393). The primary end points were overall survival, and DTA remodelling, including false lumen (FL) thrombosis and aortic redilation. The secondary end points were DTA reintervention or rupture and major bleeding events (MBEs). RESULTS: The 5-year overall survival rates were 95.6% and 94.3% in the non-antiplatelet and antiplatelet groups (P = 0.53), respectively. In the stent covering segment, the 1-year FL complete thrombosis rates were 92.1% and 92.4% in the non-antiplatelet and antiplatelet groups (P = 0.27), respectively, while in the stent uncovering segment, the 5-year FL complete thrombosis rates were 47.1% and 56.5% in the non-antiplatelet and antiplatelet groups (P = 0.12), respectively. Antiplatelet therapy was not an independent predictor of aortic redilation at the pulmonary artery bifurcation (ß±SE = -0.128 ± 0.203, P = 0.53), diaphragm (ß±SE = 0.143 ± 0.152, P = 0.35) or coeliac artery (ß±SE = 0.049 ± 0.136, P = 0.72) levels. With death as a competing risk, the cumulative incidences of DTA reintervention or rupture at 5 years were 4.6% and 4.0% in the non-antiplatelet and antiplatelet groups (sHR = 0.85, 95% CI, 0.49∼1.19; P = 0.58), respectively, and the 5-year cumulative incidences of MBEs were 2.1% and 2.3% in the non-antiplatelet and antiplatelet groups (sHR = 0.82, 95% CI, 0.56∼2.67; P = 0.62), respectively. CONCLUSIONS: Antiplatelet therapy did not impact long-term DTA FL thrombosis, redilation, reintervention or rupture, MBEs or overall survival on extensive repaired TAAD. Thus, antiplatelet therapy can be administered as indicated on extensive repaired TAAD.

A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Comparison of Safety and Effectiveness of Local or General Anesthesia after Transcatheter Aortic Valve Implantation: A Systematic Review and Meta-Analysis.

It remains controversial to choose anesthesia for transcatheter aortic valve implantation (TAVI). A meta-analysis of cohort studies was conducted to assess the efficacy and safety of local anesthesia (LA) compared to general anesthesia (GA) in TAVI. All relevant studies published from 1 January 2002, to 31 June 2022, were searched in Ovid, PubMed, Embase, Web of Science, and Cochrane Library. A total of 34 studies involving 23,480 patients were included in the meta-analysis. TAVI with LA was associated with a significant reduction in hospital stay [WMD = −2.48, 95% CI (−2.80, −2.16), p < 0.00001], operative [WMD = −12.25, 95% CI (−13.73, −10.78), p < 0.00001] and fluoroscopy time [WMD = −3.30, 95% CI (−5.40, −1.19), p = 0.002], and an increased risk of acute kidney injury [OR = 1.31, 95% CI (1.01, 1.69), p = 0.04] and a reduced incidence of major bleeding [OR = 0.59, 95% CI (0.46, 0.75), p < 0.0001] and the use of cardiovascular drugs [OR = 0.17, 95% CI (0.05, 0.57), p = 0.004]. No differences were found between LA and GA for 30-day mortality, procedural success rate, myocardial infarction, permanent pacemaker implantation, paravalvular leak, shock, and cerebrovascular events. Overall, 4.4% of LA converted to GA. Based on current evidence, our results suggested that LA strategies reduced hospital stay, operative time, fluoroscopy time, cardiovascular drug consumption, and major bleeding rates in patients undergoing TAVI but led to increased acute kidney injury rates. Further studies and randomized trials are required to verify the presented findings and to identify patients who might benefit from LA.

Dietary taurine effect on intestinal barrier function, colonic microbiota and metabolites in weanling piglets induced by LPS.

Diarrhea in piglets is one of the most important diseases and a significant cause of death in piglets. Preliminary studies have confirmed that taurine reduces the rate and index of diarrhea in piglets induced by LPS. However, there is still a lack of relevant information on the specific target and mechanism of action of taurine. Therefore, we investigated the effects of taurine on the growth and barrier functions of the intestine, microbiota composition, and metabolite composition of piglets induced by LPS. Eighteen male weaned piglets were randomly divided into the CON group (basal diet + standard saline injection), LPS group (basal diet + LPS-intraperitoneal injection), and TAU + LPS group (basal diet + 0.3% taurine + LPS-intraperitoneal injection). The results show that taurine significantly increased the ADG and decreased the F/G (p < 0.05) compared with the group of CON. The group of TAU + LPS significantly improved colonic villous damage (p < 0.05). The expression of ZO-1, Occludin and Claudin-1 genes and proteins were markedly up-regulated (p < 0.05). Based on 16s rRNA sequencing analysis, the relative abundance of Lactobacilluscae and Firmicutes in the colon was significantly higher in the LPS + TAU group compared to the LPS group (p < 0.05). Four metabolites were significantly higher and one metabolite was significantly lower in the TAU + LPS group compared to the LPS group (p < 0.01). The above results show that LPS disrupts intestinal microorganisms and metabolites in weaned piglets and affects intestinal barrier function. Preventive addition of taurine enhances beneficial microbiota, modulates intestinal metabolites, and strengthens the intestinal mechanical barrier. Therefore, taurine can be used as a feed additive to prevent intestinal damage by regulating intestinal microorganisms and metabolites.

Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response.

Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown. In this study, we used an Hsp22 knockout (KO) mouse model to determine whether loss of Hsp22 impairs cardiac growth and function with increasing age under physiological conditions. Cardiac structural and functional alterations at baseline were measured using echocardiography and invasive catheterization in Hsp22 KO mice during aging transition compared to their age-matched wild-type (WT) littermates. Our results showed that Hsp22 deletion induced progressive cardiac dilation along with declined function during the aging transition. Mechanistically, the loss of Hsp22 impaired BCL-2-associated athanogene 3 (BAG3) expression and its associated cardiac autophagy, undermined cardiac energy metabolism homeostasis and increased oxidative damage. This study showed that Hsp22 played an essential role in the non-stressed heart during the early stage of aging, which may bring new insight into understanding the pathogenesis of age-related dilated cardiomyopathy.

Cardiomyocyte PKA Ablation Enhances Basal Contractility While Eliminates Cardiac ß-Adrenergic Response Without Adverse Effects on the Heart.

RATIONALE: PKA (Protein Kinase A) is a major mediator of ß-AR (ß-adrenergic) regulation of cardiac function, but other mediators have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, how complete loss of PKA activity impacts on cardiac physiology and if it causes cardiac dysfunction have never been determined. OBJECTIVES: We set to determine how the heart adapts to the loss of cardiomyocyte PKA activity and if it elicits cardiac abnormalities. METHODS AND RESULTS: (1) Cardiac PKA activity was almost completely inhibited by expressing a PKA inhibitor peptide in cardiomyocytes (cPKAi) in mice; (2) cPKAi reduced basal phosphorylation of 2 myofilament proteins (TnI [troponin I] and cardiac myosin binding protein C), and one longitudinal SR (sarcoplasmic reticulum) protein (PLB [phospholamban]) but not of the sarcolemmal proteins (Cav1.2 α1c and PLM [phospholemman]), dyadic protein RyR2, and nuclear protein CREB (cAMP response element binding protein) at their PKA phosphorylation sites; (3) cPKAi increased the expression of CaMKII (Ca2+/calmodulin-dependent kinase II), the Cav1.2 ß subunits and current, but decreased CaMKII phosphorylation and CaMKII-mediated phosphorylation of PLB and RyR2; (4) These changes resulted in significantly enhanced myofilament Ca2+ sensitivity, prolonged contraction, slowed relaxation but increased myocyte Ca2+ transient and contraction amplitudes; (5) Isoproterenol-induced PKA and CaMKII activation and their phosphorylation of proteins were prevented by cPKAi; (6) cPKAi abolished the increases of heart rate, and cardiac and myocyte contractility by a ß-AR agonist (isoproterenol), showing an important role of PKA and a minimal role of PKA-independent ß-AR signaling in acute cardiac regulation; (7) cPKAi mice have partial exercise capability probably by enhancing vascular constriction and ventricular filling during ß-AR stimulation; and (8) cPKAi mice did not show any cardiac functional or structural abnormalities during the 1-year study period. CONCLUSIONS: PKA activity suppression induces a unique Ca2+ handling phenotype, eliminates ß-AR regulation of heart rates and cardiac contractility but does not cause cardiac abnormalities.

Effect of Multi-Pass Ultrasonic Surface Rolling on the Mechanical and Fatigue Properties of HIP Ti-6Al-4V Alloy.

The main purpose of this paper was to investigate the effect of a surface plastic deformation layer introduced by multi-pass ultrasonic surface rolling (MUSR) on the mechanical and fatigue properties of HIP Ti-6Al-4V alloys. Some microscopic analysis methods (SEM, TEM and XRD) were used to characterize the modified microstructure in the material surface layer. The results indicated that the material surface layer experienced a certain extent plastic deformation, accompanied by some dense dislocations and twin generation. Moreover, surface microhardness, residual stress and roughness values of samples treated by MUSR were also greatly improved compared with that of untreated samples. Surface microhardness and compressive residual stress were increased to 435 HV and -1173 MPa, respectively. The minimum surface roughness was reduced to 0.13 µm. The maximum depth of the surface hardening layer was about 55 µm. However, the practical influence depth was about 450 µm judging from the tensile and fatigue fracture surfaces. The ultimate tensile strength of the MUSR-treated sample increased to 990 MPa from the initial 963 MPa. The fatigue strength of the MUSR-treated sample was increased by about 25% on the base of 107 cycles, and the lifetime was prolonged from two times to two orders of magnitude at the applied stress amplitudes of 650-560 MPa. The improved mechanical and fatigue properties of MUSR-treated samples should be attributed to the combined effects of the increased microhardness and compressive residual stress, low surface roughness, grain refinement and micro-pore healing in the material surface-modified layer.