Coconstruction of Supramolecular Lithium-Conducting Cross-Linked Networks Based on PVDF and Triblock Polymer Nanomicrosphere Solid-State Polymer Electrolytes for Lithium-Metal Batteries.

Uneven lithium plating and low ionic conductivity currently impede the realization of high-capacity rechargeable lithium metal batteries. And the conventional poly(ethylene oxide) (PEO) solid-state electrolytes are unsuitable for high-energy-density Li anode applications due to their low lithium-ion transference number and high reactivity with Li metal, leading to detrimental dendrite formation and potentially hazardous exothermic reactions with the electrolyte. In this study, we employ a supramolecular approach to develop a novel polymer solid-state electrolyte based on poly(vinylidene fluoride) (PVDF) and a novel triblock polymer nanomicrosphere, (poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone), (PCL-PEG-PCL). The abundance of carbonyl and ether-oxygen functional groups in PCL-PEG-PCL enhances the lithium coordination environment within the polymer solid-state electrolyte. Additionally, the original C-F moieties of PVDF form hydrogen bonds with C-H and terminal hydroxyl groups in PCL-PEG-PCL, collectively creating a multichannel fast Li+-conducting supramolecular cross-linked network. The resulting electrolyte demonstrates a high ionic conductivity of 1.4 × 10-3 S cm-1 and an extended electrochemical window of 5.2 V. Moreover, the electrolyte exhibits a high lithium-ion transference number (tLi+ = 0.63) at room temperature and exhibits excellent interfacial compatibility with the lithium metal anode. For the resulting electrolyte utilized in LiFePO4 batteries, the capacity retention of the cells assembled with this electrolyte exceeds 91.3% after 1000 cycles at 25 °C and 2 C (0.281 mA cm-2).

Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance ß-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

Carnosol attenuates angiotensin II-induced cardiac remodeling and inflammation via directly binding to p38 and inhibiting p38 activation.

Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.

Epsilon-poly-l-lysine microneedle patch loaded with amorphous doxycycline nanoparticles for synergistic treatment of skin infection.

The development of antibiotic-loaded microneedles has been hindered for years by limited excipient options, restricted drug-loading space, poor microneedle formability, and short-term drug retention. Therefore, this study proposes a dissolving microneedle fabricated from the host-defense peptide ε-poly-l-lysine (EPL) as an antibacterial adjuvant system for delivering antibiotics. EPL serves not only as a major matrix material for the microneedle tips, but also as a broad-spectrum antibacterial agent that facilitates the intracellular accumulation of the antibiotic doxycycline (DOX) by increasing bacterial cell membrane permeability. Furthermore, the formation of physically crosslinked networks of EPL affords microneedle tips with improved formability, good mechanical properties, and amorphous nanoparticles (approximately 7.2 nm) of encapsulated DOX. As a result, a high total loading content of both antimicrobials up to 2319.1 µg/patch is achieved for efficient transdermal drug delivery. In a Pseudomonas aeruginosa-induced deep cutaneous infection model, the EPL microneedles demonstrates potent and long-term effects by synergistically enhancing antibiotic activities and prolonging drug retention in infected lesions, resulting in remarkable therapeutic efficacy with 99.91 % (3.04 log) reduction in skin bacterial burden after a single administration. Overall, our study highlights the distinct advantages of EPL microneedles and their potential in clinical antibacterial practice when loaded with amorphous DOX nanoparticles.

Metagenomic insights into protein degradation mechanisms in natural fermentation of cassava leaves.

Cassava (Manihot esculenta Crantz) leaves, the primary by-product of cassava processing, constitute a significant protein source, accounting for 18 to 38 percent on a dry weight basis. Despite their nutritional value, a substantial portion of these leaves is often discarded post-harvest, resulting in notable resource waste. This study employs metagenomic technology to investigate the protein degradation mechanism in cassava leaves, aiming to provide a technical reference for value-added of this by-product. Following a 36-hour period of natural fermentation, the protein degradation rate reached 58%, a phenomenon intricately linked to both the microbial community structure and its functional properties. Notably, Lactococcus and Enterobacter, recognized for their abundant protease activity, were predominant. Metagenomically assembled genomes further revealed Lactococcus's substantial role in producing flavors and active compounds, including amino acids and peptides. This study offers novel perspectives to the foodization and high-value utilization of cassava by-products, emphasizing the sustainable exploitation of biomass resources.

Deubiquitinase OTUD6a drives cardiac inflammation and hypertrophy by deubiquitination of STING.

BACKGROUND: Cardiac hypertrophy is a crucial pathological characteristic of hypertensive heart disease and subsequent heart failure. Deubiquitinating enzymes (DUBs) have been found to be involved in the regulation of myocardial hypertrophy. OTU Domain-Containing Protein 6a (OTUD6a) is a recently identified DUB. To date, the potential role of OTUD6a in myocardial hypertrophy has not yet been revealed. METHODS AND RESULTS: We examined the up-regulated level of OTUD6a in mouse or human hypertrophic heart tissues. Then, transverse aortic constriction (TAC)- or angiotensin II (Ang II)- induced ventricular hypertrophy and dysfunction were significantly attenuated in OTUD6a gene knockout mice (OTUD6a-/-). In mechanism, we identified that the Stimulator of Interferon Genes (STING) is a direct substrate protein of OTUD6a via immunoprecipitation assay and mass spectrometry. OTUD6a maintains STING stability via clearing the K48-linked ubiquitin in cardiomyocytes. Subsequently, OTUD6a regulates the STING-downstream NF-κB signaling activation and inflammatory gene expression both in vivo and in vitro. Inhibition of STING blocked OTUD6a overexpression-induced inflammatory and hypertrophic responses in cardiomyocytes. CONCLUSION: This finding extends our understanding of the detrimental role of OTUD6a in myocardial hypertrophy and identifies STING as a deubiquinating substrate of OTUD6a, indicating that targeting OTUD6a could be a potential strategy for the treatment of cardiac hypertrophy.

Macrophage-derived GSDMD promotes abdominal aortic aneurysm and aortic smooth muscle cells pyroptosis.

Macrophage is a vital factor in determining the fate of abdominal aortic aneurysm (AAA). The crosstalk between macrophage and other cells plays a crucial role in the development of aneurysm. Gasdermin D (GSDMD) is a vital executive protein of pyroptosis, which is a novel programmed cell death associated with inflammation. In this study, we identified aortic macrophage as the main expressing cell of GSDMD in AAA. Using Gsdmd-/-ApoE-/- mouse and AAV-F4/80-shGSDMD, we demonstrated the potential role of macrophage-derived GSDMD in AAA and aortic pyroptosis induced by Ang II in vivo. In vitro experiments showed that GSDMD promotes the pyroptosis of mouse primary peritoneal macrophages (MPMs), murine aortic vascular smooth muscle cells (MOVAS) and primary smooth muscle cells. Mechanistically, a mouse cytokine antibody array showed that Gsdmd-/- inhibited LPS + nigericin (LN)- induced secretion of multiple cytokines from MPMs. Furthermore, GSDMD is involved in the crosstalk between MPMs and MOVAS via cytokine secretion. This study provides a novel fundamental insight into macrophage-derived GSDMD in AAA and showed that GSDMD could be a promising therapeutic target for AAA.

Advances in device-based treatment of heart failure with preserved ejection fraction: evidence from clinical trials.

Heart failure with preserved ejection fraction (HFpEF) is a group of clinical syndromes that exhibit a remarkably heterogeneous phenotype, characterized by symptoms and signs of heart failure, left ventricular diastolic dysfunction, elevated levels of natriuretic peptides, and an ejection fraction greater than or equal to 50%. With the aging of the population and the escalating prevalence of hypertension, obesity, and diabetes, the incidence of HFpEF is progressively rising. Drug therapy options for HFpEF are currently limited, and the associated high risk of cardiovascular mortality and heart failure rehospitalization significantly impact patients' quality of life and longevity while imposing a substantial economic burden on society. Recent research indicates that certain device-based therapies may serve as valuable adjuncts to drug therapy in patients with specific phenotypes of HFpEF, effectively improving symptoms and quality of life while reducing the risk of readmission for heart failure. These include inter-atrial shunt and greater splanchnic nerve ablation to reduce left ventricular filling pressure, implantable heart failure monitor to guide diuresis, left atrial pacing to correct interatrial dyssynchrony, cardiac contractility modulation to enhance cardiac calcium handling, as well as renal denervation, baroreflex activation therapy, and vagus nerve stimulation to restore the autonomic imbalance. In this review, we provide a comprehensive overview of the mechanisms and clinical evidence pertaining to these devices, with the aim of enhancing therapeutic strategies for HFpEF.

Cardiovascular health and life expectancy with and without cardiovascular disease in the middle-aged and elderly Chinese population.

BACKGROUND: High cardiovascular health (CVH) was associated with lower risk of cardiovascular disease (CVD) and longer life expectancy. However, whether life years lived without CVD could increase faster than or at least at the same pace as total lifespan remains unknown. We aimed to explore the associations of CVH status with total life expectancy and life years lived with and without CVD among middle-aged and elderly men and women. METHODS: We included 65,587 participants aged ≥ 45 years from Kailuan study, who were recruited during June 2006 to October 2007. CVH was scored and classified (low [0-49 points], moderate [50-79 points] and high [80-100 points]) with Life's Essential 8, incorporating evaluations of health behaviors and factors. All-cause mortality and incident non-fatal CVD were recorded from baseline to December 31, 2020. The multi-state life table was adopted to explore the associations of CVH status with total life expectancy and life years lived with and without CVD. RESULTS: Six thousand fifty eight cases of incident non-fatal CVD and 10,580 cases of deaths were identified. Men aged 45 years with low, moderate, and high CVH had a life expectancy of 33.0, 36.5 and 38.5 years, of which 7.8 (23.6%), 6.0 (16.3%) and 3.7 years (9.6%) were spent with CVD. For women, the corresponding life expectancy was 36.6, 43.6 and 48.6 years, and the remaining life years lived with CVD were 7.8 (21.3%), 6.0 (13.7%) and 4.5 years (9.3%), respectively. The benefits of high CVH were persistent across lifespan from age 45 to 85 years and consistent when CVH was evaluated with health behaviors and factors alone. CONCLUSIONS: High CVH compared with low CVH was associated with longer total life expectancy and fewer years spent with CVD, indicating that promoting CVH is of great importance for CVD prevention and healthy ageing in China.

Intelligent Optimization Design of a Phononic Crystal Air-Coupled Ultrasound Transducer.

To further improve the operational performance of a phononic crystal air-coupled ultrasonic transducer while reducing the number of simulations, an intelligent optimization design strategy is proposed by combining finite element simulation analysis and artificial intelligence (AI) methods. In the proposed strategy, the structural design parameters of 1-3 piezoelectric composites and acoustic impedance gradient matching layer are sampled using the optimal Latin hypercube sampling (OLHS) method. Moreover, the COMSOL software is utilized to calculate the performance parameters of the transducer. Based on the simulation data, a radial basis function neural network (RBFNN) model is trained to establish the relationship between the design parameters and the performance parameters. The accuracy of the approximation model is verified through linear regression plots and statistical methods. Finally, the NSGA-II algorithm is used to determine the design parameters of the transducer. After optimization, the band gap widths of the piezoelectric composites and acoustic impedance gradient matching layer are increased by 16 kHz and 13.5 kHz, respectively. Additionally, the -6 dB bandwidth of the transducer is expanded by 11.5%. The simulation results and experimental results are consistent with the design objectives, which confirms the effectiveness of the design strategy. This work provides a feasible strategy for the design of high-performance air-coupled ultrasonic transducers, which is of great significance for the development of non-destructive testing technology.

Association of the time course of Chinese visceral adiposity index accumulation with cardiovascular events in patients with hypertension.

BACKGROUND: The Chinese visceral adiposity index (CVAI), a simple surrogate measure of visceral fat, is significantly associated with cardiovascular disease (CVD) risk in the general population. This study aimed to evaluate the association of cumulative CVAI (cumCVAI) exposure and its accumulation time course with CVD risk among patients with hypertension. METHODS: This prospective study involved 15,350 patients with hypertension from the Kailuan Study who were evaluated at least three times in the observation period of 2006 to 2014 (2006-2007, 2010-2011, and 2014-2015) and who were free of myocardial infarction and stroke before 2014. The cumCVAI was calculated as the weighted sum of the mean CVAI for each time interval (value × time). The time course of CVAI accumulation was categorized by splitting the overall accumulation into early (cumCVAI06 - 10) and late (cumCVAI10 - 14) accumulation, or the slope of CVAI versus time from 2006 to 2014 into positive and negative. RESULTS: During the 6.59-year follow-up period, 1,184 new-onset CVD events were recorded. After adjusting for confounding variables, the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD were 1.35 (1.13-1.61) in the highest quartile of cumCVAI, 1.35 (1.14-1.61) in the highest quartile of the time-weighted average CVAI, 1.26 (1.12-1.43) in those with a cumulative burden > 0, and 1.43 (1.14-1.78) for the group with a 10-year exposure duration. When considering the time course of CVAI accumulation, the HR (95% CI) for CVD was 1.33 (1.11-1.59) for early cumCVAI. When considering the combined effect of cumCVAI accumulation and its time course, the HR (95% CI) for CVD was 1.22 (1.03-1.46) for cumCVAI ≥ median with a positive slope. CONCLUSIONS: In this study, incident CVD risk depended on both long-term high cumCVAI exposure and the duration of high CVAI exposure among patients with hypertension. Early CVAI accumulation resulted in a greater risk increase than later CVAI accumulation, emphasizing the importance of optimal CVAI control in early life.

Association of Cardiovascular Health Assessed by the New Life's Essential 8 Metrics With Years Lived Without Cardiovascular Disease.

Background The American Heart Association recently proposed an updated definition of cardiovascular health (CVH) named as Life's Essential 8. We aimed to explore the association between this latest published CVH measurement and years lived without cardiovascular disease (CVD) among the Chinese population. Methods and Results We included 89 755 adults free of CVD at baseline from the Kailuan study. The CVH of each participant was scored (from 0 point to 100 points) and classified (low [0-49 points], moderate [50-79 points], and high [80-100 points]) according to Life's Essential 8, which incorporated 8 components covering health behaviors and health factors. Incident CVD was documented through follow-ups from baseline (June 2006 to October 2007) until December 31, 2020. CVD-free life years from age 30 to 80 years associated with different CVH scores were estimated using flexible parametric survival models. A total of 9977 incident CVDs were recorded. We observed a gradient relationship between CVH score and years lived without CVD. The age- and sex-adjusted CVD-free life years (95% CI) were 40.7 (40.3-41.0) years for low CVH, 43.3 (43.0-43.5) years for moderate CVH, and 45.5 (45.1-45.9) years for high CVH. Similar trends were noted when individual subtypes of CVD were investigated, and high CVH evaluated by health behaviors and health factors was also related to longer CVD-free life years. Conclusions A higher CVH evaluated by the updated Life's Essential 8 metrics was significantly associated with a greater number of life years without CVD, indicating the importance of promoting CVH for healthy aging in China.

Tussilagone attenuates atherosclerosis through inhibiting MAPKs-mediated inflammation in macrophages.

Atherosclerosis is a common chronic inflammatory disease. Recent studies have highlighted the key role of macrophages and inflammation in process of atherosclerotic lesion formation. A natural product, tussilagone (TUS), has previously exhibited anti-inflammatory activities in other diseases. In this study, we explored the potential effects and mechanisms of TUS on the inflammatory atherosclerosis. Atherosclerosis was induced in ApoE-/- mice by feeding them with a high-fat diet (HFD) for 8 weeks, followed by administration of TUS (10, 20 mg ·kg-1·d-1, i.g.) for 8 weeks. We demonstrated that TUS alleviated inflammatory response and reduced atherosclerotic plaque areas in HFD-fed ApoE-/- mice. Pro-inflammatory factor and adhesion factors were inhibited by TUS treatment. In vitro, TUS suppressed foam cell formation and oxLDL-induced inflammatory response in MPMs. RNA-sequencing analysis indicated that MAPK pathway was related to the anti-inflammation and anti-atherosclerosis effects of TUS. We further confirmed that TUS inhibited MAPKs phosphorylation in plaque lesion of aortas and cultured macrophages. MAPK inhibition blocked oxLDL-induced inflammatory response and prevented the innately pharmacological effects of TUS. Our findings present a mechanistic explanation for the pharmacological effect of TUS against atherosclerosis and indicate TUS as a potentially therapeutic candidate for atherosclerosis.

Macrophage DCLK1 promotes atherosclerosis via binding to IKKß and inducing inflammatory responses.

Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE-/- mice fed an HFD and determined that macrophage-specific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC-MS/MS analysis identified IKKß as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKß and phosphorylates IKKß at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKß and activating IKKß/NF-κB. This study reports DCLK1 as a new IKKß regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.

The effect of adverse pregnancy outcomes on vascular aging in young women: the Kailuan study.

Adverse pregnancy outcomes (APOs) are at increased future cardiovascular risk and require effective risk mitigation. However, data regarding appropriate postpartum screening for young women with APOs are lacking. We aimed to investigate the association between APOs and vascular aging by the determination of high pulse wave velocity (PWV) in young women. Women who gave birth from 1990 to 2020 and underwent brachial-ankle pulse wave velocity (baPWV) assessments in the postpartum period were recruited. We excluded women with age ≥50 years at the baPWV assessment or missing postpartum health examinations. The history of APOs including hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and low birth weight were assessed by medical records. High PWV was defined as baPWV above the 90th percentile for different age group. Multivariable Logistic regression was used to evaluate the association of APOs and high PWV. 3193 participants were included in the analysis, including 912 (28.6%) individuals with APOs. The prevalence of high PWV in the non-APO group and the APOs group were 7.19% (164) and 13.9% (127), respectively (P < 0.05). Compared with non-APO group, the OR (95% CI) of APOs group was 1.67 (1.29-2.16). The risks in the 20-29, 30-39, and 40-49 age groups were 2.51 (1.13-5.59), 1.83 (1.30-2.59), and 1.35 (0.82-2.21) (P for trend <0.05). We conclude that APOs are risk factors of vascular aging for young women and the risk decreased with increasing age. BaPWV should be an important indicator for preventive cardiovascular risk management in young women with APOs. Clinical trial registration: Registration number ChiCTR-TNRC-11001489, http://www.chictr.org.cn/showproj.aspx?proj=8050 .

Cloud-native-based flexible value generation mechanism of public health platform using machine learning.

Public health machinery learning platform based on cloud-native is a system platform that combines machine learning frameworks and cloud-native technology for public health services. The problem of how its flexible value is realized has been widely concerned by all public health network intelligent researchers. Thus, this article examines the relationship between cloud-native architecture flexibility and cloud provider value and the processes and the boundary condition by which cloud-native architecture flexibility affects cloud provider value based on innovation theory and dynamic capability theory. The results of a survey of 509 platform-related respondents in China show that cloud-native architecture flexibility is positively related to cloud provider value, and both absorptive capacity and supply chain agility mediate the above-mentioned effect. Moreover, R&D subsidies strengthen both the positive relationship between absorptive capacity and cloud provider value and the relationship between supply chain agility and cloud provider value. In this study, cloud-native architecture flexibility, unit absorptive capacity, supply chain agility and R&D subsidies are considered into a flexible value generation mechanism model that extend the relevant research on the value generation mechanism of information system under the background of network intelligence, and to provide relevant enterprises with suggestions on upgrade strategies.

A Glycolipid α-GalCer Derivative, 7DW8-5 as a Novel Mucosal Adjuvant for the Split Inactivated Influenza Vaccine.

Influenza virus infects the host and transmits through the respiratory tract (i.e., the mouth and nose); therefore, the development of intranasal influenza vaccines that mimic the natural infection, coupled with an efficient mucosal adjuvant, is an attractive alternative to current parenteral vaccines. However, with the withdrawal of cholera toxin and Escherichia coli heat-labile endotoxin from clinical use due to side effects, there are no approved adjuvants for intranasal vaccines. Therefore, safe and effective mucosal adjuvants are urgently needed. Previously, we reported that one derivative of α-Galactosylceramide (α-GalCer), 7DW8-5, could enhance the protective efficacy of split influenza vaccine by injection administration. However, the mucosal adjuvanticity of 7DW8-5 is still unclear. In this study, we found that 7DW8-5 promotes the production of secret IgA antibodies and IgG antibodies and enhances the protective efficacy of the split influenza vaccine by intranasal administration. Furthermore, co-administration of 7DW8-5 with the split influenza vaccine significantly reduces the virus shedding in the upper and lower respiratory tract after lethal challenge. Our results demonstrate that 7DW8-5 is a novel mucosal adjuvant for the split influenza vaccine.

Guanidinium-rich lipopeptide functionalized bacteria-absorbing sponge as an effective trap-and-kill system for the elimination of focal bacterial infection.

Focal bacterial infections are often difficult to treat due to the rapid emergence of antibiotic-resistant bacteria, high risk of relapse, and severe inflammation at local lesions. To address multidrug-resistant skin and soft tissue infections, a bacteria-absorbing sponge was prepared to involve a "trap-and-kill" mechanism. The system describes a guanidinium-rich lipopeptide functionalized lyotropic liquid-crystalline hydrogel with bicontinuous cubic networks. Amphiphilic lipopeptides can be spontaneously anchored to the lipid-water interface, exposing their bacterial targeting sequences to enhance antibacterial trapping/killing activity. Computational simulations supported our structural predictions, and the sponge was confirmed to successfully remove ∼98.8% of the bacteria in the medium. Release and degradation behavior studies indicated that the bacteria-absorbing sponge could degrade, mediate enzyme-responsive lipopeptide release, or generate ∼200 nm lipopeptide nanoparticles with environmental erosion. This implies that the sponge can effectively capture and isolate high concentrations of bacteria at the infected site and then sustainably release antimicrobial lipopeptides into deep tissues for the eradication of residual bacteria. In the animal experiment, we found that the antibacterial performance of the bacterial-absorbing sponge was significant, which demonstrated not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also a unique advantage to protect tissue from bacterial attack. STATEMENT OF SIGNIFICANCE: Host defense peptides/peptidomimetics (HDPs) have shown potential for the elimination of focal bacterial infections, but the application of their topical formulations suffers from time-consuming preparation processes, indistinctive toxicity reduction effects, and inefficient bacterial capture ability. To explore new avenues for the development of easily prepared, low-toxicity and high-efficiency topical antimicrobials, a guanidinium-rich lipopeptide was encapsulated in a lyotropic liquid-crystalline hydrogel (denoted as "bacteria-absorbing sponge") to achieve complementary superiorities. The superior characteristic of the bacteria-absorbing sponge involves a "trap-and-kill" mechanism, which undergoes not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also effective bacterial capture and isolating action to confine bacterial diffusion and protect tissues from bacterial attack.

Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells.

Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.