Unlocking roles of cationic and aromatic residues in peptide amphiphiles in treating drug-resistant gram-positive pathogens.

Multidrug resistance (MDR) is a rising threat to global health because the number of essential antibiotics used for treating MDR infections is increasingly compromised. In this work we report a group of new amphiphilic peptides (AMPs) derived from the well-studied G3 (G(IIKK)3I-NH2) to fight infections from Gram-positive bacteria including susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA), focusing on membrane interactions. Time-dependent killing experiments revealed that substitutions of II by WW (GWK), II by FF (GFK) and KK by RR (GIR) resulted in improved bactericidal efficiencies compared to G3 (GIK) on both S. aureus and MRSA, with the order of GWK > GIR > GFK > GIK. Electronic microscopy imaging revealed structural disruptions of AMP binding to bacterial cell walls. Fluorescence assays including AMP binding to anionic lipoteichoic acids (LTA) in cell-free and cell systems indicated concentration and time-dependent membrane destabilization associated with bacterial killing. Furthermore, AMP's binding to anionic plasma membrane via similar fluorescence assays revealed a different extent of membrane depolarization and leakage. These observations were supported by the penetration of AMPs into the LTA barrier and the subsequent structural compromise to the cytoplasmic membrane as revealed from SANS (small angle neutron scattering). Both experiments and molecular dynamics (MD) simulations revealed that GWK and GIR could make the membrane more rigid but less effective in diffusive efficiency than GIK and GFK through forming intramembrane peptide nanoaggregates associated with hydrophobic mismatch and formation of fluidic and rigid patches. The reported peptide-aggregate-induced phase-separation emerged as a crucial factor in accelerated membrane disintegration and fast bacterial killing. This work has demonstrated the importance of membrane interactions to the development of more effective AMPs and the relevance of the approaches as reported in assisting this area of research.

Laser-induced plasma micromachining on surfaces parallel to the incident laser in different solutions.

Laser-induced plasma micromachining (LIPMM) is an advanced technology that utilizes the plasma generated from laser breakdown to remove material, thereby facilitating the fabrication of microstructures. This paper explores the use of LIPMM on 304 stainless steel surfaces parallel to the laser beam in different solutions, focusing on the impact of the liquid environment on the machining process. It presents a theoretical analysis of the material removal mechanisms unique to this orientation and experimentally investigates how water, a salt solution, and ethanol affect plasma shockwave characteristics. Notably, the plasma shockwave in the salt solution demonstrates the most significant peak pressure and energy, enhancing the micromachining efficiency. These findings suggest that varying the liquid environment can significantly influence LIPMM's effectiveness, offering potential improvements in precision and control. This study broadens the understanding of LIPMM applications, especially in orientations not commonly explored, and opens new possibilities for advanced micromachining techniques in various industrial applications.

Polymicrobial brain abscesses: A complex condition with diagnostic and therapeutic challenges.

Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment.

Design and evaluation of mRNA encoding recombinant neutralizing antibodies for botulinum neurotoxin type B intoxication prophylaxis.

Among all natural and synthetic toxins, botulinum neurotoxins (BoNTs), produced by Clostridium botulinum in an anaerobic environment, are the most toxic polymer proteins. Currently, the most effective modalities for botulism prevention and treatment are vaccination and antitoxin use, respectively. However, these modalities are associated with long response time for active immunization, side effects, and donor limitations. As such, the development of more promising botulism prevention and treatment modalities is warranted. Here, we designed an mRNA encoding B9-hFc - a heavy-chain antibody fused to VHH and human Fc that can neutralize BoNT serotype B (BoNT/B) effectively - and assessed its expression in vitro and in vivo. The results confirmed that our mRNA demonstrates good expression in vitro and in vivo. Moreover, a single mRNA lipid nanoparticle injection effectively prevents BoNT/B intoxication in vivo, with effects comparable to those of protein antibodies. In conclusion, we explored and clarified whether mRNA drugs encoding neutralizing antibodies prevent BoNT/B intoxication. Our results provide an efficient strategy for further research on the prevention and treatment of intoxication by botulinum toxin.

Molecular Evolution of Protein Sequences and Codon Usage in Monkeypox Viruses.

The monkeypox virus (mpox virus, MPXV) epidemic in 2022 has posed a significant public health risk. Yet, the evolutionary principles of MPXV remain largely unknown. Here, we examined the evolutionary patterns of protein sequences and codon usage in MPXV. We first demonstrated the signal of positive selection in OPG027, specifically in the Clade I lineage of MPXV. Subsequently, we discovered accelerated protein sequence evolution over time in the variants responsible for the 2022 outbreak. Furthermore, we showed strong epistasis between amino acid substitutions located in different genes. The codon adaptation index (CAI) analysis revealed that MPXV genes tended to use more non-preferred codons compared to human genes, and the CAI decreased over time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B. While the decrease in fatality rate among the three groups aligned with the CAI pattern, it remains unclear whether this correlation was coincidental or if the deoptimization of codon usage in MPXV led to a reduction in fatality rates. This study sheds new light on the mechanisms that govern the evolution of MPXV in human populations.

Conversion obstacle from Mg-protoporphyrin IX to protochlorophyllide might be responsible for chlorophyll-deficient phenotype of the Huangjinya's albino offspring.

The albino tea cultivar is one of the most important germplasms for key gene mining and high-quality tea producing. In order to elucidate the chlorophyll-deficient mechanism of albino cultivar 'Huangjinya' and its offspring, color difference, photosynthetic pigments and the relevant genes' expression of the tender shoots were comprehensively investigated in this study. Among the tested 16 offspring, 5 exhibited albino phenotype in spring and autumn, 3 showed albino phenotype in spring but normal green in autumn, while the rests were all normal green. The shoot of albino offspring had significantly higher lightness and/or yellowness than that of green ones, and possessed dramatically lower photosynthetic pigments and chlorophyll precursor protochlorophyllide (Pchlide), as well as higher chlorophyll a/chlorophyll b but lower chlorophylls/carotenoids in comparison with green ones. Among the tested genes involved in chlorophyll and carotenoid metabolism pathways, expression of the magnesium protoporphyrin IX monomethyl ester cyclase (CRD), 3,8-divinyl chlorophyllide 8-vinyl reductase (DVR), 5-aminolevulinate dehydratase 1 (HEMB1), 1-deoxy-D-xylulose 5-phosphate synthase 1 (DXS1) and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (ISPH) was remarkably down-regulated in shoots of the albino offspring. Color difference indices of the offspring were significantly correlated with the levels of photosynthetic pigments and Pchlide, and low level of chlorophylls in shoot of albino offspring was mainly due to conversion obstacle from magnesium protoporphyrin Ⅸ (Mg-Proto IX) to Pchlide which might be attributed to down-regulatory expression of CRD and DVR.

An analytic theory for the degree of Arctic Amplification.

Arctic Amplification (AA), the amplified surface warming in the Arctic relative to the globe, is a salient feature of climate change. While the basic physical picture of AA has been depicted, how its degree is determined has not been clearly understood. Here, by deciphering atmospheric heat transport (AHT), we build a two-box energy-balance model of AA and derive that the degree of AA is a simple nonlinear function of the Arctic and global feedbacks, the meridional heterogeneity in radiative forcing, and the partial sensitivities of AHT to global mean and meridional gradient of warming. The formula captures the varying AA in climate models and attributes the spread to models' feedback parameters and AHT physics. The formula clearly illustrates how essential physics mutually determine the degree of AA and limits its range within 1.5-3.5. Our results articulate AHT as both forcing and feedback to AA, highlight its fundamental role in forming a baseline AA that exists even with uniform feedbacks, and underscore its partial sensitivities instead of its total change as key parameters of AA. The lapse-rate feedback has been widely recognized as a major contributor to AA but its effect is fully offset by the water-vapor feedback.

LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.

The skeletal muscle is the largest organ in mammals and is the primary motor function organ of the body. Our previous research has shown that long non-coding RNAs (lncRNAs) are significant in the epigenetic control of skeletal muscle development. Here, we observed progressive upregulation of lncRNA 4930581F22Rik expression during skeletal muscle differentiation. Knockdown of lncRNA 4930581F22Rik hindered skeletal muscle differentiation and resulted in the inhibition of the myogenic markers MyHC and MEF2C. Furthermore, we found that lncRNA 4930581F22Rik regulates myogenesis via the ERK/MAPK signaling pathway, and this effect could be attenuated by the ERK-specific inhibitor PD0325901. Additionally, in vivo mice injury model results revealed that lncRNA 4930581F22Rik is involved in skeletal muscle regeneration. These results establish a theoretical basis for understanding the contribution of lncRNAs in skeletal muscle development and regeneration.

3D-Printed Mullite-Reinforced SiC-Based Aerogel Composites.

There is a growing demand for thermal management materials in electronic fields. Aerogels have attracted interest due to their extremely low density and extraordinary thermal insulation properties. However, the application of aerogels is limited by high production costs and the requirement that aerogel structures not be load-bearing. In this study, mullite-reinforced SiC-based aerogel composite (MR-SiC AC) is prepared through 3D printing combined with in situ growth of SiC nanowires in post processing. The fabricated MR-SiC AC not only has ultra-low thermal conductivity (0.021 W K m-1) and high porosity (90.0%), but also a high Young's modulus (24.4 MPa) and high compressive strength (1.65 MPa), both exceeding the measurements of existing resilient aerogels by an order of magnitude. These properties make MR-SiC AC an ideal solution for the precision thermal management of lightweight structures having complex geometry for functional devices.

Mesenchymal stem cell-derived exosomal miR-26a induces ferroptosis, suppresses hepatic stellate cell activation, and ameliorates liver fibrosis by modulating SLC7A11.

Liver fibrosis is a key contributor to hepatic disease-related mortality. Exosomes derived from mesenchymal stem cells (MSCs) have been revealed to improve liver fibrosis. To explore the effect and mechanism of MSC-derived exosomal miR-26a on liver fibrosis, exosomes were separated from bone marrow-derived MSCs (BMSCs) and used to treat with LX2 cells. The miR-26a level was decreased in BMSC-derived exosomes. Treatment with exosomes isolated from human BMSCs transfected with miR-26a mimics (miR-26a mimic-Exo) decreased the 5-ethynyl-2'-deoxyuridine-positive cell rate, the protein level of α-SMA and collagen I, and the glutathione (GSH) level but enhanced the apoptosis rate and the reactive oxide species (ROS) level in LX2 cells, which were reversed by the treatment of deferoxamine. Mechanically, miR-26a directly bound SLC7A11 mRNA and negatively modulated the level of SLC7A11 in LX2 cells. Overexpression of SLC7A11 reversed the miR-26a mimic-Exo-induced alterations in the level of ROS, Fe2+, malonaldehyde, and GSH in LX2 cells. In vivo, miR-26a mimic-Exo decreased the level of SLC7A11 and attenuated CCL4-induced liver fibrosis. Collectively, miR-26a mimic-Exo induced ferroptosis to alleviate liver fibrosis by regulating SLC7A11, which may provide new strategies for the treatment of liver fibrosis, and even other relevant diseases.

Patients, healthcare providers, and general population preferences for hemodialysis vascular access: a discrete choice experiment.

Background: A patient-centered dialysis treatment option requires an understanding of patient preferences for alternative vascular accesses and nephrologists often face difficulties when recommending vascular access to end-stage kidney disease (ESKD) patients. We aimed to quantify the relative importance of various vascular access characteristics to patients, healthcare providers and general population, and how they affect acceptability for patients and healthcare providers. Methods: In a discrete choice experiment, patients with maintenance hemodialysis (MHD), healthcare providers, and individuals from the general population were invited to respond to a series of hypothetical vascular access scenarios that differed in five attributes: cumulative patency, infection rate, thrombosis rate, cost, and time to maturation. We estimated the respondents' preference heterogeneity and relative importance of the attributes with a mixed logit model (MXL) and predicted the willingness to pay (WTP) of respondents via a multinomial logit model (MNL). Results: Healthcare providers (n = 316) and the general population (n = 268) exhibited a favorable inclination toward longer cumulative patency, lower access infection rate and lower access thrombosis rate. In contrast, the patients (n = 253) showed a preference for a 3-year cumulative patency, 8% access infection rate, 35% access thrombosis rate and 1.5 access maturity time, with only the 3-year cumulative patency reaching statistical significance. Among the three respondent groups, the general population found cumulative patency less important than healthcare providers and patients did. Patients demonstrated the highest WTP for cumulative patency, indicating a willingness to pay an extra RMB$24,720(US$3,708) for each additional year of patency time. Conclusion: Patients and healthcare providers had a strong preference for vascular access with superior patency. While the general population preferred vascular access with lower thrombosis rates. These results indicate that most patients prefer autogenous arteriovenous fistula (AVF) as an appropriate choice for vascular access due to its superior patency and lower complications than other vascular access types.

Desloratadine ameliorates paclitaxel-induced peripheral neuropathy and hypersensitivity reactions in mice.

Paclitaxel (PTX) serves as a primary chemotherapy agent against diverse solid tumors including breast cancer, lung cancer, head and neck cancer and ovarian cancer, having severe adverse effects including PTX-induced peripheral neuropathy (PIPN) and hypersensitivity reactions (HSR). A recommended anti-allergic agent diphenhydramine (DIP) has been used to alleviate PTX-induced HSR. Desloratadine (DLT) is a third generation of histamine H1 receptor antagonist, but also acted as a selective antagonist of 5HTR2A. In this study we investigated whether DLT ameliorated PIPN-like symptoms in mice and the underlying mechanisms. PIPN was induced in male mice by injection of PTX (4 mg/kg, i.p.) every other day for 4 times. The mice exhibited 50% reduction in mechanical threshold, paw thermal response latency and paw cold response latency compared with control mice. PIPN mice were treated with DLT (10, 20 mg/kg, i.p.) 30 min before each PTX administration in the phase of establishing PIPN mice model and then administered daily for 4 weeks after the model was established. We showed that DLT administration dose-dependently elevated the mechanical, thermal and cold pain thresholds in PIPN mice, whereas administration of DIP (10 mg/kg, i.p.) had no ameliorative effects on PIPN-like symptoms. We found that the expression of 5HTR2A was selectively elevated in the activated spinal astrocytes of PIPN mice. Spinal cord-specific 5HTR2A knockdown by intrathecal injection of AAV9-5Htr2a-shRNA significantly alleviated the mechanical hyperalgesia, thermal and cold hypersensitivity in PIPN mice, while administration of DLT (20 mg/kg) did not further ameliorate PIPN-like symptoms. We demonstrated that DLT administration alleviated dorsal root ganglion neuronal damage and suppressed sciatic nerve destruction, spinal neuron apoptosis and neuroinflammation in the spinal cord of PIPN mice. Furthermore, we revealed that DLT administration suppressed astrocytic neuroinflammation via the 5HTR2A/c-Fos/NLRP3 pathway and blocked astrocyte-neuron crosstalk by targeting 5HTR2A. We conclude that spinal 5HTR2A inhibition holds promise as a therapeutic approach for PIPN and we emphasize the potential of DLT as a dual-functional agent in ameliorating PTX-induced both PIPN and HSR in chemotherapy. In summary, we determined that spinal 5HTR2A was selectively activated in PIPN mice and DLT could ameliorate the PTX-induced both PIPN- and HSR-like pathologies in mice. DLT alleviated the damages of DRG neurons and sciatic nerves, while restrained spinal neuronal apoptosis and CGRP release in PIPN mice. The underlying mechanisms were intensively investigated by assay against the PIPN mice with 5HTR2A-specific knockdown in the spinal cord by injection of adeno-associated virus 9 (AAV9)-5Htr2a-shRNA. DLT inhibited astrocytic NLRP3 inflammasome activation-mediated spinal neuronal damage through 5HTR2A/c-FOS pathway. Our findings have supported that spinal 5HTR2A inhibition shows promise as a therapeutic strategy for PIPN and highlighted the potential advantage of DLT as a dual-functional agent in preventing against PTX-induced both PIPN and HSR effects in anticancer chemotherapy.

Diamond with Sp2-Sp3 composite phase for thermometry at Millikelvin temperatures.

Temperature is one of the seven fundamental physical quantities. The ability to measure temperatures approaching absolute zero has driven numerous advances in low-temperature physics and quantum physics. Currently, millikelvin temperatures and below are measured through the characterization of a certain thermal state of the system as there is no traditional thermometer capable of measuring temperatures at such low levels. In this study, we develop a kind of diamond with sp2-sp3 composite phase to tackle this problem. The synthesized composite phase diamond (CPD) exhibits a negative temperature coefficient, providing an excellent fit across a broad temperature range, and reaching a temperature measurement limit of 1 mK. Additionally, the CPD demonstrates low magnetic field sensitivity and excellent thermal stability, and can be fabricated into probes down to 1 micron in diameter, making it a promising candidate for the manufacture of next-generation cryogenic temperature sensors. This development is significant for the low-temperature physics researches, and can help facilitate the transition of quantum computing, quantum simulation, and other related technologies from research to practical applications.

MEG3 rs7158663 genetic polymorphism is associated with the risk of hepatocellular carcinoma.

Recently, a meta-analysis has shown that a potentially functional genetic polymorphism (rs7158663 A > G) on the cancer-associated lncRNA MEG3 is associated with the risk of many types of cancer. Given the important role of MEG3 in the development of hepatocellular carcinoma (HCC), the current study evaluated the association of the rs7158663 genetic polymorphism with HCC risk. A total of 271 HCC patients and 267 healthy individuals were included in the current case-control study. Direct sequencing was used to detect the rs7158663 locus genotype of the included individuals. The case-control study showed that the MEG3 rs7158663 genetic polymorphism was associated with the increased risk of developing HCC [GA vs. GG: OR = 1.63, 95% CI = 1.14-2.34, p = 0.009; AA vs. GG: OR = 2.10, 95% CI = 1.10-4.08, p = 0.03; (GA + AA) vs. GG: OR = 1.70, 95% CI = 1.21-2.40, p = 0.003; A vs. G: OR = 1.53, 95% CI = 1.17-2.00, p = 0.002]. In addition, the genotype-tissue expression showed that the rs7158663 AA or GA genotype was associated with reduced MEG3 expression. Bioinformatic analysis showed that the rs7158663 genetic polymorphism not only affects the binding of transcription factors but also interacts with multiple genes through chromatin loops. In summary, the current findings suggest that the rs7158663 genetic polymorphism affecting MEG3 expression is associated with HCC risk and may serve as a marker of genetic susceptibility to HCC. However, the specific molecular mechanisms of the rs7158663 genetic polymorphism in the development of HCC need to be further revealed.

Diagnostic Accuracy of Transthoracic Echocardiography for Acute Type A Aortic Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is currently recognized as the potential first-line imaging test for patients with suspected acute type A aortic syndrome (AAAS). Direct TTE sign for detecting AAAS is positive if there is an intimal flap separating two aortic lumens or aortic wall thickening seen in the ascending aorta. Indirect TTE sign indicates high-risk features of AAAS, such as aortic root dilatation, pericardial effusion, and aortic regurgitation. Our aim is to summarize the existing clinical evidence regarding the diagnostic accuracy of TTE and to evaluate its potential role in the management of patients with suspected AAAS. METHODS: We included prospective or retrospective diagnostic cohort studies, written in any language, that specifically focused on using TTE to diagnose AAAS from databases such as PubMed, EMBASE, MEDLINE, and the Cochrane Library. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio [1], and hierarchical summary receiver-operating characteristic (HSROC) curve were calculated for TTE in diagnosing AAAS. We applied Quality Assessment of Diagnostic Accuracy (QUADAS-2) tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality assessment criteria. RESULTS: Ten studies (2886 patients) were included in the meta-analysis. The pooled sensitivity and specificity of direct TTE signs were 58% (95% CI, 38-76%) and 94% (95% CI, 89-97%). For any TTE signs, the pooled sensitivity and specificity were 91% (95% CI, 85-94%) and 74% (95% CI, 61-84%). The diagnostic accuracy of direct TTE signs was significantly higher than that of any TTE signs, as measured by the area under the HSROC curve [0.95 (95% CI, 0.92-0.96) vs. 0.87 (95% CI, 0.84-0.90)] in four studies. CONCLUSIONS: Our study suggests that TTE could serve as the initial imaging test for patients with suspected AAAS. Given its high specificity, the presence of direct TTE signs may indicate AAAS, whereas the absence of any TTE signs, combined with low clinical suspicion, could suggest a lower likelihood of AAAS.

Parental exposure to Cypermethrin causes intergenerational toxicity in zebrafish offspring.

Cypermethrin (CYP), a synthetic pyrethroid pesticide, has been detected in agriculture and aquaculture. However, there is limited knowledge about the transgenerational impacts. This study aimed to investigate the developmental toxicity of CYP on F1 larvae offspring of adult zebrafish exposed to various CYP concentrations (5, 10, and 20 µg/L) for 28 days. The results indicated that CYP accumulated in parental zebrafish, and CYP was below the limit of quantification in offspring. Paternal exposure impacted the hatching rate and heart rate of the F1 generation. Furthermore, CYP significantly impacted the development of swim bladders in progeny and dysregulated the genes relevant to swim bladder development. The neutrophil migrated to the swim bladder. The mRNA levels of the inflammatory factors were also significantly elevated. According to network toxicology, PI3-AKT may be the signaling pathway for CYP-influenced bladder development. Subsequent molecular docking and Western blot analysis showed CYP affected the PI3-AKT signaling pathway. Notably, MK-2206, a specific Akt inhibitor, rescued the CYP-induced damage of swim bladder development in offspring. The present study highlights the potential risks of CYP on the development of offspring and lasting impact in aquatic environments.

High-efficient stabilization and solidification of municipal solid waste incineration fly ash by synergy of alkali treatment and supersulfated cement.

Municipal solid waste incineration fly ash (IFA) designated as hazardous waste poses risks to environment and human health. This study introduces a novel approach for the stabilization and solidification (S/S) of IFA: a combined approach involving alkali treatment and immobilization in low-carbon supersulfated cement (SSC). The impact of varying temperatures of alkali solution on the chemical and mineralogical compositions, as well as the pozzolanic reactivity of IFA, and the removal efficiency of heavy metals and metallic aluminum (Al) were examined. The physical characteristics, hydration kinetics and effectiveness of SSC in immobilizing IFA were also analyzed. Results showed that alkali treatment at 25 °C effectively eliminated heavy metals like manganese (Mn), barium (Ba), nickel (Ni), and chromium (Cr) to safe levels and totally removed the metallic Al, while enhancing the pozzolanic reactivity of IFA. By incorporating the alkali-treated IFA and filtrate, the density, compressive strength and hydration reaction of SSC were improved, resulting in higher hydration degree, finer pore structure, and denser microstructure compared to untreated IFA. The rich presence of calcium-aluminosilicate-hydrate (C-(A)-S-H) and ettringite (AFt) in SSC facilitated the efficient stabilization and solidification of heavy metals, leading to a significant decrease in their leaching potential. The use of SSC for treating Ca(OH)2- and 25°C-treated IFA could achieve high strength and high-efficient immobilization.

Acoustic Assembly and Scanning of Superlens Arrays for High-Resolution and Large Field-of-View Bioimaging.

High-resolution and dynamic bioimaging is essential in life sciences and biomedical applications. In recent years, microspheres combined with optical microscopes have offered a low cost but promising solution for super-resolution imaging, by breaking the diffraction barrier. However, challenges still exist in precisely and parallelly superlens controlling using a noncontact manner, to meet the demands of large-area scanning imaging for desired targets. This study proposes an acoustic wavefield-based strategy for assembling and manipulating micrometer-scale superlens arrays, in addition to achieving on-demand scanning imaging through phase modulation. In experiments, acoustic pressure nodes are designed to be comparable in size to microspheres, allowing spatially dispersed microspheres to be arranged into arrays with one unit per node. Droplet microlenses with various diameters can be adapted in the array, allowing for a wide range of spacing periods by applying different frequencies. In addition, through the continuous phase shifting in the x and y directions, this acoustic superlens array achieves on-demand moving for the parallel high-resolution virtual image capturing and scanning of nanostructures and biological cell samples. As a comparison, this noncontact and cost-effective acoustic manner can obtain more than ∼100 times the acquisition efficiency of a single lens, holding promise in advancing super-resolution microscopy and subcellular-level bioimaging.

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1.

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.