Miniature three-photon microscopy maximized for scattered fluorescence collection.

In deep-tissue multiphoton microscopy, diffusion and scattering of fluorescent photons, rather than ballistic emanation from the focal point, have been a confounding factor. Here we report on a 2.17-g miniature three-photon microscope (m3PM) with a configuration that maximizes fluorescence collection when imaging in highly scattering regimes. We demonstrate its capability by imaging calcium activity throughout the entire cortex and dorsal hippocampal CA1, up to 1.2 mm depth, at a safe laser power. It also enables the detection of sensorimotor behavior-correlated activities of layer 6 neurons in the posterior parietal cortex in freely moving mice during single-pellet reaching tasks. Thus, m3PM-empowered imaging allows the study of neural mechanisms in deep cortex and subcortical structures, like the dorsal hippocampus and dorsal striatum, in freely behaving animals.

Human defensin-inspired discovery of peptidomimetic antibiotics.

SignificanceWe report the development of peptidomimetic antibiotics derived from a natural antimicrobial peptide, human α-defensin 5. By engaging multiple bacterial targets, the lead compound is efficacious in vitro and in vivo against bacteria with highly inducible antibiotic resistance, promising a useful therapeutic agent for the treatment of infections caused by antibiotic-resistant bacteria.

Role of Na/K-ATPase α1 caveolin-binding motif in adipogenesis.

Deficiencies in mice and in humans have brought to the fore the importance of the caveolar network in key aspects of adipocyte biology. The conserved N-terminal caveolin-binding motif (CBM) of the ubiquitous Na/K-ATPase (NKA) α1 isoform, which allows NKA/caveolin-1 (Cav1) interaction, influences NKA signaling and caveolar distribution. It has been shown to be critical for animal development and ontogenesis, as well as lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs). However, its role in postnatal adipogenesis has not been fully examined. Using a genetic approach to alter CBM in hiPSC-derived adipocytes (iAdi-mCBM) and in mice (mCBM), we investigated the regulatory function of NKA CBM signaling in adipogenesis. Seahorse XF cell metabolism analyses revealed impaired glycolysis and decreased ATP synthesis-coupled respiration in iAdi-mCBM. These metabolic dysfunctions were accompanied by evidence of extensive remodeling of the extracellular matrix (ECM), including increased collagen staining, overexpression of ECM marker genes, and heightened TGF-ß signaling uncovered by RNAseq analysis. Rescue of mCBM by lentiviral delivery of WT NKA α1 or treatment of mCBM hiPSCs with the TGF-ß inhibitor SB431542 normalized ECM, suggesting that NKA CBM signaling integrity is required for adequate control of TGF-ß signaling and ECM stiffness during adipogenesis. The physiological impact was revealed in mCBM male mice with reduced fat mass accompanied by histological and transcriptional evidence of elevated adipose fibrosis and decreased adipocyte size. Based on these findings, we propose that the genetic alteration of the NKA/Cav1 regulatory path uncovered in human iAdi leads to lipodystrophy in mice.NEW & NOTEWORTHY A Na/K-ATPase α1 caveolin-binding motif regulates adipogenesis. Mutation of this binding motif in the mouse leads to reduced fat with increased extracellular matrix production and inflammation. RNA-seq analysis and pharmacological interventions in human iPSC-derived adipocytes revealed that TGF-ß signal, rather than Na/K-ATPase-mediated ion transport, is a key mediator of NKA regulation of adipogenesis.

Noninvasive microvascular imaging in newborn rats using high-frequency ultrafast ultrasound.

Ultrasound imaging stands as the predominant modality for neonatal health assessment, with recent advancements in ultrafast Doppler (µDoppler) technology offering significant promise in fields such as neonatal brain imaging. Combining µDoppler with high-frequency ultrasound (HF-µDoppler) presents a potential efficient avenue to enhance in vivo microvascular imaging in small animals, notably newborn rats, a crucial preclinical animal model for neonatal disease and development research. It is necessary to verify the imaging performance of HF-µDoppler in preclinical trials. This study investigates the microvascular imaging capabilities of HF-µDoppler using a 30 MHz high-frequency linear array probe in newborn rats. Results demonstrate the clarity of cerebral microvascular imaging in rats aged 1 to 7 postnatal days, extending to whole-body microvascular imaging, encompassing the central nervous system, including the brain and spinal cord. In conclusion, HF-µDoppler technology emerges as a reliable imaging tool, offering a new perspective for preclinical investigations into neonatal diseases and development.

Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice.

Total fertilization failure (TFF) can occur during in vitro fertilization (IVF) treatments, even following intracytoplasmic sperm injection (ICSI). Various male or female factors could contribute to TFF. Increasing evidence suggested that genetic variations in PLCZ1, which encodes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase zeta-1 (PLCζ), is involved in oocyte activation and is a key male factor in TFF. In the present study, we explored the genetic variants in male individuals that led to TFF. A total of 54 couples with TFF or poor fertilization (fertilization rate < 20%) were screened, and 21 couples were determined to have a male infertility factor by the mouse oocyte activation test. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 (actin like 9) in three individuals. ACTL9 variations led to abnormal ultrastructure of the perinuclear theca (PT), and PLCζ was absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in an Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. These findings identified the role of ACTL9 in the PT structure and the correct localization of PLCζ. The results also provide a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization.

Responses of soil and rhizosphere microbial communities to Cd-hyperaccumulating willows and Cd contamination.

BACKGROUND: The pollution of soil by heavy metals, particularly Cd, is constitutes a critical international environmental concern. Willow species are renowned for their efficacy in the phytoremediation of heavy metals owing to their high Cd absorption rate and rapid growth. However, the mechanisms underlying microbial regulation for high- and low-accumulating willow species remain poorly understood. Therefore, we investigated the responses of soil and rhizosphere microbial communities to high- and low-Cd-accumulating willows and Cd contamination. We analyzed soil properties were analyzed in bulk soil (SM) and rhizosphere soil (RM) planted with high-accumulating (H) and low-accumulating (L) willow species. RESULTS: Rhizosphere soil for different willow species had more NH4+ than that of bulk soil, and RM-H soil had more than RM-L had. The available phosphorus content was greater in hyper-accumulated species than it was in lower-accumulated species, especially in RM-H. Genome sequencing of bacterial and fungal communities showed that RM-L exhibited the highest bacterial diversity, whereas RM-H displayed the greatest richness than the other groups. SM-L exhibited the highest diversity and richness of fungal communities. Ralstonia emerged as the predominant bacterium in RM-H, whereas Basidiomycota and Cercozoa were the most enriched fungi in SM-H. Annotation of the N and C metabolism pathways revealed differential patterns: expression levels of NRT2, NarB, nirA, nirD, nrfA, and nosZ were highest in RM-H, demonstrating the effects of NO3-and N on the high accumulation of Cd in RM-H. The annotated genes associated with C metabolism indicated a preference for the tricarboxylic pathway in RM-H, whereas the hydroxypropionate-hydroxybutyrate cycle was implicated in C sequestration in SM-L. CONCLUSIONS: These contribute to elucidation of the mechanism underlying high Cd accumulation in willows, particularly in respect of the roles of microbes and N and C utilization. This will provide valuable insights for repairing polluted soil using N and employing organic acids to improve heavy metal remediation efficiency.

Miniature two-photon microscopy for enlarged field-of-view, multi-plane and long-term brain imaging.

We have developed a miniature two-photon microscope equipped with an axial scanning mechanism and a long-working-distance miniature objective to enable multi-plane imaging over a volume of 420 × 420 × 180 µm3 at a lateral resolution of ~1 µm. Together with the detachable design that permits long-term recurring imaging, our miniature two-photon microscope can help decipher neuronal mechanisms in freely behaving animals.

Resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation.

OBJECTIVE: The purpose of this study was to investigate resveratrol's specific role as an anti-inflammatory and osteogenic differentiation of hPDLSCs in periodontitis and to reveal the mechanisms involved. BACKGROUND: Numerous studies have shown that inhibiting the inflammatory response of periodontal tissues and promoting the regeneration of alveolar bone are crucial treatments for periodontitis. Resveratrol has been found to have certain anti-inflammatory property. However, the anti-inflammatory mechanism and osteogenic effect of resveratrol in periodontitis are poorly understood. MATERIALS AND METHODS: We constructed an in vitro periodontitis model by LPS stimulation of hPDLSCs and performed WB, RT-qPCR, and immunofluorescence to analyze inflammatory factors and related pathways. In addition, we explored the osteogenic ability of resveratrol in in vitro models. RESULTS: In vitro, resveratrol ameliorated the inflammatory response associated with activation of the NF-κB pathway through activation of the NRF2/HO-1 pathway, characterized by inhibition of p65/p50 nuclear translocation and the proinflammatory cytokines interleukin-1ß levels. Resveratrol also has a positive effect on osteogenic differentiation. CONCLUSIONS: Observations suggest that resveratrol modulates the inflammatory response in hPDLSCs via the NRF2/HO-1 and NF-κB pathways and promotes osteogenic differentiation.

Efficacy and safety of maintenance therapy with anlotinib for advanced cholangiocarcinoma after first-line chemotherapy and the variations in efficacy based on different neutrophil-to-lymphocyte ratio (NLR).

OBJECTIVE: This study aimed to evaluate the clinical efficacy and safety of anlotinib as maintenance therapy in patients with advanced cholangiocarcinoma following first-line chemotherapy. METHODS: This retrospective study enrolled 154 patients with advanced biliary tract cancer admitted to the hospital between January 2020 and December 2022. All patients received first-line intravenous chemotherapy with gemcitabine combined with cisplatin, oxaliplatin, or tegafur. Among the 106 patients who achieved disease control, 47 received oral anlotinib hydrochloride (12 mg daily, 2 weeks on/1 week off) as maintenance therapy. Clinical efficacy, including ORR, DCR, DOR, PFS, and OS, was compared between the anlotinib maintenance and non-maintenance groups. Subgroup analysis based on NLR levels was also performed. RESULTS: Among the 47 anlotinib maintenance patients, the ORR was 21.28% and the DCR was 51.06%. The median DOR was 36 weeks, and the median PFS was 43 weeks in the anlotinib group, versus 28 weeks and 38 weeks in the non-maintenance group, respectively. The median OS was not reached in the anlotinib group but was 48 weeks in the non-maintenance group. Patients receiving anlotinib maintenance had significantly longer DOR, PFS, and OS (all p < 0.05). Patients with low NLR levels had better survival benefits from anlotinib. CONCLUSION: Maintenance therapy with anlotinib demonstrates potential efficacy and a reliable safety profile in patients with advanced cholangiocarcinoma following first-line treatment. The efficacy of anlotinib therapy appears to be influenced by NLR levels. Further validation with larger sample sizes is warranted to strengthen the robustness and reliability of the results.

The Impact of the Pneumatic Logistics Transmission System + Intelligent Robot on Blood Routine and Coagulation Function Test Outcomes.

Background: The implementation of intelligent logistics transmission systems signifies a key aspect of modernizing hospital logistics systems in today's healthcare infrastructure. The pneumatic logistics transmission system (PTS) represents a sophisticated solution for the swift and secure conveyance of medical documents, specimens, and pharmaceuticals within hospital premises. Objective: This study investigates the influence of integrating the 'pneumatic logistics transmission system + intelligent robot' on blood routine and coagulation function test outcomes. Methods: A comparative study was conducted and a total of 50 participants were included in the study. Blood samples were collected from participants, including those undergoing blood routine tests, individuals with anemia, and patients undergoing outpatient urine routine assessments. The study systematically evaluated the effects of integrating the pneumatic logistics transmission system + intelligent robot on conventional blood tests and blood coagulation function analyses. The study compared the results obtained from the two transmission methods to evaluate their effectiveness in preserving the integrity of the specimens during transit. Results: The study revealed statistically significant differences in blood counts (P < .05), hemoglobin levels, and hematocrit levels among anemia patients (P < .05), with no observed presence of white blood cells (P > .05). Furthermore, when compared to the manual transport group, the pneumatic logistics transport system + intelligent robot group exhibited statistically significant activity of coagulation factors (P < .05), while no statistical disparities were noted among coagulation function indexes (P > .05). Conclusion: The integration of pneumatic logistics with intelligent robotics in hospital transmission systems proves beneficial for transporting various medical specimens efficiently. This combined approach streamlines logistics processes and enhances overall operational effectiveness within healthcare facilities.

Subfemtowatt Laser Phase Tracking.

Low power optical phase tracking is an enabling capability for intersatellite laser interferometry, as minimum trackable power places significant constraints on mission design. Through the combination of laser stabilization and control-loop parameter optimization, we have demonstrated continuous tracking of a subfemtowatt optical field with a mean time between slips of more than 1000 s. Comparison with analytical models and numerical simulations verified that the observed experimental performance was limited by photon shot noise and unsuppressed laser frequency fluctuations. Furthermore, with two stabilized lasers, we have demonstrated 100 min of continuous phase tracking of Gravity Recovery and Climate Experiment (GRACE)-like signal dynamics with an optical carrier ranging in power between 1-7 fW with zero cycle slips. These results indicate the feasibility of future interspacecraft laser links operating with significantly reduced received optical power.

Feasibility of the novel vascular disrupting agent C118P for facilitating high-intensity focused ultrasound ablation of uterine fibroids.

OBJECTIVE: In this study, C118P, a novel vascular disrupting agent (VDA), was evaluated for its ability in improving the ablative effect of high-intensity focused ultrasound (HIFU) on uterine fibroids by reducing blood perfusion. METHODS: Eighteen female rabbits were infused with isotonic sodium chloride solution (ISCS), C118P or oxytocin for 30 min, and an HIFU ablation of the leg muscles was performed within the last 2 min. Blood pressure, heart rate and laser speckle flow imaging (LSFI) of the auricular blood vessels were recorded during perfusion. Ears with vessels, uterus and muscle ablation sites were collected and sliced for hematoxylin-eosin (HE) staining to compare vascular size, as well as nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR) staining to observe necrosis after ablation. RESULTS: Analyses revealed that the perfusion of C118P or oxytocin steadily reduced blood perfusion in the ears to approximately half by the end of the perfusion, constricted the blood vessels of the ears and uterus, and improved HIFU ablation in the muscle tissues. C118P increased blood pressure and decreased heart rate. The degree of contraction of the auricular and uterine blood vessels was positively correlated. CONCLUSION: This study confirmed that C118P could reduce blood perfusion in various tissues and had a better synergistic effect with HIFU ablation of muscle (the same tissue type as fibroids) than did oxytocin. C118P could therefore possibly replace oxytocin in facilitating HIFU ablation of uterine fibroids; however, electrocardiographic monitoring is required.

Adult Bone Marrow-Derived Mesenchymal Stem Cells Seeded on Tissue-Engineered Cardiac Patch Contribute to Myocardial Scar Remodeling and Enhance Revascularization in a Rabbit Model of Chronic Myocardial Infarction.

BACKGROUND: Although the transplantation of tissue-engineered cardiac patches with adult bone marrow-derived mesenchymal stem cells (MSCs) can enhance cardiac function after acute or chronic myocardial infarction (MI), the recovery mechanism remains controversial. This experiment aimed to investigate the outcome measurements of MSCs within a tissue-engineered cardiac patch in a rabbit chronic MI model. METHODS: This experiment was divided into four groups: left anterior descending artery (LAD) sham-operation group (N = 7), sham-transplantation (control, N = 7), non-seeded patch group (N = 7), and MSCs-seeded patch group (N = 6). PKH26 and 5-Bromo-2'-deoxyuridine (BrdU) labeled MSCs-seeded or non-seeded patches were transplanted onto chronically infarct rabbit hearts. Cardiac function was evaluated by cardiac hemodynamics. H&E staining was performed to count the number of vessels in the infarcted area. Masson staining was used to observe cardiac fiber formation and to measure scar thickness. RESULTS: Four weeks after transplantation, a remarkable improvement in cardiac functionality could be distinctly observed, which was most significant in the MSCs-seeded patch group. Moreover, labeled cells were detected in the myocardial scar, with most of them differentiated into myofibroblasts, some into smooth muscle cells, and only a few into cardiomyocytes in the MSCs-seeded patch group. We also observed significant revascularization in the infarct area implanted in either MSCs-seeded or non-seeded patches. In addition, there were significantly greater numbers of microvessels in the MSCs-seeded patch group than in the non-seeded patch group.

Enhanced Acoustic Droplet Vaporization through the Active Magnetic Accumulation of Drug-Loaded Magnetic Particle-Encapsulated Nanodroplets (MPE-NDs) in Cancer Therapy.

The application of drug-loaded nanodroplets is still limited by their insufficient accumulation owing to the enhanced permeability and retention (EPR) effect failure in cancer therapy. To overcome these limitations, we propose an alternative magnetic particle-encapsulated nanodroplet (MPE-ND) with outstanding biosafety and magnetic targeting by encapsulating fluorinated Fe3O4-SiO2 nanoparticles inside the liquid core of the nanodroplets. Meanwhile, doxorubicin (DOX) can be stably loaded into the shell through both electrostatic and hydrophobic interactions to obtain drug-loaded MPE-NDs. Both in vitro and in vivo experiments have consistently demonstrated that drug-loaded MPE-NDs can significantly increase the local drug concentration and enhance the damage of tumor tissues through acoustic droplet vaporization under a static magnetic field (eADV therapy). Histological examination reveals that eADV therapy efficiently suppresses tumor proliferation by inducing apoptosis, destroying supply vessels, and inhibiting neovascularization. Drug-loaded MPE-NDs can be expected to open a new gateway for ultrasound-triggered drug delivery and cancer treatment.

Antimicrobial and cleaning effects of ultrasonic-mediated plasma-loaded microbubbles on Enterococcus faecalis biofilm: an in vitro study.

BACKGROUND: Enterococcus faecalis (E. faecalis) is the most frequently isolated bacteria from teeth with root canal treatment failure. This study aims to evaluate the disinfection effect of ultrasonic-mediated cold plasma-loaded microbubbles (PMBs) on 7d E. faecalis biofilm, the mechanical safety and the mechanisms. METHODS: The PMBs were fabricated by a modified emulsification process and the key reactive species, nitric oxide (NO) and hydrogen peroxide (H2O2) were evaluated. The 7d E. faecalis biofilm on human tooth disk was constructed and divided into the following groups: PBS, 2.5%NaOCl, 2%CHX, and different concentrations of PMBs (108 mL-1, 107 mL-1). The disinfection effects and elimination effects were verified with confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Microhardness and roughness change of dentin after PMBs treatment were verified respectively. RESULTS: The concentration of NO and H2O2 in PMBs increased by 39.99% and 50.97% after ultrasound treatment (p < 0.05) respectively. The CLSM and SEM results indicate that PMBs with ultrasound treatment could remove the bacteria and biofilm components effectively, especially those living in dentin tubules. The 2.5% NaOCl presented an excellent effect against biofilm on dishes, but the elimination effect on dentin tubules is limited. The 2% CHX group exhibits significant disinfection effect. The biosafety tests indicated that there is no significant changes on microhardness and roughness after PMBs with ultrasound treatment (p > 0.05). CONCLUSION: PMBs combined with ultrasound treatment exhibited significant disinfection effect and biofilm removal effect, the mechanical safety is acceptable.

Data mining from process monitoring of typical polluting enterprise.

With the increasing volume of environmental monitoring data, extracting valuable insights from multivariate time series sensor data can facilitate comprehensive information utilization and support informed decision-making in environmental management. However, there is a dearth of comprehensive research on multivariate data analysis for process monitoring in typical polluting enterprises. In this study, an artificial neural network model based on back-propagation algorithm (BP-ANN) was developed to predict the wastewater and exhaust gas emissions using IoT data obtained from process monitoring of a typical polluting enterprise located in Taizhou, Zhejiang Province, China. The results indicate that the model constructed has a high predictive coefficient of determination (R2) with values of 0.8510, 0.9565, 0.9561, 0.9677, and 0.9061 for chemical oxygen demand (COD), potential of hydrogen (pH), electrical conductivity (EC), flue gas emission (FGE), and non-methane hydrocarbon concentration (NMHC) respectively. For the first time, the variable importance measure (VIM)-assisted BP-ANN was employed to investigate the internal and external correlations between wastewater and exhaust gas treatment, thereby enhancing the interpretability of mapping features in the BP-ANN model. The predicted errors for pH and FGE have been demonstrated to fall within the range of - 0.62 ~ 0.30 and - 0.21 ~ 0.15 m3/s, respectively, with average relative errors of 1.05% and 9.60%, which is advantageous in detecting anomalous data and forecasting pollution indicator values. Our approach successfully addresses the challenge of segregating data analysis for wastewater disposal and exhaust gas disposal in the process monitoring of polluting enterprises, while also unearthing potential variables that significantly contribute to the BP-ANN model, thereby facilitating the selection and extraction of characteristic variables.

Advances in the study of DNA damage and repair in mammalian oocytes.

DNA damage is one of the key factors affecting gametogenesis and embryo development. Oocytes are susceptible to DNA damage induced by various endogenous and exogenous factors (e.g., reactive oxygen species, radiation, chemotherapeutic agents, etc.). Current research has revealed that oocytes at various developmental stages are able to respond to various types of DNA damage, repairing DNA or initiating apoptosis through complex mechanisms. Primordial follicular oocytes are more susceptible to apoptosis induced by DNA damage than oocytes entering the growth stage. DNA damage is less likely to induce arrest of the meiotic maturation process in oocytes, however the developmental capacity of oocytes carrying DNA damage is significantly reduced. In clinical practice, aging, radiation and chemotherapy are common causes of oocyte DNA damage, reduced ovarian reserve and infertility in women. Therefore, various methods that can reduce DNA damage and enhance DNA repair in oocytes have been tried in an attempt to protect oocytes. In this review, we systematically summarize the mechanisms of DNA damage and repair in mammalian oocytes at various developmental stages and discuss their potential clinical value with the aim to provide new strategies for fertility protection.

DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development.

Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2-mediated histone H3 lysine-9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development. Dcaf13 is expressed from eight-cell to morula stages in both murine and human embryos, and Dcaf13 knockout in mice causes preimplantation-stage mortality. Dcaf13 knockout embryos are arrested at the eight- to sixteen-cell stage before compaction, and this arrest is accompanied by high levels of H3K9me3. Mechanistically, CRL4-DCAF13 targets SUV39H1 for polyubiquitination and proteasomal degradation and therefore facilitates H3K9me3 removal and zygotic gene expression. Taken together, CRL4-DCAF13-mediated SUV39H1 degradation is an essential step for progressive genome reprogramming during preimplantation embryonic development.

Arterial Labeling Ultrasound Subtraction Angiography (ALUSA) Based on Acoustic Phase-Change Nanodroplets.

Biomedical imaging technology (like digital subtraction angiography (DSA)) based on contrast agents has been widely employed in the diagnosis of vascular-related diseases. While the DSA achieves the high-resolution observation of specified vessels and their downstream perfusion at the cost of invasive, radioactive operation and hepatorenal toxicity. To address those problems, this study develops arterial labeling ultrasound (US) subtraction angiography (ALUSA) based on a new perfluorobutane (PFB) nanodroplets with a lower vaporization threshold through spontaneous nucleation. The nanodroplets can be selectively vaporized to microbubbles, indicating a highly echogenic signal at B-mode images only using a diagnostic transducer. By labeling a single blood vessel for nanodroplets vaporization and tracking its downstream blood perfusion in segmental renal arteries at a frame rate of 500 Hz. The results demonstrate the color-coded super-resolution ALUSA image, exhibiting the downstream arcuate and interlobular arteries of each segmental renal artery with a resolution of 36 µm in a rabbit kidney. Furthermore, ALUSA could offer the vascular structures, blood flow velocity, and direction of their primary supply vessels in the mouse breast tumor. ALUSA fills the gap of noninvasive labeling angiography in US and opens a broad vista in the diagnosis and treatment of tumor and vascular-related diseases.

Design and synthesis of novel macrolones bridged with linkers from 11,12-positions of macrolides.

Resistance to telithromycin and off-target effects associated with the metabolic instability present serious and challenging problems for the development of novel macrolides. Herein, studies of hybrids of macrolides and quinolones (termed macrolones) bridged with linkers from 11,12-cyclic carbamate of macrolides revealed different structure-activity relationships from the previously reported macrolones bridged with linkers derived from 6-, 9- and 4''-positions of macrolides. The optimized macrolone 34 g with a longer and rigid sidechain than telithromycin had improved metabolic stability compared to telithromycin (t1/2: 110 vs 32 min), whose future has been heavily clouded by metabolic issues. Moreover, 34 g was 38-fold more potent than telithromycin against A2058/2059-mutated Mycoplasma pneumoniae (8 vs 315 µM), which may be attributed to a novel mode of action between the carboxylic acid of quinolone moiety and the bacterial ribosome. This work increases the prospect for discovery of novel and safe antibacterial agents to combat serious human infectious diseases.