Non-Hermitian topological whispering gallery.

In 1878, Lord Rayleigh observed the highly celebrated phenomenon of sound waves that creep around the curved gallery of St Paul's Cathedral in London1,2. These whispering-gallery waves scatter efficiently with little diffraction around an enclosure and have since found applications in ultrasonic fatigue and crack testing, and in the optical sensing of nanoparticles or molecules using silica microscale toroids. Recently, intense research efforts have focused on exploring non-Hermitian systems with cleverly matched gain and loss, facilitating unidirectional invisibility and exotic characteristics of exceptional points3,4. Likewise, the surge in physics using topological insulators comprising non-trivial symmetry-protected phases has laid the groundwork in reshaping highly unconventional avenues for robust and reflection-free guiding and steering of both sound and light5,6. Here we construct a topological gallery insulator using sonic crystals made of thermoplastic rods that are decorated with carbon nanotube films, which act as a sonic gain medium by virtue of electro-thermoacoustic coupling. By engineering specific non-Hermiticity textures to the activated rods, we are able to break the chiral symmetry of the whispering-gallery modes, which enables the out-coupling of topological 'audio lasing' modes with the desired handedness. We foresee that these findings will stimulate progress in non-destructive testing and acoustic sensing.

LncRNA-Snhg3 regulates mouse hepatic glycogenesis under normal chow diet.

Long noncoding RNAs (lncRNAs) are strongly associated with glucose homeostasis, but their roles remain largely unknown. In this study, the potential role of lncRNA-Snhg3 in glucose metabolism was evaluated both in vitro and in vivo. Here, we found a positive relationship between Snhg3 and hepatic glycogenesis. Glucose tolerance improved in hepatocyte-specific Snhg3 knock-in (Snhg3-HKI) mice, while it worsened in hepatocyte-specific Snhg3 knockout (Snhg3-HKO) mice. Furthermore, hepatic glycogenesis had shown remarkable increase in Snhg3-HKI mice and reduction in Snhg3-HKO mice, respectively. Mechanistically, Snhg3 increased mRNA and protein expression levels of PPP1R3B through inducing chromatin remodeling and promoting the phosphorylation of protein kinase B. Collectively, these results suggested that lncRNA-Snhg3 plays a critical role in hepatic glycogenesis.

CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice.

Cardiac signaling pathways functionally important in the heart's response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted in vivo. Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion injury (IRI). Here we investigated whether somatic gene transfer of CITED4 in a clinically relevant time frame could promote recovery after IRI. Cardiac CITED4 gene delivery via intravenous AAV9 injections in wild type mice led to an approximately 3-fold increase in cardiac CITED4 expression. After 4 weeks, CITED4-treated animals developed physiological cardiac hypertrophy without adverse remodeling. In IRI, delivery of AAV9-CITED4 after reperfusion resulted in a 6-fold increase in CITED4 expression 1 week after surgery, as well as decreased apoptosis, fibrosis, and inflammatory markers, culminating in a smaller scar and improved cardiac function 8 weeks after IRI, compared with control mice receiving AAV9-GFP. Somatic gene transfer of CITED4 induced a phenotype suggestive of physiological cardiac growth and mitigated adverse remodeling after ischemic injury. These studies support the feasibility of CITED4 gene therapy delivered in a clinically relevant time frame to mitigate adverse ventricular remodeling after ischemic injury.

Oncoprotein-induced transcript 3 protein-enriched extracellular vesicles promotes NLRP3 ubiquitination to alleviate acute lung injury after cardiac surgery.

Acute lung injury (ALI) including acute respiratory distress syndrome (ARDS) is a major complication and increase the mortality of patients with cardiac surgery. We previously found that the protein cargoes enriched in circulating extracellular vesicles (EVs) are closely associated with cardiopulmonary disease. We aimed to evaluate the implication of EVs on cardiac surgery-associated ALI/ARDS. The correlations between "oncoprotein-induced transcript 3 protein (OIT3) positive" circulating EVs and postoperative ARDS were assessed. The effects of OIT3-overexpressed EVs on the cardiopulmonary bypass (CPB) -induced ALI in vivo and inflammation of human bronchial epithelial cells (BEAS-2B) were detected. OIT3 enriched in circulating EVs is reduced after cardiac surgery with CPB, especially with postoperative ARDS. The "OIT3 positive" EVs negatively correlate with lung edema, hypoxemia and CPB time. The OIT3-overexpressed EVs can be absorbed by pulmonary epithelial cells and OIT3 transferred by EVs triggered K48- and K63-linked polyubiquitination to inactivate NOD-like receptor protein 3 (NLRP3) inflammasome, and restrains pro-inflammatory cytokines releasing and immune cells infiltration in lung tissues, contributing to the alleviation of CPB-induced ALI. Overexpression of OIT3 in human bronchial epithelial cells have similar results. OIT3 promotes the E3 ligase Cbl proto-oncogene B associated with NLRP3 to induce the ubiquitination of NLRP3. Immunofluorescence tests reveal that OIT3 is reduced in the generation from the liver sinusoids endothelial cells (LSECs) and secretion in liver-derived EVs after CPB. In conclusion, OIT3 enriched in EVs is a promising biomarker of postoperative ARDS and a therapeutic target for ALI after cardiac surgery.

Suppressed Droplet Splashing on Positively Skewed Surfaces for High-Efficiency Evaporation Cooling.

Two types of functional surfaces with the same roughness but completely different surface topographies are prepared, namely positively skewed surfaces filled with micropillar arrays (Sa ≈4.4 µm, Ssk >0) and negatively skewed surfaces filled with microcavity arrays (Sa ≈4.4 µm, Ssk <0), demonstrating promoting droplet splashing. Remarkably, the critical Weber number for generating satellite droplets on the negatively skewed surfaces is significantly lower than that on the positively skewed surfaces, indicating that the negatively skewed surface with microcavity arrays is more likely to promote droplet splashing. It is mainly attributed to the fact that air on the negatively skewed surface can make the liquid film take on a Cassie-Baxter state on the surface so that the stabilizing capillary force of the liquid film exceeds the destabilizing stress of the air film. Moreover, the surface topography promoting droplet spreading and the mechanical properties of three-phase moving contact lines are analyzed from the perspective of microscopic interface mechanics. Finally, it is demonstrated the designed positively skewed surfaces can be employed for large-area heat dissipation by means of high-efficiency evaporation.

Transcriptomic and physiological analyses of Trichoderma citrinoviride HT-1 assisted phytoremediation of Cd contaminated water by Phragmites australis.

Plant growth promoting microbe assisted phytoremediation is considered a more effective approach to rehabilitation than the single use of plants, but underlying mechanism is still unclear. In this study, we combined transcriptomic and physiological methods to explore the mechanism of plant growth promoting microbe Trichoderma citrinoviride HT-1 assisted phytoremediation of Cd contaminated water by Phragmites australis. The results show that the strain HT-1 significantly promoted P. australis growth, increased the photosynthetic rate, enhanced antioxidant enzyme activities. The chlorophyll content and the activity of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) were increased by 83.78%, 23.17%, 47.60%, 97.14% and 12.23% on average, and decreased the content of malondialdehyde (MDA) by 31.10%. At the same time, strain HT-1 improved the absorption and transport of Cd in P. australis, and the removal rate of Cd was increased by 7.56% on average. Transcriptome analysis showed that strain HT-1 induced significant up-regulated the expression of genes related to oxidative phosphorylation and ribosome pathways, and these upregulated genes promoted P. australis remediation efficiency and resistance to Cd stress. Our results provide a mechanistic understanding of plant growth promoting microbe assisted phytoremediation under Cd stress.

Honeycomb effect elimination in differential phase fiber-bundle-based endoscopy.

Fiber-bundle-based endoscopy, with its ultrathin probe and micrometer-level resolution, has become a widely adopted imaging modality for in vivo imaging. However, the fiber bundles introduce a significant honeycomb effect, primarily due to the multi-core structure and crosstalk of adjacent fiber cores, which superposes the honeycomb pattern image on the original image. To tackle this issue, we propose an iterative-free spatial pixel shifting (SPS) algorithm, designed to suppress the honeycomb effect and enhance real-time imaging performance. The process involves the creation of three additional sub-images by shifting the original image by one pixel at 0, 45, and 90 degree angles. These four sub-images are then used to compute differential maps in the x and y directions. By performing spiral integration on these differential maps, we reconstruct a honeycomb-free image with improved details. Our simulations and experimental results, conducted on a self-built fiber bundle-based endoscopy system, demonstrate the effectiveness of the SPS algorithm. SPS significantly improves the image quality of reflective objects and unlabeled transparent scattered objects, laying a solid foundation for biomedical endoscopic applications.

Highly sensitive self-focused ultrasound transducer with a bionic back-reflector for multiscale-resolution photoacoustic microscopy.

In this study, we designed a self-focused ultrasonic transducer made of polyvinylidene fluoride (PVDF). This transducer involves a back-reflector, which is modeled after tapetum lucidum in the eyes of some nocturnal animals. The bionic structure reflects the ultrasound, which passes through the PVDF membrane, back to PVDF and provides a second chance for the PVDF to convert the ultrasound to electric signals. This design increases the amount of ultrasound absorbed by the PVDF, thereby improving the detection sensitivity. Both ultrasonic and photoacoustic (PA) experiments were conduct to characterize the performance of the transducer. The results show that the fabricated transducer has a center frequency of 13.07 MHz, and a bandwidth of 96% at -6 dB. With an acoustic numerical aperture (NA) of 0.64, the transducer provides a lateral resolution of 140µm. Importantly, the bionic design improves the detection sensitivity of the transducer about 30%. Finally, we apply the fabricated transducer to optical-resolution (OR) and acoustic-resolution photoacoustic microscopy (AR-PAM) to achieve multiscale-resolution PA imaging. Imaging of the bamboo leaf and the leaf skeleton demonstrates that the proposed transducer can provide high spatial resolution, better imaging intensity and contrast. Therefore, the proposed transducer design will be useful to enhance the performance of multiscale-resolution PAM.

Both protein and non-protein components in extracellular vesicles of human seminal plasma improve human sperm function via CatSper-mediated calcium signaling.

STUDY QUESTION: What is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions? SUMMARY ANSWER: EV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV. WHAT IS KNOWN ALREADY: EVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear. STUDY DESIGN, SIZE, DURATION: EV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits. MAIN RESULTS AND THE ROLE OF CHANCE: EV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.

Optical path optimization of chromatic line confocal displacement sensor for high resolution and wide range.

This study introduces the optical path-optimized dual-grating chromatic line confocal imaging (DG-LCI) technique for high-resolution and wide-range surface topography measurements. Chromatic line confocal imaging (LCI) finds extensive applications in high-speed 3D imaging of surface morphology, roughness analysis in industrial production, and quality inspection. A key advantage of LCI is its ability to achieve a large depth of focus, enabling the imaging system to measure a wide range in the Z direction. However, the challenge lies in the trade-off between the measurement range and resolution. Increasing the measurement range reduces the resolution, making it unsuitable for precise measurements required in industrial processing. Conversely, enhancing the resolution limits the measurement range, thereby sacrificing the advantage of LCI systems' broad measurement capabilities. Addressing this limitation, we propose a dual optical path dual-grating structure using a simplified and ingenious optical path optimization design. This design overcomes the challenge of sacrificing the millimeter-level measurement range while simultaneously improving the resolution. Rigorous simulations and experiments validate the effectiveness and validity of our proposed method.

Enhancing tissue imaging contrast in photoacoustic tomography using the ultrasound thermal effect.

Photoacoustic imaging is a powerful technique for obtaining high-resolution images of vascular distribution and physiological information about blood by utilizing the light absorption coefficient as an imaging contrast. However, visualizing weakly light-absorbing components without specific contrast agents or multi-wavelength techniques presents a challenge due to significant differences in light absorption between these components and blood. In this study, we propose a novel method that leverages the thermal effect of ultrasound to induce temperature differences and enhance the contrast of photoacoustic imaging. We conducted phantom experiments to verify the feasibility of our method. Our method effectively highlighted weakly light-absorbing components with strong acoustic absorption, even in the presence of highly light-absorbing components such as blood or melanin. Furthermore, it enabled the differentiation of components with similar light absorption but different acoustic absorption.

Measurement of the linewidth of a home-built vacuum ultraviolet comb by frequency comb spectroscopy on NO2.

Optical frequency comb in the vacuum ultraviolet (VUV)/extreme ultraviolet (XUV) region has attracted a great deal of attention, as it provides coherent VUV/XUV radiation source with a rather narrow bandwidth, facilitating precise spectroscopic measurements in the short wavelength regime. In this study, we report on the linewidth measurement of a home-built VUV comb centered at 148 nm using direct frequency comb spectroscopy with NO2. The measurement reveals that the upper bound of our comb linewidth is less than 28 MHz. Fitting the whole trace with different repetition rates shows that the center frequency of the excitation is 2 021.25 ± 0.24 THz (∼148.32 nm). Thus, we assigned this excitation to the transition from the 6a1 orbital (ν1'=0, ν2'=0) to the 3pσu orbital (ν1'=3, ν2'=8) in NO2. Our work demonstrates that VUV combs are potentially powerful tools for precision spectroscopic measurements in the short wavelength regime.

Timing Correlated-Electron Emission from Strong Field Atomic Double Ionization with Polarization-Gated Attoclock.

Attoclock provides a powerful tool for probing the ultrafast electron dynamics in strong laser fields. However, this technique has remained restricted to single electron or sequential double ionized electron dynamics. Here, we propose a novel attoclock scheme with a polarization-gated few-cycle laser pulse and demonstrate its application in timing the correlated-electron emission in strong field double ionization of argon. Our experimental measurements reveal that the correlated-electron emission occurs mainly through two channels with time differences of 234±22 as and 1043±73 as, respectively. Classical model calculations well reproduce the experimental results and deepen our understanding of ultrafast electron correlation dynamics.

FOXA1/2 depletion drives global reprogramming of differentiation state and metabolism in a human liver cell line and inhibits differentiation of human stem cell-derived hepatic progenitor cells.

FOXA factors are critical members of the developmental gene regulatory network (GRN) composed of master transcription factors (TF) which regulate murine cell fate and metabolism in the gut and liver. How FOXA factors dictate human liver cell fate, differentiation, and simultaneously regulate metabolic pathways is poorly understood. Here, we aimed to determine the role of FOXA2 (and FOXA1 which is believed to compensate for FOXA2) in controlling hepatic differentiation and cell metabolism in a human hepatic cell line (HepG2). siRNA mediated knockdown of FOXA1/2 in HepG2 cells significantly downregulated albumin (p < .05) and GRN TF gene expression (HNF4α, HEX, HNF1ß, TBX3) (p < .05) and significantly upregulated endoderm/gut/hepatic endoderm markers (goosecoid [GSC], FOXA3, and GATA4), gut TF (CDX2), pluripotent TF (NANOG), and neuroectodermal TF (PAX6) (p < .05), all consistent with partial/transient reprograming. shFOXA1/2 targeting resulted in similar findings and demonstrated evidence of reversibility of phenotype. RNA-seq followed by bioinformatic analysis of shFOXA1/2 knockdown HepG2 cells demonstrated 235 significant downregulated genes and 448 upregulated genes, including upregulation of markers for alternate germ layers lineages (cardiac, endothelial, muscle) and neurectoderm (eye, neural). We found widespread downregulation of glycolysis, citric acid cycle, mitochondrial genes, and alterations in lipid metabolism, pentose phosphate pathway, and ketogenesis. Functional metabolic analysis agreed with these findings, demonstrating significantly diminished glycolysis and mitochondrial respiration, with concomitant accumulation of lipid droplets. We hypothesized that FOXA1/2 inhibit the initiation of human liver differentiation in vitro. During human pluripotent stem cells (hPSC)-hepatic differentiation, siRNA knockdown demonstrated de-differentiation and unexpectedly, activation of pluripotency factors and neuroectoderm. shRNA knockdown demonstrated similar results and activation of SOX9 (hepatobiliary). These results demonstrate that FOXA1/2 controls hepatic and developmental GRN, and their knockdown leads to reprogramming of both differentiation and metabolism, with applications in studies of cancer, differentiation, and organogenesis.

Idebenone Antagonizes P53-Mediated Neuronal Oxidative Stress Injury by Regulating CD38-SIRT3 Protein Level.

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.

Synergistic Effect of Microconvex Texture and Particle Medium on the Tribological Property of the Rubber Sliding Interface.

In this study, we examined how surface topography and particle medium interact to affect the tribological performance of rubber sliding interfaces, uncovering the mechanisms of particle lubrication under various conditions. We found that microtextured surfaces, created using a mold transfer method, modestly reduced the friction coefficient of rubber under both dry and lubricated states, primarily by altering the real contact area. Additionally, the presence of different microconvex textures on the surface topography significantly influenced rubber's tribological properties. Our three-dimensional morphological analysis revealed that microtextured rubber surfaces with higher Sa, Sku, and Sal and lower Str values consistently showed lower friction coefficients during sliding. The friction mechanism was attributed to the combined effects of the material properties, surface topography, and contact area. With the addition of a particle medium, the dry friction coefficient of the rubber interface decreased but exhibited an initial increase, followed by a decrease with increasing particle diameter. When particles were mixed with a water-based cutting fluid, the concentration, diameter, and wettability of the particles significantly impacted the tribological properties due to the synergistic effects of surface topography and particle lubrication. This work enhances our understanding of tribological control for viscoelastic materials through surface design, providing a theoretical basis for the tribological optimization of rubber surfaces.

Armored Superhydrophobic Surfaces with Excellent Drag Reduction in Complex Environmental Conditions.

Superhydrophobic surfaces (SHSs) have possibilities for achieving significantly reduced solid-liquid frictional drag in the marine sector due to their excellent water-repelling properties. Although the stability of SHSs plays a key role in drag reduction, little consideration was given to the effect of extreme environments on the ability of SHSs to achieve drag reduction underwater, particularly when subjected to acidic conditions. Here, we propose interconnected microstructures to protect superhydrophobic coatings with the aim of enhancing the stability of SHSs in extreme environments. The stability of armored SHSs (ASHSs) was demonstrated by the contact angle and bounce time of droplets on superhydrophobic surfaces treated by various methods, resulting in an ASHS surface with excellent stability under extreme environmental conditions. Additionally, inspired by microstructures protecting superhydrophobic nanomaterials from frictional wear, the armored superhydrophobic spheres (ASSPs) were designed to explain from theoretical and experimental perspectives why ASSPs can achieve sustainable drag reduction and demonstrate that the ASSPs can achieve drag reduction of over 90.4% at a Reynolds number of 6.25 × 104 by conducting water entry experiments on spheres treated in various solutions. These studies promote a fundamental understanding of what drives the application of SHSs under extreme environmental conditions and provide practical strategies to maximize frictional drag reduction.

Macrophage-Targeted GSH-Depleting Nanocomplexes for Synergistic Chemodynamic Therapy/Gas Therapy/Immunotherapy of Intracellular Bacterial Infection.

Intracellular pathogens can survive inside the macrophages to protect themselves from eradication by the innate immune system and conventional antibiotics, resulting in severe bacterial infections. In this work, an antibiotic-free nanocomplex (HA/GA-Fe@NO-DON), exhibiting macrophage-targeted synergistic gas therapy (nitric oxide, NO)/chemodynamic therapy/immunotherapy, was reported. HA/GA-Fe nanoparticles were synthesized by the strong coordination interactions among carboxyl groups of hyaluronic acid (HA), polyphenol groups of gallic acid (GA), and Fe(II) ions. The hydrophobic glutathione (GSH)-responsive NO donor (NO-DON) was encapsulated in HA/GA-Fe nanoparticles to form the final nanocomplexes (HA/GA-Fe@NO-DON). HA on the nanocomplexes guides the macrophage-specific uptake and intracellular accumulation. After the uptake, HA/GA-Fe@NO-DON nanocomplexes could not only generate highly toxic hydroxyl radicals (•OH) by the Fenton reaction and GSH depletion but also release NO when stimulated by intracellular GSH. Meanwhile, the nanocomplexes could trigger an efficient proinflammation immune response to reinforce the antibacterial activity. This work presents the development of antibiotic-free macrophage-targeted HA/GA-Fe@NO-DON nanocomplexes as an effective adjuvant nanomedicine with synergistic gas therapy/chemodynamic therapy/immunotherapy for eliminating intracellular bacterial infection.

Cascade-Targeted Nanoplatforms for Synergetic Antibiotic/ROS/NO/Immunotherapy against Intracellular Bacterial Infection.

Intracellular bacteria in dormant states can escape the immune response and tolerate high-dose antibiotic treatment, leading to severe infections. To overcome this challenge, cascade-targeted nanoplatforms that can target macrophages and intracellular bacteria, exhibiting synergetic antibiotic/reactive oxygen species (ROS)/nitric oxide (NO)/immunotherapy, were developed. These nanoplatforms were fabricated by encapsulating trehalose (Tr) and vancomycin (Van) into phosphatidylserine (PS)-coated poly[(4-allylcarbamoylphenylboric acid)-ran-(arginine-methacrylamide)-ran-(N,N'-bisacryloylcystamine)] nanoparticles (PABS), denoted as PTVP. PS on PTVP simulates a signal of "eat me" to macrophages to promote cell uptake (the first-step targeting). After the uptake, the nanoplatform in the acidic phagolysosomes could release Tr, and the exposed phenylboronic acid on the nanoplatform could target bacteria (the second-step targeting). Nanoplatforms can release Van in response to infected intracellular overexpressed glutathione (GSH) and weak acid microenvironment. l-arginine (Arg) on the nanoplatforms could be catalyzed by upregulated inducible nitric oxide synthase (iNOS) in the infected macrophages to generate nitric oxide (NO). N,N'-Bisacryloylcystamine (BAC) on nanoplatforms could deplete GSH, allow the generation of ROS in macrophages, and then upregulate proinflammatory activity, leading to the reinforced antibacterial capacity. This nanoplatform possesses macrophage and bacteria-targeting antibiotic delivery, intracellular ROS, and NO generation, and pro-inflammatory activities (immunotherapy) provides a new strategy for eradicating intracellular bacterial infections.

Predictors of mortality for dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 and optimal treatment.

OBJECTIVES: To explore the risk factors of early death in dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM). To explore the optimal treatment regimen for patients with anti-MDA5-DM. METHODS: Patients with newly onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for 6 months. Patients were divided into five groups based on initial treatments. The major outcome was mortality in 6 months. Secondary outcomes included remission and severe infection. RESULTS: A total of 214 patients were included in the study. During 6 month follow-up, 63 patients (30.14%) died, 112 patients (53.59%) achieved remission, 52 patients (24.88%) experienced serious infection and 5 patients (2.34%) were lost. Independent risk factors of mortality in the first 6 months after diagnosis were as follows: age> 53 years, skin ulcer, peripheral blood lymphocyte count (LYMP)≤ 0.6×109/L, lactate dehydrogenase (LDH) > 500 U/L, C reactive protein (CRP) > 5mg/L, anti-Ro52 antibody and ground-glass opacity (GGO) score> 2. On the contrary, prophylactic use of the compound sulfamethoxazole (SMZ Co) was independent protective factor. The five-category treatment was not an independent influencing factor of early death, but subgroup analysis found that patients with rapidly progressive interstitial lung disease (RPILD) responded better to a triple combination of high-dose glucocorticoids (GC), calcineurin inhibitors (CNI) and cyclophosphamide (CYC) or a triple combibation of GC, CNI and tofacitinib (TOF). CONCLUSIONS: Advanced age, skin ulcer, lymphopenia, anti-Ro52 antibody and higher levels of LDH, CRP and GGO score increase the risk of early death for MDA5-DM, while prophylactic use of SMZ Co is protective. Aggressive therapy with combined immunosuppressants may improve the short-term prognosis of anti-MDA5-DM with RPILD.