Single-cell sequencing reveals distinct immune cell features in cutaneous lesions of pemphigus vulgaris and bullous pemphigoid.

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two common subtypes of autoimmune bullous disease (AIBD). The key role of circulating autoreactive immune cells contributing to skin damage of AIBD has been widely recognized. Nevertheless, the immune characteristics in cutaneous lesions remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scRNA-seq) to generate transcriptional profiles for cells and T/B cell clonetype in skin lesions of BP and PV. We found that the proportions of NK&T, macrophages/ dendritic cells, B cells, and mast cells increased in BP and PV lesions. Then, BP and PV cells constituted over 75% of all myeloid cell subtypes, CD4+ T cell subtypes and CD8+ T cell subtypes. Strikingly, CD8+ Trm was identified to be expanded in PV, and located in the intermediate state of the pseudotime trajectory from CD8+ Tm to CD8+ Tem. Interestingly, CD8+ Tem and CD4+ Treg highly expressed exhaustion-related genes, especially in BP lesions. Moreover, the enhanced cell communication between stromal cells and immune cells like B cells and macrophages/ dendritic cells was also identified in BP and PV lesions. Finally, clone expansion was observed in T cells of BP and PV compared with HC, while CD8+ Trm represented the highest ratio of hyperexpanded TCR clones among all T cell subtypes. Our study generally depicts a large and comprehensive single-cell landscape of cutaneous lesions and highlights immune cell features in BP and PV. This offers potential research targets for further investigation.

Femtosecond Laser Maskless Optical Projection Lithography of Cartilage PCM Inspired 3D Protein Matrix to Chondrocyte Phenotype.

Hydrogels containing chondrocytes have exhibited excellent potential in regenerating hyaline cartilage. However, chondrocytes are vulnerable to dedifferentiation during in vitro culture, leading to fibrosis and mechanical degradation of newly formed cartilage. It is proposed to modulate cartilage formation via the developed chondrocyte pericellular matrix (PCM) -like scaffolds for the first time, in which the S, M, and L-sized scaffolds are fabricated by femtosecond laser maskless optical projection lithography (FL-MOPL) of bovine serum albumin-glyceryl methacrylate hydrogel. Chondrocytes on the M PCM-like scaffold can maintain round morphology and synthesize extracellular matrix (ECM) to induce regeneration of hyaline cartilage microtissues by geometrical restriction. A series of M PCM-like scaffolds is fabricated with different stiffness and those with a high Young's modulus are more effective in maintaining the chondrocyte phenotype. The proposed PCM-like scaffolds are effective in modulating cartilage formation influenced by pore size, depth, and stiffness, which will pave the way for a better understanding of the geometric cues of mechanotransduction interactions in regulating cell fate and open up new avenues for tissue engineering.

Intratumor microbiome-derived butyrate promotes lung cancer metastasis.

Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3 years, recurrence group) and longer (>3 years, non-recurrence group) recurrence-free survival. By using 16S sequencing, we find that intratumor microbiome diversity is lower in the recurrence group and butyrate-producing bacteria are enriched in the recurrence group. The intratumor microbiome signature and circulating microbiome DNA can accurately predict LC recurrence. We prove that intratumor injection of butyrate-producing bacteria Roseburia can promote subcutaneous tumor growth. Mechanistically, bacteria-derived butyrate promotes LC metastasis by increasing expression of H19 in tumor cells through inhibiting HDAC2 and increasing H3K27 acetylation at the H19 promoter and inducing M2 macrophage polarization. Depletion of macrophages partially abolishes the metastasis-promoting effect of butyrate. Our results provide evidence for the cross-talk between the intratumor microbiome and LC metastasis and suggest the potential prognostic and therapeutic value of the intratumor microbiome.

FTO-mediated autophagy inhibition promotes non-small cell lung cancer progression by reducing the stability of SESN2 mRNA.

The role of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, in non-small cell lung cancer (NSCLC) has recently received widespread attention. However the underlying mechanisms of FTO-mediated autophagy regulation in NSCLC progression remain elusive. In this study, we found that FTO was significantly upregulated in NSCLC, and downregulation of FTO suppressed the growth, invasion and migration of NSCLC cells by inducing autophagy. FTO knockdown resulted in elevated m6A levels in NSCLC cells. Methylated RNA immunoprecipitation sequencing showed that sestrin 2 (SESN2) was involved in m6A regulation during autophagy in NSCLC cells. Interestingly, m6A modifications in exon 9 of SESN2 regulated its stability. FTO deficiency promoted the binding of insulin-like growth factor 2 mRNA-binding protein 1 to SESN2 mRNA, enhancing its stability and elevating its protein expression. FTO inhibited autophagic flux by downregulating SESN2, thereby promoting the growth, invasion and migration of NSCLC cells. Besides, the mechanism by which FTO blocked SESN2-mediated autophagy activation was associated with the AMPK-mTOR signaling pathway. Taken together, these findings uncover an essential role of the FTO-autophagy-SESN2 axis in NSCLC progression.

Novel inhalation therapy in pulmonary fibrosis: principles, applications and prospects.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.

Multipatterned Chondrocytes' Scaffolds by FL-MOPL with a BSA-GMA Hydrogel to Regulate Chondrocytes' Morphology.

Repairing articular cartilage damage is challenging due to its low regenerative capacity. In vitro, cartilage regeneration is a potential strategy for the functional reconstruction of cartilage defects. A hydrogel is an advanced material for mimicking the extracellular matrix (ECM) due to its hydrophilicity and biocompatibility, which is known as an ideal scaffold for cartilage regeneration. However, chondrocyte culture in vitro tends to dedifferentiate, leading to fibrosis and reduced mechanical properties of the newly formed cartilage tissue. Therefore, it is necessary to understand the mechanism of modulating the chondrocytes' morphology. In this study, we synthesize photo-cross-linkable bovine serum albumin-glycidyl methacrylate (BSA-GMA) with 65% methacrylation. The scaffolds are found to be suitable for chondrocyte growth, which are fabricated by homemade femtosecond laser maskless optical projection lithography (FL-MOPL). The large-area chondrocyte scaffolds have holes with interior angles of triangle (T), quadrilateral (Q), pentagon (P), hexagonal (H), and round (R). The FL-MOPL polymerization mechanism, swelling, degradation, and biocompatibility of the BSA-GMA hydrogel have been investigated. Furthermore, cytoskeleton and nucleus staining reveals that the R-scaffold with larger interior angle is more effective in maintaining chondrocyte morphology and preventing dedifferentiation. The scaffold's ability to maintain the chondrocytes' morphology improves as its shape matches that of the chondrocytes. These results suggest that the BSA-GMA scaffold is a suitable candidate for preventing chondrocyte differentiation and supporting cartilage tissue repair and regeneration. The proposed method for chondrocyte in vitro culture by developing biocompatible materials and flexible fabrication techniques would broaden the potential application of chondrocyte transplants as a viable treatment for cartilage-related diseases.

RFX1 regulates foam cell formation and atherosclerosis by mediating CD36 expression.

BACKGROUND AND AIMS: Atherosclerosis (AS) is a continuously low-grade inflammatory disease, and monocyte-derived macrophages play a vital role in AS pathogenesis. Regulatory factor X1 (RFX1) has been reported to participate in differentiation of various cells. Our previous report showed that RFX1 expression in CD14+ monocytes from AS patients was decreased and closely related to AS development. Macrophages mostly derive from monocytes and play an important role in AS plaque formation and stability. However, the functions of RFX1 in the formation of macrophage-derived foam cells and consequent AS development are unclear. METHODS: We explored the effects of RFX1 on oxidation low lipoprotein (ox-LDL)-stimulated foam cell formation and CD36 expression by increasing or silencing Rfx1 expression in mouse peritoneal macrophages (PMAs). The ApoE-/-Rfx1f/f or ApoE-/-Rfx1f/f Lyz2-Cre mice fed a high-fat diet for 24 weeks were used to further examine the effect of RFX1 on AS pathogenesis. We then performed dual luciferase reporter assays to study the regulation of RFX1 for CD36 transcription. RESULTS: Our results demonstrate that RFX1 expression was significantly reduced in ox-LDL induced foam cells and negatively correlated with lipid uptake in macrophages. Besides, Rfx1 deficiency in myeloid cells aggravated atherosclerotic lesions in ApoE-/- mice. Mechanistically, RFX1 inhibited CD36 expression by directly regulating CD36 transcription in macrophages. CONCLUSIONS: The reduction of RFX1 expression in macrophages is a vital determinant for foam cell formation and the initiation of AS, proving a potential novel approach for the treatment of AS disease.

Traditional Chinese medicine inspired dual-drugs loaded inhalable nano-therapeutics alleviated idiopathic pulmonary fibrosis by targeting early inflammation and late fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a highly debilitating and fatal chronic lung disease that is difficult to cure clinically. IPF is characterized by a gradual decline in lung function, which leads to respiratory failure and severely affects patient quality of life and survival. Oxidative stress and chronic inflammation are believed to be important pathological mechanisms underlying the onset and progression of IPF, and the vicious cycle of NOX4-derived ROS, NLRP3 inflammasome activation, and p38 MAPK in pulmonary fibrogenesis explains the ineffectiveness of single-target or single-drug interventions. In this study, we combined astragaloside IV (AS-IV) and ligustrazine (LIG) based on the fundamental theory of traditional Chinese medicine (TCM) of "tonifying qi and activating blood" and loaded these drugs onto nanoparticles (AS_LIG@PPGC NPs) that were inhalable and could penetrate the mucosal barrier. Our results suggested that inhalation of AS_LIG@PPGC NPs significantly improved bleomycin-induced lung injury and fibrosis by regulating the NOX4-ROS-p38 MAPK and NOX4-NLRP3 pathways to treat and prevent IPF. This study not only demonstrated the superiority, feasibility, and safety of inhalation therapy for IPF intervention but also confirmed that breaking the vicious cycle of ROS and the NLRP3 inflammasome is a promising strategy for the successful treatment of IPF. Moreover, this successful nanoplatform is a good example of the integration of TCM and modern medicine.

Investigating the mechanism of Sinisan formula in depression treatment: a comprehensive analysis using GEO datasets, network pharmacology, and molecular docking.

The herbal formula Sinisan (SNS) is a commonly used treatment for depression; however, its mechanism of action remains unclear. This article uses a combination of the GEO database, network pharmacology and molecular docking technologies to investigate the mechanism of action of SNS. The aim is to provide new insights and methods for future depression treatments. The study aims to extract effective compounds and targets for the treatment of depression from the T CMSP database. Relevant targets were searched using the GEO, Disgenet, Drugbank, PharmGKB and T T D databases, followed by screening of core targets. In addition, GO and KEGG pathway enrichment analyses were performed to explore potential pathways for the treatment of depression. Molecular docking was used to evaluate the potential targets and compounds and to identify the optimal core protein-compound complex. Molecular dynamics was used to further investigate the dynamic variability and stability of the complex. The study identified 118 active SNS components and 208 corresponding targets. Topological analysis of P P I networks identified 11 core targets. GO and KEGG pathway enrichment analyses revealed that the mechanism of action for depression involves genes associated with inflammation, apoptosis, oxidative stress, and the MAP K3 and P I3K-Akt signalling pathways. Molecular docking and dynamics simulations showed a strong binding affinity between these compounds and the screened targets, indicating promising biological activity. The present study investigated the active components, targets and pathways of SNS in the treatment of depression. Through a preliminary investigation, key signalling pathways and compounds were identified. These findings provide new directions and ideas for future research on the therapeutic mechanism of SNS and its clinical application in the treatment of depression.Communicated by Ramaswamy H. Sarma.

Network pharmacology and molecular docking to study the potential molecular mechanism of Qi Fu Yin for diabetic encephalopathy.

Diabetic encephalopathy is a chronic complication of diabetes that lacks an optimized treatment strategy. The present study sought to elucidate the potential molecular mechanism of Qi Fu Yin in improving diabetic encephalopathy through network pharmacology. The active components and target information of Qi Fu Yin were obtained from the TCMSP and Swiss target databases, while the target information of diabetic encephalopathy was sourced from Gene cards, OMIM, and Pharm Gkb databases. Enrichment analyses of KEGG and GO were conducted utilizing drug-disease common targets, while protein-protein interactions were predicted through the utilization of the STRING database platform. Subsequently, molecular docking was executed via Auto Dock Vina to authenticate the interaction between core components and core targets. The findings revealed that Qi Fu Yin exhibited 178 common targets with diabetic encephalopathy, and the enrichment analyses demonstrated that these targets were associated with lipid and atherosclerosis, AGE-RAGE signaling pathways, and other related pathways. The findings of the molecular docking indicated a favorable binding affinity between the active components of drug and the core targets, with EGF and quercetin exhibiting the most notable docking score. Additionally, the molecular dynamics simulation corroborated this high affinity. These results suggested that the active ingredients of Qi Fu Yin, including quercetin and kaempferol, may modulated the expression of genes such as IL10, TNF, EGF, and MMP2, thereby activating the AGE-RAGE signaling pathways and potentially serving as a therapeutic intervention for diabetic encephalopathy.Communicated by Ramaswamy H. Sarma.

Natural Product Cordycepin (CD) Inhibition for NRP1/CD304 Expression and Possibly SARS-CoV-2 Susceptibility Prevention on Cancers.

NRP1/CD304 is a typical membrane-bound co-receptor for the vascular endothelial cell growth factor (VEGF), semaphorin family members, and viral SARS-CoV-2. Cordycepin (CD) is a natural product or active gradient from traditional Chinese medicine (TCM) from Cordyceps militaris Link and Ophiocordyceps sinensis (Berk.). However, NRP1 expression regulation via CD in cancers and the potential roles and mechanisms of SARS-CoV-2 infection are not clear. In this study, online databases were analyzed, Western blotting and quantitative RT-PCR were used for NRP1 expression change via CD, molecular docking was used for NRP/CD interaction, and a syncytial formation assay was used for CD inhibition using a pseudovirus SARS-CoV-2 entry. As a result, we revealed that CD inhibits NRP1 expressed in cancer cells and prevents viral syncytial formation in 293T-hACE2 cells, implying the therapeutic potential for both anti-cancer and anti-viruses, including anti-SARS-CoV-2. We further found significant associations between NRP1 expressions and the tumor-immune response in immune lymphocytes, chemokines, receptors, immunostimulators, immune inhibitors, and major histocompatibility complexes in most cancer types, implying NRP1's roles in both anti-cancer and anti-SARS-CoV-2 entry likely via immunotherapy. Importantly, CD also downregulated the expression of NRP1 from lymphocytes in mice and downregulated the expression of A2AR from the lung cancer cell line H1975 when treated with CD, implying the NRP1 mechanism probably through immuno-response pathways. Thus, CD may be a therapeutic component for anti-cancer and anti-viral diseases, including COVID-19, by targeting NRP1 at least.

Exploring the repairing mechanisms of reduced graphene oxide (rGo) on the dysregulation of Xenopus Laevis larva hypothalamus-pituitary-thyroid (HPT) axis caused by chiral triazole fungicide metconazole.

Replacing chair fungicide racemate marketed product by its enantiomer with high activity and low environmental risk for application is a more environmentally friendly methods to control crop diseases. Moreover, carbon-based nanomaterials, with the desirable chemical and mechanical properties, exhibits latent reduce fungicide toxicity capability, while the mechanism is still poorly understood. Therefore, the present study characterized the toxicity of rac-metconazole (Mez; (1RS,5RS;1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H)) and its two cis-enantiomers as well as the repairing effect of reduced graphene oxide (rGo) on Xenopus Laevis larva by examining growth appearance indexes, Mez bioaccumulation, and hypothalamus-pituitary-thyroid (HPT) axis related hormone contents and gene expression after 14 and 28 days exposure. Compared with two cis-Mez, rac-Mez was preferentially bioaccumulated in tadpoles, and rac-Mez treatment showed a higher toxicity effect on tadpole including growth stage and body weight inhibition by dysregulating tadpole thyroid stimulating hormone (TSH) and thyroid hormone (TH) contents and related gene expression. Enantioselectivity was observed in two cis-Mez treatments. Compared with R,S-Mez, S,R-Mez treatment showed more severe damage on tadpole HPT axis related physiological and biochemical processes. rGo could effectively decrease the toxicity of Mez, especially shown the capacity of repairing the hormone dysregulation caused by R,S-Mez treatment. Moreover, the addition of rGo can decrease the bioaccumulation of Mez in tadpoles. Therefore, R,S-Mez is less toxic to Xenopus Laevis larva growth, and its toxicity could be effectively repaired by the addition of rGO.

Regulatory factor X1 induces macrophage M1 polarization by promoting DNA demethylation in autoimmune inflammation.

Abnormal macrophage polarization is generally present in autoimmune diseases. Overwhelming M1 macrophage activation promotes the continuous progression of inflammation, which is one of the reasons for the development of autoimmune diseases. However, the underlying mechanism is still unclear. Here we explore the function of Regulatory factor X1 (RFX1) in macrophage polarization by constructing colitis and lupus-like mouse models. Both in vivo and in vitro experiments confirmed that RFX1 can promote M1 and inhibit M2 macrophage polarization. Furthermore, we found that RFX1 promoted DNA demethylation of macrophage polarization-related genes by increasing APOBEC3A/Apobec3 expression. We identified a potential RFX1 inhibitor, adenosine diphosphate (ADP), providing a potential strategy for treating autoimmune diseases.

Cross-Scale Topography Achieved by MOPL with Positive Photoresist to Regulate the Cell Behavior.

Cross-scale micro-nano structures play an important role in semiconductors, MEMS, chemistry, and cell biology. Positive photoresist is widely used in lithography due to the advantages of high resolution and environmental friendliness. However, cross-scale micro-nano structures of positive photoresist are difficult to flexibly pattern, and the feature resolution is limited by the optical diffraction. Here, cross-scale patterned micro-nano structures are achieved using the positive photoresist based on the femtosecond laser maskless optical projection lithography (MOPL) technique. The dependence between exposure dose and groove width is comprehensively analyzed, and a feature size of 112 nm is obtained at 110 µW. Furthermore, large-area topography considering cell size is efficiently fabricated by the MOPL technique, which enables the regulation of cell behavior. The proposed protocol of achieving cross-scale structures with the exact size by MOPL of positive photoresist would provide new avenues for potential applications in nanoelectronics and tissue engineering.

Impacts of shipyard oil leakage on the PAHs and PCBs occurrence in Xiangshan Bay, China.

Here, we studied the shipyard impacts on the distribution of PAHs and PCBs in the semi-enclosed Xiangshan Bay, an important mariculture zone in China. The results showed that the shipyard caused a pollution plume for PAHs but not for PCBs. As characteristic pollutants of oil leakage, the PAHs had concentrations of up to 55.82 ng L-1 in the water, 2235.04 ng g-1 in suspended particulate matter (SPM), and 1489.60 ng g-1 in sediment. The PAHs in water and SPM were dominated by phenanthrene and pyrene that were mostly derived from lubricant and diesel, while those in sediments were dominated by the high-molecular-weight PAHs, such as indeno[1,2,3-c,d]pyrene. In contrast, the PCBs concentrations reached up to 10.17 ng L-1, 79.72 ng g-1, and 124.33 ng g-1 in the seawater, SPM, and sediment samples, respectively, and they did not show spatial patterns affected by the shipyard. Moreover, the health risk assessment indicated that the shipyard discharge caused a substantial PAHs ecological risk to the adjacent and downstream water environment. Therefore, point source discharge in semi-enclosed bays should be paid close attention to due to the strong pollutant transport effect.

Dynamic Color-Switching of Hydrogel Micropillar Array under Ethanol Vapor for Optical Encryption.

Responsive structural colors from artificially engineered micro/nanostructures are critical to the development of anti-counterfeiting, optical encryption, and intelligent display. Herein, the responsive structural color of hydrogel micropillar array is demonstrated under the external stimulus of ethanol vapor. Micropillar arrays with full color are fabricated via femtosecond laser direct writing by controlling the height and diameter of the micropillars according to the FDTD simulation. Color-switching of the micropillar arrays is achieved in <1 s due to the formation of liquid film among micropillars. More importantly, the structural color blueshift of the micropillar arrays is sensitive to the micropillar diameter, instead of the micropillar height. The micropillar array with a diameter of 772 nm takes 400 ms to complete blueshift under ethanol vapor, while that with a diameter of 522 nm blueshifts at 2400 ms. Microscale patterns are realized by employing the size-dependent color-switching of designed micropillar arrays under ethanol vapor. Moreover, Morse code and directional blueshift of structural colors are realized in the micropillar arrays. The advantages of controllable color-switching of the hydrogel micropillar array would be prospective in the areas of optical encryption, dynamic display, and anti-counterfeiting.

Synthesis of biocompatible BSA-GMA and two-photon polymerization of 3D hydrogels with free radical type I photoinitiator.

Although the development of three-dimensional (3D) printing technology is growing rapidly in the biomedical field, it remains a challenge to achieve arbitrary 3D structures with high resolution and high efficiency. Protein hydrogels fabricated by two- photon polymerization (TPP) have excellent mechanical properties, high precision, and 3D architecture. However, a large number of the amino acid group in bovine serum albumin (BSA) would be consumed when the protein-based hydrogels use dyes of free radical type II photoinitiators. In this study, we use glycidyl methacrylate (GMA) to modify BSA molecules to obtain a series of BSA-GMA materials, allowing the protein material to be two-photon polymerized with a water-soluble free radical type I photoinitiator. The precisely controllable 3D structure of the BSA-GMA hydrogel was fabricated by adjusting the concentration of the precursor solution, the degree of methacrylation, and the processing parameters of the TPP technique. Importantly, BSA-GMA materials are free of acidic hazardous substances. Meanwhile, the water-soluble initiator lithium phenyl (2,4,6-trimethylbenzoyl) phosphite (LAP) allows TPP on the vinyl group of the GMA chain and thus without consuming its amino acid group. The as-prepared BSA-GMA hydrogel structure exhibits excellent autofluorescence imaging, pH responsiveness, and biocompatibility, which would provide new avenues for potential applications in tissue engineering and biomedical fields to meet specific biological requirements.

Recent Advances for Dynamic-Based Therapy of Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease, which may lead to high morbidity and mortality. Currently, the clinical treatment strategy for AS is administering drugs and performing surgery. However, advanced therapy strategies are urgently required because of the deficient therapeutic effects of current managements. Increased number of energy conversion-based organic or inorganic materials has been used in cancer and other major disease treatments, bringing hope to patients with the development of nanomedicine and materials. These treatment strategies employ specific nanomaterials with specific own physiochemical properties (external stimuli: light or ultrasound) to promote foam cell apoptosis and cholesterol efflux. Based on the pathological characteristics of vulnerable plaques, energy conversion-based nano-therapy has attracted increasing attention in the field of anti-atherosclerosis. Therefore, this review focuses on recent advances in energy conversion-based treatments. In addition to summarizing the therapeutic effects of various techniques, the regulated pathological processes are highlighted. Finally, the challenges and prospects for further development of dynamic treatment for AS are discussed.

Dual-Stimuli Cooperative Responsive Hydrogel Microactuators Via Two-Photon Lithography.

With the development of bionics as well as materials science, intelligent soft actuators have shown promising applications in many fields such as soft robotics, sensing, and remote manipulation. Microfabrication technologies have enabled the reduction of the size of responsive soft actuators to the micron level. However, it is still challenging to construct microscale actuators capable of responding to different external stimuli in complex and diverse conditions. Here, this work demonstrates a dual-stimuli cooperative responsive hydrogel microactuator by asymmetric fabrication via femtosecond laser direct writing. The dual response of the hydrogel microstructure is achieved by employing responsive hydrogel with functional monomer 2-(dimethylamino)ethyl methacrylate. Raman spectra of the hydrogel microstructures suggest that the pH and temperature response of the hydrogel is generated by the changes in tertiary amine groups and hydrogen bonds, respectively. The asymmetric hydrogel microstructures show opposite bending direction when being heated to high temperature or exposed to acid solution, and can independently accomplish the grasp of polystyrene microspheres. Moreover, this work depicts the cooperative response of the hydrogel microactuator to pH and temperature at the same time. The dual-stimuli cooperative responsive hydrogel microactuators will provide a strategy for designing and fabricating controllable microscale actuators with promising applications in microrobotics and microfluidics.

Mechanical thrombectomy combined with intravenous thrombolysis for acute ischemic stroke: a systematic review and meta-analyses.

To assess the clinical value of mechanical thrombectomy (MT) combined with intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) by comparing it with the MT alone. In this study, we conducted a comprehensive meta-analysis of both observational and randomized controlled studies (RCTs) to investigate various outcomes. Our search for relevant studies was conducted between January 2011 and June 2022 in four major databases: PubMed, Embase, WOS, and Cochrane Library. We collected data on several outcomes, including functional independence (FI; defined as modified Rankin Scale score of 0 to 2), excellent outcomes (mRS 0-1), successful recanalization (SR), symptomatic intracerebral hemorrhage (sICH), any intracerebral hemorrhage (aICH), and mortality at three months or discharge. The primary efficacy outcome and safety outcome were FI and sICH, respectively, whereas excellent outcomes and SR were considered secondary efficacy outcomes. Additionally, mortality and aICH were analyzed as secondary safety outcomes. We employed the Mantel-Haenszel fixed-effects model for RCTs when I2 < 50%, otherwise the random-effects model was utilized. For observational studies and subgroup analyses, we used the random-effects model to minimize potential bias. A total of 55 eligible studies (nine RCTs and 46 observational studies) were included. For RCTs, the MT + IVT group was superior in FI (OR: 1.27, 95% CI: 1.11-1.46), excellent outcomes (OR: 1.21, 95% CI: 1.03-1.43), SR (OR: 1.23, 95% CI: 1.05-1.45), mortality (OR: 0.72, 95% CI: 0.54-0.97) in crude analyses. In adjusted analyses, the MT + IVT group reduced the risk of mortality (OR: 0.65, 95% CI: 0.49-0.88). However, the difference in FI between the MT + IVT group and the MT alone group was not significant (OR: 1.17, 95% CI: 0.99-1.38, Fig. 3a). For observational studies, the results of FI (OR: 1.34, 95% CI: 1.16-1.33), excellent outcomes (OR: 1.30, 95% CI: 1.09-1.54), SR (OR: 1.23, 95% CI: 1.05-1.44), mortality (OR: 0.70, 95% CI: 0.64-0.77) in the MT + IVT group were better. Additionally, the MT + IVT group increased the risk of hemorrhagic transformation (HT) including sICH (OR: 1.16, 95% CI: 1.11-1.21) and aICH (OR: 1.24, 95% CI: 1.05-1.46) in crude analyses. In adjusted analyses, significant better outcomes were seen in the MT + IVT group on FI (OR: 1.36, 95% CI: 1.21-1.52), excellent outcomes (OR: 1.49, 95% CI: 1.26-1.75), and mortality (OR: 0.73, 95% CI: 0.56-0.94). The MT + IVT therapy did improve the prognosis for AIS patients and did not increase the risk of HT compared with MT alone therapy.