Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity.

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.

Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

Efficient Fizeau drag from Dirac electrons in monolayer graphene.

Fizeau demonstrated in 1850 that the speed of light can be modified when it is propagating in moving media1. However, such control of the light speed has not been achieved efficiently with a fast-moving electron media by passing an electrical current. Because the strong electromagnetic coupling between the electron and light leads to the collective excitation of plasmon polaritons, it is hypothesized that Fizeau drag in electron flow systems manifests as a plasmonic Doppler effect. Experimental observation of the plasmonic Doppler effect in electronic systems has been challenge because the plasmon propagation speed is much faster than the electron drift velocity in conventional noble metals. Here we report direct observation of Fizeau drag of plasmon polaritons in strongly biased monolayer graphene by exploiting the high electron mobility and the slow plasmon propagation of massless Dirac electrons. The large bias current in graphene creates a fast-drifting Dirac electron medium hosting the plasmon polariton. This results in non-reciprocal plasmon propagation, where plasmons moving with the drifting electron media propagate at an enhanced speed. We measure the Doppler-shifted plasmon wavelength using cryogenic near-field infrared nanoscopy, which directly images the plasmon polariton mode in the biased graphene at low temperature. We observe a plasmon wavelength difference of up to 3.6 per cent between a plasmon moving with and a plasmon moving against the drifting electron media. Our findings on the plasmonic Doppler effect provide opportunities for electrical control of non-reciprocal surface plasmon polaritons in non-equilibrium systems.

Surface spectroscopy and surface-bulk hybridization of Weyl semimetals.

Weyl semimetal showing open-arc surface states is a prominent example of topological quantum matter in three dimensions. With the bulk-boundary correspondence present, nontrivial surface-bulk hybridization is inevitable but less understood. Spectroscopies have been often limited to verifying the existence of surface Fermi arcs, whereas its spectral shape related to the hybridization profile in energy-momentum space is not well studied. We present an exactly solvable formalism at the surface for a wide range of prototypical Weyl semimetals. The resonant surface state and the bulk influence coexist as a surface-bulk hybrid and are treated in a unified manner. Directly accessible to angle-resolved photoemission spectroscopy, we analytically reveal universal information about the system obtained from the spectroscopy of resonant topological states. We systematically find inhomogeneous and anisotropic singular responses around the surface-bulk merging borderline crossing Weyl points, highlighting its critical role in the Weyl topology. The response in scanning tunneling spectroscopy is also discussed. The results will provide much-needed insight into the surface-bulk-coupled physical properties and guide in-depth spectroscopic investigation of the nontrivial hybrid in many topological semimetal materials.

Sulfion oxidation assisting self-powered hydrogen production system based on efficient catalysts from spent lithium-ion batteries.

Converting spent lithium-ion batteries (LIBs) and industrial wastewater into high-value-added substances by advanced electrocatalytic technology is important for sustainable energy development and environmental protection. Here, we propose a self-powered system using a home-made sulfide fuel cell (SFC) to power a two-electrode electrocatalytic sulfion oxidation reaction (SOR)-assisted hydrogen (H2) production electrolyzer (ESHPE), in which the sulfion-containing wastewater is used as the liquid fuel to produce clean water, sulfur, and hydrogen. The catalysts for the self-powered system are mainly prepared from spent LIBs to reduce the cost, such as the bifunctional Co9S8 catalyst was prepared from spent LiCoO2 for SOR and hydrogen evolution reaction (HER). The Fe-N-P codoped coral-like carbon nanotube arrays encapsulated Fe2P (C-ZIF/sLFP) catalyst was prepared from spent LiFePO4 for oxygen reduction reaction. The Co9S8 catalyst shows excellent catalytic activities in both SOR and HER, evidenced by the low cell voltage of 0.426 V at 20 mA cm-2 in ESHPE. The SFC with Co9S8 as anode and C-ZIF/sLFP as cathode exhibits an open-circuit voltage of 0.69 V and long discharge stability for 300 h at 20 mA cm-2. By integrating the SFC and ESHPE, the self-powered system delivers an impressive hydrogen production rate of 0.44 mL cm-2 min-1. This work constructs a self-powered system with high-performance catalysts prepared from spent LIBs to transform sulfion-containing wastewater into purified water and prepare hydrogen, which is promising to achieve high economic efficiency, environmental remediation, and sustainable development.

Uncoordinated chemistry enables highly conductive and stable electrolyte/filler interfaces for solid-state lithium-sulfur batteries.

Composite-polymer-electrolytes (CPEs) embedded with advanced filler materials offer great promise for fast and preferential Li+ conduction. The filler surface chemistry determines the interaction with electrolyte molecules and thus critically regulates the Li+ behaviors at the interfaces. Herein, we probe into the role of electrolyte/filler interfaces (EFI) in CPEs and promote Li+ conduction by introducing an unsaturated coordination Prussian blue analog (UCPBA) filler. Combining scanning transmission X-ray microscope stack imaging studies and first-principle calculations, fast Li+ conduction is revealed only achievable at a chemically stable EFI, which can be established by the unsaturated Co-O coordination in UCPBA to circumvent the side reactions. Moreover, the as-exposed Lewis-acid metal centers in UCPBA efficiently attract the Lewis-base anions of Li salts, which facilitates the Li+ disassociation and enhances its transference number (tLi+). Attributed to these superiorities, the obtained CPEs realize high room-temperature ionic conductivity up to 0.36 mS cm-1 and tLi+ of 0.6, enabling an excellent cyclability of lithium metal electrodes over 4,000 h as well as remarkable capacity retention of 97.6% over 180 cycles at 0.5 C for solid-state lithium-sulfur batteries. This work highlights the crucial role of EFI chemistry in developing highly conductive CPEs and high-performance solid-state batteries.

Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSCs function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone 3 modifications at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Inhibition of the RLR signaling pathway by SARS-CoV-2 ORF7b is mediated by MAVS and abrogated by ORF7b-homologous interfering peptide.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and characterized by dysregulated immune response. Studies have shown that the SARS-CoV-2 accessory protein ORF7b induces host cell apoptosis through the tumor necrosis factor alpha (TNF-α) pathway and blocks the production of interferon beta (IFN-ß). The underlying mechanism remains to be investigated. In this study, we found that ORF7b facilitated viral infection and production, and inhibited the RIG-I-like receptor (RLR) signaling pathway through selectively interacting with mitochondrial antiviral-signaling protein (MAVS). MAVS439-466 region and MAVS Lys461 were essential for the physical association between MAVS and ORF7b, and the inhibition of the RLR signaling pathway by ORF7b. MAVSK461/K63 ubiquitination was essential for the RLR signaling regulated by the MAVS-ORF7b complex. ORF7b interfered with the recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) and the activation of the RLR signaling pathway by MAVS. Furthermore, interfering peptides targeting the ORF7b complex reversed the ORF7b-suppressed MAVS-RLR signaling pathway. The most potent interfering peptide V disrupts the formation of ORF7b tetramers, reverses the levels of the ORF7b-inhibited physical association between MAVS and TRAF6, leading to the suppression of viral growth and infection. Overall, this study provides a mechanism for the suppression of innate immunity by SARS-CoV-2 infection and the mechanism-based approach via interfering peptides to potentially prevent SARS-CoV-2 infection.IMPORTANCEThe pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and continues to be a threat to public health. It is imperative to understand the biology of SARS-CoV-2 infection and find approaches to prevent SARS-CoV-2 infection and ameliorate COVID-19. Multiple SARS-CoV-2 proteins are known to function on the innate immune response, but the underlying mechanism remains unknown. This study shows that ORF7b inhibits the RIG-I-like receptor (RLR) signaling pathway through the physical association between ORF7b and mitochondrial antiviral-signaling protein (MAVS), impairing the K63-linked MAVS polyubiquitination and its recruitment of tumor necrosis factor receptor-related factor 6 (TRAF6) to MAVS. The most potent interfering peptide V targeting the ORF7b-MAVS complex may reverse the suppression of the MAVS-mediated RLR signaling pathway by ORF7b and prevent viral infection and production. This study may provide new insights into the pathogenic mechanism of SARS-CoV-2 and a strategy to develop new drugs to prevent SARS-CoV-2 infection.

Itaconate inhibits CD103 + T RM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM . APPROACH AND RESULTS: The numbers of intrahepatic CD103 + T RM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T RM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103 + T RM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103 + T RM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103 + T RM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8 + T cells. Moreover, 4-OI reduced intrahepatic CD103 + T RM and ameliorated liver injury in murine models of PSC. CONCLUSIONS: Itaconate exerted immunomodulatory activity on CD103 + T RM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103 + T RM with itaconate has therapeutic potential in PSC.

GPRASP1 loss-of-function links to arteriovenous malformations by endothelial activating GPR4 signals.

Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies.

Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia.

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3- and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3- secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.

High-frequency repetitive transcranial magnetic stimulation promotes ipsilesional functional hyperemia and motor recovery in mice with ischemic stroke.

Neurovascular decoupling plays a significant role in dysfunction following an ischemic stroke. This study aimed to explore the effect of low- and high-frequency repetitive transcranial magnetic stimulation on neurovascular remodeling after ischemic stroke. To achieve this goal, we compared functional hyperemia, cerebral blood flow regulatory factors, and neurochemical transmitters in the peri-infract cortex 21 days after a photothrombotic stroke. Our findings revealed that low- and high-frequency repetitive transcranial magnetic stimulation increased the real-time cerebral blood flow in healthy mice and improved neurobehavioral outcomes after stroke. Furthermore, high-frequency (5-Hz) repetitive transcranial magnetic stimulation revealed stronger functional hyperemia recovery and increased the levels of post-synaptic density 95, neuronal nitric oxide synthase, phosphorylated-endothelial nitric oxide synthase, and vascular endothelial growth factor in the peri-infract cortex compared with low-frequency (1-Hz) repetitive transcranial magnetic stimulation. The magnetic resonance spectroscopy data showed that low- and high-frequency repetitive transcranial magnetic stimulation reduced neuronal injury and maintained excitation/inhibition balance. However, 5-Hz repetitive transcranial magnetic stimulation showed more significant regulation of excitatory and inhibitory neurotransmitters after stroke than 1-Hz repetitive transcranial magnetic stimulation. These results indicated that high-frequency repetitive transcranial magnetic stimulation could more effectively promote neurovascular remodeling after stroke, and specific repetitive transcranial magnetic stimulation frequencies might be used to selectively regulate the neurovascular unit.

Robust miniature Cas-based transcriptional modulation by engineering Un1Cas12f1 and tethering Sso7d.

The miniature V-F CRISPR-Cas12f system has been repurposed for gene editing and transcription modulation. The small size of Cas12f satisfies the packaging capacity of adeno-associated virus (AAV) for gene therapy. However, the efficiency of Cas12f-mediated transcriptional activation varies among different target sites. Here, we developed a robust miniature Cas-based transcriptional activation or silencing system using Un1Cas12f1. We engineered Un1Cas12f1 and the cognate guide RNA and generated miniCRa, which led to a 1,319-fold increase in the activation of the ASCL1 gene. The activity can be further increased by tethering DNA-binding protein Sso7d to miniCRa and generating SminiCRa, which reached a 5,628-fold activation of the ASCL1 gene and at least hundreds-fold activation at other genes examined. We adopted these mutations of Un1Cas12f1 for transcriptional repression and generated miniCRi or SminiCRi, which led to the repression of ∼80% on average of eight genes. We generated an all-in-one AAV vector AIOminiCRi used to silence the disease-related gene SERPINA1. AIOminiCRi AAVs led to the 70% repression of the SERPINA1 gene in the Huh-7 cells. In summary, miniCRa, SminiCRa, miniCRi, and SminiCRi are robust miniature transcriptional modulators with high specificity that expand the toolbox for biomedical research and therapeutic applications.

PRMT5-mediated homologous recombination repair is essential to maintain genomic integrity of neural progenitor cells.

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.

Nonequilibrium topological spin textures in momentum space.

SignificanceOptically excited systems can host unprecedented phenomena and reveal key information. The spin-channel physics in the photoexcited dynamics of quantum matter remains largely unexplored. This study finds the topological surface state under contemporary time-resolved pump-probe spectroscopy an exceptionally capable platform in this regard. Spin signals exhibit interesting tornado-like spiral patterns, and the unusual topological optical activity can be indicative of spintronic applications. This exemplifies a purely nonequilibrium topological winding phenomenon, where all the hidden helicity factors in the light-matter-coupled system are robustly encoded. These results open a direction of nonequilibrium topological spin states in quantum materials.

Injectable Fluorescent Neural Interfaces for Cell-Specific Stimulating and Imaging.

Building on current explorations in chronic optical neural interfaces, it is essential to address the risk of photothermal damage in traditional optogenetics. By focusing on calcium fluorescence for imaging rather than stimulation, injectable fluorescent neural interfaces significantly minimize photothermal damage and improve the accuracy of neuronal imaging. Key advancements including the use of injectable microelectronics for targeted electrical stimulation and their integration with cell-specific genetically encoded calcium indicators have been discussed. These injectable electronics that allow for post-treatment retrieval offer a minimally invasive solution, enhancing both usability and reliability. Furthermore, the integration of genetically encoded fluorescent calcium indicators with injectable bioelectronics enables precise neuronal recording and imaging of individual neurons. This shift not only minimizes risks such as photothermal conversion but also boosts safety, specificity, and effectiveness of neural imaging. Embracing these advancements represents a significant leap forward in biomedical engineering and neuroscience, paving the way for advanced brain-machine interfaces.

Compressible and Elastic Reduced Graphene Oxide Sponge for Stable and Dendrite-Free Lithium Metal Anodes.

Dendritic Li deposition, an unstable solid-electrolyte interphase (SEI), and a nearly infinite relative volume change during cycling are three major obstacles to the practical application of Li metal batteries. Herein, we introduce a compressible and elastic reduced graphene oxide sponge (rGO-S) to simultaneously eliminate Li dendrite growth, stabilize the SEI, and accommodate the volume change. The volume change is contained by compressing and expanding the rGO-S anode, which effectively releases the Li plating-induced stress during cycling. The smooth and dense Li metal is deposited on rGO-S without dendrites, which preserves the SEI, reduces consumption of the electrolyte, and prevents the formation of Li debris. The half-cells employing rGO-S show a steady and high Coulombic efficiency. The Li@rGO-S symmetric cells demonstrate excellent cycling stability over 1200 cycles with a low overpotential. When paired with LiFePO4 (LFP), the Li@rGO-S||LFP full cells exhibit a high specific capacity (150.3 mAh g-1 at 1C), superior rate performance, and good capacity retention.

Sildenafil increases AAV9 transduction after a systemic administration and enhances AAV9-dystrophin therapeutic effect in mdx mice.

Adeno-associated virus (AAV) vectors have been successfully used to deliver genes for treating rare diseases. However, the systemic administration of high AAV vector doses triggers several adverse effects, including immune response, the asymptomatic elevation of liver transaminase levels, and complement activation. Thus, improving AAV transduction and reducing AAV dosage for treatment is necessary. Recently, we found that a phosphodiesterase-5 inhibitor significantly promoted AAV9 transduction in vitro by regulating the caveolae and macropinocytosis pathways. When AAV9-Gaussian luciferase (AAV9-Gluc) and AAV9-green fluorescent protein (AAV9-GFP) were injected intravenously into mice pre-treated with sildenafil, the expressions of Gluc in the plasma and GFP in muscle tissues significantly increased (P < 0.05). Sildenafil also improved Evans blue permeation in tissues. Additionally, we found that sildenafil promoted Treg proliferation, inhibited B-cell activation, and decreased anti-AAV9 IgG levels (P < 0.05). Furthermore, sildenafil significantly promoted Duchenne muscular dystrophy gene therapy efficacy using AAV9 in mdx mice; it increased micro-dystrophin gene expression, forelimb grip strength, and time spent on the rotarod test, decreased serum creatine kinase levels, and ameliorated histopathology by improving muscle cell morphology and reducing fibrosis (P < 0.05). These results show that sildenafil significantly improved AAV transduction, suppressed the levels of anti-AAV9 IgG, and enhanced the efficacy of gene therapy.

Self-Assembly of Ultrathin, Ultrastrong Layered Membranes by Protic Solvent Penetration.

Flexible membranes with ultrathin thickness and excellent mechanical properties have shown great potential for broad uses in solid polymer electrolytes (SPEs), on-skin electronics, etc. However, an ultrathin membrane (<5 µm) is rarely reported in the above applications due to the inherent trade-off between thickness and antifailure ability. We discover a protic solvent penetration strategy to prepare ultrathin, ultrastrong layered films through a continuous interweaving of aramid nanofibers (ANFs) with the assistance of simultaneous protonation and penetration of a protic solvent. The thickness of a pure ANF film can be controlled below 5 µm, with a tensile strength of 556.6 MPa, allowing us to produce the thinnest SPE (3.4 µm). The resultant SPEs enable Li-S batteries to cycle over a thousand times at a high rate of 1C due to the small ionic impedance conferred by the ultrathin characteristic and regulated ionic transportation. Besides, a high loading of the sulfur cathode (4 mg cm-2) with good sulfur utilization was achieved at a mild temperature (35 °C), which is difficult to realize in previously reported solid-state Li-S batteries. Through a simple laminating process at the wet state, the thicker film (tens of micrometers) obtained exhibits mechanical properties comparable to those of thin films and possesses the capability to withstand high-velocity projectile impacts, indicating that our technique features a high degree of thickness controllability. We believe that it can serve as a valuable tool to assemble nanomaterials into ultrathin, ultrastrong membranes for various applications.

Machine Learning for Experimental Reactivity of a Set of Metal Clusters toward C-H Activation.

Understanding the mechanisms of C-H activation of alkanes is a very important research topic. The reactions of metal clusters with alkanes have been extensively studied to reveal the electronic features governing C-H activation, while the experimental cluster reactivity was qualitatively interpreted case by case in the literature. Herein, we prepared and mass-selected over 100 rhodium-based clusters (RhxVyOz- and RhxCoyOz-) to react with light alkanes, enabling the determination of reaction rate constants spanning six orders of magnitude. A satisfactory model being able to quantitatively describe the rate data in terms of multiple cluster electronic features (average electron occupancy of valence s orbitals, the minimum natural charge on the metal atom, cluster polarizability, and energy gap involved in the agostic interaction) has been constructed through a machine learning approach. This study demonstrates that the general mechanisms governing the very important process of C-H activation by diverse metal centers can be discovered by interpreting experimental data with artificial intelligence.