Advanced Science

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Online ISSN: 2198-3844

Disciplines: General & Introductory Materials Science

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Aβ disintegrate FapC and CsgA amyloids of P. aeruginosa and E. coli. A–C) ThT assay showing disintegration of 50 µm FapC or CsgA preformed fibrils at 37 °C in the presence of 0 to 7.5 µm of Aβ monomers (n = 3). D) TEM images of FapC and CsgA fibrils incubated with or without Aβ (3.5 µm), FapC incubated with Aβ shows small amorphous species whereas short length fibrils were produced from CsgA' interaction with Aβ (scale bar: 100 nm). E) Dynamic light scattering (DLS) was performed to further characterized the change in fibrils size (n = 3). Both FapC or CsgA with Aβ showed significant size reduction (**, p < 0.005). F) In CD spectra, FapC or CsgA incubated with Aβ showed negative peaks at 222/212 nm and 222/208 nm respectively, whereas the fibrils incubated without Aβ showed minima at 214 nm. Thus, showing that Aβ induces a noticeable transition from β‐sheet to α‐helices. G) Secondary structures of FapC and CsgA alone and with Aβ. In FapC fibrils incubated with Aβ, β‐sheet content was reduced to 32% from 47% whereas for CsgA fibrils, β‐sheet content was decreased from 42% to 39%. A11 oligomers and anti‐Aβ immunostaining (H) and fluorescence quantification (I) of FapC + Aβ mixture showed positive staining for Aβ while negative for A11. Aβ oligomers formed under similar in vitro conditions were used as a positive control for A11 staining. J,K) FapC and CsgA binding affinity with Aβ was analyzed with ELISA and the dissociation constant (Kd) was calculated. CsgA showed significantly higher (22.9 ± 4.5 µm) dissociation with Aβ in comparison to FapC 6.2 ± 1.9 µm (*, p < 0.05).

Aβ dissolved the biofilms made by the live culture of P. aeruginosa (PAO1) and E. coli (K‐12). A) Schematic illustration of Aβ dissolving microbial biofilms. B,C) K‐12, PAO1, CsgA mutant (MC4100), and FapC mutant (Pseudomonas UK4) cultures (optical density OD 0.3) were grown for 48 h in the wells of 96‐well plates with peg lid and biofilms were formed on the pegs. The biofilms were incubated with Aβ (0–7.5 µm) and stained with crystal violet dye (n = 3). Aβ at 3.5 µm significantly reduced biofilm synthesis (*, p < 0.05). D) PAO1 and K‐12 microbial cultures were grown overnight on small (100 mm) glass petri dishes. Biofilms formed at the glass surfaces were gently washed with PBS and treated with Aβ (3.5 µm) for 24 h (37 °C). After incubation with Aβ, biofilms were treated with 0.1% crystal violet stain for 15 min and images were taken by a stereomicroscope and brightfield channel (scale bar: 100 µm). Biofilms treated with Aβ were disintegrated in contrast to PBS control. ThT (100 µm, 15 min) labelled biofilms showed similar biofilm breakage into smaller fragments with Aβ (scale bar: 100 µm). Similarly, TEM was used to examine the fragmented morphology of disintegrated microbial biofilms treated with Aβ. K‐12 showed 400–500 nm and for PAO1 100–200 nm biofilm chunks were observed (scale bar: 200 nm).

SEM imaging of PAO1 and K‐12 biofilms after treatment with Aβ. Microbial cultures treated with Aβ were further examined in SEM. K‐12 and PAO1 cultures treated with Aβ (3.5 µm) both revealed substantial reduction in fimbriae‐like biofilm structures in Aβ treated samples, as compared to PBS‐treated samples.

Aβ targets and co‐localises with FapC and CsgA amyloids in vivo. 5 days post‐fertilization (dfp) zebrafish larvae were selected and cerebrally microinjected (50 nL) with Alexa647 labelled 1 µm Aβ. A) Whole‐mount fluorescent imaging detected Aβ‐Alexa647 around main artery notochord and no fluoresce was observed in control larvae. B) In another group of 5 dfp zebrafish larvae, unlabelled Aβ peptide (50 nL, 1 µm) was cerebrally microinjected (n = 20). After 4 h trunk was separated from the head and homogenized. MALDI analysis from trunk regions detected Aβ peak at a molecular weight of 4538 mz⁻¹. C) Microbial amyloids FapC or CsgA were labelled with Alexa488 and microinjected to the tail region of 5 dfp zebrafish larvae together with Aβ‐Alexa647 cerebrally microinjected. Larvae (lateral side) at 4 h post microinjection were fluorescently imaged, Aβ was found to be colocalized with D) FapC or E) CsgA, while no fluorescence was observed in control F). G) Pearson's Coefficient revealed significant colocalization of Aβ with FapC or CsgA (**, p < 0.005).

A) Aβ increases the anti‐microbial susceptibility of P. aeruginosa and E. coli. Microbial cultures of PAO1 and K‐12 were grown overnight (OD 0.3, at 37 °C) and subjected to series of dilutions of Aβ (0–1 µm) and Pen (0–5 × 10⁻² U mL⁻¹) Strep (0–5 × 10⁻² µg mL⁻¹) in LB media (n = 6). Biofilm swabs form pegs were streaked on LB agar plate and number of surviving colonies were counted. B) Concentration‐dependent antimicrobial effect with Pen, Strep effect was evident, C) whereas Aβ antimicrobial effect was diminished at higher concentrations. To examine the anti‐microbial susceptibility of PAO1 and K‐12, microbial cultures were treated overnight with selected concentrations of Aβ (0.05 µm) mixed with Pen (5 × 10⁻⁶ U mL⁻¹) Strep (5 × 10⁻⁶ µg mL⁻¹) in LB media. Biofilm swabs were streaked on LB agar plate (D) that presented a significant reduction in the number of surviving colonies (E) (*, p < 0.05).

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Alzheimer's Progenitor Amyloid‐β Targets and Dissolves Microbial Amyloids and Impairs Biofilm Function

August 2023

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1,125 Reads

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Ka Hang Karen Chung

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338 reads in the past 30 days

Fundamentals of sound absorption. A) Schematic of the principle of sound transmission through the air. B) Schematic of the sound dissipation mechanisms through a porous absorber, and illustration of the physics of the viscous flow and thermal boundary layers. C) Schematic of the sound absorption measurement using the impedance tube technique. D) Illustrations of two common types of sound absorption curves.

An overview of the types of lattice structures. The fundamental features and examples of unit cells of A) truss, B) TPMS, C) plate, and D) hybrid lattice structures. For the hybrid structures, references used are as follows. TPMS hybrids: Reproduced with permission.[⁵⁹] Copyright 2019, Elsevier. BCC with hollow prismatic struts: Reproduced with permission.[⁵²] Copyright 2023, Elsevier. Truss in plate: Reproduced with permission.[⁶¹] Copyright 2023, Wiley. Interpenetrating: Reproduced with permission.[⁶⁴] Copyright 2021, Elsevier. Tube and plate: Reproduced with permission.[¹⁶] Copyright 2023, American Chemical Society. Self‐defined curvature: Reproduced with permission.[⁵⁶] Copyright 2019, Elsevier. E) Illustrations of the other characteristics of lattices, including the relative density, cell size, and repetition.

An overview of the current research on lattice structures for sound absorption, including illustrations of their structure and typical sound absorption curves. Lattices with absorption curves consisting of distinct resonance peaks. A) Illustrations of 3D printed metal FCC‐based truss and plate lattices and their sound absorption curves. Reproduced with permission.[¹¹] Copyright 2021, Wiley. B) Illustration of an interpenetrating lattice, and the sound absorption curves of the interpenetrating lattice and its constituents. Reproduced with permission.[¹⁴] Copyright 2023, American Chemical Society. C) Illustration of a bamboo‐inspired lattice, and the sound absorption curves of the bamboo‐inspired lattice and its solid truss and hollow truss counterparts. Reproduced with permission.[¹⁶] Copyright 2023, American Chemical Society. D) Illustrations of pore and cavity lattices and their sound absorption curves. Reproduced with permission.[¹⁸] Copyright 2020, Elsevier. E) Illustration of a simple cubic lattice, and the sound absorption curves of its low relative density and high relative density structures. Reproduced with permission.[¹⁰] Copyright 2022, Whoice Publishing. F) Illustration of primitive, gyroid, and diamond TPMS lattices and their sound absorption curves. Reproduced with permission.[²¹] Copyright 2020, Taylor & Francis. G) Illustration of a hollow truss lattice, and the sound absorption curves of the hollow truss and its constituent phases. Reproduced with permission.[¹³] Copyright 2022, Wiley. H) Illustration and the sound absorption curves of a truss lattice and its sonic blackhole composites. Reproduced with permission.[⁹] Copyright 2023, Elsevier. I) Illustration of a parallel heterogeneous lattice structure and its sound absorption curve. Reproduced with permission.[¹²] Copyright 2021, Wiley. J) Illustration of a functionally graded truss lattice, and the sound absorption curves of the functionally graded truss and its uniform counterpart. Reproduced with permission.[²⁷] Copyright 2019, Elsevier.

Schematic of the transfer matrix calculations for modelling the effective acoustic impedance for multi‐feature sound absorbers under the rigid backing condition. The A) case for multi‐layered absorber in series and the B) case for absorbers with heterogeneous features in parallel.

On the Helmholtz resonance mechanism and MLHR‐based lattice structures. A) The cross sectional view of a typical Helmholtz resonator and key acoustical geometries influencing its resonant frequency. B) The morphology of a MLHR, or MPP, and illustrations of the key acoustical geometries influencing its resonant frequency, and the transfer matrices. C) Illustrations of a cubic plate lattice with unit that resembles a Helmholtz resonator, and how the discretization of its layers to be modelled as an MLHR. Reproduced with permission.[¹⁷] Copyright 2022, Taylor & Francis. D) Illustrations of the Helmholtz acoustical geometries, from the cross sectional view, of a truss lattice. Reproduced with permission.[¹³] Copyright 2022, Wiley. E) Illustrations of the Helmholtz acoustical geometries of a plate lattice with pores. F) For a complex plate lattice, illustration of the i) Helmholtz acoustical geometries of the unit cell, and ii) discretization of the lattice into two types of layers, revealing its representative equivalent circuit. Reproduced with permission.[¹¹] Copyright 2021, Wiley.

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3D‐Printed Lattice Structures for Sound Absorption: Current Progress, Mechanisms and Models, Structural‐Property Relationships, and Future Outlook

November 2023

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284 reads in the past 30 days

Advances in Printed Electronic Textiles

November 2023

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290 Reads

Md Rashedul Islam

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177 reads in the past 30 days

Bioinspired Double‐Broadband Switchable Microwave Absorbing Grid Structures with Inflatable Kresling Origami Actuators

November 2023

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153 reads in the past 30 days

Atomic Layer Deposition—A Versatile Toolbox for Designing/Engineering Electrodes for Advanced Supercapacitors

November 2023

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153 Reads

Mohd Zahid Ansari

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Iftikhar Hussain

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Debananda Mohapatra

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Advanced Science is an interdisciplinary premium open access journal covering fundamental and applied research in materials science, physics and chemistry, medical and life sciences, as well as engineering. Advanced Science publishes cutting-edge research, selected through a strict and fair reviewing process and presented using highest quality production standards to create a premium open access journal. Top science enjoying maximum accessibility is the aim of this vibrant and innovative research publication platform.

Synthesis and characterizations of ZAlum adjuvant. a) Schematic illustration of the construction of ZAlum and ZAlum/OVA. b) TEM image of ZAlum. Scale bar = 500 nm. c) XRD patterns (Cu Kα radiation, from 5° to 80°) of ZAlum (red) and Alum (blue). a.u., arbitrary units. d) EDS mapping of a single ZAlum. Scale bar = 100 nm. e) Particle size distribution and Zeta potential (inset) of ZAlum (red) and Alum (blue) were elucidated via dynamic light scattering. f) Evaluation of relative hydrophobicity through Rose Bengal adsorption onto ZAlum (red) and Alum (blue). g) Colloidal stability of ZAlum/OVA nanovaccines in medium with 10% FBS by monitoring the particle size over time. Data are presented as the mean ± s.d. (n = 3).

Erythrocyte‐assisted systemic delivery enables dual accumulation of ZAlum/OVA nanovaccines in the spleen and tumor. a) Schematic illustrating the erythrocyte‐assisted systemic delivery approach, resulting in the accumulation of ZAlum/OVA nanovaccines in both the spleen and tumor. b,c) Representative ex vivo fluorescent images of livers (b) and spleens (c) at 24 h preinjected with different dosages of sRBCs (0, 1, 2 and 3 D) before Cy5‐labelled ZAlum/OVA nanovaccines administration. 1 D = 2×10⁸ cells. d) Spleen/liver accumulation ratios were computed based on fluorescence intensity data from (b) and (c) (n = 5). e) The mass of Zn per g of spleen after ZAlum/OVA nanovaccine injection with or without 3 D sRBCs pre‐injection (n = 3). f) Fluorescence quantification of tumors in (g) (n = 5). (g) Representative ex vivo fluorescent images of tumors at 24 h after i.v. injection of Cy5‐labelled ZAlum/OVA nanovaccines with or without 3 D sRBCs pre‐injection. h) The % ID per g of tumors after i.v. injection of ZAlum/OVA nanovaccines with or without sRBCs pre‐injection (n = 3). Data are presented as the mean ± s.d. Statistical significance was tested by one‐way ANOVA with Tukey's post hoc test.

ZAlum adjuvant enhances MHC‐I antigen presentation of DCs by inducing the autophagy pathway. a) Flow cytometry analysis of antigen uptake efficiency. b) Bio‐TEM images of DC2.4 cells following different treatments for 24 h. Vacuoles following autophagy are denoted by red arrows. Scale bar = 2 µm. c) Western blot analysis of LC3B‐I/II and P62 protein in DCs with different treatments. Rapamycin was used as a positive control. d‐j) DC2.4 cells were subjected to the following treatments: 1, control; 2, OVA; 3, Zn²⁺+OVA; 4, Alum/OVA; 5, Zn²⁺+ Alum/OVA; 6, ZAlum/OVA. d‐f) The expression of OVA‐specific MHC‐I presentation (d,e) and MHC‐II presentation (f) of DCs. g) Schematic illustration of ZAlum adjuvant enhances cross‐antigen presentation via the autophagy pathway. h‐j) The expression of CD86 (h), CD80 (i), and CD40 (j) on DC2.4 cells with different treatments. Data are presented as the means ± s.d. (n = 3). Statistical significance was tested by one‐way ANOVA with Tukey's post hoc test.

ZAlum/OVA nanovaccines trigger cell apoptosis and induce ICD in vitro. Tumor cells were subsequently treated as follows: 1, control; 2, OVA; 3, Zn²⁺+OVA; 4, Alum/OVA; 5, Zn²⁺+ Alum/OVA; 6, ZAlum/OVA. a) CLSM images (from up to down) of intracellular ROS level (DCFH‐DA staining) and mitochondrial membrane potential (JC‐1 staining) in B16F10‐OVA cells after incubating with indicated treatments. The increased JC‐1 monomer signal (green) denotes the decrease of mitochondrial membrane potential. Scale bar = 50 µm. b) ROS level in E.G7‐OVA cells with indicated treatments for flow cytometry analysis. c) The cell apoptosis study of B16F10‐OVA tumor cells after 24 h by Annevix‐V/PI kit. d) CLSM images (from up to down) of intracellular HMGB1 and CRT distribution in B16F10‐OVA cells treated with indicated treatments. Scale bar = 20 µm. e,f) Quantification of relative HMGB1 (e) and CRT (f) levels in (d). g,h) Quantitative analysis of the intracellular ATP level in B16F10‐OVA cells (g) and E.G7‐OVA cells (h) after different treatments. i,j) Phagocytosis of dying B16F10‐OVA cells (i) and E.G7‐OVA cells (j) by DC2.4 cells. Data are presented as the means ± s.d. (n = 3). Statistical significance was tested by one‐way ANOVA with Tukey's post hoc test.

Tumor therapeutic efficacy on melanoma and lymphoma mice. B16F10‐OVA and E.G7‐OVA tumor‐bearing mice were subsequently treated as follows: G1, control; G2, Zn²⁺+OVA; G3, ZAlum/OVA; G4, sRBC+ZAlum/OVA. a) Schematic illustrating the therapeutic procedure on the melanoma mice. b,c) The average (b) and individual (c) volume of the melanoma tumor with indicated treatments (n = 6). d) Representative TUNEL staining of melanoma tumors. Scale bar = 50 µm. e) Quantification of TUNEL‐positive cells (n = 3). f,g) Quantification of relative CRT (f) and HMGB1 (g) levels in (h) (n = 3). h) CRT exposure and HMGB1 release in tumor tissue from B16F10‐OVA tumor‐bearing mice with indicated treatments. Scale bar = 100 µm. i) Schematic illustrating the therapeutic procedure on the lymphoma mice. sj,k) The average (j) and individual (k) volume of the lymphoma tumor with indicated treatments (n = 6). Data are presented as the means ± s.d. Statistical significance was tested by one‐way ANOVA with Tukey's post hoc test.

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An Immunomodulatory Zinc‐Alum/Ovalbumin Nanovaccine Boosts Cancer Metalloimmunotherapy Through Erythrocyte‐Assisted Cascade Immune Activation

December 2023

Jing Zhao

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Lingxiao Zhang

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Pin Li

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Fangyuan Li

Cancer therapeutic vaccines are powerful tools for immune system activation and eliciting protective responses against tumors. However, their efficacy has often been hindered by weak and slow immune responses. Here, the authors introduce an immunization strategy employing senescent erythrocytes to facilitate the accumulation of immunomodulatory zinc‐Alum/ovalbumin (ZAlum/OVA) nanovaccines within both the spleen and solid tumors by temporarily saturating liver macrophages. This approach sets the stage for boosted cancer metalloimmunotherapy through a cascade immune activation. The accumulation of ZAlum/OVA nanovaccines in the spleen substantially enhances autophagy‐dependent antigen presentation in dendritic cells, rapidly initiating OVA‐specific T‐cell responses against solid tumors. Concurrently, ZAlum/OVA nanovaccines accumulated in the tumor microenvironment trigger immunogenic cell death, leading to the induction of individualized tumor‐associated antigen‐specific T cell responses and increased T cell infiltration. This erythrocyte‐assisted cascade immune activation using ZAlum/OVA nanovaccines results in rapid and robust antitumor immunity induction, holding great potential for clinical cancer metalloimmunotherapy.

Working states of aqueous Zn ion batteries. a) Summary of typical cathode materials and challenges of aqueous Zn ion batteries. b) The decoupled design for an aqueous Zn ion battery, which is separated by an ion selected membrane into an acidic chamber for ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ (de)intercalation and a neutral chamber for Zn stripping/deposition.

Electrochemical performance and corresponding structural evolution. a) Raman spectra of water and NaClO4 electrolyte. b) and c) The radial distribution function and coordinated number of NaClO4 and H⁺ + NaClO4 electrolyte. The dotted and the solid lines represent the coordinated number and the radial distribution function. d) Galvanostatic charge–discharge profiles of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation in H⁺ + NaClO4 electrolyte of first three cycles at the current density of 250 mA g⁻¹. e) CV curves of the first three cycles at the scan rate of 3 mV s⁻¹. f) Sampling sites in the CV curve. g) In situ XRD analysis of graphite structure in first two cycles. h) ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation mode.

Structure conversion during charge/discharge cycles. a‐c) HRTEM images of pristine, full charge, and discharge graphite electrodes. Insets are calculated interlayer spacings. d) Raman spectra of the pristine, fully charged, and discharged graphite electrodes. e) Magnified Raman spectra of G band. f) and g) X‐ray photoelectron spectroscopy of C 1s and Cl 2p of graphite at various potentials. h) The charge density difference of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ in graphite layers, and blue and yellow colors represent losing and accumulating electrons, respectively.

Theoretical investigations of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ (de)intercalation mechanism. a) Solvation mode of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ in the electrolyte. b) The ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation process that undergoes desolvation, adsorption and intercalation. c) The adsorption energy and intercalation energy of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation for stages 1 to 3. d) The activation energy of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation processes based on electrochemical impedance spectroscopy tests. e) The diffusion energy barrier of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ intercalation in graphite layers.

Electrochemical evaluations of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ (de)intercalation in the Zn‐graphite battery. a) CV curves of ClO4−${\mathrm{ClO}}_{\mathrm{4}}^ - $ (de)intercalation at different scan rates. b) log (i) versus log (v) plot at peak current and b values of four peaks by linear fit. c) Surface pseudocapacitive contribution at different scan rates. d) Charge/discharge profiles at different current densities. e) The decoupled configuration of the Zn‐graphite battery. f) The charge/discharge profiles of the first three cycles of decoupled aqueous Zn ion battery at the current of 100 mA g⁻¹. g) Rate capability and corresponding Coulombic efficiency of decoupled aqueous Zn‐ion battery. h) Cyclability at the current density of 200 mA g⁻¹. i) The comparison of the potential window between this work and recently reported aqueous Zn‐ion batteries.

Decoupled Design for Highly Efficient Perchlorate Anion Intercalation and High‐Energy Rechargeable Aqueous Zn‐Graphite Batteries

December 2023

Ying Zheng

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Ting Deng

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Xiaoyuan Shi

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Weitao Zheng

Seeking new cathode chemistry with high onset potential and compatibility with electrolytes has become a challenge for aqueous Zn ion batteries. Anion intercalation in graphite (4.5 V vs Li⁺/Li) possesses the potentiality but usually shows a competitive relationship with oxygen evolution reaction (OER) in aqueous solutions. Herein, a decoupled design is proposed to optimize a full utilization of perchlorate ion intercalation in graphite cathode by pH adjustment. Benefiting from the decoupled design, high Coulombic efficiency is obtained by decelerating the kinetic of OER in acidic media. The decoupled Zn‐graphite battery exhibits a wide potential window of 2.01 V, as well as an attractive energy density of 231 Wh kg⁻¹. In addition, a Zn‐graphite battery with SO42−${\mathrm{SO}}_4^{2 - }$ insertion is assembled, which demonstrates the capability of the proposed decoupled strategy to integrate novel electrode chemistries for high‐performance aqueous Zn‐based energy storage systems.

Results of leaching (left) and cycle (right) experiments. Reaction conditions: 1a (0.5 mmol), 2a (2 equiv), 3a (1.5 equiv), NaOtBu (1.5 equiv), recycled CuCl@POL‐NHC‐Ph (20 mg), DMF (0.25 M), 60 °C, 7 h. Isolated yield. The filtering time is ≈1 min.

Characterization results. a) Scanning electron microscopy image of CuCl@POL‐NHC‐Ph. b) TEM image of CuCl@POL‐NHC‐Ph. c) HAADF image of CuCl@POL‐NHC‐Ph. d) Energy‐dispersive X‐ray spectroscopy elemental mapping analysis of CuCl@POL‐NHC‐Ph. e) N2 adsorption–desorption isotherms, f) pore size distribution curves, g) Cu 2p XPS spectra of fresh CuCl@POL‐NHC‐Ph, and h) thermogravimetric analysis of CuCl@POL‐NHC‐Ph.

Results of DFT calculation.

Status of research on alkyne 1,2‐carboboration reactions.

Scope of alkynes for 1,2‐carboboration with 1‐iodobutane and B2pin2. [a] Reaction conditions: 1 (0.5 mmol), 2a (2 equiv), 3a (1.5 equiv), NaOtBu (1.5 equiv), CuCl@POL‐NHC‐Ph (20 mg, 4.67 wt.% Cu), DMF (0.25 M), 60°C, 7 h. Isolated yield. The value of β‐[B]:α‐[B] was determined by ¹H NMR. [b] Room temperature. [c] 1 Equiv B2pin2. [d] The reaction time was 12 h.

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Copper‐Metallized Porous N‐Heterocyclic Carbene Ligand Polymer‐Catalyzed Regio‐ and Stereoselective 1,2‐Carboboration of Alkynes

December 2023

Jun‐Song Jia

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Jin‐Rong Luo

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Wen‐Hao Li

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Hai‐Tao Tang

Alkenylboronates are highly versatile building blocks and valuable reagents in the synthesis of complex molecules. Compared with that of monosubstituted alkenylboronates, the synthesis of multisubstituted alkenylboronates is challenging. The copper‐catalyzed carboboration of alkynes is an operationally simple and straightforward method for synthesizing bis/trisubstituted alkenylboronates. In this work, a series of copper‐metallized N‐Heterocyclic Carbene (NHC) ligand porous polymer catalysts are designed and synthesized in accordance with the mechanism of carboboration. By using CuCl@POL‐NHC‐Ph as the optimal nanocatalyst, this study realizes the β‐regio‐ and stereoselective (syn‐addition) 1,2‐carboboration of alkynes (regioselectivity up to >99:1) with satisfactory yields and a wide range of substrates. This work not only overcomes the selectivity of carboboration but also provides a new strategy for the design of nanocatalysts and their application in organic synthesis.

Energy band diagram and proposed concept of the photodetector based on PG system (TaSe4)2I at room temperature.

Photo response characterization of (TaSe4)2I. a) SEM image of the prepared sample on CaF2 substrate (top panel) and optical image of the prepared exfoliated nanoribbon device on 285 nm SiO2/Si substrate (down panel, sample S1, Supporting Information). The channel area is ≈1um². b) Typical photoresponse under λ = 635 nm and λ = 4.64 µm excitation based on (TaSe4)2I nanoribbon device. c) Voltage‐dependent photoresponse under λ = 4.64 µm excitation. d) Top panel: Transmittance spectra from UV to LWIR region. Down panel: Photo responsivity from UV to LWIR region. e) Power‐dependent photo response in LWIR region. f) Photo response time from UV to LWIR region. The power density is fixed ≈6.7 mW mm⁻² for (b–d) and (f).

The photo response mechanism of (TaSe4)2I nanoribbons. a) TA setup. b) 2D TA spectrum under probe wavelength range of 4100–5100 nm. c) 2D TA spectrum under probe wavelength range of 6000–7000 nm. d) Nano‐FTIR absorption measurement under MWIR pulsed laser excitation on a 80 nm‐thick sample. e,f) Typical extracted carrier dynamics at probe wavelength of λ = 4300 and 6500 nm.

Responsivity, NEP, and detectivity comparison with reported single low‐dimensional materials‐based photodetectors.[4a‐d,5b,6,27,30,31,37] a) 1D PD is short for quasi‐1D 1D nanowire/nanoribbon‐based photodetectors; b) 2D PD is short for 2D material‐based photodetectors). c) NEP value comparison based on low‐dimensional materials worked within MWIR and LWIR region.[4a,b,37h,38] d) Measured detectivity comparison with reported single 2D material‐based photodetectors from MWIR region to LWIR region.[6b,37h,38a,39] The working temperature is room temperature unless it is specially labeled. The lines in Figure 4b are guiding to the eyes. Symbol ▲ indicates the defect related trap states to tune the photoresponse.

Ultrabroadband High Photoresponsivity at Room Temperature Based on Quasi‐1D Pseudogap System (TaSe4)2I

December 2023

Jialin Li

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Qing Li

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Junjian Mi

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[...]

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Limin Tong

Narrow bandgap materials have garnered significant attention within the field of broadband photodetection. However, the performance is impeded by diminished absorption near the bandgap, resulting in a rapid decline in photoresponsivity within the mid‐wave infrared (MWIR) and long‐wave infrared (LWIR) regions. Furthermore, they mostly worked in cryogenic temperature. Here, without the assistance of any complex structure and special environment, it is realized high responsivity covering ultra‐broadband wavelength range (Ultraviolet (UV) to LWIR) in a single quasi‐1D pseudogap (PG) system (TaSe4)2I nanoribbon, especially high responsivity (From 23.9 to 8.31 A W⁻¹) within MWIR and LWIR region at room temperature (RT). Through direct probing the carrier relaxation process with broadband time‐resolved transient absorption spectrum measurement, the underlying mechanism of majorly photoconductive effect is revealed, which causes an increased spectral weight extended to PG region. This work paves the way for realizing high‐performance uncooled MWIR and LWIR detection by using quasi‐1D PG materials.

a) Absorption spectrum of P3HT. b) device structure of the PM‐OPD based on the P3HT:PC71BM:CsPbBr3 NC ternary blend, in which positively polarized CsPbBr3 NCs within the photoactive layer trigger electrostatic interactions to electrons trapped in the PC71BM domains. c,d) Energy band diagram of c) the electric‐double‐layer‐based and d) ionic‐polarizable‐nanocrystal‐embedded PM‐OPDs under illumination.

a–f) 2D‐GIXD patterns of P3HT:PC71BM:CsPbBr3 NC (100:1:X, w/w; X = 0, 2, 4, 6, 8, and 10) blend films. g,h) Line‐cut profiles of P3HT:PC71BM:CsPbBr3 NC blend films along the g) qxy and h) qz axes.

EQE spectra of the optimized PM‐OPDs based on the P3HT:PC71BM:CsPbBr3 NC (100:1:X, w/w; X = 0, 2, 4, 6, 8, and 10) ternary blend films, measured under different reverse biases (−5, −10, −15, and −20 V).

a) ln(JsT⁻²) versus T⁻¹ plots derived from the temperature‐dependent J–V curves of the PM‐OPDs with (100:1:6, w/w) and without (100:1:0, w/w) CsPbBr3 NC. b) Experimental (solid lines with symbols) and simulated (dotted lines) R( = Jph/P)–V curves of the CsPbBr3‐NC‐free and CsPbBr3‐NC‐free PM‐OPDs.

a) Specific detectivity spectra of the optimized PM‐OPDs with (100:1:6, w/w) and without (100:1:0, w/w) CsPbBr3 NC. b–d) Bode b) and Jph–P c,d) plots of the optimized CsPbBr3‐NC‐free and CsPbBr3‐NC‐embedded PM‐OPDs. All measurements were conducted under a constant bias of −20 V.

Boosting the Performance of Photomultiplication‐Type Organic Photodiodes by Embedding CsPbBr3 Perovskite Nanocrystals

December 2023

Mingyun Kang

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Dong Hyeon Lee

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Juhee Kim

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Dae Sung Chung

In this study, it is demonstrated that CsPbBr3 perovskite nanocrystals (NCs) can enhance the overall performances of photomultiplication‐type organic photodiodes (PM‐OPDs). The proposed approach enables the ionic‐polarizable CsPbBr3 NCs to be evenly distributed throughout the depletion region of Schottky junction interface, allowing the entire trapped electrons within the depletion region to be stabilized, in contrast to previously reported interface‐limited strategies. The optimized CsPbBr3‐NC‐embedded poly(3‐hexylthiophene‐diyl)‐based PM‐OPDs exhibit exceptionally high external quantum efficiency, specific detectivity, and gain–bandwidth product of 2,840,000%, 3.97 × 10¹⁵ Jones, and 2.14 × 10⁷ Hz, respectively. 2D grazing‐incidence X–ray diffraction analyses and drift–diffusion simulations combined with temperature‐dependent J–V characteristic analyses are conducted to investigate the physics behind the success of CsPbBr3‐NC‐embedded PM‐OPDs. The results show that the electrostatic interactions generated by the ionic polarization of NCs effectively stabilize the trapped electrons throughout the entire volume of the photoactive layer, thereby successfully increasing the effective energy depth of the trap states and allowing efficient PM mechanisms. This study demonstrates how a hybrid‐photoactive‐layer approach can further enhance PM‐OPD when the functionality of inorganic inclusions meets the requirements of the target device.

The comparison of bare metal anode (Li, Zn) and COFs@metal anode (Li, Zn) for rechargeable batteries after cycling.

Development of COFs applied for Li and Zn metal anodes in rechargeable batteries.

a) COF models for various dimensions; b) hexagonal COF; c) rectangular COF; d) diamond COF; e) triangle COF; f) the different series of COF.

Different synthesis methods of COFs.

a) Reaction scheme of TpPa from Tp and Pa. b) Lithiophilic sites (N and O) in TpPa. c) Diagram of mechanical test by AFM. d) AFM images before and after puncture by the probe tip with loading force of 2 µN for TpPa, PVDF, P(VDF‐TrFE), and P(VDF‐TrFE‐CFE) films. e) CE of Li||Cu, Li||TpPa‐Cu cells and f) corresponding Li nucleation overpotentials at the first or 50th cycles in (e). Reproduced with permission.[¹⁰⁸] Copyright 2021, Wiley‐VCH GmbH.

+7

A Review on Covalent Organic Frameworks as Artificial Interface Layers for Li and Zn Metal Anodes in Rechargeable Batteries

December 2023

Yunyu Zhao

·

Kaiyong Feng

·

Yingjian Yu

Li and Zn metals are considered promising negative electrode materials for the next generation of rechargeable metal batteries because of their non‐toxicity and high theoretical capacity. However, the uneven deposition of metal ions (Li⁺, Zn²⁺) and the uncontrolled growth of dendrites result in poor electrochemical stability, unsatisfactory cycle life, and rapid capacity decay of batteries assembled with Li and Zn electrodes. Owing to the unique internal directional channels and abundant redox active sites of covalent organic frameworks (COFs), they can be used to promote uniform deposition of metal ions during stripping/electroplating through interface modification strategies, thereby inhibiting dendrite growth. COFs provide a new perspective in addressing the challenges faced by the anodes of Li metal batteries and Zn ion batteries. This article discusses the stability and types of COFs, and summarizes some novel COF synthesis methods. Additionally, it reviews the latest progress and optimization methods of using COFs for metal anodes to improve battery performance. Finally, the main challenges faced in these areas are discussed. This review will inspire future research on metal anodes in rechargeable batteries.

a) SEM image of BP. b) TEM and c) HRTEM images of BP. d) Lattice fringes and e) the corresponding fast flourier transform (FFT) pattern. f) Schematic of the operando‐pH and in situ QCM characterization. The left Zn is stripped and deposited onto the right Zn with a current density of 2 mA cm⁻². g) Frequency/mass signals and h) in situ pH alterations in f). i) Optical pictures of GF and BP@GF separators. j) SEM images under different magnifications and the corresponding EDS mapping of BP@GF separator. k) Initial plating voltage profiles of Zn||Cu half‐cells with GF and BP@GF separators at 2 mA cm⁻². Ex situ SEM images of plated Zn on Cu foil with various capacities for l) GF and m) BP@GF separators.

XPS spectra of S‐2p and P‐2p orbits for the platted Zn (10 mAh cm⁻²) in the Zn||Cu half‐cells with a) GF and b,c) BP@GF separators. d) 3D views of the PO4⁻ signals by TOF‐SIMS. e) Schematic of the in situ electrochemical GC device for quantitative detection of hydrogen evolution. Time‐resolved EC‐GC profiles and the corresponding contour maps of Zn||Zn symmetrical cells with f) GF and g) BP@GF separators at 5 mA cm⁻². h) Quantitative results of hydrogen evolution. i) Calculated HER free energy diagram of Zn (002), ZPO (100), and (101). j) Tafel curves of symmetric cell configurations with GF and BP@GF separators.

a) CE tests of Zn||Cu half‐cells with GF, GF#anode, GF#electrolyte, and BP@GF at 5 mA cm⁻² and 1 mAh cm⁻². GF, GF#anode, GF#electrolyte and BP@GF represent Zn||Cu half‐cell with GF separator and 2 m ZnSO4, ZPO@Zn||Cu half‐cell with GF separator and 2 m ZnSO4, Zn||Cu half‐cell with GF separator and 20 mM H3PO4/2 m ZnSO4, and Zn||Cu half‐cell with BP@GF separator and 2 m ZnSO4, respectively. The inset is the GCD curve in GF case. Time–voltage curves of Zn||Zn symmetrical cells with GF and BP@GF separators at b) 5 mA cm⁻² and 1 mAh cm⁻², c) 50 mA cm⁻² and 1 mAh cm⁻² and d) 50 mA cm⁻² and 10 mAh cm⁻². e) Comparison of the CPC and areal capacity between our work and very recent reports. Top‐view SEM mages (left), 3D confocal images (top right), and cross‐sectional images produced by FIB (lower right) of cycled Zn (100 h) in the Zn||Zn symmetrical cells with f) GF and g) BP@GF separators. h) XRD patterns of pristine Zn and cycled Zn (100 h) in the Zn||Zn symmetrical cells with GF and BP@GF separators.

Schematic diagram of a) challenges for Zn anode and b) mechanisms of BP@GF separator for improving the Zn issues. c) Cycle and d) Rate performances of Zn||V2O5·nH2O cells with GF and BP@GF separators. The mass loading of V2O5·nH2O is ≈1.5 mg cm⁻². e) GCD curves of Zn||V2O5·nH2O cell with BP@GF separator in d). f) Schematic illustration of the manufacture of cathode with high mass loadings. g) Photograph of V2O5·nH2O@FCP cathode, highlighting the flexibility and integrity in the bending state. h) Cycle performances of Zn||V2O5·nH2O@FCP cells with BP@GF separators at various high mass loadings. i) Cycle performances of Zn||V2O5·nH2O@FCP pouch cells with GF and BP@GF separators. j) The corresponding GCD curves of cells in i). k) Comparison of the cumulative capacity and areal capacity for the coin and pouch cells between our work and very recent reports.

Hydrolysis of Solid Buffer Enables High‐Performance Aqueous Zinc Ion Battery

December 2023

Hao Cheng

·

Shichao Zhang

·

Wenxuan Guo

·

[...]

·

Yingying Lu

Aqueous zinc (Zn) ion batteries (AZIBs) have not yet fulfilled their talent of high safety and low cost since the anode/electrolyte interface (AEI) has long been impeded by hydrogen evolution, surface corrosion, dendritic growth, and by‐product accumulation. Here, the hydrolysis of solid buffers is elaborately proposed to comprehensively and enduringly handle these issues. Take 2D layered black phosphorus (BP) as a hydrolytic subject. It is reported that the phosphoric acid generated by hydrolysis in an aqueous electrolyte produces a zinc phosphate (ZPO) rich solid electrolyte interphase (SEI) layer, which largely inhibits the dendrite growth, surface corrosion, and hydrogen evolution. Meanwhile, the hydrolytic phosphoric acid stabilizes the pH value near AEI, avoiding the accumulation of alkaline by‐products. Notably, compared with the disposable ZPO engineerings of anodic SEI pre‐construction and electrolyte additive, the hydrolysis strategy of BP can realize a dramatically prolonged protective effect. As a result, these multiple merits endow BP modified separator to achieve improved stripping/plating stability toward Zn anode with more than ten times lifespan enhancement in Zn||Zn symmetrical cell. More encouragingly, when coupled with a V2O5·nH2O cathode with ultra‐high loadings (34.1 and 28.7 mg cm⁻²), the cumulative capacities are remarkably promoted for both coin and pouch cells.

Characterization of CeO2 NPs, LDH and LDH‐CeO2. a) HRTEM and the corresponding SAED pattern and b) ABF‐STEM images of CeO2‐OA. Scale bar: 5 and 2 nm. c) Schematic diagram of atomic arrangement of CeO2‐OA NPs. d) TEM images of LDH‐CeO2 and corresponding SAED pattern in the inset. Scale bar: 200 nm. e) Elemental mapping images and f) EDS spectra of LDH‐CeO2. Scale bar: 50 nm. g) XRD patterns of LDH (black), CeO2‐OA (blue) and LDH‐CeO2 (red). h) FTIR spectra of LDH (black), CeO2‐OA (green), CeO2‐PEG‐COOH (blue) and LDH‐CeO2 (red). i) Zeta‐potentials of CeO2, LDH and LDH‐CeO2, and all values are presented as means ± s.d.

Enhanced ROS scavenging via acid neutralization by LDH‐CeO2. a) ESR spectra of •OH trapped by DMPO of different treatment groups. b) UV–vis absorbance spectra of MB after different treatments. c) Inhibition rate of H2O2 (CAT‐mimic activity) of different groups. d) ESR spectra of O2•‐ generated by OX + X system treated by various groups. e) Inhibition rates on O2•‐ (SOD‐mimic activity) by different groups. f) Inhibition rates on H2O2 and O2•‐ of LDH‐CeO2 under acidic condition for varied time periods. g) Mechanism of ROS scavenging ability of CeO2 NPs assisted by acid neutralization of LDH. All values are presented as means ± s.d, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, two‐tailed Student's t‐test.

Scavenging of ROS and subsequent anti‐inflammatory immune modulation on macrophages by LDH‐CeO2 in vitro. a) Confocal images and b) quantifications of DCFH‐DA⁺ (green) cells incubated with different groups. Scale bar: 50 µm. c) Flow cytometry analyses and d) corresponding quantifications of DCFH‐DA⁺ cells after different treatments. e) Flow cytometry analyses and f) corresponding quantifications of CD86⁺ macrophages treated by various groups. g) Flow cytometry analyses and h) corresponding quantifications of F4/80⁺CD86⁺ BMDMs after different treatments. Cytokines in supernatants collected from different groups measured by ELISA of i) IL‐6, j) TNF‐α and k) IL‐10. All values are presented as means ± s.d, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, two‐tailed Student's t‐test.

Remodeling the in vitro osteoclastic and osteogenic activity by LDH‐CeO2. a) Observations of osteoclast formation (pink) from the fusion of macrophage cells and its prevention by LDH‐CeO2 and b) corresponding quantifications. Scale bar: 50 µm. c) Measurements of Osteoblast apoptosis by flow cytometry and d) corresponding quantifications of different treatments. Osteogenesis activity of osteoblasts (MC3T3‐E1) characterized by e) Alizarin red staining and f) corresponding Alizarin red positive area quantifications after various treatments. Scale bar: 100 µm. g) ALP staining and h) ALP positive area quantification after various treatments for analysis of osteogenesis activity of osteoblasts. Scale bar: 100 µm. All values are presented as means ± s.d, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, two‐tailed Student's t‐test.

In vivo therapeutic effect of LDH‐CeO2 in AIA models. a) Schematic illustration of animal experiment for evaluating the RA therapeutic efficacy of LDH‐CeO2. b) Joint swelling measurements of RA model mice during immunization and therapeutic periods. c) Joint swelling quantifications at the end of therapy. d) Representative reconstructed 3D micro‐CT images of joints collected from different groups. Scale bar: 2 mm. Bone related parameters of e) BV/TV, f) Tb. N (mm⁻¹) and g) Tb. Sp (mm) calculated from reconstructed images. h) Representative H&E staining sections of joints from different groups. Inflammatory cell infiltration (blue arrow), hyperplastic synovial tissue (orange arrow), bone erosion (red arrow) and invasion of pannus tissues (green arrow). Scale bar: 1.25 mm, 200 µm. i) Calculation result of histological score from H&E sections. All values are presented as means ± s.d, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not significant, two‐tailed Student's t‐test.

+2

Anti‐Acidification and Immune Regulation by Nano‐Ceria‐Loaded Mg–Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy

December 2023

Hao Fu

·

Yuedong Guo

·

Wenming Fang

·

[...]

·

Jianlin Shi

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H⁺) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H⁺ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria‐loaded magnesium aluminum layered double hydroxide (LDH‐CeO2), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H⁺ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant‐induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone‐repairing effects of inorganic nanocatalytic material.

A) SEM image of TA/Fu‐TS (Insert: the photo of nanogels); B) TEM image of TA/Fu‐TS (Insert: the detail of TA/Fu‐TS); C) Cryo‐TEM image of TA/Fu‐TS (Insert: the schematic of TA/Fu‐TS); D,E) Size distributions and release profiles; F) TEM images of degraded TA/Fu‐TS.

A) The cellular viability of HSF and BMDM treated TA/Fu‐TS; B) CLSM images of HSF and BMDM treated TA/Fu‐TS; C) Ultrastructural observation of HSF and BMDM treated TA/Fu‐TS (white and black arrows: intact and cracked TA/Fu‐TS); D) CLSM images of macrophage phenotype‐switching; E,F) The biomarkers of inflammation inhibition and fibrosis suppression in mono‐culture models; G) Schematic of co‐culture models; H) Fibrosis‐related protein expressions in co‐culture models; and J,I) The biomarker detection of inflammation inhibition and fibrosis suppression in co‐culture models.

A) Schematic of in vitro/vivo transdermal delivery; B) CLSM images of HS in vitro/vivo administered with TA/Fu‐TS; C) Retention amounts of TA and 5‐Fu in HS tissues after in vitro/vivo admonition; D) Penetration details of TA/Fu‐TS; E,F) TEM image of TA/Fu‐TS transdermal delivering to HSF and macrophage (white and black arrows: TA/Fu‐TS in ECM and cytoplasm, red arrows: phagosome).

A) The appearance changes of HS; B) Statistics of SEI after treatment (*: p<0.05); C) Masson and Sirius red staining; D) Statistical analysis of the ratio of Col I to Col III (*: p<0.05); D,E) Ultra‐features of collagen in treated HS tissues; F) Statistical analysis of the collagen diameter in treated HS tissues.

A) CLSM images of macrophage phenotype‐switching in vivo; B,C) Immunohistochemical and statistical analysis of inflammation‐related biomarkers (*: p<0.05); D) Heatmap of the top inflammation‐related DEGs after being further screened (HS tissues as RNA‐seq samples, n = 3); E) GO of the DEGs showing the enriched mainly altered molecular events.

+2

Transdermal Transfersome Nanogels Control Hypertrophic Scar Formation via Synergy of Macrophage Phenotype‐Switching and Anti‐Fibrosis Effect

December 2023

Yunsheng Chen

·

Kun Chen

·

Shan Zhong

·

[...]

·

Zheng Zhang

Hypertrophic scar (HS), which results from prolonged inflammation and excessive fibrosis in re‐epithelialized wounds, is one of the most common clinical challenges. Consequently, sophisticated transdermal transfersome nanogels (TA/Fu‐TS) are prepared to control HS formation by synergistically inhibiting inflammation and suppressing fibrosis. TA/Fu‐TSs have unique structures comprising hydrophobic triamcinolone acetonide (TA) in lipid multilayers and hydrophilic 5‐fluorouracil in aqueous cores, and perform satisfactorily with regard to transdermal co‐delivery to macrophages and HS fibroblasts in emerging HS tissues. According to the in vitro/vivo results, TA/Fu‐TSs not only promote macrophage phenotype‐switching to inhibit inflammation by interleukin‐related pathways, but also suppress fibrosis to remodel extracellular matrix by collagen‐related pathways. Therefore, TA/Fu‐TSs overcome prolonged inflammation and excessive fibrosis in emerging HS tissues, and provide an effective therapeutic strategy for controlling HS formation via their synergy of macrophage phenotype‐switching and anti‐fibrosis effect.

Macrophages influence the progression of LF. A) The process of M1 and M2 macrophages induced by LPS and IL‐4. B‐C) Detection of iNOS and CD206 expression in M1 and M2 macrophages by flow cytometry. D) CLSM images of immunofluorescence staining of α‐SMA of HSC after activated by M1 macrophage supernatant. Scale bar = 20 µm. E) Western blot analysis of α‐SMA in HSCs induced by M1 macrophages supernatant. The expression of collagen I, α‐SMA, and vimentin were normalized to the expression of β‐actin (n = 3). F) The process of M1 macrophage phenotype reversion by MFG‐E8. G) Detection of iNOS and CD206 expression by flow cytometry after incubation with MFG‐E8. Data represented mean ± SD, *p < 0.05, ***p < 0.001.

Expression of CXCL1 and CD147 in activated HSCs. A) CLSM images of CXCL1 (red) and α‐SMA (green) immunostaining in activated and quiet HSCs. Scale bars = 10 µm. B) Detection of CXCL1 and SMA expression in activated HSCs by flow cytometry. C) Western blot analysis of USP1, CXCL1, and α‐SMA in HSCs after undergoing different treatments. (n = 3, mean ± SD). D) CLSM images of CD147 (red) and collagen I (green) immunostaining in activated and quiet HSCs. Scale bars = 10 µm. E) CLSM images of CXCL1 (red) and CD147 (green) immunostaining in HSCs after being stimulated by TGF‐β. Scale bars = 10 µm. F,G) Detection of CXCL1/collagen I and CD147/CXCL1 co‐expression in activated HSCs by flow cytometry. H) Western blot analysis of CD147, CXCL1, and α‐SMA in HSCs after undergoing different treatments. The expression of CD147, CXCL1, and α‐SMA were normalized to the expression of β‐actin. (n = 3). Data represented mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001.

Characterization of MUA/Y lipid nanoparticles. A) The illustration on the formation of A/Y and MUA/Y. B) The DLE% and EE% of AC73 in MUA/Y lipid nanoparticles at different drug/phospholipid ratios (n = 3). C) The fluorescent spectrum of FITC excited RhB treated with RhB‐MFG‐E8@FITC/Y lipid nanoparticles. D) The structural changes of MFG‐E8 were verified by circular dichroism (CD). E) Size distribution and TEM result of MUA/Y. TEM Scale bar = 500 nm. F) In vitro colloidal stability of MUA/Y in water, PBS, and FBS for 72 h (n = 3). G) Time‐dependent AC73 release of free AC73 and MUA/Y in PBS at pH 5.0, and 7.4 (n = 3). H) ROS response ability of MUA/Y lipid nanoparticles. Scale bars = 100 µm. Data were represented as mean ± SD.

Characterization of collagen phagocytosis, cellular uptake, and endosome escape of MUA/Y lipid nanoparticles. A) The process of collagen phagocytosis mediates by MFG‐E8. B) The process of MFG‐E8 mediated macrophages ablate collagen. C) Fluorescence intensity in HSCs detected by fluorescence microscopy. Scale bars = 100 µm. D) FITC‐modified collagen was endocytosed by RAW264.7. The image was captured by CLSM. Scale bars = 10 µm. E) The process of MUA/Y endocytosed escape in HSCs. F) CLSM images of cellular uptake of free C6, C6/Y, and MUC6/Y under 2 and 4 h. Scale bars = 20 µm. G) Transfection efficiency of siLuc loaded lipid nanoparticles detected by fluorescence microscopy. Scale bars = 100 µm. H) Semiquantitative analyze of the Luc positive area of fluorescent cells. (n = 3). Data represented mean ± SD. ns: no significant difference, *p < 0.05, ***p < 0.001.

Mechanisms of MUA/Y lipid nanoparticles in HSCs. A) Mechanisms of HSCs activation and recovery after treatment. B) The expression of CXCL1, CD147, Sp‐1, Erk1/2, Smad2, fibronectin, collagen I, and α‐SMA in HSCs undergoing different formulations. 1 means PBS group, 2 means TGF group, 3 means free AC73 group, 4 means siUSP1/Y, 5 means AC/Y, 6 means UA/Y. C–E) Densitometric quantification of western blotting results in each group. The expression of α‐SMA, collagen I and CD147 were normalized to β‐actin. (n = 3). F) Images for cell scratch assay of HSCs at 0 and 24 h (n = 3). Scale bars = 100 µm. G) Semi‐quantified of the scratch area of each group, the scratch area in each groups were normalized to PBS group (n = 3). H,I) CLSM images of CD147 (green)/CoI (red) and SMA (green)/CXCL1 (red) immunostaining in HSCs after treatment (n = 3). Scale bars = 100 µm. Data were represented as mean ± SD, ns: no significant difference, *p < 0.05, **p < 0.01, ***p < 0.001.

+3

An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis

December 2023

Bo‐Wen Duan

·

Yan‐Jun Liu

·

Xue‐Na Li

·

[...]

·

Hu‐Lin Jiang

In advanced liver fibrosis (LF), macrophages maintain the inflammatory environment in the liver and accelerate LF deterioration by secreting proinflammatory cytokines. However, there is still no effective strategy to regulate macrophages because of the difficulty and complexity of macrophage inflammatory phenotypic modulation and the insufficient therapeutic efficacy caused by the extracellular matrix (ECM) barrier. Here, AC73 and siUSP1 dual drug‐loaded lipid nanoparticle is designed to carry milk fat globule epidermal growth factor 8 (MFG‐E8) (named MUA/Y) to effectively inhibit macrophage proinflammatory signals and degrade the ECM barrier. MFG‐E8 is released in response to the high reactive oxygen species (ROS) environment in LF, transforming macrophages from a proinflammatory (M1) to an anti‐inflammatory (M2) phenotype and inducing macrophages to phagocytose collagen. Collagen ablation increases AC73 and siUSP1 accumulation in hepatic stellate cells (HSCs) and inhibits HSCs overactivation. Interestingly, complete resolution of liver inflammation, significant collagen degradation, and HSCs deactivation are observed in methionine choline deficiency (MCD) and CCl4 models after tail vein injection of MUA/Y. Overall, this work reveals a macrophage‐focused regulatory treatment strategy to eliminate LF progression at the source, providing a new perspective for the clinical treatment of advanced LF.

a) Schematic illustration of the synthesis of C2’‐modified TCy5 dyes. b) Comparison of the photophysical properties of the meso‐modified TCy5 dyes and the C2’‐modified TCy5 dyes.

Evaluation of the photophysical properties of the cyanine dyes. a) Absorbance spectra of the various dyes in DCM (2 µM). b) Fluorescence spectra of the various dyes in DCM (2 µM). c) Relationship between the dye Φf of dyes and the para‐substituent constant (σp). d) Fluorescence spectra of C2‐NO2 in 1, 5‐pentanediol (red), and ethanol (black) at 20 °C. e) DPBF degradation induced by C2‐NH2 and C2‐NO2 under 660 nm light irradiation (5 mW cm⁻²) for different durations. f) Normalized DPBF absorbance at 415 nm, demonstrating the degradation induced by different compounds under 660 nm light irradiation. g) Relationship between the ΦΔrel values of the dyes and σp. h) Fluorescence response of DHR123 (10 µM) in the presence of aqueous solutions of C2‐NH2, C2‐H, meso‐NO2, and C2‐NO2 (5 µM) in aqueous solution under 660 nm light irradiation. i) Fluorescence response of DHE (15 µM) in the presence of aqueous solution of C2‐NH2 (5 µM) under 660 nm light irradiation.

Results of quantum chemical calculations. a) Schematic illustrations of the TICT and PET mechanisms in the C2’ aryl‐modified thio‐pentamethine cyanine dyes. b) Energy levels and oscillator strengths f) of the key states involved during the inter‐system crossing of TCy5‐H (left panel), C2‐NO2 (the middle panel), and C2‐NH2 (the right panel) in DCM. The inset shows the ΔES−T and SOC values of the representative states. c) Optimized geometries, and the corresponding electron and hole distributions of representative states of TCy5‐H (left panel), C2‐NO2 (the middle panel), and C2‐NH2 (the right panel). FC: Franck Condon state; LE: adiabatically locally excited state; ET: adiabatically electron‐transfer state; TICT: twisted intramolecular charge transfer state.

Experimental results of ultrafast spectroscopy and kinetic fitting results. a) Femtosecond transient absorption spectra of C2‐NO2 in DCM (λex = 680 nm). b) Kinetic traces and fitting lines of C2‐NO2 at the representative ESA and GSB wavelengths. c) Decay trace recorded at 685 nm for C2‐NO2 excited at 610 nm (10 µM in deaerated DCM) at 25 °C. d) Femtosecond transient absorption spectra of C2‐NH2 in DCM (λex = 680 nm). e) Kinetic traces and fitting lines of C2‐NH2 at representative ESA and GSB wavelengths. f) Decay trace recorded at 674 nm for C2‐NH2 excited at 610 nm (10 µM in deaerated DCM) at 25 °C.

Verification of the evolution of C2‐NO2 to C2‐NH2 in aqueous solvent and cells. a) Schematic illustration of the conversion of C2‐NO2 to C2‐NH2 in the presence of NTR. b) Fluorescence intensity of C2‐NO2 (10 µM) treated with NTR (10 µg mL⁻¹) as a function of time. c) Fluorescence intensities of the HepG2 cells incubated with C2‐NO2 (5 µM) under normoxic, hypoxic with dicumarin pretreatment, and hypoxic conditions (n = 3). d) Cytotoxicity of C2‐NO2 toward HepG2 cells in the dark and with light irradiation (660 nm, 20 mW cm⁻², 15 min) under normoxic and hypoxic conditions. e) Cytotoxicities of different dyes (4 µM) toward HepG2 cells in the dark and with light irradiation (660 nm, 20 mW cm⁻², 15 min) under normoxic and hypoxic conditions. f) Imaging of the calcium‐AM/PI staining of cells after different treatments. g) Intracellular ROS production by C2‐NO2 in HepG2 cells monitored by the DCFH‐DA and DHE assays under different conditions. Data are expressed as the mean ± standard deviation (SD) *p < 0.1, **p < 0.01, ***p < 0.001, and ****p < 0.0001, as determined by Student's t‐test.

+1

Aryl‐Modified Pentamethyl Cyanine Dyes at the C2’ Position: A Tunable Platform for Activatable Photosensitizers

December 2023

Fuping Han

·

Syed Ali Abbas Abedi

·

Shan He

·

[...]

·

Xiaojun Peng

Pentamethyl cyanine dyes are promising fluorophores for fluorescence sensing and imaging. However, advanced biomedical applications require enhanced control of their excited‐state properties. Herein, a synthetic approach for attaching aryl substituents at the C2’ position of the thio‐pentamethine cyanine (TCy5) dye structure is reported for the first time. C2’‐aryl substitution enables the regulation of both the twisted intramolecular charge transfer (TICT) and photoinduced electron transfer (PET) mechanisms to be regulated in the excited state. Modulation of these mechanisms allows the design of a nitroreductase‐activatable TCy5 fluorophore for hypoxic tumor photodynamic therapy and fluorescence imaging. These C2’‐aryl TCy5 dyes provide a tunable platform for engineering cyanine dyes tailored to sophisticated biological applications, such as photodynamic therapy.

Fungal infection triggers the formation of several DHBA sugar conjugates in tea plants. A) The phenotype of tea leaves and lesion statistics chart after fungal infection. Bar = 1 cm. B) The relative content of SA after Pcs infection. C,D) The relative contents of DHBA and DHBA glycosides after Pcs infection. Control, inoculated with pure water. An unknown compound was identified as a novel DHBA sugar conjugate (x‐DHBA Glc) due to its similarity in mass spectrum fragment with the conjugated forms of 2,3‐ and 2,5‐DHBA. Data are presented as mean ± sd of at least three replicates. E) Homologous genes expression of UGT89A2 (TEA015768, TEA017395, TEA010182). F, Homologous genes expression of UGT76D1 (TEA008557, TEA029948, TEA031670).

Candidate UGTs identified by gene expression and DHBA sugar conjugate correlation analysis during pathogen infection. A) A correlation analysis between the expression levels of putative UGT genes and the concentration of 2,3‐, X‐, 2,5‐DHBA glycosides response to Pcs infection. Numbers represent the correlation coefficient. *p < 0.05, **p < 0.01. B) The relative contents of DHBA glucosides after SA treatment. C) The expression of putative genes by SA treatment.

Enzymatic analysis with different substrates and identification of enzymatically formed products by LC–MS. A) Sugar specific screening UGT95B17 with different sugar donors. Activity screening of UGT95B17 protein with different substrates. The activity of 3,4‐DHBA was set as 100%. Values are expressed as the mean ± standard deviation of triplicate samples. B) Phylogenetic analysis of UGT95B17 and other identified functional UGTs. Product formed from C) 3,4‐DHBA, D) 2,3‐DHBA, E) 2,4‐DHBA, and F) 2,5‐DHBA when the substrates were incubated with UDP‐glucose and recombinant UGT95B17 and empty vector control (CK).

2,4‐DHBA glucoside was identified and labeled 2,4‐DHBA was detected after feeding [¹³C6] SA in tea plants. The identity of 2,4‐DHBA glucoside in untreated leaves (A), tea leaves exposed to 5 mm SA (B) and 2,4‐DHBA (C) for 24 h, and 2,4‐DHBA glucoside addition (D) was confirmed by LC–MS. F, The identity of labeled 2,4‐DHBA from tea leaves fed with water as control and [¹³C6] SA.

Identification of CsSH1 in Vitro and in Vivo. A) Biochemical reaction catalyzed by recombinant CsSH1 in vitro. B) HPLC profiles of 30‐min reaction of the recombinant CsSH1, CsSH2 protein and empty vector (EV) extracts incubated with SA. C) The CsSH1 enzymatic products to 2,3‐,2,4‐ and 2,5‐DHBA also have the same tandem ESI–mass spectra MS2, respectively. D) The relative expression levels of CsSH1 in AsODN and sODN plants. E) Quantitative analysis of SA in AsODN and sODN plants. F) Quantitative analysis of DHBAs and glycosides in AsODN and sODN plants.

+5

2,4‐Dihydroxybenzoic Acid, a Novel SA Derivative, Controls Plant Immunity via UGT95B17‐Mediated Glucosylation: A Case Study in Camellia Sinensis

December 2023

Mengqian Lu

·

Yifan Zhao

·

Yingying Feng

·

[...]

·

Chuankui Song

The plant hormone salicylic acid (SA) plays critical roles in plant innate immunity. Several SA derivatives and associated modification are identified, whereas the range and modes of action of SA‐related metabolites remain elusive. Here, the study discovered 2,4‐dihydroxybenzoic acid (2,4‐DHBA) and its glycosylated form as native SA derivatives in plants whose accumulation is largely induced by SA application and Ps. camelliae‐sinensis (Pcs) infection. CsSH1, a 4/5‐hydroxylase, catalyzes the hydroxylation of SA to 2,4‐DHBA, and UDP‐glucosyltransferase UGT95B17 catalyzes the formation of 2,4‐DHBA glucoside. Down‐regulation reduced the accumulation of 2,4‐DHBA glucosides and enhanced the sensitivity of tea plants to Pcs. Conversely, overexpression of UGT95B17 increased plant disease resistance. The exogenous application of 2,4‐DHBA and 2,5‐DHBA, as well as the accumulation of DHBA and plant resistance comparison, indicate that 2,4‐DHBA functions as a potentially bioactive molecule and is stored mainly as a glucose conjugate in tea plants, differs from the mechanism described in Arabidopsis. When 2,4‐DHBA is applied exogenously, UGT95B17‐silenced tea plants accumulated more 2,4‐DHBA than SA and showed induced resistance to Pcs infection. These results indicate that 2,4‐DHBA glucosylation positively regulates disease resistance and highlight the role of 2,4‐DHBA as potentially bioactive molecule in the establishment of basal resistance in tea plants.

Identification of BHLHE40 in pancreatic ductal adenocarcinoma and its upstream regulators. A) UP: Illustrations of the identification strategies of transcription factors. DOWN: Venn diagram of intersected transcription factors with H3K27ac and chromatin openness gain peaks and elevated mRNA expression. B) Integrative Genomics Viewer plots showing ATAC‐ and ChIP‐seq profiles of indicated changes of chromatin openness or H3K27ac enrichment in the BHLHE40 gene locus. C) Protein levels of BHLHE40 and H3K27ac significantly decreased after the EP300 knockdown. D) Negative correlation between the expression of BHLHE40 and IC50 score of rapamycin was confirmed by Spearman correlation analysis. The ordinate shows the distribution of the IC50 score, and the abscissa shows the various expression levels of the samples (P = 0.000277, ρ = −0.27, n = 179). E) Rapamycin, an mTOR inhibitor, was selected to treat PANC‐1 and BxPC‐3 cell lines, and a significant decrease in phosphorylated mTOR and BHLHE40 levels was observed in a dose‐dependent manner. F) Acetylation of EP300 and histone H3 in PANC and BxPC‐3 cells treated with or without mTORC1 inhibitor (Rapamycin at 10 × 10⁻⁶ m). Immunoprecipitated EP300 and lysate histone H3 were analyzed using western blotting with anti‐acetyl‐lysine and anti‐acetyl‐histone H3 antibodies, respectively. G) Immunohistochemistry assay validated that the levels of BHLHE40 were higher in tumoral tissues than in adjacent tissues. Scale bar, 200 µm (upper), 50 µm (bottom). H) Comparison of H‐scores between tumoral and adjacent tissues for BHLHE40 immunohistochemistry staining. I) Expressed transcriptional factors ranked by mean log2 fold‐change in primary PCa tumoral versus adjacent tissues in TCGA‐PAAD datasets. BHLHE40 was labeled and ranked in the front. J) Kaplan–Meier analysis in the RJ‐1 dataset suggested that patients with high BHLHE40 levels experienced worse overall survival outcomes than those with low BHLHE40 levels (P = 0.0004, n = 92). Data presentation: H) Data were the mean ± s.d. of n = 84 samples for each group. Statistical analysis: spearman rank correlation test for (D); paired two‐sided t‐test for (H); log‐rank test for (J). Source data are provided as described in availability of data and materials section. *P < 0.05.

BHLHE40 promotes PCa proliferation and liver metastases in vitro and in vivo. A) Western blot of BHLHE40 knockdown efficiency in PANC‐1 cell lines. B,C) Effects of BHLHE40 knockdown on the proliferation and migration ability of the PANC‐1 cell lines were measured using CCK‐8 and wound‐healing assays. D) PCa, PANC‐1, and BxPC‐3 (gross anatomy also shown in Figure S3, Supporting Information) cells stably transfected with BHLHE40 sh ctrl or sh #1 were injected subcutaneously into 4 week old BALB/c male nude mice (n = 5 for each group). Representative images are of dissected xenogeneic tumors from nude mice in each group. E) Tumor volumes were measured and calculated after subcutaneous injection. F) Tumor tissues were subjected to Ki‐67 staining. Scale bar, 100 µm. G) Representative micro‐PET/CT image of the metastatic xenograft mouse model. H) BHLHE40 knockdown decreased the mean SUV value of metastatic liver tumors, reinforcing the role of BHLHE40 in promoting metastasis in vivo. I) Western blot of BHLHE40 overexpression efficiency in MIA PaCa‐2 cell lines. J,K) Effects of BHLHE40 overexpression on the proliferation ability of the MIA PaCa‐2 cell line was measured using the CCK‐8 and colony formation assays. L–N) Representative pictures of two PCa organoids (PTO1 and PTO2) transfected with BHLHE40 knockdown vectors or control lentivirus for 10 d (scale bar, 200 µm, left panel) and quantified via organoid diameters (right panel). PET, positron emission tomography; mean SUV, mean standardized uptake value; "B sh" or “BHLHE40 sh,” short for BHLHE40 short hairpin RNA. Data presentation: B,E,J,M,N) data were the mean ± s.d. of n = 6 independent experiments; E) data were the mean ± s.d. of n = 5 independent experiments; H) data were the mean ± s.d. of n = 4 independent experiments; C,K) Data were the mean ± s.d. of n = 3 independent experiments. Statistical analysis: two‐way ANOVA for (B,E,J); unpaired two‐sided t‐test for (C,H,K,M,N). * P < 0.05, ** P < 0.01, *** P < 0.001.

Overexpression of BHLHE40 promotes tumorigenesis via altering the oncogenic transcriptome in PCa cells. A) Integrated analysis flowchart of RNA‐ and ChIP‐seq in PANC‐1 cells. Downregulated genes after BHLHE40 knockdown with log2 fold change >1.5 times were intersected with binding loci of BHLHE40. B) Bubble plot showing GO enrichment analysis of downregulated genes related to fatty acid metabolism after BHLHE40 knockdown. C) Pie chart of the distributions of BHLHE40‐binding regions. D) Close view of the SREBF1 gene loci and BHLHE40 ChIP‐seq signal in PANC‐1 and BxPC‐3 cells. E) Luciferase reporter assay results showed that BHLHE40 overexpression promoted the luciferase activity of the pGL4.10‐SREBF1 promoter (WT) rather than the mutant promoter. F) Enrichment levels of H3K4me3 at the promoter region of SREBF1 in BHLHE40 knockdown or control PANC‐1 cell were determined via ChIP‐qPCR assay. G) Representative images of SREBF1 IHC staining of PCa tumor and para‐tumor tissues. Scale bar, 200 µm (upper) or 50 µm (bottom). H) High SREBF1 protein levels also correlated with reduced overall survival (OS) outcomes based on the analysis of tissue microarray data from the RJ‐1 dataset. I,J) Expression levels of SREBF1 and subsequent fatty acid metabolism related proteins (HMGCS1, ORP1, LSS, and SCD1) were measured using western blot and qPCR assays in BHLHE40 knockdown or control PANC‐1 cells. K) Representative images of double immunofluorescence staining of SREBF1 (green) and BHLHE40 (red) in PTO1. DAPI (blue) was used for nuclei counterstaining. Data presentation: E,F,J) data were the mean ± s.d. of n = 3 independent experiments. Statistical analysis: one‐sided Fisher's exact test for (B); unpaired two‐sided t‐test for E,F,J); log‐rank test for (H); *P < 0.05, **P < 0.01, ***P < 0.001.

BHLHE40 facilitates the linking of the enhancer and promoter regions upstream of the SREBF1 locus. A) In situ Hi‐C maps of PANC‐1 and HPNE cells, ATAC‐seq of PANC‐1 cells with or without BHLHE40 knockdown, and BHLHE40 ChIP‐seq tracks surrounding the SREBF1 locus. Dots with a black diamond show the potential enhancer‐promoter loops. B) 3C assays were performed to evaluate the existence of an intrachromosomal loop between the promoter and super‐enhancer regions of SREBF1 in PANC‐1 cells when BHLHE40 was knocked down or recovered with wild type or mutant BHLHE40. Nonligated DNA was the negative control. C) Rank ordering of super‐enhancers (ROSE) algorithm was used to predict the putative super enhancers mediated by BHLHE40 via comparing the differential H3K27ac peaks near SREBF1 in BHLHE40 knockdown cells with controls. D) BHLHE40 overexpression could not rescue the SREBF1 expression levels in the sgSREBF1‐E. E) Interactions of BHLHE40 with Pol II, BRD4, and MED1 were verified using immunoprecipitation (IP) assay. F) BRD4, MED1, and Pol II enrichment at the promoter region of SREBF1 in BHLHE40 knockdown or control PANC‐1 cells were determined via ChIP‐qPCR assays. Data presentation: F) data were the mean ± s.d. of n = 3 independent experiments. Statistical analysis: unpaired two‐sided t‐test for (F); *P < 0.05, **P < 0.01, ***P < 0.001.

BHLHE40 forms phase‐separated condensates in vitro and in vivo. A) Plotting of intrinsic disorder for BHLHE40 using PONDR VSL2 displays the amino acid location (x‐axis) and PONDR VSL2 score (y‐axis). Black bar designates the IDR under investigation. B) Representative images of droplet formation at different protein concentrations. BHLHE40 (177–319) was added to the droplet formation buffer to the final concentrations indicated. Scale bar, 10 µm. C) Time‐lapse images of the purified BHLHE40 (177–319) showed that a droplet fusion event occurred. Scale bar, 10 µm. D) Immunostaining of endogenous BHLHE40 (green) and DNA (4,6‐diamidino‐2‐phenylindole (DAPI), blue) in the indicated PTO1 and PTO2. E) Images from the fluorescence recovery after photobleaching (FRAP) experiment with overexpressed mEGFP‐BHLHE40 FL and mEGFP‐BHLHE40 (177–319) cells. Scale bar, 20 µm. F,G) Quantification of FRAP data for mEGFP‐BHLHE40 (full length) and mEGFP‐BHLHE40 (Δ177–319aa) puncta. Bleaching occurs at t = 0 s, and background‐subtracted fluorescence intensities are plotted relative to a pre‐bleach time point (t = −3 s) for both the bleached area and unbleached control.

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BHLHE40 Inhibits Ferroptosis in Pancreatic Cancer Cells via Upregulating SREBF1

December 2023

Yizhi Cao

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Xuelong Wang

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Yang Liu

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[...]

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Baiyong Shen

Pancreatic cancer (PCa) is one of the most fatal human malignancies. The enhanced infiltration of stromal tissue into the PCa tumor microenvironment limits the identification of key tumor‐specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multiomics analyses of the paired PCa organoids indicate that the basic helix‐loop‐helix transcription factor 40 (BHLHE40) is significantly upregulated in tumor samples. Increased chromatin accessibility at the promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation‐seq, RNA‐seq, and high‐throughput chromosome conformation capture data, together with chromosome conformation capture assays, indicate that BHLHE40 not only regulates sterol regulatory element‐binding factor 1 (SREBF1) transcription as a classic transcription factor but also links the enhancer and promoter regions of SREBF1. It is found that the BHLHE40‐SREBF1‐stearoyl‐CoA desaturase axis protects PCa cells from ferroptosis, resulting in the reduced accumulation of lipid peroxidation. Moreover, fatostatin, an SREBF1 inhibitor, significantly suppresses the growth of PCa tumors with high expressions of BHLHE40. This study highlights the important roles of BHLHE40‐mediated lipid peroxidation in inducing ferroptosis in PCa cells and provides a novel mechanism underlying SREBF1 overexpression in PCa.

Crystal structure and magnetic susceptibility of AgCrSe2. a) Crystal structure of AgCrSe2 (space group R3m). The polarization direction P and the symmetry allowed Hall pseudovector σ (corresponding to an anomalous Hall conductivity σxy) are marked. b) Magnetic susceptibility measured with an applied 1 T magnetic field along and perpendicular to the c‐axis, respectively.

Spontaneous AHE observed in AgCrSe2. a) Hall resistivity (ρxyTOT(H)$\rho _{xy}^{TOT}(H)$), as well as b) normalized longitudinal resistivity (ρxxTOT(H)/ρxxTOT(H=0)$\rho _{xx}^{TOT}(H)/\rho _{xx}^{TOT}(H=0)$), measured simultaneously with H applied along the c‐axis. The curves are offset vertically for clarity. Inset of a): a schematic illustrating the measurement setup. c) ρxyA=ρxyTOT−ρxy0$\rho _{xy}^A= \rho _{xy}^{TOT} - \rho _{xy}^0$ is plotted as a function of H at 2 K. The resistivity shows a clear jump and saturates at a critical field Hc. d) Magnetization M versusH measured at 2 K with the magnetic field applied along the c‐axis. e) Temperature evolution of the zero‐field component ρxyA(H=0)$\rho _{xy}^A (H=0)$ and f) the corresponding σyxA$\sigma _{yx}^A$ obtained by inverting the resistivity tensor. Error bars include the uncertainty in extracting the zero‐field resistivity from the Hall measurements.

Angular dependence of the AHE. a) Illustration of the measurement setup for the angular dependent AHE. The current is applied in the ab‐plane, and the magnetic field is rotating relative to the c‐axis. b) ρxyA(H)$\rho _{xy}^A(H)$ measured at different rotation angles at fixed temperature 5 K. c) Angular dependence of the zero‐field resistivity ρxyA$\rho _{xy}^A$. ρxyA$\rho _{xy}^A$ remains a plateau up to θ ≈ 80°, and then drops abruptly to near zero when H is aligned to the ab‐plane (θ = 90°). Error bars reflect an estimate of the uncertainty in extracting the resistivity jumps.

Gate‐tunable AHE in a AgCrSe2 thin flake. a) Conductance as a function of the applied gate voltage measured at 230 K. The inset shows a schematic of the device measurement setup. The ionic liquid (DEME‐TFSI) covers both the side gate electrode and the thin flake. b) σyxA(H)$\sigma _{yx}^A(H)$ and c) normalized longitudinal resistivity (ρxxTOT(H)/ρxxTOT(H=0)$\rho _{xx}^{TOT}(H)/\rho _{xx}^{TOT}(H=0)$) modulated by the ionic gating. The data were obtained at T = 10 K with the magnetic field applied along the c‐axis. The applied VG$V_{\textnormal {G}}$ and the carrier density n2D extracted from the field linear part of the Hall effect at each VG are labeled beside the curves. d) σyxA$\sigma _{yx}^A$ as a function of the doping level.

Theoretical calculations of AHE in AgCrSe2. a) Model of ferromagnetic Cr atoms in a monolayer. The mirror symmetry plane My$\mathcal {M}_y$ is marked in gray color. The mirror symmetry translation coupled with time reversal symmetry TMy$\mathcal {T}\mathcal {M}_y$ allows for a Hall vector (right panel). b) Model of Cr atoms in the collinear antiferromagnetic states. The unit cell translation coupled with time reversal tT$t\mathcal {T}$ cancels the Hall vector. c) Model of Cr atoms in the noncollinear states. The unit cell translation coupled with rotation symmetry tC3z$t\mathcal {C}_{3z}$ is marked. d) Spin‐projected energy bands and e) energy dependent anomalous Hall conductivity in ferromagnetic states with spins aligned parallel to the x‐axis. f) Spin‐projected energy bands and g) energy dependent anomalous Hall conductivity in antiferromagnetic states in a simplified noncollinear structure. The calculations, for stoichimetric AgCrSe2, put the Fermi level in the bandgap. In the real crystals, non‐stoichiometry places it in the hole bands, where the calculations give a finite σxy with a strong doping dependence, qualitatively in accord with the results of our gating experiments.

Observation of the Anomalous Hall Effect in a Layered Polar Semiconductor

December 2023

Seo‐Jin Kim

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Jihang Zhu

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Mario M. Piva

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[...]

·

Haijing Zhang

Progress in magnetoelectric materials is hindered by apparently contradictory requirements for time‐reversal symmetry broken and polar ferroelectric electronic structure in common ferromagnets and antiferromagnets. Alternative routes can be provided by recent discoveries of a time‐reversal symmetry breaking anomalous Hall effect (AHE) in noncollinear magnets and altermagnets, but hitherto reported bulk materials are not polar. Here, the authors report the observation of a spontaneous AHE in doped AgCrSe2, a layered polar semiconductor with an antiferromagnetic coupling between Cr spins in adjacent layers. The anomalous Hall resistivity 3 μΩcm$\mu \Omega \, \textnormal {cm}$ is comparable to the largest observed in compensated magnetic systems to date, and is rapidly switched off when the angle of an applied magnetic field is rotated to ≈80° from the crystalline c‐axis. The ionic gating experiments show that the anomalous Hall conductivity magnitude can be enhanced by modulating the p‐type carrier density. They also present theoretical results that suggest the AHE is driven by Berry curvature due to noncollinear antiferromagnetic correlations among Cr spins, which are consistent with the previously suggested magnetic ordering in AgCrSe2. The results open the possibility to study the interplay of magnetic and ferroelectric‐like responses in this fascinating class of materials.

A) Top and B) Side views of the overall structure of Cu41. Hydrogen atoms of ligands are omitted for clarity.

Analysis of the crystal structure of Cu41(SR)15Cl3(PR3)6. A) Formation of the Cu29 core by Cu4 sharing of three Cu13 units. B) ligand motif of the cluster. C) Linking of motifs with the Cu29 core. Carbon and fluorine atoms of ligands are omitted for clarity.

A) The intracluster π···π interactions in Cu41. B) Intercluster C─H···F interactions in the unit cell of Cu41. The red/black dashed lines correspond to the C─H···F interactions or π···π interactions, respectively. Atom colors: Cu = brown, S = yellow, P = purple, Cl = green, F = chartreuse, C = gray.

A) ESI–MS data of [Cu41(SC6H3F2)15Cl5(P(PhF)3)x(H)23]²⁻ (x = 0–6) (black trace) and [Cu41(SC6H3F2)15(P(PhF)3)xCl5D23]²⁻ (x = 0–6) (red trace) in negative‐ion mode. (B and C) Comparison of experimental mass spectra of the [Cu41(SC6H3F2)15(P(PhF)3)6Cl5H23]²⁻ species and [Cu41(SC6H3F2)15(P(PhF)3)xCl5D23]²⁻ with their simulated ones, respectively.

Optimal hydride sites in the [Cu41(SR)15(PR3)6Cl3H25]²⁻.

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Total Structure, Structural Transformation and Catalytic Hydrogenation of [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25] Constructed from Twisted Cu13 Units

December 2023

Huimin Zhou

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Tengfei Duan

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Zidong Lin

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[...]

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Manzhou Zhu

Herein, a remarkable achievement in the synthesis and characterization of an atomically precise copper‐hydride nanocluster, [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25]²⁻ via a mild one‐pot reaction is presented. Through X‐ray crystallography analysis, it is revealed that [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25]²⁻ exhibits a unique shell–core–shell structure. The inner Cu29 kernel is composed of three twisted Cu13 units, connected through Cu4 face sharing. Surrounding the metal core, two Cu6 metal shells, resembling a protective sandwich structure are observed. This arrangement, along with intracluster π···π interactions and intercluster C─H···F─C interactions, contributes to the enhanced stability of [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25]²⁻. The presence, number, and location of hydrides within the nanocluster are established through a combination of experimental and density functional theory investigations. Notably, the addition of a phosphine ligand triggers a fascinating nanocluster‐to‐nanocluster transformation in [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25]²⁻, resulting in the generation of two nanoclusters, [Cu14(SC6H3F2)3(PPh3)8H10]⁺ and [Cu13(SC6H3F2)3(P(PhF)3)7H10]⁰. Furthermore, it is demonstrated that [Cu41(SC6H3F2)15Cl3(P(PhF)3)6(H)25]²⁻ exhibits catalytic activity in the hydrogenation of nitroarenes. This intriguing nanocluster provides a unique opportunity to explore the assembly of M13 units, similar to other coinage metal nanoclusters, and investigate the nanocluster‐to‐nanocluster transformation in phosphine and thiol ligand co‐protected copper nanoclusters.

GG1234/bhBMP‐2 vesicular condensate formation in sodium acetate solution. a) Turbidimetric titration curve obtained by mixing different ratios of GG1234 and bhBMP‐2 in 50 mm sodium acetate solutions at different pH values. b) Morphological state diagram of the GG1234/bhBMP‐2 mixture in sodium acetate solutions at different pH values and salt concentrations for a 1:1 mixing ratio of GG1234 and bhBMP‐2. c) Optical microscopic image of the mixture of 2 mg mL⁻¹ GG1234 simple coacervate solution (60 mM sodium acetate, pH 3.4) and 2 mg mL⁻¹ bhBMP‐2 solution (60 mm sodium acetate, pH 3.4). d) Optical microscopic image of the mixture of 2 mg mL⁻¹ GG1234 in distilled water and 2 mg mL⁻¹ bhBMP‐2 solution (120 mm sodium acetate, pH 3.4). e) Morphological state diagram of different mixing ratios of GG1234 and bhBMP‐2 in 60 mm sodium acetate solutions at different pH values: spherical droplets (filled black circles with gray background), vesicular condensates (open circles with dark blue background), and the mixture of the spherical droplets and the vesicular condensates (filled inverted triangles with light blue background).

$GG1234/bhBMP‐2 vesicular condensate structure. a) 3D label‐free RI image of the vesicular condensates using optical diffraction tomography. The right image shows the cross‐sectional slices of a single vesicular condensate RI distribution along the x‐y plane. The left images show the overall RI distribution of the cross‐sectional slice at Z = 19.16 µm (left bottom) and a 3D rendered image of the RI distribution (left top). Confocal fluorescence microscopy images of the vesicular condensates obtained by rhodamine‐labeled b) bhBMP‐2 and c) FITC‐labeled GG1234. d) Dual‐color fluorescence image of the labeled vesicular condensates. e) Fluorescence intensity profile of the cross‐sectional line of the labeled vesicular condensate (white box in (d)). f) The formation of GG1234/bhBMP‐2 vesicular condensates 20 s after the addition of bhBMP‐2 to GG1234 simple coacervates. g) The formation of GG1234/bhBMP‐2 vesicular condensates 5 min after the addition of bhBMP‐2 to GG1234 simple coacervates. h) Molecular dynamics snapshot of the GG1234 dense slab in coexistence with the bhBMP‐2 solutions. i) Density profile of bhBMP‐2 across the simulation box in (h), which indicates the accumulation of bhBMP‐2 at the interface of the GG1234 slab. j) The MSD of the GG1234 protein center of mass within the dense slab of GG1234 at high (H0 = 1.0 kBT) and low (H0 = 0.25 kBT) hydrophobicity scales; the corresponding diffusion coefficients are obtained by calculating the slope of the MSD.$

Schematic illustration of a proposed mechanism of the formation of membrane‐less vesicle‐like GG1234/bhBMP‐2 compartments. Vesicle‐like structure formation is processed through the following steps: 1) GG1234 spherical droplets are formed by simple coacervation in the absence of bhBMP‐2. 2) The addition of bhBMP‐2 triggers coacervate rearrangement via noncovalent interaction rearrangement from GG1234 simple coacervation to GG1234/bhBMP‐2 complex coacervation. Then, the liquid‐like GG1234/bhBMP‐2 complex coacervate is transformed to a gel‐like GG1234/bhBMP‐2 complex with a vesicle‐like structure due to the increased hydrophobicity.

Spontaneous Transition of Spherical Coacervate to Vesicle‐Like Compartment

December 2023

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1 Read

Hyunsuk Choi

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Yuri Hong

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·

[...]

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Yoo Seong Choi

Numerous biological systems contain vesicle‐like biomolecular compartments without membranes, which contribute to diverse functions including gene regulation, stress response, signaling, and skin barrier formation. Coacervation, as a form of liquid–liquid phase separation (LLPS), is recognized as a representative precursor to the formation and assembly of membrane‐less vesicle‐like structures, although their formation mechanism remains unclear. In this study, a coacervation‐driven membrane‐less vesicle‐like structure is constructed using two proteins, GG1234 (an anionic intrinsically disordered protein) and bhBMP‐2 (a bioengineered human bone morphogenetic protein 2). GG1234 formed both simple coacervates by itself and complex coacervates with the relatively cationic bhBMP‐2 under acidic conditions. Upon addition of dissolved bhBMP‐2 to the simple coacervates of GG1234, a phase transition from spherical simple coacervates to vesicular condensates occurred via the interactions between GG1234 and bhBMP‐2 on the surface of the highly viscoelastic GG1234 simple coacervates. Furthermore, the shell structure in the outer region of the GG1234/bhBMP‐2 vesicular condensates exhibited gel‐like properties, leading to the formation of multiphasic vesicle‐like compartments. A potential mechanism is proposed for the formation of the membrane‐less GG1234/bhBMP‐2 vesicle‐like compartments. This study provides a dynamic process underlying the formation of biomolecular multiphasic condensates, thereby enhancing the understanding of these biomolecular structures.

a) Schematic diagram of preparing perovskite films using the two‐step sequential method. b) ESP map of trioctylphosphine oxide (TOPO). The blue and the red indicate electronegative and electropositive parts, respectively. c) The mechanism diagram of lattice strain regulation and/or defect passivation added with CsI and/or TOPO.

XRD patterns of perovskite films: a) control and Cs⁺ doped (2.5 mol% CsI (CsI2.5), 5.0 mol% CsI (CsI5.0), and 7.5 mol% CsI (CsI7.5)); b) added with TOPO (0.1 mol% TOPO (TOPO0.1), 0.2 mol% TOPO (TOPO0.2) and 0.3 mol% TOPO (TOPO0.3)) and c) added with CsI5.0 and TOPO with different concentrations. d–f) The FWHM for the corresponding perovskite films. g–i) The W–H plots of the corresponding perovskite films.

Top‐view SEM images of perovskite films: a) the control, b) CsI5.0, c) CsI5.0+TOPO0.2. Insets show the water contact angles for the corresponding film surfaces. The grain size statistics of perovskite films: d) the control, e) CsI5.0, f) CsI5.0+TOPO0.2. AFM images of perovskite films: g) the control, h) CsI5.0, i) CsI5.0+TOPO0.2.

a) FTIR spectra for DMF, TOPO dissolved in DMF and PbI2+TOPO dissolved in DMF. The XPS spectra for the control and TOPO0.2 perovskite films: b) Pb 4f, c) I 3d. The PL spectra of perovskite films on glass substrates for d) the control and doped with CsI (CsI2.5, CsI5.0 and CsI7.5), e) added with TOPO (TOPO0.1, TOPO0.2 and TOPO0.3) and f) the target (CsI5.0+TOPO0.2). g–i) TRPL spectra of the corresponding perovskite films on glass substrates.

a) The n–i–p structure of PSC device. b) Illuminated J–V curves of the control, CsI5.0 and CsI5.0+TOPO0.2 devices with reverse and forward scans. c) Steady‐state current density and PCE output for the corresponding devices measured at the maximum power point. d) EQE and integrated JSC of the corresponding devices. e) The Mott–Schottky measurement at 1m Hz for the corresponding devices. f) Nyquist plots of electrochemical impedance spectroscopy (EIS) under dark condition and g) The J–V characteristic curves of the control, CsI5.0 and CsI5.0+TOPO0.2 devices in dark. h) The VOC dependence of light intensity for the corresponding devices. i) Illuminated J–V curves of the champion device prepared with the target film.

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Strain Regulation and Defect Passivation of FA‐Based Perovskite Materials for Highly Efficient Solar Cells

December 2023

Linfeng Zhang

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Guohui Luo

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Weihao Zhang

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[...]

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Can Cui

Formamidine lead triiodide (FAPbI3) perovskites have attracted increasing interest for photovoltaics attributed to the optimal bandgap, high thermal stability, and the record power conversion efficiency (PCE). However, the materials still face several key challenges, such as phase transition, lattice defects, and ion migration. Therefore, external ions (e.g., cesium ions (Cs⁺)) are usually introduced to promote the crystallization and enhance the phase stability. Nevertheless, the doping of Cs⁺ into the A‐site easily leads to lattice compressive strain and the formation of pinholes. Herein, trioctylphosphine oxide (TOPO) is introduced into the precursor to provide tensile strain outside the perovskite lattice through intermolecular forces. The special strain compensation strategy further improves the crystallization of perovskite and inhibits the ion migration. Moreover, the TOPO molecule significantly passivates grain boundaries and undercoordinated Pb²⁺ defects via the forming of P═O─Pb bond. As a result, the target solar cell devices with the synergistic effect of Cs⁺ and TOPO additives have achieved a significantly improved PCE of 22.71% and a high open‐circuit voltage of 1.16 V (voltage deficit of 0.36 V), with superior stability under light exposure, heat, or humidity conditions.

The NCS point‐groups[2a] and the relationship between symmetry‐breaking and property‐emerging.

a) The ∞[Sr9Ge3O5S37] chain located in the threefold axis positions; b) the ∞[Sr3Ge2O2S19] framework composed of ∞[Sr3GeO2S19] chain and Ge(2)OS3 tetrahedra located in the screw axis positions; c) the structure of Sr18Ge9O5S31 viewing along the c axis. d) ∞[Sr9Ge3O5S37] chain; e) ∞[Sr3GeO2S19] chain and Ge(2)OS3 tetrahedron; f) Ge‐based tetrahedra in aligned in unit cell viewing along the b axis. The S atoms in (a,b), Sr─S, and Sr─O bonds in (a–c) were omitted for clarity.

a) View the hourglass‐like groups on the threefold axes of Sr18Ge9O5S31 along c axis; b) view the hourglass‐like groups on the threefold axes of Sr18Ge9O5S31 along b axis; c) the isolated hourglass‐like groups [Sr3OGeS3]²⁺ and [Sr3SGeS3]²⁺; d) the bond angles in [Sr3OGeS3]²⁺ and [Sr3SGeS3]²⁺; e) the dihedral angles of [Sr3OGeS3]²⁺ and [Sr3SGeS3]²⁺ groups.

a,b) The single crystal structures of the two enantiomers of Sr18Ge9O5S31 exhibiting enantiomer 1 and enantiomer 2, respectively; c) the space group table diagram of R3; d) 32 and 31 screw axes are occupied by the counterclockwise rotating Ge(2)OS3 and clockwise rotating Ge(1)S4 groups in enantiomer 1, respectively; e) 31 and 32 screw axes are occupied by clockwise rotating Ge(2)OS3 and counterclockwise rotating Ge(1)S4 groups in enantiomer 2, respectively; f) the CD and corresponding UV−vis absorption spectra of Sr18Ge9O5S31 measured with the sample prepared through mixing pure polycrystalline with KBr at 1:150. All Sr and S atoms have been omitted for clarity.

The piezoelectric force microscopy images of Sr18Ge9O5S31. a) Out‐of‐plane phase; b) out‐of‐plane amplitude; c) topography image; d) phase hysteresis loop and amplitude butterfly loop.

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Chiral and Polar Duality Design of Heteroanionic Compounds: Sr18Ge9O5S31 Based on [Sr3OGeS3] and [Sr3SGeS3] Groups

December 2023

Shaoxin Cui

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Hongping Wu

·

Xinkang Dong

·

[...]

·

Hongwei Yu

Chirality and polarity are the two most important and representative symmetry‐dependent properties. For polar structures, all the twofold axes perpendicular to the principal axis of symmetry should be removed. For chiral structures, all the mirror‐related symmetries and inversion axes should be removed. Especially for duality (polarity and chirality), all of the above symmetries should be broken and that also represents the highest‐level challenge. Herein, a new symmetry‐breaking strategy that employs heteroanionic groups to construct hourglass‐like [Sr3OGeS3]²⁺ and [Sr3SGeS3]²⁺ groups to design and synthesize a new oxychalcogenide Sr18Ge9O5S31 with chiral‐polar duality is proposed. The presence of two enantiomers of Sr18Ge9O5S31 is confirmed by the single‐crystal X‐ray diffraction. Its optical activity and ferroelectricity are also studied by solid‐state circular dichroism spectroscopy and piezoresponse force microscopy, respectively. Further property measurements show that Sr18Ge9O5S31 possesses excellent nonlinear optical properties, including the strong second harmonic generation efficiency (≈2.5 × AGS), large bandgap (3.61 eV), and wide mid‐infrared transparent region (≈15.3 µm). These indicate that the unique microstructure groups of heteroanionic materials are conducive to realizing symmetry‐breaking and are able to provide some inspiration for exploring the chiral‐polar duality materials.

Diagram illustration of the proposed information metasurface, which includes PIN diodes and RMS power detectors that are incorporated into an elaborately designed metasurface structure. The meta‐atom serves as a 1‐bit reflection phase modulator and an RF power sensor simultaneously. The MCU can analyze the collected RSSP data provided by the sensing module for intelligent sensing, and the metasurface is encoded to realize self‐adaptive beamforming, in which the coding pattern is generated based on the estimated target location.

a) 3D schematic of the designed SFPRS meta‐atom. b) Side view of the SFPRS meta‐atom with an illustration of the EM‐wave routes. c) Simulated reflection amplitudes and phases of the meta‐atom. d) Measured reflection amplitudes and phases of the meta‐atom. e) Surface current distribution under the illumination of traverse‐electric (TE) polarized wave at 0° and 40°. f) Simulated reflection amplitudes and phases of the meta‐atom under TE‐polarized oblique incidence.

a) Schematic diagram of the configuration in the full‐wave simulation, including boundary condition and wave port. b) Side view of the power flow distributions with two digital states under normal incidence. c) Sketch of the configuration of the LMH2110 RMS power detector. d) Simulated sensing losses of the meta‐atom with two digital states in the x‐ and y‐polarizations. e) Parametric analysis of W2 to reveal the mechanism of keeping the sensing loss under two digital states the same. f) Incident energy transforms to copolarization reflection Rco, sensing loss S, cross‐polarization reflection Rcross, and absorption A, where 1(100%) = Rco + S + Rcross + A. The percentage of each energy part is demonstrated in Figure 3f.

Theoretical analyses of the proposed near‐field DNS estimation and the experimental verification at 3.45 GHz. a) Theoretical EM model of the target and the information metasurface. b) Illustration of the experimental setup for DNS estimation. c) Calculated RSSPs under the target locations of (600 mm, −40°), (800 mm, 60°), and (1000 mm, −20°). d) Measured RSSPs under the target locations of (600 mm, −40°), (800 mm, 60°), and (1000 mm, −20°). e) The angle deviations between the actual incident angle and the estimated angle at different test angles θi. f) Locations of the anchor points and test points during DNS estimations. g) Simulated pattern errors at four test points. h) Measured pattern errors at four test points.

Near‐field EM ranging performance at 3.45 GHz. a) Locations of transmitting antennas with the anchor points marked in blue dots and the test points marked in red pentagrams during the EM ranging. b) Received signal strength of the central 4 × 4 elements of the metasurface under the target locations of (600 mm, 0°), (800 mm, 0°), (1000 mm, 0°), and (1000 mm, 30°). c) A curve illustrating the relationship between the RSSI and the distance H is generated by fitting the measured RSSIs at the anchor points. RSSIs at the testing points are very close to the fitting curve, indicating good EM ranging performance. d) Simulated sensing losses and measured RSSIs against the incident angle at distance H = 800 mm. The orange solid line is the raw measured RSSIs, and the reddish‐brown dotted line denotes the post‐processed results.

+3

Simultaneously Intelligent Sensing and Beamforming Based on an Adaptive Information Metasurface

December 2023

Rui Zhe Jiang

·

Qian Ma

·

Ze Gu

·

[...]

·

Tie Jun Cui

Due to its ability to adapt to a variety of electromagnetic (EM) environments, the sensing‐enabled metasurface has garnered significant attention. However, large‐scale EM‐field sensing to obtain more information is still very challenging. Here, an adaptive information metasurface is proposed to enable intelligent sensing and wave manipulating simultaneously or more specifically, to realize intelligent target localization and beam tracking adaptively. The metasurface is composed of an array of meta‐atoms, and each is loaded with two PIN diodes and a sensing‐channel structure, for polarization‐insensitive and programmable beamforming and sensing. By controlling the state of the PIN diode, the proposed meta‐atom has 1‐bit phase response in the designed frequency band, while the sensing loss keeps higher than ‐10 dB for both “ON” and “OFF” states. Hence there is nearly no interaction between the beamforming and sensing modes. Experiments are conducted to show multiple functions of the metasurface, including intelligent target sensing and self‐adaptive beamforming, and the measured results are in good agreement with the numerical simulations and theoretical calculations.

Preparation and characterization of DMPtNPS. A,B) Comparison of HIF‐1α mRNA expression and the single sample gene set enrichment analysis (ssGSEA) of hypoxia score between normal and rectal cancer tissues (normal, n = 84; tumor, n = 101). C) Comparison of hypoxia score ssGSEA between radioresistant and radiosensitive tissues (resistant, n = 28; sensitive, n = 44). D) Comparison of Kaplan‐Meier survival curves of patients with high and low hypoxia scores (hypoxia‐high, n = 50; hypoxia‐low, n = 49). E) Preparation of DMPtNPS‐L, DMPtNPS‐M, and DMPtNPS‐H were prepared using varying molar ratios of H2PtCl6 and NaBH4. F) The analysis of the compatible characteristic binding energy between silicon (Si) and platinum (Pt) in DMPtNPS‐L, ‐M, and ‐H. G) The Si and Pt element counts were quantified using energy dispersive X‐ray spectroscopy (EDS) in the three types of DMPtNPS. H) X‐ray photoelectron spectroscopy (XPS) was employed to analyze DMPtNPS‐L, ‐M, and ‐H. I) The fluorescence intensity of Ru(dpp)3Cl2 in DMPtNPS with hydrogen peroxide (H2O2, 100 × 10⁻⁶ m) at different co‐incubation times. ns indicates not significant, *P < 0.05, **P < 0.01. Data are presented as mean ± standard deviation (SD).

The in vitro radiosensitizing impact of DMPtNPS. A) CLSM images of CT26 cells and B) in HCT116 cells after coincubated with Cy5DMPtNPS at different time points. C) Cell viability (n = 6) and D) clonogenic assay of CT26 cells after treatment with DM or DMPtNPS with or without X‐ray (6 Gy) irradiation for 48 h. E) Cell viability (n = 6) and F) clonogenic assay of HCT116 cells after treatment with DM or DMPtNPS with or without X‐ray (6 Gy) irradiation for 48 h. G) Calcein‐AM / PI staining of CT26 cells or H) HCT116 cells with or without X‐ray irradiation after co‐incubated with DM or DMPtNPS. Quantitative analysis of apoptotic cells in I) CT26 cells, n = 3 or J) in HCT116 cells, n = 3. CLSM images and quantitative analysis of intracellular ROS generation in K) CT26 cells, n = 3 and L) HCT116 cells, n = 3 after coincubated with PBS, DM, or DMPtNPS with or without X‐ray. Scale bar, 200 µm. M) CLSM images of N) γ‐H2AX in CT26 cells and in HCT116 cells after receiving different as indicated. ns indicates not significant, *P < 0.05, **P < 0.01. Data are presented as mean ± SD. Scale bar, 50 µm.

DMPtNPS enhanced RT‐induced immunogenic cell death. A) CLSM images of the exposure of calreticulin (CRT) in CT26 cells and B) in HCT116 cells after receiving different treatments as indicated, scale bar, 50 µm. C) Quantitative analysis of CRT exposure (n = 3), D) extracellular ATP levels (n = 3) and E) HMGB1 levels in CT26 cells after receiving different as indicated (n = 3). F) Quantitative analysis of CRT exposure (n = 3). G) extracellular ATP (n = 3), and H) HMGB1 levels in HCT116 cells after receiving different as indicated, n = 3. ns indicates not significant, *P < 0.05, **P < 0.01. Data are presented as mean ± standard deviation (SD). I) Schematic representation of DC maturation induced by ICD, resulting in CD8⁺T cell activation. J) Quantitative analysis of mature DCs (CD80⁺CD86⁺) in DC1 (CD11C⁺CD8a⁺) in the different treatment groups (n = 3). K) Quantitative analysis of cytokines levels associated with mature DCs in the different treatment groups. L) ELISpot analysis of IFN‐γ after receiving different treatments as indicated, n = 4.

In vivo radiosensitizing effect of DMPtNPS. A) Evaluation of in vivo radiosensitization effect of DMPtNPS using a CT26‐bearing mouse model. B) Ex vivo fluorescence imaging and quantitative analysis of major organs dissected from mice after intravenous injection of DMPtNPS at 24 and 48 h (n = 3). C) Measurement of body weight loss in CT26‐bearing mice after receiving different treatments (n = 6 mice per group). D) Tumor volume curve of mice after receiving PBS, DM, or DMPtNPS with or without X‐ray (6 Gy) (n = 6 mice per group). E) Kaplan–Meier survival curves of mice after receiving different treatments (n = 6 mice per group). F) Histological examination of tumor tissues using H&E staining (scale bar, 100 µm), Ki67 staining, immunofluorescence analysis of TUNEL (green), γ‐H2AX (red), and HIF‐1α (green) at day 5 after receiving different treatments. Scale bar, 50 µm. G) Western blot analysis of γ‐H2AX and HIF‐1α at day 5 after receiving different treatments. H) GSEA is based on differentially expressed genes between the DMPtNPS + RT group and the RT group (n = 4 mice per group). I) Schematic diagram illustrating the radiosensitizing effect of DMPtNPS. ns indicates not significant, *P < 0.05, **P < 0.01. Data are presented as mean ± SD.

Biregulation of TiME induced by DMPtNPS and RT. A) Western blot analysis of HMGB1, cGAS, STING, phosphorylated‐STING, TBK1, phosphorylated‐TBK1, IRF3, phosphorylated‐IRF3, and PD‐L1 at day 5 after receiving different treatments. B) Immunofluorescence analysis of CRT (green), PD‐L1 (red), NF‐κB (red), and Foxp3 (red) on day 5 after receiving different treatments. Scale bar, 50 µm. C) Enrichment of DC‐related pathway in DMPtNPS + RT group compared to the RT alone as determined by GSEA analysis. Flow cytometry analysis of D) tumor‐infiltrating CD4⁺T cells (n = 5), E) CD8⁺T cells (n = 5). F) Heatmap showing the levels of anti‐tumor and pro‐tumor cytokines in tumor tissues from different treatment groups (n = 5). G) Enrichment of positive and negative immune response based on GSEA analysis in DMPtNPS + RT and RT alone (n = 4). H) Flow cytometry analysis of Tregs (CD25⁺Foxp3⁺) in tumors (n = 5). ns indicates not significant, *P < 0.05, **P < 0.01. Data are presented as mean ± SD. I) Schematic illustration of the biregulation of TiME induced by DMPtNPS and RT.

+4

STING Agonist‐Loaded Nanoparticles Promotes Positive Regulation of Type I Interferon‐Dependent Radioimmunotherapy in Rectal Cancer

December 2023

Lei Wang

·

Han Zhou

·

Qingjing Chen

·

[...]

·

Da Zhang

Hypoxia‐associated radioresistance in rectal cancer (RC) has severely hampered the response to radioimmunotherapy (iRT), necessitating innovative strategies to enhance RC radiosensitivity and improve iRT efficacy. Here, a catalytic radiosensitizer, DMPtNPS, and a STING agonist, cGAMP, are integrated to overcome RC radioresistance and enhance iRT. DMPtNPS promotes efficient X‐ray energy transfer to generate reactive oxygen species, while alleviating hypoxia within tumors, thereby increasing radiosensitivity. Mechanistically, the transcriptomic and immunoassay analysis reveal that the combination of DMPtNPS and RT provokes bidirectional regulatory effects on the immune response, which may potentially reduce the antitumor efficacy. To mitigate this, cGAMP is loaded into DMPtNPS to reverse the negative impact of DMPtNPS and RT on the tumor immune microenvironment (TiME) through the type I interferon‐dependent pathway, which promotes cancer immunotherapy. In a bilateral tumor model, the combination treatment of RT, DMPtNPS@cGAMP, and αPD‐1 demonstrates a durable complete response at the primary site and enhanced abscopal effect at the distant site. This study highlights the critical role of incorporating catalytic radiosensitizers and STING agonists into the iRT approach for RC.

DFT simulation of the passivation effect for CH3COO⁻ and HCOO⁻ on the perovskite surface. a) Schematic representation of the formation of halide vacancies. b) Absorption and PL spectrum of perovskite films with annealing and without annealing. Inset: Integral area ratio of I/Pb by X‐ray photoelectron spectroscopy. The density of states (DOS) of the c): defect free, defect with VI⁻, and d): passivated CH3COO⁻ terminated surfaces, HCOO⁻ terminated surfaces. e) Bonding energy of CH3COO⁻ and HCOO⁻ with Pb²⁺ by crystal orbital overlap population simulation.

X‐ray photoelectron spectroscopy of a) Pb 4f, b) I 3d, and c) Fourier transform infrared spectroscopy for control, NH4CH3COO and NH4HCOO‐doped films. d–f): Transient absorption spectra at different delay times. g–i) Transient absorption line graph at delay times of 1, 10, 100, 500 ps and 1 ns.

a) Steady‐state photoluminescence spectra and normalized time‐resolved photoluminescence decays b) for control, NH4CH3COO and NH4HCOO‐doped perovskite film. c) Thermal admittance measurement. d–f) Space charge limited current measurement for these devices. The structure is FTO/SnO2/perovskite/PCBM/Ag. g–i) Conductive atomic force microscopic images of control, NH4CH3COO and NH4HCOO‐doped perovskite film.

a) Cross‐sectional SEM image of PSCs. b) J–V curves of PSCs based on the control, NH4CH3COO, and NH4HCOO‐doped devices under reverse scan. Inset: steady PCE of the champion devices c) External quantum efficiency. d) Impedance spectroscopy measurement e) Voc versus light intensity and f) Mott‐Schottky measurement based on these devices. g) The efficiency of unencapsulated devices decreases after operating at the standard light in N2 atmosphere over 1200 h. All the error bars represent the standard deviation for six devices.

Eliminating Halogen Vacancies Enables Efficient MACL‐Assisted Formamidine Perovskite Solar Cells

December 2023

Zhiyong Liu

·

Tianxiao Liu

·

Meng Li

·

[...]

·

Mingjian Yuan

Methylammonium chloride (MACl) additive is almost irreplaceable in high‐performance formamidine perovskite photovoltaics. Nevertheless, Some of the problems that can arise from adding MACl are rarely mentioned. Herein, it is proposed for the first time that the addition of MACl would cause the non‐stoichiometric ratio in the perovskite film, resulting in the halogen vacancy. It is demonstrated that the non‐synchronous volatilization of methylamine cations and chloride ions leads to the formation of halogen vacancy defects. To solve this problem, the NH4HCOO is introduced into the perovskite precursor solution to passivate the halogen vacancy. The HCOO⁻ ions have a strong force with lead ions and can fill the halogen vacancy defects. Consequently, the champion devices' power conversion efficiency (PCE) can be improved from 21.23% to 23.72% with negligible hysteresis. And the unencapsulated device can still retain >90% of the initial PCE even operating in N2 atmosphere for over 1200 h. This work illustrates another halogen defect source in the MACl‐assisted formamidine perovskite photovoltaics and provides a new route to obtain high‐performance perovskite solar cells.

Schematic overview of metal ions‐related nanomedicines for tumor therapy.

Schematic diagram of antitumor mechanisms of Ca²⁺ overload‐based nanomedicines.

Fe²⁺ chelating mediated antitumor therapy. A) Schematic diagram of synthesis and antitumor mechanism of the nanomedicine co‐delivering DFO and HIF1α inhibitor YC1. B) Cell proliferation, assessed using EdU incorporation, following treatment of pancreatic cell lines. C) Tumor volume changes and D) Iron in tumor tissues with different treatments. Reproduced with permission.[⁵⁴] Copyright 2019, American Chemical Society.

Schematic illustrations of ferroptosis‐mediated antitumor immune responses. A) Synthetic process of Fe3O4‐SAS@PLT nanoparticles. B) Scheme of ferroptosis mechanisms of Fe3O4‐SAS@PLT nanoparticles. C) Scheme of regulation of tumor microenvironment by Fe3O4‐SAS@PLT nanoparticles. D) Representative flow cytometric analysis of CD86⁺/CD80⁺ cells gated on CD11c⁺ cells (left) and CD11c⁺CD206⁺ cells (right). E) Survival analysis of mice treated with different formulas. F) The number of lung metastasis nodules. Reproduced with permission.[⁶³] Copyright 2020, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Copper chelator‐loaded nanomedicines for tumor therapy. A) Illustration of the co‐delivery of Cu⁺ chelator and chemotherapeutics as a new strategy for tumor theranostic. B) Tumor growth curve and C) Tumor weight of different groups. D) Histochemistry analysis of heart, liver, spleen, lung, and kidney sections stained with hematoxylin and eosin (H&E). Reproduced with permission.[⁷⁹] Copyright 2020, Elsevier.

+3

Nanoenabled Intracellular Metal Ion Homeostasis Regulation for Tumor Therapy

December 2023

Lihua Xu

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Mingzheng Peng

·

Tingting Gao

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[...]

·

Pengju Wang

Endogenous essential metal ions play an important role in many life processes, especially in tumor development and immune response. The approval of various metallodrugs for tumor therapy brings more attention to the antitumor effect of metal ions. With the deepening understanding of the regulation mechanisms of metal ion homeostasis in vivo, breaking intracellular metal ion homeostasis becomes a new means to inhibit the proliferation of tumor cells and activate antitumor immune response. Diverse nanomedicines with the loading of small molecular ion regulators or metal ions have been developed to disrupt metal ion homeostasis in tumor cells, with higher safety and efficiency than free small molecular ion regulators or metal compounds. This comprehensive review focuses on the latest progress of various intracellular metal ion homeostasis regulation‐based nanomedicines in tumor therapy including calcium ion (Ca²⁺), ferrous ion (Fe²⁺), cuprous ion (Cu⁺), managanese ion (Mn²⁺), and zinc ion (Zn²⁺). The physiological functions and homeostasis regulation processes of ions are summarized to guide the design of metal ion regulation‐based nanomedicines. Then the antitumor mechanisms of various ions‐based nanomedicines and some efficient synergistic therapies are highlighted. Finally, the challenges and future developments of ion regulation‐based antitumor therapy are also discussed, hoping to provide a reference for finding more effective metal ions and synergistic therapies.

AC‐derived DNA upregulates ALOX12 expression in efferocytosing macrophages. A) Gene expression analysis for specialized pro‐resolving mediator (SPM) biosynthetic enzymes in human primary monocyte‐derived macrophages (MoDMs) incubated with ACsat 3:1 AC:macrophage ratio for indicated times as determined by RT‐qPCR. N = 6 human donors. B) Flow cytometry analysis of the percentage of ALOX12⁺ cells in AC‐negative macrophages (“AC– macrophage”; negative for CypHer5E‐ACs), compared to macrophages that had either: bound but not internalized ACs (“ACbound macrophage”; low intensity for CypHer5E‐ACs) or macrophages that had internalized ACs (“ACingested macrophage”; high intensity for CypHer5E‐ACs) after efferocytosis of CypHer5E‐labeled ACs (3:1 AC:macrophage ratio) by human MoDM for indicated amounts of time. Insets show representative contour plot for AC–, ACbound, and ACingested macrophage gating and corresponding histograms for ALOX12 MFI. N = 3 human donors. C) Fluorescence microscopy analysis of human MoDM stained with ALOX12 antibody followed by Alexa Fluor 488‐conjugated secondary antibody. Macrophages were classified into “AC‐“ (no associated AC), “ACbound” (AC signal within a 5 µm zone of interest around a macrophage), or “ACingested” (high intensity for CypHer5E that overlaps with macrophage). Horizontal lines inside violin plots indicate median (solid) and quartiles (dashed); N = 5 human donors. D) Flow cytometry analysis of the percentage of ACbound and ACingested macrophages in human MoDM cultures pre‐treated with or without 10 µm cytochalasin D for 2 h followed by efferocytosis of CypHer5E‐labelled ACs (3:1 AC:macrophage ratio) for 24 h. E) Flow cytometry analysis of the percentage of ALOX12⁺ macrophages in human MoDM cultures pre‐treated with or without 10 µm cytochalasin D for 2 h followed by efferocytosis of CypHer5E‐labelled ACs (3:1 AC:macrophage ratio) for 24 h. (F,G) Flow cytometry analysis of the percentage ALOX12⁺ cells in human MoDM; F) Comparison of ALOX12 frequency in macrophages efferocytosing CypHer5E‐labelled ACs (3:1 AC:macrophage ratio) versus macrophages phagocytosing 4 µm FluoSpheres Y/G polystyrene beads; G) Comparison of ALOX12 frequency in macrophages that have phagocytosed 5 µm uncoated Control polystyrene beads or phosphatidylserine (PtdSer)‐coated polystyrene beads, versus macrophages that have efferocytosed CypHer5E‐labelled ACs (3:1 AC:macrophage ratio) that were either untreated or pre‐treated with 100 µg mL DNase I for 1 hr prior to the assay. N = 6 human donors. H) Flow cytometry analysis of the percentage ALOX12⁺ cells in human MoDM after 24 h of efferocytosis of CypHer5E‐labelled ACs by macrophages pre‐treated with DMSO vehicle, TLR9 inhibitor (1 µg mL⁻¹ ODN INH‐18), or Aryl hydrocarbon receptor (AhR) inhibitor (5 µm CH‐223191) for 1 h. N = 6 human donors. I) Quantification of endogenous MCTR levels using LC‐MS/MS in human MoDMs incubated with ACs at 3:1 AC:macrophage ratio for indicated intervals. N = 7 human donors. J) Quantification of endogenous MCTR levels using LC‐MS/MS in human MoDMs pre‐treated with AhR inhibitor (5 µm CH‐223191) for 1 h, followed by incubation with ACs at 3:1 AC:macrophage ratio for 24 hrs. N = 3 human donors. Data are shown as mean log2 fold change (for A) or as mean ± SD (B,D‐J). Statistical significance was determined using one‐way ANOVA (E,I,J) or two‐way ANOVA (A,C,D,F,G,H) with Holm‐Sidak multiple comparison correction, or Kruskal‐Wallis test with Dunn's post hoc multiple comparison correction (B). *p <0.05, **p <0.01, ***p <0.001 versus “No ACs” control (for A,B) or as indicated in the graphs.

ALOX12 metabolizes docosahexaenoic acid to produce MCTRs in efferocytosing macrophages, while loss of MCTR formation abrogates the efferocytic ability of macrophages at sites of high AC burden. A–C) In vivo dexamethasone‐induced thymus apoptosis model with i.p. injection of 250 µg dexamethasone (Dex) or DMSO Vehicle (Veh) control for 18 h; (A) Flow cytometry analysis of Annexin V+ AC median fluorescence intensity (MFI) in F4/80⁺CD64⁺ thymic macrophages. Unst = unstained control; (B) Representative dot plots for F4/80⁺CD64⁺ thymic macrophage gating and histograms of Annexin V median fluorescence intensity (MFI); (C) Quantification of endogenous MCTR levels using LC‐MS/MS in Dex‐injured thymus. N = 4 mice per group. (D–F) Surgical injury‐induced tissue regeneration model using the planarian flatworm Dugesia japonica; (D) Schematic overview of experimental model; (E) Quantification of ACs by TUNEL assay in D. japonica planarians uninjured or 4 h post‐amputation (hpa). Unst = unstained control. Representative images of TUNEL signal (red) overlayed on brightfield images of planarians are shown in inset micrographs, where scale bar = 200 µm. N = 3 (Uncut) or 6 (4 hpa) planarians per group; (F) Quantification of endogenous MCTR levels using LC‐MS/MS in D. japonica planarians uninjured or surgically‐injured tissue sections at 1 to 4 h post‐amputation (hpa). N = 3 independent replicates per group comprised of 30 planarians per replicate. (G–I) In vivo dexamethasone‐induced thymus apoptosis model with i.p. injection of 250 µg dexamethasone or DMSO Vehicle (No Dex) control in Alox12/15‐KO or wild‐type C56BL/6J mice for 18 h; (G) Quantification of endogenous MCTR levels using LC‐MS/MS. (H) Flow cytometry analysis of Annexin V+ AC geometric mean fluorescence intensity (gMFI) in F4/80⁺CD64⁺ thymic macrophages, with mice that were not treated with dexamethasone indicated by “No Dex” horizontal dashed line. Unst = unstained control sample. Insets show representative dot plots for F4/80⁺CD64⁺ thymic macrophage gating and histograms of Annexin V MFI; (I) Flow cytometry analysis of the poportion of FVD Aqua⁺ dead cells in the thymus, with mice that were not treated with dexamethasone indicated by “No Dex” horizontal dashed line. The “No Dex” and “Unst” groups are shared between panels H & K and I & L. N = 8 mice per group. J‐L) In vivo dexamethasone‐induced thymus apoptosis model with i.p. injection of 250 µg dexamethasone or DMSO Vehicle (No Dex) control in MacAlox12/15 KO or Alox12/15‐floxed (Control) littermates for 18 h; (J) Quantification of endogenous MCTR levels using LC‐MS/MS. MCTR1 and MCTR3 were below limits of quantitation; (K) Flow cytometry analysis of Annexin V+ AC geometric mean fluorescence intensity (gMFI) in F4/80⁺CD64⁺ thymic macrophages, with mice that were not treated with dexamethasone indicated by “No Dex” horizontal dashed line. Unst = unstained control sample; (L) Flow cytometry analysis of the proportion of FVD Aqua⁺ dead cells in the thymus, with mice that were not treated with dexamethasone indicated by “No Dex” horizontal dashed line. The “No Dex” and “Unst” groups are shared between panels H & K and I & L. N = 8 mice per group. Data are shown as mean ± SD. Statistical significance was determined using two‐tailed Student's T‐test (A,C,E,H,I,K,L), one sample Wilcoxon signed‐rank test (G,J), or one‐way ANOVA with Holm‐Sidak multiple comparison correction (F). *p <0.05, **p <0.01, ***p <0.001 as indicated.

MCTRs promote continual efferocytosis in macrophages. A,B) Continual efferocytosis of successive rounds of ACs by (A) human MoDMs, or (B) mouse BMDM. Macrophages were loaded with phrodo Red‐labeled ACs (3:1 ratio) for 1 h followed by washing and a 2 h rest period prior to incubation with CypHer5E‐labeled ACs (3:1 ratio) for 3 h. MoDMs and BMDMs were incubated with 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 15 min prior to first round of pHrodo Red‐labeled ACs (“Pre‐treatment”) or 15 min prior to the second round of CypHer5E‐labeled ACs (“Interjacent treatment”). N = 5 human donors (for A), or N = 3 mice (for B). C) Percentage of AC‐positive macrophages 45 min after addition of phrodo Red‐labeled ACs (3:1 ratio) to MoDMs incubated with 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 15 min prior to AC addition. N = 7 human donors. D) Efferocytosis of phrodo Red‐labeled ACs (3:1 ratio) by MoDMs incubated with Vehicle (0.05% EtOH), 1 nm MCTR1, MCTR2, or MCTR3 individually, or 0.33 nm of MCTR1, MCTR2, and MCTR3 combined for 15 min. The Vehicle, MCTR1, MCTR2, and MCTR3 groups are shared with Figure 6J. N = 3 human donors. E) Quantification of ACs by TUNEL assay in surgically injured D. japonica planarians incubated with 0.1‐10 nm MCTR1, MCTR2, MCTR3, or Vehicle (Planaria water containing 0.05% EtOH) for 4 h. Representative images are displayed below bar graphs, where white dotted lines delineate Planaria. Scale bar = 200 µm. N = 8 planarians per group. Data are shown as mean ± SD. p‐values were calculated using two‐way ANOVA with Holm‐Sidak multiple comparison correction. *p <0.05, ##/**p <0.01, ###/***p <0.001 as indicated or versus Vehicle control (for D and E).

12‐lipoxygenase‐expressing macrophages upregulate efferocytosis in neighboring cells, while defective continual efferocytosis in macrophages lacking 12‐lipoxygenase activity is rescued by MCTR treatment. A) Efferocytosis of phrodo Red‐labeled ACs (3:1 AC:macrophage ratio) by MoDMs transfected with plasmids encoding for either human ALOX12 C‐terminally fused to green fluorescent protein (pCMV‐ALOX12‐GFP) or GFP control vector. Efferocytosis was measured over time in GFP⁺ cells, in cells that were within a 50 µm diameter around GFP⁺ cells (“Within 50 µm Ø around GFP⁺”), or in cells that were neither GFP⁺ or near GFP⁺ cells (GFP–) within the same well using high‐content imaging. N = 3 human donors. B) Efferocytosis of phrodo Red‐labeled ACs (3:1 AC:macrophage ratio) by mouse BMDM from macrophage‐specific (Cx3cr1:cre‐driven) Alox12/15‐deficient mice (MacAlox12/15 KO) or Alox12/15‐floxed littermates (Control) either by themselves or co‐cultured at indicated MacAlox12/15 KO:Control ratios measured over time using high‐content imaging. N = 4 mice. C) Efferocytosis of CypHer5E‐labeled ACs (3:1 AC:macrophage ratio) by CellBrite Green‐labeled MacAlox12/15 KO BMDM co‐cultured with PKH26‐labeled Control BMDM at indicated MacAlox12/15 KO:Control cell ratios, where efferocytosis by CellBrite Green⁺ KO BMDMs was assessed for cells that were within a 50 µm diameter around PKH26⁺ Control BMDMs (“<50 µm from Control”) versus cells that were further away (“>50 µm from Control”). N = 3 mice. Micrographs on the right show representative fluorescence microscopy images from “MacAlox12/15 KO” (top) and “4:1 MacAlox12/15 KO to Control” groups at 3 h post‐AC addition. Scale bar = 50 µm. D) Fluorescence microscopy analysis of thymi from MacAlox12/15 KO or Alox12/15‐floxed littermates (Control) that were i.p. injected with 250 µg dexamethasone for 18 h. TUNEL⁺ AC efferocytosis by F4/80⁺Alox12/15⁺ thymic macrophages were compared to F4/80⁺ macrophages within a 50 µm diameter area around F4/80⁺Alox12/15⁺ thymic macrophages (<50 µmØ) versus F4/80⁺ macrophages outside of such an area (>50 µmØ). TUNEL‐only stained sections included as negative control (“Neg. control”). N = 3 mice per group. E) Efferocytosis of phrodo Red‐labeled ACs 3:1 AC:macrophage ratio) by BMDM pre‐incubated 15 min with 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH). N = 3 mice per group. F) Continual efferocytosis of successive rounds of ACs by mouse BMDM. BMDMs from MacAlox12/15 KO mice or Alox12/15‐floxed littermates (Control) were loaded with phrodo Red‐labeled ACs (3:1 ratio) for 1 h followed by washing and a 2 h rest period prior to loading with CypHer5E‐labeled ACs (3:1 ratio) for 3 h. BMDMs were incubated with 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 15 min prior to first round of phrodo Red‐labeled ACs (“Pre‐treatment”) or after the first round of ACs but prior to the second round of CypHer5E‐labeled ACs (“Interjacent treatment”). N = 3 mice per group. G) In vivo continual efferocytosis of phrodo Red‐labeled ACs by CD3⁻CD19⁻SiglecF⁻CD102⁺CD11bhiF4/80hi large peritoneal macrophages or CD3⁻CD19⁻SiglecF⁻CD102⁻CD11bmedF4/80lo small peritoneal macrophages in MacAlox12/15 KO mice or Alox12/15‐floxed littermates (Control). Mice were i.p. injected with 3.33 × 10⁶ unlabeled ACs in 100 µL PBS, followed 2 h later by 10 ng MCTR3 and 3.33 × 10⁶ phrodo Red‐labeled ACs in 100 µL PBS each. Peritoneal lavages were harvested 45 min after injection of MCTR3 and the second round of ACs, stained with fluorescently conjugated antibodies against the peritoneal macrophage markers mentioned above, and analysed by flow cytometry. N = 3 mice for Control and MacAlox12/15 KO groups and N = 4 mice for MacAlox12/15 KO +MCTR3 group. Data are shown as mean ± SD. Statistical significance was determined using two‐way ANOVA with Holm‐Sidak multiple comparison correction. *p <0.05, **p <0.01, ***p <0.001 as indicated in the graphs.

MCTRs regulate macrophage Rac1 activity and enhance initial AC uptake in a Rac1‐dependent manner. A,B) Phosphoproteomic profiling of human MoDMs treated with 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 5 min or 15 min. N = 4 human donors. Datasets for 5 min and 15 min MCTR treatment were combined prior to downstream analyses. (A) REACTOME pathway analysis showing top pathways associated with significantly differentially phosphorylated peptides. (B) Scatter plot of p‐values and odd ratios from Enrichr protein‐protein interaction hub analysis of significantly differentially phosphorylated peptides associated with the REACTOME pathway “Signaling by Rho GTPases”. C) Schematic overview of Rac1 activity cycling required for successful efferocytosis. (D‐E) Activity heatmap of the Rho GTPases Rac1 D) and RhoA (E) as measured by G‐LISA in human MoDMs incubated with 10 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for indicated time periods. N = 6 human donors (for Rac1) or 2 human donors (for RhoA). F) (Top) Representative micrographs of Phalloidin‐stained macrophage F‐actin and phrodo Red‐labeled ACs. (Bottom) Quantification of AC‐associated F‐actin in Phalloidin‐stained MoDMs pre‐incubated with Rac1 inhibitor (100 µm NSC23766) or DMSO control (0.05% DMSO) for 20 h, followed by 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 15 min. MoDMs were then loaded with phrodo Red‐labeled ACs (3:1 ratio) for 15‐ or 45‐min. Scale bar = 20 µm. N = 3 human donors for 15 min time point; N = 5 human donors for 45 min time point. G) Efferocytosis of phrodo Red‐labeled ACs (3:1 ratio) by MoDMs pre‐incubated with Rac1 inhibitor (100 µm NSC23766), RhoA inhibitor (0.5 µg mL⁻¹ CT04), or DMSO control (0.05% DMSO) for 20 h followed by 1 nm MCTR1, MCTR2, MCTR3, or Vehicle (0.05% EtOH) for 15 min. N = 7 human donors. H) Quantification of ACs by TUNEL assay in surgically injured D. japonica planarians incubated in Planaria water for 3 h followed by Rac1 inhibitor (100 µm NSC23766) or DMSO control (0.1% DMSO), combined with 10 nm MCTR1, MCTR2, MCTR3, or Vehicle (Planaria water containing 0.05% EtOH) for 1 h. N = 10‐11 planarians per group. Data are shown as mean –log10 p‐values (for A), as geometric mean fold change (for D‐E), or as mean ± SD (F‐H). p‐values were calculated using two‐way ANOVA with Holm‐Sidak multiple comparison correction. *p <0.05, **p <0.01, ***p <0.001 versus time point 0 (for D,E), Vehicle control (for G), or as indicated.

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Efferocyte‐Derived MCTRs Metabolically Prime Macrophages for Continual Efferocytosis via Rac1‐Mediated Activation of Glycolysis

December 2023

Duco Steven Koenis

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Roberta de Matteis

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Vinothini Rajeeve

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[...]

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Jesmond Dalli

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12‐lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add‐back of MCTRs. Mechanistically, MCTR‐mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR‐mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.

a) XRD patterns of the BTAS glass ceramics crystallized under different electric field strengths. The inset is the variations of the (110) peak position and the crystallinity in different BTAS glass ceramics. b) Raman spectra of the corresponding BTAS glass ceramics at room temperature. c) Morphology of BTAS‐3 glass ceramic observed by HRTEM. The insets are SAED pattern and the grain size distribution histogram. d) Lattice fringes of the BTAS‐3 glass ceramic. e HAADF‐STEM images of the BTAS‐3 glass ceramic together with schematic diagrams of cubic BaTiO3 crystal structure under different project vectors.

a) XPS high resolution spectra deconvoluted results of the Ba 3d5/2 peaks. b) XPS high resolution spectra deconvoluted results of the O 1s peaks. c) XPS high resolution spectra deconvoluted results of Ti 2p peaks. d) The relative contents of BaII, OI and OII for different BTAS glass ceramic samples based on the deconvoluted results of Ba 3d5/2 and O 1s peaks. e) The first‐derivative EPR spectra of BTAS‐0, 1, 2, 3, 5, and 7 glass ceramics. f Sketches of defect formation processes without and with electric field assistance during crystallization.

a) Temperature dependent dielectric constant and loss measured at the frequency of 0.5 kHz. b) Weibull distribution of dielectric breakdown strength Eb of the glass ceramics with a thickness of 0.05 ± 0.01 mm at room temperature. ‐Z′′ versus frequency curves at different temperatures of c) BTAS‐0, d) BTAS‐3, and e) BTAS‐5. f) Ea and DBS as a function of various electric field strengths applied during crystallization. g) Cole‐Cole plots of BTAS‐0, BTAS‐3, and BTAS‐5 at 580 °C. The inset is the equivalent circuit of “brickwork” model. h Variations of ΔR and ΔC for the BTAS glass ceramics.

P‐E loops at a frequency of 10 Hz of a) BTAS‐0, b) BTAS‐3 glass ceramics with a thickness of 0.05 ± 0.01 mm and an electrode diameter of 1.5‐2.0 mm. c) Wrec and η of the different BTAS glass ceramic samples. d) A comparison of energy storage performance of the BTAS‐2 and BTAS‐3 glass ceramics with the other glass ceramics and dielectric ceramics so far reported. KNN, BFO and BT represent K0.5Na0.5NO3, BiFeO3 and BaTiO3, respectively.

a) The time dependent curves of discharge current of the BTAS‐3 glass ceramic with a thickness of 0.05 ± 0.01 mm and an electrode diameter of 1.5‐2.0 mm. The inset corresponds to the Wd versus time curve and Pd value. b) Discharge behavior of the BTAS‐3 glass ceramic in the temperature range of 30–150 °C. The inset displays the corresponding Wd value. c) P‐E loops of the BTAS‐3 glass ceramic at different temperatures in the range from 30 to 150 °C. The inset gives the temperature dependence of Wrec and η. d) The Wrec and η values of the BTAS‐3 glass ceramic as a function of the cycling number at room temperature. The inset shows the typical P‐E loops after various cycling numbers.

Boosting Energy Storage Performance of Glass Ceramics via Modulating Defect Formation During Crystallization

December 2023

Fei Shang

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Juwen Wei

·

Jiwen Xu

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[...]

·

Huarui Xu

Along with the demand for further miniaturization of high and pulsed power devices, it becomes more and more important to realize ultrahigh recoverable energy storage density (Wrec) with high energy storage efficiency (η) and ultrahigh discharge energy storage density (Wd) accompanied by high power density (Pd) in dielectrics. To date, it remains, however, a big challenge to achieve high Wrec or Wd in glass ceramics compared to other dielectric energy storage materials. Herein, a strategy of defect formation modulation is applied to form “amorphous‐disordered‐ordered” microstructure in BaTiO3‐based glass ceramics so as to achieve a high Wrec of 12.04 J cm⁻³ with a high η of 81.1% and an ultrahigh Wd of 11.98 J cm⁻³ with a superb Pd of 973 MW cm⁻³. This work demonstrates a feasible route to obtain glass ceramics with an outstanding energy storage performance and proves the enormous potential of glass ceramics in high and pulsed power applications.

Design and characterization of LET‐EVs‐miRNA‐125b. A) Schematic diagram of the preparation of LET‐EVs‐miRNA125b. LET was modified on the surface by donor cell modification and miRNA‐125b was loaded into EVs by transfection. B) Schematics of the construction and production of the LAMP‐2B‐LET fusion protein plasmid. C) Size distribution and particles of EVs and LET‐EVs, measured using NTA. The average sizes of EVs and LET‐EVs were 135.8 and 133.6 nm, respectively. D) The morphology of EVs and LET‐EVs was a typical cup‐shaped structure detected by TEM (Scale bar: 200 nm). E) EV‐positive (LAMP‐2B, CD63, CD81, and TSG101) and ‐negative (Calnexin) markers were detected in LAMP‐2B‐EVs, LAMP‐2B‐LET‐EVs, and their donor cells by western blotting. F) The loading efficiency of miRNA‐125b‐5p was detected using qRT‐PCR to compare the relative expression of miRNA‐125b‐5p between LET‐EVs and LET‐EVs‐miRNA‐125b (n = 3).

Uptake and distribution of LET‐EVs and EVs in vivo and in vitro. A) Fluorescence microscope of cellular uptake of DIL‐labeled LET‐EVs and EVs after 2 and 24 h of incubation with HPMVECs. The stains used were as follows: DIL‐labeled EVs (Orange), F‐actin (Green), and DAPI (Blue) (Scale bar: 25 µm). B) Quantification of EVs integrated fluorescence density based on ImageJ analysis. The uptake efficiency of DIL‐labeled LET‐EVs was higher than that of DIL‐EVs. C) Imaging of ALI mice after 0, 2, and 48 h of administration of DIR, DIR‐EVs, and DIR‐LET‐EVs. Compared with the DIR and DIR‐EVs groups, the fluorescence signal of LET‐EVs was mainly accumulated in the epigastric region after 2 h. D) Fluorescence imaging of tissues from ALI mice in the DIR, DIR‐EVs, and DIR‐LET‐EVs groups after 48 h. Compared with the DIR and DIR‐EVs groups, the signal in the DIR‐LET‐EVs groups was mainly aggregated in lung tissues. E) Quantitative analysis of mean fluorescence intensities in different tissues following administration of EVs and LET‐EVs. F) The clearance of EVs in lung tissues was calculated by dividing average lung signals by average liver signals. G) Uptake of DIL‐EVs and DIL‐LET‐EVs by endothelial cells in lung tissues. Immunofluorescence staining was performed in lung sections using an antibody against CD31 (endothelial cell marker, green). Nuclei were stained with DAPI (Scale bar: 100 µm). All the data are presented as the mean ± SD (n = 3). *p < 0.05, ***p < 0.001 compared with the EVs group by unpaired Student's t‐tests.

LET‐EVs‐miRNA‐125b ameliorates ALI in mice. A) Schematic diagram depicting the timeline of intratracheal administration of 1 mg kg⁻¹ LPS, treatment with LET‐EVs‐miRNA‐125b after 4 h, and subsequent analysis of lung injury parameters after 48 h. B) Wet‐to‐Dry weight ratio of lung tissues. C) Total protein concentration in BALF. D) Representative images of lung tissues after staining with Evans blue. The concentration of Evans Blue in lung tissues was detected using a microplate reader. W/D ratio, BALF protein concentration, and the concentration of Evans blue in lung tissues were decreased after treatment with LET‐EVs‐miRNA‐125b compared to those in the PBS group. E) Representative images of H&E‐stained lung tissue sections. The pathological lung injury score was calculated according to the H&E‐staining. F) The morphology of the lung tissues showed an increase in the number of alveoli/hpf and decreased alveolar septal thickness and mean linear intercept after treatment with LET‐EVs‐miRNA‐125b, compared to that in the PBS group. G,H) TUNEL staining of apoptotic cells and KI67 staining of proliferating cells in lung tissue sections (Scale bar: 100 µm). ImageJ was used to quantify fluorescence intensity. Many cells in the PBS group were apoptotic and a few cells were proliferating. After treatment with LET‐EVs‐miRNA‐125b, a large number of cells were proliferating and cell apoptosis was inhibited. All data are presented as the mean ± SD (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, compared with the PBS treatment group by unpaired Student's t‐tests. #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001, compared with the LET‐EVs‐miRNA‐125b treatment group by unpaired Student's t‐tests. ∆p < 0.05, ∆∆∆∆p < 0.0001 of the EVs treatment group compared with the EVs‐miRNA‐125b treatment group by unpaired Student's t‐tests.

LET‐EVs‐miRNA‐125b inhibits inflammatory response in ALI mice. A) Representative images of Wright‐Giemsa staining of BALF cells in different groups (Scale bar: 100 µm). B) The numbers of macrophages and neutrophils in BALF. After LPS stimulation, a large number of neutrophils and macrophages were aggregated in the alveoli/interstitium and the recruitment was reduced in the LET‐EVs‐miRNA‐125b treatment group. C) The concentration of IL‐6, IL‐10, TNF‐α, IL‐1β, MIP‐2, and IFN‐γ in BALF detected by Elisa.

The distribution and expression of junction proteins in lung tissues and cell models after treatment with LET‐EVs‐miRNA‐125b. A–C) Immunofluorescence staining showing ZO‐1 (Green), Occludin (Green), and VE‐cadherin (Green) expression in lung tissues. CD31 (Red) was used to label endothelial cells. Nuclei were stained with DAPI (Blue) (Scale bar: 100 µm). The fluorescence intensity was low in the PBS group and exhibited a fragmented staining pattern. After treatment with LET‐EVs‐miRNA‐125b, the fluorescence intensity was significantly higher with continuous membrane staining. D) ZO‐1, Occludin, and VE‐cadherin expression in lung tissues in different groups, detected by western blotting. The levels of ZO‐1, Occludin, and VE‐cadherin were quantitated using ImageJ and normalized to β‐Actin. The expressions of ZO‐1, Occludin, and VE‐cadherin in the PBS group were significantly decreased but were restored to different degrees after treatment with EVs, miRNA‐125b, EVs‐miRNA‐125b, and LET‐EVs‐miRNA‐125b. E) Schematic diagram depicting the establishment of an endothelial barrier injury cell model. HUVECs were seeded in Transwell filter inserts to form a cell monolayer. TEER values were measured to assess the integrity of the endothelial barrier. The data were normalized to the control group. F) ZO‐1, Occludin, and VE‐cadherin expression in endothelial cells in different groups detected using western blotting. The levels of ZO‐1, Occludin, and VE‐cadherin were quantitated using ImageJ and normalized to GAPDH. All data are presented as the mean ± SD (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, compared with the PBS treatment group by unpaired Student's t‐tests. #p < 0.05, ##p < 0.01, ###p < 0.001, compared with the LET‐EVs‐miRNA‐125b treatment group by unpaired Student's t‐tests. ∆p < 0.05, ∆∆p < 0.01, the EVs treatment group compared with the EVs‐miRNA‐125b treatment group by unpaired Student's t‐tests.

+3

Endothelium‐Derived Engineered Extracellular Vesicles Protect the Pulmonary Endothelial Barrier in Acute Lung Injury

December 2023

Zhengyan Gu

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Mingxue Sun

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Jihao Liu

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[...]

·

Qingqiang Xu

Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium‐derived engineered extracellular vesicles (eEVs) that deliver microRNA‐125b‐5p (miRNA‐125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell‐targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA‐125b is loaded into EVs. Finally, LET‐EVs‐miRNA‐125b is constructed. The results show that compared to the EVs, miRNA‐125b, and EVs‐miRNA‐125b, LET‐EVs‐miRNA‐125b exhibit the most significant treatment efficacy in ALI. Moreover, LET‐EVs‐miRNA‐125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET‐EVs‐miRNA‐125b downregulates early growth response‐1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET‐EVs‐miRNA‐125b can treat ALI by protecting the endothelial barrier integrity.