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1.
Small ; : e2401565, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38745539

RESUMO

Stretchable strain sensors play a crucial role in intelligent wearable systems, serving as the interface between humans and environment by translating mechanical strains into electrical signals. Traditional fiber strain sensors with intrinsic uniform axial strain distribution face challenges in achieving high sensitivity and anisotropy. Moreover, existing micro/nano-structure designs often compromise stretchability and durability. To address these challenges, a novel approach of using 3D printing to fabricate MXene-based flexible sensors with tunable micro and macrostructures.  Poly(tetrafluoroethylene) (PTFE) as a pore-inducing agent is added into 3D printable inks to achieve controllable microstructural modifications. In addition to microstructure tuning, 3D printing is employed for macrostructural design modifications, guided by finite element modeling (FEM) simulations. As a result, the 3D printed sensors exhibit heightened sensitivity and anisotropy, making them suitable for tracking static and dynamic displacement changes. The proposed approach presents an efficient and economically viable solution for standardized large-scale production of advanced wire strain sensors.

2.
Natl Sci Rev ; 11(6): nwae135, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38770531

RESUMO

Lipid nanoparticles (LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

3.
Inorg Chem ; 63(19): 8977-8987, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38690714

RESUMO

Integration of hydrogen evolution with the oxidation of organic substances in one electrochemical system is highly desirable. However, achieving selective oxidation of organic substances in the integrated system is still highly challenging. In this study, a phosphorylated NiMoO4 nanoneedle-like array was designed as the catalytic active electrode for the integration of highly selective electrochemical dehydrogenation of tetrahydroisoquinolines (THIQs) with hydrogen production. The leaching of anions, including MoO42- and PO43-, facilitates the reconstruction of the catalyst. As a result, nickel oxyhydroxides with the doping of PO43- and richness of defects are in situ formed. In situ Raman and density functional theory calculations have shown that the high catalytic activity is attributed to the in situ formed PO43- involved NiOOH substance. In the dehydrogenation process, the involved C-H bond but not the N-H bond is first destroyed. A two-electrode system was then fabricated with the optimized electrode that shows a benchmark current density of 10 mA cm-2 at 1.783 V, providing a yield of 70% for dihydroisoquinolines. A robust stability was also shown for this integrated electrochemical system. The understanding of the reconstruction behavior and the achievement of selective dehydrogenation will provide some hints for electrochemical synthesis.

4.
ACS Macro Lett ; 13(5): 550-557, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38634712

RESUMO

Highly ordered, network-nanostructured polymers offer compelling geometric features and application potential. However, their practical utilization is hampered by the restricted accessibility. Here, we address this challenge using commercial Pluronic surfactants with a straightforward modification of tethering polymerizable groups. By leveraging lyotropic self-assembly, we achieve facile production of double-gyroid mesophases, which are subsequently solidified via photoinduced cross-linking. The exceptionally ordered periodicities of Ia3d symmetry in the photocured polymers are unambiguously confirmed by synchrotron small-angle X-ray scattering (SAXS), which can capture single-crystal-like diffraction patterns. Electron density maps reconstructed from SAXS data complemented by transmission electron microscopy analysis further elucidate the real-space gyroid assemblies. Intriguingly, by tuning the cross-linking through thiol-acrylate chemistry, the mechanical properties of the polymer are modulated without compromising the integrity of Ia3d assemblies. The 3-D percolating gyroid nanochannels demonstrate an ionic conductivity that surpasses that of disordered structures, offering promising prospects for scalable fabrication.

5.
Small ; : e2301074, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38659180

RESUMO

The coating of filter media with silver is typically achieved by chemical deposition and aerosol processes. Whilst useful, such approaches struggle to provide uniform coating and are prone to blockage. To address these issues, an in situ method for coating glass fibers is presented via the dopamine-mediated electroless metallization method, yielding filters with low air resistance and excellent antibacterial performance. It is found that the filtration efficiency of the filters is between 94 and 97% and much higher than that of silver-coated filters produced using conventional dipping methods (85%). Additionally, measured pressure drops ranged between 100 and 150 Pa, which are lower than those associated with dipped filters (171.1 Pa). Survival rates of Escherichia coli and Bacillus subtilis bacteria exposed to the filters decreased to 0 and 15.7%±1.49, respectively after 2 h, with no bacteria surviving after 6 h. In contrast, survival rates of E. coli and B. subtilis bacteria on the uncoated filters are 92.5% and 89.5% after 6 h. Taken together, these results confirm that the in situ deposition of silver onto fiber surfaces effectively reduces pore clogging, yielding low air resistance filters that can be applied for microbial filtration and inhibition in a range of environments.

6.
Adv Healthc Mater ; : e2400102, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38657167

RESUMO

The phosphorylated noncollagenous proteins (NCPs) play a vital role in manipulating biomineralization, while the mechanism of phosphorylation of NCPs in intrafibrillar mineralization of collagen fibril has not been completely deciphered. Poly(vinylphosphonic acid) (PVPA) and sodium trimetaphosphate (STMP) as templating analogs of NCPs induce hierarchical mineralization in cooperation with indispensable sequestration analogs such as polyacrylic acid (PAA) via polymer-induced liquid-like precursor (PILP) process. Herein, STMP-Ca and PVPA-Ca complexes are proposed to achieve rapid intrafibrillar mineralization through polyelectrolyte-Ca complexes pre-precursor (PCCP) process. This strategy is further verified effectively for remineralization of demineralized dentin matrix both in vitro and in vivo. Although STMP micromolecule fails to stabilize amorphous calcium phosphate (ACP) precursor, STMP-Ca complexes facilely permeate into intrafibrillar interstices and trigger phase transition of ACP to hydroxyapatite within collagen. In contrast, PVPA-stabilized ACP precursors lack liquid-like characteristic and crystallize outside collagen due to rigid conformation of PVPA macromolecule, while PVPA-Ca complexes infiltrate into partial intrafibrillar intervals under electrostatic attraction and osmotic pressure as evidenced by intuitionistic 3D stochastic optical reconstruction microscopy (3D-STORM). The study not only extends the variety and size range of polyelectrolyte for PCCP process but also sheds light on the role of phosphorylation for NCPs in biomineralization.

7.
Nanoscale ; 16(18): 8778-8790, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38634463

RESUMO

As fossil fuels continue to deplete, the development of sustainable and green energy sources has become crucial for human societal advancement. Among the various renewable energies, solar energy stands out as a promising substitute for conventional fossil fuels, offering widespread availability and a pollution-free solution. Solar cells, as devices that convert solar energy, are garnering significant focus. However, the intermittent nature of solar energy results in a high dependence on weather conditions of solar cells. Integrated solar cell-energy storage systems that integrate solar cells and energy storage devices may solve this problem by storing the generated electricity and managing the energy output. This review delves into the latest developments in integrated solar cell-energy storage systems, marrying various solar cells with either supercapacitors or batteries. It highlights their construction, material composition, and performance. Additionally, it discusses prevailing challenges and future possibilities, aiming to spark continued advancement and innovation in the sector.

8.
Aging (Albany NY) ; 16(5): 4541-4562, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38428403

RESUMO

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 µM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 µM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.


Assuntos
Galactose , Insuficiência Ovariana Primária , Humanos , Feminino , Camundongos , Animais , Galactose/toxicidade , Sirtuína 1/genética , Sirtuína 1/metabolismo , Peróxido de Hidrogênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Camundongos Endogâmicos C57BL , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Insuficiência Ovariana Primária/genética , Células da Granulosa/metabolismo , Senescência Celular , RNA Mensageiro/metabolismo
9.
Gels ; 10(3)2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38534605

RESUMO

The remarkable flexibility and heightened sensitivity of flexible sensors have drawn significant attention, setting them apart from traditional sensor technology. Within this domain, hydrogels-3D crosslinked networks of hydrophilic polymers-emerge as a leading material for the new generation of flexible sensors, thanks to their unique material properties. These include structural versatility, which imparts traits like adhesiveness and self-healing capabilities. Traditional templating-based methods fall short of tailor-made applications in crafting flexible sensors. In contrast, 3D printing technology stands out with its superior fabrication precision, cost-effectiveness, and satisfactory production efficiency, making it a more suitable approach than templating-based strategies. This review spotlights the latest hydrogel-based flexible sensors developed through 3D printing. It begins by categorizing hydrogels and outlining various 3D-printing techniques. It then focuses on a range of flexible sensors-including those for strain, pressure, pH, temperature, and biosensors-detailing their fabrication methods and applications. Furthermore, it explores the sensing mechanisms and concludes with an analysis of existing challenges and prospects for future research breakthroughs in this field.

10.
J Mater Chem B ; 12(13): 3209-3225, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38497405

RESUMO

Photodynamic therapy (PDT) exhibits great application prospects in future clinical oncology due to its spatiotemporal controllability and good biosafety. However, the antitumor efficacy of PDT is seriously hindered by many factors, including tumor hypoxia, limited light penetration ability, and strong defense mechanisms of tumors. Considering that it is difficult to completely solve the first two problems, enhancing the lethality of antitumor PDT has become a good idea to extend its clinical application. Herein, we summarize the nanoplatform-involved strategies to effectively amplify the tumoricidal capability of current PDT and then discuss the present bottlenecks and prospects of the nanoplatform-based PDT sensitization strategies in tumor therapy. We hope this review will provide some references for others to design high-performance PDT nanoplatforms for tumor therapy.


Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias/terapia
11.
Angew Chem Int Ed Engl ; 63(18): e202401903, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38380841

RESUMO

In this study, we introduce a novel approach for synthesizing two-dimensional (2D) MXene heterostructures featuring a sandwiched and cross-linked network structure. This method addresses the common issue of activity degradation in 2D nanomaterials caused by inevitable aggregation. By utilizing the distinct surface characteristics of MXene, we successfully induced the growth of various 2D nanomaterials on MXene substrates. This strategy effectively mitigates self-stacking defects and augments the exposure of surface areas. In particular, the obtained 2D-2D MXene@NiCo-layered double hydroxide (MH-NiCo) heterostructures exhibit enhanced structural stability, improved chemical reversibility, and heightened charge transfer efficiency, outperforming pure NiCo LDH. The aqueous MH-Ni4Co1//Zn@carbon cloth (MH-Ni4Co1//Zn@CC) battery demonstrates exceptional performance with a remarkable specific capacity of 0.61 mAh cm-2, maintaining 96.6 % capacitance after 2300 cycles. Additionally, it achieves an energy density of 1.047 mWh cm-2 and a power density of 32.899 mW cm-2. This research not only paves the way for new design paradigms in energy-related nanomaterials but also offers invaluable insights for the application and optimization of 2D-2D heterostructures in advanced electrochemical devices.

12.
Sci Adv ; 10(7): eadl1299, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38363846

RESUMO

Reservoir computing is a powerful neural network-based computing paradigm for spatiotemporal signal processing. Recently, physical reservoirs have been explored based on various electronic devices with outstanding efficiency. However, the inflexible temporal dynamics of these reservoirs have posed fundamental restrictions in processing spatiotemporal signals with various timescales. Here, we fabricated thin-film transistors with controllable temporal dynamics, which can be easily tuned with electrical operation signals and showed excellent cycle-to-cycle uniformity. Based on this, we constructed a temporal adaptive reservoir capable of extracting temporal information of multiple timescales, thereby achieving improved accuracy in the human-activity-recognition task. Moreover, by leveraging the former computing output to modify the hyperparameters, we constructed a closed-loop architecture that equips the reservoir computing system with temporal self-adaptability according to the current input. The adaptability is demonstrated by accurate real-time recognition of objects moving at diverse speed levels. This work provides an approach for reservoir computing systems to achieve real-time processing of spatiotemporal signals with compound temporal characteristics.

13.
Nat Commun ; 15(1): 1132, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38326298

RESUMO

The exponential growth of various complex images is putting tremendous pressure on storage systems. Here, we propose a memristor-based storage system with an integrated near-storage in-memory computing-based convolutional autoencoder compression network to boost the energy efficiency and speed of the image compression/retrieval and improve the storage density. We adopt the 4-bit memristor arrays to experimentally demonstrate the functions of the system. We propose a step-by-step quantization aware training scheme and an equivalent transformation for transpose convolution to improve the system performance. The system exhibits a high (>33 dB) peak signal-to-noise ratio in the compression and decompression of the ImageNet and Kodak24 datasets. Benchmark comparison results show that the 4-bit memristor-based storage system could reduce the latency and energy consumption by over 20×/5.6× and 180×/91×, respectively, compared with the server-grade central processing unit-based/the graphics processing unit-based processing system, and improve the storage density by more than 3 times.

14.
Nanoscale Adv ; 6(2): 467-480, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38235102

RESUMO

Calcium carbonate (CaCO3), possessing excellent biocompatibility, bioactivity, osteoconductivity and superior biodegradability, may serve as an alternative to hydroxyapatite (HAp), the natural inorganic component of bone and dentin. Intrafibrillar mineralization of collagen with CaCO3 was achieved through the polymer-induced liquid precursor (PILP) process for at least 2 days. This study aims to propose a novel pathway for rapid intrafibrillar mineralization with CaCO3 by sequential application of the carbonate-bicarbonate buffer and polyaspartic acid (pAsp)-Ca suspension. Fourier transform infrared (FTIR) spectroscopy, zeta potential measurements, atomic force microscopy/Kelvin probe force microscopy (AFM/KPFM), and three-dimensional stochastic optical reconstruction microscopy (3D STORM) demonstrated that the carbonate-bicarbonate buffer significantly decreased the surface potential of collagen and CO32-/HCO3- ions could attach to collagen fibrils via hydrogen bonds. The electropositive pAsp-Ca complexes and free Ca2+ ions are attracted to and interact with CO32-/HCO3- ions through electrostatic attractions to form amorphous calcium carbonate that crystallizes gradually. Moreover, like CaCO3, strontium carbonate (SrCO3) can deposit inside the collagen fibrils through this pathway. The CaCO3-mineralized collagen gels exhibited better biocompatibility and cell proliferation ability than SrCO3. This study provides a feasible strategy for rapid collagen mineralization with CaCO3 and SrCO3, as well as elucidating the tissue engineering of CaCO3-based biomineralized materials.

15.
Medicine (Baltimore) ; 103(4): e36882, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38277536

RESUMO

RATIONALE: Dentinogenesis imperfecta (DI) is an autosomal-dominant disorder. The most common clinical manifestations, including obliterated tooth tissues and severe tooth wear, usually lead to tooth extractions. It remains a great challenge for dentists to preserve the residual tooth tissue and establish the esthetics and occlusion of dentitions. PATIENTS CONCERNS: 25-year-old twin sisters, who had suffered from dentinogenesis imperfecta type II for more than 10 years, presented with continuous tooth wear and discomfort from wearing a removable partial denture for more than 3 years. DIAGNOSIS: Intraoral examination showed extensive tooth wear with enamel exfoliation and typical amber-brown color with an opalescent discoloration. Their panoramic radiographs revealed completely obliterated tooth tissues and severe tooth wear. INTERVENTIONS AND OUTCOMES: The dentitions were restored with post-and-core crowns and pin lays after preparing root post paths and pin holes guided by computer-aided design/computer-aided manufacturing (CAD/CAM) procedures, resulting in a successful repair. LESSONS: Severe tooth wear and tooth tissue obliteration are typical clinical manifestations in DI-affected dentitions, increasing the complexity and difficulty in dental restorations. Early diagnosis and appropriate treatments are essential to achieve a favorable prognosis. CAD/CAM procedures, permitting accurate and effective treatment, possess promising potential in the treatment of DI-affected dentitions.


Assuntos
Dentinogênese Imperfeita , Desgaste dos Dentes , Dente , Adulto , Humanos , Coroas , Dentinogênese Imperfeita/reabilitação , Reabilitação Bucal , Feminino
16.
Small ; 20(15): e2307736, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38009506

RESUMO

Herein, a drug-loading nanosystem that can in situ form drug depository for persistent antitumor chemotherapy and immune regulation is designed and built. The system (DOX@MIL-LOX@AL) is fabricated by packaging alginate on the surface of Doxorubicin (DOX) and lactate oxidase (LOX) loaded MIL-101(Fe)-NH2 nanoparticle, which can easily aggregate in the tumor microenvironment through the cross-linking with intratumoral Ca2+. Benefiting from the tumor retention ability, the fast-formed drug depository will continuously release DOX and Fe ions through the ATP-triggered slow degradation, thus realizing persistent antitumor chemotherapy and immune regulation. Meanwhile, LOX in the non-aggregated nanoparticles is able to convert the lactic acid to H2O2, which will be subsequently decomposed into ·OH by Fe ions to further enhance the DOX-induced immunogenic death effect of tumor cells. Together, with the effective consumption of immunosuppressive lactic acid, long-term chemotherapy, and oxidation therapy, DOX@MIL-LOX@AL can execute high-performance antitumor chemotherapy and immune activation with only one subcutaneous administration.


Assuntos
Nanopartículas , Microambiente Tumoral , Peróxido de Hidrogênio , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/farmacologia , Ácido Láctico , Linhagem Celular Tumoral
17.
J Endocrinol ; 260(2)2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-37991884

RESUMO

Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2-CREB signaling pathway in an AR-independent manner.


Assuntos
Receptores Androgênicos , Testosterona , Animais , Masculino , Camundongos , Androgênios/farmacologia , Androgênios/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Receptores Androgênicos/metabolismo , Testosterona/metabolismo
18.
Front Optoelectron ; 16(1): 39, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38038763

RESUMO

Manganese dioxide (MnO2), as a cathode material for multivalent ion (such as Mg2+ and Al3+) storage, is investigated due to its high initial capacity. However, during multivalent ion insertion/extraction, the crystal structure of MnO2 partially collapses, leading to fast capacity decay in few charge/discharge cycles. Here, through pre-intercalating potassium-ion (K+) into δ-MnO2, we synthesize a potassium ion pre-intercalated MnO2, K0.21MnO2·0.31H2O (KMO), as a reliable cathode material for multivalent ion batteries. The as-prepared KMO exhibits a high reversible capacity of 185 mAh/g at 1 A/g, with considerable rate performance and improved cycling stability in 1 mol/L MgSO4 electrolyte. In addition, we observe that aluminum-ion (Al3+) can also insert into a KMO cathode. This work provides a valid method for modification of manganese-based oxides for aqueous multivalent ion batteries.

19.
iScience ; 26(12): 108371, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38025791

RESUMO

Memory-augmented neural network (MANN) has received increasing attention as a promising approach to achieve lifelong on-device learning, of which implementation of the explicit memory is vital. Content addressable memory (CAM) has been designed to accelerate the explicit memory by harnessing the in-memory-computing capability. In this work, a CAM cell with quadratic code is proposed, and a 1Mb Flash-based multi-bit CAM chip capable of computing Euclidean (L2) distance is fabricated. Compared with ternary CAM, the latency and energy are significantly reduced by 5.3- and 46.6-fold, respectively, for the MANN on Omniglot dataset. Besides, the recognition accuracy has slight degradation (<1%) even after baking for 105 s at 200°C, demonstrating the robustness to environmental disturbance. Performance evaluation indicates a reduction of 471-fold in latency and 1267-fold in energy compared with GPU for search operation. The proposed robust and energy-efficient CAM provides a promising solution to implement lifelong on-device machine intelligence.

20.
Cell Stem Cell ; 30(12): 1624-1639.e8, 2023 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-37989316

RESUMO

Reactivating silenced γ-globin expression through the disruption of repressive regulatory domains offers a therapeutic strategy for treating ß-hemoglobinopathies. Here, we used transformer base editor (tBE), a recently developed cytosine base editor with no detectable off-target mutations, to disrupt transcription-factor-binding motifs in hematopoietic stem cells. By performing functional screening of six motifs with tBE, we found that directly disrupting the BCL11A-binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparison with other clinical and preclinical strategies using Cas9 nuclease or conventional BEs (ABE8e and hA3A-BE3), we found that tBE-mediated disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and ß-thalassemia patient hematopoietic stem/progenitor cells while exhibiting no detectable DNA or RNA off-target mutations. Durable therapeutic editing by tBE persisted in repopulating hematopoietic stem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating ß-hemoglobinopathies.


Assuntos
Edição de Genes , Hemoglobinopatias , Humanos , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , gama-Globinas/genética , gama-Globinas/metabolismo , Sistemas CRISPR-Cas , Mutação/genética , Hemoglobinopatias/genética , Hemoglobinopatias/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Fatores de Transcrição/metabolismo
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