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Zanthoxyli radix is a popular tea among the elderly, and it is believed to have a positive effect on Alzheimer’s disease. In this study, a highly effective three-step strategy was proposed for comprehensive analysis of the active components and biological functions of Zanthoxylum nitidum(ZN), including high-resolution LC-Q-TOF mass spectrometry (HRMS), multivariate statistical analysis for heterogeneity (MSAH), and experimental and virtual screening for bioactivity analysis (EVBA). A total of 117 compounds were identified from the root, stem, and leaf of ZN through HRMS. Bioactivity assays showed that the order of acetylcholinesterase (AChE) inhibitory activity from strong to weak was root > stem > leaf. Nitidine, chelerythrine, and sanguinarine were found to be the main differential components of root, stem, and leaf by OPLS-DA. The IC50values of the three compounds are 0.81 ± 0.02, 0.14 ± 0.01, and 0.48 ± 0.01 μM respectively, indicating that they are potent and high-quality AChE inhibitors. Molecular docking showed that pi-pi T-shaped interactions and pi-lone pairs played important roles in AChE inhibition. This study not only explains the biological function of Zanthoxyli radix in alleviating Alzheimer’s disease to some extent, but also lays the foundation for the development of stem and leaf of ZN.

Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Nav1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABAA) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25’s dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.

• Graphene/WSe-based VTFT that combines photonic and neuromorphic elements is reported. • The VTFT exhibits high switching ratios and carrier mobility (65.52 cm2 V−1 s−1). • Incorporating Au nanoparticles in the device enhances contact and tuned synaptic properties. • The fabricated VTFT exhibits excellent photosensitive synaptic responses to UV light. The development of artificial photosensitive synapses with high sensitivity and biomimetic properties that combine innovative concepts and neuromorphic architectures is crucial to achieving highly integrated and flexible intelligent visual systems. Recently, graphene heterostructure-based photosensitive synaptic transistors have been extensively studied for this purpose. However, compared to traditional transistors, vertical structure thin film transistors (VTFTs) with ultra-short channels and advantages, such as high integration, have yet to be investigated in photosensitive synapses. Here, we report an ultra-thin VTFT featuring a graphene/W x Se x –1 van der Waals heterostructure that combines photonic and neuromorphic elements. We demonstrate a VTFT in which the channel layer is formed by covalently bonded W x Se x –1 nanomaterials produced by introducing Se atoms on the surface of a tungsten metal thin film deposited via radio-frequency sputtering. This structure successfully simulated the main synaptic function, exhibited photosensitive synaptic responses to ultraviolet (λ = 365 nm) light, and demonstrated highly reliable electrical performance. Furthermore, the incorporation of gold nanoparticles changed the photosensitive synaptic response properties of the graphene/W x Se x –1 heterostructure from excitatory to inhibitory, showing a responsivity of about ∼14 A W–1, which was attributed to the heterojunction interface resonant effects and efficient charge transfer induced by localized surface plasmons. This further enabled optical artificial synaptic applications while operating with low voltage spikes and low light intensity. This work provides a novel strategy for integrating and developing biological and nano-electronic systems. [ABSTRACT FROM AUTHOR]

Bifunctional ligands possessing both μOR agonism and σ1R antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the μOR agonism activity of most dual ligands diminishes compared with classical opioids, raising concern about their effectiveness in managing nociceptive pain. In this study, a new class of dual μOR agonist/σ1R antagonist was reported. Through structure–activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar μOR agonism activity (EC50: 0.6 ± 0.2 nM) and good σ1R inhibitory activity (Ki: 363.7 ± 5.6 nM) with excellent selectivity. Compound 4xexhibited robust analgesic effects in various pain models, with significantly reduced side effects. Importantly, compound 4xalso possessed good safety profiles and no abnormalities were observed in biological parameters even under a high dosage. Our findings suggest that 4xmay be a promising lead compound for developing safer opioids and warrants further in-depth studies.

Low-strength and highly compressible excavated clayey soils are common in geotechnical engineering, which cannot serve as a bearing stratum and typically end up being disposed of in landfills. Autoclaved aerated concrete powder (AACP) is a lightweight and porous waste material, with its stockpiles rapidly accumulating worldwide. To promote sustainable development in geotechnical engineering, a type of composite admixture consisting of cement and AACP was developed to modify clayey soils in this study. The physical and mechanical properties of untreated and the composite admixture-treated soil samples were investigated via Atterberg limits, compaction, bender element, constraint compression, free swell, and unconfined compressive strength (UCS) tests. The physicochemical and microstructural observations, including soil pH, scanning electron microscopy, and mercury intrusion porosimetry analyses, were conducted to interpret the macroscopic mechanical behaviors. Test results showed that the incorporation of AACP improved the workability of clayey soils, while cement further enhanced their mechanical properties. Hydration compounds primarily filled the voids with a diameter ranging from 0.1 to 1 µm. From the perspective of volume change behavior, 8% cement content was recommended. Shear wave velocity showed a strong correlation with the UCS, demonstrating that the bender element technique was an effective non-destructive tool for assessing the strength of compacted samples.

Excess copper accumulation in the body can lead to various health complications including Parkinson’s disease, Alzheimer’s disease, gastrointestinal disorders, liver damage, and hemolytic anemia. As such, the development of effective strategies to remove excess copper is critical for preventing these adverse health outcomes. In this study, a copolymer (P(MPC/LysA)) comprising 2-(methacryloyloxy)ethyl phosphorylcholine (MPC) and l-lysinylacrylamide (LysA) was synthesized via reversible addition–fragmentation chain transfer (RAFT) radical polymerization. Under different pH conditions, the pendant primary amine (–NH3+) and carboxy groups (–COOH) of LysA underwent protonation and deprotonation, resulting in cationic, zwitterionic, and anionic structures. The copolymer exhibited a zwitterionic structure under physiological conditions due to the pH-independent neutral charge of MPC. The LysA residues formed a complex with copper (II) ions (Cu2+) under neutral-basic conditions, with two pendant l-lysine residues forming a complex with one Cu2+molecule. The addition of Cu2+to an aqueous solution of P(MPC/LysA) at pH 7.4 resulted in the formation of interpolymer aggregates due to Cu2+/LysA complex formation. Overall, this study reveals that P(MPC/LysA) has potential for use in removing excess Cu2+in the body by forming water-soluble aggregates with Cu2+at physiological pH.

Cell-free DNA (cfDNA) in blood, viewed as a surrogate for tumor biopsy, has many clinical applications, including diagnosing cancer, guiding cancer treatment and monitoring treatment response. All these applications depend on an indispensable, yet underdeveloped task: detecting somatic mutations from cfDNA. The task is challenging because of the low tumor fraction in cfDNA. Recently, we developed the computational method cfSNV, the first method that comprehensively considers the properties of cfDNA for the sensitive detection of mutations from cfDNA. cfSNV vastly outperformed the conventional methods that were developed primarily for calling mutations from solid tumor tissues. cfSNV can accurately detect mutations in cfDNA even with medium-coverage (e.g., ≥200×) sequencing, which makes whole-exome sequencing (WES) of cfDNA a viable option for various clinical utilities. Here, we present a user-friendly cfSNV package that exhibits fast computation and convenient user options. We also built a Docker image of it, which is designed to enable researchers and clinicians with a limited computational background to easily carry out analyses on both high-performance computing platforms and local computers. Mutation calling from a standard preprocessed WES dataset (~250× and ~70 million base pair target size) can be carried out in 3 h on a server with eight virtual CPUs and 32 GB of random access memory.

This study is intended to investigate oral exostoses of 5 sample populations, spanning over 6000 years, from the same region of Northern China, to determine the significance of sex and age on the development of oral exostoses during each time period. The samples analyzed were 306 dry jaws from human skeletons, which were excavated from 4 archeological sites: Banpo (6700–5600 y BP), Shaolingyuan (3000 y BP), Shanren (2200 y BP), and Chang’an (1000–1300 y BP), as well as the modern Xi’an district. The sex and the age of the samples at death were estimated. The degree of buccal exostosis (BE), torus mandibularis (TM), and torus palatinus (TP) and the TP shape were recorded. The results showed BEs in the Banpo and Chang’an regions, TMs in the Banpo region were more often diagnosed in males than in females. Conversely, females in Shaolingyuan showed a higher prevalence and severity of TM than that in males. The occurrence of BEs in the Shanren and Xi’an regions, TMs in the Banpo, Chang’an, and Xi’an regions, as well as TPs in the Banpo region significantly increased with age at death. In conclusion, sex differences and increasing trends with age in relation to oral exostoses were found in samples from Northern China during the past six millennia.

Vanadium diselenide (VSe2) exhibits versatile electronic and magnetic properties in the trigonal prismatic (H-) and octahedral (T-) phases. Compared to the metallic T-phase, the H-phase with a tunable semiconductor property is predicted to be a ferrovalley material with spontaneous valley polarization. Herein we report an epitaxial growth of the monolayer 2D VSe2on a mica substrate via the chemical vapor deposition (CVD) method by introducing salt in the precursor. Our first-principles calculations suggest that the monolayer H-phase VSe2with a large lateral size is thermodynamically favorable. The honeycomb-like structure and the broken symmetry are directly observed by spherical aberration-corrected scanning transmission electron microscopy (STEM) and confirmed by giant second harmonic generation (SHG) intensity. The p-type transport behavior is further evidenced by the temperature-dependent resistance and field-effect device study. The present work introduces a new phase-stable 2D transition metal dichalcogenide, opening the prospect of novel electronic and spintronics device design.

Lateral superlattices have been a research focus due to the strain induced in their coherent structure, while the growth of a large size heterostructure with high density of heterointerfaces remains challenging. In this work, we report a gap-filling approach to synthesize large-scale lateral mesh heterostructures of WS2embedded in a MoS2matrix. This synthesis method utilizes the uniformly distributed gaps in single crystalline MoS2, made by the sulfur substitution-induced transformation of metastable-MoTe2as the growth pattern, for the second material growth. By finely controlling the growth kinetics, a highly crystalline WS2/MoS2lateral heterostructure mesh is successfully grown. Optical images and Raman mapping show a clear spatial distribution of WS2channels embedded in MoS2. The coherent epitaxial nature is further confirmed by scanning transmission electron microscopy, showing insignificant dislocation at the interfaces. Density function theory simulation suggests that the growth of WS2starts from the edges of cracked MoS2. The MoS2/WS2/MoS2heterostructure device demonstrates an intrinsic electric barrier formed at the interfaces. This work provides a new tool for the practical preparation of large-scale high density 2D heterostructures.

•The copolymer pSB10H1 demonstrates a salt-water absorption rate in a 0.9 wt% NaCl solution.•A novel zwitterionic superabsorbent polymer (ZSAP) was synthesized.•ZSAP effectively showcased enhanced salt-water absorption capacity, CRC, and AUL.•Zwitterionic and hydroxyl moieties are key in governing SAP saltwater absorption.

Background: While the impact of telephone follow-up (TFU) for older emergency department (ED) patients is controversial, its effects on the Asian population remain uncertain. In this study, we evaluated the effectiveness of a novel computer assisted TFU model specifically for this demographic. Methods: At a Taiwanese tertiary medical center, we developed a TFU protocol that included a referral and case management system within the ED hospital information system. We provided TFU to older discharged patients between April 1, 2021, and May 31, 2021. We compared this cohort with a non-TFU cohort of older ED patients and analyzed demographic characteristics and post-ED discharge outcomes. Results: The TFU model was successfully implemented, with 395 patients receiving TFU and 191 without TFU. TFU patients (median age: 76 years, male proportion: 48.9%) differed from non-TFU patients (median age: 74 years, male proportion: 43.5%). Compared with the non-TFU cohort, the multivariate logistic regression analysis revealed that the TFU cohort had a lower total medical expenditure < 1 month (adjusted odds ratio [AOR]: 0.32; 95% CI: 0.21 − 0.47 for amounts exceeding 5,000 New Taiwan Dollars), and higher satisfaction (AOR: 2.80; 95% CI: 1.46 − 5.36 for scores > 3 on a five-point Likert Scale). However, the TFU cohort also had a higher risk of hospitalization < 1 month (AOR: 2.50; 95% CI: 1.31 − 4.77) compared to the non-TFU cohort. Conclusion: Computer-assisted TFU appears promising. Further research involving a larger number of patients and validation in other hospitals is necessary to bolster the evidence and extend the findings to a broader context.

Aims: A computerized tool and interdisciplinary care were implemented to develop a novel model for older patients with delirium in the emergency department (ED). Methods: We developed a computerized tool using a delirium triage screen and brief confusion assessment in the hospital information system, performed education for the healthcare providers, and developed a continuous care protocol. Comparisons for outcomes between pre- and post-intervention periods were performed. Results: Compared with the pre-intervention period, patients in the post-intervention period had shorter hospitalization stay, lower expenditure of hospitalization, more likely to return home, lower ED revisits of ≤ 3 days, re-hospitalization of ≤ 14 days, and mortality of ≤ 1 month. All mentioned differences were not statistically significant. Conclusions: A novel model was successfully developed for delirium management in older patients in the ED. Outcome differences were not significant; however, the result is promising, which gives us an important reference in the future.

Aim: Home healthcare (HHC) provides continuous care for disabled patients. However, HHC referral after the emergency department (ED) discharge remains unclear. Thus, this study aimed its clarification. Methods: A computer-assisted HHC referral by interdisciplinary collaboration among emergency physicians, case managers, nurse practitioners, geriatricians, and HHC nurses was built in a tertiary medical center in Taiwan. Patients who had HHC referrals after ED discharge between February 1, 2020 and September 31, 2020, were recruited into the study. A non-ED HHC cohort who had HHC referrals after hospitalization from the ED was also identified. Comparison for clinical characteristics and uses of medical resources was performed between ED HHC and non-ED HHC cohorts. Results: The model was successfully implemented. In total, 34 patients with ED HHC and 40 patients with non-ED HHC were recruited into the study. The female proportion was 61.8% and 67.5%, and the mean age was 81.5 and 83.7 years in ED HHC and non-ED HHC cohorts, respectively. No significant difference was found in sex, age, underlying comorbidities, and ED diagnoses between the two cohorts. The ED HHC cohort had a lower median total medical expenditure within 3 months (34,030.0 vs. 56,624.0 New Taiwan Dollars, p= 0.021) compared with the non-ED HHC cohort. Compared to the non-ED HHC cohort, the ED HHC cohort had a lower ≤ 1 month ED visit, ≤ 6 months ED visit, and ≤ 3 months hospitalization; however, differences were not significant. Conclusion: An innovative ED HHC model was successfully implemented. Further studies with more patients are warranted to investigate the impact.

Linear magnetoresistance (LMR) is usually observed in topological quantum materials and plausibly connected with the topologically nontrivial surface state with Dirac-cone-like linear dispersion because the frequently encountered large Hall resistivity can be trivially mixed into the LMR via charge inhomogeneity. Herein, by applying an optimal gate voltage to nodal-line semimetal ZrGeSe two-dimensional (2D) layers with specific thicknesses, we observe a giant nonsaturated LMR of 8 × 104% at 2 K and a magnetic field of 9 T. This giant LMR is accompanied by a very small Hall resistivity, which is inconsistent with the charge inhomogeneity mechanism. Our systematic results confirm that the giant LMR is maximized when the topological semimetal is in the “even-metal” regime and suppressed upon evolution to the normal “odd-metal” regime. The “even-to-odd” transition is universal regardless of the thicknesses of the crystals. A comparison with Abrikosov’s quantum LMR theory indicates that the observed LMR cannot be trivial.

The objective of this study was to find the role of LncRNA SNHG12 in the regulation of hypertensive vascular endothelial injury. LncRNA SNHG12 and miR‐25‐3p expression were detected by quantitative RT‐PCR. Protein levels of Sirtuin 6 (SIRT6), endothelial cell (EC) senescence markers p16 and p21, and EC marker CD31 were measured by Western blot. The apoptosis of HUVECs was detected by flow cytometry. The binding between LncRNA SNHG12 and miR‐25‐3p was verified by dual luciferase reporter gene assay and RNA pull‐down assay. As a result, LncRNA SNHG12 was down‐regulated in aortic primary ECs isolated from Ang II‐induced hypertensive mice and 1 kidney/deoxycorticosterone acetate/salt‐induced hypertensive mice. In Ang II‐treated HUVECs, the expression level of SNHG12 was reduced and the overexpression of SNHG12 inhibited EC senescence markers p16 and p21 expressions, the apoptosis of HUVECs, and caspase‐3 activity. Further investigation confirmed that LncRNA SNHG12 bound to miR‐25‐3p, and negatively regulated miR‐25‐3p expression. MiR‐25‐3p directly targeted SIRT6 and negatively regulated SIRT6 expression. In addition, SNHG12 overexpression inhibited Ang II‐induced HUVECs injury through regulating miR‐25‐3p. Finally, in vivo experiments showed LncRNA SNHG12 overexpression alleviated vascular endothelial injury in Ang II‐induced hypertensive mice. In conclusion, LncRNA SNHG12 alleviates vascular endothelial injury induced by hypertension through miR‐25‐3p/SIRT6 pathway. LncRNA SNHG12 alleviates vascular endothelial injury in Ang II‐induced hypertension through miR‐25‐3p/SIRT6 pathway.

MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.

ABSTRACTPost-translational modifications on nucleosomal histones represent a key epigenetic regulatory mechanism to mediate the complex gene expression, DNA replication, and cell cycle changes that occur in embryonic cells undergoing lineage specification, maturation, and differentiation during development. Here, we investigated the dynamics of 13 key histone marks in epidermal cells at three distinct stages of embryonic skin development and identified significant changes that corresponded with the maturation of the proliferative basal epidermal cells and terminally differentiated cells in the stratified layers. In particular, H3K4me3 and H3K27ac were accumulated and became more prominent in the basal cells at later stages of epidermal development, while H3K27me3 was found to be low in the basal cells but highly enriched in the differentiated suprabasal cell types. Constitutive heterochromatin marked by H4K20me3 was also significantly elevated in differentiated epidermal cells at late gestation stages, which exhibited a concomitant loss of H4K16 acetylation. These differential chromatin profiles were established in the embryonic skin by gestation day 15 and further amplified at E18 and in postnatal skin. Our results reveal the dynamic chromatin states that occur as epidermal progenitor cells commit to the lineage and differentiate into the different cells of the stratified epidermis and provide insight to the underlying epigenetic pathways that support normal epidermal development and homoeostasis.

By weak bonding method, the first OLED display with 620°C LTPS TFT and touch sensor, without PI substrate, formed on glass substrates are transferred to non‐PI flexible substrates respectively. After transfer, the display image is free from defect and touch sensor functions normally. The advantages of transferring are shown.

By weak bonding method, the first organic light‐emitting diode (OLED) display with 620°C low‐temperature poly‐silicon (LTPS) thin film transistor (TFT) and touch sensor, without polyimide (PI) substrate, formed on glass substrates is transferred to non‐PI flexible substrates. After transfer, the display image is free from defect, and touch sensor functions normally. Compared with device made on PI substrate, the advantages of device stability and pitch variation by transferring are shown. Replacing coating‐type yellowish PI substrate with lamination‐type transparent non‐PI substrate, not only the TFT stability after stress improves greatly, but also the manufacturing cost of substrate decreases apparently. In addition, without using organic PI substrate through LTPS array process, the process temperature is raised to 620°C so that better TFT property can be obtained for various applications.

The metal–semiconductor interface fabricated by conventional methods often suffers from contamination, degrading transport performance. Herein, we propose a one-pot chemical vapor deposition (CVD) process to create a two-dimensional (2D) MoO2–MoSe2heterostructure by growing MoO2seeds under a hydrogen environment, followed by depositing MoSe2on the surface and periphery. The ultraclean interface is verified by cross-sectional scanning transmission electron microscopy and photoluminescence. Along with the high work function of semimetallic MoO2(Ef= −5.6 eV), a high-rectification Schottky diode is fabricated based on this heterostructure. Furthermore, the Schottky diode exhibits an excellent photovoltaic effect with a high open-circuit voltage of 0.26 eV and ultrafast photoresponse, owing to the naturally formed metal–semiconductor contact with suppressed pinning effect. Our method paves the way for the fabrication of an ultraclean 2D metal–semiconductor interface, without defects or contamination, offering promising prospects for future nanoelectronics.

A biocompatible and antifouling polymeric medical coating was developed through rational design for anchoring pendant groups for the modification of stainless steel. Zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) was copolymerized individually with three anchoring monomers of carboxyl acrylamides with different alkyl spacers, including acryloylglycine (2-AE), 6-acrylamidohexanoic acid (6-AH), and 11-acrylamidoundecanoic acid (11-AU). The carboxylic acid groups are responsible for the stable grafting of copolymers onto stainless steel via a coordinative interaction with metal oxides. Due to hydrophobic interaction and hydrogen bonding, the anchoring monomers enable the formation of self-assembling structures in solution and at a metallic interface, which can play an important role in the thin film formation and functionality of the coatings. Therefore, surface characterizations of anchoring monomers on stainless steel were conducted to analyze the packing density and strength of the intermolecular hydrogen bonds. The corresponding copolymers were synthesized, and their aggregate structures were assessed, showing micelle aggregation for copolymers with higher hydrophobic compositions. The synergistic effects of inter/intramolecular interactions and hydrophobicity of the anchoring monomers result in the diversity of the thickness, surface coverage, wettability, and friction of the polymeric coatings on stainless steel. More importantly, the antifouling properties of the coatings against bacteria and proteins were strongly correlated to thin film formation. Ultimately, the key lies in deciphering the molecular structure of the anchoring pendants in thin film formation and assessing the effectiveness of the coatings, which led to the development of medical coatings through the graft-onto approach.

The controlled vapor-phase synthesis of two-dimensional (2D) transition metal dichalcogenides (TMDs) is essential for functional applications. While chemical vapor deposition (CVD) techniques have been successful for transition metal sulfides, extending these methods to selenides and tellurides often faces challenges due to uncertain roles of hydrogen (H2) in their synthesis. Using CVD growth of MoSe2as an example, this study illustrates the role of a H2-free environment during temperature ramping in suppressing the reduction of MoO3, which promotes effective vaporization and selenization of the Mo precursor to form MoSe2monolayers with excellent crystal quality. As-synthesized MoSe2monolayer-based field-effect transistors show excellent carrier mobility of up to 20.9 cm2/(V·s) with an on–off ratio of 7 × 107. This approach can be extended to other TMDs, such as WSe2, MoTe2, and MoSe2/WSe2in-plane heterostructures. Our work provides a rational and facile approach to reproducibly synthesize high-quality TMD monolayers, facilitating their translation from laboratory to manufacturing.