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1.
J Hazard Mater ; 382: 121056, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470305

RESUMO

We report a new 7-nitrobenzo-2-oxa-1, 3-diazolyl (NBD)-based chemosensor containing a piperazine derivative, NBDP, for detection of mercury ions in almost 100% aqueous medium. The chemosensor shows sensing exclusively toward Hg2+ with a switch-on fluorescence response at 543 nm, which could be attributed to the blocking of PET (photo-induced electron transfer) process upon complexation with mercury ions. The molar ratio of Hg(Ⅱ) to NBDP in the complex is 1:1 based on the Job's plot and HRMS studies. Optimized configurations of NBDP and NBDP-Hg2+ complexes were simulated by means of DFT calculations. The reversible fluorescence response with low detection limit (19.2 nM) in the pH range of 6.0-7.5 renders NBDP a promising candidate for Hg2+ detection in neutral aqueous environments. For the practical application of the chemosensor, test strips were successfully fabricated for rapid detection of Hg2+ ions. Moreover, the utility of NBDP showing the mercury recognition in Human liver cancer cells (SMMC-7721) and zebrafish as well as in live tissues of Arabidopsis thaliana has been demonstrated as monitored by fluorescence imaging.

2.
Mol Med Rep ; 20(5): 4695-4705, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702022

RESUMO

Treatment of cancer­induced bone pain (CIBP) is challenging in clinical settings. Oxycodone (OXY) is used to treat CIBP; however, a lack of understanding of the mechanisms underlying CIBP limits the application of OXY. In the present study, all rats were randomly divided into three groups: The sham group, the CIBP group, and the OXY group. Then, a rat model of CIBP was established by inoculation of Walker 256 tumor cells from rat tibia. Phosphoproteomic profiling of the OXY­treated spinal dorsal cords of rats with CIBP was performed, and 1,679 phosphorylated proteins were identified, of which 160 proteins were significantly different between the CIBP and sham groups, and 113 proteins were significantly different between the CIBP and OXY groups. Gene Ontology analysis revealed that these proteins mainly clustered as synaptic­associated cellular components; among these, disks large homolog 3 expression was markedly increased in rats with CIBP and was reversed by OXY treatment. Subsequent domain analysis of the differential proteins revealed several significant synaptic­associated domains. In conclusion, synaptic­associated cellular components may be critical in OXY­induced analgesia in rats with CIBP.

3.
J Am Chem Soc ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707779

RESUMO

Rubriflordilactone B (1) is a schinortriterpenoid isolated by Sun and colleagues, which possesses a tetrasubstituted benzene moiety and eight stereocenters. The previous synthesis of 1 by Li and co-workers uncovered the existence of its naturally occurring stereoisomer "pseudorubriflordilactone B". Here we report a collaborative study by the two groups that elucidates the structure of pseudorubriflordilactone B to be 16,17-bis-epi-rubriflordilactone B (26). Chemical synthesis served as an important tool in the structure determination. Taking advantage of a modular synthetic route, we systematically "mutated" the configurations of C-23, C-22, C-20, and C-16/C-17 located at the right-hand domain of 1, and thus prepared its fifteen stereoisomers for spectrum comparison. The 1H NMR spectra of synthetic 26 in deuterated chloroform and pyridine were identical to those of authentic pseudorubriflordilactone B, respectively. This synthetic sample displayed anti-HIV activity (EC50 = 0.288 µM) in vitro.

4.
Science ; 366(6468): 1024-1028, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31754004

RESUMO

Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals.

5.
Anal Chem ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31694368

RESUMO

Detecting the effects of low oxygen on cell function is often dependent on monitoring the expression of a number of hypoxia markers. The time dependence of the appearance and stability of these markers varies between cell lines. Assessing cellular marker dynamics is also critical to determining how quickly cells respond to transient changes in oxygen levels that occurs with cycling hypoxia. We fabricated a manifold designed to use flow-encoding to produce sequential changes in gas mixtures delivered to a permeable-bottom 96-well plate. We show how this manifold and plate design can be used to expose cells to either static or cycling hypoxic conditions for eight different time periods thereby facilitating the study of the time-response of cells to altered oxygen environments. Using this device, we monitored the time-dependence of molecular changes in human PANC-1 pancreatic carcinoma and Caco-2 colon adenocarcinoma cells exposed to increasing periods of static or cycling hypoxia. Using immunohistochemistry, both cell lines show detectable levels of the marker protein hypoxia-inducible factor-1α (HIF-1α) after 3 h of exposure to static hypoxia. Cycling hypoxia increased the expression level of HIF-1α compared to static hypoxia. Both static and cycling hypoxia also increased glucose uptake and aldehyde dehydrogenase activity. This new device offers a facile screening approach to determine the kinetics of cellular alterations under varying oxygen conditions.

6.
Neurosci Lett ; : 134595, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682872

RESUMO

The pathogenesis of cancer induced bone pain (CIBP) is extremely complex, and glutamate receptor dysfunction plays an important role in the formation of CIBP. Synapse-associated protein 102 (SAP102) anchors glutamate receptors in the postsynaptic membrane. However, its effect on hyperalgesia formation in CIBP has not been clarified. This study investigated the role of SAP102 in the formation of hyperalgesia in rats with CIBP SAP102 is present in spinal dorsal horn neurons, but not in astrocytes or microglia. NMDAR-NR2B is localized with neurons. In addition, SAP102 and NMDAR-NR2B expression levels in spinal dorsal horn tissues were detected by Western blot and co-immunoprecipitation. Intrathecal injection of lentiviral vector of RNAi to knockdown SAP102 expression in the spinal dorsal horn significantly attenuated abnormal mechanic pain when compared to non-coding lentiviral vector. These findings indicate that SAP102 can anchor NMDA receptors to affect hyperalgesia formation in bone cancer pain.

8.
ACS Appl Mater Interfaces ; 11(47): 43996-44006, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31682099

RESUMO

Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the π-π stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.

9.
J Exp Clin Cancer Res ; 38(1): 478, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31775888

RESUMO

BACKGROUND: KH-type splicing regulatory protein (KHSRP) plays an important role in cancer invasion, but the relevant mechanism is not well known. In the present study, we investigated the function and potential molecular mechanism of KHSRP in non-small cell lung cancer (NSCLC) metastasis and elucidated its clinical significance. METHODS: Isobaric tags for relative and absolute quantitation and the SWATH™ approach were combined with nanoliquid chromatography-tandem mass spectrometry analysis to identify metastasis-associated nucleoproteins in NSCLC. Real-time PCR and Western blot were used to screen for metastasis-associated candidate molecules. Gene knockdown and overexpression were used to investigate their functions and molecular mechanisms in lung cancer cells. Coimmunoprecipitation (Co-IP) experiments were performed to identify the interactions between candidate molecules and their interacting proteins. Gene expression and its association with multiple clinicopathologic characteristics were analyzed by immunohistochemistry (IHC) and Western blot in human lung cancer specimens. RESULTS: KHSRP was identified as a metastasis-associated candidate molecule. In NSCLC cell lines, knockdown of KHSRP significantly reduced lung cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas overexpression of KHSRP did the opposite. Mechanistically, the protein heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) was identified to interact with KHSRP using Co-IP experiments. In NSCLC cell lines, overexpression of HNRNPC significantly promoted lung cancer cell proliferation, migration, and invasion in vitro and in vivo. KHSRP and HNRNPC may induce human lung cancer cell invasion and metastasis by activating the IFN-α-JAK-STAT1 signaling pathway. Drastically higher expression levels of KHSRP and HNRNPC were observed in lung cancer tissues compared to those in adjacent noncancerous tissues. Increased KHSRP and HNRNPC expression was significantly associated with advanced tumor stages and metastasis (both lymph node and distant). Kaplan-Meier survival analysis showed that patients with high KHSRP and HNRNPC expression levels were predicted to have the shortest survival times and to have a poor prognosis. CONCLUSIONS: KHSRP plays an important role in NSCLC metastasis and may serve as a potential prognostic marker and novel therapeutic target for lung cancer metastasis treatment.

10.
Sci Rep ; 9(1): 14154, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578355

RESUMO

This study aimed to evaluate the disparity in the under-five mortality rate (U5MR) between minority and non-minority areas in Sichuan Province in Western China. Data for this study was obtained from the National Health Statistics Survey System. The Cochran-Armitage trend test was used to analyze the time trend of the U5MR. We conducted Poisson regression model to compare the differences of U5MRs between minority and non-minority areas. The U5MR in Sichuan province was reduced by 62.19% from 2008 to 2017, with the minority and non-minority areas reduced by 60.48% and 65.39%, respectively. The under-five mortality risk in minority areas was approximately 1.791 times (95% CI: 1.790-1.793; P < 0.01) that in non-minority areas. The primary cause of death of children under-five years old in minority areas was the respiratory disease, which was significantly higher than that in non-minority areas (P all < 0.01). The U5MR significantly declined both in minority and non-minority areas in Sichuan Province in Western China from 2008 to 2017. However, disparities still existed between minority and non-minority areas. Respiratory diseases were the main causes of death in minority areas and corresponding rates were higher than those in non-minority areas.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31595640

RESUMO

Single-ligand-based electronically conductive porous coordination polymers/metal-organic frameworks (EC-PCPs/MOFs) fail to meet the requirements of numerous electronic applications owing to their limited tunability in terms of both conductivity and topology. In this study, a new 2D π-conjugated EC-MOF containing copper units with mixed trigonal ligands was developed: Cu3 (HHTP)(THQ) (HHTP=2,3,6,7,10,11-hexahydrotriphenylene, THQ=tetrahydroxy-1,4-quinone). The modulated conductivity (σ≈2.53×10-5  S cm-1 with an activation energy of 0.30 eV) and high porosity (ca. 441.2 m2 g-1 ) of the Cu3 (HHTP)(THQ) semiconductive nanowires provided an appropriate resistance baseline and highly accessible areas for the development of an excellent chemiresistive gas sensor.

13.
J Stroke Cerebrovasc Dis ; : 104388, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31575472

RESUMO

BACKGROUND: Persistent primitive trigeminal artery (PPTA) is a rare remnant between the internal carotid artery (ICA) and the basilar artery into adulthood. PPTA generally lacks specific clinical manifestations and occasionally accompanies with other cerebrovascular diseases. CASE PRESENTATION: We reported a 48-year-old Chinese woman who had repeated episodes of transient ischemic attack presented to our hospital. She had no related risk factors of ischemic cerebrovascular diseases. Magnetic resonance image findings demonstrated acute cerebral infraction in centrum semiovale. Magnetic resonance angiography findings indicated right PPTA and ipsilateral hypoplasia of ICA distal anastomosis. CONCLUSIONS: To the best of our knowledge, this is the first report that acute cerebral infarction in a patient with the right PPTA and ipsilateral hypoplasia of ICA distal anastomosis. According to the literature, congenital factor may play an important role in the formation of these vascular anomalies.

14.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658764

RESUMO

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

15.
Hepatol Int ; 13(6): 736-747, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31486964

RESUMO

BACKGROUND AND AIMS: Surgical resection for hepatocellular carcinoma (HCC) is potentially curative, but long-term survival remains unsatisfactory. There is currently no effective neoadjuvant or adjuvant therapy for HCC. We sought to evaluate the impact of preoperative transcatheter arterial chemoembolization (TACE) on long-term prognosis after surgical resection of huge HCCs (≥ 10 cm). METHODS: Using a multicenter database, consecutive patients who underwent curative-intent resection for huge HCC without macrovascular invasion between 2004 and 2014 were identified. The association between preoperative TACE with perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) was assessed before and after propensity score matching (PSM). RESULTS: Among the 377 enrolled patients, 88 patients (23.3%) received preoperative TACE. The incidence of perioperative mortality and morbidity was comparable among patients who did and did not undergo preoperative TACE (3.4% vs. 2.4%, p= 0.704, and 33.0% vs. 31.1%, p= 0.749, respectively). PSM analysis created 84 matched pairs of patients. In examining the entire cohort as well as the PSM cohort, median OS (overall cohort: 32.8 vs. 22.3 months, p= 0.035, and PSM only: 32.8 vs. 18.1 months, p= 0.023, respectively) and RFS (12.9 vs. 6.4 months, p= 0.016, and 12.9 vs. 4.1 months, p= 0.009, respectively) were better among patients who underwent preoperative TACE vs. patients who did not. After adjustment for other confounding factors on multivariable analyses, preoperative TACE remained independently associated with a favorable OS and RFS after the resection of huge HCC. CONCLUSION: Preoperative TACE did not increase perioperative morbidity or mortality, yet was associated with an improved OS and RFS after liver resection of huge HCC (≥ 10 cm).

16.
Int J Mol Sci ; 20(19)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547176

RESUMO

Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during (HBOD) or after (HBOA) noise exposure. Morphology of neurons was assayed by hematoxylin-eosin or Nissl staining. Ceramide (Cer) level was measured through immunohistochemistry analysis. Apoptotic neurons were counted using transferase-mediated dUTP nick end labeling (TUNEL) staining. We demonstrated that the intense, broad band noise raised the threshold of auditory brainstem response, evoked neuronal degeneration or apoptosis and triggered the Cer accumulation in AC, all of which were restored significantly by HBOP, but not HBOD or HBOA. Cer over-generation reversed the advantages of HBOP significantly, while its curtailment recapitulated the effect. Next, noise exposure raised the superoxide or malondialdehyde (MDA) production which was blocked by HBOP or Cer repression. Oxidative control not only attenuated the hearing loss or neurodegeneration but, in turn, reduced the Cer formation significantly. In summary, mutual regulation between Cer and oxidative stress underlies the HBOP's curative effect on hearing loss and neuronal damage in noise-exposed mice.

17.
Theranostics ; 9(20): 5810-5827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534521

RESUMO

TCF12, which is known to be involved in the regulation of cell growth and differentiation, has been reported to function as an oncogene or a tumor suppressor gene in the progression of various malignant tumors. However, its function and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. Methods: Stable ectopic TCF12 expression or knockdown in HCC cell lines was established by lentiviral infection. Then, MTT, colony formation, migration, invasion and HUVECs tube formation assays as well as an orthotopic xenograft model were used to investigate the biologic function of TCF12 in HCC cells in vitro and in vivo. Subsequently, RNA-Seq analysis was utilized to explore the target genes regulated by TCF12. RT-qPCR, western blotting, a dual-luciferase reporter assay, Ch-IP, CHIP-Seq and functional rescue experiments were used to confirm the target gene regulated by TCF12. Finally, RT-qPCR, western blot and immunohistochemical (IHC) staining were performed to detect the expression level of TCF12 and to analyze the correlation of TCF12 with downstream genes as well as the clinical significance of TCF12 in human primary HCC. Results: Our functional studies revealed that stable overexpression of TCF12 in human HCC cells enhanced cell proliferation, migration and invasion in vitro and in vivo, whereas knockdown of TCF12 showed opposing effects. Mechanistically, CXCR4 was a downstream target of TCF12, and TCF12 directly bound to the CXCR4 promoter to regulate its expression. Moreover, CXCR4, with its ligand CXCL12, played a critical role in tumor progression induced by TCF12 via activation of the MAPK/ERK and PI3K/AKT signaling pathways. Clinically, IHC analysis revealed that TCF12 was significantly associated with poor survival of HCC patients and that TCF12 expression was closely correlated with CXCR4 expression in primary HCC tissues. Conclusion: Our findings are the first to indicate that TCF12 could promote the tumorigenesis and progression of HCC mainly by upregulating CXCR4 expression and is a prognostic indicator for patients with HCC.

18.
Eur J Surg Oncol ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31543386

RESUMO

BACKGROUND: The Barcelona Clinic Liver Cancer (BCLC) categorizes a patient with performance status (PS)-1 as advanced stage of hepatocellular carcinoma (HCC) and surgical resection is not recommended. In real-world clinical practice, PS-1 is often not a contraindication to surgery for HCC. The aim of current study was to define the impact of PS on the surgical outcomes of patients undergoing liver resection for HCC. METHODS: 1,531 consecutive patients who underwent a curative-intent resection of HCC between 2005 and 2015 were identified using a multi-institutional database. After categorizing patients into PS-0 (n = 836) versus PS-1 (n = 695), perioperative mortality and morbidity, overall survival (OS) and recurrence-free survival (RFS) were compared. RESULTS: Overall perioperative mortality and major morbidity among patients with PS-0 (n = 836) and PS-1 (n = 695) were similar (1.4% vs. 1.6%, P = 0.525 and 9.7% vs. 10.2%, P = 0.732, respectively). In contrast, median OS and RFS was worse among patients who had PS-1 versus PS-0 (34.0 vs. 107.6 months, and 20.5 vs. 60.6 months, both P < 0.001, respectively). On multivariable Cox-regression analyses, PS-1 was independently associated with worse OS (HR: 1.301, 95% CI: 1.111-1.523, P < 0.001) and RFS (HR: 1.184, 95% CI: 1.034-1.358, P = 0.007). CONCLUSIONS: Patients with PS-1 versus PS-0 had comparable perioperative outcomes. However, patients with PS-1 had worse long-term outcomes as PS-1 was independently associated with worse OS and RFS. Routine exclusion of HCC patients with PS-1 from surgical resection as recommended by the BCLC guidelines is not warranted.

20.
Inorg Chem ; 58(17): 11807-11818, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31398054

RESUMO

Lead halide perovskite nanocrystals (NCs) exhibit great application potential in optoelectronic devices because of their tunable band gaps and facile colloidal synthesis, but they suffer from serious lead toxicity and instability. It is highly desirable to substitute lead with other elements to acquire nontoxic and environmentally friendly lead-free perovskite NCs for optoelectronic devices. Here, we report a general method for the colloidal synthesis of a series of bismuth/antimony-based halide perovskite NCs with various constituents and optical band gaps from 1.97 to 3.15 eV. In our proposed synthetic system, 1-dodecanol is adopted as the solvent instead of the conventionally used 1-octadecene to realize size controllability of bismuth/antimony-based metal halide perovskite NCs. It is found that 1-dodecanol can act as a surfactant to tightly adsorb on the surface of bismuth/antimony-based halide perovskite NCs, enabling their small sizes (∼2 nm) and high dispersibility. Simultaneously, the band gaps of bismuth/antimony-based halide (A3B2X9, where A = CH3NH3, Cs, or Rb, B = Bi or Sb, and X = Cl, Br, or I) perovskite NCs can be systematically tuned by the atomic substitution of A, B, or X lattice sites. Moreover, to show the optoelectronic application potential of these lead-free halide perovskite NCs, a solar cell based on colloidal Cs3Bi2I9 perovskite NCs is demonstrated. The developed colloidal synthesis of bismuth/antimony-based halide NCs in 1-dodecanol will offer an alternative route to fabricating lead-free halide perovskite optoelectronic devices.

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