Publications by authors named "Jun Yin"

1,125 Publications

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The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors.

Nat Commun 2021 Sep 13;12(1):5397. Epub 2021 Sep 13.

Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Acute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9-driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors.
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http://dx.doi.org/10.1038/s41467-021-25664-7DOI Listing
September 2021

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies.

Invest New Drugs 2021 Sep 13. Epub 2021 Sep 13.

Division of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA.

Purpose: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response.

Methods: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length.

Results: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients.

Conclusions: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.
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http://dx.doi.org/10.1007/s10637-021-01175-6DOI Listing
September 2021

Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials.

J Natl Cancer Inst 2021 Sep 10. Epub 2021 Sep 10.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Background: Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.

Methods: Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.

Results: Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.

Conclusion: Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.
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http://dx.doi.org/10.1093/jnci/djab187DOI Listing
September 2021

Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL.

Blood Adv 2021 Sep 7. Epub 2021 Sep 7.

University of Chicago, Chicago, Illinois, United States.

Post-remission strategies after dasatinib-corticosteroid induction in adults with Ph-positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated the feasibility and efficacy of dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N=65) with Ph-positive ALL received dasatinib and dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone based on age and donor availability, and dasatinib-based maintenance. Key efficacy endpoints were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87). The complete remission rate was 98.5%. With a median follow up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFSs were 49%, 29%, and 34% and 5-year OSs were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P=0.002) and OS (median 16 months vs not reached, P=0.05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib and dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of treatment failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse.
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http://dx.doi.org/10.1182/bloodadvances.2021004813DOI Listing
September 2021

Underlying mechanisms for the impacts of molecular structures and water chemistry on the enrichment of poly/perfluoroalkyl substances in aqueous aerosol.

Sci Total Environ 2021 Aug 30;803:150003. Epub 2021 Aug 30.

Key Laboratory of Pollution Processes and Environmental Criteria, Ministry of Education, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300071, PR China. Electronic address:

Enrichment of ionic poly/perfluoroalkyl substances (PFASs) in aqueous aerosol (AA) is an important pathway for them to enter atmosphere. In this study, the enrichment behaviors of 12 legacy and emerging PFASs in AA in both single solute and mixed solutions were investigated. The enrichment factors (EF) displayed a general increasing trend with the fluorinated carbon chain length. For the first time, a robust Quantitative Structure-Property Relationship (QSPR) model coupled with partial least-square method was established with fifteen quantum chemical descriptors. Four molecular descriptors, including dipole moment (μ), molecular weight (MW), the maximal value of the molecular surface potential (V) and molecular volume (V) were identified as the key structural variables affecting the PFASs enrichment. Inorganic salts and humic acid (HA) which are common in seawater, facilitated the PFASs enrichment as a result of enhanced hydrophobicity and the bridging effect caused by divalent cations. The typical cationic and anionic surfactants, cetyltrimethylammonium bromide and sodium dodecyl sulfate, both inhibited the enrichment due to the competition between PFASs and surfactants. It is interesting that 6:2 chlorinated polyfluorinated ether sulfonate (F53B) had the highest EF among the 12 PFASs, implying its strong potential of atmosphere transport.
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http://dx.doi.org/10.1016/j.scitotenv.2021.150003DOI Listing
August 2021

High serum complement component C4 as a unique predictor of unfavorable outcomes in diabetic stroke.

Metab Brain Dis 2021 Sep 4. Epub 2021 Sep 4.

Departments of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Previous studies demonstrated that diabetic stroke patients had a poor prognosis and excess complement system activation in the peripheral blood. In this study, the association of serum complement levels with the prognosis of diabetic stroke was examined. Patients with acute ischemic stroke were recruited and were divided into two groups according to their history of diabetes. Baseline data on the admission, including C3 and C4 were collected. Neurologic function at discharge was the primary outcome and was quantified by the National Institutes of Health Stroke Scale (NIHSS). A total of 426 patients with acute ischemic stroke (116 diabetic strokes and 310 non-diabetic strokes) were recruited in this study. There were significant differences between the two groups in hypertension, coronary disease, triglyceride, high-density lipoprotein cholesterol, fasting blood sugar, C4, and mortality rates. Furthermore, the values of complement protein levels were divided into tertiles. In the diabetic stroke group, serum C4 level at the acute phase in the upper third was independently associated with NIHSS score at discharge and concurrent infection. These associations were not significant in non-diabetic stroke. High serum C4 level at admission, as a unique significant predictor, was associated with unfavorable clinical outcomes in the diabetic stroke, independently of traditional risk factors.
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http://dx.doi.org/10.1007/s11011-021-00834-0DOI Listing
September 2021

The diagnostic profile of rare acute myelomegakaryoblastic leukemia.

Leuk Lymphoma 2021 Sep 3:1-8. Epub 2021 Sep 3.

Division of Hematology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China.

Acute myelomagakaryocytic leukemia is a diagnostic and therapeutic challenge owing to its heterogeneity and overlapping features with other types of acute leukemia. In order to build a diagnostic profile, we analyzed the biological, clinical and hematologic characteristics of acute myelomagakaryocytic leukemia. We found that, in three patients diagnosed with acute myelomagakaryocytic leukemia, there were two types of leukemia cells. One type was myeloblastic with positive peroxidase (POX) stainig and the expression of antigens CD13 and CD33. The other type was megakaryoblastic with negative POX staining and the expression of antigens CD36, CD41, CD42a and CD61. Three patients displayed the same cytogenetic abnormality, a (9: 22) translocation. Among the three patients with RT-PCR, two patients displayed BCR-ABL fusion gene amplification and one patient showed a previously undescribed OTT-MAL fusion gene amplification.
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http://dx.doi.org/10.1080/10428194.2021.1955878DOI Listing
September 2021

phase1RMD: An R package for repeated measures dose-finding designs with novel toxicity and efficacy endpoints.

PLoS One 2021 2;16(9):e0256391. Epub 2021 Sep 2.

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America.

Traditional dose-finding designs are substantially inefficient for targeted agents and cancer immunotherapies by failing to incorporate efficacy signals, mild and moderate adverse events, and late, cumulative toxicities. However, the lack of user-friendly software is a barrier to the practical use of the novel phase I designs, despite their demonstrated superiority of traditional 3+3 designs. To overcome these barriers, we present an R package, phase1RMD, which provides a comprehensive implementation of novel designs with repeated toxicity measures and early efficacy. A novel phase I repeated measures design that used a continuous toxicity score from multiple treatment cycles was implemented. Furthermore, in studies where preliminary efficacy is evaluated, an adaptive, multi-stage design to identify the most efficacious dose with acceptable toxicity was demonstrated. Functions are provided to recommend the next dose based on the data collected in a phase I trial, as well as to assess trial characteristics given design parameters via simulations. The repeated measure designs accurately estimated both the magnitude and direction of toxicity trends in late treatment cycles, and allocated more patients at therapeutic doses. The R package for implementing these designs is available from the Comprehensive R Archive Network. To our best knowledge, this is the first software that implement novel phase I dose-finding designs that simultaneously accounts for the multiple-grade toxicity events over multiple treatment cycles and a continuous early efficacy outcome. With the software published on CRAN, we will pursue the implementation of these designs in phase I trials in real-life settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256391PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412295PMC
September 2021

Emotion Analysis of Personalized Color of Beauty Package Based on NCD Image Positioning.

Front Psychol 2021 5;12:727788. Epub 2021 Aug 5.

School of Design, Jiangnan University, Wuxi, China.

Based on the Nippon Color & Design (NCD) system, this study aims to accurately discover the color preferences and image positioning of different female groups in China and, thus, to establish a color reference system, which is suitable for the packaging of beauty products. We first selected middle-aged women in the rural area of northern China as the studied group. Then, we conducted an extensive questionnaire survey on their color preferences focusing on their psychological characteristics and perception rules of emotional needs for colors. After that, we extracted colors from samples and classified them using the NCD system research method. Finally, we conducted a systematic analysis and verification to determine the color emotional preference of this group. We investigate the color preference of targeted customers to establish the image space of beauty product packaging. By applying SPSS for the factor analysis, we study the rural women in northern China, who are less concerned about fashion. We focus on the accurate positioning between the interaction of color, women, and environment throughout the color design process. We have conducted a series of comparative analyses of popular beauty products among the rural women. The results can accurately reflect the brand definition and positioning of color semantics and, thus, provide invaluable information for future beauty packaging designs and marketing promotion strategy.
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http://dx.doi.org/10.3389/fpsyg.2021.727788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375384PMC
August 2021

Kinetic photovoltage along semiconductor-water interfaces.

Nat Commun 2021 Aug 17;12(1):4998. Epub 2021 Aug 17.

Key Laboratory for Intelligent Nano Materials and Devices of the Ministry of Education, State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing, People's Republic of China.

External photo-stimuli on heterojunctions commonly induce an electric potential gradient across the interface therein, such as photovoltaic effect, giving rise to various present-day technical devices. In contrast, in-plane potential gradient along the interface has been rarely observed. Here we show that scanning a light beam can induce a persistent in-plane photoelectric voltage along, instead of across, silicon-water interfaces. It is attributed to the following movement of a charge packet in the vicinity of the silicon surface, whose formation is driven by the light-induced potential change across the capacitive interface and a high permittivity of water with large polarity. Other polar liquids and hydrogel on silicon also allow the generation of the in-plane photovoltage, which is, however, negligible for nonpolar liquids. Based on the finding, a portable silicon-hydrogel array has been constructed for detecting the shadow path of a moving Cubaris. Our study opens a window for silicon-based photoelectronics through introducing semiconductor-water interfaces.
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http://dx.doi.org/10.1038/s41467-021-25318-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371154PMC
August 2021

circ_C20orf11 enhances DDP resistance by inhibiting miR-527/YWHAZ through the promotion of extracellular vesicle-mediated macrophage M2 polarization in ovarian cancer.

Cancer Biol Ther 2021 Aug 12:1-15. Epub 2021 Aug 12.

Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, P.R. China.

Ovarian cancer is a fatal gynecologic tumor, and conventional treatment is mainly limited by chemoresistance. The mechanism contributing to chemoresistance in ovarian cancer has yet to be established. This study aimed to investigate the specific role of circ_C20orf11 in regulating chemoresistance to cisplatin (DDP)in ovarian cancer. We first established two DDP-resistant ovarian cancer cell lines. Then, we identified the effect of circ_C20orf11 on specific cellular characteristics (proliferation, apoptosis, DDP resistance) via a series of experiments. The binding sites between circ_C20orf11 and miR-527 and between miR-527 and YWHAZ were predicted using a bioinformatics tool and confirmed with a dual-luciferase reporter assay. Furthermore, extracellular vesicles (EVs) derived from DDP-resistant cell lines were identified, and the effect of EVs on macrophage polarization was examined. circ_C20orf11 was upregulated in ovarian cancer. Increased circ_C20orf11 expression enhanced DDP resistance and cell proliferation and reduced cell apoptosis in DDP-resistant cell lines after DDP treatment by sponging miR-527 and promoting YWHAZ expression. In addition, we found that DDP-resistant cell-derived EVs can induce macrophage M2 polarization, whereas silencing of circ_C20orf11 inhibited EV-induced macrophage M2 polarization. Consistent with these results, silencing of circ_C20orf11 enhanced sensitivity to DDP in vivo. Importantly, we proved that circ_C20orf11 expression was upregulated in EVs extracted from the serum of DDP-resistant patients. Our study demonstrated that silencing circ_C20orf11 sensitizes ovarian cancer to DDP by promoting miR-527/YWHAZ signaling and EV-mediated macrophage M2 polarization.
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http://dx.doi.org/10.1080/15384047.2021.1959792DOI Listing
August 2021

Fluorescence Probe for Imaging -Methyl-d-aspartate Receptors and Monitoring GSH Selectively Using Two-Photon Microscopy.

Anal Chem 2021 08 12;93(33):11612-11616. Epub 2021 Aug 12.

Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea.

-Methyl-d-aspartate (NMDA) is an excitotoxic amino acid used to identify a specific subset of glutamate receptors. The activity of NMDA receptors is closely related to the redox level of the biological system. Glutathione (GSH) as an antioxidant plays a key role with regard to modulation of the redox environment. In this work we designed and developed a GSH-specific fluorescent probe with the capability of targeting NMDA receptors, which was composed of a two-photon naphthalimide fluorophore, a GSH-reactive group sulfonamide, and an ifenprodil targeting group for the NMDA receptor. This probe exhibited high selectivity toward GSH in comparison to other similar amino acids. Two-photon fluorescence microscopy allowed this probe to successfully monitor GSH in neuronal cells and hippocampal tissues with an excitation at 750 nm. It could serve as a potential practical imaging tool to explore the function of GSH and related biological processes in the brain.
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http://dx.doi.org/10.1021/acs.analchem.1c02350DOI Listing
August 2021

Manipulating crystallization dynamics through chelating molecules for bright perovskite emitters.

Nat Commun 2021 Aug 10;12(1):4831. Epub 2021 Aug 10.

Department of Physics, Chemistry and Biology (IFM), Linköping University, Linköping, Sweden.

Molecular additives are widely utilized to minimize non-radiative recombination in metal halide perovskite emitters due to their passivation effects from chemical bonds with ionic defects. However, a general and puzzling observation that can hardly be rationalized by passivation alone is that most of the molecular additives enabling high-efficiency perovskite light-emitting diodes (PeLEDs) are chelating (multidentate) molecules, while their respective monodentate counterparts receive limited attention. Here, we reveal the largely ignored yet critical role of the chelate effect on governing crystallization dynamics of perovskite emitters and mitigating trap-mediated non-radiative losses. Specifically, we discover that the chelate effect enhances lead-additive coordination affinity, enabling the formation of thermodynamically stable intermediate phases and inhibiting halide coordination-driven perovskite nucleation. The retarded perovskite nucleation and crystal growth are key to high crystal quality and thus efficient electroluminescence. Our work elucidates the full effects of molecular additives on PeLEDs by uncovering the chelate effect as an important feature within perovskite crystallization. As such, we open new prospects for the rationalized screening of highly effective molecular additives.
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http://dx.doi.org/10.1038/s41467-021-25092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355273PMC
August 2021

Preliminary Study on Apoptotic Proteins in Platelet from Adult Patients with Chronic Immune Thrombocytopenic Purpura.

Acta Haematol 2021 Aug 10:1-7. Epub 2021 Aug 10.

Department of Clinical Laboratory Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.

Background: Adult chronic idiopathic thrombocytopenic purpura (ITP) is a chronic and usually lifelong hemorrhagic disorder in which enhanced platelet destruction and -weakened platelet production lead to thrombocytopenia. In this study, the p38 mitogen-activated protein kinase (p38-MAPK), early growth response 1 (EGR-1), p53, Bcl-xL, Bak, Bax, and reactive oxygen species (ROS) in platelets from adult patients with chronic ITP were investigated.

Methods: Platelets were isolated from blood samples collected from 20 adult patients with chronic ITP and 20 healthy volunteers. p38-MAPK, EGR-1, p53, Bcl-xL, Bak, Bax, and ROS were determined by flow cytometry, and the results were analyzed by EXPO32 ADC.

Results: Flow cytometry showed the expression levels of p38-MAPK (61.66 ± 19.38% vs. 27.52 ± 14.34%), EGR-1 (62.22 ± 20.48% vs. 9.05 ± 5.79%), p53 (56.82 ± 20.07% vs. 4.35 ± 2.04%), Bak (39.86 ± 11.45% vs. 20.82 ± 11.85%), Bax (36.85 ± 15.99% vs. 6.69 ± 5.01%), and ROS (19.98 ± 1.47% vs. 1.29 ± 0.10%) were all elevated (p < 0.05 compared with healthy volunteers). In addition, pro-survival Bcl-xL (5.38 ± 1.52% vs. 21.20 ± 6.04%) was decreased markedly in platelets from adult patients with chronic ITP (p < 0.05 compared with healthy volunteers).

Conclusions: Our findings reveal that platelets in adults with chronic ITP display a proapoptotic gene expression phenotype, based on the enhanced expression of p38-MAPK, EGR-1, p53, Bak, Bax, and ROS, and attenuated expression of Bcl-xL, suggesting increased sensitivity toward apoptosis.
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http://dx.doi.org/10.1159/000517812DOI Listing
August 2021

Cloud cooling effects of afforestation and reforestation at midlatitudes.

Proc Natl Acad Sci U S A 2021 Aug;118(33)

Department of Civil and Environmental Engineering, Princeton University, Princeton, NJ 08544;

Because of the large carbon sequestration potential, reforestation and afforestation (R&A) are among the most prominent natural climate solutions. However, while their effectiveness is well established for wet tropics, it is often argued that R&A are less advantageous or even detrimental at higher latitudes, where the reduction of forest albedo (the amount of reflected solar radiation by a surface) tends to nullify or even overcome the carbon benefits. Here, we carefully analyze the situation for R&A at midlatitudes, where the warming effects due to vegetation albedo are regarded to be almost balanced by the cooling effects from an increased carbon storage. Using both satellite data and atmospheric boundary-layer models, we show that by including cloud-albedo effects due to land-atmosphere interactions, the R&A cooling at midlatitudes becomes prevalent. This points to a much greater potential of R&A for wet temperate regions than previously considered.
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http://dx.doi.org/10.1073/pnas.2026241118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379994PMC
August 2021

Novel Host Protein TBC1D16, a GTPase Activating Protein of Rab5C, Inhibits Prototype Foamy Virus Replication.

Front Immunol 2021 22;12:658660. Epub 2021 Jul 22.

Hubei Province Key Laboratory of Allergy and Immunology, Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.

Prototype foamy virus (PFV) is a member of the oldest family of retroviruses and maintains lifelong latent infection in the host. The lifelong latent infection of PFV may be maintained by the restriction factors of viral replication in the host. However, the mechanisms involved in PFV latent infection are poorly understood. Here, we found that TBC1D16, a TBC domain-containing protein, is significantly down-regulated after PFV infection. Tre2/Bub2/Cdc16 (TBC) domain-containing proteins function as Rab GTPase-activating proteins (GAPs) and are participates in the progression of some diseases and many signaling pathways. However, whether TBC proteins are involved in PFV replication has not been determined. Here, we found that TBC1D16 is a novel antiviral protein that targets Rab5C to suppress PFV replication. Overexpression TBC1D16 inhibited the transcription and expression of Tas and Gag, and silencing TBC1D16 enhanced the PFV replication. Moreover, the highly conserved amino acid residues R494 and Q531 in the TBC domain of TBC1D16 were essential for inhibiting PFV replication. We also found that TBC1D16 promoted the production of PFV-induced IFN-β and the transcription of downstream genes. These results suggest that TBC1D16 might be the first identified TBC proteins that inhibited PFV replication and the mechanism by which TBC1D16 inhibited PFV replication could provide new insights for PFV latency.
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http://dx.doi.org/10.3389/fimmu.2021.658660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339588PMC
July 2021

A high-contrast photoacoustic agent with near-infrared emission.

Methods Enzymol 2021 19;657:223-247. Epub 2021 Jul 19.

Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, International Joint Research Center for Intelligent Biosensing Technology and Health, College of Chemistry, Central China Normal University, Wuhan, PR China. Electronic address:

Benzobisthiadiazole as a typical electron acceptor, has been widely used to design fluorescent dyes and photoacoustic (PA) agents. With the strategy of constructing donor-acceptor-donor (D-A-D) type of electron characteristics, benzobisthiadiazole derivatives tend to behave stable in near-infrared absorption and emission, which is beneficial to PA imaging. In this chapter, two molecular design strategies are combined to improve the photoacoustic imaging effects of new PA contrast agent IR-1302 NPs, by installing strengthened conjugated bridges and electron donors. The nanoparticles exhibit high-contrast noninvasive photoacoustic imaging in tumor models with longer wavelength absorption and emission and show potential as a clinic contrast agent.
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http://dx.doi.org/10.1016/bs.mie.2021.06.037DOI Listing
August 2021

Osmaindenes: Synthesis and Reversible Mechanochromism Characteristics.

Chemistry 2021 Aug 4. Epub 2021 Aug 4.

Central China Normal University, College of Chemistry, CHINA.

A series of novel osmaindenes 1 - 6 bearing different substituents (CF 3 , H, I, Br, OCH 3 , N(Ph) 2 ) has been synthesized by nucleophilic reaction of water with the corresponding aromatic osmanaphthalyne complexes. All osmaindenes 1 - 6 have been characterized by elemental analysis (EA) and nuclear magnetic resonance (NMR) spectroscopy, although the low solubilities of 3 and 4 precluded the accumulation of their 13 C NMR spectra. Osmaindenes 2 , 3 and 5 have also been characterized by single-crystal X-ray diffraction analysis. Subsequently, through solid-state fluorescence spectroscopy, mechanochromic studies, and powder X-ray diffraction (XRD) analysis, we found that osmaindenes 1 - 6 fluoresce at wavelengths in the range 500-800 nm, while also displaying reversible mechanochromic properties. The solid-state fluorescence emission of 1 after grinding extends into the near-infrared region. This research provides new insight into the design and synthesis of metallic materials with excellent mechanochromic properties.
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http://dx.doi.org/10.1002/chem.202102180DOI Listing
August 2021

Wheat SHORT ROOT LENGTH 1 gene TaSRL1 regulates root length in an auxin-dependent pathway.

J Exp Bot 2021 Jul 30. Epub 2021 Jul 30.

National Key Facility for Crop Gene Resources and Genetic Improvement/Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing 100081, China.

Root is the unique organ of water and nutrients uptake and sensing environmental stimulus in the soil. The optimization of root system architecture contributes to the stress tolerance and yield improvement. ERF (ETHYLENE RESPONSIVE FACTOR) is one of plant specific transcription factor families associated with various developmental processes and stress tolerance. We cloned a novel ERF transcription factor gene TaSRL1 (SHORT ROOT LENGTH 1) from wheat (Triticum aestivum) which is mainly expressed in root. Ectopic expression of TaSRL1 in rice exhibited short root length and plant height. TaSRL1 regulated expression of genes related to auxin synthesis, transport and signaling. Further studies revealed that TaSRL1 induced expression of the auxin transport gene TaPIN2 by directly binding to its promoter, while the interaction of TaSRL1 and TaTIFY9 repressed TaPIN2 expression. Sequence polymorphisms and association analysis showed that TaSRL1-4A was associated with root depth and angle, plant height and 1000-grain weight of wheat. The haplotype Hap-4A-2 with shallow roots, short plant height and high 1000-grain weight has been positively selected in the Chinese wheat breeding process. Therefore, we demonstrated that TaSRL1 functions as a direct regulator of TaPIN2 in the auxin-dependent pathway, and integrates auxin and JA signaling by interacting with TaTIFY9 to repress root growth. Furthermore, the molecular marker of TaSRL1-4A is valuable for the improvement of root system, plant architecture and yield in wheat breeding process.
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http://dx.doi.org/10.1093/jxb/erab357DOI Listing
July 2021

Histone Deacetylase SIRT1 promotes loss of primary cilia in Cholangiocarcinoma.

Hepatology 2021 Jul 29. Epub 2021 Jul 29.

The Hormel Institute, University of Minnesota, Austin, MN, USA.

Background And Aims: Sirtuin 1 (SIRT1) is a complex NAD -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a novel mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA).

Approach And Results: A significant overexpression of SIRT1 was detected in human CCA specimens, and CCA cells including, HuCCT1, KMCH, and WITT1 as compared to normal cholangiocytes (H69 and NHC). siRNA-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation while, overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD+ producing enzyme Nicotinamide phosphoribosyl transferase (NAMPT) increased ciliary length and frequency in CCA cells and in SIRT1 overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins including α-Tubulin, ARL13B and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol, reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (Gli1, p-Erk, and IL-6) expression.

Conclusion: In conclusion, these results reveal the tumorigenic role of SIRT1 via modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA utilizing SIRT1 as a target.
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http://dx.doi.org/10.1002/hep.32080DOI Listing
July 2021

Complement C3 Aggravates Post-epileptic Neuronal Injury Via Activation of TRPV1.

Neurosci Bull 2021 Jul 26. Epub 2021 Jul 26.

Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China.

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Recent studies have shown that complement component 3 (C3) aggravate the neuronal injury in epilepsy. And our previous studies revealed that TRPV1 (transient receptor potential vanilloid type 1) is involved in epilepsy. Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood. We found that in a mouse model of status epilepticus (SE), complement C3 derived from astrocytes was increased and aggravated neuronal injury, and that TRPV1-knockout rescued neurons from the injury induced by complement C3. Circular RNAs are abundant in the brain, and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV1 and exacerbated neuronal injury. Mechanistically, disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury. This study provides support for the hypothesis that the C3-TRPV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.
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http://dx.doi.org/10.1007/s12264-021-00750-4DOI Listing
July 2021

Three-dimensional gait quantitative analysis in postoperative rehabilitation of lumbar degenerative diseases: a self-controlled before-after study.

Am J Transl Res 2021 15;13(6):6913-6920. Epub 2021 Jun 15.

Department of Spine Surgery, Qilu Hospital of Shandong University (Qingdao) Qingdao, Shandong Province, China.

Objective: To evaluate the efficacy of three-dimensional (3-D) gait quantitative analysis in the surgical treatment and postoperative rehabilitation in patients with lumbar degenerative diseases.

Methods: This is a prospective study with self-controll before -after. A total of 48 patients with lumbar degenerative diseases and treated in our hospital were enrolled in the observation group, 40 healthy individuals were included in the control group. Gait analysis was carried out with 3-D motion acquisition and analysis system. The 3-D gait quantitative parameters of the two groups were compared preoperatively. These include time-distance parameters (gait speed, stride frequency, stride length, support phase), hip joint flexion angle and gait deviation index (GDI). The 3-D gait quantitative parameters in the observation group were analyzed post operation and during rehabilitation. Pearson correlation coefficient was used to evaluate the correlation between 3-D gait quantitative parameters and the patient's visual analog score (VAS), Japanese Orthopedic Association (JOA) score and Oswestry Disability Index (ODI).

Results: Compared with the healthy group, the time-distance parameters and the kinematics parameters of lower extremity joints in the observation group were significantly decreased (both P<0.001). The gait index indicated that there were significant gait abnormalities in the observation group (P<0.001). Two weeks after operation, the patient's VAS score, JOA score and ODI were significantly improved compared to the results preoperatively, as well as the 3-D gait quantitative parameters (all P<0.05). Further improvement was then observed after 12 weeks of rehabilitation training (all P<0.05), and the patient's gait was close to normal. Pearson correlation analysis showed that the improvement of the 3-D gait quantitative parameters positively correlated with VAS score, JOA score and ODI (all P<0.001).

Conclusion: The 3-D gait quantitative analysis can effectively evaluate the effect of operation and rehabilitation training.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290730PMC
June 2021

Pentacyclic Triterpenoid Saponins, Poterinasides A-J, from Silverweed Cinquefoil Roots Promising Hepatoprotective and Anti-inflammatory Agents.

J Org Chem 2021 Aug 21;86(16):11220-11236. Epub 2021 Jul 21.

Department of Pharmacognosy and Utilization Key Laboratory of Northeast Plant Materials, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.

Silverweed cinquefoil roots, as dietary supplements, foods, and medicines, are widely used in western areas of China, specifically in Tibet Autonomous Region and Gansu and Qinghai Provinces. In this paper, 10 new natural pentacyclic triterpenoid saponins (-), named poterinasides A-J, along with 14 known compounds (-) were isolated and purified from silverweed cinquefoil roots. The chemical structures of - were established by extensive analysis of 1D and 2D NMR data and mass spectrometric data. Poterinasides A (), B (), and G () with the unique position of substituents on the E ring had never been discovered in natural products before. Saponins -, , and displayed potent hepatoprotective activities, and -, , , , , , and - showed outstanding anti-inflammatory effects. On the basis of the present results, some structure-activity relationships were summarized, in which 3α-OH, 19β-CH, 20α-CH, 20β-CH, 21α-OH, and 30-OH groups in isolated pentacyclic triterpenoid saponins were found to strengthen the hepatoprotective and anti-inflammatory activities, respectively. Further, the following pharmacophore-based virtual screening and docking studies on special targets proteins, SIRT1 and COX-2, revealed roughly similar results with the structure-activity relationships, and this combination method was used for the first time for active natural compound screening.
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http://dx.doi.org/10.1021/acs.joc.1c00812DOI Listing
August 2021

LINC01224/ZNF91 Promote Stem Cell-Like Properties and Drive Radioresistance in Non-Small Cell Lung Cancer.

Cancer Manag Res 2021 13;13:5671-5681. Epub 2021 Jul 13.

Departments of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, People's Republic of China.

Background: Radioresistance is the main reason for the failure of radiotherapy in non-small-cell lung cancer (NSCLC); however, the molecular mechanism of radioresistance is still unclear.

Methods: An RNA-Seq assay was used to screen differentially expressed long non-coding RNAs (lncRNAs) and genes in irradiation-resistant NSCLC cells. RT-PCR and Western blotting assays were performed to analyze the expressions of lncRNAs and genes. The chromosome conformation capture (3C) assay was performed to measure chromatin interactions. Cell cytotoxicity, cell apoptosis, sphere formation and Transwell assays were performed to assess cellular function.

Results: In this study, it was found that LINC01224 increased during the induction of radioresistance in NSCLC cells. LINC01224 was located within the enhancer of ZNF91, and LINC01224 could affect the transcription of ZNF91 by regulating the long-range interactions between the ZNF91 enhancer and promoter. Moreover, upregulation of LINC01224 and ZNF91 could promote irradiation resistance by regulating the stem cell-like properties of NSCLC cells. In addition, high expression levels of LINC01224 and ZNF91 in tissue samples were associated with radioresistance in NSCLC patients.

Conclusion: Our findings demonstrated that LINC01224/ZNF91 drove radioresistance regulation by promoting the stem cell-like properties in NSCLC.
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http://dx.doi.org/10.2147/CMAR.S313744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286114PMC
July 2021

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis.

Ther Adv Med Oncol 2021 30;13:17588359211020547. Epub 2021 Jun 30.

Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs).

Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions.

Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( = 0.0034 and  < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( < 0.001).

Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.
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http://dx.doi.org/10.1177/17588359211020547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252342PMC
June 2021

Enhancement of Room-Temperature Photoluminescence and Valley Polarization of Monolayer and Bilayer WS via Chiral Plasmonic Coupling.

ACS Appl Mater Interfaces 2021 Jul 14;13(29):35097-35104. Epub 2021 Jul 14.

Department of Physics, OSED, Fujian Provincial Key Laboratory of Semiconductor Materials and Applications, Xiamen University, Xiamen 361005, P. R. China.

Transition-metal dichalcogenides with intrinsic spin-valley degree of freedom have enabled great potentials for valleytronic and optoelectronic applications. However, the degree of valley polarization is usually low under nonresonant excitation at room temperature due to the phonon-assisted intervalley scattering. Here, achiral and chiral Au arrays are designed to enhance the optical response and valley polarization in monolayer and bilayer WS. A considerable band edge emission with 7 times increment is realized under the resonant coupling with Au dimer-prism arrays. Valley polarization enhancement is quantitatively predicted by the inherent mechanisms from elevated electromagnetic field intensity and radiation efficiency and further realized in polarized photoluminescence. A tunable valley polarization up to 30.0% is achieved in bilayer WS under a nonresonant excitation at room temperature. All of these results provide a promising route toward the development of room-temperature valley-dependent optoelectronic devices.
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http://dx.doi.org/10.1021/acsami.1c06622DOI Listing
July 2021

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).

Blood Adv 2021 07;5(13):2775-2787

University of Chicago Comprehensive Cancer Center, Chicago, IL.

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.
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http://dx.doi.org/10.1182/bloodadvances.2021004233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288671PMC
July 2021

Dual-Mode Plasmonic Coupling-Enhanced Color Conversion of Inorganic CsPbBr Perovskite Quantum Dot Films.

ACS Appl Mater Interfaces 2021 Jul 12;13(28):32856-32864. Epub 2021 Jul 12.

Collaborative Innovation Center for Optoelectronic Semiconductors and Efficient Devices, Jiujiang Research Institute, Department of Physics / Pen-Tung Sah Institute of Micro-Nano Science and Technology, Xiamen University, Xiamen, Fujian 361005, China.

Plasmonic coupling has been demonstrated to be an effective manipulation strategy for emission enhancement in low-dimensional semiconductor materials. Here, dual-mode plasmonic resonances based on a metal dimer structure were proposed to simultaneously enhance the absorption under short-wavelength excitation and excitons' emission at longer wavelengths for CsPbBr perovskite quantum dots (QDs). Large-area metal nanodimer arrays with well-controlled local surface plasmon resonance were facilely fabricated by a simple method combined with metal angular deposition and nanosphere lithography. With the addition of an optimized polymethyl methacrylate spacer, the effective plasmonic coupling and interfacial passivation of QDs were successfully achieved in the hybrid system. As a result, the QD films exhibited a significant and approximately 3.95-fold overall fluorescence enhancement when using blue light excitation, showing the novel advantages of dual-mode plasmonic coupling of semiconductor quantum structures for color conversion applications.
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http://dx.doi.org/10.1021/acsami.1c02801DOI Listing
July 2021

Sulfonate-Assisted Surface Iodide Management for High-Performance Perovskite Solar Cells and Modules.

J Am Chem Soc 2021 Jul 8;143(28):10624-10632. Epub 2021 Jul 8.

Pen-Tung Sah Institute of Micro-Nano Science and Technology, OSED, Jiujiang Research Institute, State Key Laboratory for Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, National & Local Joint Engineering Research Center of Preparation Technology of Nanomaterials, Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

Owing to the ionic nature of lead halide perovskites, their halide-terminated surface is unstable under light-, thermal-, moisture-, or electric-field-driven stresses, resulting in the formation of unfavorable surface defects. As a result, nonradiative recombination generally occurs on perovskite films and deteriorates the efficiency, stability, and hysteresis performances of perovskite solar cells (PSCs). Here, a surface iodide management strategy was developed through the use of cesium sulfonate to stabilize the perovskite surface. It was found that the pristine surface of common perovskite was terminated with extra iodide, that is, with an I/Pb ratio larger than 3, explaining the origination of surface-related problems. Through post-treatment of perovskite films by cesium sulfonate, the extra iodide on the surface was facilely removed and the as-exposed Pb cations were chelated with sulfonate anions while maintaining the original 3D perovskite structure. Such iodide replacement and lead chelating coordination on perovskite could reduce the commonly existing surface defects and nonradiative recombination, enabling assembled PSCs with an efficiency of 22.06% in 0.12 cm cells and 18.1% in 36 cm modules with high stability.
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http://dx.doi.org/10.1021/jacs.1c03419DOI Listing
July 2021

Cytosolic Protein Delivery for Intracellular Antigen Targeting Using Supercharged Polypeptide Delivery Platform.

Nano Lett 2021 07 6;21(14):6022-6030. Epub 2021 Jul 6.

Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.

Despite the well-recognized clinical success of therapeutic proteins, especially antibodies, their inability to penetrate the cell membrane restricts them to secretory extracellular or membrane-associated targets. Developing a direct cytosolic protein delivery system would offer unique opportunities for intracellular target-related therapeutic proteins. Here, we generated a supercharged polypeptide (SCP) with high cellular uptake efficiency, endosomal escape ability, and good biosafety and developed an SCP with an unnatural amino acid containing the phenylboronic acid (PBA) group, called PBA-SCP. PBA-SCP is capable of potently delivering proteins with various isoelectric points and molecular sizes into the cytosol of living cells without affecting their bioactivities. Importantly, cytosolically delivered antibodies remain functional and are capable of targeting, labeling, and manipulating diverse intracellular antigens. This study demonstrates an efficient and versatile intracellular protein delivery platform, especially for antibodies, and provides new possibilities for expanding protein-based therapeutics to intracellular "undruggable" targets.
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http://dx.doi.org/10.1021/acs.nanolett.1c01190DOI Listing
July 2021
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