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1.
Cell Mol Immunol ; 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210395

RESUMO

The viral reservoir is the major hurdle in developing and establishing an HIV cure. Understanding factors affecting the size and decay of this reservoir is crucial for the development of therapeutic strategies. Recent work highlighted that CD8+ T cells are involved in the control of viral replication in ART-treated HIV-1-infected individuals, but how CD8+ T cells sense and restrict the HIV reservoir are not fully understood. Here, we demonstrate that a population of unconventional CD45RA+, PanKIR+, and/or NKG2A+ virtual memory CD8+ T cells (TVM cells), which confer rapid and robust protective immunity against pathogens, plays an important role in restraining the HIV DNA reservoir in HIV-1-infected patients with effective ART. In patients undergoing ART, TVM cells negatively correlate with HIV DNA and positively correlate with circulating IFN-α2 and IL-15. Moreover, TVM cells constitutively express high levels of cytotoxic granule components, including granzyme B, perforin and granulysin, and demonstrate the capability to control HIV replication through both cytolytic and noncytolytic mechanisms. Furthermore, by using an ex vivo system, we showed that HIV reactivation is effectively suppressed by TVM cells through KIR-mediated recognition. This study suggests that TVM cells are a promising target to predict posttreatment virological control and to design immune-based interventions to reduce the reservoir size in ART-treated HIV-1-infected individuals.

3.
Emerg Infect Dis ; 26(6)2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32125269

RESUMO

Since early January 2020, after the outbreak of 2019 novel coronavirus infection in Wuhan, China, ≈365 confirmed cases have been reported in Shenzhen, China. The mode of community and intrafamily transmission is threatening residents in Shenzhen. Strategies to strengthen prevention and interruption of these transmissions should be urgently addressed.

4.
6.
AIDS ; 34(2): 189-195, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634199

RESUMO

OBJECTIVE: CD4CD19 conjugates play an important role in regulating antibody responses and follicular helper T cells development in animal models. However, little is known regarding the characteristic of CD4CD19 conjugates in humans with chronic HIV-1 infection. METHODS: The numbers of CD4CD19 conjugates were counted in 86 HIV-1-infected patients, including 66 typical progressors and 20 complete responders. CD4CD19 conjugates were sorted by flow cytometry and dissociated into CD4 T singlets and CD19 B singlets. The phenotypes of these cells were analyzed in both typical progressors and complete responders, and the levels of HIV-1 DNA in CD4CD19 conjugates were measured in 10 complete responders. RESULTS: We identified CD4CD19 cells as one type of T-B conjugate in peripheral blood, and the numbers and percentages of CD4CD19 conjugates decreased with HIV-1 disease progression. Phenotypic analysis showed CD4CD19 conjugates expressed higher levels of surface CD32. mRNA analysis found that the mRNA levels for CD32b were significantly higher compared with CD32a in CD4CD19 conjugates. Further analysis found that CD4CD19 conjugates expressed higher levels of CCR7 and CXCR5 than CD4 T and CD19 B singlets. A virus infectivity assay showed that CD4CD19 conjugates expressed higher levels of HIV-1-p24 than CD4CD19 cells. CD4CD19 conjugates in lymph node from typical progressors expressed higher levels of HIV-1-p24 than CD4CD19 conjugates in respective peripheral blood. Importantly, CD4CD19 conjugates from complete responders contained higher levels of HIV-1 DNA than total CD4 T cells. CONCLUSION: Our study indicates that CD4CD19 conjugates actively participate in HIV-1 infection and latency, and may serve as a new cellular target to eliminate latency.

7.
Front Immunol ; 10: 2465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681335

RESUMO

Background: Treg cells represent important viral reservoirs during chronic HIV infection. CD39 is closely involved in Treg-mediated immunosuppressive effects. However, CD39 expression on nTregs and mTregs and a relationship with HIV DNA levels during HIV infection is still unclear. In this study, we analyzed the distribution of HIV DNA in Treg subsets and the association between HIV DNA and CD39 expression on Treg subsets. Methods: Sixty-two HIV-infected patients with different HIV stages and 14 uninfected individuals were enrolled. nTregs (CD4+CD25+CD127lowCD45RO-) and mTregs (CD4+CD25+CD127lowCD45RO+) were isolated by magnetic selection and flow cytometric sorting. HIV DNA was quantified by real-time polymerase chain reaction (PCR). CD39 expression on nTregs and mTregs was analyzed by flow cytometry. Results: Higher levels of HIV DNA were detected in mTregs than those in nTregs during chronic HIV infection. The frequency of CD39+ nTregs and HIV DNA levels in nTregs were increased in patients with advanced HIV infection. Furthermore, HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency. CD39+ nTreg frequency was also increased in immune non-responders. Conclusions: mTregs and nTregs are both important reservoirs of virus during chronic HIV infection and HIV DNA levels increase in nTregs in patients with advanced HIV infection. We observed increased frequency of CD39+ nTregs and HIV DNA levels in nTregs in patients with advanced HIV infection. HIV DNA levels in nTregs correlated positively with CD39+ nTreg frequency.

8.
Hepatol Int ; 13(5): 521-533, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31352593

RESUMO

At the time of hepatocellular carcinoma (HCC) diagnosis, patients are most often at an advanced stage; however, the current treatment regimens remain unsatisfactory. Thus, novel and more powerful therapeutic approaches for advanced HCC are urgently required. Exacerbation of immunotolerant signals and/or escaping immunosurveillance leads to the development of HCC, which appears to be a rational reason to use immunotherapy to restore anticancer immunity. Several novel immunotherapeutic methods, including the use of immune checkpoint inhibitors, new types of immune cell adoption [e.g., chimeric antigen receptor T cell (CAR-T), TCR gene-modified T cells and stem cells], and microRNAs have been used in clinical trials for the treatment of HCC. However, some crucial issues remain to be addressed for such novel immunotherapy techniques. Finally, immunotherapy is now standing on the threshold of great advances in the fight against HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Imunoterapia , Neoplasias Hepáticas/imunologia , Carcinoma Hepatocelular/terapia , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/terapia
9.
J Viral Hepat ; 26(10): 1146-1155, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31087479

RESUMO

Hepatitis B virus (HBV) infection continues to be a major public health issue worldwide. HBsAg loss is associated with functional remission and improved long-term outcome, and is considered to be a 'functional cure' (also referred to as clinical or immunologic cure) for chronic hepatitis B. This ideal goal of therapy can be achieved using optimized combination regimens with direct-acting antivirals [eg nucleos(t)ide analogues (NAs)] and immunomodulators [eg pegylated interferon alpha2a (Peg-IFN)] in selected patients with chronic hepatitis B. Among different combination therapies currently available, those with NA lead-in followed by Peg-IFN in virally suppressed patients has been demonstrated to be effective. This review provides an updated overview of the evidence supporting the use of combination therapies and summarizes expert consensus on the roadmap to attain functional cure for chronic hepatitis B patients.

10.
Antivir Ther ; 24(4): 237-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30882363

RESUMO

BACKGROUND: A unique chronic hepatitis B patient was followed over 189 months of nucleoside/nucleotide analogue (NA) therapies with the analysis of multiple drug-resistance HBV mutants. METHODS: Clonal sequencing (≥20 clones/sample) was performed on sera sampled at 41 time points, and the phenotypic features of eight representative mutants were analysed. RESULTS: Lamivudine (LAM)-, adefovir dipivoxil (ADV)-, entecavir (ETV)- and repeat ADV-resistance mutants emerged upon individual sequential NA monotherapy. The efficacy of NA combination rescue therapies ranked as LAM+ADV < ETV+ADV < ETV+ tenofovir disoproxil fumarate (TDF). Specifically, LAM+ADV and ETV+ADV suppressed viral loads to <100 IU/ml for a long period of time, either with or without late stage HBV DNA fluctuations. Furthermore, ETV+TDF suppressed the viral load to <10 IU/ml. During the LAM+ADV and ETV+ADV combination therapies, ETV-resistance mutants dominated at most time points, and multidrug-resistance (MDR) mutants that harboured LAM-, ETV- and ADV-resistance mutations were intermittently detected. Interestingly, the rtA181T-causative sW172stop to sW172non-stop mutation transition was observed at HBV DNA fluctuations. In a phenotypic analysis, two MDR strains had cross-resistance to LAM, ETV and ADV, and a lower susceptibility to TDF (<10-fold decrease compared with the wild-type strain). In contrast, the natural replication capacity was inversely associated with the number of primary resistant mutations which would limit MDR mutant development. CONCLUSIONS: Taken together, viral drug susceptibility, replication capacity, and perhaps immunological adaptation may play coordinated roles in the fitness of drug-resistance mutants. ETV+TDF therapy is the preferred option for treating chronic hepatitis B patients with multiple drug failure.

11.
Clin Immunol ; 202: 40-48, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30914281

RESUMO

γδ T cells are a unique population of lymphocytes that have regulatory roles in patients with chronic hepatitis B (CHB); however, their role in acute hepatitis B (AHB) infection remains unclear. Phenotype and function of γδ T cells were analyzed in 29 AHB patients, 28 CHB patients, and 30 healthy controls (HCs) using immunofunctional assays. Compared with HCs and CHB patients, decreased peripheral and increased hepatic γδ T cells were found in AHB patients. Increased hepatic γδ T cells in AHB patients were attributed to elevated hepatic chemokine levels. Peripheral γδ T cells exhibited highly activated and terminally differentiated memory phenotype in AHB patients. Consistently, peripheral γδ T cells in AHB patients showed increased cytotoxic capacity and enhanced antiviral activity which was further proved in longitudinal study. Activated γδ T cells in AHB patients exhibited increased cytotoxicity and capacity for viral clearance associated with liver injury and the control of infection.


Assuntos
Hepatite B/imunologia , Linfócitos Intraepiteliais/imunologia , Doença Aguda , Adolescente , Adulto , Quimiocinas/imunologia , Doença Crônica , DNA Viral/análise , Feminino , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(3): 259-264, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-30907351

RESUMO

OBJECTIVE: To study the features of serum metabolites in preterm infants based on gas chromatography-mass spectrometry (GC-MS), and to find differentially expressed metabolites in the serum of preterm infants. METHODS: Serum samples were collected from 19 preterm infants and 20 full-term infants before feeding. GC-MS was used to measure metabolic profiles, and the metabolic features of 397 serum metabolites in preterm infants were analyzed. RESULTS: There was a significant difference in serum metabolic features between the preterm and full-term infants before feeding. There were significant differences between the full-term and preterm infants in the levels of metabolites such as O-phosphonothreonine, digicitrin, tannic acid, and fructose-1,6-diphosphate (P<0.01), suggesting that the above differentially expressed metabolites were highly differentiated between the preterm and full-term infants. Most differentially expressed metabolites were involved in the metabolic pathways such as ABC transporters, ß-alanine and pyrimidines and were correlated with some clinical parameters (albumin and total bilirubin) (P<0.05). CONCLUSIONS: There is a significant difference in serum metabolites between preterm and full-term infants before feeding. Metabolomics plays an important role in improving metabolic disorders and exploring metabolism-related diseases in preterm infants.


Assuntos
Metaboloma , Metabolômica , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Redes e Vias Metabólicas
13.
Immunol Lett ; 213: 55-61, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30849400

RESUMO

Circulating T follicular helper (cTFH) cells have been demonstrated to be involved in B-cell-mediated alloreactive responses in kidney and liver transplantation; however, whether these cells are involved in acute liver allograft rejection after liver transplantation, and which subsets are involved, remains to be clarified. The present study aimed to investigate the profiles of cTFH cells in acute liver allograft rejection, including the CXC motif receptor 3 (CXCR3)+ chemokine receptor 6 (CCR6)- subset, the CXCR3-CCR6- subset, and the CXCR3-CCR6+ subset. Twelve liver transplant patients with acute rejection (AR) and 20 with no acute rejection (NAR) were enrolled in the study. The results showed that the proportion of CXCR3-CCR6-CXCR5+CD4+ T cells was significantly increased and the proportion of CXCR3-CCR6+CXCR5+CD4+ T cells was significantly decreased in patients with AR compared with patients with NAR. In addition, the proportion of CXCR3-CCR6-CXCR5+CD4+ T cells was positively correlated with the proportion of B cells in patients with AR. The level of serum interleukin (IL)-21 was higher in the AR group than in the NAR groups. Furthermore, the proportion of CXCR3-CCR6-CXCR5+CD4+ T cells was positively correlated with alanine amino transferase (ALT), whereas the proportion of CXCR3-CCR6+ CXCR5+CD4+ T cells was negatively correlated with ALT. B cells and TFH cells were detected in follicular-like structures in liver allograft tissues from patients with AR. These results suggest that CXCR3-CCR6-CXCR5+CD4+ T cells may be involved in acute allograft rejection after liver transplantation.

14.
Chem Sci ; 10(1): 284-292, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30713638

RESUMO

Triblock copolymer of poly(ethylene glycol)-b-poly(2-dimethylaminoethyl methacrylate)-b-poly(pyrenylmethyl methacrylate) (PEG-b-PDMAEMA-b-PPy) has been developed for use as an ideal gene delivery system, which showed both high stability under physiological conditions and efficient gene release in a mimetic cancer environment. The siRNA release from this system without external stimulation was 16% in 1 h and then remained steady. However, the photo-triggered siRNA release was 78% within 1 h and was higher than 91% after 24 h. The remarkable contrast between the stability and release efficiency of these siRNA-condensed micelleplexes before and after photo-irradiation has been rationalized by the light- and pH-induced structural transitions of the triblock copolymer micelles. The negligible cytotoxicity, high cellular uptake efficiency, and remarkable knockdown efficiency shown in in vitro tests further revealed the promising potential of these triblock copolymer micelleplexes for use in stimuli-responsive gene therapy.

15.
Antiviral Res ; 164: 131-138, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30796932

RESUMO

This study aimed to clarify whether rtA186T and rtI163V substitutions of hepatitis B virus (HBV) contributed to entecavir (ETV) resistance. A total of 22,009 Chinese patients with chronic HBV infection who received resistance testing at Beijing 302 Hospital from 2007 to 2016 were enrolled. Among them, 6170 patients had been treated with ETV. The HBV reverse transcriptase gene was screened by direct sequencing and verified by clonal sequencing. Phenotypic analysis was performed for evaluating replication capacity and drug susceptibility. Classical ETV-resistance mutations rtT184/S202/M250substitution+rtM204V/I±L180M (LAM-r), rtA186T, and rtI163V were detected in 1252 (5.69%), 14 (0.06%), and 230 (1.05%) of the 22,009 patients, respectively. The rtA186T mutation always coexisted with LAM-r, but not with rtI163V. The 14 rtA186T-positive patients were all treated with LAM and ETV, and the emergence of the rtA186T+LAM-r was closely associated with virological breakthrough or inadequate virological response to ETV. By contrast, the emergence of rtI163V was not related to ETV treatment. Six rtA186T-positive patients were followed up longitudinally, showing that these patients all had received sequential adefovir and LAM monotherapies prior to ETV treatment. Compared to wild-type strain, two patient-derived mutants' rtL180M+A186T+M204V and rtL180M+T184S+A186T+M204V had 86.7% and 89.2% decreased replication capacity, 210- and 555-fold increased ETV resistance, respectively; and artificial elimination of rtA186T largely restored their ETV sensitivity. The rtA186T mutants remained sensitive to tenofovir. In conclusion, our study confirmed that rtA186T plus LAM-r is a novel ETV-resistance mutation pattern which conferred ETV resistance in multiple Chinese patients.

16.
Cell Mol Immunol ; 16(6): 602-610, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30327490

RESUMO

Granulocyte colony-stimulating factor (GM-CSF), produced by CD4+ T cells, has recently been implicated in the pathogenesis of inflammatory diseases, such as multiple sclerosis and juvenile arthritis. However, the role of GM-CSF-producing CD4+ T cells in sepsis remains unknown. This study reports peripheral changes in GM-CSF-producing CD4+ T cells in septic patients and the possible underlying mechanism by which GM-CSF influences the outcome of sepsis. Forty-three septic patients, 20 SIRS patients, and 20 healthy controls were enrolled in this study and followed for 28 days to assess mortality. We measured the peripheral frequency of GM-CSF+CD4+ T cells and recorded their associated relationship with disease progression. Our data demonstrated that peripheral GM-CSF-producing CD4+ T cells were significantly higher in septic patients than in both SIRS patients and healthy controls. These cells exhibit a memory phenotype and impaired IFN-γ-secreting capacity in sepsis patients. Using a receiver operating curve analysis with 8.01% as a cut-off point, the percentage of GM-CSF+CD4+ T cells could predict the outcome of septic patients. Combined with the increase in GM-CSF-producing CD4+ T cells, inflammatory cytokines IL-1ß and IL-6 were also upregulated. Using an in vitro neutrophil model, we found that GM-CSF inhibited C3aR expression, while inducing IL-8 production. Furthermore, this effect was transferrable in plasma from sepsis patients and was attenuated by inhibition of GM-CSF using an anti-GM-CSF antibody. These results indicate that GM-CSF-producing CD4+ T cells may serve as a marker of sepsis severity. Thus, targeting GM-CSF overproduction may benefit sepsis patients.

17.
J Gastroenterol Hepatol ; 34(1): 12-21, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30311701

RESUMO

BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.


Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Adulto , Alanina Transaminase/sangue , Antivirais/efeitos adversos , Aspartato Aminotransferases/sangue , Austrália , Benzofuranos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Farmacorresistência Viral/genética , Extremo Oriente , Feminino , Genótipo , Hepacivirus/enzimologia , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Federação Russa , Resposta Viral Sustentada , Tailândia , Vietnã , Proteínas não Estruturais Virais/metabolismo , Adulto Jovem
18.
Pediatrics ; 143(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30591617

RESUMO

We report the case of a 6-year-old boy with citrin deficiency and advanced hepatocellular carcinoma diagnosed by using imaging. He exhibited intrahepatic cholestasis 2 days after his birth and was misdiagnosed with inspissated bile syndrome at that time. The symptoms of jaundice spontaneously resolved when he was 5 months old. However, his transaminase levels remained elevated for ∼6 years, for which he received no treatment. He preferred a high-protein, high-fat, low-carbohydrate diet, which has been observed in many patients with citrin deficiency, but no clinical features of adult-onset type II citrullinemia were observed. At the age of 6 years, he was admitted to our hospital with a nonviral infection and high α-fetoprotein level; results from an abdominal MRI and computed tomography revealed multiple tumors in the liver. Because of his history of intrahepatic cholestasis in the neonatal period, he was suspected to have citrin deficiency. A genetic analysis of solute carrier family 25, member 13 revealed the presence of a homozygous 851del4 mutation, and a diagnosis of citrin deficiency was made. The patient did not qualify for liver transplantation and died 2 months later, after discharge from our hospital. Thus, this case reveals that not all patients with neonatal intrahepatic cholestasis spontaneously and totally improve, and this case is used to emphasize that patients with neonatal intrahepatic cholestasis should be managed carefully, especially in the stage of failure to thrive and dyslipidemia caused by citrin deficiency, which may lead to advanced hepatocellular carcinoma.


Assuntos
Proteínas de Ligação ao Cálcio/sangue , Carcinoma Hepatocelular/diagnóstico , Citrulinemia/complicações , Neoplasias Hepáticas/diagnóstico , Estadiamento de Neoplasias , Transportadores de Ânions Orgânicos/sangue , Carcinoma Hepatocelular/complicações , Criança , Citrulinemia/sangue , Citrulinemia/diagnóstico , Evolução Fatal , Humanos , Neoplasias Hepáticas/complicações , Masculino , Tomografia Computadorizada por Raios X
19.
Stem Cell Res Ther ; 9(1): 353, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572947

RESUMO

A 27-year-old male with HIV-associated naïve and high-risk Burkitt's lymphoma sequentially received short-term, high-dose non-myeloablative chemotherapy and autologous CD34-positive stem cell transfusion in the setting of combined antiretroviral therapy (cART). Prompt hematopoietic recovery was observed after 2 weeks and clinical remission from Burkitt's lymphoma within approximately 30 months after transplantation. The HIV RNA load was inhibited persistently, and drug resistance was not observed. The CD4+ T cell count approached 323 cells/µL in a recent follow-up study. This case suggests that the use of intensive non-myeloablative chemotherapy with transplantation, combined with antiretroviral therapy, in HIV-related naive and high-risk Burkitt's lymphoma was tolerated and safe.


Assuntos
Antirretrovirais/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/terapia , Infecções por HIV/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo/métodos , Adulto , Antirretrovirais/farmacologia , Linfoma de Burkitt/patologia , Terapia Combinada , Infecções por HIV/patologia , Humanos , Masculino , Condicionamento Pré-Transplante
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