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1.
Exp Hematol ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31369790

RESUMO

Exosomes are virus-size membrane-bound vesicles of endocytic origin present in all body fluids. Plasma of AML patients is significantly enriched in exosomes, which carry a cargo of immunosuppressive molecules and deliver them to recipient immune cells, suppressing their functions. However, whether these exosomes originate from leukemic blasts or from various normal cells in the bone marrow or other tissues is unknown. In the current study, we developed an AML PDX model in mice and studied the molecular cargo and immune cell effects of the AML PDX exosomes in parallel with the exosomes from plasma of the corresponding AML patients. Fully engrafted AML PDX mice produced exosomes with characteristics similar to those of exosomes isolated from plasma of the AML patients who had donated the cells for engraftment. The engrafted leukemic cells produced exosomes that carried human proteins and leukemia-associated antigens, confirming the human origin of these exosomes. Furthermore, the AML-derived exosomes carried immunosuppressive proteins responsible for immune cell dysfunctions. Our studies of exosomes in AML PDX mice serve as a proof of concept that AML blasts are the source of immunosuppressive exosomes with a molecular profile that mimics the content and functions of the parental cells.

2.
Virology ; 536: 20-26, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31394408

RESUMO

The Coxsackievirus and adenovirus receptor (CAR) is both a viral receptor and cell adhesion protein. CAR has two transmembrane isoforms that localize distinctly in polarized epithelial cells. Whereas the seven exon-encoded isoform (CAREx7) exhibits basolateral localization, the eight exon-encoded isoform (CAREx8) can localize to the apical epithelial surface where it can mediate luminal adenovirus infection. To further understand the distinct biological functions of these two isoforms, CRISPR/Cas9 genomic editing was used to specifically delete the eighth exon of the CXADR gene in a Madine Darby Canine Kidney (MDCK) cell line with a stably integrated lentiviral doxycycline-inducible CAREx8 cDNA. The gene-edited clone demonstrated a significant reduction in adenovirus susceptibility when both partially and fully polarized, and doxycycline-induction of CAREx8 restored sensitivity to adenovirus. These data reinforce the importance of CAREx8 in apical adenovirus infection and provide a new model cell line to probe isoform specific biological functions of CAR.

3.
J Obstet Gynaecol ; : 1-2, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31335266

RESUMO

The induction of labour is required for various indications in obstetrics. Various regimens and drugs are advocated for use in labour induction. Mifepristone is one such drug which has a definite role in first and second-trimester pregnancy terminations. However, its role in the third-trimester is still being reviewed. In the present study, the effect of mifepristone on cervical ripening was assessed and results interpreted. Impact statement What is already known on the subject? The role of mifepristone in termination of pregnancies at term is controversial. Some studies report onset of labour after giving mifepristone whereas others do not report any significant role. What do the results of the study add? Mifepristone has a role in improving Bishop score and can be used as a pre-induction cervical ripening agent before using other methods for labour induction. It does not report any adverse effects on the mother or foetus. What are the implications of these findings for clinical practice and/or further research? Mifepristone needs to be studied more in term pregnancies as induction of labour is increasingly required in today's scenario for various reasons. However, its role in improving the Bishop score as found in this study helps in decreasing dose of other labour inducing agents.

4.
Sci Rep ; 9(1): 9958, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292468

RESUMO

The morphogenesis of the nervous system requires coordinating the specification and differentiation of neural precursor cells, the establishment of neuroepithelial tissue architecture and the execution of specific cellular movements. How these aspects of neural development are linked is incompletely understood. Here we inactivate a major regulator of embryonic neurogenesis - the Delta/Notch pathway - and analyze the effect on zebrafish central nervous system morphogenesis. While some parts of the nervous system can establish neuroepithelial tissue architecture independently of Notch, Notch signaling is essential for spinal cord morphogenesis. In this tissue, Notch signaling is required to repress neuronal differentiation and allow thereby the emergence of neuroepithelial apico-basal polarity. Notch-mediated suppression of neurogenesis is also essential for the execution of specific morphogenetic movements of zebrafish spinal cord precursor cells. In the wild-type neural tube, cells divide at the organ midline to contribute one daughter cell to each organ half. Notch signaling deficient animals fail to display this behavior and therefore form a misproportioned spinal cord. Taken together, our findings show that Notch-mediated suppression of neurogenesis is required to allow the execution of morphogenetic programs that shape the zebrafish spinal cord.

5.
Indian J Med Res ; 149(2): 263-269, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31219092

RESUMO

Background & objectives: Antimicrobial resistance is a major challenge in the treatment of typhoid fever with limited choices left to empirically treat these patients. The present study was undertaken to determine the current practices of antibiotic use in children attending a tertiary care hospital in north India. Methods: This was a descriptive observational study in children suffering from enteric fever as per the case definition including clinical and laboratory parameters. The antibiotic audit in hospitalized children was measured as days of therapy per 1000 patient days and in outpatient department (OPD) as antibiotic prescription on the treatment card. Results: A total of 128 children with enteric fever were included in the study, of whom, 30 were hospitalized and 98 were treated from OPD. The mean duration of fever was 9.5 days at the time of presentation. Of these, 45 per cent were culture positive with Salmonella Typhi being aetiological agent in 68 per cent followed by S. Paratyphi A in 32 per cent. During hospitalization, the average length of stay was 10 days with mean duration of defervescence 6.4 days. Based on antimicrobial susceptibility ceftriaxone was given to 28 patients with mean duration of treatment being six days. An additional antibiotic was needed in six patients due to clinical non-response. In OPD, 79 patients were prescribed cefixime and additional antibiotic was needed in five during follow up visit. Interpretation & conclusions: Based on our findings, ceftriaxone and cefixime seemed to be the first line of antibiotic treatment for typhoid fever. Despite susceptibility, clinical non-response was seen in around 10 per cent of the patients who needed combinations of antibiotics.

6.
Carcinogenesis ; 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31245809

RESUMO

Circulating tumor-derived exosomes (TEX) interact with a variety of cells in cancer-bearing hosts, leading to cellular reprogramming which promotes disease progression.  To study TEX effects on the development of solid tumors, immunosuppressive exosomes carrying PD-L1 and FasL were isolated from supernatants of murine or human HNSCC cell lines. TEX were delivered (IV) to immunocompetent C57BL/6 mice bearing pre-malignant oral/esophageal lesions induced by the carcinogen, 4-Nitroquinoline 1-oxide (4NQO). Progression of the premalignant oropharyngeal lesions to malignant tumors was monitored. A single TEX injection increased the number of developing tumors (6.2 vs 3.2 in control mice injected with PBS; p < 0.0002) and overall tumor burden per mouse (p < 0.037). The numbers of CD4+ and CD8+ T lymphocytes infiltrating the developing tumors were coordinately reduced (p < 0.01) in mice injected with SCCVII-derived TEX relative to controls. Notably, TEX isolated from mouse or human tumors had similar effects on tumor development and immune cells. A single IV injection of TEX was sufficient to condition mice harboring pre-malignant OSCC lesions for accelerated tumor progression in concert with reduced immune cell migration to the tumor.

7.
Development ; 146(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31253635

RESUMO

Muscle stem cells hold a great therapeutic potential in regenerating damaged muscles. However, the in vivo behavior of muscle stem cells during muscle growth and regeneration is still poorly understood. Using zebrafish as a model, we describe the in vivo dynamics and function of embryonic muscle progenitor cells (MPCs) in the dermomyotome. These cells are located in a superficial layer external to muscle fibers and express many extracellular matrix (ECM) genes, including collagen type 1 α2 (col1a2). Utilizing a new col1a2 transgenic line, we show that col1a2+ MPCs display a ramified morphology with dynamic cellular processes. Cell lineage tracing demonstrates that col1a2+ MPCs contribute to new myofibers in normal muscle growth and also during muscle regeneration. A combination of live imaging and single cell clonal analysis reveals a highly choreographed process of muscle regeneration. Activated col1a2+ MPCs change from the quiescent ramified morphology to a polarized and elongated morphology, generating daughter cells that fuse with existing myofibers. Partial depletion of col1a2+ MPCs severely compromises muscle regeneration. Our work provides a dynamic view of embryonic muscle progenitor cells during zebrafish muscle growth and regeneration.

8.
Indian J Med Res ; 149(3): 404-411, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31249207

RESUMO

Background & objectives: : Azithromycin has been in use as an alternate treatment option for enteric fever even when the guidelines on the susceptibility testing were not available. There is lack of data on susceptibility and mechanisms of resistance of azithromycin in Salmonella Typhi and S. Paratyphi A. The aim of the present study was to determine the azithromycin susceptibility and resistance mechanisms in typhoidal salmonellae isolates archived in a tertiary care centre in north India for a period of 25 years. Methods: : Azithromycin susceptibility was determined in 602 isolates of S. Typhi (469) and S. Paratyphi A (133) available as archived collection isolated during 1993 to 2016, by disc diffusion and E-test method.PCR was done for ereA, ermA, ermB, ermC, mefA, mphA and msrA genes from plasmid and genomic DNA and sequencing was done to detect mutations in acrR, rplD and rplV genes. Results: : Azithromycin susceptibility was seen in 437/469 [93.2%; 95% confidence interval (CI), 90.5 to 95.1%] isolates of S. Typhi. Amongst 133 isolates of S. Paratyphi A studied, minimum inhibitory concentration (MIC) of ≤16 mg/l was found in 102 (76.7%; 95% CI, 68.8 to 83.0). MIC value ranged between 1.5 and 32 mg/l with an increasing trend in MIC50and MIC90with time. Mutations were found in acrR in one and rplV in two isolates of S. Typhi. No acquired mechanism for macrolide resistance was found. Interpretation & conclusions: : Azithromycin could be considered as a promising agent against typhoid fever on the basis of MIC distribution in India. However, due to emergence of resistance in some parts, there is a need for continuous surveillance of antimicrobial susceptibility and resistance mechanisms. There is also a need to determine the breakpoints for S. Paratyphi A.

9.
Hum Mutat ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

10.
J Dermatolog Treat ; : 1-5, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030594

RESUMO

BACKGROUND: There has been an alarming increase in recalcitrant dermatophytosis in recent years. The standard treatment guidelines no longer seem effective in achieving clearance and results in high failure rates. OBJECTIVE: To evaluate the efficacy and safety of oral terbinafine and itraconazole combination therapy in the management of dermatophytosis. METHODS: Clinically diagnosed and KOH positive patients of tinea corporis/cruris/faciei were randomly divided into three groups and given terbinafine 250 mg, itraconazole 200 mg and a combination of both once daily taken on the same day respectively for 3 weeks. Partial responders at the end of the therapy were given same treatment for additional 3 weeks. Clinical parameters namely itching, erythema, and scaling were evaluated at baseline, 3, 6, and 9 weeks. Adverse effects were noted at the end of therapy. RESULTS: Maximum clinical and mycological cure was achieved in group III (receiving combination therapy) (90%) followed by group II (receiving itraconazole) (50%) and group I (receiving terbinafine) (35%). The combination therapy of oral terbinafine and itraconazole was found to be as safe as monotherapy without any significant adverse effects. CONCLUSIONS: The combination of systemic terbinafine and itraconazole therapy may be an effective and safe therapeutic strategy in the management of dermatophytosis.

11.
Cells ; 8(2)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30700008

RESUMO

As the primary cellular location for respiration and energy production, mitochondria serve in a critical capacity to the cell. Yet, by virtue of this very function of respiration, mitochondria are subject to constant oxidative stress that can damage one of the unique features of this organelle, its distinct genome. Damage to mitochondrial DNA (mtDNA) and loss of mitochondrial genome integrity is increasingly understood to play a role in the development of both severe early-onset maladies and chronic age-related diseases. In this article, we review the processes by which mtDNA integrity is maintained, with an emphasis on the repair of oxidative DNA lesions, and the cellular consequences of diminished mitochondrial genome stability.

12.
Sci Rep ; 9(1): 1434, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723266

RESUMO

Leptospirosis is the most emerging zoonotic disease of epidemic potential caused by pathogenic species of Leptospira. The bacterium invades the host system and causes the disease by interacting with the host proteins. Analyzing these pathogen-host protein interactions (PHPIs) may provide deeper insight into the disease pathogenesis. For this analysis, inter-species as well as intra-species protein interactions networks of Leptospira interrogans and human were constructed and investigated. The topological analyses of these networks showed lesser connectivity in inter-species network than intra-species, indicating the perturbed nature of the inter-species network. Hence, it can be one of the reasons behind the disease development. A total of 35 out of 586 PHPIs were identified as key interactions based on their sub-cellular localization. Two outer membrane proteins (GpsA and MetXA) and two periplasmic proteins (Flab and GlyA) participating in PHPIs were found conserved in all pathogenic, intermediate and saprophytic spp. of Leptospira. Furthermore, the bacterial membrane proteins involved in PHPIs were found playing major roles in disruption of the immune systems and metabolic processes within host and thereby causing infectious disease. Thus, the present results signify that the membrane proteins participating in such interactions hold potential to serve as effective immunotherapeutic candidates for vaccine development.

13.
J Med Chem ; 62(4): 1875-1886, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688460

RESUMO

The presence of lipopolysaccharide and emergence of drug resistance make the treatment of Gram-negative bacterial infections highly challenging. Herein, we present the synthesis and antibacterial activities of cholic acid-peptide conjugates (CAPs), demonstrating that valine-glycine dipeptide-derived CAP 3 is the most effective antimicrobial. Molecular dynamics simulations and structural analysis revealed that a precise intramolecular network of CAP 3 is maintained in the form of evolving edges, suggesting intramolecular connectivity. Further, we found high conformational rigidity in CAP 3 that confers maximum perturbations in bacterial membranes relative to other small molecules. Interestingly, CAP 3-coated catheters did not allow the formation of biofilms in mice, and treatment of wound infections with CAP 3 was able to clear the bacterial infection. Our results demonstrate that molecular conformation and internal connectivity are critical parameters to describe the antimicrobial nature of compounds, and the analysis presented here may serve as a general principle for the design of future antimicrobials.

14.
Bioconjug Chem ; 30(3): 721-732, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30669829

RESUMO

A major impediment to developing effective antimicrobials against Gram-negative bacteria like Salmonella is the ability of the bacteria to develop resistance against existing antibiotics and the inability of the antimicrobials to clear the intracellular bacteria residing in the gastrointestinal tract. As the critical balance of charge and hydrophobicity is required for effective membrane-targeting antimicrobials without causing any toxicity to mammalian cells, herein we report the synthesis and antibacterial properties of cholic acid-derived amphiphiles conjugated with alkyl chains of varied hydrophobicity. Relative to other hydrophobic counterparts, a compound with hexyl chain (6) acted as an effective antimicrobial against different Gram-negative bacteria. Apart from its ability to permeate the outer and inner membranes of bacteria; compound 6 can cross the cellular and lysosomal barriers of epithelial cells and macrophages and kill the facultative intracellular bacteria without disrupting the mammalian cell membranes. Oral delivery of compound 6 was able to clear the Salmonella-mediated gut infection and inflammation, and was able to combat persistent, stationary, and multi-drug-resistant clinical strains. Therefore, our study reveals the ability of cholic acid-derived amphiphiles to clear intracellular bacteria and Salmonella-mediated gut infection and inflammation.

15.
Genome Res ; 29(1): 29-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30552103

RESUMO

In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which gene transcription is coordinately regulated in response to steroid hormones. Here we further describe that responsive TADs contain 20- to 100-kb-long clusters of intermingled estrogen receptor (ESR1) and progesterone receptor (PGR) binding sites, hereafter called hormone-control regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ESR1 and PGR. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters in their TADs even in the absence of hormones in ESR1+-PGR+ cells. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms that integrate different signals, resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors but also as local and global genome organizers.


Assuntos
Receptor alfa de Estrogênio/biossíntese , Estrogênios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Progesterona/farmacologia , Receptores de Progesterona/biossíntese , Elementos de Resposta , Transdução de Sinais/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Humanos , Células MCF-7 , Receptores de Progesterona/genética
16.
Int J Dev Biol ; 62(9-10): 647-652, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30378390

RESUMO

The polyamines putrescine, spermidine and spermine are essential polycations involved in the regulation of cellular proliferation. They exert dynamic effects on nucleic acids and macromolecular synthesis in vitro but their specific functions in vivo are poorly understood. Here, we have modulated the spermidine levels either by overexpressing the S-adenosylmethionine decarboxylase (samdc) gene or treating the cells with methylglyoxal-bis (guanylhydrazone) (MGBG), an inhibitor of SAMDC. In Dictyostelium, overexpression of SAMDC slowed cell proliferation, delayed development and arrested cells in the S-phase of the cell cycle. Treatment with MGBG reduced cell proliferation and stimulated development, but in samdcOE cells, it increased cell proliferation suggesting critical levels of spermidine to be important. In samdcOE cells, spermidine levels remained high throughout development but only small changes in the spermine levels were observed. Initial putrescine levels did increase but reverted to wild-type levels after the mound stage. As tight regulation of polyamine homeostasis is required, we identified genes that could be involved in its maintenance. In conclusion, we characterised samdcOE cells and observed the maintenance of polyamine homeostasis during the development of Dictyostelium cells.

17.
Sci Total Environ ; 653: 264-273, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30412871

RESUMO

The attention of current work was on the fabrication of effective nanoadsorbent of hydroxyapatite (HAp) for the controlled release of atrazine (ATZ) formulation. The ATZ-HAp complex (ATZ@HAp) was able to inhibit the growth of Brassica sp. under in situ conditions. This developed methodology aspires to cease the agricultural runoffs of ATZ applied with the HAp adjuvant and ensure their effective functioning. The efficacy of the protocol was mainly accomplished by adsorbing ATZ over the surface of HAp NPs that restricted its premature runoff and promoted the prolonged herbicidal efficiency. The influence of fundamental parameters i.e., HAp dose, ATZ dose and initial pH on the adsorption process was investigated systematically. The suitability of ATZ@HAp complex for real world application was adjudged after proofing its toxicological behaviour and its role in Zea mays plantations. The complex was found to be non-toxic and nurturing due to its phosphate rich nature. Further investigations of ATZ@HAp complex and its effect on the non-target species will help in establishing an effective framework for their commercial use in agricultural practices.

18.
PLoS Genet ; 14(11): e1007775, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30388110

RESUMO

Development of a functional musculoskeletal system requires coordinated generation of muscles, bones, and tendons. However, how axial tendon cells (tenocytes) are generated during embryo development is still poorly understood. Here, we show that axial tenocytes arise from the sclerotome in zebrafish. In contrast to mouse and chick, the zebrafish sclerotome consists of two separate domains: a ventral domain and a previously undescribed dorsal domain. While dispensable for sclerotome induction, Hedgehog (Hh) signaling is required for the migration and maintenance of sclerotome derived cells. Axial tenocytes are located along the myotendinous junction (MTJ), extending long cellular processes into the intersomitic space. Using time-lapse imaging, we show that both sclerotome domains contribute to tenocytes in a dynamic and stereotypic manner. Tenocytes along a given MTJ always arise from the sclerotome of the adjacent anterior somite. Inhibition of Hh signaling results in loss of tenocytes and enhanced sensitivity to muscle detachment. Together, our work shows that axial tenocytes in zebrafish originate from the sclerotome and are essential for maintaining muscle integrity.

19.
Mol Cell ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30472187

RESUMO

The post-translational modification of key residues at the C-terminal domain of RNA polymerase II (RNAP2-CTD) coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes. Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases, including cancer. We show that, among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 results in accumulation of RNAP2 at transcription start sites, reduced gene expression, and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells.

20.
Front Oncol ; 8: 445, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30370252

RESUMO

Exosomes produced by tumor cells have been shown to reprogram functions of human immune cells. Molecular cargos of exosomes isolated from supernatants of HPV(+) and HPV(-) head and neck cancer (HNC) cell lines or from HNC patients' plasma were compared. The exosome protein profiles resembled those of respective parent tumor cells. Only HPV(+) exosomes carried E6/E7, p16, and survivin. HPV(-) exosomes were negative for cyclin D1 and carried low p53 levels. Immunomodulatory molecules (TGF-ß, FasL, OX40, OX40L, and HSP70) were carried by HPV(+) and HPV(-) exosomes. These exosomes co-incubated with human T cells induced apoptosis and suppressed T cell activation and proliferation. HPV(-) exosomes suppressed DC maturation and expression of antigen processing machinery (APM) components. In contrast, HPV(+) exosomes promoted DC maturation and did not suppress expression of APM components in mature DCs. While DCs readily internalized exosomes, T lymphocytes resisted their uptake during the initial 12 h co-culture. Thus, HPV(+) exosomes capable of sustaining DC functions may play a key role in promoting anti-tumor immune responses thereby improving outcome in patients with HPV(+) cancers.

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