Publications by authors named "Maryam Yousefi"

78 Publications

A functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer.

Cancer Discov 2021 Feb 19. Epub 2021 Feb 19.

Department of Genetics, Stanford University School of Medicine

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multi-step process, however the importance and specific roles of many of these genes during tumor initiation, growth and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of forty-eight known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, while the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1325DOI Listing
February 2021

Improvement of biodiesel production from palm oil by co-immobilization of Thermomyces lanuginosa lipase and Candida antarctica lipase B: Optimization using response surface methodology.

Int J Biol Macromol 2021 Feb 28;170:490-502. Epub 2020 Dec 28.

Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

Candida antarctica lipase B (CALB) and Thermomyces lanuginose lipase (TLL) were co-immobilized on epoxy functionalized silica gel via an isocyanide-based multicomponent reaction. The immobilization process was carried out in water (pH 7) at 25 °C, rapidly (3 h) resulting in high immobilization yields (100%) with a loading of 10 mg enzyme/g support. The immobilized preparations were used to produce biodiesel by transesterification of palm oil. In an optimization study, response surface methodology (RSM) and central composite rotatable design (CCRD) methods were used to study the effect of five independent factors including temperature, methanol to oil ratio, t-butanol concentration and CALB:TLL ratio on the yield of biodiesel production. The optimum combinations for the reaction were CALB:TLL ratio (2.1:1), t-butanol (45 wt%), temperature (47 °C), methanol: oil ratio (2.3). This resulted in a FAME yield of 94%, very close to the predicted value of 98%.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.12.181DOI Listing
February 2021

Performance of photocatalytic ozonation process for pentachlorophenol (PCP) removal in aqueous solution using graphene-TiO nanocomposite (UV/G-TiO/O).

J Environ Health Sci Eng 2020 Dec 7;18(2):1083-1097. Epub 2020 Oct 7.

Department of Environmental Health Engineering, Health Sciences Research Center, Faculty of Health, Mazandaran University of Medical Sciences, Sari, Iran.

The aim of this study was to evaluate the efficiency of photocatalytic ozonation process using graphene-dioxide titanium nanocomposite in removing Pentachlorophenol (PCP) from aqueous solutions. In this study, nanocomposites with graphene to TiO(G/T) ratios of 1:10 and 1:20 were synthesized by hydrothermal method, and its characteristics were assessed using various analyses, SEM, XRD, FTIR, TEM, BET and TGA. In this process, the effects of parameters including O concentration (0.25-1.25 mg/L), nanocomposite concentration (50-500 mg/L), initial PCP concentration (10-100 mg/L), and time (10-60 min), were studied. The results showed that PCP removal efficiency was increased by decreasing solute concentration. Increasing nanocomposite dose to 100 mg/L was led to an increase in efficiency (99.1%), but then a decreasing trend was observed. Increasing the concentration of ozone, up to specific value, also enhanced the efficiency but then had a negative effect on process efficiency. Furthermore, the optimum ratio of the catalyst was determined to be 1:20. The highest efficiency of the process for initial pentachlorophenol concentration of 100 mg/L was obtained 98.82% in optimum conditions (catalyst dose of 100 mg/L and 60 min). It is concluded that the photocatalytic ozonation process using graphene-dioxide titanium nanocomposite had the highest efficiency in removal and mineralization of PCP.
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http://dx.doi.org/10.1007/s40201-020-00529-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721932PMC
December 2020

Cell culture demonstrates superior sensitivity over one step real time RT PCR and nested VP1 amplification for Enteroviruses.

J Virol Methods 2021 01 14;287:113994. Epub 2020 Oct 14.

Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Food Microbiology Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

This study evaluated and compared the sensitivity profile of routine cell culture, nested VP1 amplification and one step real time RT PCR for Enteroviruses. Serially diluted spiked samples of four model viruses (EV71, CVA16, CVB5 and PV1) and 32 true positive samples including Poliovirus (PV1 & PV3), Coxsackie virus (CVB5, CVB3, CVB1 & CVA4, 10, 16), Echovirus (Echo 6, 7, 11, 13, 18, 25 & 30) and Enterovirus 71 (E71), and 32 true negative stool samples were subjected to cell culture, nested RT PCR and one step real time RT PCR. The result of sensitivity test indicated superior sensitivity with one step real time RT PCR (75 %, 24/32) against cell culture (71.9 %, 23/32) and nested RT PCR (65.6 %, 21/32). The most specific test was cell culture (100 %, 32/32), followed by nested RT PCR (96.9 %, 31/32). Positive predictive values were 100 %: 23/23, 95.5 %; 21/22 and 88.9 %; 24/27, for cell culture, nested RT PCR and one step real time RT PCR, respectively, and one step real time RT PCR had the highest negative predictive value (78.4 %, 29/37). Overall result indicate relatively high analytical sensitivity with all the tests, suggesting superior performance by cell culture. Therefore, cell culture is the gold standard. However, considering intensive nature of cell cultures and prolong window for results, it is wise to consider one step real time RT PCR in routine diagnosis for its added advantages. Meanwhile, selecting a combination of tests can maximize detection, depending on the laboratory strength.
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http://dx.doi.org/10.1016/j.jviromet.2020.113994DOI Listing
January 2021

Porcine pancreas lipase as a green catalyst for synthesis of bis-4-hydroxy coumarins.

Bioorg Chem 2020 10 25;103:104139. Epub 2020 Jul 25.

Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran. Electronic address:

4-Hydroxycoumarins represents an important structural motif in life sciences molecules with remarkable biological properties. 4-Hydroxycoumarins are important precursors in the synthesis of organic compounds and critical pharmacophores in medicinal chemistry. One of the derivatives of this compound is biscoumarin, which has anticoagulant medicinal properties. Porcine pancreas lipase (PPL) has been used as an efficient green biocatalyst for the synthesis of bis-4-hydroxycoumarin compounds and expands the biocatalytic promiscuity of lipase in organic synthesis. Some aromatic aldehydes have been used in this investigation for screening and examining the ability of enzyme in knoevenagel condensation. Various parameters including temperature, solvent, and the amount of biocatalyst were investigated, ethanol, 45 °C and 10 mg of PPL gave rise to best yields. Bis-4-hydroxy coumarin compounds were synthesized under mild reaction conditions with high conversion yields (81-88%).
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http://dx.doi.org/10.1016/j.bioorg.2020.104139DOI Listing
October 2020

Soluble enzyme cross-linking via multi-component reactions: a new generation of cross-linked enzymes.

Chem Commun (Camb) 2020 Aug 22;56(67):9683-9686. Epub 2020 Jul 22.

Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

By using a isocyanide-based multi-component reaction for the immobilization of the soluble forms of Rhizomucor miehei lipase (RML) and Thermomyces lanuginosa lipase (TLL), the first step of enzyme aggregation or crystallization in the traditional methods of cross-linking was bypassed. High immobilization yields and specific activities were achieved for both lipases.
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http://dx.doi.org/10.1039/d0cc03429kDOI Listing
August 2020

An energy-landscape integrated analysis to evaluate agroecological scarcity.

Sci Total Environ 2020 Oct 5;739:139998. Epub 2020 Jun 5.

Metropolitan Laboratory of Ecology and Territory of Barcelona, IERMB, Autonomous University of Barcelona, 08193 Bellaterra, Spain. Electronic address:

Agrarian landscapes theoretically provide ecosystem services that meet the demands of a wide range of socioecological processes. Consequently, any landscape agroecology approach must tackle the dynamic interaction of land-use distribution and associated social metabolism at different spatiotemporal scales. An agroecological scarcity case study explores how driven agricultural energy flows interact with landscape complexity in arid landscapes of 46 counties in the Qazvin Province (Iran). An Energy-Landscape Integrated Analysis (ELIA) was performed to correlate the energy reinvestment (E) and energy redistribution (I) present within the social metabolism network, with landscape complexity (Le) measured in terms of spatial patterns and related ecological processes. As well, a cluster analysis was run to establish agrarian landscape typologies based on the ELIA indicators. The results of this study provide an explicit sketch of the four strategies that society in Qazvin Province has developed within the dry environments that sustain it. Our findings confirm the hypothesis that there is a positive relationship between optimizing non-dissipative internal energy loops and landscape complexity, which can explain agroecosystem sustainability. This research enables us to define spatially informed agroecological transitions from a territorially explicit socioecological perspective and will make a significant contribution to decisions on agricultural policies given different land-use strategies, especially under scenarios of ecological scarcity.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139998DOI Listing
October 2020

Molecular characterization of non-polio enteroviruses isolated from children with acute flaccid paralysis in IRAN, 2015-2018.

Virus Genes 2020 Oct 25;56(5):531-536. Epub 2020 May 25.

Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

In addition to polioviruses, non-polio enteroviruses (NPEVs) are frequently isolated from patients with acute flaccid paralysis (AFP) worldwide. In polio-free countries, there have been expectations that with disappearing wild poliovirus from the community, the rate of AFP would decrease, but the increasing number of AFP cases proved this notion to be wrong. There are speculations that NPEVs might be the cause of increasing AFP rate. The aim of this study was to investigate frequency, genetic diversity, circulation patterns of NPEVs isolated from AFP cases in Iran from 2015 to 2018. Fifty-three NPEVs were isolated from stool specimens of AFP cases during four years of AFP surveillance. Nested PCR and VP1 sequencing revealed 20 NPEV types in which Echovirus 3 (13.2%), Echovirus 6 (13.2%), Echovirus 7 (7.5%), Echovirus 13 (7.5%) and Echovirus 21 (7.5%) were the most frequent. Coxsackie B viruses were isolated for the first time in AFP cases in Iran. The phylogenetic analysis of Echovirus 3 and Echovirus 6 revealed that Iranian echovirus strains belonged to the same cluster, indicating these viruses have been circulating in Iran for a long time. Compared to global Echovirus 3 and Echovirus 6 references, Echovirus 3 and Echovirus 6 strains detected in this study were closely related to Indian and Malaysia strains, respectively. The results of this study demonstrated a wide variety of NPEV types in Iranian patients, some of which had not been reported in previous studies. Moreover, this study highlights the need for NPEV surveillance in AFP cases.
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http://dx.doi.org/10.1007/s11262-020-01768-yDOI Listing
October 2020

CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities.

Nature 2020 04 11;580(7801):136-141. Epub 2020 Mar 11.

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Cancer genomics studies have identified thousands of putative cancer driver genes. Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.
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http://dx.doi.org/10.1038/s41586-020-2099-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368463PMC
April 2020

Fine Modulation of the Catalytic Properties of Lipase Driven by Different Immobilization Strategies for the Selective Hydrolysis of Fish Oil.

Molecules 2020 Jan 27;25(3). Epub 2020 Jan 27.

'Nanobiotechnology for Life Sciences' Group, Department of Chemistry in Pharmaceutical Sciences Dept., Faculty of Pharmacy, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal s/n, E-28040 Madrid, Spain.

Functional properties of each enzyme strictly depend on immobilization protocol used for linking enzyme and carrier. Different strategies were applied to prepare the immobilized derivatives of lipase (RML) and chemically aminated RML (NH-RML). Both RML and NH-RML forms were covalently immobilized on glyoxyl sepharose (Gx-RML and Gx-NH-RML), glyoxyl sepharose dithiothreitol (Gx-DTT-RML and Gx-DTT-NH-RML), activated sepharose with cyanogen bromide (CNBr-RML and CNBr-NH-RML) and heterofunctional epoxy support partially modified with iminodiacetic acid (epoxy-IDA-RML and epoxy-IDA-NH-RML). Immobilization varied from 11% up to 88% yields producing specific activities ranging from 0.5 up to 1.9 UI/mg. Great improvement in thermal stability for Gx-DTT-NH-RML and epoxy-IDA-NH-RML derivatives was obtained by retaining 49% and 37% of their initial activities at 70 °C, respectively. The regioselectivity of each derivative was also examined in hydrolysis of fish oil at three different conditions. All the derivatives were selective between cis-5,8,11,14,17-eicosapentaenoic acid (EPA) and cis-4,7,10,13,16,19-docosahexaenoic acid (DHA) in favor of EPA. The highest selectivity (32.9 folds) was observed for epoxy-IDA-NH-RML derivative in the hydrolysis reaction performed at pH 5 and 4 °C. Recyclability study showed good capability of the immobilized biocatalysts to be used repeatedly, retaining 50-91% of their initial activities after five cycles of the reaction.
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http://dx.doi.org/10.3390/molecules25030545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037125PMC
January 2020

Vaccine-Derived Poliovirus Infection among Patients with Primary Immunodeficiency and Effect of Patient Screening on Disease Outcomes, Iran.

Emerg Infect Dis 2019 11;25(11):2005-2012

Patients with immunodeficiency-associated vaccine-derived poliovirus (iVDPV) are potential poliovirus reservoirs in the posteradication era that might reintroduce polioviruses into the community. We update the iVDPV registry in Iran by reporting 9 new patients. In addition to national acute flaccid paralysis surveillance, cases were identified by screening nonparalyzed primary immunodeficiency (PID) patients. Overall, 23 iVDPV patients have been identified since 1995. Seven patients (30%) never had paralysis. Poliovirus screening accelerated the iVDPV detection rate in Iran after 2014.The iVDPV infection rate among nonparalyzed patients with adaptive PID was 3.1% (7/224), several folds higher than previous estimates. Severe combined immunodeficiency patients had the highest risk for asymptomatic infection (28.6%) compared with other PIDs. iVDPV2 emergence has decreased after the switch from trivalent to bivalent oral poliovirus vaccine in 2016. However, emergence of iVDPV1 and iVDPV3 continued. Poliovirus screening in PID patients is an essential step in the endgame of polio eradication.
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http://dx.doi.org/10.3201/eid2511.190540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810208PMC
November 2019

Thiolated chitosan-lauric acid as a new chitosan derivative: Synthesis, characterization and cytotoxicity.

Int J Biol Macromol 2019 Sep 19;136:823-830. Epub 2019 Jun 19.

Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Chitosan as a biopolymer is an attractive vehicle for biomedical applications due to its unique characteristics. In order to improve chitosan's physicochemical features, chemical modification has been carried out to make it more suitable for such approaches. The aim of this study was to prepare and evaluate thiolated chitosan-lauric acid as a new chitosan derivative for biomedical use. Lauric acid was introduced to chitosan via stable amide bond between carboxylic acid group of fatty acid and the amine in the chitosan and thiolation was carried out using thioglycolic acid. Resulted polymers were characterized by FTIR, H NMR and TGA. Moreover, cell viability assessment of new derivative was performed using MTT method. FTIR and H NMR results showed that both substitution reactions were successfully completed. Furthermore, new synthesized polymer had no significant cytotoxicity against normal gingiva human cells (HGF1-PI 1).These findings confirm that this new derivative can be introduced as a suitable polymer for biomedical purposes such as mucosal drug delivery.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.06.132DOI Listing
September 2019

Piperazine: An excellent catalyst for the synthesis of 2-amino-3-cyano-4H-pyrans derivatives in aqueous medium.

Bioorg Chem 2018 12 23;81:326-333. Epub 2018 Aug 23.

Department of Chemistry, College of Sciences, Guilan University, Rasht 41335-19141, Iran. Electronic address:

An improved, forthright, and highly efficient one-pot synthesis of a wide range of pharmaceutically exciting diverse kind of functionalized 2-amino-3-cyano-4H-pyrans and especially bis-pyrans compounds is developed using piperazine as a low-cost and environmentally benign commercially available basic catalyst in aqueous media. The attractive features of this process are simple procedure, short reaction times, high yields, no column chromatographic separation and commercial availability and recyclability of the catalyst. Also, piperazine can catalyze the synthesis of the target compounds on a larger scale. Furthermore, rational mechanism was suggested via GC-Mass analysis of the trapped intermediates.
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http://dx.doi.org/10.1016/j.bioorg.2018.08.026DOI Listing
December 2018

Covalent immobilization of laccase by one pot three component reaction and its application in the decolorization of textile dyes.

Int J Biol Macromol 2018 Dec 17;120(Pt A):144-151. Epub 2018 Aug 17.

Bioprocess Engineering Department, Institute of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran.

In present study, laccase from Myceliophthora thermophila, was immobilized on epoxy-functionalized silica via one-pot three component reaction as a novel and efficient method for immobilization. The results revealed immobilization of 50 mg of M. thermophila laccase on 1 g of the supports in presence of cyclohexyl isocyanide after 12 h of incubation. The immobilized enzyme exhibited notable activity (50 U/g) with improved stability toward pH, temperature and organic solvents. Laccase derivative was used for decolorization of five textile dyes (acid orange 156, acid red 52, coomassie brilliant blue, methyl violet, malachite green) with or without the redox mediators such as 1-hydroxybenzotriazole (HBT), catechol, syringaldehyde and N-hydroxyphthalimide (HPT). The results showed that laccase/mediator systems were effective biocatalysts for the treatment of textile dyes.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.08.077DOI Listing
December 2018

Enteroviruses and Adenoviruses in stool specimens of paralytic children- can they be the cause of paralysis?

Iran J Microbiol 2018 Jun;10(3):194-201

Virology Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Background And Objectives: Acute flaccid paralysis (AFP) is a complicated clinical syndrome with a wide range of potential etiologies. Several infectious agents including different virus families have been isolated from AFP cases. In most surveys, Non-polio Enteroviruses (NPEVs) have been detected as main infectious agents in AFP cases; however, there are also some reports about isolation in these patients. In this study, NPEVs and in stool specimens of AFP cases with or without Residual Paralysis (RP) with negative results for poliovirus are investigated.

Materials And Methods: Nucleic acid extractions from 55 AFP cases were examined by nested PCR or semi-nested PCR with specific primers to identify NPEVs or , respectively. VP1 (for ) and hexon (for ) gene amplification products were sequenced and compared with available sequences in the GenBank.

Results: From 55 fecal (37 RP+ and 18 RP-) specimens, 7 NPEVs (12.7%) (2 cases in RP+) and 7 (12.7%) (4 cases in RP+) were identified. types 3, 17 and 30, A8, and 80 were among NPEVs and type 2 and 41 were also identified.

Conclusion: Our finding shows that NPEVs and may be isolated from the acute flaccid paralyses but there is no association between the residual paralyses and virus detection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087694PMC
June 2018

Isolation and identification of specific bacteriophage against enteropathogenic Escherichia coli (EPEC) and in vitro and in vivo characterization of bacteriophage.

FEMS Microbiol Lett 2018 08;365(16)

Department of Biostatistics, Faculty of medical sciences, Tarbiat Modares University, Tehran 3551713146, Iran.

In recent years, the increasing resistance of enteropathogenic Escherichia coli (EPEC) to commonly used antibiotics has made it difficult to choose the best treatment option. Bacteriophage therapy could be a potent alternative to antibiotic therapy for antibiotic-resistant bacteria. The aim of the present study was to isolate and identify a specific bacteriophage against EPEC and characterize bacteriophage in vitro and in vivo. The specific bacteriophage was isolated, and the effect of phage therapy on 48 mice (Balb/c) was investigated. Animals were divided into six groups, including A: PBS (negative control); B: bacteria (positive control); C: bacteria + ciprofloxacin (after 24 h); D: bacteria + bacteriophage (after 24 h); E: bacteria + ciprofloxacin + bacteriophage (after 24 h) and F: bacteriophage + bacteria (after 24 h). Specific bacteriophage against EPEC was isolated from hospital sewage. The bacteriophage had an icosahedral head (120 nm) and a tail (138 nm). The single dose of the bacteriophage (2 × 109 pfu ml-1) was able to control the infection. Unfortunately, because of the misuse of antibiotics by EPEC infected patients, the antibiotic resistant bacteria will become prevalent in the future and the treatment of EPEC infection is going to become more difficult than ever.
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http://dx.doi.org/10.1093/femsle/fny136DOI Listing
August 2018

A novel approach for bioconjugation of Rhizomucor miehei lipase (RML) onto amine-functionalized supports; Application for enantioselective resolution of rac-ibuprofen.

Int J Biol Macromol 2018 Oct 30;117:523-531. Epub 2018 May 30.

Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.

Since the amine groups are highly reactive toward various functional moieties, the formation of covalent bonds between a biomolecule and an insoluble amine-functionalized support is the most frequently used technique in immobilization protocols. A new approach based on the Ugi four-component reaction was used for immobilization of Rhizomucor miehei lipase (RML) as a model enzyme on amine-functionalized silica and silica nanoparticles (SBA-15). For this, the amine-modified supports were prepared and the structural properties of the functionalized supports, prior to and after functionalization were characterized by using IR, SEM, TGA, DTA, TEM. Immobilization of RML on the aminated carriers was performed under extremely mild conditions (25 °C, pH 7). The results revealed very rapid immobilization of 150 and 200 mg of RML on 1 g of silica-NH and SBA-NH, respectively, producing 95-100% of immobilization yield. The specific activity and optimum pH of the immobilized preparations and the effect of temperature and co-solvents on their stabilities as well as the reusability of the derivatives were tested. The immobilized preparations were also used as enantioselective catalyst in kinetic resolution of racemic ibuprofen. Among them, Silica-RML showed the best selectivity with 92.2% enantiomeric excess (ee) and E-value of 33.9.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.05.218DOI Listing
October 2018

Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells.

Stem Cell Reports 2018 03 1;10(3):703-711. Epub 2018 Mar 1.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool. Cell-autonomous activity of mechanistic target of rapamycin complex 1 (mTORC1) governs the sensitivity of reserve ISCs to injury. CR inhibits mTORC1 in these cells, protecting them against DNA damage, while mTORC1 stimulation, either genetically or through nutrient sensing, sensitizes reserve ISCs to injury, thus compromising regeneration of the epithelium. These data delineate a critical role for mTORC1 in epithelial regeneration and inform clinical strategies based on nutrient modulation.
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http://dx.doi.org/10.1016/j.stemcr.2018.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919411PMC
March 2018

Biotransformation of two furanocoumarins by the fungi species Aspergillus sp. PTCC 5266 and Aspergillus niger PTCC 5010.

Nat Prod Res 2019 Mar 22;33(6):835-842. Epub 2018 Feb 22.

c Nanobiotechnology Research Center , Avicenna Research Institute, ACECR , Tehran , Iran.

The microbial transformations of peucedanin and oreoselon by the fungi Aspergillus niger and Aspergillus sp. were investigated for the first time. Incubation of peucedanin with A. niger yielded a new hydroxylated metabolite with high yield (56%), which was characterized as 2-(1-hydroxypropan-2-yl)-3-methoxy-7H-furo[3,2-g]chromen-7-one. Oreoselon was converted to a new reduced metabolite methyl 3-(2,3-dihydro-6-hydroxy-2-isopropyl-3-oxobenzofuran-5-yl)propanoate in biotransformation by Aspergillus sp. The structures of the metabolites were determined by spectroscopic methods including IR, EI-MS, H NMR, C NMR, and elemental analysis.
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http://dx.doi.org/10.1080/14786419.2017.1413563DOI Listing
March 2019

Immobilization of laccase on epoxy-functionalized silica and its application in biodegradation of phenolic compounds.

Int J Biol Macromol 2018 Apr 21;109:443-447. Epub 2017 Dec 21.

Novozymes A/S, Krogshøjvej 36, 2880 Bagsværd, Copenhagen, Denmark.

A novel method of laccase immobilization on epoxy-functionalized silica particles was developed. Laccase from Myceliophthora thermophila was covalently immobilized onto epoxy-functionalized matrix by nucleophilic attack of amino groups of laccase to epoxy groups of the support. The enzyme loading on the support was about 30 mg/g under the optimum conditions (pH 4.5, 24 h). The effect of pH, temperature and organic solvent on immobilized enzyme activity was determined and compared with those of free enzyme. In general the immobilized enzyme was found to be stabilized compared to the free enzyme. Lineweaver-Burk plots were used to calculate kinetic parameters for ABTS oxidation. K values were 24.0 and 25.3 μM while v values were 10.0 and 1.6 μM min for free and immobilized laccase, respectively. The performance of the biocatalyst was evaluated by the degradation of phenolic compounds including phenol, p-chlorophenol and catechol. The removal efficiency of catechol by immobilized laccase was about 95% after 2 h.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.12.102DOI Listing
April 2018

Accuracy of Endoscopy in Predicting the Depth of Mucosal Injury Following Caustic Ingestion; a Cross-Sectional Study.

Emerg (Tehran) 2017 22;5(1):e72. Epub 2017 Jun 22.

Hearing Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Esophagogastroduodenoscopy (EGD) is currently considered as the primary method of determining the degree of mucosal injury following caustic ingestion. The present study aimed to evaluate the screening performance characteristics of EGD in predicting the depth of gastrointestinal mucosal injuries following caustic ingestion.

Methods: Adult patients who were referred to emergency department due to ingestion of corrosive materials, over a 7-year period, were enrolled to this diagnostic accuracy study. Sensitivity, specificity, positive and negative predictive values as well as negative and positive likelihood ratios of EGD in predicting the depth of mucosal injury was calculated using pathologic findings as the gold standard.

Results: 54 cases with the mean age of 35 ± 11.2 years were enrolled (59.25% male). Primary endoscopic results defined 28 (51.85%) cases as second grade and 26 (48.14%) as third grade of mucosal injury. On the other hand, pathologic findings reported 21 (38.88%) patients as first grade, 14 (25.92%) as second, and 19 patients (35.18%) as third grade. Sensitivity and specificity of endoscopy for determining grade II tissue injury were 50.00 (23.04-76.96) and 47.50 (31.51-63.87), respectively. These measures were 100.00 (82.35-100) and 80.00 (63.06-91.56), respectively for grade III. Accuracy of EGD was 87.03% for grade III and 48.14% for grade II.

Conclusion: Based on the findings of the present study, endoscopic grading of caustic related mucosal injury based on the Zargar's classification has good accuracy in predicting grade III (87%) and fail accuracy in grade II injuries (48%). It seems that we should be cautious in planning treatment for these patients solely based on endoscopic results.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703749PMC
June 2017

Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy.

Sci Rep 2017 10 17;7(1):13373. Epub 2017 Oct 17.

Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

Our recent findings strongly support the idea of PLAC1 being as a potential immunotherapeutic target in prostate cancer (PCa). Here, we have generated and evaluated an anti-placenta-specific1 (PLAC1)-based antibody drug conjugate (ADC) for targeted immunotherapy of PCa. Prostate cancer cells express considerable levels of PLAC1. The Anti-PLAC1 clone, 2H12C12, showed high reactivity with recombinant PLAC1 and selectivity recognized PLAC1 in prostate cancer cells but not in LS180 cells, the negative control. PLAC1 binding induced rapid internalization of the antibody within a few minutes which reached to about 50% after 15 min and almost completed within an hour. After SN38 conjugation to antibody, a drug-antibody ratio (DAR) of about 5.5 was achieved without apparent negative effect on antibody affinity to cell surface antigen. The ADC retained intrinsic antibody activity and showed enhanced and selective cytotoxicity with an IC50 of 62 nM which was about 15-fold lower compared to free drug. Anti-PLAC1-ADC induced apoptosis in human primary prostate cancer cells and prostate cell lines. No apparent cytotoxic effect was observed in in vivo animal safety experiments. Our newly developed anti-PLAC1-based ADCs might pave the way for a reliable, efficient, and novel immunotherapeutic modality for patients with PCa.
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http://dx.doi.org/10.1038/s41598-017-13682-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645454PMC
October 2017

The histone variant macroH2A confers functional robustness to the intestinal stem cell compartment.

PLoS One 2017 21;12(9):e0185196. Epub 2017 Sep 21.

Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.

A stem cell's epigenome directs cell fate during development, homeostasis, and regeneration. Epigenetic dysregulation can lead to inappropriate cell fate decisions, aberrant cell function, and even cancer. The histone variant macroH2A has been shown to influence gene expression, guide cell fate, and safeguard against genotoxic stress. Interestingly, mice lacking functional macroH2A histones (hereafter referred to as macroH2A DKO) are viable and fertile; yet suffer from increased perinatal death and reduced weight and size compared to wildtype (WT). Here, we ask whether the ostensible reduced vigor of macroH2A DKO mice extends to intestinal stem cell (ISC) function during homeostasis, regeneration, and oncogenesis. Lgr5-eGFP-IRES-CreERT2 or Hopx-CreERT2::Rosa26-LSL-tdTomato ISC reporter mice or the C57BL/6J-Apcmin/J murine intestinal adenoma model were bred into a macroH2A DKO or strain-matched WT background and assessed for ISC functionality, regeneration and tumorigenesis. High-dose (12Gy) whole-body γ-irradiation was used as an injury model. We show that macroH2A is dispensable for intestinal homeostasis and macroH2A DKO mice have similar numbers of active crypt-base columnar ISCs (CBCs). MacroH2A DKO intestine exhibits impaired regeneration following injury, despite having significantly more putative reserve ISCs. DKO reserve ISCs disproportionately undergo apoptosis compared to WT after DNA damage infliction. Interestingly, a macroH2A DKO background does not significantly increase tumorigenesis in the Apcmin model of intestinal adenoma. We conclude that macroH2A influences reserve ISC number and function during homeostasis and regeneration. These data suggest macroH2A enhances reserve ISC survival after DNA damage and thus confers functional robustness to the intestinal epithelium.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608326PMC
October 2017

Epidemiologic Features and Outcomes of Caustic Ingestions; a 10-Year Cross-Sectional Study.

Emerg (Tehran) 2017 2;5(1):e56. Epub 2017 Feb 2.

Clinical Research Development Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Introduction: Caustic ingestions are among the most prevalent causes of toxic exposure. The present 10-year survey aimed to evaluate the epidemiologic features and outcomes of caustic ingestion cases presenting to emergency department.

Methods: This is a retrospective cross-sectional study on patients who were admitted to a referral toxicology center during 2004 to 2014, following caustic ingestion. Baseline characteristics, presenting chief complaint, severity of mucosal injury, complications, imaging and laboratory findings as well as outcomes (need for ICU admission, need for surgery, mortality) were recorded, reviewing patients' medical profile, and analyzed using SPSS 22.

Results: 348 patients with mean age of 37.76 ± 17.62 years were studied (55.6% male). The mean amount of ingested caustic agent was 106.69 ± 100.24 mL (59.2 % intentional). Intentional ingestions (p < 0.0001), acidic substance (p = 0.054), and higher volume of ingestion (p = 0.021) were significantly associated with higher severity of mucosal damage. 28 (8%) cases had died, 53 (15.2%) were admitted to ICU, and 115 (33%) cases underwent surgery.

Conclusion: It seems that, suicidal intention, higher grade of mucosal injury, higher volume of ingestion, lower level of consciousness, lower serum pH, and higher respiratory rate are among the most important predictors of need for ICU admission, need for surgery, and mortality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585826PMC
February 2017

Hierarchy and Plasticity in the Intestinal Stem Cell Compartment.

Trends Cell Biol 2017 10 18;27(10):753-764. Epub 2017 Jul 18.

Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Somatic stem cells maintain tissue homeostasis by organizing themselves in such a way that they can maintain proliferative output while simultaneously protecting themselves from DNA damage that may lead to oncogenic transformation. There is considerable debate about how such stem cell compartments are organized. Burgeoning evidence from the small intestine and colon provides support for a two-stem cell model involving an actively proliferating but injury-sensitive stem cell and a rare, injury-resistant pool of quiescent stem cells. Parallel with this evidence, recent studies have revealed considerable plasticity within the intestinal stem cell (ISC) compartment. We discuss the evidence for plasticity and hierarchy within the ISC compartment and how these properties govern tissue regeneration and contribute to oncogenic transformation leading to colorectal cancers.
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http://dx.doi.org/10.1016/j.tcb.2017.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612891PMC
October 2017

Molecular typing of non-polio enteroviruses isolated from acute flaccid paralysis cases in Iran from 2010 to 2015.

Virol Sin 2017 Jun;32(3):249-252

National Polio Laboratory, Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, 14716-13151, Iran.

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http://dx.doi.org/10.1007/s12250-017-3945-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598875PMC
June 2017

Optimized protocol for soluble prokaryotic expression, purification and structural analysis of human placenta specific-1(PLAC1).

Protein Expr Purif 2017 05 16;133:139-151. Epub 2017 Mar 16.

Nanobiotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran; Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Placenta specific -1 (PLAC1) has been recently introduced as a small membrane-associated protein mainly involved in placental development. Expression of PLAC1 transcript has been documented in almost one hundred cancer cell lines standing for fourteen distinct cancer types. The presence of two disulfide bridges makes difficult to produce functional recombinant PLAC1 in soluble form with high yield. This limitation also complicates the structural studies of PLAC1, which is important for prediction of its physiological roles. To address this issue, we employed an expression matrix consisting of two expression vectors, five different E. coli hosts and five solubilization conditions to optimize production of full and truncated forms of human PLAC1. The recombinant proteins were then characterized using an anti-PLAC1-specific antibody in Western blotting (WB) and enzyme linked immunosorbent assay (ELISA). Structure of full length protein was also investigated using circular dichroism (CD). We demonstrated the combination of Origami™ and pCold expression vector to yield substantial amount of soluble truncated PLAC1 without further need for solubilization step. Full length PLAC1, however, expressed mostly as inclusion bodies with higher yield in Origami™ and Rosetta2. Among solubilization buffers examined, buffer containing Urea 2 M, pH 12 was found to be more effective. Recombinant proteins exhibited excellent reactivity as detected by ELISA and WB. The secondary structure of full length PLAC1 was considered by CD spectroscopy. Taken together, we introduced here a simple, affordable and efficient expression system for soluble PLAC1 production.
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http://dx.doi.org/10.1016/j.pep.2017.03.011DOI Listing
May 2017

Msi RNA-binding proteins control reserve intestinal stem cell quiescence.

J Cell Biol 2016 Nov 31;215(3):401-413. Epub 2016 Oct 31.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Regeneration of the intestinal epithelium is driven by multiple intestinal stem cell (ISC) types, including an active, radiosensitive Wnt ISC that fuels turnover during homeostasis and a reserve, radioresistant Wnt ISC capable of generating active Wnt ISCs. We examined the role of the Msi family of oncoproteins in the ISC compartment. We demonstrated that Msi proteins are dispensable for normal homeostasis and self-renewal of the active ISC, despite their being highly expressed in these cells. In contrast, Msi proteins are required specifically for activation of reserve ISCs, where Msi activity is both necessary and sufficient to drive exit from quiescence and entry into the cell cycle. Ablation of Msi activity in reserve ISCs rendered the epithelium unable to regenerate in response to injury that ablates the active stem cell compartment. These findings delineate a molecular mechanism governing reserve ISC quiescence and demonstrate a necessity for the activity of this rare stem cell population in intestinal regeneration.
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http://dx.doi.org/10.1083/jcb.201604119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100293PMC
November 2016

Primary retroperitoneal mature cystic teratoma in an adult: A case report.

Int J Surg Case Rep 2016 11;28:285-288. Epub 2016 Oct 11.

Clinical Research Development Center of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Background: Mature cystic teratoma is one of the most common tumors of the ovaries; however, primary retroperitoneal lesions are rare entities in adults.

Case Summary: We report a case of a 33 year-old woman noticing a mass in her epigastric and left upper abdominal region without any specific signs and symptoms. Radiological evaluation revealed a retroperitoneal mass with extension from the posterior aspect of the pancreas to the pelvic cavity, composed of calcifications and cystic elements.

Conclusion: The tumor was resected through a midline laparotomy and the pathology report confirmed the diagnosis of a mature cystic teratoma with no evidence of malignancy or immature components.
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http://dx.doi.org/10.1016/j.ijscr.2016.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072139PMC
October 2016

Vaccine-Derived Polioviruses and Children with Primary Immunodeficiency, Iran, 1995-2014.

Emerg Infect Dis 2016 10;22(10):1712-9

Widespread use of oral poliovirus vaccine has led to an ≈99.9% decrease in global incidence of poliomyelitis (from ≈350,000 cases in 1988 to 74 cases in 2015) and eradication of wild-type poliovirus serotypes 2 and 3. However, patients with primary immunodeficiency might shed vaccine-derived polioviruses (VDPVs) for an extended period, which could pose a major threat to polio eradication programs. Since 1995, sixteen VDPV populations have been isolated from 14 patients with immunodeficiency in Iran. For these patients, vaccine-associated paralysis, mostly in >1 extremity, was the first manifestation of primary immunodeficiency. Seven patients with humoral immunodeficiency cleared VDPV infection more frequently than did 6 patients with combined immunodeficiencies. Our results raise questions about manifestations of VDPVs in immunodeficient patients and the role of cellular immunity against enterovirus infections. On the basis of an association between VDPVs and immunodeficiency, we advocate screening of patients with primary immunodeficiency for shedding of polioviruses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038407PMC
http://dx.doi.org/10.3201/eid2210.151071DOI Listing
October 2016