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Publications (10 of 15) Show all publications
Manukyan, L., Dunder, L., Lind, P. M., Bergsten, P. & Lejonklou, M. H. (2019). Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring. Environmental Research, 172, 127-136
Open this publication in new window or tab >>Developmental exposure to a very low dose of bisphenol A induces persistent islet insulin hypersecretion in Fischer 344 rat offspring
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 172, p. 127-136Article in journal (Refereed) Published
Abstract [en]

Background: In children with obesity, accentuated insulin secretion has been coupled with development of type 2 diabetes mellitus (T2DM). Bisphenol A (BPA) is a chemical with endocrine- and metabolism-disrupting properties which can be measured in a majority of the population. Exposure to BPA has been associated with the development of metabolic diseases including T2DM.

Objective: The aim of this study was to investigate if exposure early in life to an environmentally relevant low dose of BPA causes insulin hypersecretion in rat offspring.

Methods: Pregnant Fischer 344 rats were exposed to 0.5 (BPA0.5) or 50 (BPA50) jig BPA/kg BW/day via drinking water from gestational day 3.5 until postnatal day 22. Pancreata from dams and 5- and 52-week-old offspring were procured and islets were isolated by collagenase digestion. Glucose-stimulated insulin secretion and insulin content in the islets were determined by ELISA.

Results: Basal (5.5 mM glucose) islet insulin secretion was not affected by BPA exposure. However, stimulated (11 mM glucose) insulin secretion was enhanced by about 50% in islets isolated from BPA0.5-exposed 5- and 52 week-old female and male offspring and by 80% in islets from dams, compared with control. In contrast, the higher dose, BPA50, reduced stimulated insulin secretion by 40% in both 5- and 52-week-old female and male offspring and dams, compared with control.

Conclusion: A BPA intake 8 times lower than the European Food Safety Authority's (EFSA's) current tolerable daily intake (TDI) of 4 mu g/kg BW/day of BPA delivered via drinking water during gestation and early development causes islet insulin hypersecretion in rat offspring up to one year after exposure. The effects of BPA exposure on the endocrine pancreas may promote the development of metabolic disease including T2DM.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Keywords
Bisphenol A, Endocrine disruptor, Fischer 344 rats, Insulin hypersecretion, Islets of Langerhans
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:uu:diva-387967 (URN)10.1016/j.envres.2019.02.009 (DOI)000468377500014 ()30782532 (PubMedID)
Funder
Swedish Research Council Formas, 216-2012-475Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 170504
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved
Manukyan, L., Pengfei, L., Gustafsson, S. & Mihranyan, A. (2019). Growth Media Filtration Using Nanocellulose-based Virus Removal Filter for Upstream Biopharmaceutical Processing. Journal of Membrane Science, 572, 464-474
Open this publication in new window or tab >>Growth Media Filtration Using Nanocellulose-based Virus Removal Filter for Upstream Biopharmaceutical Processing
2019 (English)In: Journal of Membrane Science, ISSN 0376-7388, E-ISSN 1873-3123, Vol. 572, p. 464-474Article in journal (Refereed) Published
Abstract [en]

The feasibility of using nanocellulose-based mille-feuille filter paper for upstream applications in serum-free growth media filtration, i.e. Dulbecco’s modified Eagle’s medium (DMEM) and Luria-Bertani medium (LBM), was tested. The filter performance with respect to F.174 bacteriophage (28nm) removal as a model small-size virus was characterized for filters of varying thicknesses, i.e. 11 and 33 mu m, at varying operating pressures, i.e. 1 and 3bar. The filters demonstrated generally good model small-size virus removal properties with LRV = 5, especially for 33 mu m filters. The 33 mu m filters were more robust and exhibited better virus removal and throughput properties than 11 mu m filters, although their flux was generally lower. The performance of the 33 and 11 mu m nanocellulose-based filter papers was further verified for upscaled bioporcessing by 10-fold increase in the loading volume. The results of the present work show that the 33 mu m nanocellulose-based filter paper could be an interesting alternative for large volume cell culture medium filtration during upstream bioprocessing.

Keywords
Cell culture media, Phi Chi 174 bacteriophage, size-exclusion virus filtration, filter fouling, microorganism contamination
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-366416 (URN)10.1016/j.memsci.2018.11.002 (DOI)000453402100046 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0190Stiftelsen Olle Engkvist Byggmästare, 2015/717
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2020-01-29Bibliographically approved
Wu, L., Manukyan, L., Mantas, A. & Mihranyan, A. (2019). Nanocellulose-Based Nanoporous Filter Paper for Virus Removal Filtration of Human Intravenous Immunoglobulin. ACS APPLIED NANO MATERIALS, 2(10), 6352-6359
Open this publication in new window or tab >>Nanocellulose-Based Nanoporous Filter Paper for Virus Removal Filtration of Human Intravenous Immunoglobulin
2019 (English)In: ACS APPLIED NANO MATERIALS, ISSN 2574-0970, Vol. 2, no 10, p. 6352-6359Article in journal (Refereed) Published
Abstract [en]

Human intravenous immunoglobulin (IVIG) is a highly valuable plasma-derived biotherapeutic with several important clinical indications in primary and acquired immunodeficiencies as well as autoimmune diseases, especially neuropathies. Ensuring the viral safety of plasma-derived products, such as human WIG, is mandatory. Viral filtration is commonly used to affect viral removal in the manufacture of plasma products. Viral filtration of large volumes of a IVIG feed solution can take significant time, the required filter area can be large, and the resultant total cost of filtration is considerable. Therefore, there is a need for a high-capacity filter, which can process large volumes of plasma-derived biotherapeutic products within a short time at reduced cost. Here, we describe for the first time the performance of a nanocellulose-based virus removal filter paper in the processing of human IVIG, which has the potential to address the above- stated issues. The filter exhibited 5-6 log virus clearance of Phi X174 (28 nm; pI 6.6) or MS2 (27 nm; pI 3.9) phages during the filtration of spiked IVIG solutions (11 mg/mL, pH 4.9). To simulate real-life production conditions, filtration at 288 L/m(2), corresponding to 3 kg of protein/m(2), at 3 bar was undertaken. No substantial filter fouling was evident, with the flux remaining stable throughout filtration at 20-30 L/m(2).h. The predicted volumetric capacity V-max was >= 1700 L/m(2), which corresponds to the processing of >= 19 kg/m(2) of immunoglobulins. A number of characterization tests encompassing size-exclusion high-pressure liquid chromatography, dynamic light scattering, and polyacrylamide gel electrophoresis confirmed immunoglobulin integrity before and after filtration. This study has shown that a mille-feuille filter paper manufacturing process offers the possibility of producing cost-efficient viral removal filters with the required performance capabilities suitable for the processing of plasma-derived immunoglobulins and recombinant monoclonal antibodies.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
Keywords
plasma, immunoglobulin, size-exclusion filtration, mille-feuille filter paper, Cladophora cellulose
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-406180 (URN)10.1021/acsanm.9b01351 (DOI)000507667200031 ()
Funder
Knut and Alice Wallenberg Foundation, 2018.01141Swedish Research Council, 2016-05715EU, Horizon 2020
Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-06Bibliographically approved
Gustafsson, O., Manukyan, L., Gustafsson, S., Tummala, G. K., Zaman, S., Begum, A., . . . Mihranyan, A. (2019). Scalable and Sustainable Total Pathogen Removal Filter Paper for Point-of-Use Drinking Water Purification in Bangladesh. ACS SUSTAINABLE CHEMISTRY & ENGINEERING, 7(17), 14373-14383
Open this publication in new window or tab >>Scalable and Sustainable Total Pathogen Removal Filter Paper for Point-of-Use Drinking Water Purification in Bangladesh
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2019 (English)In: ACS SUSTAINABLE CHEMISTRY & ENGINEERING, ISSN 2168-0485, Vol. 7, no 17, p. 14373-14383Article in journal (Refereed) Published
Abstract [en]

This article describes for the first time the full cycle of development from raw material cultivation to real-life application of a truly sustainable and scalable filter paper material intended for point-of-use drinking water purification in Bangladesh. The filter paper, featuring tailored pathogen removal properties, is produced from nanocellulose extracted from Pithophora green macroalgae, growing locally in Bangladesh, a new unexploited resource that can address a global problem. We demonstrate that the Pithophora cellulose filter paper can be used as a total pathogen barrier to remove all types of infectious viruses and bacteria from water. The performance of the filter is validated using surrogate latex nanobeads, in vitro model viruses, and real-life water samples collected from the Turag River and Dhanmondi Lake in Dhaka, Bangladesh. Access to clean drinking water is a persistent problem in Bangladesh, affecting tens of millions of people every day. The mortality rate due to water-borne diarreal infections, including viral infections, among susceptible population groups, especially among children under age of 5, is still very high. The proposed solution can dramatically improve the quality of lives for millions of people in the entire Southeast Asian region including and beyond the borders of Bangladesh.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
Keywords
Pithophora algae cellulose, Cladophora algae cellulose, Water-borne infections, Viruses, Filtration
National Category
Water Engineering
Identifiers
urn:nbn:se:uu:diva-395692 (URN)10.1021/acssuschemeng.9b03905 (DOI)000484071600008 ()
Funder
Swedish Research Council, 2016-05715Knut and Alice Wallenberg Foundation, KAW 2013.0190
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2020-01-29Bibliographically approved
Manukyan, L., Padova, J. & Mihranyan, A. (2019). Virus removal filtration of chemically defined Chinese Hamster Ovary cells medium with nanocellulose-based size exclusion filter. Biologicals (Print), 59, 62-67
Open this publication in new window or tab >>Virus removal filtration of chemically defined Chinese Hamster Ovary cells medium with nanocellulose-based size exclusion filter
2019 (English)In: Biologicals (Print), ISSN 1045-1056, E-ISSN 1095-8320, Vol. 59, p. 62-67Article in journal (Refereed) Published
Abstract [en]

Sterility of bioreactors in biotherapeutic processing remains a significant challenge. Virus removal size-exclusion filtration is a robust and highly efficient approach to remove viruses. This article investigates the virus removal capacity of nanocellulose-based filter for upstream bioprocessing of chemically defined Chinese hamster ovary (CHO) cells medium containing Pluronic F-68 (PowerCHO (TM), Lonza) and supplemented with insulin-transferrinselenium (ITS) at varying process parameters. Virus retention was assessed by spiking ITS-supplemented PowerCHO (TM) medium with small-size Phi X174 phage (28 nm) as a surrogate for mammalian parvoviruses. The nanocellulose-based size exclusion filter showed high virus retention capacity (over 4 log(10)) and high flow rates (around 180 L m(-2) h(-1)). The filter had no impact on ITS supplements during filtration. It was further shown that the filtered PowerCHO (TM) medium supported cell culture growth with no impact on cell viability, morphology, and confluence. The results of this work show new opportunities in developing cost-efficient virus removal filters for upstream bioprocessing.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2019
Keywords
Mille-feuille filter paper, Upstream bioprocessing, Viral safety, Cell culture media, Steam sterilization
National Category
Nano Technology Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-387972 (URN)10.1016/j.biologicals.2019.03.001 (DOI)000469891500009 ()30871931 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationStiftelsen Olle Engkvist Byggmästare
Available from: 2019-06-27 Created: 2019-06-27 Last updated: 2020-01-31Bibliographically approved
Wu, L., Manukyan, L., Mantas, A. & Mihranyan, A. (2019). Virus removal nanofiltration of intravenous immunoglobulin using nanocellulose-based filter paper. In: : . Paper presented at Plasma Product Biotechnology.
Open this publication in new window or tab >>Virus removal nanofiltration of intravenous immunoglobulin using nanocellulose-based filter paper
2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Replacement therapy using plasma-derived Factor IX products is a life-saving treatment for patients with hemophilia B. Ensuring viral safety of plasma-derived Factor IX products is a critical issue during their bioprocessing. Although nanofiltration is an attractive method for clearing viruses from plasma-derived Factor IX products, it is not easy to implement in practice. Various large molecular weight protein impurities and/or soluble aggregates, which are not retained on sterilizing grade 0.2 μm filters, may cause filter fouling and thereby interrupt the manufacturing. Here, for the first time, the nanofiltration of coagulation factor IX-rich prothrombin complex concentrate is shown using a nanocellulose-based virus removal filter paper, aka the mille-feuille filter paper. Furthermore, a new method of soluble aggregate removal is developed. As a result, high product recovery and high virus clearance capacity are demonstrated. The mille-feuille filter paper has a tailored pore size in the nm-range in the region most suitable for targeted removal of soluble protein aggregates and small-size viruses from biologics solutions. The filter paper is produced according to traditional paper making technology and consists of 100% cellulose nanofibers. The mille-feuille filter paper offers new possibilities in developing cost-efficient and robust bioprocesses for manufacturing plasma-derived hemophilia products.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-395263 (URN)
Conference
Plasma Product Biotechnology
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2020-01-29Bibliographically approved
Stenlid, R., Manell, H., Halldin, M., Kullberg, J., Ahlström, H., Manukyan, L., . . . Forslund, A. (2018). High DPP-4 concentrations in adolescents are associated with low intact GLP-1. Journal of Clinical Endocrinology and Metabolism, 103(8), 2958-2966
Open this publication in new window or tab >>High DPP-4 concentrations in adolescents are associated with low intact GLP-1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 8, p. 2958-2966Article in journal (Refereed) Published
Abstract [en]

Context: Dipeptidyl Peptidase-4 (DPP-4) metabolizes glucagon-like peptide-1 (GLP-1) and increased DPP4 levels are associated with obesity and visceral adiposity in adults.

Objective: Investigating DPP-4 levels in adolescents and association with, firstly, circulating intact GLP-1 levels and glucose tolerance, secondly, BMI, and, thirdly visceral, subcutaneous and liver fat compartments.

Design: Cross-sectional study, July 2012 to April 2015.

Setting: Pediatric obesity clinic, Uppsala University Hospital.

Patients and participants: Children and adolescents with obesity (n=59) and lean controls (n=21), age 8-18.

Main outcome measures: BMI SDS, fasting plasma concentrations of DPP-4, total and intact GLP-1, fasting and OGTT concentrations of glucose and visceral (VAT) and subcutaneous (SAT) adipose tissue volumes and liver fat fraction.

Results: Plasma DPP-4 decreased with age both in obese (41 ng/ml per year) and lean subjects (48 ng/ml per year). Plasma DPP-4 was higher in males both in the obesity and lean group. When adjusting for age and sex, plasma DPP-4 was negatively associated with intact GLP-1 at fasting, B=-12.3, 95% CI [-22.9, -1.8] and during OGTT, B=-12.1, 95% CI [-22.5, -1.7]. No associations were found between DPP-4 and plasma glucose measured at fasting or after a 2-hour OGTT. Plasma DPP-4 was 19% higher in the obese subjects. Among adipose tissue compartments the strongest association was with VAT, B=0.05, 95% CI [-0.02, 0.12].

Conclusions: In adolescents, high plasma DPP-4 concentrations are associated with low proportion of intact GLP-1, high BMI, young age and male sex. The observed associations are compatible with an increased metabolism of GLP-1 in childhood obesity.

Place, publisher, year, edition, pages
Endocrine Society, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354234 (URN)10.1210/jc.2018-00194 (DOI)000442236900022 ()29850829 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153Swedish Diabetes Association, DIA 2016-146Ernfors Foundation, 160504Swedish Research Council, 2016-01040EXODIAB - Excellence of Diabetes Research in SwedenErik, Karin och Gösta Selanders Foundation
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2019-03-28Bibliographically approved
Gustafsson, O., Manukyan, L. & Mihranyan, A. (2018). High-Performance Virus Removal Filter Paper for Drinking Water Purification. Global Challenges, 2(7), Article ID 1800031.
Open this publication in new window or tab >>High-Performance Virus Removal Filter Paper for Drinking Water Purification
2018 (English)In: Global Challenges, ISSN 2056-6646, Vol. 2, no 7, article id 1800031Article in journal (Refereed) Published
Abstract [en]

Access to drinking water is one of the greatest global challenges today. In this study, the virus removal properties of mille‐feuille nanocellulose‐based filter papers of varying thicknesses from simulated waste water (SWW) matrix are evaluated for drinking water purification applications. Filtrations of standard SWW dispersions at various total suspended solid (TSS) content are performed, including spiking tests with 30 nm surrogate latex particles and 28 nm ΦX174 bacteriophages. Filter papers of thicknesses 9 and 29 µm are used, and the filtrations are performed at two different operational pressures, i.e., 1 and 3 bar. The presented data using SWW matrix show, for the first time, that a filter paper made from 100% nanocellulose has the capacity to efficiently remove even the smallest viruses, i.e., up to 99.9980–99.9995% efficiency, at industrially relevant flow rates, i.e., 60–500 L m−2 h−1, and low fouling, i.e., V max > 103–104 L m−2. The filter paper presented in this work shows great promise for the development of robust, affordable, and sustainable water purification systems.

Keywords
Cladophora sp. algae cellulose, drinking water, mille-feuille filter, nanocellulose, water purification
National Category
Water Engineering
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-365152 (URN)10.1002/gch2.201800031 (DOI)000439785900003 ()
Funder
Knut and Alice Wallenberg FoundationStiftelsen Olle Engkvist ByggmästareSwedish Research Council
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2020-01-29Bibliographically approved
Manukyan, L. & Mihranyan, A. (2018). Nanocellulose-based size exclusion filters as an efficient and convenient virus barrier filter. Paper presented at 255th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nexus of Food, Energy, and Water, MAR 18-22, 2018, New Orleans, USA.. Abstract of Papers of the American Chemical Society, 255
Open this publication in new window or tab >>Nanocellulose-based size exclusion filters as an efficient and convenient virus barrier filter
2018 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Microbiology Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-366848 (URN)000435537701452 ()
Conference
255th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nexus of Food, Energy, and Water, MAR 18-22, 2018, New Orleans, USA.
Note

Meeting Abstract: 336

Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2020-01-29Bibliographically approved
Gustafsson, O., Gustafsson, S., Manukyan, L. & Mihranyan, A. (2018). Significance of Brownian Motion for Nanoparticle and Virus Capture in Nanocellulose-Based Filter Paper. Membranes, 8(4), Article ID 90.
Open this publication in new window or tab >>Significance of Brownian Motion for Nanoparticle and Virus Capture in Nanocellulose-Based Filter Paper
2018 (English)In: Membranes, ISSN 2077-0375, E-ISSN 2077-0375, Vol. 8, no 4, article id 90Article in journal (Refereed) Published
Abstract [en]

Pressure-dependent breakthrough of nanobioparticles in filtration was observed and it was related to depend on both convective forces due to flow and diffusion as a result of Brownian motion. The aim of this work was to investigate the significance of Brownian motion on nanoparticle and virus capture in a nanocellulose-based virus removal filter paper through theoretical modeling and filtration experiments. Local flow velocities in the pores of the filter paper were modeled through two different approaches (i.e., with the Hagen–Poiseuille equation) and by evaluating the superficial linear flow velocity through the filter. Simulations by solving the Langevin equation for 5 nm gold particles and 28 nm ΦX174 bacteriophages showed that hydrodynamic constraint is favored for larger particles. Filtration of gold nanoparticles showed no difference in retention for the investigated fluxes, as predicted by the modeling of local flow velocities. Filtration of ΦX174 bacteriophages exhibited a higher retention at higher filtration pressure, which was predicted to some extent by the Hagen–Poiseuille equation but not by evaluation of the superficial linear velocity. In all, the hydrodynamic theory was shown able to explain some of the observations during filtration.

National Category
Nano Technology
Identifiers
urn:nbn:se:uu:diva-362868 (URN)10.3390/membranes8040090 (DOI)000455071400005 ()30301138 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationStiftelsen Olle Engkvist ByggmästareSwedish Research Council
Available from: 2018-10-11 Created: 2018-10-11 Last updated: 2020-01-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-3314-5284

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