| 1. |
- Mullins, N., et al.
(author)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
- Wang, J., et al.
(author)
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Final report of the CCQM-K145 : Toxic and essential elements in bovine liver
- 2020
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In: Metrologia. - : IOP Publishing Ltd. - 0026-1394 .- 1681-7575. ; 57:1 A
-
Journal article (peer-reviewed)abstract
- Liver plays a major role in metabolism and acts as a source of energy for the body by storing glycogen. With the growing interest and investigation in the biological effects in recent years, it is important and necessary to develop accurate and comparable analytical methods for elements in bio-samples. It has, however, been 10 years since the tissue sample (bovine liver) of CCQM-K49 key comparison. The purpose of CCQM-K145 is to ensure the comparable and traceable measurement results for essential and toxic elements such as P, S, Zn, Mn, Ni, Mo, Sr, Cr, Co, Pb, As and Hg in bovine liver among NMIs and other designated measurement bodies worldwide. The comparison was agreed by IAWG as 6th IAWG Benchmarking Exercise with Zn and Ni as exemplary elements at the meeting in Korea in the early October 2016. The results of CCQM-K145 are expected to cover the measurement capability and support CMCs claiming for inorganic elements in the similar biological tissue materials and food samples. 30 NMIs and DIs registered in CCQM-K145. With respect to the methodology, a variety of techniques such as IDMS, ICP-OES, ICP-MS(non-ID), AAS and NAA were adopted by the participants. For Zn, Ni, Sr, Pb and Hg measurements, most participants chose ID-ICP-MS method, which showed the better performance in terms of consistency and reliability of the measurement results. In aspect of the traceability for the measurement results in CCQM-K145, most participants used their own (in house) CRMs or other NMI's CRMs to guarantee trace to SI unit. Most participants used similar matrix CRMs for quality control or method validation. Base on different statistic way to calculate the reference mass fraction values and associated uncertainties for each measurand, removal of the suspected extreme values, and discussion at the IAWG meetings, the median values are proposed as the KCRV for Zn, Ni, Mn, Mo, Cr, Pb and Hg; the arithmetic mean values are proposed as the KCRV for P, S, Sr, Co and As. In general, the performances of the majority of CCQM-K145 participants are very good, illustrating their measurement capabilities for Zn, Ni, P, S, Mn, Mo, Sr, Cr, As, Co, Pb and Hg in a complex biological tissue matrix. Bovine liver contains many kinds of nutrients and microelements, it can be regarded as a typical representative material of biological tissue and food. In CCQM-K145, the analytes involved alkali metals and transition elements, metalloids/semi-metals and non metals with a range of mass fraction from mg/g to μg/kg. CCQM-K145 also tested the ability of NMIs/DIs to determine elements that were easy to be lost and polluted, and interfered significantly. The chemical pretreatment methods of samples used in the comparison is suitable for general food and biological matrix samples. A variety of measurement methods used in the comparison represent the main instrumental technology for elemental analysis. Therefore, for supporting CMC claim, CCQM-K145 is readily applicable to measurement of more elements in a wide range of biological materials (including liquids and solids) and meat products. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 3. |
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| 4. |
- Daehn, I., et al.
(author)
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Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis
- 2014
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In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738. ; 124:4, s. 1608-1621
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Journal article (peer-reviewed)abstract
- Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-beta activation in podocytes; however, it is not clear how TGF-beta signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-beta signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.
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| 5. |
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| 6. |
- Flores, H., et al.
(author)
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Impact of climate change on Antarctic krill
- 2012
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In: Marine Ecology-Progress Series. - : Inter-Research Science Center. - 0171-8630 .- 1616-1599. ; 458, s. 1-19
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Journal article (peer-reviewed)abstract
- Antarctic krill Euphausia superba (hereafter 'krill') occur in regions undergoing rapid environmental change, particularly loss of winter sea ice. During recent years, harvesting of krill has in creased, possibly enhancing stress on krill and Antarctic ecosystems. Here we review the overall impact of climate change on krill and Antarctic ecosystems, discuss implications for an ecosystem-based fisheries management approach and identify critical knowledge gaps. Sea ice decline, ocean warming and other environmental stressors act in concert to modify the abundance, distribution and life cycle of krill. Although some of these changes can have positive effects on krill, their cumulative impact is most likely negative. Recruitment, driven largely by the winter survival of larval krill, is probably the population parameter most susceptible to climate change. Predicting changes to krill populations is urgent, because they will seriously impact Antarctic ecosystems. Such predictions, however, are complicated by an intense inter-annual variability in recruitment success and krill abundance. To improve the responsiveness of the ecosystem-based management approach adopted by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), critical knowledge gaps need to be filled. In addition to a better understanding of the factors influencing recruitment, management will require a better understanding of the resilience and the genetic plasticity of krill life stages, and a quantitative understanding of under-ice and benthic habitat use. Current precautionary management measures of CCAMLR should be maintained until a better understanding of these processes has been achieved. [GRAPHICS] .
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| 7. |
- Kainu, T, et al.
(author)
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Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus
- 2000
-
In: Proceedings of the National Academy of Sciences. - 1091-6490. ; 97:17, s. 9603-9608
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Journal article (peer-reviewed)abstract
- A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations.
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| 8. |
- Lindberg, K., et al.
(author)
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The HILUS-Trial—a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy
- 2021
-
In: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864. ; 16:7, s. 1200-1210
-
Journal article (peer-reviewed)abstract
- Introduction: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. Methods: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. Results: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0–10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the “hottest” 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. Conclusions: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions). © 2021 International Association for the Study of Lung Cancer
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| 9. |
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| 10. |
- Rozenblum, E, et al.
(author)
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A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes
- 2002
-
In: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 110:2, s. 111-121
-
Journal article (peer-reviewed)abstract
- Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.7-Mb genomic map with 90% sequence coverage. This area contains eight known genes, two hypothetical proteins, 24 additional Unigene clusters, and approximately 100 predicted genes and exons. We have determined the cDNA and genomic sequence, and tissue expression profiles for the KIAA1008 protein (homologous to the yeast mitotic control protein dis3+), KLF12 (AP-2 repressor), progesterone induced blocking factor 1, zinc finger transcription factor KLF5, and LIM domain only-7, and for the hypothetical proteins FLJ22624 and FLJ21869. Mutation screening of the five known genes in 19 breast cancer families has revealed numerous polymorphisms, but no deleterious mutations. These data provide a basis and resources for further analyses of this chromosomal region in the development of cancer.
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| 11. |
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| 12. |
- Sticker, D., et al.
(author)
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Using oxygen-consuming thermoset plastics to generate hypoxic conditions in microfluidic devices for potential cell culture applications
- 2020
-
In: 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017. - : Chemical and Biological Microsystems Society. ; , s. 812-813
-
Conference paper (peer-reviewed)abstract
- The precise control of the oxygen concentration in a cellular environment allows the study of cells under physiologically relevant conditions. This work reports on a novel method for the generation of reduced dissolved oxygen concentrations in microfluidic chambers for cell- and organ-on-chip applications. Using a thermoset polymeric material (OSTEMERTM), which effectively scavenges dissolved oxygen (DO), microfluidic devices have been fabricated where oxygen was rapidly depleted from the microfluidic chamber. It is shown that hypoxic and anaerobic conditions can be generated through the inherent scavenging property of the material itself, without any additional chemical additives.
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| 13. |
- Attner, P, et al.
(author)
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A 4-year consecutive study of post-tonsillectomy haemorrhage
- 2009
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In: ORL. - : S. Karger AG. - 1423-0275 .- 0301-1569. ; 71:5, s. 273-278
-
Journal article (peer-reviewed)abstract
- <i>Objective:</i> To analyse consecutive material over a period of 4 years concerning the incidence and consequences of post-tonsillectomy haemorrhages (PTH). <i>Design:</i> Prospective study. <i>Setting:</i> University hospital. <i>Participants:</i> All non-oncological cases of tonsillectomy (TE) and adenotonsillectomy (TA) performed at the ENT department at the Karolinska University Hospital between March 2000 and April 2004. <i>Main Outcome Measures:</i> Rate, timing and classification of PTH. <i>Results:</i> During the study period, 2,813 cases (mean age 13 ± 12.8 years; SD) of TE and TA were included. The majority (62%) were children aged below 12 years, and 69% were performed as day surgery. In total, 212 (7.5%) patients were readmitted due to PTH, of which 98 (3.4%) presented with ongoing haemorrhage. The rates of primary and secondary bleeding were 1.9 and 5.5%, respectively. The PTH occurred in 0–19 days post-operatively, in a typical twin peak mode around the day of surgery and then days 4–7. No case of serious PTH was noted. Multiple bleedings (2–3 times) occurred in 19 patients. Only a minority (31%) of the single PTH patients required active treatment, surgery in the theatre (35 patients) or diathermy under local anaesthesia in the emergency room (24 patients). However, almost all received systemic haemostatic treatment. Three patients required blood transfusion due to repeated PTH. Of the 114 patients that did not present with an active PTH, only 1 returned to the operating theatre due to later bleeding. Almost half (43%) of the patients with multiple episodes of PTH had also experienced primary bleedings. <i>Conclusions:</i> A primary PTH seems to indicate a risk of further episodes of bleedings, and should necessitate extra post-operative observation. Patients with a history of a single self-limiting PTH showed low risk of developing a haemorrhage requiring return to the theatre.
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| 14. |
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| 15. |
- Domínguez-Gil, B., et al.
(author)
-
The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
-
In: Transplantation. ; 106:11, s. 2111-2117
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 16. |
- Ebefors, Kerstin, 1977, et al.
(author)
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Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
- 2019
-
In: Kidney International. - : Elsevier BV. - 0085-2538. ; 96:4, s. 957-970
-
Journal article (peer-reviewed)abstract
- Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-beta receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondria! reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.
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| 17. |
- Fischbach, M., et al.
(author)
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Measurement by magnetic resonance imaging of the peritoneal membrane in contact with dialysate in rats
- 2005
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In: Adv Perit Dial. - 1197-8554. ; 21, s. 17-20
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Journal article (peer-reviewed)abstract
- To be optimal, a peritoneal dialysis prescription should consider the peritoneal surface area recruitment. In fact, as shown by computed tomography imaging, only a fraction of the available anatomic peritoneum is in contact with the dialysate (PDF). Various factors may dynamically affect the recruitment of the wetted membrane: posture, fill volume, PDF composition (biocompatibility), and pharmacologic agents (phospholipids). To precisely determine the peritoneal membrane recruitment capacity, we developed an animal model. In 5/6 bi-nephrectomized rats on peritoneal dialysis, between week 6 and week 8 post surgery, we used MRI to assess the contact area, with the dialysate acting as the contrast medium (fill volume: 10 mL per 100-g rat body weight). The MRI protocol consisted of axially oriented, turbo spin-echo, 3-mm slice, T2 weighted sequences. The contact area was measured using an adapted three-dimensional MRI reconstruction software based on DICOM (digital imaging and communications in medicine) images. The MRI studies (n=10) were successful. They showed that only a fraction of the presumed anatomic area (30% - 40%) was in contact with the PDF Peritoneal MRI in rats is a method that shows potential for assessing peritoneal contact area and its variation under experimental conditions.
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| 18. |
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| 19. |
- Fischbach, M., et al.
(author)
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The influence of peritoneal surface area on dialysis adequacy
- 2005
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In: Perit Dial Int. - 0896-8608. ; 25 Suppl 3
-
Journal article (peer-reviewed)abstract
- In children, the prescription of peritoneal dialysis is based mainly on the choice of the peritoneal dialysis fluid, the intraperitoneal fill volume (mL/m2 body surface area (BSA)], and the contact time. The working mode of the peritoneal membrane as a dialysis membrane is more related to a dynamic complex structure than to a static hemodialyzer. Thus, the peritoneal surface area impacts on dialysis adequacy. In fact, the peritoneal surface area may be viewed as composed of three exchange entities: the anatomic area, the contact area, and the vascular area. First, in infants, the anatomic area appears to be two-fold larger than in adults when expressed per kilogram body weight. On the other hand, the anatomic area becomes independent of age when expressed per square meter BSA. Therefore, scaling of the intraperitoneal fill volume by BSA (m2) is necessary to prevent a too low ratio of fill volume to exchange area, which would result in a functional "hyperpermeable" peritoneal exchange. Second, the contact area, also called the wetted membrane, is only a portion of the anatomic area, representing 30% to 60% of this area in humans, as measured by computed tomography. Both posture and fill volume may affect the extent of recruitment of contact area. Finally, the vascular area is influenced by the availability of both the anatomic area and the recruited contact area. This surface is governed essentially by both peritonealvascular perfusion, represented by the mesenteric vascular flow and, hence, by the number of perfused capillaries available for exchange. This vascular area is dynamically affected by different factors, such as composition of the peritoneal fluid, the fill volume, and the production of inflammatory agents. Peritoneal dialysis fluids that will be developed in the future for children should allow an optimization of the fill volume owing to a better tolerance in terms of lower achieved intraperitoneal pressure for a given fill volume. Moreover, future peritoneal dialysis fluids should protect the peritoneal membrane from hyperperfusion (lower glucose degradation products).
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| 20. |
- Fischbach, M., et al.
(author)
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The peritoneal membrane: a dynamic dialysis membrane in children
- 2003
-
In: Adv Perit Dial. ; 19, s. 265-8
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Journal article (peer-reviewed)abstract
- Peritoneal dialysis prescription in children should be individualized--based not only on numerical targets (Kt/Vurea, Kcreat), but also on consideration of the peritoneal membrane, a dynamic dialysis membrane. In fact, the effective peritoneal surface area is at least a triple entity: an anatomic area, a contact area, and an exchange area. The anatomic area appears to be twice as large in infants as in adults if expressed per kilogram of body weight (BW), although the area is independent of age if expressed per square meter of body surface area (BSA). Therefore, scaling of the intraperitoneal fill volume (IPV) by BSA in square meters is necessary to avoid a low IPV/area ratio, which results in a functionally "hyperpermeable" peritoneal exchange. The contact area (the wetted membrane) is only a fraction of the anatomic area--that is, 30%-60% in humans (by computed tomography). Contact area depends on a variety of factors, such as posture and fill volume, that affect the degree of recruitment of membrane contact area. The exchange area is influenced by both the anatomic are and the contact area. However, it is mainly governed by the specific vascular area as determined by the peritoneal vascular perfusion and the capillaries available for exchange. Vascular area is dynamically affected by a variety of factors, such as the composition of the peritoneal dialysis fluid, the fill volume, and possible inflammatory agents.
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| 21. |
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| 22. |
- Giovannucci, Tatiana A., et al.
(author)
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Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy
- 2022
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In: Autophagy. - : Taylor & Francis. - 1554-8627 .- 1554-8635. ; 18:7, s. 1486-1502
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Journal article (peer-reviewed)abstract
- The ubiquitin-proteasome system (UPS) and macroautophagy/autophagy are the main proteolytic systems in eukaryotic cells for preserving protein homeostasis, i.e., proteostasis. By facilitating the timely destruction of aberrant proteins, these complementary pathways keep the intracellular environment free of inherently toxic protein aggregates. Chemical interference with the UPS or autophagy has emerged as a viable strategy for therapeutically targeting malignant cells which, owing to their hyperactive state, heavily rely on the sanitizing activity of these proteolytic systems. Here, we report on the discovery of CBK79, a novel compound that impairs both protein degradation by the UPS and autophagy. While CBK79 was identified in a high-content screen for drug-like molecules that inhibit the UPS, subsequent analysis revealed that this compound also compromises autophagic degradation of long-lived proteins. We show that CBK79 induces non-canonical lipidation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) that requires ATG16L1 but is independent of the ULK1 (unc-51 like autophagy activating kinase 1) and class III phosphatidylinositol 3-kinase (PtdIns3K) complexes. Thermal preconditioning of cells prevented CBK79-induced UPS impairment but failed to restore autophagy, indicating that activation of stress responses does not allow cells to bypass the inhibitory effect of CBK79 on autophagy. The identification of a small molecule that simultaneously impairs the two main proteolytic systems for protein quality control provides a starting point for the development of a novel class of proteostasis-targeting drugs.
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| 23. |
- Giovannucci, TA, et al.
(author)
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Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound
- 2021
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-
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Journal article (peer-reviewed)abstract
- Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.
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| 24. |
- Gram, D., et al.
(author)
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Residual positioning errors and uncertainties for pediatric craniospinal irradiation and the impact of image guidance
- 2020
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In: Radiation Oncology. - : Springer Science and Business Media LLC. - 1748-717X. ; 15:1
-
Journal article (peer-reviewed)abstract
- Background Optimal alignment is of utmost importance when treating pediatric patients with craniospinal irradiation (CSI), especially with regards to field junctions and multiple isocenters and techniques applying high dose gradients. Here, we investigated the setup errors and uncertainties for pediatric CSI using different setup verification protocols. Methods A total of 38 pediatric patients treated with CSI were identified for whom treatment records and setup images were available. The setup images were registered retrospectively to the reference image using an automated tool and matching on bony anatomy, subsequently, the impact of different correction protocols was simulated. Results For an action-level (AL)-protocol and a non-action level (NAL)-protocol, the translational residual setup error can be as large as 24 mm for an individual patient during a single fraction, and the rotational error as large as 6.1 degrees. With daily IGRT, the maximum setup errors were reduced to 1 mm translational and 5.4 degrees rotational versus 1 mm translational and 2.4 degrees rotational for 3- and 6- degrees of freedom (DoF) couch shifts, respectively. With a daily 6-DoF IGRT protocol for a wide field junction irradiation technique, the residual positioning uncertainty was below 1 mm and 1 degrees for translational and rotational directions, respectively. The largest rotational uncertainty was found for the patients' roll even though this was the least common type of rotational error, while the largest translational uncertainty was found in the patients' anterior-posterior-axis. Conclusions These results allow for informed margin calculation and robust optimization of treatments. Daily IGRT is the superior choice for setup of pediatric patients treated with CSI, although centers that do not have this option could use the results presented here to improve their margins and uncertainty estimates for a more accurate treatment alignment.
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| 25. |
- Granqvist, Anna, et al.
(author)
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Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome
- 2006
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In: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 291
-
Journal article (peer-reviewed)abstract
- Proteoglycans (PG) are important for the glomerular barrier, for cell signaling and for the anchorage of cells to the glomerular basement membrane. They are, however, complex macromolecules, and their production has not yet been thoroughly investigated for podocytes. In the present study, we have studied the biosynthesis of proteoglycans by highly differentiated human podocytes and in rats. The cells were treated with puromycin aminonucleoside (PAN, a nephrosis inducing agent), steroids (used as primary treatment for nephrotic syndrome) or both. Analysis was made by Taqman(R)real-time PCR, Western blot and by metabolic labeling with (35)S and (3)H. We found that podocytes produce versican, syndecan-1, decorin and biglycan together with the previously known PGs syndecan-4, glypican and perlecan. PAN treatment down-regulated the mRNA and the protein expression of both versican (by 24+/-6%, p<0.01, for mRNA and by 50% for protein) and perlecan (by 14+/-5%, p<0.05, for mRNA and by 50% for protein). The decreased expression was confirmed by studying the glomerular gene expression in rats treated with PAN during a time course study. In addition, puromycin decreased the expression of enzymes involved in the glycosaminoglycan (GAG) biosynthesis. Steroid treatment decreased perlecan (by 24+/-3%, p<0.01) and syndecan-1 expression (by 30+/-4%, p<0.01), but increased the expression of decorin 2.5-fold. The observed alterations of proteoglycan synthesis induced by PAN may lead to decreased glomerular anionic charge and disturbed podocyte morphology, factors that are important for the development of a nephrotic syndrome.
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| 26. |
- Gustafsson, Erika, et al.
(author)
-
Directed evolution of chemotaxis inhibitory protein of Staphylococcus aureus generates biologically functional variants with reduced interaction with human antibodies
- 2010
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In: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 23:2, s. 91-101
-
Journal article (peer-reviewed)abstract
- Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is a protein that binds and blocks the C5a receptor (C5aR) and formylated peptide receptor, thereby inhibiting the immune cell recruitment associated with inflammation. If CHIPS was less reactive with existing human antibodies, it would be a promising anti-inflammatory drug candidate. Therefore, we applied directed evolution and computational/rational design to the CHIPS gene in order to generate new CHIPS variants displaying lower interaction with human IgG, yet retaining biological function. The optimization was performed in four rounds: one round of random mutagenesis to add diversity into the CHIPS gene and three rounds of DNA recombination by Fragment INduced Diversity (FIND((R))). Every round was screened by phage selection and/or ELISA for decreased interaction with human IgG and retained C5aR binding. The mean binding of human anti-CHIPS IgG decreased with every round of evolution. For further optimization, new amino acid substitutions were introduced by rational design, based on the mutations identified during directed evolution. Finally, seven CHIPS variants with low interaction with human IgG and retained C5aR blocking capacity could be identified.
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| 27. |
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| 28. |
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| 29. |
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| 30. |
- Haraldsson, P, et al.
(author)
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Dose response characteristics and basic dose distribution data for a polymerization-based dosemeter gel evaluated using MR
- 2000
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In: British Journal of Radiology. - : British Institute of Radiology. - 0007-1285 .- 1748-880X. ; 73:865, s. 58-65
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Journal article (peer-reviewed)abstract
- A safe and reproducible mixing procedure for the manufacture of a polymerization-based dosemeter gel evaluated using MRI (PoMRI) is presented. The dose response, obtained by irradiating gel-filled vials with absorbed doses in the interval 0-20 Gy and evaluated with respect to 1/T2, was found to be linear in the interval 0-8 Gy, with a sensitivity of 0.211 s-1Gy-1 (r2 = 0.998) at 1.5 T. Evaluation of the same set of vials with respect to 1/T1 gave a sensitivity of 0.018 s-1Gy-1 (r2 = 0.960). PoMRI and diode data were compared for standard photon and electron treatment beams. A deviation of less than 3% was found between the two methods for central depth dose curves as well as dose profiles (2 mm for electrons in the steep dose gradient regions). The importance of the method used for background correction for the reliability of the results was also evaluated. Barex (with a wall thickness of 1.5 mm) was investigated for use as phantom material and found to be favourable compared with glass. The results obtained in this study show that PoMRI has excellent potential as a 3D detector.
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| 31. |
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| 32. |
- Hill, Daniel, et al.
(author)
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Microfluidic and Transducer Technologies for Lab on a Chip Applications
- 2010
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In: 2010 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC). - : IEEE conference proceedings. - 9781424441242 ; , s. 305-307
-
Conference paper (peer-reviewed)abstract
- Point-of-care diagnostic devices typically require six distinct qualities: they must deliver at least the same sensitivity and selectivity, and for a cost per assay no greater than that of today's central lab technologies, deliver results in a short period of time (<15 min at GP; <2h in hospital), be portable or at least small in scale, and require no or extremely little sample preparation. State-of-the-art devices deliver information of several markers in the same measurement.
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| 33. |
- Isaksson, P., et al.
(author)
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Promoting mental health in Swedish preschool-teacher views
- 2017
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In: Health Promotion International. - : Oxford University Press (OUP). - 0957-4824 .- 1460-2245. ; 32:1, s. 53-61
-
Journal article (peer-reviewed)abstract
- The promotion of childhood mental health is an important investment for the future. Many young children spend a large amount of time in preschool, which have unique opportunities to promote mental health at an early stage. The aim of this study was to illuminate teachers' views of what they do in ordinary work to promote mental health among preschool children. This qualitative study had a descriptive and exploratory design and qualitative content analysis was utilized. Six focus group interviews with preschool teachers, concerning families from different cultural, geographical and socioeconomic backgrounds, were conducted in a county in the southwest of Sweden. Both manifest and latent content appeared. Three categories, 'structured world', 'pleasant climate' and 'affirming the child' and 10 subcategories emerged. The latent content of these categories is described under the theme 'creating an atmosphere where each child can flourish in harmony with their environment'. The results show teachers different working approaches with mental health in preschool and together with previous research these results can provide a basis of knowledge for preschool teachers and inspire them to develop and maintain their health-promoting work. In future studies it should be particularly interesting to investigate how the promotive way to work can be transferred to strengthen mental health throughout the school years.
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| 34. |
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| 35. |
- Kristjansson, S., et al.
(author)
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Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response
- 2005
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In: J Allergy Clin Immunol. - : Elsevier BV. - 0091-6749. ; 116:4, s. 805-11
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Journal article (peer-reviewed)abstract
- BACKGROUND: Respiratory syncytial virus (RSV) infections during infancy are considered to be a risk factor for developing asthma and possibly allergic sensitization. OBJECTIVE: The aim of this study was to investigate the cytokines, chemokines, and eosinophil cationic protein in the nasopharyngeal secretions of infants < or = 7 months of age with RSV infections or other respiratory viral infections and healthy infants as controls. Groups were also analyzed according to age, < or = 3 months and >3 months, and the levels were compared within and between groups. RESULTS: Thirty-nine infants with RSV, 9 with influenza or parainfluenza virus infections and 50 controls with no history of infections, were enrolled in the study. The RSV-infected infants had significantly higher levels of IL-4; macrophage inflammatory protein 1beta, a chemoattractant for T cells; and eosinophil cationic protein in nasopharyngeal secretions compared with the control group. The levels of the TH2 cytokine IL-4 were significantly higher in RSV-infected infants < or = months of age compared with RSV-infected infants >3 months of age. In infants < or = 3 months of age, infections with influenza or parainfluenza virus caused TH2-like responses similar to those produced by RSV. CONCLUSION: Infections with RSV as well as with influenza and parainfluenza virus during early infancy preferentially promote a TH2-like response in the nose with local production of IL-4, IL-5, and macrophage inflammatory protein 1beta and infiltration and activation of eosinophils.
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| 36. |
- Ladds, Marcus J. G. W., et al.
(author)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 37. |
- Ladds, MJGW, et al.
(author)
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Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2071-
-
Journal article (peer-reviewed)abstract
- The original PDF version of this Article listed the authors as “Marcus J.G.W. Ladds,” where it should have read “Marcus J. G. W. Ladds, Ingeborg M. M. van Leeuwen, Catherine J. Drummond et al.#”.Also in the PDF version, it was incorrectly stated that “Correspondence and requests for materials should be addressed to S. Lín.”, instead of the correct “Correspondence and requests for materials should be addressed to S. Laín.”This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.
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| 38. |
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| 39. |
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| 40. |
- Leifsdottir, Kristin, et al.
(author)
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The cerebrospinal fluid proteome of preterm infants predicts neurodevelopmental outcome
- 2022
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In: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 10
-
Journal article (peer-reviewed)abstract
- BackgroundSurvival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants. MethodsTwenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured. ResultsThe CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18-24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development. ConclusionOur data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome.
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| 41. |
- Medvedevskikh, Maria, et al.
(author)
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Report of the CCQM-K130 : Nitrogen mass fraction measurements in glycine
- 2017
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In: Metrologia. - 0026-1394 .- 1681-7575. ; 54:1A
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Journal article (peer-reviewed)abstract
- Mass fraction of nitrogen is very important pointer because the results of these measurements are often used for determination of protein mass fraction that is an important indicator of the quality of the vast majority of food products and raw materials, in particular dry milk powder. Proteins-enzymes catalyze chemical reactions, protein along with fats and carbohydrates is one of the indicators characterizing the energy value of food, so its definition is mandatory for all food products. The aim of this key comparison CCQM-K130 and pilot study P166 is to support National Measurement Institutes (NMIs) and Designated Institutes (DIs) to demonstrate the validity of the procedures the employed for determination of nitrogen mass fraction in glycine. The study material for this key comparison and pilot study has been selected to be representative as one of the aminoacid-the simplest part of the protein. Glycine is an amino acid, single acid that does not have any isomers (melting point-290 °C; specific heat of evaporation-528,6 J/kg; specific melting heat-981,1 J/kg; pKa-2,34, molar mass-75,07 g/mol, density-1,607 g/cm3). Ural Scientific Research Institute for Metrology (UNIIM) acted as the coordinating laboratory of this comparison and pilot study. Eight NMIs participated in this key comparison and two NMIs participated in Pilot study. The results of Pilot study are excluded from the Report B.
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| 42. |
- Niquil, N., et al.
(author)
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Shifting levels of ecological network's analysis reveals different system properties
- 2020
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In: Philosophical Transactions of the Royal Society B-Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 375:1796
-
Journal article (peer-reviewed)abstract
- Network analyses applied to models of complex systems generally contain at least three levels of analyses. Whole-network metrics summarize general organizational features (properties or relationships) of the entire network, while node-level metrics summarize similar organization features but consider individual nodes. The network- and node-level metrics build upon the primary pairwise relationships in the model. As with many analyses, sometimes there are interesting differences at one level that disappear in the summary at another level of analysis. We illustrate this phenomenon with ecosystem network models, where nodes are trophic compartments and pairwise relationships are flows of organic carbon, such as when a predator eats a prey. For this demonstration, we analysed a time-series of 16 models of a lake planktonic food web that describes carbon exchanges within an autumn cyanobacteria bloom and compared the ecological conclusions drawn from the three levels of analysis based on inter-time-step comparisons. A general pattern in our analyses was that the closer the levels are in hierarchy (node versus network, or flow versus node level), the more they tend to align in their conclusions. Our analyses suggest that selecting the appropriate level of analysis, and above all regularly using multiple levels, may be a critical analytical decision. This article is part of the theme issue 'Unifying the essential concepts of biological networks: biological insights and philosophical foundations'.
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| 43. |
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| 44. |
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| 45. |
- Redfors, Björn, et al.
(author)
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Angiographic findings and survival in patients undergoing coronary angiography due to sudden cardiac arrest in western Sweden.
- 2015
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In: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 90:May 2015, s. 13-20
-
Journal article (peer-reviewed)abstract
- AIM: Sudden cardiac arrest (SCA) accounts for more than half of all deaths from coronary heart disease. Time to return of spontaneous circulation is the most important determinant of outcome but successful resuscitation also requires percutaneous coronary intervention in selected patients. However, proper selection of patients is difficult. We describe data on angiographic finding and survival from a prospectively followed SCA patient cohort.METHODS: We merged the RIKS-HIA registry (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) and SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for patients hospitalized in cardiac care units in Western Sweden between January 2005 and March 2013. We performed propensity score-adjusted logistic and Cox proportional-hazards regression analyses on complete-case data as well as on imputed data sets.RESULTS: 638 consecutive patients underwent coronary angiography due to SCA. Severity of coronary artery disease was similar among SCA patients and patients undergoing coronary angiography due to suspected coronary artery disease (n=37,142). An acute occlusion was reported in the majority of SCA patients and was present in 37% of patients who did not have ST-elevation on the post resuscitation ECG. 31% of SCA patients died within 30 days. Long-term risk of death among patients who survived the first 30 days was higher in patients with SCA compared to patients with acute coronary syndromes (P<0.001).CONCLUSIONS: Coronary artery disease and acute coronary occlusions are common among patients who undergo coronary angiography after sudden cardiac arrest. These patients have a substantial mortality risk both short- and long-term.
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| 46. |
- Singh, A., et al.
(author)
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High glucose causes dysfunction of the human glomerular endothelial glycocalyx
- 2011
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In: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 300:1
-
Journal article (peer-reviewed)abstract
- The endothelial glycocalyx is a gel-like layer which covers the luminal side of blood vessels. The glomerular endothelial cell (GEnC) glycocalyx is composed of proteoglycan core proteins, glycosaminoglycan (GAG) chains, and sialoglycoproteins and has been shown to contribute to the selective sieving action of the glomerular capillary wall. Damage to the systemic endothelial glycocalyx has recently been associated with the onset of albuminuria in diabetics. In this study, we analyze the effects of high glucose on the biochemical structure of the GEnC glycocalyx and quantify functional changes in its protein-restrictive action. We used conditionally immortalized human GEnC. Proteoglycans were analyzed by Western blotting and indirect immunofluorescence. Biosynthesis of GAG was analyzed by radiolabeling and quantified by anion exchange chromatography. FITC-albumin was used to analyze macromolecular passage across GEnC monolayers using an established in vitro model. We observed a marked reduction in the biosynthesis of GAG by the GEnC under high-glucose conditions. Further analysis confirmed specific reduction in heparan sulfate GAG. Expression of proteoglycan core proteins remained unchanged. There was also a significant increase in the passage of albumin across GEnC monolayers under high-glucose conditions without affecting interendothelial junctions. These results reproduce changes in GEnC barrier properties caused by enzymatic removal of heparan sulfate from the GEnC glycocalyx. They provide direct evidence of high glucose-induced alterations in the GEnC glycocalyx and demonstrate changes to its function as a protein-restrictive layer, thus implicating glycocalyx damage in the pathogenesis of proteinuria in diabetes.
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| 47. |
- Singh, A., et al.
(author)
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Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx
- 2013
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
-
Journal article (peer-reviewed)abstract
- Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S35 and 3H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress.
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| 48. |
- Sticker, Drago, et al.
(author)
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Oxygen Management at the Microscale : A Functional Biochip Material with Long-Lasting and Tunable Oxygen Scavenging Properties for Cell Culture Applications
- 2019
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In: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 11:10, s. 9730-9739
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Journal article (peer-reviewed)abstract
- Oxygen plays a pivotal role in cellular homeostasis, and its partial pressure determines cellular function and fate. Consequently, the ability to control oxygen tension is a critical parameter for recreating physiologically relevant in vitro culture conditions for mammalian cells and microorganisms. Despite its importance, most microdevices and organ-on-a-chip systems to date overlook oxygen gradient parameters because controlling oxygen often requires bulky and expensive external instrumental setups. To overcome this limitation, we have adapted an off-stoichiometric thiol-ene-epoxy polymer to efficiently remove dissolved oxygen to below 1 hPa and also integrated this modified polymer into a functional biochip material. The relevance of using an oxygen scavenging material in microfluidics is that it makes it feasible to readily control oxygen depletion rates inside the biochip by simply changing the surface-to-volume aspect ratio of the microfluidic channel network as well as by changing the temperature and curing times during the fabrication process.
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| 49. |
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| 50. |
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