| 1. |
- Niemi, MEK, et al.
(author)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Romagnoni, A, et al.
(author)
-
Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data
- 2019
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 10351-
-
Journal article (peer-reviewed)abstract
- Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.
|
|
| 3. |
- Craddock, Nick, et al.
(author)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
|
|
| 4. |
- Chakraborty, S., et al.
(author)
-
Phenotypic and genomic analyses of bacteriophages targeting environmental and clinical CS3-expressing enterotoxigenic Escherichia coli (ETEC) strains
- 2018
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
-
Journal article (peer-reviewed)abstract
- Diarrhea due to infection of enterotoxigenic Escherichia coli (ETEC) is of great concern in several low and middle-income countries. ETEC infection is considered to be the most common cause of diarrhea in Bangladesh and is mainly spread through contaminated water and food. ETEC pathogenesis is mediated by the expression of enterotoxins and colonization factors (CFs) that target the intestinal mucosa. ETEC can survive for extended time periods in water, where they are likely to be attacked by bacteriophages. Antibiotic resistance is common amongst enteric pathogens and therefore is the use of bacteriophages (phage) as a therapeutic tool an interesting approach. This study was designed to identify novel phages that specifically target ETEC virulence factors. In total, 48 phages and 195 ETEC isolates were collected from water sources and stool samples. Amongst the identified ETEC specific phages, an enterobacteria phage T7, designated as IMM-002, showed a significant specificity towards colonization factor CS3-expressing ETEC isolates. Antibody-blocking and phage-neutralization assays revealed that CS3 is used as a host receptor for the IMM-002 phage. The bacterial CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated) defence mechanism can invoke immunity against phages. Genomic analyses coupled with plaque assay experiments indicate that the ETEC CRISPR-Cas system is involved in the resistance against the CS3-specific phage (IMM-002) and the previously identified CS7-specific phage (IMM-001). As environmental water serves as a reservoir for ETEC, it is important to search for new antimicrobial agents such as phages in environmental water as well as the human gut. A better understanding of how the interplay between ETEC-specific phages and ETEC isolates affects the ETEC diversity, both in environmental ecosystems and within the host, is important for the development of new treatments for ETEC infections.
|
|
| 5. |
|
|
| 6. |
- von Mentzer, Astrid, 1983, et al.
(author)
-
Long-read-sequenced reference genomes of the seven major lineages of enterotoxigenic Escherichia coli (ETEC) circulating in modern time
- 2021
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
-
Journal article (peer-reviewed)abstract
- Enterotoxigenic Escherichia coli (ETEC) is an enteric pathogen responsible for the majority of diarrheal cases worldwide. ETEC infections are estimated to cause 80,000 deaths annually, with the highest rates of burden, ca 75 million cases per year, amongst children under 5 years of age in resource-poor countries. It is also the leading cause of diarrhoea in travellers. Previous large-scale sequencing studies have found seven major ETEC lineages currently in circulation worldwide. We used PacBio long-read sequencing combined with Illumina sequencing to create high-quality complete reference genomes for each of the major lineages with manually curated chromosomes and plasmids. We confirm that the major ETEC lineages all harbour conserved plasmids that have been associated with their respective background genomes for decades, suggesting that the plasmids and chromosomes of ETEC are both crucial for ETEC virulence and success as pathogens. The in-depth analysis of gene content, synteny and correct annotations of plasmids will elucidate other plasmids with and without virulence factors in related bacterial species. These reference genomes allow for fast and accurate comparison between different ETEC strains, and these data will form the foundation of ETEC genomics research for years to come.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- von Mentzer, Astrid, 1983, et al.
(author)
-
Identification of enterotoxigenic Escherichia coli (ETEC) clades with long-term global distribution
- 2014
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:12, s. 1321-1326
-
Journal article (peer-reviewed)abstract
- Enterotoxigenic Escherichia coil (ETEC), a major cause of infectious diarrhea, produce heat-stable and/or heat-labile enterotoxins and at least 25 different colonization factors that target the intestinal mucosa. The genes encoding the enterotoxins and most of the colonization factors are located on plasmids found across diverse E. coli serogroups. Whole-genome sequencing of a representative collection of ETEC isolated between 1980 and 2011 identified globally distributed lineages characterized by distinct colonization factor and enterotoxin profiles. Contrary to current notions, these relatively recently emerged lineages might harbor chromosome and plasmid combinations that optimize fitness and transmissibility. These data have implications for understanding, tracking and possibly preventing ETEC disease.
|
|
| 10. |
|
|
| 11. |
- Carpenter, Katharine A., et al.
(author)
-
Turn structures in CGRP C-terminal analogues promote stable arrangements of key residue side chains
- 2001
-
In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 40:28, s. 8317-8325
-
Journal article (peer-reviewed)abstract
- The 37-amino acid calcitonin gene-related peptide (CGRP) is a potent endogenous vasodilator thought to be implicated in the genesis of migraine attack. CGRP antagonists may thus have therapeutic value for the treatment of migraine. The CGRP C-terminally derived peptide [D(31),P(34),F(35)]CGRP(27-37)-NH(2) was recently identified as a high-affinity hCGRP(1) receptor selective antagonist. Reasonable CGRP(1) affinity has also been demonstrated for several related analogues, including [D(31),A(34),F(35)]CGRP(27-37)-NH(2). In the study presented here, conformational and structural features in CGRP(27-37)-NH(2) analogues that are important for hCGRP(1) receptor binding were explored. Structure-activity studies carried out on [D(31),P(34),F(35)]CGRP(27-37)-NH(2) resulted in [D(31),P(34),F(35)]CGRP(30-37)-NH(2), the shortest reported CGRP C-terminal peptide analogue exhibiting reasonable hCGRP(1) receptor affinity (K(i) = 29.6 nM). Further removal of T(30) from the peptide's N-terminus greatly reduced receptor affinity from the nanomolar to micromolar range. Additional residues deemed critical for hCGRP(1) receptor binding were identified from an alanine scan of [A(34),F(35)]CGRP(28-37)-NH(2) and included V(32) and F(37). Replacement of the C-terminal amide in this same peptide with a carboxyl, furthermore, resulted in a greater than 50-fold reduction in hCGRP(1) affinity, thus suggesting a direct role for the amide moiety in receptor binding. The conformational properties of two classes of CGRP(27-37)-NH(2) peptides, [D(31),X(34),F(35)]CGRP(27-37)-NH(2) (X is A or P), were examined by NMR spectroscopy and molecular modeling. A beta-turn centered on P(29) was a notable feature consistently observed among active peptides in both series. This turn led to exposure of the critical T(30) residue to the surrounding environment. Peptides in the A(34) series were additionally characterized by a stable C-terminal helical turn that resulted in the three important residues (T(30), V(32), and F(37)) adopting consistent interspatial positions with respect to one another. Peptides in the P(34) series were comparatively more flexible at the C-terminus, although a large proportion of the [D(31),P(34),F(35)]CGRP(27-37)-NH(2) calculated conformers contained a gamma-turn centered on P(34). These results collectively suggest that turn structures at both the C-terminus and N-terminus of CGRP(27-37)-NH(2) analogues may help to appropriately orient critical residues (T(30), V(32), and F(37)) for hCGRP(1) receptor binding.
|
|
| 12. |
- Erensoy, Gizem, 1988, et al.
(author)
-
Dynamic Release from Acetalated Dextran Nanoparticles for Precision Therapy of Inflammation
- 2024
-
In: ACS Applied Bio Materials. - 2576-6422. ; 7
-
Journal article (peer-reviewed)abstract
- Polymer-based nanoparticles (NPs) that react to altered physiological characteristics have the potential to enhance the delivery of therapeutics to a specific area. These materials can utilize biochemical triggers, such as low pH, which is prone to happen locally in an inflammatory microenvironment due to increased cellular activity. This reduced pH is neutralized when inflammation subsides. For precise delivery of therapeutics to match this dynamic reaction, drug delivery systems (DDS) need to not only release the drug (ON) but also stop the release (OFF) autonomously. In this study, we use a systematic approach to optimize the composition of acetalated dextran (AcDex) NPs to start (ON) and stop (OFF) releasing model cargo, depending on local pH changes. By mixing ratios of AcDex polymers (mixed NPs), we achieved a highly sensitive material that was able to rapidly release cargo when going from pH 7.4 to pH 6.0. At the same time, the mix also offered a stable composition that enabled a rapid ON/OFF/ON/OFF switching within this narrow pH range in only 90 min. These mixed NPs were also sensitive to biological pH changes, with increased release in the presence of inflammatory cells compared to healthy cells. Such precise and controllable characteristics of a DDS position mixed NPs as a potential treatment platform to inhibit disease flare-ups, reducing both systemic and local side effects to offer a superior treatment option for inflammation compared to conventional systems.
|
|
| 13. |
- Jarlert, Anders, et al.
(author)
-
Revivalist women in social and spiritual interaction
- 2020
-
In: Penser l'Histoire religieuse au XXIe Siècle : Thinking about Religious History in the 21st Century - Thinking about Religious History in the 21st Century. - 9791091592284 ; 42, s. 289-297
-
Book chapter (peer-reviewed)
|
|
| 14. |
- Joffre, Enrique, et al.
(author)
-
Identification of new heat-stable (STa) enterotoxin allele variants produced by human enterotoxigenic Escherichia coli (ETEC)
- 2016
-
In: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221 .- 1618-0607. ; 306:7, s. 586-594
-
Journal article (peer-reviewed)abstract
- We describe natural variants of the heat stable toxin (STa) produced by enterotoxigenic Escherichia coli (ETEC) isolates collected worldwide. Previous studies of ETEC isolated from human diarrheal cases have reported the existence of three natural STa gene variants estA1, estA2 and estA3/4 where the first variant encodes STp (porcine, bovine, and human origin) and the two latter ones encode STh (human origin). We identified STa sequences by BLASTn and profiled ST amino acid polymorphisms in a collection of 118 clinical ETEC isolates from children and adults from Asia, Africa and, Latin America that were characterized by whole genome sequencing. Three novel variants of STp and STh were found and designated STa5 and STa6, and STa7, respectively. Presence of glucose significantly decreased the production of STh and STp toxin variants (p < 0.05) as well as downregulated the gene expression (STh: p < 0.001, STp: p < 0.05). We found that the ETEC isolates producing the most common STp variant, STa5, co-expressed coli surface antigen CS6 and was significantly associated with disease in adults in this data set (p < 0.001). Expression of mature STa5 peptide as well as gene expression of tolC, involved in ST secretion, increased in response to bile (p < 0.05). ETEC expressing the common STh variant STa3/4 was associated with disease in children (p < 0.05). The crp gene, that positively regulate estA3/4 encoding STa3/4, and estA3/4 itself had decreased transcriptional levels in presence of bile. Since bile levels in the intestine are lower in children than adults, these results may suggest differences in pathogenicity of ETEC in children and adult populations. (C) 2016 The Author(s). Published by Elsevier GmbH.
|
|
| 15. |
|
|
| 16. |
- Tobias, Joshua, 1969, et al.
(author)
-
Stability of the Encoding Plasmids and Surface Expression of CS6 Differs in Enterotoxigenic Escherichia coli (ETEC) Encoding Different Heat-Stable (ST) Enterotoxins (STh and STp)
- 2016
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:4
-
Journal article (peer-reviewed)abstract
- Enterotoxigenic Escherichia coli (ETEC), one of the most common reasons of diarrhea among infants and children in developing countries, causes disease by expression of either or both of the enterotoxins heat-labile (LT) and heat-stable (ST; divided into human-type [STh] and porcine-type [STp] variants), and colonization factors (CFs) among which CS6 is one of the most prevalent ETEC CFs. In this study we show that ETEC isolates expressing CS6+STh have higher copy numbers of the cssABCD operon encoding CS6 than those expressing CS6+STp. Long term cultivation of up to ten over-night passages of ETEC iso-lates harboring CS6+STh (n = 10) or CS6+STp (n = 15) showed instability of phenotypic expression of CS6 in a majority of the CS6+STp isolates, whereas most of the CS6+STh isolates retained CS6 expression. The observed instability was a correlated with loss of genes cssA and cssD as examined by PCR. Mobilization of the CS6 plasmid from an unstable CS6+STp isolate into a laboratory E. coli strain resulted in loss of the plasmid after a single over-night passage whereas the plasmid from an CS6+STh strain was retained in the laboratory strain during 10 passages. A sequence comparison between the CS6 plasmids from a stable and an unstable ETEC isolate revealed that genes necessary for plasmid stabilization, for example pemI, pemK, stbA, stbB and parM, were not present in the unstable ETEC isolate. Our results indicate that stable retention of CS6 may in part be affected by the stability of the plasmid on which both CS6 and STp or STh are located.
|
|
| 17. |
- Trabert, Britton, et al.
(author)
-
Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations
- 2019
-
In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 111:2, s. 129-136
-
Journal article (peer-reviewed)abstract
- Background: Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations.Methods: Studies included: 1) a case-control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case-control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression.Results: In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk.Conclusions: In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.
|
|
| 18. |
- von Mentzer, Astrid, 1983, et al.
(author)
-
Identification and characterization of the novel colonization factor CS30 based on whole genome sequencing in enterotoxigenic Escherichia coli (ETEC)
- 2017
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Journal article (peer-reviewed)abstract
- The ability to colonize the small intestine is essential for enterotoxigenic Escherichia coli (ETEC) to cause diarrhea. Although 22 antigenically different colonization factors (CFs) have been identified and characterized in ETEC at least 30% of clinical ETEC isolates lack known CFs. Ninety-four whole genome sequenced "CF negative" isolates were searched for novel CFs using a reverse genetics approach followed by phenotypic analyses. We identified a novel CF, CS30, encoded by a set of seven genes, csmA-G, related to the human CF operon CS18 and the porcine CF operon 987P (F6). CS30 was shown to be thermo-regulated, expressed at 37 degrees C, but not at 20 degrees C, by SDS-page and mass spectrometry analyses as well as electron microscopy imaging. Bacteria expressing CS30 were also shown to bind to differentiated human intestinal Caco-2 cells. The genes encoding CS30 were located on a plasmid (E873p3) together with the genes encoding LT and STp. PCR screening of ETEC isolates revealed that 8.6% (n = 13) of "CF negative" (n = 152) and 19.4% (n = 13) of " CF negative" LT + STp (n = 67) expressing isolates analyzed harbored CS30. Hence, we conclude that CS30 is common among " CF negative" LT + STp isolates and is associated with ETEC that cause diarrhea. RAHAM JM, 1985, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES
|
|
| 19. |
- von Mentzer, Ula, 1995, et al.
(author)
-
Synovial fluid profile dictates nanoparticle uptake into cartilage - implications of the protein corona for novel arthritis treatments
- 2022
-
In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1522-9653 .- 1063-4584. ; 30:10, s. 1356-1364
-
Journal article (peer-reviewed)abstract
- Objective: Drug delivery strategies for joint diseases need to overcome the negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency by harnessing the anionic charge of the cartilage but have neglected to address potential interactions with the protein-rich biological environment of the joint space. We aimed to evaluate the effects of hard protein coronas derived from osteoarthritis (OA) and rheumatoid arthritis (RA) patient synovial fluids as well as the commonly used fetal calf serum (FCS) on nanoparticle (NP) uptake into tissues and cells. Methods: We developed a NP panel with varying PEGylation and incubated them with synovial fluid from either OA, RA patients or FCS. We evaluated the effects of the formed NP-biocorona complex uptake into the porcine articular cartilage explants, chondrocytes and monocyte cell lines and primary patient FLS cells. Proteins composing hard biocoronas were identified using a quantitative proteomics approach. Results: Formed biocoronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes. The most suitable NP for potential OA applications was identified. A variety of proteins that were found on all NPs, irrespective of surface modifications. NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences. Conclusions: This study demonstrates the impact of protein coronas from OA and RA patient synovial fluids on NP uptake into cartilage, emphasizing the importance of biological microenvironment considerations for successful translation of drug delivery vehicles into clinics.
|
|
| 20. |
- von Mentzer, U., et al.
(author)
-
Synovial fluid profile dictates nanoparticle uptake into cartilage-implications of the protein corona for novel arthritis treatments
- 2022
-
In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 30:10, s. 1356-1364
-
Journal article (peer-reviewed)abstract
- Objective: Drug delivery strategies for joint diseases need to overcome the negatively charged cartilage matrix. Previous studies have extensively investigated particle approaches to increase uptake efficiency by harnessing the anionic charge of the cartilage but have neglected to address potential interactions with the protein-rich biological environment of the joint space. We aimed to evaluate the effects of hard protein coronas derived from osteoarthritis (OA) and rheumatoid arthritis (RA) patient synovial fluids as well as the commonly used fetal calf serum (FCS) on nanoparticle (NP) uptake into tissues and cells.Methods: We developed a NP panel with varying PEGylation and incubated them with synovial fluid from either OA, RA patients or FCS. We evaluated the effects of the formed NP-biocorona complex uptake into the porcine articular cartilage explants, chondrocytes and monocyte cell lines and primary patient FLS cells. Proteins composing hard biocoronas were identified using a quantitative proteomics approach. Results: Formed biocoronas majorly impacted NP uptake into cartilage tissue and dictated their uptake in chondrocytes and monocytes. The most suitable NP for potential OA applications was identified. A variety of proteins that were found on all NPs, irrespective of surface modifications. NP-, and protein-specific differences were also observed between the groups, and candidate proteins were identified that could account for the observed differences.Conclusions: This study demonstrates the impact of protein coronas from OA and RA patient synovial fluids on NP uptake into cartilage, emphasizing the importance of biological microenvironment considerations for successful translation of drug delivery vehicles into clinics. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).
|
|
