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| 3. |
- Michel, M., et al.
(författare)
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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
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Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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| 6. |
- Efe, C., et al.
(författare)
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Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome
- 2021
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Ingår i: Journal of Gastroenterology and Hepatology. - : Wiley. - 0815-9319 .- 1440-1746. ; 36:4, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5%vs86.1%,P < 0.001) and seropositive for anti-mitochondrial antibodies (88%vs84%,P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8%vs43.6%,P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76vs1.98 x upper limit of normal [ULN],P = 0.006), aspartate aminotransferase (1.29vs1.50 x ULN,P < 0.001), and total bilirubin (0.53vs0.58 x ULN,P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3%vs16.1%,P = 0.07) and Paris II response (71.4%vs69.4%,P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8%vs90.7%,P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjogren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. Conclusions Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.
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| 8. |
- Hakkinen, K, et al.
(författare)
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Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder
- 2022
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Ingår i: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1473-1150 .- 1470-269X. ; 22:3, s. 166-172
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.
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| 11. |
- Teixeira, G. Q., et al.
(författare)
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Terminal complement complex formation is associated with intervertebral disc degeneration
- 2021
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Ingår i: European Spine Journal. - : Springer Science and Business Media LLC. - 0940-6719 .- 1432-0932. ; 30, s. 217-226
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The complement system is a crucial part of innate immunity. Recent work demonstrated an unexpected contribution to tissue homeostasis and degeneration. This study investigated for the first time, in human disc tissues, the deposition profile of the complement activation product terminal complement complex (TCC), an inflammatory trigger and inducer of cell lysis, and its inhibitor CD59, and their correlation with the degree of disc degeneration (DD). Methods Disc biopsies were collected from patients diagnosed with DD (n = 39, age 63 +/- 12) and adolescent idiopathic scoliosis (AIS,n = 10, age 17 +/- 4) and compared with discs from healthy Young (n = 11, age 7 +/- 7) and Elder (n = 10, age 65 +/- 15) donors. Immunohistochemical detection of TCC and CD59 in nucleus pulposus (NP), annulus fibrosus (AF) and endplate (EP) was correlated with age, Pfirrmann grade and Modic changes. Results Higher percentage of TCC+ cells was detected in the NP and EP of DD compared to Elder (P < 0.05), and in the EP of Young versus Elder (P < 0.001). In DD, TCC deposition was positively correlated with Pfirrmann grade, but not with Modic changes, whereas for Young donors, a negative correlation was found with age, indicating TCC's involvement not only in DD, but also in early stages of skeletal development. Higher CD59 positivity was found in AIS and DD groups compared to Young (P < 0.05), and it was negatively correlated with the age of the patients. Conclusion TCC deposition positively correlated with the degree of disc degeneration. A functional relevance of TCC may exist in DD, representing a potential target for new therapeutics.
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| 15. |
- Ceder, Mikaela M., et al.
(författare)
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The glycine receptor alpha 3 subunit mRNA expression shows sex-dependent differences in the adult mouse brain
- 2023
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Ingår i: BMC Neuroscience. - : Springer Nature. - 1471-2202. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background The glycinergic system plays an important inhibitory role in the mouse central nervous system, where glycine controls the excitability of spinal itch- and pain-mediating neurons. Impairments of the glycine receptors can cause motor and sensory deficits. Glycine exerts inhibition through interaction with ligand-gated ion channels composed of alpha and beta subunits. We have investigated the mRNA expression of the glycine receptor alpha 3 (Glra3) subunit in the nervous system as well as in several peripheral organs of female and male mice.Results Single-cell RNA sequencing (scRNA-seq) data analysis on the Zeisel et al. (2018) dataset indicated widespread but low expression of Glra3 in vesicular glutamate transporter 2 (Vglut2, Slc17a6) positive and vesicular inhibitory amino acid transporter (Viaat, Slc32a1)positive neurons of the mouse central nervous system. Highest occurrence of Glra3 expression was identified in the cortex, amygdala, and striatal regions, as well as in the hypothalamus, brainstem and spinal cord. Bulk quantitative real-time-PCR (qRT-PCR) analysis demonstrated Glra3 expression in cortex, amygdala, striatum, hypothalamus, thalamus, pituitary gland, hippocampus, cerebellum, brainstem, and spinal cord. Additionally, male mice expressed higher levels of Glra3 in all investigated brain areas compared with female mice. Lastly, RNAscope spatially validated Glra3 expression in the areas indicated by the single-cell and bulk analyses. Moreover, RNAscope analysis confirmed co-localization of Glra3 with Slc17a6 or Slc32a1 in the central nervous system areas suggested from the single-cell data.Conclusions Glra3 expression is low but widespread in the mouse central nervous system. Clear sex-dependent differences have been identified, indicating higher levels of Glra3 in several telencephalic and diencephalic areas, as well as in cerebellum and brainstem, in male mice compared with female mice.
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| 23. |
- Mushtaq, M., et al.
(författare)
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Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:27, s. 15673-15683
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Tidskriftsartikel (refereegranskat)abstract
- Stemness encompasses the capability of a cell for self-renewal and differentiation. The stern cell maintains a balance between proliferation, quiescence, and regeneration via interactions with the microenvironment. Previously, we showed that ectopic expression of the mitochondrial ribosomal protein S18-2 (MRPS18-2) led to immortalization of primary fibroblasts, accompanied by induction of an embryonic stern cell (ESC) phenotype. Moreover, we demonstrated interaction between S18-2 and the retinoblastoma-associated protein (RB) and hypothesized that the simultaneous expression of RB and S18-2 is essential for maintaining cell sternness. Here, we experimentally investigated the role of S18-2 in cell sternness and differentiation. Concurrent expression of RB and S18-2 resulted in immortalization of Rb1(-/-) primary mouse embryonic fibroblasts and in aggressive tumor growth in severe combined immunodeficiency mice. These cells, which express both RB and S18-2 at high levels, exhibited the potential to differentiate into various lineages in vitro, including osteogenic, chondrogenic, and adipogenic lineages. Mechanistically, S18-2 formed a multimeric protein complex with prohibitin and the ring finger protein 2 (RNF2). This molecular complex increased the monoubiquitination of histone H2A(Lys119), a characteristic trait of ESC5, by enhanced E3-ligase activity of RNF2. Furthermore, we found enrichment of KLF4 at the S18-2 promoter region and that the S18-2 expression is positively correlated with KLF4 levels. Importantly, knockdown of S18-2 in zebrafish larvae led to embryonic lethality. Collectively, our findings suggest an important role for S18-2 in cell sternness and differentiation and potentially also in cancerogenesis.
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| 24. |
- Mörtzell Henriksson, Monica, et al.
(författare)
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Analyses of registry data of patients with anti-GBM and antineutrophil cytoplasmatic antibody-associated (ANCA) vasculitis treated with or without therapeutic apheresis
- 2021
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Ingår i: Transfusion and Apheresis Science. - : Elsevier BV. - 1473-0502 .- 1878-1683. ; 60:6
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic apheresis (TA) as a treatment for antibody-associated vasculitis (AAV) was questioned by the PEXIVAS although the MEPEX study favored TA. The aim of this study was to evaluate the efficacy of TA to improve renal function in patients consecutively included in the WAA-apheresis registry versus patients not treated with TA. Materials and methods: Included were 192 patients that suffered from anti-glomerular basement membrane disease (anti-GBM, n = 28) and antineutrophil cytoplasmic antibody-associated vasculitis of MPO or PR3 origin. Of these 119 had performed TA and the other 73 had not performed TA for theses diagnoses (CTRL). Results: Elderly had an increased risk to die within 12 months (p = 0.002). All 28 anti-GBM had renal involvement, 21 dialysis dependent. At 3 month nine (36 %) did not need dialysis. Baseline data regarding renal function of AAV patients, subtype MPO and PR3, were worse in the TA groups than in CTRL. Recovery out of dialysis was better for the PR3-TA group compared with 1) the controls of MEPEX (RR 0.59, CI 0.43−0.80) and 2) the MPO-TA patients (RR 0.28, CI 0.12−0.68). The MPO-TA recovered similarly as the MEPEX-CTRL. Renal function improved most for TA-patients from baseline during the first 3 months (MPO-TA and PR3-TA) and stabilized thereafter and less for MPO-CTRL and PR3-CTRL. Conclusion: PR3-TA patients seem to have best chances to get out of dialysis. PR3-TA and MPO-TA improved residual renal function better than CTRL. The present study recommends reconsiderations to use TA for AAV especially those with PR3-vasculitis with severe renal vasculitis.
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| 25. |
- Navarro, AM, et al.
(författare)
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p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids
- 2020
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 11:1, s. 52-
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we take advantage of human induced pluripotent stem (iPS) cell-derived neural stem cells and brain organoids to study the role of p53 during human brain development. We knocked down (KD) p53 in human neuroepithelial stem (NES) cells derived from iPS cells. Upon p53KD, NES cells rapidly show centrosome amplification and genomic instability. Furthermore, a reduced proliferation rate, downregulation of genes involved in oxidative phosphorylation (OXPHOS), and an upregulation of glycolytic capacity was apparent upon loss of p53. In addition, p53KD neural stem cells display an increased pace of differentiating into neurons and exhibit a phenotype corresponding to more mature neurons compared to control neurons. Using brain organoids, we modeled more specifically cortical neurogenesis. Here we found that p53 loss resulted in brain organoids with disorganized stem cell layer and reduced cortical progenitor cells and neurons. Similar to NES cells, neural progenitors isolated from brain organoids also show a downregulation in several OXPHOS genes. Taken together, this demonstrates an important role for p53 in controlling genomic stability of neural stem cells and regulation of neuronal differentiation, as well as maintaining structural organization and proper metabolic gene profile of neural progenitors in human brain organoids.
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| 26. |
- Nyberg, Oskar, 1985-, et al.
(författare)
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Poultry manure fertilization of Egyptian aquaculture ponds brings more cons than pros
- 2024
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Ingår i: Aquaculture. - 0044-8486 .- 1873-5622. ; 590
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Tidskriftsartikel (refereegranskat)abstract
- Aquaculture is a crucial sector for Egyptian food production, providing a cheap source of animal protein while securing income and employment for a substantial part Egypt's population. Nile tilapia (Oreochromis niloticus) is the most commonly produced fish, usually farmed in earthen ponds around the Northern Delta Lakes. A common practice among farms is to fertilize ponds with chicken manure (CM) in order to increase nutrient levels and promote phytoplankton, consumed by the fish. However, with reports of use of antibiotics in Egypt's poultry sector, and that CM contains residues of antibiotics, antibiotic resistant pathogens and antibiotic resistance genes (ARGs) are production benefits large enough to compensate a potential health hazard?Using production data from 501 aquaculture farms and fish pond sediment from 28 ponds we evaluated potential benefits in yields and profitability for farms using CM for fertilization, and used qPCRs to screen sediments for three antibiotic resistance genes coding for resistance to the most commonly used antibiotics in the poultry sector. The analysis showed no significant benefits to fish yields or profitability in farms where CM was applied, but a risk of significantly increased nutrient loads. Meanwhile, we detected increased abundances of tetA and tetW resistance genes in fish pond sediment where CM was applied. With the risk of disseminating ARGs and causing eutrophication of local waterways, we recommend that Egyptian tilapia pond farmers refrain from using CM and adopt best management practices for increasing farm profitability in order to to reduce environmental and health hazards.
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| 27. |
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| 28. |
- Verberk, Janneke D. M., et al.
(författare)
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The augmented value of using clinical notes in semi-automated surveillance of deep surgical site infections after colorectal surgery
- 2023
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Ingår i: Antimicrobial Resistance and Infection Control. - 2047-2994. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients who underwent colorectal surgery, an existing semi-automated surveillance algorithm based on structured data achieves high sensitivity in detecting deep surgical site infections (SSI), however, generates a significant number of false positives. The inclusion of unstructured, clinical narratives to the algorithm may decrease the number of patients requiring manual chart review. The aim of this study was to investigate the performance of this semi-automated surveillance algorithm augmented with a natural language processing (NLP) component to improve positive predictive value (PPV) and thus workload reduction (WR).MethodsRetrospective, observational cohort study in patients who underwent colorectal surgery from January 1, 2015, through September 30, 2020. NLP was used to detect keyword counts in clinical notes. Several NLP-algorithms were developed with different count input types and classifiers, and added as component to the original semi-automated algorithm. Traditional manual surveillance was compared with the NLP-augmented surveillance algorithms and sensitivity, specificity, PPV and WR were calculated.ResultsFrom the NLP-augmented models, the decision tree models with discretized counts or binary counts had the best performance (sensitivity 95.1% (95%CI 83.5-99.4%), WR 60.9%) and improved PPV and WR by only 2.6% and 3.6%, respectively, compared to the original algorithm.ConclusionsThe addition of an NLP component to the existing algorithm had modest effect on WR (decrease of 1.4-12.5%), at the cost of sensitivity. For future implementation it will be a trade-off between optimal case-finding techniques versus practical considerations such as acceptability and availability of resources.
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| 29. |
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| 30. |
- Weman, Hannah M., 1993-, et al.
(författare)
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Spinal Glycine Receptor Alpha 3 Cells Communicate Sensations of Chemical Itch in Hairy Skin
- 2024
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 44:19
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Tidskriftsartikel (refereegranskat)abstract
- Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, but the identity and role of the glycineregulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 (Glra3) subunit-expressing neurons in Glra3-Cre female and male mice. Glra3-Cre(+) neurons express Glra3, are located mainly in laminae III-VI, and respond to glycine. Chemogenetic activation of spinal Glra3-Cre(+) neurons induced biting/licking, stomping, and guarding behaviors, indicative of both a nociceptive and pruriceptive role for this population. Chemogenetic inhibition did not affect mechanical or thermal responses but reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for these neurons. Spinal cells activated by compound 48/80 or chloroquine express Glra3, further supporting the phenotype. Retrograde tracing revealed that spinal Glra3-Cre(+) neurons receive input from afferents associated with pain and itch, and dorsal root stimulation validated the monosynaptic input. In conclusion, these results show that spinal Glra3(+) neurons contribute to acute communication of compound 48/80- and chloroquine-induced itch in hairy skin.
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| 35. |
- Argyropoulos, Dimitris D. S., et al.
(författare)
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Kraft Lignin: A Valuable, Sustainable Resource, Opportunities and Challenges
- 2023
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Ingår i: ChemSusChem. - : John Wiley and Sons Inc. - 1864-5631 .- 1864-564X. ; 16:23
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Forskningsöversikt (refereegranskat)abstract
- Kraft lignin, a by-product from the production of pulp, is currently incinerated in the recovery boiler during the chemical recovery cycle, generating valuable bioenergy and recycling inorganic chemicals to the pulping process operation. Removing lignin from the black liquor or its gasification lowers the recovery boiler load enabling increased pulp production. During the past ten years, lignin separation technologies have emerged and the interest of the research community to valorize this underutilized resource has been invigorated. The aim of this Review is to give (1) a dedicated overview of the kraft process with a focus on the lignin, (2) an overview of applications that are being developed, and (3) a techno-economic and life cycle asseeements of value chains from black liquor to different products. Overall, it is anticipated that this effort will inspire further work for developing and using kraft lignin as a commodity raw material for new applications undeniably promoting pivotal global sustainability concerns.
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| 36. |
- Arias Tellez, Maria Jose, et al.
(författare)
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Association of Neck Circumference with Anthropometric Indicators and Body Composition Measured by DXA in Young Spanish Adults
- 2020
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Due to a clinical and public health interest of neck circumference (NC), a better understanding of this simple anthropometric measurement, as a valid marker of body composition is necessary. Methods: A total of 119 young healthy adults participated in this study. NC was measured over the thyroid cartilage and perpendicular to the longitudinal axis of the neck. Body weight, height, waist circumference (WC), and hip circumference were measured. A Dual X-ray absorptiometry (DXA) scan was used to determine fat mass, lean mass, and visceral adipose tissue (VAT). Additionally, body mass index (BMI) and triponderal mass index (TMI), the waist to hip and waist to height ratios, and the fat mass and lean mass indexes (FMI and LMI, respectively) were calculated. Results: NC was positively associated in women (W) and men (M), with BMI (rW = 0.70 and rM = 0.84, respectively), TMI (rW = 0.63 and rM = 0.80, respectively), WC (rW = 0.75 and rM = 0.86, respectively), VAT (rW = 0.74 and rM = 0.82, respectively), Waist/hip (rW = 0.51 and rM = 0.67, respectively), Waist/height (rW = 0.68 and rM = 0.83, respectively) and FMI (rW = 0.61 and rM = 0.81, respectively). The association between NC and indicators of body composition was however weaker than that observed by BMI, TMI, WC and Waist/height in both women and men. It is of note that in women, NC was associated with FMI, VAT and LMI independently of BMI. In men, adding NC to anthropometric variables did not improve the prediction of body composition, while slight improvements were observed in women. Conclusions: Taken together, the present study provides no indication for NC as a useful proxy of body composition parameters in young adults, yet future studies should explore its usefulness as a measure to use in combination with BMI, especially in women.
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| 37. |
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| 38. |
- Berglund, Jennie, et al.
(författare)
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Wood hemicelluloses exert distinct biomechanical contributions to cellulose fibrillar networks
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Hemicelluloses, a family of heterogeneous polysaccharides with complex molecular structures, constitute a fundamental component of lignocellulosic biomass. However, the contribution of each hemicellulose type to the mechanical properties of secondary plant cell walls remains elusive. Here we homogeneously incorporate different combinations of extracted and purified hemicelluloses (xylans and glucomannans) from softwood and hardwood species into self-assembled networks during cellulose biosynthesis in a bacterial model, without altering the morphology and the crystallinity of the cellulose bundles. These composite hydrogels can be therefore envisioned as models of secondary plant cell walls prior to lignification. The incorporated hemicelluloses exhibit both a rigid phase having close interactions with cellulose, together with a flexible phase contributing to the multiscale architecture of the bacterial cellulose hydrogels. The wood hemicelluloses exhibit distinct biomechanical contributions, with glucomannans increasing the elastic modulus in compression, and xylans contributing to a dramatic increase of the elongation at break under tension. These diverging effects cannot be explained solely from the nature of their direct interactions with cellulose, but can be related to the distinct molecular structure of wood xylans and mannans, the multiphase architecture of the hydrogels and the aggregative effects amongst hemicellulose-coated fibrils. Our study contributes to understanding the specific roles of wood xylans and glucomannans in the biomechanical integrity of secondary cell walls in tension and compression and has significance for the development of lignocellulosic materials with controlled assembly and tailored mechanical properties.
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| 39. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 40. |
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| 41. |
- Chary, Killian, et al.
(författare)
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Transforming sustainable aquaculture by applying circularity principles
- 2024
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Ingår i: Reviews in Aquaculture. - 1753-5123 .- 1753-5131. ; 16:2, s. 656-673
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Forskningsöversikt (refereegranskat)abstract
- A circular economy is considered one way to reduce environmental impacts of human activities, by more efficient use of resources and recovery, resulting in less waste and emissions compared to linear take-make-dispose systems. Muscat et al. developed five ecological principles to guide biomass use towards a circular economy. A few studies have demonstrated environmental benefits of applying these principles to land-based food systems, but to date, these principles have not been explored in aquaculture. The current study expands on these principles and provides a narrative review to (i) translate them to aquaculture, while identifying implications for the main species and production systems, and (ii) identify the main pathways to make aquaculture more circular. We show that the underlying concepts of the ‘safeguard’, ‘entropy’, and ‘recycle’ principles have been well researched and sometimes well implemented. In contrast, the ‘avoid’ and ‘prioritise’ principles have been explored much less; doing so would provide an opportunity to decrease environmental impacts of aquaculture at the food-system level. One example is prioritising the production of species that contribute to food and nutrition security, have low environmental impacts and thinking at wider food system scale to avoid feed-food competition in aquaculture. We identified six priorities that could make aquaculture more circular: (i) increase production and demand for the most essential species, (ii) decrease food loss and waste at farm and post-harvest stages, (iii) support nutrient recycling practices at multiple scales, (iv) adapt aquafeed formulations, (v) inform consumers about benefits of species of low trophic levels and other environmentally friendly aquatic foods, and (vi) address urgent research gaps.
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| 42. |
- Chen, C., et al.
(författare)
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Increasing Childrens physical Activity by Policy (CAP) in preschools within the Stockholm region : study protocol for a pragmatic cluster-randomized controlled trial
- 2022
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Ingår i: Trials. - : BMC. - 1745-6215. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Systematic reviews suggest that preschool environmental/organizational changes may be effective in increasing physical activity (PA) levels of preschool children, but evidence is scarce regarding feasible, effective, and equitable interventions that can be scaled up. Specifically, it is essential to understand whether introducing a multicomponent organizational change in terms of policy in the preschool context may be beneficial for childrens PA levels and concomitant health outcomes. To bridge this knowledge gap, our main aim is to examine the feasibility and effectiveness of a policy package in increasing PA levels in preschool children, using a large-scale pragmatic cluster-randomized controlled trial. Methods: This proposed study is a pragmatic cluster-randomized controlled trial with two conditions (intervention and control with a 1:1 ratio) with preschools as clusters and the unit of randomization. We aim to recruit approximately 4000 3-5-year-old children from 90 preschools and retain more than 2800 children from 85 preschools to provide adequate statistical power for the analyses. The intervention to implement is a co-created, multicomponent policy package running for 6 months in preschools randomized to intervention. Change in accelerometer measured PA levels in children between intervention and control from pre- and post-intervention will be the primary outcome of the study, while secondary outcomes include health outcomes such as musculoskeletal fitness, psychosocial functioning, and absence due to illness in children among others. Implementation will be studied carefully using both quantitative (dose, fidelity) and qualitative (interview) methodologies. The change in primary and secondary outcomes, from pre- to post-intervention, will be analyzed with linear mixed-effect models (to allow both fixed and random effects) nested on a preschool level. Discussion: This is a large-scale co-creation project involving the City of Stockholm, childcare stakeholders, preschool staff, and the research group with the potential to influence more than 30,000 preschool children within the Stockholm area. The study will add reliable evidence for the implementation of PA policies at the organizational level of preschools and clarify its potential effect on objectively measured PA and health markers in children.
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| 43. |
- Chotiwan, Nunya, et al.
(författare)
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Type I interferon shapes brain distribution and tropism of tick-borne flavivirus
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.
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| 44. |
- De-la-O, A., et al.
(författare)
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Association of Energy and Macronutrients Intake with S-Klotho Plasma Levels in Middle-Aged Sedentary Adults: A Cross-Sectional Study
- 2022
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Ingår i: The Journal of Nutrition, Health & Aging. - : SPRINGER FRANCE. - 1279-7707 .- 1760-4788. ; 26, s. 360-367
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Tidskriftsartikel (refereegranskat)abstract
- Background The ageing process can be influenced by energy intake and different macronutrients within the diet. The soluble form of the a-Klotho gene (called S-Klotho) is widely considered as a powerful anti-ageing biomarker. Objective To analyze the association of energy, dietary energy density and macronutrient intake with S-Klotho plasma levels in middle-aged sedentary adults. Methods A total of 72 (52.8% women) middle-aged sedentary adults (53.7 +/- 5.2 years old) participated in the study. Energy and macronutrients intake (i.e. fat, carbohydrate and protein) were assessed using three non-consecutive 24-h recalls. S-Klotho plasma levels were measured in the Ethylenediaminetetraacetic acid (EDTA) plasma using a solid-phase sandwich enzyme-linked immunosorbent assay. Results No association was observed between energy, dietary energy density or macronutrient intake and S-Klotho plasma levels in men (all P >= 0.1). We found an inverse association between energy, protein and carbohydrate intake with S-Klotho plasma levels in women (all P <= 0.043), which disappeared after controlling for age, lean mass index and sedentary time. An inverse association was observed between dietary energy density and S-Klotho plasma levels in women after controlling for covariates (all P <= 0.05). Conclusion In summary, the present study showed an inverse association of dietary energy density with S-Klotho plasma levels in middle-aged women. In addition, our data suggest that the associations between energy and macronutrient intake could be highly dependent on lean mass and sedentary time.
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| 45. |
- Demmelmaier, Ingrid, 1960-, et al.
(författare)
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Does exercise intensity matter for fatigue during (neo-)adjuvant cancer treatment? The Phys-Can randomized clinical trial
- 2021
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : Wiley. - 0905-7188 .- 1600-0838. ; 31:5, s. 1144-1159
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Tidskriftsartikel (refereegranskat)abstract
- Exercise during cancer treatment improves cancer-related fatigue (CRF), but the importance of exercise intensity for CRF is unclear. We compared the effects of high- vs low-to-moderate-intensity exercise with or without additional behavior change support (BCS) on CRF in patients undergoing (neo-)adjuvant cancer treatment. This was a multicenter, 2x2 factorial design randomized controlled trial (Clinical Trials NCT02473003) in Sweden. Participants recently diagnosed with breast (n = 457), prostate (n = 97) or colorectal (n = 23) cancer undergoing (neo-)adjuvant treatment were randomized to high intensity (n = 144), low-to-moderate intensity (n = 144), high intensity with BCS (n = 144) or low-to-moderate intensity with BCS (n = 145). The 6-month exercise intervention included supervised resistance training and home-based endurance training. CRF was assessed by Multidimensional Fatigue Inventory (MFI, five subscales score range 4-20), and Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F, score range 0-52). Multiple linear regression for main factorial effects was performed according to intention-to-treat, with post-intervention CRF as primary endpoint. Overall, 577 participants (mean age 58.7 years) were randomized. Participants randomized to high- vs low-to-moderate-intensity exercise had lower physical fatigue (MFI Physical Fatigue subscale; mean difference −1.05 [95% CI: −1.85, −0.25]), but the difference was not clinically important (ie <2). We found no differences in other CRF dimensions and no effect of additional BCS. There were few minor adverse events. For CRF, patients undergoing (neo-)adjuvant treatment for breast, prostate or colorectal cancer can safely exercise at high- or low-to-moderate intensity, according to their own preferences. Additional BCS does not provide extra benefit for CRF in supervised, well-controlled exercise interventions.
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| 46. |
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| 47. |
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| 48. |
- Espinoza, JA, et al.
(författare)
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The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity
- 2020
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 27:2, s. 773-789
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy.
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| 49. |
- Gineste, Charlotte, et al.
(författare)
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Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control
- 2022
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Ingår i: iScience. - : Elsevier. - 2589-0042. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. By comparing adult mouse skeletal muscle fibers, isolated either by mechanical dissection or by collagenase-induced ECM digestion, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling. RNA-sequencing showed striking differences in gene expression patterns between the two isolation methods with enzymatically dissociated fibers resembling myopathic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria following enzymatic dissociation. Repeated contractions resulted in a prolonged mitochondrial Ca2+ accumulation in enzymatically dissociated fibers, which was partially prevented by cyclophilin inhibitors. Of importance, muscle fibers of mice with severe mitochondrial myopathy show pathognomonic mitochondrial Ca2+ accumulation during repeated contractions and this accumulation was concealed with enzymatic dissociation, making this an ambiguous method in studies of native intracellular Ca2+ fluxes.
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