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| 2. |
- Mahdessian, Diana, et al.
(författare)
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Spatiotemporal dissection of the cell cycle with single-cell proteogenomics
- 2021
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 590:7847
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Tidskriftsartikel (refereegranskat)abstract
- Spatial and temporal variations among individual human cell proteomes are comprehensively mapped across the cell cycle using proteomic imaging and transcriptomics. The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer(1-3). The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.
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| 3. |
- Mutanen, Annika, et al.
(författare)
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A nordic multicenter study on contemporary outcomes of pediatric short bowel syndrome in 208 patients
- 2023
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Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 42:7, s. 1095-1103
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Despite advances in the management of short bowel syndrome related intestinal failure (SBS-IF), large-scale contemporary pediatric studies are scarce. The aim of this multicenter study was to assess key outcomes and clinical prognostic factors in a recent Nordic pediatric SBS-IF population.Methods: Patients with SBS-IF treated during 2010-2019, whose parenteral support (PS) started at age <1 year and continued >60 consecutive days were included and retrospectively reviewed. All six participating centers followed multidisciplinary SBS-IF management. Risk factors for PS dependency, intestinal failure associated liver disease (IFALD) and mortality were assessed with Cox regression and Kaplan Meier analyses. IFALD was defined with serum liver biochemistry levels.Results: Among 208 patients, SBS-IF resulted from NEC in 49%, gastroschisis w/wo atresia in 14%, small bowel atresia in 12%, volvulus in 11%, and other diagnoses in 14%. Median age-adjusted small bowel length was 43% (IQR 21-80%). After median follow up of 4.4 years (IQR 2.5-6.9), enteral autonomy was reached by 76%, none had undergone intestinal transplantation, and overall survival was 96%. Half of deaths (4/8) were caused by septic complications. Although biochemical cholestasis occurred only in 3% at latest follow-up and none of deaths were directly caused by IFALD, elevated liver biochemistry (HR 0.136; P = 0.017) and shorter remaining small bowel (HR 0.941; P = 0.040) predicted mortality. Shorter remaining small bowel and colon, and presence of end-ostomy were the main predictors of PS dependency, but not IFALD. Patients with NEC reached enteral autonomy more efficiently and had decreased incidence of IFALD compared to other etiologies.Conclusions: Although with current multidisciplinary management, prognosis of pediatric SBS is encouraging, septic complications and IFALD still associated with the remaining low mortality rate.
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| 4. |
- Stenström, Lovisa, et al.
(författare)
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Mapping the nucleolar proteome reveals a spatiotemporal organization related to intrinsic protein disorder
- 2020
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Ingår i: Molecular Systems Biology. - : Wiley. - 1744-4292 .- 1744-4292. ; 16:8
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Tidskriftsartikel (refereegranskat)abstract
- The nucleolus is essential for ribosome biogenesis and is involved in many other cellular functions. We performed a systematic spatiotemporal dissection of the human nucleolar proteome using confocal microscopy. In total, 1,318 nucleolar proteins were identified; 287 were localized to fibrillar components, and 157 were enriched along the nucleoplasmic border, indicating a potential fourth nucleolar subcompartment: the nucleoli rim. We found 65 nucleolar proteins (36 uncharacterized) to relocate to the chromosomal periphery during mitosis. Interestingly, we observed temporal partitioning into two recruitment phenotypes: early (prometaphase) and late (after metaphase), suggesting phase-specific functions. We further show that the expression ofMKI67 is critical for this temporal partitioning. We provide the first proteome-wide analysis of intrinsic protein disorder for the human nucleolus and show that nucleolar proteins in general, and mitotic chromosome proteins in particular, have significantly higher intrinsic disorder level compared to cytosolic proteins. In summary, this study provides a comprehensive and essential resource of spatiotemporal expression data for the nucleolar proteome as part of the Human Protein Atlas.
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| 5. |
- Stenström, Lovisa
(författare)
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The spatiotemporal protein landscape of human cells
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the spatiotemporal mapping of proteins at a subcellular level. In other words, determining the cellular location of proteins over time. From a biological point of view, knowledge about protein location is fundamental to understand protein function. In the longer run, this also means better understanding of cells in the context of health and disease, since protein malfunction and mislocalization are two important factors during disease development. Using an antibody-based imaging approach, Paper I contains a subcellular map of 12 003 protein in 30 different cellular structures, freely accessible as part of the Human Protein Atlas (www.proteinatlas.org). Apart from enabling exploration of the organellar proteomes, we conclude that half of the human proteins localize to multiple compartments, and that almost one fifth display cell-to-cell variations in terms of protein expression. Paper II aimed to decrease the cumbersome work of manual protein location annotations by leveraging the power of the crowd through citizen science. By integrating the image-classification task into a video game with a massive player base, EVE online, protein location labels could be efficiently and rapidly assessed compared to manual curation from a few experts. To compare the performance of the players, a deep learning classifier was developed. The algorithm was capable of classifying protein location in images containing several challenging localization problems, such as multilocalizing proteins, cell line variations and rare classes. Using the protein location data from Paper I and Paper II, Paper III presents an image-based characterization of the nucleolar proteome. In total, 1 318 nucleolar proteins are included, of which 157 localizes to a fourth nucleolar compartment, the nucleolar rim. Additionally, 65 proteins were detected on the chromosomal periphery during mitosis, and these could be further divided into two recruitment phenotypes with different temporal profiles. Also, the mitotic chromosome proteins are enriched for intrinsically disordered domains, suggesting liquid-like properties of the perichromosomal layer. Paper IV presents a systematic dissection of the variable proteome drafted in Paper I. We show evidence for 539 proteins being correlated to cell cycle variations, of which a minority are also cycling at a transcriptional level, suggesting protein regulation at a translational or post-translational level. Additionally, we detected hundreds of proteins with previously unknown relations to mitosis and the cell cycle, many being linked to proliferation and oncogenic functions.In conclusion, Paper I and Paper II provide a basis for further in-depth studies of proteins at a subcellular level, while Paper III and Paper IV show how this resource can be used to study proteins in space and time. The results enable system-level investigation of protein dynamics, as well as provide exciting insights into organellar organization, such as the nucleolus.
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| 6. |
- Telborn, Lovisa, et al.
(författare)
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Children with Hirschsprung’s Disease Report Dietary Effects on Gastrointestinal Complaints More Frequently than Controls
- 2023
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Ingår i: Children. - 2227-9067. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Hirschspung’s disease (HD) is a congenital gastrointestinal (GI) disorder frequently accompanied by GI complaints. Despite the lack of evidence regarding whether diet affects GI symptoms, advice on dietary changes is common. The aim was to investigate self-reported dietary effects on GI symptoms, comparing children with HD with healthy children. This was an observational, cross-sectional, self-reported case-control study using the validated Diet and Bowel Function questionnaire. All children with HD aged 1–18 years were surgically treated during 2003–2021 at a national HD center, and their parents were invited to participate. Healthy children served as controls. The data were presented as median (range) and n (%). 71/85 children with HD (6 years (1–17); 76% boys) and 265/300 controls (9 years (1–18); 52% boys) participated. Dietary effects on GI symptoms were reported more frequently by children with HD than controls (55/71 [77%] vs. 137/265 [52%], p ≤ 0.001), as were dietary adjustments to improve GI symptoms (49/71 [69%] vs. 84/265 [32%], p ≤ 0.001), and social limitations due to dietary adjustments (20/48 [42%] vs. 22/121 [18%], p = 0.002). Of 90 food items, children with HD reported that more of the items induced GI symptoms compared to controls (7 (0–66) vs. 2 (0–34), p = 0.001). Diet-induced GI symptoms and dietary adjustments’ impact on daily life are reported more frequently by children with HD than controls. Moreover, the number and types of food items causing GI symptoms differ. The results indicate the need for disease-specific dietary advice to improve support for families of children with HD.
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| 7. |
- Telborn, Lovisa, et al.
(författare)
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Diet and bowel function in children with Hirschsprung's disease : development and content validation of a patient-reported questionnaire
- 2023
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Ingår i: BMC Nutrition. - : BioMed Central (BMC). - 2055-0928. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAlthough dietary adjustments are recommended frequently for bowel symptoms, evidence of diet's impact on bowel function is lacking. The aim was to develop a patient-reported outcome instrument, for children with and without Hirschsprung's disease (HD), to explore experiences of dietary effects on bowel function.MethodsChildren with and without HD and their parents participated. Questionnaire items regarding the impact of diet on bowel function originated from focus group discussions. Specific food items, reported in the literature or in focus groups to cause bowel functional effects, were listed requesting each item's effect size and effect type. Content validity was tested within two separate semistructured interviews. A pilot test was performed. Assessing comprehension, relevance and wording clarity structurally, revisions were made accordingly. Children's bowel function was assessed through the validated Rintala Bowel Function Score.ResultsA total of 13 children with and without HD, median age 7 (range 2-15) years, and 18 parents participated in the validation. Each question's relevance had been ranked highly early in the validation process but most questions needed refining for improving clarity and comprehension. Wordings regarding bowel symptoms and emotions connected to food in particular were perceived to be sensitive and complex. Specifically wording regarding some bowel symptoms (gases, pain) and parental stress emotions (guilt, ambivalence) were, consistent with participants' opinions, subjected to multiple step revisions. Following the validation process, which included two semistructure interviews with different participants and then a pilot test with a third cohort, a full track overview of changes and rewording made in all steps of the validation process was presented. The final questionnaire then comprised 13 questions assessing foods' significance for bowel function, emotions, social impact and 90 specific food items' possible effects and effect sizes on bowel function.ConclusionsThe Diet and Bowel Function questionnaire, enabling answering by children, was developed and the content validated qualitatively. This report presents insights into the whole validation process, declaring reasons for the selected question- and answering options, and their wordings. The Diet and Bowel Function questionnaire can be used as a survey questionnaire to enhance understanding of dietary effects on bowel function in children, and its results can be supportive in improving dietary-treatment programs.
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| 8. |
- Telborn, Lovisa, et al.
(författare)
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Diet plays a central role in parental self-treatment of children with Hirschsprung’s disease : a qualitative study
- 2021
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253.
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Tidskriftsartikel (refereegranskat)abstract
- AimHirschsprung's disease is a congenital disorder requiring surgery. Most children operated on for Hirschsprung's disease experience postoperative bowel dysmotility. Although various food is known to influence bowel motility, evidence of diet's role and dietary guidelines in treatment of bowel dysfunction in Hirschsprung's disease is lacking. The aim was to explore parental experiences of dietary effects on bowel function in children with Hirschsprung's disease.MethodsA qualitative study including three focus groups with ten parents of children with Hirschsprung's disease at a national Hirschsprung's disease centre. Data were analysed through content analysis.ResultsParents emphasised diet as a strong influencer on their child's bowel function in Hirschsprung's disease. They expressed great concerns about their responsibility and strived hard to explore and adjust dietary habits to control the child's bowel function. Families’ daily and social lives were influenced by the child's diet and bowel function. The parents desired dietary support and guidelines to improve their confidence in self-treatment of Hirschsprung's disease.ConclusionDietary habits play a key role in parental self-treatment of bowel function in their children with Hirschsprung's disease. Dietary guidelines for patients with Hirschsprung's disease are anticipated.
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| 9. |
- Telborn, Lovisa, et al.
(författare)
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Self-Reported Effects of Diet on Gastrointestinal Symptoms in Healthy Children
- 2023
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition. - 1536-4801. ; 77:3, s. 433-438
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Evidence on dietary effects on gastrointestinal (GI) symptoms in healthy children is lacking. Despite this, dietary advice is still common practice in the treatment of children's GI symptoms. The aim was to investigate self-reported dietary effects on GI symptoms in healthy children. METHODS: In this observational cross-sectional study on children, a validated self-reporting questionnaire including 90 specified food items was used. Healthy children aged 1-18 years old and their parents were invited to participate. Descriptive data were presented as median (range) and n (%). RESULTS: In total, 265 of 300 children (9 years [1-18]; 52% boys) answered the questionnaire. Overall, 21 of 265 (8%) reported that diet induced GI symptoms regularly. In total, 2 (0-34) food items were reported per child as inducing GI symptoms. The most frequently reported items were beans (24%), plums (21%), and cream (14%). More children with GI symptoms (constipation, abdominal pain, troublesome gases) than with No/Seldom GI symptoms reported that diet could potentially induce GI symptoms (17/77 [22%] vs 4/188 [2%], P ≤ 0.001). Furthermore, they adjusted their diet to regulate GI symptoms (16/77 [21%] vs 8/188 [4%], P ≤ 0.001). CONCLUSIONS: Few healthy children reported that diet induced GI symptoms, and only a minority of food items were reported to induce GI symptoms. Children who had already experienced GI symptoms reported that diet impacted on GI symptoms to a greater, but still very limited, extent. Results can be used to determine accurate expectations and goals of dietary treatment of GI symptoms in children.
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