| 1. |
- Patterson, Nick, et al.
(författare)
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Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
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Tidskriftsartikel (refereegranskat)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
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| 2. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 3. |
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| 4. |
- Hallman, David, 1979-, et al.
(författare)
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Symposium: Arbete, individ och nacksmärta : Forskning vid Forte-centret “Kroppen i arbete – från problem till potential”
- 2018
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Ingår i: FALF KONFERENS 2018 Arbetet - problem eller potential för en hållbar livsmiljö? 10-12 juni 2018 i Gävle. - Gävle : Gävle University Press. - 9789188145284 ; , s. 102-
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Konferensbidrag (refereegranskat)abstract
- Besvär ifrån kroppens muskler och leder såsom nack- och ryggbesvär är fortfarande ett stort problem inom arbetslivet. Muskuloskeletal diagnos är den vanligaste orsaken till lång sjukfrånvaro inom privat sektor och näst vanligast inom kommuner och landsting. Orsakerna till dessa besvär kan vara relaterade till exponering både under arbete och på fritid, men även till individfaktorer. Vår forskargrupp har en bred ansats för att fylla kunskapsluckor inom detta område och kommer att presentera resultat från flera forskningsprojekt i symposiet Arbete, individ och nacksmärta.Långvarigt sittande har blivit alltmer vanligt förekommande i många yrkesgrupper. Långvarigt sittande och låg fysisk aktivitet har också uppmärksammats som ett betydande hälsoproblem i dagens arbetsliv och även som en möjlig riskfaktor för smärta i nacke-skuldra. Men forskningen om betydelsen av långvarigt sittande för smärta i nacke-skuldra är fortfarande begränsad. Likaså är det oklart om huvudets hållning vid sittandet och nackens funktion, exempelvis nackens rörelsefunktion och styrka, har betydelse för besvärsutveckling. Statiskt arbete med nacken i vridna och böjda positioner misstänks vara en riskfaktor för nack-skuldersmärta i yrken såsom tandläkare, men det är oklart varför vissa exponerade individer drabbas medan andra inte får ont. För de med långvarig smärta krävs ofta rehabiliterande åtgärder, och hur väl dessa åtgärder lyckas kan även det vara beroende av individens fysiska och psykosociala arbetsmiljö. Individens arbetsmiljö påverkar således inte bara risken för om man får besvär utan kan också ha betydelse för hur rehabiliteringen av besvären lyckas.Syftet med detta symposium är att presentera studier från Centrum för belastningsskadeforskning som handlar om nacksmärta i arbetslivet, sammanfatta kunskapsläget inom området och diskutera hur arbetet kan utformas för att bli hållbart och inkluderande. De forskningsexempel som presenteras berör stillasittande och hållning i arbetslivet och dess tänkbara konsekvenser för nacksmärta och hälsa, riskfaktorer för nacksmärta i tandläkaryrket och arbetsmiljöns betydelse för resultatet av rehabilitering vid nacksmärta. Symposiet avslutas med en frågestund och gemensam diskussion.
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| 5. |
- Heiden, Thomas
(författare)
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Clinical fluorescence cytometry : improvements to preparation methods and instrumentation
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fluorescence cytometry, which can be carried out by flow or image cytometry (FCM, ICM), provides a highly sensitive and specific tool for quantitative analysis of cell material. It is emerging from being a pure research method and becoming an important adjunct to clinical practice. To better realize its potential, more research is needed. This thesis focuses on improvements to preparation methods and instrumentation. DNA flow cytometry of cells from solid tumors can be used to analyze ploidy and proliferation in tumor cell populations and it appears to hold a considerable potential in terms of predicting the aggressiveness of the lesions. In this thesis, a technique for enucleation of tissues is presented that is based on formalin fixation and protease treatment. In fresh tissues, the procedure generates minimal amounts of debris and, in both embedded and fresh tissues, it produces suspensions of cell nuclei with good stainability of DNA and extremely low levels of aggregation. Low debris and aggregate levels are advantageous for high sensitivity in the analysis. The new method was applied to the preparation of fresh tumor tissues and compared with the widely used Vindelöv technique. We found that it is preferable to use the new method since it produces less debris and aggregates. Furthermore, different algorithms for post-acquisition subtraction of "background" were compared. The best correction was obtained with a combined cut-nuclei aggregate correction algorithm. To give a quantitative estimate of the certainty of S-phase measurement for proliferation analysis, a procedure was developed, that takes into account the magnitude of the "background", the resolution of the analysis, the ploidy level and the number of measured cells. A significant correlation was found between S-phase values measured by FCM and ICM in paired clinical samples. The low coefficient of correlation in this comparison was attributed to the high random error due to low cell numbers in ICM histograms. In the analysis of cells labeled with multiple fluorophores, the sensitivity of the fluorescence analysis can be reduced as a result of spectral overlap of the dyes; such overlap often gives contributions of one fluorochrome's fluorescence in the other's analysis. To obtain specific isolation of fluorochrome emission in double fluorescence FCM, the comparatively simple and inexpensive two-wavelength optics that uses a single mercury arc lamp was implemented. With this optical system, correlated measurements of cellular DNA and protein were done. Furthermore, another low-budget optical system for specific fluorescence analysis by FCM was developed employing a combination of mercury arc lamp and argon-ion laser. This system was used in an assay for analysis of ploidy, proliferation and apoptosis in paraffin-embedded material. In retrospective investigations, such analysis has the potential to provide integrated information about tumor cell gain and cell loss, i.e. tumor growth. Furthermore, a double fluorescence microscope was developed for simultaneous visual perception of two specific fluorescence images in real-time and quantitative measurement.
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| 6. |
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| 7. |
- Luengo, Alba, et al.
(författare)
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Increased demand for NAD + relative to ATP drives aerobic glycolysis
- 2021
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-4164 .- 1097-2765. ; 81:4, s. 691-707.e6
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Tidskriftsartikel (refereegranskat)abstract
- Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP. Aerobic glycolysis is associated with proliferation in many biological contexts, yet what drives this phenotype has not been fully explained. Luengo et al. show that cells engage in aerobic glycolysis when the demand for NAD+ exceeds the demand for ATP, which leads to impaired NAD+ regeneration by mitochondrial respiration.
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| 8. |
- Qazi, Khaleda Rahman, et al.
(författare)
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Extremely Preterm Infants Have Significant Alterations in Their Conventional T Cell Compartment during the First Weeks of Life
- 2020
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 204:1, s. 68-77
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Tidskriftsartikel (refereegranskat)abstract
- Extremely preterm neonates are particularly susceptible to infections, likely because of severely impaired immune function. However, little is known on the composition of the T cell compartment in early life in this vulnerable population. We conducted a comprehensive phenotypic flow cytometry-based longitudinal analysis of the peripheral conventional T cell compartment of human extremely low gestational age neonates (ELGAN) with extremely low birth weight (ELBW; amp;lt;1000 g) participating in a randomized placebo-controlled study of probiotic supplementation. PBMCs from ELGAN/ELBW neonates were collected at day 14, day 28, and postmenstrual week 36. Comparisons were made with full-term 14-d-old neonates. Total CD4(+) and CD8(+) T cell frequencies were markedly lower in the preterm neonates. The reduction was more pronounced among the CD8(+) population, resulting in an increased CD4/CD8 ratio. The preterm infants were also more Th2 skewed than the full-term infants. Although the frequency of regulatory T cells seemed normal in the ELGAN/ELBW preterm neonates, their expression of the homing receptors alpha 4 beta 7, CCR4, and CCR9 was altered. Notably, ELGAN/ELBW infants developing necrotizing enterocolitis before day 14 had higher expression of CCR9 in CD4(+)T cells at day 14. Chorioamnionitis clearly associated with reduced T regulatory cell frequencies and functional characteristics within the preterm group. Finally, probiotic supplementation with Lactobacillus reuteri did not impose any phenotypic changes of the conventional T cell compartment. In conclusion, notable immaturities of the T cell compartment in ELGAN/ELBW neonates may at least partially explain their increased susceptibility to severe immune-mediated morbidities.
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| 9. |
- Rahman Qazi, Khaleda, et al.
(författare)
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Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating gamma delta T and natural killer cells
- 2021
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Ingår i: Clinical & Translational Immunology (CTI). - : Wiley. - 2050-0068. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. Extremely low gestational age neonates with extremely low birthweight (ELGAN/ELBW) are highly susceptible to infection. This is linked to their relatively immature immune system which is not yet fully compatible with an extra-uterine environment. Here, we performed a longitudinal characterisation of unconventional T and natural killer (NK) cells in ELGAN/ELBW during their first months of life. Methods. Peripheral blood mononuclear cells were collected from 97 ELGAN/ELBW at 14 and 28 days of life and at a time point corresponding to postmenstrual week 36 + 0. gamma delta T-cell, NKT-cell, mucosa-associated invariant T-cell and NK cell frequencies and characteristics were analysed by flow cytometry. As control, cells from 14-day-old full-term (FT) infants were included. Results. Extreme prematurity had significant bearing on gamma delta T-cell and NK cell frequencies and characteristics. ELGAN/ELBW had significantly higher proportions of gamma delta T cells that were skewed towards effector and effector memory phenotypes, characteristics that were maintained throughout the study period. Expression of the gut homing receptor CCR9 was also more common in gamma delta T cells from ELGAN/ELBW. Conversely, NK cell frequencies were markedly lower and skewed towards a cytotoxic phenotype in the ELGAN/ELBW group at 14 days of age. Culture-proven sepsis with an onset during the first 14 days after birth further manifested these differences in the gamma delta T- and NK cell populations at 14 days of age. Conclusion. Prematurity strongly influences the levels of gamma delta T and NK cells, in particular in cases where sepsis debuts during the first 2 weeks of life.
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| 10. |
- van der Heiden, Marieke, et al.
(författare)
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Characterization of the gamma delta T-cell compartment during infancy reveals clear differences between the early neonatal period and 2 years of age
- 2020
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Ingår i: Immunology and Cell Biology. - : Wiley. - 0818-9641 .- 1440-1711. ; 98:1, s. 79-87
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Tidskriftsartikel (refereegranskat)abstract
- gamma delta T cells are unconventional T cells that function on the border of innate and adaptive immunity. They are suggested to play important roles in neonatal and infant immunity, although their phenotype and function are not fully characterized in early childhood. We aimed to investigate gamma delta T cells in relation to age, prematurity and cytomegalovirus (CMV) infection. Therefore, we used flow cytometry to characterize the gamma delta T-cell compartment in cord blood and peripheral blood cells from 14-day-, 2-year- and 5-year-old children, as well as in peripheral blood samples collected at several time points during the first months of life from extremely premature neonates. gamma delta T cells were phenotypically similar at 2 and 5 years of age, whereas cord blood was divergent and showed close proximity to gamma delta T cells from 14-day-old neonates. Interestingly, 2-year-old children and adults showed comparable V delta 2(+) gamma delta T-cell functionality toward both microbial and polyclonal stimulations. Importantly, extreme preterm birth compromised the frequencies of V delta 1(+) cells and affected the functionality of V delta 2(+) gamma delta T cells shortly after birth. In addition, CMV infection was associated with terminal differentiation of the V delta 1(+) compartment at 2 years of age. Our results show an adult-like functionality of the gamma delta T-cell compartment already at 2 years of age. In addition, we demonstrate an altered gamma delta T-cell phenotype early after birth in extremely premature neonates, something which could possible contribute to the enhanced risk for infections in this vulnerable group of children.
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