| 1. |
- 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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| 2. |
- Gustafsson, Per, et al.
(författare)
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Heritability of cortisol regulation in children.
- 2011
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Ingår i: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Australian Academic Press. - 1832-4274 .- 1839-2628. ; 14:6, s. 553-61
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Tidskriftsartikel (refereegranskat)abstract
- The normal development of cortisol regulation during childhood is thought to be influenced by a complex interplay between environmental and genetic factors.
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| 3. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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AMPA silencing is a prerequisite for developmental long-term potentiation in the hippocampal CA1 region.
- 2008
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Ingår i: Journal of neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598.
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Tidskriftsartikel (refereegranskat)abstract
- AMPA unsilencing is an often proposed expression mechanism both for developmental LTP, involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3-CA1 connection naïve (non-stimulated) synapses are AMPA-signaling, and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test pulse synaptic activation (AMPA silencing). To investigate to what extent LTP at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus, this early, or developmental, LTP is nothing more than an unsilencing (de-depression), and stabilization, of the AMPA signaling that was lost by the prior AMPA silencing. This de-depression and stabilization of AMPA signaling was mimicked by the presence of the PKA-activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a "genuine" potentiation (as opposed to a de-depression) not explained by unsilencing and stabilization of AMPA-labile synapses. This "genuine", or mature, LTP rose from close to nothing of total LTP prior to P13, to about 70 % of total LTP at P16, and to about 90 % of total LTP at P30. Developmental LTP, by stabilization of AMPA labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.
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| 4. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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Reversible synaptic depression in developing rat CA3-CA1 synapses explained by a novel cycle of AMPA silencing-unsilencing
- 2007
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Ingår i: JOURNAL OF NEUROPHYSIOLOGY. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 98:5, s. 2604-2611
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Tidskriftsartikel (refereegranskat)abstract
- In the developing hippocampus, experiments using whole cell recordings have shown that a small number of synaptic activations can convert many glutamate synapses to AMPA silent synapses. This depression of AMPA signaling is induced by low-frequency (0.05–0.2 Hz) activation, does not require N-methyl-d-aspartate or metabotropic glutamate receptor activation for its induction, and does not readily reverse after stimulus interruption. Here we show, using field recordings and perforated patch-clamp recordings of transmission in developing CA3–CA1 synapses, that this synaptic depression also can be observed under more noninvasive recording conditions. Moreover, under these conditions, the synaptic depression spontaneously recovers within 20 min by the absence of synaptic activation alone, with a time constant of ∼7 min as determined by field excitatory postsynaptic potential recordings. Thus as for the expression of long-term potentiation (LTP), recovery from this depression is susceptible to whole cell dialysis (“wash-out”). In contrast to LTP-induced unsilencing, the AMPA signaling after stimulus interruption was again labile, resumed stimulation resulted in renewed depression. The present study has thus identified a novel cycle for AMPA signaling in which the nascent glutamate synapse cycles between an AMPA silent state, induced by a small number of synaptic activations, and a labile AMPA signaling, induced by prolonged inactivity.
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| 5. |
- Abrahamsson, Therése, 1976, et al.
(författare)
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Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat.
- 2005
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 569:Pt 3, s. 737-50
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic activation at low frequency is often used to probe synaptic function and synaptic plasticity, but little is known about how such low-frequency activation itself affects synaptic transmission. In the present study, we have examined how the perforant path-dentate granule cell (PP-GC) synapse adapts to low-frequency activation from a previously non-activated (naive) state. Stimulation at 0.2 Hz in acute slices from developing rats (7-12 days old) caused a gradual depression of the AMPA EPSC (at -80 mV) to about half within 50 stimuli. This synaptic fatigue was unaffected by the NMDA and metabotropic glutamate (mGlu) receptor antagonists d-AP5 and LY-341495. A smaller component of this synaptic fatigue was readily reversible when switching to very low-frequency stimulation (0.033-0.017 Hz) and is attributed to a reversible decrease in release probability, which is probably due to depletion of readily releasable vesicles. Thus, it was expressed to the same extent by AMPA and NMDA EPSCs, and was associated with a decrease in quantal content (measured as 1/CV(2)) with no change in the paired-pulse ratio. The larger component of the synaptic fatigue was not readily reversible, was selective for AMPA EPSCs and was associated with a decrease in 1/CV(2), thus probably representing silencing of AMPA signalling in a subset of synapses. In adult rats (> 30 days old), the AMPA silencing had disappeared while the low-frequency depression remained unaltered. The present study has thus identified two forms of synaptic plasticity that contribute to fatigue of synaptic transmission at low frequencies at the developing PP-GC synapse; AMPA silencing and a low-frequency depression of release probability.
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| 6. |
- Andersson, Isabelle, et al.
(författare)
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The IT Phenomenon in the Multinational Enterprise
- 2012
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Annan publikation (populärvet., debatt m.m.)abstract
- ForewordIn the last ten years (that I have been doing research and teaching at Mälardalen University) I have studied how information technology has become increasingly important in companies’ activities – in their daily business as well as in its implications for firms in general. What occurs to me is that, when the issue becomes a topic of academic research, information technology is studied from different perspectives in different areas of research – sometimes it is treated as a topic in itself, and sometimes as part of a business strategy or marketing activity. I have often asked myself when information technology will become regarded as an aspect of the business administration taught at universities. To some extent I think it already is, although it is not yet formally considered to be an aspect of business administration.As a lecturer, I have focused mainly on international business. In many of the seminars that I have lead, the issue of information technology has been discussed as something that the students believe will change the way that multinational enterprises can and do coordinate and control their organisations and acquire the information they need concerning their markets. (The use of information technology states that that is the case). The issue of how and to what end multinational enterprises use information technology has often been raised, but it seems that the literature comes up short in providing a holistic view of this matter. There are many studies on different aspects, and some of them present empirical data, but it seems there is a lack of major contemporary studies showing general results on the phenomenon of information technology in multinational enterprises. This is no surprise, since a study of this kind would cost a great deal of resources in terms of time as well as professors and doctoral candidates.This book is a work that partly fills the gap in the literature. It discusses and assembles literature on information technology as a feature of the multinational enterprise, but to some extent it also theorises on the role of IT in multinational enterprises. The students behind this work have carried out extensive literature reviews in many of the fields that encompass information technology in business in general and in large international companies in particular. They have arranged the literature and present it in a way they think is suitable in order to provide an overall picture of information technology in multinational enterprises. The study of the literature has thrown up questions, which have been asked of representatives of multinational companies and so “cases” are presented, i.e.Iexamples demonstrating the use of information technology. As a whole, this book fulfils its aim, which is to present the use of information technology in multinational companies in theory and in practice and to show that information technology as used by companies is a part of business administration as we know it. Of course there are questions that remain unanswered. Some of them are stated as topics for further research at the end of this work.I feel content to use this book as a textbook on undergraduate courses dealing with the management of multinational enterprises, since the use of information technology is an important part of these. I feel proud that it is my students who (may I add, without much help from my part) have produced this work.Cecilia Lindh, supervisor
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| 7. |
- Axaeus, Jennie, 1974-, et al.
(författare)
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Portar till språk och litteratur : CSL 2007
- 2007
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Språk och litteratur öppnar portar till nya världar. Detta var temat för 2007 års CSL-dag. I denna bok har vi samlat fjorton av bidragen som presenterades på konferensen, skrivna av forskare och studenter vid Karlstads universitet.Håller engelskan på att förstöra svenskan? Är dagens elever sämre på att skriva än ungdomarna var för tjugo år sedan? Skall vi ha en litteraturkanon i skolan - och läser eleverna över huvud taget böcker nu för tiden? Detta är några av de frågor som ställs i artiklarna där svaren kanske kan överraska.Andra artiklar handlar om hur man stimulerar elever till att läsa och skriva, problematiken när det gäller att undervisa i svenska som andraspråk och varför elever väljer - eller inte väljer - att studera något annat främmande språk än engelska. Porten kanske finns där - men den är inte alltid helt lätt att öppna!
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| 8. |
- Battista, Simone, et al.
(författare)
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Factors Associated with Adherence To a Supervised Exercise Intervention for Osteoarthritis : Data From the Swedish Osteoarthritis Registry
- 2023
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Ingår i: Arthritis Care and Research. - : WILEY. - 2151-4658 .- 2151-464X.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To explore how lifestyle and demographic, socioeconomic and disease-related factors are associated with supervised exercise adherence in an osteoarthritis (OA) management programme and their ability to explain exercise adherence.METHODS: A cohort register-based study on participants from the 'Swedish Osteoarthritis Registry' who attended the exercise part of a nationwide Swedish OA management programme. We ran a multinomial logistic regression to determine the association of exercise adherence with the abovementioned factors. We calculated their ability to explain exercise adherence with the McFadden R2 .RESULTS: Our sample comprises 19,750 (73% female sex; age: 67 (SD: 8.94)) participants. Among them, 5,862 (30%) reached a low level of adherence, 3,947 (20%) a medium level and 9,941 (50%) a high level. After a listwise deletion, the analysis was run on n=16,685 (85%), with low levels of adherence as the reference category. Some factors were positively associated with high levels of adherence, such as older age (relative risk ratio (RRR) =1.01, 95% CI 1.01-1.02 (per year)), and the 'arthritis-specific self-efficacy' (1.04, 95% CI 1.02-1.07 (per 10-point increase)). Others were negatively associated with high levels of adherence, such as 'female' sex (0.82, 95% CI [0.75-0.89]), having a 'medium' (0.89, 95% CI [0.81; 0.98] or a 'high' level of education (0.84, 95% CI [0.76-0.94]). Nevertheless, the investigating factors could explain 1% of the variability in exercise adherence (R2 = 0.012).CONCLUSION: Despite the associations reported above, the low-explained variability suggests that strategies based on lifestyle and demographic, socioeconomic and disease-related factors are unlikely to improve exercise adherence significantly.
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| 9. |
- Battista, Simone, et al.
(författare)
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Income-Related Inequality Changes in Osteoarthritis First-Line Interventions : A Cohort Study
- 2024
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Ingår i: Archives of Physical Medicine and Rehabilitation. - 0003-9993. ; 105:3, s. 452-460
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine income-related inequality changes in the outcomes of an osteoarthritis (OA) first-line intervention.DESIGN: Retrospective cohort study.SETTING: Swedish health care system.PARTICIPANTS: We included 115,403 people (age: 66.2±9.7 years; females 67.8%; N=115,403) with knee (67.8%) or hip OA (32.4%) recorded in the "Swedish Osteoarthritis Registry" (SOAR).INTERVENTIONS: Exercise and education.MAIN OUTCOME MEASURES: Erreygers' concentration index (E) measured income-related inequalities in "Pain intensity," "Self-efficacy," "Use of NSAIDs," and "Desire for surgery" at baseline, 3-month, and 12-month follow-ups and their differences over time. E-values range from -1 to +1 if the health variables are more concentrated among people with lower or higher income. Zero represents perfect equality. We used entropy balancing to address demographic and outcome imbalances and bootstrap replications to estimate confidence intervals for E differences over time.RESULTS: Comparing baseline to 3 months, "pain" concentrated more among individuals with lower income initially (E=-0.027), intensifying at 3 months (difference with baseline: E=-0.011 [95% CI: -0.014; -0.008]). Similarly, the "Desire for surgery" concentrated more among individuals with lower income initially (E=-0.009), intensifying at 3 months (difference with baseline: E=-0.012 [-0.018; -0.005]). Conversely, "Self-efficacy" concentrated more among individuals with higher income initially (E=0.058), intensifying at 3 months (difference with baseline: E=0.008 [0.004; 0.012]). Lastly, the "Use of NSAIDs" concentrated more among individuals with higher income initially (E=0.068) but narrowed at 3 months (difference with baseline: E=-0.029 [-0.038; -0.021]). Comparing baseline with 12 months, "pain" concentrated more among individuals with lower income initially (E=-0.024), intensifying at 12 months (difference with baseline: E=-0.017 [-0.022; -0.012]). Similarly, the "Desire for surgery" concentrated more among individuals with lower income initially (E=-0.016), intensifying at 12 months (difference with baseline: E=-0.012 [-0.022; -0.002]). Conversely, "Self-efficacy" concentrated more among individuals with higher income initially (E=0.059), intensifying at 12 months (difference with baseline: E=0.016 [0.011; 0.021]). The variable 'Use of NSAIDs' was not recorded in the SOAR at 12-month follow-up.CONCLUSION: Our results highlight the increase of income-related inequalities in the SOAR over time.
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| 10. |
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