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| 3. |
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| 4. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 5. |
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| 6. |
- Drake, Thomas M., et al.
(författare)
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Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction
- 2019
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 45:12, s. 2319-2324
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology Introduction: Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods: A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results: 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions: Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.
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| 7. |
- Threlfell, S., et al.
(författare)
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Striatal Dopamine Transporter Function Is Facilitated by Converging Biology of alpha-Synuclein and Cholesterol
- 2021
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Ingår i: Frontiers in Cellular Neuroscience. - : Frontiers Media SA. - 1662-5102. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Striatal dopamine transporters (DAT) powerfully regulate dopamine signaling, and can contribute risk to degeneration in Parkinson's disease (PD). DATs can interact with the neuronal protein alpha-synuclein, which is associated with the etiology and molecular pathology of idiopathic and familial PD. Here, we tested whether DAT function in governing dopamine (DA) uptake and release is modified in a human-alpha-synuclein-overexpressing (SNCA-OVX) transgenic mouse model of early PD. Using fast-scan cyclic voltammetry (FCV) in ex vivo acute striatal slices to detect DA release, and biochemical assays, we show that several aspects of DAT function are promoted in SNCA-OVX mice. Compared to background control alpha-synuclein-null mice (Snca-null), the SNCA-OVX mice have elevated DA uptake rates, and more pronounced effects of DAT inhibitors on evoked extracellular DA concentrations ([DA](o)) and on short-term plasticity (STP) in DA release, indicating DATs play a greater role in limiting DA release and in driving STP. We found that DAT membrane levels and radioligand binding sites correlated with alpha-synuclein level. Furthermore, DAT function in Snca-null and SNCA-OVX mice could also be promoted by applying cholesterol, and using Tof-SIMS we found genotype-differences in striatal lipids, with lower striatal cholesterol in SNCA-OVX mice. An inhibitor of cholesterol efflux transporter ABCA1 or a cholesterol chelator in SNCA-OVX mice reduced the effects of DAT-inhibitors on evoked [DA](o). Together these data indicate that human alpha-synuclein in a mouse model of PD promotes striatal DAT function, in a manner supported by extracellular cholesterol, suggesting converging biology of alpha-synuclein and cholesterol that regulates DAT function and could impact DA function and PD pathophysiology.
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| 8. |
- Fernandes, SJ, et al.
(författare)
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Non-parametric combination analysis of multiple data types enables detection of novel regulatory mechanisms in T cells of multiple sclerosis patients
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 11996-
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Tidskriftsartikel (refereegranskat)abstract
- Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system with prominent neurodegenerative components. The triggering and progression of MS is associated with transcriptional and epigenetic alterations in several tissues, including peripheral blood. The combined influence of transcriptional and epigenetic changes associated with MS has not been assessed in the same individuals. Here we generated paired transcriptomic (RNA-seq) and DNA methylation (Illumina 450 K array) profiles of CD4+ and CD8+ T cells (CD4, CD8), using clinically accessible blood from healthy donors and MS patients in the initial relapsing-remitting and subsequent secondary-progressive stage. By integrating the output of a differential expression test with a permutation-based non-parametric combination methodology, we identified 149 differentially expressed (DE) genes in both CD4 and CD8 cells collected from MS patients. Moreover, by leveraging the methylation-dependent regulation of gene expression, we identified the gene SH3YL1, which displayed significant correlated expression and methylation changes in MS patients. Importantly, silencing of SH3YL1 in primary human CD4 cells demonstrated its influence on T cell activation. Collectively, our strategy based on paired sampling of several cell-types provides a novel approach to increase sensitivity for identifying shared mechanisms altered in CD4 and CD8 cells of relevance in MS in small sized clinical materials.
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| 9. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 10. |
- Planell, N, et al.
(författare)
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STATegra: Multi-Omics Data Integration - A Conceptual Scheme With a Bioinformatics Pipeline
- 2021
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Ingår i: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 12, s. 620453-
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Tidskriftsartikel (refereegranskat)abstract
- Technologies for profiling samples using different omics platforms have been at the forefront since the human genome project. Large-scale multi-omics data hold the promise of deciphering different regulatory layers. Yet, while there is a myriad of bioinformatics tools, each multi-omics analysis appears to start from scratch with an arbitrary decision over which tools to use and how to combine them. Therefore, it is an unmet need to conceptualize how to integrate such data and implement and validate pipelines in different cases. We have designed a conceptual framework (STATegra), aiming it to be as generic as possible for multi-omics analysis, combining available multi-omic anlaysis tools (machine learning component analysis, non-parametric data combination, and a multi-omics exploratory analysis) in a step-wise manner. While in several studies, we have previously combined those integrative tools, here, we provide a systematic description of the STATegra framework and its validation using two The Cancer Genome Atlas (TCGA) case studies. For both, the Glioblastoma and the Skin Cutaneous Melanoma (SKCM) cases, we demonstrate an enhanced capacity of the framework (and beyond the individual tools) to identify features and pathways compared to single-omics analysis. Such an integrative multi-omics analysis framework for identifying features and components facilitates the discovery of new biology. Finally, we provide several options for applying the STATegra framework when parametric assumptions are fulfilled and for the case when not all the samples are profiled for all omics. The STATegra framework is built using several tools, which are being integrated step-by-step as OpenSource in the STATegRa Bioconductor package.1
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| 11. |
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| 12. |
- Berglund, E. C., et al.
(författare)
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Freeze-Drying as Sample Preparation for Micellar Electrokinetic Capillary Chromatography-Electrochemical Separations of Neurochemicals in Drosophila Brains
- 2013
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 85:5, s. 2841-2846
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Tidskriftsartikel (refereegranskat)abstract
- Micellar electrokinetic capillary chromatography with electrochemical detection has been used to quantify biogenic amines in freeze-dried brains of Drosophila melanogaster. Freeze-drying samples offers a way to preserve the biological sample while making dissection of these tiny samples easier and faster. Fly samples were extracted in cold acetone and dried in a rotary evaporator. Extraction and drying times were optimized in order to avoid contamination by red pigment from the fly eyes and still have intact brain structures. Single freeze-dried fly brain samples were found to produce representative electropherograms as a single hand-dissected brain sample. With utilization of the faster dissection time that freeze-drying affords, the number of brains in a fixed homogenate volume can be increased to concentrate the sample. Thus, concentrated brain samples containing five or fifteen preserved brains were analyzed for their neurotransmitter content, and four analytes; N-acetyloctopamine, N-acetylserotonin, N-acetyltyramine, and N-acetyldopamine were found to correspond well with previously reported values.
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| 13. |
- Berntorp, Erik, et al.
(författare)
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Identifying non-responsive bleeding episodes in patients with haemophilia and inhibitors: a consensus definition.
- 2011
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; Okt, s. 202-210
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Tidskriftsartikel (refereegranskat)abstract
- Summary. Assessing response to treatment with bypassing agents presents a substantial challenge in the treatment of patients with haemophilia and inhibitors. Rapid and accurate identification of bleeding episodes that are non-responsive to bypassing therapy with either Factor Eight Inhibitor Bypassing Activity (FEIBA; Baxter AG) or recombinant activated factor VII (rFVIIa; NovoSeven(®), Novo Nordisk A/S) is essential to guide treatment decisions and optimize patient outcomes through early intervention. Although both bypassing agents are effective, differential responses to therapy necessitate multiple therapeutic options. This article provides a consensus definition for non-life-threatening joint and muscle bleeds that are non-responsive to bypassing agents. An international panel of seven physicians met in December 2008 to develop the consensus definition using a modified National Institutes of Health Consensus Development Conference method. The consequent definition of non-life-threatening bleeding episodes that are non-responsive to bypassing treatment provides a global picture of the condition of the patient during such an event. Identification of non-responsiveness is based on various criteria: pain, swelling/tension, mobility, patient perception and laboratory parameters. Criteria can be assessed subjectively by the patient/parent and/or objectively by the clinician. Although the precise timing of each determination should be at the discretion of the physician, bleeds should be considered non-responsive if the clinical situation meets the specified criteria 24 h from the start of treatment. Although it is not intended to replace clinical judgment, this definition can guide the optimal course of treatment for patients with haemophilia and inhibitors.
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| 14. |
- Boger, E., et al.
(författare)
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Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs
- 2016
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 5:4, s. 201-210
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug-and formulation-specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose-only inhalation. As the model clearly distinguishes among drug-specific, formulation-specific, and system-specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug-receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.
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| 16. |
- Brusselaers, N., et al.
(författare)
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Evaluation of science advice during the COVID-19 pandemic in Sweden
- 2022
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Ingår i: Humanities & Social Sciences Communications. - : Springer Science and Business Media LLC. - 2662-9992. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Sweden was well equipped to prevent the pandemic of COVID-19 from becoming serious. Over 280 years of collaboration between political bodies, authorities, and the scientific community had yielded many successes in preventive medicine. Sweden's population is literate and has a high level of trust in authorities and those in power. During 2020, however, Sweden had ten times higher COVID-19 death rates compared with neighbouring Norway. In this report, we try to understand why, using a narrative approach to evaluate the Swedish COVID-19 policy and the role of scientific evidence and integrity. We argue that that scientific methodology was not followed by the major figures in the acting authorities-or the responsible politicians-with alternative narratives being considered as valid, resulting in arbitrary policy decisions. In 2014, the Public Health Agency merged with the Institute for Infectious Disease Control; the first decision by its new head (Johan Carlson) was to dismiss and move the authority's six professors to Karolinska Institute. With this setup, the authority lacked expertise and could disregard scientific facts. The Swedish pandemic strategy seemed targeted towards "natural" herd-immunity and avoiding a societal shutdown. The Public Health Agency labelled advice from national scientists and international authorities as extreme positions, resulting in media and political bodies to accept their own policy instead. The Swedish people were kept in ignorance of basic facts such as the airborne SARS-CoV-2 transmission, that asymptomatic individuals can be contagious and that face masks protect both the carrier and others. Mandatory legislation was seldom used; recommendations relying upon personal responsibility and without any sanctions were the norm. Many elderly people were administered morphine instead of oxygen despite available supplies, effectively ending their lives. If Sweden wants to do better in future pandemics, the scientific method must be re-established, not least within the Public Health Agency. It would likely make a large difference if a separate, independent Institute for Infectious Disease Control is recreated. We recommend Sweden begins a self-critical process about its political culture and the lack of accountability of decision-makers to avoid future failures, as occurred with the COVID-19 pandemic.
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| 17. |
- Ding, J., et al.
(författare)
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Inhibition of HMGCoA Reductase Reveals An Unexpected Role for Cholesterol During PGC Migration in the Mouse.
- 2008
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Ingår i: BMC developmental biology. - 1471-213X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Primordial germ cells (PGCs) are the embryonic precursors of the sperm and eggs. Environmental or genetic defects that alter PGC development can impair fertility or cause formation of germ cell tumors. RESULTS: We demonstrate a novel role for cholesterol during germ cell migration in mice. Cholesterol was measured in living tissue dissected from mouse embryos and was found to accumulate within the developing gonads as germ cells migrate to colonize these structures. Cholesterol synthesis was blocked in culture by inhibiting the activity of HMG CoA reductase (HMGCR) resulting in germ cell survival and migration defects. These defects were rescued by co-addition of isoprenoids and cholesterol, but neither compound alone was sufficient. In contrast, loss of the last or penultimate enzyme in cholesterol biosynthesis did not alter PGC numbers or position in vivo. However embryos that lack these enzymes do not exhibit cholesterol defects at the stage at which PGCs are migrating. This demonstrates that during gestation, the cholesterol required for PGC migration can be supplied maternally. CONCLUSIONS: In the mouse, cholesterol is required for PGC survival and motility. It may act cell-autonomously by regulating clustering of growth factor receptors within PGCs or non cell-autonomously by controlling release of growth factors required for PGC guidance and survival.
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| 21. |
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| 22. |
- Hu, Keke, et al.
(författare)
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Electrochemical Measurements Reveal Reactive Oxygen Species in Stress Granules**
- 2021
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Ingår i: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 60:28, s. 15302-15306
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Tidskriftsartikel (refereegranskat)abstract
- Stress granules (SGs) are membrane-less organelles that assemble in the cytoplasm to organize cellular contents and promote rapid adaptation during stress. To understand how SGs contribute to physiological functions, we used electrochemical measurements to detect electroactive species in SGs. With amperometry, we discovered that reactive oxygen species (ROS) are encapsulated inside arsenite-induced SGs, and H2O2 is the main species. The release kinetics of H2O2 from single SGs and the number of H2O2 molecules were quantified. The discovery that SGs contain ROS implicates them as communicators of the cellular stresses rather than a simple endpoint. This may explain how SGs regulate cellular metabolism and stress responses. This may also help better understand their cytoprotective functions in pathological conditions associated with SGs such as neurodegenerative diseases (NDs), cancers and viral infections. © 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
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| 23. |
- Hu, K. K., et al.
(författare)
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Single Exosome Amperometric Measurements Reveal Encapsulation of Chemical Messengers for Intercellular Communication
- 2023
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Ingår i: Journal of the American Chemical Society. - 0002-7863. ; 145:21, s. 11499-11503
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Tidskriftsartikel (refereegranskat)abstract
- In multicellular organisms, cellstypically communicateby sendingand receiving chemical signals. Chemical messengers involved in theexocytosis of neuroendocrine cells or neurons are generally assumedto only originate from the fusing of intracellular large dense corevesicles (LDCVs) or synaptic vesicles with the cellular membrane followingstimulation. Accumulated evidence suggests that exosomes oneof the main extracellular vesicles (EVs)carrying cell-dependentDNA, mRNA, proteins, etc., play an essential role in cellular communication.Due to experimental limitations, it has been difficult to monitorthe real-time release of individual exosomes; this restricts a comprehensiveunderstanding of the basic molecular mechanisms and the functionsof exosomes. In this work, we introduce amperometry with microelectrodesto capture the dynamic release of single exosomes from a single livingcell, distinguish them from other EVs, and differentiate the moleculesinside exosomes and those secreted from LDCVs. We show that, similarto many LDCVs and synaptic vesicles, exosomes released by neuroendocrinecells also contain catecholamine transmitters. This finding revealsa different mode of chemical communication via exosome-encapsulatedchemical messengers and a potential interconnection between the tworelease pathways, changing the canonical view of exocytosis of neuroendocrinecells and possibly neurons. This defines a new mechanism for chemicalcommunication at the fundamental level and opens new avenues in theresearch of the molecular biology of exosomes in the neuroendocrineand central nervous systems.
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| 24. |
- Kular, L, et al.
(författare)
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Epigenetic clock indicates accelerated aging in glial cells of progressive multiple sclerosis patients
- 2022
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Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14, s. 926468-
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS) characterized by irreversible disability at later progressive stages. A growing body of evidence suggests that disease progression depends on age and inflammation within the CNS. We aimed to investigate epigenetic aging in bulk brain tissue and sorted nuclei from MS patients using DNA methylation-based epigenetic clocks.MethodsWe applied Horvath’s multi-tissue and Shireby’s brain-specific Cortical clock on bulk brain tissue (n = 46), sorted neuronal (n = 54), and glial nuclei (n = 66) from post-mortem brain tissue of progressive MS patients and controls.ResultsWe found a significant increase in age acceleration residuals, corresponding to 3.6 years, in glial cells of MS patients compared to controls (P = 0.0024) using the Cortical clock, which held after adjustment for covariates (Padj = 0.0263). The 4.8-year age acceleration found in MS neurons (P = 0.0054) did not withstand adjustment for covariates and no significant difference in age acceleration residuals was observed in bulk brain tissue between MS patients and controls.ConclusionWhile the findings warrant replication in larger cohorts, our study suggests that glial cells of progressive MS patients exhibit accelerated biological aging.
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| 25. |
- Kurczy, Michael, 1980, et al.
(författare)
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Mass spectrometry imaging of mating Tetrahymena show that changes in cell morphology regulate lipid domain formation
- 2010
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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. ; 107:7, s. 2751-2756
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Tidskriftsartikel (refereegranskat)abstract
- Mass spectrometry imaging has been used here to suggest that changes in membrane structure drive lipid domain formation in mating single-cell organisms. Chemical studies of lipid bilayers in both living and model systems have revealed that chemical composition is coupled to localized membrane structure. However, it is not clear if the lipids that compose the membrane actively modify membrane structure or if structural changes cause heterogeneity in the surface chemistry of the lipid bilayer. We report that time-of-flight secondary ion mass spectrometry images of mating Tetrahymena thermophila acquired at various stages during mating demonstrate that lipid domain formation, identified as a decrease in the lamellar lipid phosphatidylcholine, follows rather than precedes structural changes in the membrane. Domains are formed in response to structural changes that occur during cell-to-cell conjugation. This observation has wide implications in all membrane processes.
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| 26. |
- Kurczy, Michael, 1980, et al.
(författare)
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Nanotome Cluster Bombardment to Recover Spatial Chemistry After Preparation of Biological Samples for SIMS Imaging
- 2010
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Ingår i: Journal of the American Society for Mass Spectrometry. - : American Chemical Society (ACS). - 1044-0305 .- 1879-1123. ; 21:5, s. 833-836
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Tidskriftsartikel (refereegranskat)abstract
- A C-60(+) cluster ion projectile is employed for sputter cleaning biological surfaces to reveal spatio-chemical information obscured by contamination overlayers. This protocol is used as a supplemental sample preparation method for time of flight secondary ion mass spectrometry (ToF-SIMS) imaging of frozen and freeze-dried biological materials. Following the removal of nanometers of material from the surface using sputter cleaning, a frozen-patterned cholesterol film and a freeze-dried tissue sample were analyzed using ToF-SIMS imaging. In both experiments, the chemical information was maintained after the sputter dose, due to the minimal chemical damage caused by C-60(+) bombardment. The damage to the surface produced by freeze-drying the tissue sample was found to have a greater effect on the loss of cholesterol signal than the sputter-induced damage. In addition to maintaining the chemical information, sputtering is not found to alter the spatial distribution of molecules on the surface. This approach removes artifacts that might obscure the surface chemistry of the sample and are common to many biological sample preparation schemes for ToF-SIMS imaging.
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| 27. |
- Lanekoff, Ingela, 1975, et al.
(författare)
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Mass spectrometry imaging of freeze-dried membrane phospholipids of dividing Tetrahymena pyriformis
- 2013
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Ingår i: Surface and Interface Analysis. - : Wiley. - 0142-2421 .- 1096-9918. ; 45:1, s. 211-214
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Tidskriftsartikel (refereegranskat)abstract
- Time of Flight secondary ion mass spectrometry (TOF-SIMS) has been used to explore the distribution of phospholipids in the plasma membrane of Tetrahymena pyriformis during cell division. The dividing cells were freeze-dried prior to analysis followed by line scan and region of interest analysis at various stages of cell division. The results showed no signs of phospholipid domain formation at the junction between the dividing cells. Instead the results showed that the sample preparation technique had a great impact on one of the examined phospholipids, namely phosphatidylcholine (PC). Phosphatidylcholine and 2-aminoethylphosphonolipid (2-AEP) have therefore been evaluated in Tetrahymena cells that have been subjected to different sample preparation techniques: freeze drying ex situ, freeze fracture, and freeze fracture with partial or total freeze drying in situ. The result suggests that freeze drying ex situ causes the celia to collapse and cover the plasma membrane.
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| 28. |
- Majdi, Soodabeh, 1980, et al.
(författare)
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Extracellular ATP regulates the vesicular pore opening in chromaffin cells and increases the fraction released during individual exocytosis events
- 2019
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 10:5, s. 2459-2466
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Tidskriftsartikel (refereegranskat)abstract
- Adenosine triphosphate (ATP) is the main energy source for cellular metabolism. Besides that, ATP is a neurotransmitter and a cotransmitter that acts on purinergic receptors present either pre-or postsynaptically. Almost all types of secretory vesicles from any neuron or animal species contain high concentrations of ATP, being an essential factor in the accumulation of neurotransmitters. In this work, we studied the effects of ATP on quantum catecholamine release and vesicular storage in chromaffin cells. We combined three electrochemical methods: Conventional amperometry with intracellular vesicle impact electrochemical cytometry and vesicle impact electrochemical cytometry. We found that extracellular ATP increased the released quantal fraction of catecholamine but not its vesicular content. Studying the dynamics of exocytosis events in ATP treated cells showed that ATP affects the release fusion pore. To elucidate the mechanisms of the observed ATP effects, cells and vesicles were pharmacologically treated with suramin (a purinergic blocker) and ARL-67156 (an antagonist of ecto-ATPases). The data indicate that the catecholamine content of vesicles increased compared to control after these drugs. Our data suggest that ATP acting on purinergic receptors increases the quantum releasable size through an increased fusion pore opening and that ARL-67156 and/or suramin protect the vesicle from neurotransmitter leakage by functioning as competitive inhibitors to ATP. © 2019 American Chemical Society.
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| 29. |
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| 30. |
- Passarelli, Melissa, 1983, et al.
(författare)
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C-60-SIMS studies of glycerophospholipid in a LIPID MAPS model system: KDO2-Lipid A stimulated RAW 264.7 cells
- 2013
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Ingår i: Surface and Interface Analysis. - : Wiley. - 0142-2421 .- 1096-9918. ; 45:1, s. 298-301
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Tidskriftsartikel (refereegranskat)abstract
- Although secondary ion mass spectrometry (SIMS) has been successfully employed for mapping lipid distributions at the cellular level, the identification of intact lipid species in situ is often complicated by isobaric interference. The high mass resolution and tandem MS capabilities of a C60-QSTAR hybrid instrument has been utilized to identify over 50 lipid species from mouse macrophages (RAW 264.7). In this investigation, lipid assignments made based on mass accuracy were confirmed with tandem MS analyses. Data obtained from C60-SIMS was compared to liquid chromatography (LC)-MS data obtained by the LIPID MAPS consortium. A majority of the lipids detected with LC-MS, but not detected with C60-SIMS, were present at concentrations below 2.0 pmol/µg of DNA. Matrix-related effects prevented the detection of lipids with the glycerophosphoethanolamine (PE) headgroup, glycerophosphoserine (PS) headgroup and lipids with polyunsaturated fatty acyl chains in the C60-SIMS analyses. Lipid distributions obtained from a lawn of RAW 264.7 cells stimulated with the endotoxin KDO2-Lipid A were also studied. The results obtained with C60-SIMS agreed with the established LC-MS data for the glycerophosphoinositol lipid class (PI) with adequate molecular sensitivity achieved with as few as 500 cells.
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| 31. |
- Passarelli, Melissa, 1983, et al.
(författare)
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Single-Cell Lipidomics: Characterizing and Imaging Lipids on the Surface of Individual Aplysia californica Neurons with Cluster Secondary Ion Mass Spectrometry
- 2013
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 85:4, s. 2231-2238
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Tidskriftsartikel (refereegranskat)abstract
- Neurons isolated from Aplysia californica, an organism with a well-defined neural network, were imaged with secondary ion mass spectrometry, C-60-SIMS. A major lipid component of the neuronal membrane was identified as 1-hexadecyl-2-octadecenoyl-sn-glycero-3-phosphocholine [PC(16:0e/18:1)] using tandem mass spectrometry (MS/MS). The assignment was made directly off the sample surface using a C-60-QSTAR instrument, a prototype instrument that combines an ion source with a commercial electrospray ionization/matrix-assisted laser desorption ionization (ESI/MALDI) mass spectrometer, Normal phase liquid chromatography mass spectrometry (NP-LC-MS) was used to confirm the assignment. Cholesterol and vitamin E were also identified with in situ tandem MS analyses that were compared to reference spectra obtained from purified compounds. In order to improve sensitivity on the single-cell level, the tandem MS spectrum of vitamin E reference material was used to extract and compile all the vitamin E related peaks from the cell image. The mass spectrometry images heterogeneous distributions cif intact lipid species, PC(16:0e/18:1), vitamin E, and cholesterol on the surface of a single neuron. The ability to detect these molecules and determine their relative distribution on the single-cell level shows that the C-60-QSTAR is a potential platform for studying important biochemical processes, such as neuron degeneration.
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| 32. |
- Piwowar, A. M., et al.
(författare)
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C60-ToF SIMS imaging of frozen hydrated HeLa cells
- 2013
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Ingår i: Surface and Interface Analysis. - : Wiley. - 0142-2421 .- 1096-9918. ; 45:1, s. 302-304
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Tidskriftsartikel (refereegranskat)abstract
- Sample preparation continues to be a major challenge for SIMS studies of biological materials. Maintaining the native hydrated state of the material is important for preserving both chemical and spatial information. Here, we discuss a method that combines a sample wash and dry protocol followed by plunge-freezing in liquid ethane for a frozen-hydrated analysis of mammalian cells (HeLa). This method allows for the removal of the growth medium and maintains the hydrated state of the cells so that they can be prepared frozen-hydrated without the need for a freeze-fracture device. The cells, which were grown on silicon, were successfully regrown after the cleaning procedure, confirming that a significant portion of the cells remain undamaged during the wash and dry procedure. Results from preliminary SIMS measurements show that is it possible to detect a large variety of biomolecular signals, including intact lipids from the plasma membrane in the mass range of 700–900Da from single cells, with little external water interference at the surface.
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| 33. |
- Ray, Lara A., et al.
(författare)
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The future of translational research on alcohol use disorder
- 2021
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Ingår i: Addiction Biology. - : WILEY. - 1355-6215 .- 1369-1600. ; 26:2
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Forskningsöversikt (refereegranskat)abstract
- In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.
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| 34. |
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| 35. |
- Sharma, Sapna, et al.
(författare)
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A global database of lake surface temperatures collected by in situ and satellite methods from 1985–2009
- 2015
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Ingår i: Scientific Data. - : Macmillan Publishers Limited. - 2052-4463. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Global environmental change has influenced lake surface temperatures, a key driver of ecosystem structure and function. Recent studies have suggested significant warming of water temperatures in individual lakes across many different regions around the world. However, the spatial and temporal coherence associated with the magnitude of these trends remains unclear. Thus, a global data set of water temperature is required to understand and synthesize global, long-term trends in surface water temperatures of inland bodies of water. We assembled a database of summer lake surface temperatures for 291 lakes collected in situ and/or by satellites for the period 1985–2009. In addition, corresponding climatic drivers (air temperatures, solar radiation, and cloud cover) and geomorphometric characteristics (latitude, longitude, elevation, lake surface area, maximum depth, mean depth, and volume) that influence lake surface temperatures were compiled for each lake. This unique dataset offers an invaluable baseline perspective on global-scale lake thermal conditions as environmental change continues.
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| 36. |
- Sombers, L A, et al.
(författare)
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High Osmolarity and L-DOPA Augment Release via the Fusion Pore in PC12 Cells
- 2007
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Ingår i: Chemphyschem. - : Wiley. - 1439-4235 .- 1439-7641. ; 8:17, s. 2471-2477
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Tidskriftsartikel (refereegranskat)abstract
- We have amperometrically measured dopamine release from rat pheochromocytoma cells (PC12 cells) in high osmolarity conditions with and without L-3,4-dihydroxyphenylalanine (L-DOPA) treatment. We observe an increase in the number of release events displaying a prespike feature or foot when the cells are stimulated in high osmolarity saline. We also see an increase in foot area and duration when cells are stimulated in high osmolarity saline, or high osmolarity saline subsequent to incubation with the dopamine precursor L-DOPA in isotonic saline, which serves to increase the vesicle size. The data suggest that membrane biophysics are an important component in defining the rate, duration and amount of neurotransmitter release via the fusion pore.
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| 37. |
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| 38. |
- Svensson, Frida, 1980, et al.
(författare)
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Ruthenium(II) Complex Enantiomers as Cellular Probes for Diastereomeric Interactions in Confocal and Fluorescence Lifetime Imaging Microscopy
- 2011
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Ingår i: Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 2:5, s. 397-401
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Tidskriftsartikel (refereegranskat)abstract
- Ruthenium dipyridophenazine (dppz) complexes are sensitive luminescent probes for hydrophobic environments. Here, we apply multi-frequency fluorescence lifetime imaging microscopy (FLLM) to Delta and Lambda enantiomers of lipophilic ruthenium dppz complexes in live and fixed cells, and their different lifetime staining patterns are related to conventional intensity-based microscopy. Excited-state lifetimes of the enantiomers determined from FLIM measurements correspond well with spectroscopically measured emission decay curves in pure microenvironments of DNA, phospholipid membranes, or a model protein. We show that FLIM can be applied to monitor the long-lived excited states of ruthenium complex enantiomers and, combined with confocal microscopy, give new insight into their biomolecular binding and reveal differences in the microenvironment probed by the complexes.
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Wittenberg, N J, et al.
(författare)
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Short-Chain Alcohols Promote Accelerated Membrane Distention in a Dynamic Liposome Model of Exocytosis
- 2008
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 0743-7463 .- 1520-5827. ; 24:6, s. 2637-2642
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Tidskriftsartikel (refereegranskat)abstract
- We have used amperometric measurements in a model system consisting of two liposomes connected with a membrane nanotube to monitor catechol release during artificial exocytosis and thereby to elucidate the effect of small-chain alcohols on this dynamic membrane process. To determine the rate of membrane shape change, catechol release during membrane distention was monitored amperometrically, and the presence of alcohols in the buffer was shown to accelerate the membrane distention process in a concentration-dependent manner. Compression isotherms for the same lipid composition in the absence and presence of ethanol and 1-propanol were measured to determine how these short-chain alcohols affect the lipid packing in monolayers. The isotherms show a marked decrease in lipid packing density that is dependent on the particular alcohol and its concentration. Comparison of the electrochemical and isotherm results suggests a correlation between decreasing lipid packing density and increasing rates of membrane shape change.
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