| 1. |
- Abazov, V. M., et al.
(författare)
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The upgraded DO detector
- 2006
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Ingår i: Nuclear Instruments and Methods in Physics Research Section A. - : Elsevier BV. - 0168-9002 .- 1872-9576. ; 565:2, s. 463-537
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Tidskriftsartikel (refereegranskat)abstract
- The DO experiment enjoyed a very successful data-collection run at the Fermilab Tevatron collider between 1992 and 1996. Since then, the detector has been upgraded to take advantage of improvements to the Tevatron and to enhance its physics capabilities. We describe the new elements of the detector, including the silicon microstrip tracker, central fiber tracker, solenoidal magnet, preshower detectors, forward muon detector, and forward proton detector. The uranium/liquid -argon calorimeters and central muon detector, remaining from Run 1, are discussed briefly. We also present the associated electronics, triggering, and data acquisition systems, along with the design and implementation of software specific to DO.
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| 2. |
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| 3. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 4. |
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| 5. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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| 6. |
- Hudson, Lawrence N., et al.
(författare)
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The PREDICTS database : a global database of how local terrestrial biodiversity responds to human impacts
- 2014
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Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 4:24, s. 4701-4735
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Tidskriftsartikel (refereegranskat)abstract
- Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
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| 7. |
- Chalmers, J. R., et al.
(författare)
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Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME)
- 2014
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 1365-2133 .- 0007-0963. ; 171:6, s. 1318-1325
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Tidskriftsartikel (refereegranskat)abstract
- This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure.
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| 8. |
- Cicardi, M., et al.
(författare)
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Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema
- 2010
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 363:6, s. 532-541
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)
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| 9. |
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| 10. |
- Province, M. A., et al.
(författare)
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CYP2D6 Genotype and Adjuvant Tamoxifen : Meta-Analysis of Heterogeneous Study Populations
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - New York, USA : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 95:2, s. 216-227
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Tidskriftsartikel (refereegranskat)abstract
- The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Holgate, S. T., et al.
(författare)
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Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma
- 2004
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222. ; 34:4, s. 632-638
-
Tidskriftsartikel (refereegranskat)abstract
- Background Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. Objective This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. Methods After a run-in period when an optimized fluticasone dose (greater than or equal to1000 mug/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. Results Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a greater than or equal to50% dose reduction (P=0.001). Fluticasone dose reduction to less than or equal to500 mug/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. Conclusion Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.
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| 16. |
- Jonkman, Nini H., et al.
(författare)
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Do self-management interventions work in patients with heart failure? An individual patient data meta-analysis
- 2016
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 133:12, s. 1189-1198
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: -Self-management interventions are widely implemented in care for patients with heart failure (HF). Trials however show inconsistent results and whether specific patient groups respond differently is unknown. This individual patient data meta-analysis assessed the effectiveness of self-management interventions in HF patients and whether subgroups of patients respond differently.METHODS AND RESULTS: -Systematic literature search identified randomized trials of self-management interventions. Data of twenty studies, representing 5624 patients, were included and analyzed using mixed effects models and Cox proportional-hazard models including interaction terms. Self-management interventions reduced risk of time to the combined endpoint HF-related hospitalization or all-cause death (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.71-0.89), time to HF-related hospitalization (HR, 0.80; 95%CI, 0.69-0.92), and improved 12-month HF-related quality of life (standardized mean difference 0.15; 95%CI, 0.00-0.30). Subgroup analysis revealed a protective effect of self-management on number of HF-related hospital days in patients <65 years (mean number of days 0.70 days vs. 5.35 days; interaction p=0.03). Patients without depression did not show an effect of self-management on survival (HR for all-cause mortality, 0.86; 95%CI, 0.69-1.06), while in patients with moderate/severe depression self-management reduced survival (HR, 1.39; 95%CI, 1.06-1.83, interaction p=0.01).CONCLUSIONS: -This study shows that self-management interventions had a beneficial effect on time to HF-related hospitalization or all-cause death, HF-related hospitalization alone, and elicited a small increase in HF-related quality of life. The findings do not endorse limiting self-management interventions to subgroups of HF patients, but increased mortality in depressed patients warrants caution in applying self-management strategies in these patients.
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| 17. |
- Ålander, J., et al.
(författare)
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Microsomal glutathione transferase 1 exhibits one-third-of-the-sites-reactivity towards glutathione
- 2009
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Ingår i: Archives of Biochemistry and Biophysics. - : Elsevier BV. - 0003-9861 .- 1096-0384. ; 487:1, s. 42-48
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Tidskriftsartikel (refereegranskat)abstract
- The trimeric membrane protein microsomal glutathione transferase 1 (MGST1) possesses glutathione transferase and peroxidase activity. Previous data indicated one active site/trimer whereas structural data suggests three GSH-binding sites. Here we have determined ligand interactions of MGST1 by several techniques. Nanoelectrospray mass spectrometry of native MGST1 revealed binding of three GSH molecules/trimer and equilibrium dialysis showed three product molecules/trimer (K(d) = 320 +/- 50 mu M). All three product molecules Could be competed out with GSH. Reinvestigation of GSH-binding showed one high affinity site per trimer, consistent with earlier data. Using single turnover stopped flow kinetic measurements, Kd could be determined for a low affinity GSH-binding site (2.5 +/- 0.5 mu M). Thus we can reconcile previous observations and show here that MGST1 contains three active sites with different affinities for GSH and that only the high affinity site is catalytically competent.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Ermund, Anna, et al.
(författare)
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The normal trachea is cleaned by MUC5B mucin bundles from the submucosal glands coated with the MUC5AC mucin
- 2017
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 492:3, s. 331-337
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Tidskriftsartikel (refereegranskat)abstract
- To understand the mucociliary clearance system, mucins were visualized by light, confocal and electron microscopy, and mucus was stained by Alcian blue and tracked by video microscopy on tracheal explants of newborn piglets. We observed long linear mucus bundles that appeared at the submucosal gland openings and were transported cephalically. The mucus bundles were shown by mass spectrometry and immunostaining to have a core made of MUC5B mucin and were coated with MUC5AC mucin produced by surface goblet cells. The transport speed of the bundles was slower than the airway surface liquid flow. We suggest that the goblet cell MUC5AC mucin anchors the mucus bundles and thus controls their transport. Normal clearance of the respiratory tree of pigs and humans, both rich in submucosal glands, is performed by thick and long mucus bundles. (C) 2017 The Authors. Published by Elsevier Inc.
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| 26. |
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| 27. |
- Holgate, S. T., et al.
(författare)
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Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma
- 2004
-
Ingår i: Clin Exp Allergy. ; 34:4
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. OBJECTIVE: This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. METHODS: After a run-in period when an optimized fluticasone dose (> or =1000 microg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. RESULTS: Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a > or =50% dose reduction (P=0.001). Fluticasone dose reduction to < or =500 microg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. CONCLUSION: Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.
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| 28. |
- Jonkman, Nini H., et al.
(författare)
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What Are Effective Program Characteristics of Self-Management Interventions in Patients With Heart Failure? : An Individual Patient Data Meta-analysis
- 2016
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164 .- 1532-8414. ; 22:11, s. 861-871
-
Tidskriftsartikel (refereegranskat)abstract
- Background To identify those characteristics of self-management interventions in patients with heart failure (HF) that are effective in influencing health-related quality of life, mortality, and hospitalizations.Methods and Results Randomized trials on self-management interventions conducted between January 1985 and June 2013 were identified and individual patient data were requested for meta-analysis. Generalized mixed effects models and Cox proportional hazard models including frailty terms were used to assess the relation between characteristics of interventions and health-related outcomes. Twenty randomized trials (5624 patients) were included. Longer intervention duration reduced mortality risk (hazard ratio 0.99, 95% confidence interval [CI] 0.97–0.999 per month increase in duration), risk of HF-related hospitalization (hazard ratio 0.98, 95% CI 0.96–0.99), and HF-related hospitalization at 6 months (risk ratio 0.96, 95% CI 0.92–0.995). Although results were not consistent across outcomes, interventions comprising standardized training of interventionists, peer contact, log keeping, or goal-setting skills appeared less effective than interventions without these characteristics.Conclusion No specific program characteristics were consistently associated with better effects of self-management interventions, but longer duration seemed to improve the effect of self-management interventions on several outcomes. Future research using factorial trial designs and process evaluations is needed to understand the working mechanism of specific program characteristics of self-management interventions in HF patients.
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| 29. |
- Trillo-Muyo, Sergio, 1983, et al.
(författare)
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Granule-stored MUC5B mucins are packed by the non-covalent formation of N-terminal head-to-head tetramers
- 2018
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 293:15, s. 5746-5754
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Tidskriftsartikel (refereegranskat)abstract
- Most MUC5B mucin polymers in the upper airways of humans and pigs are produced by submucosal glands. MUC5B forms N-terminal covalent dimers that are further packed into larger assemblies because of low pH and high Ca2+ in the secretory granule of the mucin-producing cell. We purified the recombinant MUC5B N-terminal covalent dimer and used single-particle electron microscopy to study its structure under intracellular conditions. We found that, at intragranular pH, the dimeric MUC5B organized into head-to-head noncovalent tetramers where the von Willebrand D1-D2 domains hooked into each other. These N-terminal tetramers further formed long linear complexes from which, we suggest, the mucin domains and their C termini project radially outwards. Using conventional and video microscopy, we observed that, upon secretion into the submucosal gland ducts, a flow of bicarbonate-rich fluid passes the mucin-secreting cells. We suggest that this unfolds and pulls out the MUC5B assemblies into long linear threads. These further assemble into thicker mucin bundles in the glandular ducts before emerging at the gland duct opening. We conclude that the combination of intracellular packing of the MUC5B mucin and the submucosal gland morphology creates an efficient machine for producing linear mucin bundles.
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| 30. |
- Axen, Iben, et al.
(författare)
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Misinformation, chiropractic, and the COVID-19 pandemic
- 2020
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Ingår i: Chiropractic and Manual Therapies. - : BioMed Central (BMC). - 2045-709X. ; 28:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: In March 2020, the World Health Organization elevated the coronavirus disease (COVID-19) epidemic to a pandemic and called for urgent and aggressive action worldwide. Public health experts have communicated clear and emphatic strategies to prevent the spread of COVID-19. Hygiene rules and social distancing practices have been implemented by entire populations, including 'stay-at-home' orders in many countries. The long-term health and economic consequences of the COVID-19 pandemic are not yet known.Main text: During this time of crisis, some chiropractors made claims on social media that chiropractic treatment can prevent or impact COVID-19. The rationale for these claims is that spinal manipulation can impact the nervous system and thus improve immunity. These beliefs often stem from nineteenth-century chiropractic concepts. We are aware of no clinically relevant scientific evidence to support such statements. We explored the internet and social media to collect examples of misinformation from Europe, North America, Australia and New Zealand regarding the impact of chiropractic treatment on immune function. We discuss the potential harm resulting from these claims and explore the role of chiropractors, teaching institutions, accrediting agencies, and legislative bodies.Conclusions: Members of the chiropractic profession share a collective responsibility to act in the best interests of patients and public health. We hope that all chiropractic stakeholders will view the COVID-19 pandemic as a call to action to eliminate the unethical and potentially dangerous claims made by chiropractors who practise outside the boundaries of scientific evidence.
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| 31. |
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| 32. |
- Chabris, CF, et al.
(författare)
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Most reported genetic associations with general intelligence are probably false positives
- 2012
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Ingår i: Psychological science. - : SAGE Publications. - 1467-9280 .- 0956-7976. ; 23:11, s. 1314-1323
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Tidskriftsartikel (refereegranskat)abstract
- General intelligence ( g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms (SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD, DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4, DISC1, APOE, and SNAP25) using data sets from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all three data sets, only 1 was nominally significant. By contrast, power analyses showed that we should have expected 10 to 15 significant associations, given reasonable assumptions for genotype effect sizes. For positive controls, we confirmed accepted genetic associations for Alzheimer’s disease and body mass index, and we used SNP-based calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics of psychology and social science requires approaches that go beyond the examination of candidate genes.
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| 33. |
- Chauvier, D, et al.
(författare)
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Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor.
- 2011
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.
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| 34. |
- Chen, G., et al.
(författare)
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Abilities of the BRICHOS domain to prevent neurotoxicity and fibril formation are dependent on a highly conserved Asp residue
- 2022
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Ingår i: RSC Chemical Biology. - : Royal Society of Chemistry (RSC). - 2633-0679. ; 3:11, s. 1342-1358
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Tidskriftsartikel (refereegranskat)abstract
- Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but to what extent the respective mechanisms are overlapping is not fully understood. The BRICHOS domain constitutes a disease-associated chaperone family, with activities against amyloid neurotoxicity, fibril formation, and amorphous protein aggregation. Here, we show that the activities of BRICHOS against amyloid-induced neurotoxicity and fibril formation, respectively, are oppositely dependent on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families. The conserved Asp in its ionized state promotes structural flexibility and has a pKa value between pH 6.0 and 7.0, suggesting that chaperone effects can be differently affected by physiological pH variations.
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| 35. |
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| 36. |
- Hong, Sanghee, et al.
(författare)
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Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States
- 2021
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Ingår i: Cancer. - : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 127:4, s. 609-618
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.Methods: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.Results: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08;P= .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08;P= .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15;P= .0004). CCS was not significantly associated with survival, relapse, or NRM.Conclusions: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.
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| 37. |
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| 38. |
- Smith, Gregory C., et al.
(författare)
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Polar ocean observations: A critical gap in the observing system and its effect on environmental predictions from hours to a season
- 2019
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- There is a growing need for operational oceanographic predictions in both the Arctic and Antarctic polar regions. In the former, this is driven by a declining ice cover accompanied by an increase in maritime traffic and exploitation of marine resources. Oceanographic predictions in the Antarctic are also important, both to support Antarctic operations and also to help elucidate processes governing sea ice and ice shelf stability. However, a significant gap exists in the ocean observing system in polar regions, compared to most areas of the global ocean, hindering the reliability of ocean and sea ice forecasts. This gap can also be seen from the spread in ocean and sea ice reanalyses for polar regions which provide an estimate of their uncertainty. The reduced reliability of polar predictions may affect the quality of various applications including search and rescue, coupling with numerical weather and seasonal predictions, historical reconstructions (reanalysis), aquaculture and environmental management including environmental emergency response. Here, we outline the status of existing near-real time ocean observational efforts in polar regions, discuss gaps, and explore perspectives for the future. Specific recommendations include a renewed call for open access to data, especially real-time data, as a critical capability for improved sea ice and weather forecasting and other environmental prediction needs. Dedicated efforts are also needed to make use of additional observations made as part of the Year of Polar Prediction (YOPP; 2017-19) to inform optimal observing system design. To provide a polar extension to the Argo network, it is recommended that a network of ice-borne sea ice and upper-ocean observing buoys be deployed and supported operationally in ice-covered areas together with autonomous profiling floats and gliders (potentially with ice detection capability) in seasonally-ice covered seas. Finally, additional efforts to better measure and parameterize surface exchanges in polar regions are much needed to improve coupled environmental prediction.
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| 39. |
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| 41. |
- Vargas, Hebert Alberto, et al.
(författare)
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Bone Metastases in Castration-Resistant Prostate Cancer : Associations between Morphologic CT Patterns, Glycolytic Activity, and Androgen Receptor Expression on PET and Overall Survival
- 2014
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 271:1, s. 220-229
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16 beta-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. Materials and Methods: This is a retrospective study of 38 patients with castration- resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. Results: n 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = -0.3007; P < .001; reader 2: r = -0.3147; P < .001) and FDHT (reader 1: r = -0.2680; P = .001; reader 2: r = -0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P < .001) and reader 2 (HR, 1.026-1.082; P <= .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P =.02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). Conculsion: In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival.
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| 42. |
- Vargas, Hebert Alberto, et al.
(författare)
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Response.
- 2015
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Ingår i: Radiology. - 0033-8419 .- 1527-1315. ; 274:2
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Tidskriftsartikel (refereegranskat)
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| 43. |
- Ambort, Daniel, 1978, et al.
(författare)
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Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin.
- 2012
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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. - 1091-6490 .- 0027-8424. ; 109:15, s. 5645-50
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Tidskriftsartikel (refereegranskat)abstract
- MUC2, the major colonic mucin, forms large polymers by N-terminal trimerization and C-terminal dimerization. Although the assembly process for MUC2 is established, it is not known how MUC2 is packed in the regulated secretory granulae of the goblet cell. When the N-terminal VWD1-D2-D'D3 domains (MUC2-N) were expressed in a goblet-like cell line, the protein was stored together with full-length MUC2. By mimicking the pH and calcium conditions of the secretory pathway we analyzed purified MUC2-N by gel filtration, density gradient centrifugation, and transmission electron microscopy. At pH 7.4 the MUC2-N trimer eluted as a single peak by gel filtration. At pH 6.2 with Ca(2+) it formed large aggregates that did not enter the gel filtration column but were made visible after density gradient centrifugation. Electron microscopy studies revealed that the aggregates were composed of rings also observed in secretory granulae of colon tissue sections. The MUC2-N aggregates were dissolved by removing Ca(2+) and raising pH. After release from goblet cells, the unfolded full-length MUC2 formed stratified layers. These findings suggest a model for mucin packing in the granulae and the mechanism for mucin release, unfolding, and expansion.
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| 44. |
- Arnott, Shelley E., et al.
(författare)
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Widespread variation in salt tolerance within freshwater zooplankton species reduces the predictability of community-level salt tolerance
- 2023
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Ingår i: Limnology and Oceanography Letters. - : John Wiley & Sons. - 2378-2242. ; 8:1, s. 8-18
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Tidskriftsartikel (refereegranskat)abstract
- The salinization of freshwaters is a global threat to aquatic biodiversity. We quantified variation in chloride (Cl-) tolerance of 19 freshwater zooplankton species in four countries to answer three questions: (1) How much variation in Cl- tolerance is present among populations? (2) What factors predict intraspecific variation in Cl- tolerance? (3) Must we account for intraspecific variation to accurately predict community Cl- tolerance? We conducted field mesocosm experiments at 16 sites and compiled acute LC(50)s from published laboratory studies. We found high variation in LC(50)s for Cl- tolerance in multiple species, which, in the experiment, was only explained by zooplankton community composition. Variation in species-LC50 was high enough that at 45% of lakes, community response was not predictable based on species tolerances measured at other sites. This suggests that water quality guidelines should be based on multiple populations and communities to account for large intraspecific variation in Cl- tolerance.
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| 45. |
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| 46. |
- Benjamin, DJ, et al.
(författare)
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The Promises and Pitfalls of Genoeconomics*
- 2012
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Ingår i: Annual review of economics. - : Annual Reviews. - 1941-1383 .- 1941-1391. ; 4, s. 627-
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Tidskriftsartikel (refereegranskat)abstract
- This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms.
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| 47. |
- Boucher, L. M., et al.
(författare)
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Expanding conceptualizations of harm reduction: results from a qualitative community-based participatory research study with people who inject drugs
- 2017
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Ingår i: Harm Reduction Journal. - : Springer Science and Business Media LLC. - 1477-7517. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: The perspectives of people who use drugs are critical in understanding why people choose to reduce harm in relation to drug use, what practices are considered or preferred in conceptualizations of harm reduction, and which environmental factors interfere with or support the use of harm reduction strategies. This study explores how people who inject drugs (PWID) think about harm reduction and considers the critical imperative of equity in health and social services delivery for this community. Methods: This community-based participatory research study was conducted in a Canadian urban centre. Using a peer-based recruitment and interviewing strategy, semi-structured qualitative interviews were conducted by and with PWID. The Vidaview Life Story Board, an innovative tool where interviewers and participant co-construct a visual "life-scape" using a board, markers, and customized picture magnets, was used to facilitate the interviews. The topics explored included injection drug use and harm reduction histories, facilitators and barriers to using harm reduction strategies, and suggestions for improving services and supports. Results: Twenty-three interviews with PWID (14 men and 9 women) were analysed, with a median age of 50. Results highlighted an expanded conceptualization of harm reduction from the perspectives of PWID, including motivations for adopting harm reduction strategies and a description of harm reduction practices that went beyond conventional health-focused concerns. The most common personal practices that PWID used included working toward moderation, employing various cognitive strategies, and engaging in community activities. The importance of social or peer support and improving self-efficacy was also evident. Further, there was a call for less rigid eligibility criteria and procedures in health and social services, and the need to more adequately address the stigmatization of drug users. Conclusions: These findings demonstrated that PWID incorporate many personal harm reduction practices in their daily lives to improve their well-being, and these practices highlight the importance of agency, self-care, and community building. Health and social services are needed to better support these practices because the many socio-structural barriers this community faces often interfere with harm reduction efforts. Finally, "one size does not fit all" when it comes to harm reduction, and more personalized or de-medicalized conceptualizations are recommended.
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| 48. |
- Bourret, K, et al.
(författare)
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Evidence-informed framework for gender transformative continuing education interventions for midwives and midwifery associations
- 2023
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Ingår i: BMJ global health. - : BMJ. - 2059-7908. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Continuing education for midwives is an important investment area to improve the quality of sexual and reproductive health services. Interventions must take into account and provide solutions for the systemic barriers and gender inequities faced by midwives. Our objective was to generate concepts and a theoretical framework of the range of factors and gender transformative considerations for the development of continuing education interventions for midwives.MethodsA critical interpretive synthesis complemented by key informant interviews, focus groups, observations and document review was applied. Three electronic bibliographic databases (CINAHL, EMBASE and MEDLINE) were searched from July 2019 to September 2020 and were again updated in June 2021. A coding structure was created to guide the synthesis across the five sources of evidence.ResultsA total of 4519 records were retrieved through electronic searches and 103 documents were included in the critical interpretive synthesis. Additional evidence totalled 31 key informant interviews, 5 focus groups (Democratic Republic of Congo and Tanzania), 24 programme documents and field observations in the form of notes. The resulting theoretical framework outlines the key considerations including gender, the role of the midwifery association, political and health systems and external forces along with key enabling elements for the design, implementation and evaluation of gender transformative continuing education interventions.ConclusionInvestments in gender transformative continuing education for midwives, led by midwifery associations, can lead to the improvement of midwifery across all United Nations’ target areas including governance, health workforce, health system arrangements and education.
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| 49. |
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| 50. |
- Busenlehner, Laura S., et al.
(författare)
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Location of substrate binding sites within the integral membrane protein microsomal glutathione transferase-1
- 2007
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 46:10, s. 2812-2822
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Tidskriftsartikel (refereegranskat)abstract
- Microsomal glutathione transferase-1 (MGST1) is a trimeric, membrane-bound enzyme with both glutathione (GSH) transferase and hydroperoxidase activities. As a member of the MAPEG superfamily, MGST1 aids in the detoxication of numerous xenobiotic substrates and in cellular protection from oxidative stress through the GSH-dependent reduction of phospholipid hydroperoxides. However, little is known about the location of the different substrate binding sites, including whether the transferase and peroxidase activities overlap structurally. Although molecular density attributed to GSH has been observed in the 3.2 A resolution electron crystallographic structure of MGST1, the electrophilic and phospholipid hydroperoxide substrate binding sites remain elusive. Amide H-D exchange kinetics and H-D ligand footprinting experiments indicate that GSH and hydrophobic substrates bind within similar, but distinct, regions of MGST1. Site-directed mutagenesis, guided by the H-D exchange results, demonstrates that specific residues within the GSH footprint effect transferase activity toward 1-chloro-2,4-dinitrobenzene. In addition, cytosolic residues surrounding the chemical stress sensor C49 but not modeled in the crystal structure appear to play an important role in the formation of the binding site for hydrophobic substrates. Although the fatty acid/phospholipid binding site structurally overlaps that for GSH, it does not appear to be localized to the same region as other hydrophobic substrates. Finally, H-D exchange mass spectrometry reveals a specific conformational transition that may mediate substrate binding and/or product release. Such structural changes in MGST1 are essential for activation of the enzyme and are important for its biological function.
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