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| 2. |
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| 3. |
- van Bragt, JJMH, et al.
(författare)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 4. |
- Fabian, ID, et al.
(författare)
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Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries
- 2021
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Ingår i: The British journal of ophthalmology. - : BMJ. - 1468-2079 .- 0007-1161. ; 105:10, s. 1435-1443
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Tidskriftsartikel (refereegranskat)abstract
- The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.ConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.
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| 5. |
- Duran-Castells, C., et al.
(författare)
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Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction
- 2023
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Ingår i: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 97:2
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Tidskriftsartikel (refereegranskat)abstract
- Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure.IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD(+) deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction.
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| 6. |
- Heaney, Liam G., et al.
(författare)
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Eosinophilic and Noneosinophilic Asthma : An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort
- 2021
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Ingår i: Chest. - : Elsevier BV. - 0012-3692. ; 160:3, s. 814-830
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Tidskriftsartikel (refereegranskat)abstract
- Background: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). Results: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. Interpretation: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.
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| 7. |
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| 8. |
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| 9. |
- Perez-de-Llano, Luis, et al.
(författare)
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Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma
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Ingår i: Annals of Allergy, Asthma and Immunology. - 1081-1206.
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. Objective: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. Methods: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). Results: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti–IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. Conclusion: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. Trial Registration: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).
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| 10. |
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| 11. |
- Bushnell, Eric A. C., et al.
(författare)
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The first branching point in porphyrin biosynthesis : a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
- 2011
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Ingår i: Journal of Computational Chemistry. - New York : John Wiley & Sons. - 0192-8651 .- 1096-987X. ; 32:5, s. 822-834
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Tidskriftsartikel (refereegranskat)abstract
- In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.
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| 15. |
- Kroes, JA, et al.
(författare)
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Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis
- 2023
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Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking non-standardized, patient-level registry-data. Mepolizumab has shown clinical efficacy in RCTs and prospective real-world studies and could therefore serve as a proof of principle for this novel approach.AimTo harmonize data from 10 national severe asthma registries and characterize patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns.MethodsIn this observational cohort study, registry data (5871 patients) were extracted for harmonization. Where harmonization was possible, patients who initiated mepolizumab between 1-1-2016 and 31-12-2021 were examined. Changes of a 12 (range 11–18) months period in frequent (≥2) exacerbations, maintenance OCS use and dose were analyzed in a privacy-preserving manner using meta-analysis of generalized estimating equation parameters. Periods before and during the COVID-19 pandemic were analyzed separately.ResultsIn 912 patients who fulfilled selection criteria mepolizumab significantly reduced frequent exacerbations (OR;95%CI: 0.18;0.13–0.25), maintenance OCS use (OR;95%CI: 0.75;0.61–0.92) and dose (mean; 95%CI: −3.93 mg·day−1; −5.24–2.62) in the Pre-Pandemic group, with similar trends in the Pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns.ConclusionsBy harmonizing patient-level registry data and applying federated analysis, SHARP demonstrated the real-wold effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.
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| 16. |
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| 17. |
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| 18. |
- Tomar, AS, et al.
(författare)
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Retinoblastoma seeds: impact on American Joint Committee on Cancer clinical staging
- 2023
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Ingår i: The British journal of ophthalmology. - : BMJ. - 1468-2079 .- 0007-1161. ; 107:1, s. 127-132
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether the American Joint Committee on Cancer (AJCC) clinical category cT2b needs to be subclassified by the type and distribution of retinoblastoma (RB) seeding.MethodsMulticentre, international registry-based data were collected from RB centres enrolled between January 2001 and December 2013. 1054 RB eyes with vitreous or subretinal seeds from 18 ophthalmic oncology centres, in 13 countries within six continents were analysed. Local treatment failure was defined as the use of secondary enucleation or external beam radiation therapy (EBRT) and was estimated with the Kaplan-Meier method.ResultsClinical category cT2b included 1054 eyes. Median age at presentation was 16.0 months. Of these, 428 (40.6%) eyes were salvaged, and 430 (40.8%) were treated with primary and 196 (18.6%) with secondary enucleation. Of the 592 eyes that had complete data for globe salvage analysis, the distribution of seeds was focal in 143 (24.2%) and diffuse in 449 (75.8%). The 5-year Kaplan-Meier cumulative globe-salvage (without EBRT) was 78% and 49% for eyes with focal and diffuse RB seeding, respectively. Cox proportional hazards regression analysis confirmed a higher local treatment failure risk with diffuse seeds as compared with focal seeds (hazard rate: 2.8; p<0.001). There was insufficient evidence to prove or disprove an association between vitreous seed type and local treatment failure risk(p=0.06).ConclusionThis international, multicentre, registry-based analysis of RB eyes affirmed that eyes with diffuse intraocular distribution of RB seeds at diagnosis had a higher risk of local treatment failure when compared with focal seeds. Subclassification of AJCC RB category cT2b into focal vs diffuse seeds will improve prognostication for eye salvage.
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| 19. |
- De Cossío, Maria E Fernández, et al.
(författare)
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Human monoclonal antibodies against an epitope on the class 5c outer membrane protein common to many pathogenic strains of Neisseria meningitidis
- 1992
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 166:6, s. 1322-1328
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria meningitidis is a causative agent of meningitis. Despite vaccination programs, it still causes a large number of deaths in young children. Early diagnosis followed by passive immunization with human monoclonal antibodies could be an approach to effective therapy. Peripheral blood lymphocytes from normal, healthy blood donors and from vaccinated individuals were immunized in vitro, using outer membrane proteins purified from A. meningitidis B:4:P1,15. The immunized human B cells were Epstein-Barr virus transformed and fused to a heteromyeloma. Several stable human hybridoma cell lines were established and two, secreting antibodies against the 31-kDa class 5c outer membrane protein, were characterized further. The human antibodies were of IgG1 and IgG3 isotypes, with κ light chains. The recognized epitope was commonly found among pathogenic strains of N. meningitidis; thus, these human monoclonal antibodies may be important in the evaluation of N. meningitidis infections.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Gomez-Llano, Miguel A., et al.
(författare)
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Sexual conflict and ecology : Species composition and male density interact to reduce male mating harassment and increase female survival
- 2018
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Ingår i: Evolution. - : Wiley. - 0014-3820. ; 72:4, s. 906-915
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Tidskriftsartikel (refereegranskat)abstract
- Sexual conflict is a pervasive evolutionary force that can reduce female fitness. Experimental evolution studies in the laboratory might overestimate the importance of sexual conflict because the ecological conditions in such settings typically include only a single species. Here, we experimentally manipulated conspecific male density (high or low) and species composition (sympatric or allopatric) to investigate how ecological conditions affect female survival in a sexually dimorphic insect, the banded demoiselle (Calopteryx splendens). Female survival was strongly influenced by an interaction between male density and species composition. Specifically, at low conspecific male density, female survival increased in the presence of heterospecific males (C. virgo). Behavioral mating experiments showed that interspecific interference competition reduced conspecific male mating success with large females. These findings suggest that reproductive interference competition between con- and heterospecific males might indirectly facilitate female survival by reducing mating harassment from conspecific males. Hence, interspecific competitors can show contrasting effects on the two sexes thereby influencing sexual conflict dynamics. Our results call for incorporation of more ecological realism in sexual conflict research, particularly how local community context and reproductive interference competition between heterospecific males can affect female fitness.
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| 24. |
- Gómez-Llano, Miguel, et al.
(författare)
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Environmental variation shapes and links parasitism to sexual selection
- 2023
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Ingår i: Evolutionary Ecology. - : Springer. - 0269-7653 .- 1573-8477. ; 37:4, s. 585-600
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Tidskriftsartikel (refereegranskat)abstract
- Parasite-driven population divergence in hosts can be exacerbated by environmental factors affecting host parasitism, as well as by increasing sexual selection against parasitized hosts. Environmental factors can influence parasitism directly by affecting parasite survival, and indirectly by affecting host condition, which can in turn shape host sexual selection. To disentangle these potential alternative paths, we used a damselfly (host) - water mite (parasite) system to examine how environmental factors directly and indirectly drive heterogeneity in parasitism across populations and influence the strength of sexual selection acting against parasitized males. We found substantial heterogeneity in parasitism across populations, driven mainly by lake pH, and damselfly density. Although this heterogeneity in parasitism did not translate directly into variation in sexual selection, the density of predatory fish increased sexual selection strength, likely through the effects on damselfly condition. These results imply that parasitism alone may not cause differences in sexual selection across populations, but when linked with underlying environmental conditions, parasitism can increase the strength of selection. More broadly, these results suggest that elucidating how parasitism may drive sexual selection requires consideration of the intwined effects of ecological processes.
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| 25. |
- Gómez-Llano, Miguel, et al.
(författare)
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Interactions between fitness components across the life cycle constrain competitor coexistence
- 2023
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Ingår i: Journal of Animal Ecology. - : John Wiley & Sons. - 0021-8790 .- 1365-2656. ; 92:12, s. 2297-2308
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Tidskriftsartikel (refereegranskat)abstract
- Numerous mechanisms can promote competitor coexistence. Yet, these mechanisms are often considered in isolation from one another. Consequently, whether multiple mechanisms shaping coexistence combine to promote or constrain species coexistence remains an open question.Here, we aim to understand how multiple mechanisms interact within and between life stages to determine frequency-dependent population growth, which has a key role stabilizing local competitor coexistence.We conducted field experiments in three lakes manipulating relative frequencies of two Enallagma damselfly species to evaluate demographic contributions of three mechanisms affecting different fitness components across the life cycle: the effect of resource competition on individual growth rate, predation shaping mortality rates, and mating harassment determining fecundity. We then used a demographic model that incorporates carry-over effects between life stages to decompose the relative effect of each fitness component generating frequency-dependent population growth.This decomposition showed that fitness components combined to increase population growth rates for one species when rare, but they combined to decrease population growth rates for the other species when rare, leading to predicted exclusion in most lakes.Because interactions between fitness components within and between life stages vary among populations, these results show that local coexistence is population specific. Moreover, we show that multiple mechanisms do not necessarily increase competitor coexistence, as they can also combine to yield exclusion. Identifying coexistence mechanisms in other systems will require greater focus on determining contributions of different fitness components across the life cycle shaping competitor coexistence in a way that captures the potential for population-level variation.
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| 26. |
- Gómez-Llano, Miguel, et al.
(författare)
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Male harm suppresses female fitness, affecting the dynamics of adaptation and evolutionary rescue
- 2024
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Ingår i: Evolution Letters. - : Oxford University Press. - 2056-3744. ; 8:1, s. 149-160
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Tidskriftsartikel (refereegranskat)abstract
- One of the most pressing questions we face as biologists is to understand how climate change will affect the evolutionary dynamics of natural populations and how these dynamics will in turn affect population recovery. Increasing evidence shows that sexual selection favors population viability and local adaptation. However, sexual selection can also foster sexual conflict and drive the evolution of male harm to females. Male harm is extraordinarily widespread and has the potential to suppress female fitness and compromise population growth, yet we currently ignore its net effects across taxa or its influence on local adaptation and evolutionary rescue. We conducted a comparative meta-analysis to quantify the impact of male harm on female fitness and found an overall negative effect of male harm on female fitness. Negative effects seem to depend on proxies of sexual selection, increasing inversely to the female relative size and in species with strong sperm competition. We then developed theoretical models to explore how male harm affects adaptation and evolutionary rescue. We show that, when sexual conflict depends on local adaptation, population decline is reduced, but at the cost of slowing down genetic adaptation. This trade-off suggests that eco-evolutionary feedback on sexual conflict can act like a double-edged sword, reducing extinction risk by buffering the demographic costs of climate change, but delaying genetic adaptation. However, variation in the mating system and male harm type can mitigate this trade-off. Our work shows that male harm has widespread negative effects on female fitness and productivity, identifies potential mechanistic factors underlying variability in such costs across taxa, and underscores how acknowledging the condition-dependence of male harm may be important to understand the demographic and evolutionary processes that impact how species adapt to environmental change.
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| 27. |
- Gomez, R, et al.
(författare)
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Dynamic localization of SMC5/6 complex proteins during mammalian meiosis and mitosis suggests functions in distinct chromosome processes
- 2013
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 126:18Pt 18, s. 4239-4252
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Tidskriftsartikel (refereegranskat)abstract
- Four members of the structural maintenance of chromosome (SMC) protein family have essential functions in chromosome condensation (SMC2/4) and sister-chromatid cohesion (SMC1/3). The SMC5/6 complex has been implicated in chromosome replication, DNA repair, and chromosome segregation in somatic cells, but its possible functions during mammalian meiosis are unknown. Here, we find that in mouse spermatocytes SMC5 and SMC6 are located at the central region of the synaptonemal complex from zygotene until diplotene. During late diplotene both proteins load to the chromocenters, where they colocalize with DNA Topoisomerase IIα, and then accumulate at the inner domain of the centromeres during the first and second meiotic divisions. Interestingly, SMC6 and DNA Topoisomerase IIα colocalize at stretched strands that join kinetochores during the metaphase II to anaphase II transition, and are both observed on stretched lagging chromosomes at anaphase II following Etoposide treatment. During mitosis SMC6 and DNA Topoisomerase IIα colocalize at the centromeres and chromatid axes. Our results are consistent with the participation of SMC5 and SMC6 in homologous chromosome synapsis during prophase I, chromosome and centromere structure during meiosis I and mitosis, and, with DNA Topoisomerase IIα, in regulating centromere cohesion during meiosis II.
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| 28. |
- Lipfert, Jan, et al.
(författare)
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Radiation Induced Damage in Serine Phosphate : Insights into a Mechanism for Direct DNA Strand Breakage
- 2004
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 108:23, s. 8036-8042
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Tidskriftsartikel (refereegranskat)abstract
- The radiation-induced decomposition mechanisms of l-O-serine phosphate and the properties of the resulting radicals are explored at the hybrid Hartree−Fock−density functional theory level B3LYP, incorporating a polarized continuum model (IEF-PCM). Three different radical products were identified in earlier experimental studies, formed through deamination (radical I), decarboxylation plus radical exchange (radical II), or dephosphorylation (radical III) reactions, respectively. The calculated hyperfine coupling constants of the resulting radicals agree well with experimental data. The computed energetics for the two competing mechanisms resulting from electron capture, radicals I and III, show that the deamination reaction is barrierless, whereas the dephosphorylation reaction requires an initial electronic redistribution and formation of a phosphoranyl radical with trigonal bipyramidal geometry. From this, the dephosphorylation reaction has to overcome a barrier of approximately 26 kcal/mol, which explains the predominance of radical I over radical III in the experimental measurements. For radical II, the initial decarboxylation step resulting from electron loss was explored and found to proceed without barriers. The results of the current study have implications for radiation-induced damage of amino acids. In addition, serine phosphate is a model of a DNA sugar−phosphate fragment, and thus we may obtain new insights into a possible mechanism for cleavage of the phosphate ester bond of the DNA backbone leading to strand break.
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| 29. |
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| 30. |
- Llano, Jorge, et al.
(författare)
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First Principles Electrochemical Study of Redox Events in DNA Bases and Chemical Repair in Aqueous Solution
- 2004
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - 1463-9076 .- 1463-9084. ; 6, s. 2426-2433
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Tidskriftsartikel (refereegranskat)abstract
- Primary and secondary radiation-induced damage to DNA, and chemical repair of the lesions on the nucleobases in solution involve a cascade of proton transfer (PT), electron transfer (ET), and proton-coupled electron transfer (PT-ET) reactions. The rate constants of these reactions depend on the standard Gibbs energy changes that can be derived from experiment. We here apply a first principles approach to calculate standard Gibbs energy changes of proton, electron, and proton-coupled electron transfer reactions in solution, wherein electrons and protons participate as independent ions; data that is fully compatible with that experimentally derived. Hence, the thermodynamic feasibility of ET and PT-ET pathways for these reactions depending on the effective concentration of hydrogen ions can be directly rationalized from first principles. The focus of this study is the primary and secondary ionization events in nucleobases in the presence of hydrogen atoms, solvated electrons and protons in aqueous solution, leading to the formation of nucleobase radical anions B˙−, radical cations B˙+ and their major deprotonated radical forms B(–H)˙. We also examine the chemical repair reaction by thiols, B(–H)˙(aq)+RSH(aq)=B(aq)+RS˙(aq), where B=A,G,C,T. Our results for the chemical repair of B(–H)˙ suggest that a PT-ET pathway should be favored for A and C at any pH, whereas for G and T, a PT-ET pathway is preferred at acidic and near neutral pH, but in the pH range 9-11, the ET pathway would dominate.
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| 31. |
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| 32. |
- Llano, Jorge, et al.
(författare)
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Mechanism of Hydroxyl Radical Addition to Imidazole and Subsequent Water Elimination
- 1999
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 103:26, s. 5598-5607
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Tidskriftsartikel (refereegranskat)abstract
- The addition reaction of the hydroxyl radical to imidazole and subsequent elimination of water to form the 1-dehydroimidazolyl radical is investigated using MP2 and B3LYP methods, including large basis sets and SCI-PCM modeling of solvent effects. It is found that the barrier to addition of the hydroxyl radical at the 5-position is energetically favored over addition to the 2- or 4-positions by 2−3 kcal/mol at the SCI-PCM/MP2/6-311G(2df,p)//MP2/6-31G(d,p) level, whereas the corresponding B3LYP calculations yield a barrier-free addition at the 5-position. The lower barrier and NBO analysis explain the experimentally observed specificity for the 5-hydroxylation of imidazole and histidine, albeit the 2-adduct is about 4 kcal/mol more stable than the 5-adduct. The NBO energetic analysis shows that the exoanomeric effect stabilizes the transition state at the 5-position about 0.3 kcal/mol more than that at the 2-position. Moreover, the π-interaction between the attacking nonbonding spin orbital of the hydroxyl radical and the π-cloud of imidazole is the least for the transition state at the 5-position, favoring the σC5-O bond formation. The 5-hydroxyimidazolyl radical undergoes a slow elimination of water (the added OH group and the hydrogen at the N1 position) to yield the 1-dehydroimidazolyl radical. The base-catalyzed dehydration profile was modeled in two steps at the B3LYP/6-311G(2df,p)//6-31G(d,p) level. The PES for the dehydration reaction seems rather flat. The first step is a barrier-free loss of the proton at N1 induced by the hydroxide ion to yield the 1-dehydro-5-hydroxyimidazolyl radical anion. In the second step, the hydroxide ion is regenerated from the intermediate to yield the final product with a barrier of 2.7 kcal/mol. The calculated hyperfine structures in the presence of the continuum solvent model for the 5-hydroxyimidazolyl and 1-dehydroimidazolyl radicals are in close agreement with the experimental ones recorded in aqueous solution.
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| 33. |
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| 34. |
- Llano, Jorge, 1968-
(författare)
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Modern Computational Physical Chemistry : An Introduction to Biomolecular Radiation Damage and Phototoxicity
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The realm of molecular physical chemistry ranges from the structure of matter and the fundamental atomic and molecular interactions to the macroscopic properties and processes arising from the average microscopic behaviour.Herein, the conventional electrodic problem is recast into the simpler molecular problem of finding the electrochemical, real chemical, and chemical potentials of the species involved in redox half-reactions. This molecular approach is followed to define the three types of absolute chemical potentials of species in solution and to estimate their standard values. This is achieved by applying the scaling laws of statistical mechanics to the collective behaviour of atoms and molecules, whose motion, interactions, and properties are described by first principles quantum chemistry. For atomic and molecular species, calculation of these quantities is within the computational implementations of wave function, density functional, and self-consistent reaction field theories. Since electrons and nuclei are the elementary particles in the realm of chemistry, an internally consistent set of absolute standard values within chemical accuracy is supplied for all three chemical potentials of electrons and protons in aqueous solution. As a result, problems in referencing chemical data are circumvented, and a uniform thermochemical treatment of electron, proton, and proton-coupled electron transfer reactions in solution is enabled.The formalism is applied to the primary and secondary radiation damage to DNA bases, e.g., absorption of UV light to yield electronically excited states, formation of radical ions, and transformation of nucleobases into mutagenic lesions as OH radical adducts and 8-oxoguanine. Based on serine phosphate as a model compound, some insight into the direct DNA strand break mechanism is given.Psoralens, also called furocoumarins, are a family of sensitizers exhibiting cytostatic and photodynamic actions, and hence, they are used in photochemotherapy. Molecular design of more efficient photosensitizers can contribute to enhance the photophysical and photochemical properties of psoralens and to reduce the phototoxic reactions. The mechanisms of photosensitization of furocoumarins connected to their dark toxicity are examined quantum chemically.
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| 35. |
- Llano, Jorge, et al.
(författare)
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Oxidation Pathways in Adenine and Guanine in Aqueous Solution from First Principles Electrochemistry
- 2004
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - 1463-9076 .- 1463-9084. ; 6, s. 4707-4713
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Tidskriftsartikel (refereegranskat)abstract
- The 8-oxo-7,8-dehydropurine tautomers (8-oxoA and 8-oxoG) are mutagenic lesions found in DNA. Two experimental pathways have been proposed for the formation of 8-oxoG: one initiated by deprotonation of the OH˙ radical adduct at the 8-position of guanine (G8OH˙) and the other initiated by a proton-coupled one-electron oxidation of G8OH˙. We here report standard Gibbs energies of the above processes involving proton transfer (PT), electron transfer (ET), and proton-coupled electron transfer (PT–ET) reactions calculated from first principles using DFT (B3LYP) and a continuum solvent model (IEF-PCM). The computed data show that the former pathway is unlikely to occur for A8OH˙ and G8OH˙ in neutral aqueous solution, because of the very low acidity of the hydrogen at the 8-position. In contrast, the latter route involving proton-coupled one-electron oxidations of A8OH˙ and G8OH˙ are exergonic by about 25 kcal mol−1 in aqueous solution. Energetically, adenine and guanine behave similarly toward oxidation to yield 8-oxoA and 8-oxoG. However, the calculated standard Gibbs energetics confirms that the ease of ionization of the native and oxidized forms of nucleobases B to yield the radical cations B˙+ or their deprotonation products B(–H)˙ is 8-oxoG > G > 8-oxoA > A > C > T in aqueous solution. Consequently, 8-oxoG will most readily trap radical cations and neutral radicals in DNA, since it can reduce any nucleobase radical cation B˙+ (via ET) or its deprotonation product B(–H)˙ (via PT–ET) back to the native form of the nucleobase.
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| 38. |
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| 39. |
- Mokhlesi, Babak, et al.
(författare)
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The Effect of Hospital Discharge with Empiric Noninvasive Ventilation on Mortality in Hospitalized Patients with Obesity Hypoventilation Syndrome An Individual Patient Data Meta-Analysis
- 2020
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Ingår i: Proceedings of the American Thoracic Society online. - : American Thoracic Society. - 1546-3222 .- 1943-5665. ; 17:5, s. 627-637
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Forskningsöversikt (refereegranskat)abstract
- Rationale: Hospitalized patients with acute-on-chronic hypercapnic respiratory failure due to obesity hypoventilation syndrome (OHS) have increased short-term mortality. It is unknown whether prescribing empiric positive airway pressure (PAP) at the time of hospital discharge reduces mortality compared with waiting for an outpatient evaluation (i.e., outpatient sleep study and outpatient PAP titration).Objectives: An international, multidisciplinary panel of experts developed clinical practice guidelines on OHS for the American Thoracic Society. The guideline panel asked whether hospitalized adult patients with acute-on-chronic hypercapnic respiratory failure suspected of having OHS, in whom the diagnosis has not yet been made, should be discharged from the hospital with or without empiric PAP treatment until the diagnosis of OHS is either confirmed or ruled out.Methods: A systematic review with individual patient data meta-analyses was performed to inform the guideline panel’s recommendation. Grading of Recommendations, Assessment, Development, and Evaluation was used to summarize evidence and appraise quality.Results: The literature search identified 2,994 articles. There were no randomized trials. Ten studies met a priori study selection criteria, including two nonrandomized comparative studies and eight nonrandomized noncomparative studies. Individual patient data on hospitalized patients who survived to hospital discharge were obtained from nine of the studies and included a total of 1,162 patients (1,043 discharged with PAP and 119 discharged without PAP). Empiric noninvasive ventilation was prescribed in 91.5% of patients discharged on PAP, and the remainder received empiric continuous PAP. Discharge with PAP reduced mortality at 3 months (relative risk 0.12, 95% confidence interval 0.05–0.30, risk difference −14.5%). Certainty in the estimated effects was very low.Conclusions: Hospital discharge with PAP reduces mortality following acute-on-chronic hypercapnic respiratory failure in patients with OHS or suspected of having OHS. Well-designed clinical trials are needed to confirm this finding.
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| 40. |
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| 41. |
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| 42. |
- Svensson, Erik I., et al.
(författare)
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Frequency Dependence and Ecological Drift Shape Coexistence of Species with Similar Niches
- 2018
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Ingår i: American Naturalist. - : University of Chicago Press. - 0003-0147 .- 1537-5323. ; 191:6, s. 691-703
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Tidskriftsartikel (refereegranskat)abstract
- The coexistence of ecologically similar species might be counteracted by ecological drift and demographic stochasticity, both of which erode local diversity. With niche differentiation, species can be maintained through performance trade-offs between environments, but trade-offs are difficult to invoke for species with similar ecological niches. Such similar species might then go locally extinct due to stochastic ecological drift, but there is little empirical evidence for such processes. Previous studies have relied on biogeographical surveys and inferred process from pattern, while experimental field investigations of ecological drift are rare. Mechanisms preserving local species diversity, such as frequency dependence (e.g., rare-species advantages), can oppose local ecological drift, but the combined effects of ecological drift and such counteracting forces have seldom been investigated. Here, we investigate mechanisms between coexistence of ecologically similar but strongly sexually differentiated damselfly species (Calopteryx virgo and Calopteryx splendens). Combining field surveys, behavioral observations, experimental manipulations of species frequencies and densities, and simulation modeling, we demonstrate that species coexistence is shaped by the opposing forces of ecological drift and negative frequency dependence (rare-species advantage), generated by interference competition. Stochastic and deterministic processes therefore jointly shape coexistence. The role of negative frequency dependence in delaying the loss of ecologically similar species, such as those formed by sexual selection, should therefore be considered in community assembly, macroecology, macroevolution, and biogeography.
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| 43. |
- Svensson, Erik I, et al.
(författare)
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Sex differences in local adaptation : what can we learn from reciprocal transplant experiments?
- 2018
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Ingår i: Philosophical Transactions of the Royal Society of London. Biological Sciences. - : ROYAL SOC. - 0962-8436 .- 1471-2970. ; 373:1757
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Forskningsöversikt (refereegranskat)abstract
- Local adaptation is of fundamental interest to evolutionary biologists. Traditionally, local adaptation has been studied using reciprocal transplant experiments to quantify fitness differences between residents and immigrants in pairwise transplants between study populations. Previous studies have detected local adaptation in some cases, but others have shown lack of adaptation or even maladaptation. Recently, the importance of different fitness components, such as survival and fecundity, to local adaptation have been emphasized. Here, we address another neglected aspect in studies of local adaptation: sex differences. Given the ubiquity of sexual dimorphism in life histories and phenotypic traits, this neglect is surprising, but may be partly explained by differences in research traditions and terminology in the fields of local adaptation and sexual selection. Studies that investigate differences in mating success between resident and immigrants across populations tend to be framed in terms of reproductive and behavioural isolation, rather than local adaptation. We briefly review the published literature that bridges these areas and suggest that reciprocal transplant experiments could benefit from quantifying both male and female fitness components. Such a more integrative research approach could clarify the role of sex differences in the evolution of local adaptations.
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| 44. |
- Urban, Mark C., et al.
(författare)
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When and how can we predict adaptive responses to climate change?
- 2024
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Ingår i: Evolution Letters. - : Oxford University Press. - 2056-3744. ; 8:1, s. 172-187
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Tidskriftsartikel (refereegranskat)abstract
- Predicting if, when, and how populations can adapt to climate change constitutes one of the greatest challenges in science today. Here, we build from contributions to the special issue on evolutionary adaptation to climate change, a survey of its authors, and recent literature to explore the limits and opportunities for predicting adaptive responses to climate change. We outline what might be predictable now, in the future, and perhaps never even with our best efforts. More accurate predictions are expected for traits characterized by a well-understood mapping between genotypes and phenotypes and traits experiencing strong, direct selection due to climate change. A meta-analysis revealed an overall moderate trait heritability and evolvability in studies performed under future climate conditions but indicated no significant change between current and future climate conditions, suggesting neither more nor less genetic variation for adapting to future climates. Predicting population persistence and evolutionary rescue remains uncertain, especially for the many species without sufficient ecological data. Still, when polled, authors contributing to this special issue were relatively optimistic about our ability to predict future evolutionary responses to climate change. Predictions will improve as we expand efforts to understand diverse organisms, their ecology, and their adaptive potential. Advancements in functional genomic resources, especially their extension to non-model species and the union of evolutionary experiments and "omics," should also enhance predictions. Although predicting evolutionary responses to climate change remains challenging, even small advances will reduce the substantial uncertainties surrounding future evolutionary responses to climate change. Preventing biological impacts from climate change will require accurate predictions about which species and ecosystems are most at risk and how best to protect them. Despite some progress, most predictive efforts still omit the potential for evolution to mediate climate change impacts. Here, we evaluate what is predictable now, in the future, and likely never based on recent literature, a survey of authors, and authors' contributions to a special issue on climate change evolution. Evidence indicates a growing ability to predict at least some components underlying evolutionary dynamics. For instance, the direct effects of climate change often alter natural selection regimes that could elicit evolutionary responses assuming sufficient additive genetic variation. We found no evidence for an increase or decrease in evolvability under future climate conditions, but we did find an overall moderate level of evolvability. However, the specific genetics underlying potential adaptive changes are still a "black box" that remains difficult to predict. We not only discuss the opportunities afforded by new genomic techniques to elucidate these genetic black boxes but also caution that the costs and limitations of such techniques for many species might not warrant their general practicality. We highlight further progress and challenges in predicting gene flow and population persistence, both of which can facilitate evolutionary rescue. We finish by listing ten activities that are needed to accelerate future progress in predicting climate change evolution. Despite the many complexities, we are relatively optimistic that evolutionary responses to climate change are becoming more accurate through time, especially assuming a more focused effort to fill key knowledge gaps in the coming years.
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