| 1. |
- Ademuyiwa, Adesoji O., et al.
(author)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Hudson, Lawrence N, et al.
(author)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Journal article (peer-reviewed)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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| 3. |
- Debette, Stéphanie, et al.
(author)
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Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 47, s. 78-83
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Journal article (peer-reviewed)abstract
- Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1–3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1 1,393 CeAD cases and 1 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 1 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 1 × 1 10−3; combined P = 1 1.00 × 1 10−1111). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6–9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.
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| 4. |
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| 5. |
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| 6. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 7. |
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| 8. |
- Anheden, Marie, et al.
(author)
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Value chain for production of bio-oil from kraft lignin for use as bio-jet fuel
- 2017
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In: The 7th Nordic Wood Biorefinery Conference held in Stockholm, Sweden, 28-30 Mar. 2017. - Stockholm : RISE Bioekonomi. - 9789186018207 ; , s. 104-109
-
Conference paper (peer-reviewed)abstract
- The LignoJet project aimed to achieve an intermediate lignin-oil product miscible with fossil feedstock and with a significantly reduced oxygen content. A technical concept for production has been studied that involves combined catalysed depolymerisation and hydrodeoxygenation, so called hydrogenolytic depolymerisation, of kraft lignin. Kraft lignin was separated through membrane ultrafiltration from softwood and eucalyptus black liquor followed by precipitation through LignoBoost technology. A difference in lignin properties was observed between ultrafiltration of softwood and eucalyptus black liquor through 15 and 150kDa ceramic membranes. Lignin-oils with similar oxygen content were produced regardless of origin and fractionation technique. A lignin-oil with favourable properties as precursor for refinery integration for jet fuel production as produced in small-scale batch experiments using nickel-based catalyst. Stable pumpable oils with melting point of less than 25-50 deg C and with 20-30% lower oxygen content and aromatic content were obtained that would be suitable as jet fuel precursors. The estimated production cost was found to be competitive with that of other liquid biofuels, while additional revenues could potentially be achieved by also producing chemical and materials from suitable fractions of the lignin-oil.
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| 9. |
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| 10. |
- Bocchetta, Martina, et al.
(author)
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The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey.
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 11:2, s. 195-206
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Journal article (peer-reviewed)abstract
- We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.
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| 11. |
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| 12. |
- Di Martino, Maria Letizia, et al.
(author)
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Barcoded Consortium Infections Resolve Cell Type-Dependent Salmonella enterica Serovar Typhimurium Entry Mechanisms
- 2019
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In: mBio. - : AMER SOC MICROBIOLOGY. - 2161-2129 .- 2150-7511. ; 10:3
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Journal article (peer-reviewed)abstract
- Bacterial host cell invasion mechanisms depend on the bacterium's virulence factors and the properties of the target cell. The enteropathogen Salmonella enterica serovar Typhimurium (S. Tm) invades epithelial cell types in the gut mucosa and a variety of immune cell types at later infection stages. The molecular mechanism(s) of host cell entry has, however, been studied predominantly in epithelial cell lines. S. Tm uses a type three secretion system (TTSS-1) to translocate effectors into the host cell cytosol, thereby sparking actin ruffle-dependent entry. The ruffles also fuel cooperative invasion by bystander bacteria. In addition, several TTSS-1-independent entry mechanisms exist, involving alternative S. Tm virulence factors, or the passive uptake of bacteria by phagocytosis. However, it remains ill-defined how S. Tm invasion mechanisms vary between host cells. Here, we developed an internally controlled and scalable method to map S. Tm invasion mechanisms across host cell types and conditions. The method relies on host cell infections with consortia of chromosomally tagged wild-type and mutant S. Tm strains, where the abundance of each strain can be quantified by qPCR or amplicon sequencing. Using this methodology, we quantified cooccurring TTSS-1-dependent, cooperative, and TTSS-1-independent invasion events in epithelial, monocyte, and macrophage cells. We found S. Tm invasion of epithelial cells and monocytes to proceed by a similar MOI-dependent mix of TTSS-1-dependent and cooperative mechanisms. TTSS-1-independent entry was more frequent in macrophages. Still, TTSS-1-dependent invasion dominated during the first minutes of interaction also with this cell type. Finally, the combined action of the SopB/SopE/SopE2 effectors was sufficient to explain TTSS-1-dependent invasion across both epithelial and phagocytic cells. IMPORTANCE Salmonella enterica serovar Typhimurium (S. Tm) is a widespread and broad-host-spectrum enteropathogen with the capacity to invade diverse cell types. Still, the molecular basis for the host cell invasion process has largely been inferred from studies of a few selected cell lines. Our work resolves the mechanisms that Salmonellae employ to invade prototypical host cell types, i.e., human epithelial, monocyte, and macrophage cells, at a previously unattainable level of temporal and quantitative precision. This highlights efficient bacterium-driven entry into innate immune cells and uncovers a type III secretion system effector module that dominates active bacterial invasion of not only epithelial cells but also monocytes and macrophages. The results are derived from a generalizable method, where we combine barcoding of the bacterial chromosome with mixed consortium infections of cultured host cells. The application of this methodology across bacterial species and infection models will provide a scalable means to address host-pathogen interactions in diverse contexts.
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| 13. |
- Eriksson Baaz, Maria, 1971-, et al.
(author)
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Moving Out of the Backstage : How Can We Decolonize Research?
- 2019
-
Other publication (other academic/artistic)abstract
- Research here in the DRC is like the coltan and other minerals. Other countries that don’t have access to it claim it and benefit from it. It is the same with research. The research would not be possible without us. Still it is people from the outside who profit from it, get visibility, funding and are called experts. At the same time we – the ones who provide access, adapt the methodology and questions and collect the data in very precarious circumstances – get little compensation and are not acknowledged. It is sort of a continuation of colonial relations.
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| 14. |
- Foote, Andrew D., et al.
(author)
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Genome-culture coevolution promotes rapid divergence of killer whale ecotypes
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Analysing population genomic data from killer whale ecotypes, which we estimate have globally radiated within less than 250,000 years, we show that genetic structuring including the segregation of potentially functional alleles is associated with socially inherited ecological niche. Reconstruction of ancestral demographic history revealed bottlenecks during founder events, likely promoting ecological divergence and genetic drift resulting in a wide range of genome-wide differentiation between pairs of allopatric and sympatric ecotypes. Functional enrichment analyses provided evidence for regional genomic divergence associated with habitat, dietary preferences and post-zygotic reproductive isolation. Our findings are consistent with expansion of small founder groups into novel niches by an initial plastic behavioural response, perpetuated by social learning imposing an altered natural selection regime. The study constitutes an important step towards an understanding of the complex interaction between demographic history, culture, ecological adaptation and evolution at the genomic level.
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| 15. |
- Fors, Andreas, 1977, et al.
(author)
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Person-centred care after acute coronary syndrome, from hospital to primary care - A randomised controlled trial
- 2015
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 187, s. 693-699
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Journal article (peer-reviewed)abstract
- AIM: To evaluate if person-centred care can improve self-efficacy and facilitate return to work or prior activity level in patients after an event of acute coronary syndrome. METHOD: 199 patients with acute coronary syndrome <75years were randomly assigned to person-centred care intervention or treatment as usual and followed for 6months. In the intervention group a person-centred care process was added to treatment as usual, emphasising the patient as a partner in care. Care was co-created in collaboration between patients, physicians, registered nurses and other health care professionals and documented in a health plan. A team-based partnership across three health care levels included transparent knowledge about the disease and medical state to achieve agreed goals during recovery. Main outcome measure was a composite score of changes in general self-efficacy >/=5units, return to work or prior activity level and re-hospitalisation or death. RESULTS: The composite score showed that more patients (22.3%, n=21) improved in the intervention group at 6months compared to the control group (9.5%, n=10) (odds ratio, 2.7; 95% confidence interval: 1.2-6.2; P=0.015). The effect was driven by improved self-efficacy >/=5units in the intervention group. Overall general self-efficacy improved significantly more in the intervention group compared with the control group (P=0.026). There was no difference between groups on re-hospitalisation or death, return to work or prior activity level. CONCLUSION: A person-centred care approach emphasising the partnership between patients and health care professionals throughout the care chain improves general self-efficacy without causing worsening clinical events.
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| 16. |
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| 17. |
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| 18. |
- Fuks, Kateryna B., et al.
(author)
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Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE)
- 2017
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:13, s. 983-990
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Journal article (peer-reviewed)abstract
- Aims We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter <= 2.5 mu m (PM2.5), <= 10 mu m (PM10), >2.5, and <= 10 mu m (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP >= 140mmHg or diastolic BP >= 90mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI): 1.08; 1.37] per 5 mu g/m(3)) and PM2.5 absorbance (RR 1.13 [95% CI: 1.02; 1.24] per 10(-5) m(-1)). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.
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| 19. |
- Georganaki, Maria
(author)
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Vascular targeting for enhanced cancer immunotherapy
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Induced angiogenesis and chronic inflammation are major components of tumor immunosuppression. The scope of this thesis is to understand the role of the vasculature in anti-tumor immunity and thereby to improve cancer immunotherapy.The anti-tumor effects of anti-angiogenic therapies range from vessel normalization to directly affecting immune responses. In Paper I, we demonstrate that VEGF, a major pro-angiogenic factor, inhibits TNFα-induced endothelial activation via interfering with the NF-κB pathway and suppressing T-cell chemoattractants. Sunitinib, an anti-angiogenic tyrosine kinase inhibitor targeting VEGFR2 signaling, enhanced T-cell recruitment and reverted endothelial cell anergy by upregulating pro-inflammatory cytokines in murine melanomas. Therefore, in Paper II, we study the anti-tumor potential of combining sunitinib treatment with CD40-stimulating immunotherapy. CD40 activation leads to increased anti-tumor T-cell responses. The combination therapy was superior in restricting tumor growth and enhancing survival, associated with decreased immunosuppression and increased endothelial activation leading to improved T-cell recruitment. In Paper III, RNA-sequencing reveals that tumor endothelial cells are capable of acquiring negative feedback mechanisms secondary to CD40 immunotherapy by upregulating immunosuppressive genes such as IDO1. Co-administration of agonistic CD40 antibody treatment with an IDO1 inhibitor delayed tumor growth, associated with increased intratumoral T-cell activation.In Paper IV, we investigate ELTD1, an orphan adhesion G protein-coupled receptor, which is upregulated in high-grade glioma vessels. ELTD1 deficiency did not affect developmental angiogenesis in mice but increased tumor growth. Interestingly, ELTD1 loss improved glioma vessel perfusion and reduced permeability and hypoxia. Thus, ELTD1 targeting may normalize tumor vessels, potentially enhancing drug delivery.In Paper V, we demonstrate that ectopic expression of specific cytokines in murine gliomas induces tertiary lymphoid organ- (TLO-) TLO-like structures in the brain. TLOs, mainly composed of T- and B-cell clusters and high endothelial venules, are onsite preservers of robust immune responses. In line with this, increased survival of mice with gliomas overexpressing either LT-αβ or LIGHT was associated with alleviated tumor immunosuppresion. This suggests that TLO-inducing agents may improve cancer immunotherapy for glioma treatment.Collectively, this thesis demonstrates that the tumor vasculature is crucial for anti-tumor immune responses and that vascular targeting can enhance cancer immunotherapy.
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| 20. |
- Granevik Lindström, Maria, et al.
(author)
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The Antibacterial Effect of Nd:YAG Laser Treatment of Teeth with Apical Periodontitis : A Randomized Controlled Trial
- 2017
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In: Journal of Endodontics. - : Elsevier. - 0099-2399 .- 1878-3554. ; 43:6, s. 857-863
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Journal article (peer-reviewed)abstract
- INTRODUCTION: The aim of this blind, in vivo, randomized controlled trial was to evaluate the antibacterial effect of Nd:YAG laser irradiation in endodontic treatment of single-rooted teeth with apical periodontitis. The hypothesis was that mechanical enlargement of the root canal and Nd:YAG laser irradiation would yield more negative bacterial samples than conventional treatment. METHODS: Forty-one patients (45 teeth) were allocated to the laser (n = 22) or control (n = 23) group. The teeth in the laser group were instrumented, irrigated with saline, and irradiated with Nd:YAG laser according to a standard protocol. The teeth in the control group were similarly instrumented but irrigated with 1% unbuffered sodium hypochlorite and 15% EDTA solution. Bacterial samples were taken before and after treatment, blinded, and immediately sent for culturing and analysis. RESULTS: The initial bacterial samples were positive in 20 of 22 teeth in the laser group and 18 of 23 (P = .414) in the control group. After the initial treatment, negative bacterial samples were found in 11 teeth in the laser group and 13 (P = .768) in the control group. After 2 to 4 days with no antibacterial dressing in the root canals, 5 teeth in the laser group and 9 (P = .337) in the control group yielded negative bacterial samples. CONCLUSIONS: After intervention, neither the test group nor the control group yielded predictable negative bacterial samples. Thus, the results failed to verify the hypothesis that Nd:YAG laser irradiation would yield significantly more negative bacterial samples than conventional irrigation with 1% unbuffered sodium hypochlorite solution.
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| 21. |
- Grellier, James, et al.
(author)
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BlueHealth : A study programme protocol for mapping and quantifying the potential benefits to public health and well-being from Europe's blue spaces
- 2017
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In: BMJ Open. - : BMJ. - 2044-6055. ; 7:6
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Journal article (peer-reviewed)abstract
- Introduction Proximity and access to water have long been central to human culture and accordingly deliver countless societal benefits. Over 200 million people live on Europe's coastline, and aquatic environments are the top recreational destination in the region. In terms of public health, interactions with 'blue space' (eg, coasts, rivers, lakes) are often considered solely in terms of risk (eg, drowning, microbial pollution). Exposure to blue space can, however, promote health and well-being and prevent disease, although underlying mechanisms are poorly understood. Aims and methods The BlueHealth project aims to understand the relationships between exposure to blue space and health and well-being, to map and quantify the public health impacts of changes to both natural blue spaces and associated urban infrastructure in Europe, and to provide evidence-based information to policymakers on how to maximise health benefits associated with interventions in and around aquatic environments. To achieve these aims, an evidence base will be created through systematic reviews, analyses of secondary data sets and analyses of new data collected through a bespoke international survey and a wide range of community-level interventions. We will also explore how to deliver the benefits associated with blue spaces to those without direct access through the use of virtual reality. Scenarios will be developed that allow the evaluation of health impacts in plausible future societal contexts and changing environments. BlueHealth will develop key inputs into policymaking and land/water-use planning towards more salutogenic and sustainable uses of blue space, particularly in urban areas. Ethics and dissemination Throughout the BlueHealth project, ethics review and approval are obtained for all relevant aspects of the study by the local ethics committees prior to any work being initiated and an ethics expert has been appointed to the project advisory board. So far, ethical approval has been obtained for the BlueHealth International Survey and for community-level interventions taking place in Spain, Italy and the UK. Engagement of stakeholders, including the public, involves citizens in many aspects of the project. Results of all individual studies within the BlueHealth project will be published with open access. After full anonymisation and application of any measures necessary to prevent disclosure, data generated in the project will be deposited into open data repositories of the partner institutions, in line with a formal data management plan. Other knowledge and tools developed in the project will be made available via the project website (www.bluehealth2020.eu). Project results will ultimately provide key inputs to planning and policy relating to blue space, further stimulating the integration of environmental and health considerations into decision-making, such that blue infrastructure is developed across Europe with both public health and the environment in mind.
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| 22. |
- Hibar, Derrek P., et al.
(author)
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Novel genetic loci associated with hippocampal volume
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 23. |
- Hosokawa, Hiroyuki, et al.
(author)
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Bcl11b sets pro-T cell fate by site-specific cofactor recruitment and by repressing Id2 and Zbtb16
- 2018
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In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 19:12, s. 1427-1440
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Journal article (peer-reviewed)abstract
- Multipotent progenitor cells confirm their T cell–lineage identity in the CD4–CD8– double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.
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| 24. |
- Huyghe, Jeroen R., et al.
(author)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Journal article (peer-reviewed)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 25. |
- Kobayashi, Kensei, et al.
(author)
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Laboratory Studies of Methane and Its Relationship to Prebiotic Chemistry
- 2017
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In: Astrobiology. - : Mary Ann Liebert Inc. - 1531-1074 .- 1557-8070. ; 17:8, s. 786-812
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Research review (peer-reviewed)abstract
- To examine how prebiotic chemical evolution took place on Earth prior to the emergence of life, laboratory experiments have been conducted since the 1950s. Methane has been one of the key molecules in these investigations. In earlier studies, strongly reducing gas mixtures containing methane and ammonia were used to simulate possible reactions in the primitive atmosphere of Earth, producing amino acids and other organic compounds. Since Earth's early atmosphere is now considered to be less reducing, the contribution of extraterrestrial organics to chemical evolution has taken on an important role. Such organic molecules may have come from molecular clouds and regions of star formation that created protoplanetary disks, planets, asteroids, and comets. The interstellar origin of organics has been examined both experimentally and theoretically, including laboratory investigations that simulate interstellar molecular reactions. Endogenous and exogenous organics could also have been supplied to the primitive ocean, making submarine hydrothermal systems plausible sites of the generation of life. Experiments that simulate such hydrothermal systems where methane played an important role have consequently been conducted. Processes that occur in other Solar System bodies offer clues to the prebiotic chemistry of Earth. Titan and other icy bodies, where methane plays significant roles, are especially good targets. In the case of Titan, methane is both in the atmosphere and in liquidospheres that are composed of methane and other hydrocarbons, and these have been studied in simulation experiments. Here, we review the wide range of experimental work in which these various terrestrial and extraterrestrial environments have been modeled, and we examine the possible role of methane in chemical evolution.
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| 26. |
- Kusmierek, Maria, et al.
(author)
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A bacterial secreted translocator hijacks riboregulators to control type III secretion in response to host cell contact
- 2019
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In: PLoS Pathogens. - : Public Library Science. - 1553-7366 .- 1553-7374. ; 15:6
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Journal article (peer-reviewed)abstract
- Numerous Gram-negative pathogens use a Type III Secretion System (T3SS) to promote virulence by injecting effector proteins into targeted host cells, which subvert host cell processes. Expression of T3SS and the effectors is triggered upon host cell contact, but the underlying mechanism is poorly understood. Here, we report a novel strategy of Yersinia pseudotuberculosis in which this pathogen uses a secreted T3SS translocator protein (YopD) to control global RNA regulators. Secretion of the YopD translocator upon host cell contact increases the ratio of post-transcriptional regulator CsrA to its antagonistic small RNAs CsrB and CsrC and reduces the degradosome components PNPase and RNase E levels. This substantially elevates the amount of the common transcriptional activator (LcrF) of T3SS/Yop effector genes and triggers the synthesis of associated virulence-relevant traits. The observed hijacking of global riboregulators allows the pathogen to coordinate virulence factor expression and also readjusts its physiological response upon host cell contact. Author summary Many bacterial pathogens sense contact to host cells and respond by inducing expression of crucial virulence factors. This includes the type III secretion systems (T3SSs) and their substrates, which manipulate different host cell functions to promote colonization and survival of the pathogen within its host. In this study, we used enteropathogenic Yersinia pseudotuberculosis to elucidate the molecular mechanism of how cell contact is transmitted and translated to trigger this process. We found that multiple global riboregulators control the decay and/or translation of the major transcriptional activator of the T3SS. In the absence of cell contact, these important RNA regulators are coopted by one of the substrate proteins of the T3SS to repress expression of the secretion machinery. Translocation of the substrate protein upon cell contact relieves riboregulator-mediated repression. This leads to a strong induction of the master regulator of T3SS/effector gene expression promoting an increase of the virulence potential and provokes a fast adaptation of the pathogen's fitness, e.g. to compensate for the imposed energetic burden.
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| 27. |
- Moshontz, Hannah, et al.
(author)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
-
In: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
-
Journal article (peer-reviewed)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 28. |
- Oanh, Ho Ngoc Hoang, 1986-
(author)
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Regulation of the multi-functional protein YscU in assembly of the Yersinia type III secretion injectisome
- 2017
-
Doctoral thesis (other academic/artistic)abstract
- Yersinia pseudotuberculosis is a Gram-negative zoonotic pathogenic bacterium causing gastroenteritis in human and animals. It shares a conserved virulence plasmid encoding for a needle-like secretion machinery, or type III secretion system, which can be found in other pathogenic Gram-negative bacteria. The type III secretion system (T3SS) is a macromolecular assembly that enables pathogenic effector proteins (or Yersinia outer proteins, Yops) to be transported into eukaryotic host cells. This export machinery is assembled in a highly ordered stepwise mechanism. The activation of T3SS is also dependent on calcium concentration, temperature, and pH of the growth media as mimic factors for host cell’s contact. The T3SS-associated inner-membrane protein, YscU, of Yersinia is proposed to function as a substrate specificity switch protein and forms basal structure of T3SS. YscU has four α helical transmembrane domain and a soluble cytoplasmic domain YscUC which undergoes auto-proteolysis at a conserved N↑PTH motif. The auto-proteolysis process, which is required for the assembly of the injectisome and secretion of Yops, results in a 10-kDa C-terminal polypeptide fragment, denoted YscUCC and 6-kDa N-terminal fragment YscUCN. In this thesis, we showed that YscUC dissociation was important for Yops secretion and resulted in unfolded YscUCN and oligomeric YscUCC. By combination in vivo and in vitro methods, growth media conditions as calcium, temperature, and pH were indicated to control secretion by regulation of YscUC dissociation. The calcium-binding isotherm to YscUC was fit best with a one-site binding model resulting in Kd 800 µM, which is identical to calcium level that blocks secretion in vivo. YscU is also the key protein for the T3SS pH dependence, demonstrated by thermal unfolding profile and secondary structure of protein were altered between pH 7.4 and 6.0. In addition, bacterial inner membrane was proposed to assist the YscUCN folding, monitored by using lipid bilayer as a mimic environment in nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopy. This binding is important for Yops secretion and YscUC is anchored to bacterial membrane upon dissociation. The other substrate specificity switch protein YscP has function as a “molecular ruler” controlling length of the secretion needle. Previous genetic experiments have suggested that YscP and YscU interact physically, when mutation at defined residues on yscU (suppressor mutants) rescued Yops secretion in null-yscP mutant. In this research, direct binding of YscU and YscP was proved as weak but important interaction with Kd 430 mM by application of NMR and the binding interface of YscP was centred on the last helix of YscUC. Furthermore, we found that the YscP interaction could inhibit YscU auto-proteolysis. Studying the dissociation kinetic of suppressor YscUC variants at temperature 30 and 37oC provides strong support to a model where YscU is a temperature sensor for T3SS and YscUC dissociation is required for Yops secretion. Interestingly, the NPTH motif is conserved through most of YscU family members, meaning that role of dissociation may be conserved also in other bacterial injectisomes. To this end, the dissociation of YscU can be used as a therapeutic target in drug discovery. We attempted to identify the small-molecules that can hinder YscU dissociation. The small compound methyl(5-methyl-2-phenyl-1,3-thiazolidin-4-yl)acetate was found to be able to inhibit dissociation and to crystalize full YscUC, which has never been successfully done before. Finally, we found that the inner-rod protein YscI is binding to YscUC with a 1:1 stoichiometry as shown with pull-down assays and isothermal titration calorimetry. Taken together we have made several discoveries that expand the functional palette of YscU and all these functions were shown to have biological relevance with Yops secretion levels. In light of the strong sequence conservation between T3SS utilizing pathogenic bacteria the findings are likely to be general characters.
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| 29. |
- Robinson-Cohen, C., et al.
(author)
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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23
- 2018
-
In: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 29:10, s. 2583-2592
-
Journal article (peer-reviewed)abstract
- Background Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. Methods We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. Results We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. Conclusions Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
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| 30. |
- Robinson-Cohen, Cassianne, et al.
(author)
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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23
- 2018
-
In: Journal of the American Society of Nephrology. - : AMER SOC NEPHROLOGY. - 1046-6673 .- 1533-3450. ; 29:10, s. 2583-2592
-
Journal article (peer-reviewed)abstract
- Background: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.Methods: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m(2) to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.Results: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0x10(-24)), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.Conclusions: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
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| 31. |
- Robinson-Cohen, Cassianne, et al.
(author)
-
Genetic Variants Associated with Circulating Parathyroid Hormone.
- 2017
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In: Journal of the American Society of Nephrology : JASN. - 1533-3450. ; 28:5, s. 1553-1565
-
Journal article (peer-reviewed)abstract
- Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.
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| 32. |
- Rodrigues, Maria Valentina Marin, et al.
(author)
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THESES db : The algae 18S rDNA sequence-structure database for inferring phylogenies
- 2017
-
In: Phycologia. - : Informa UK Limited. - 0031-8884 .- 2330-2968. ; 56:2, s. 186-192
-
Journal article (peer-reviewed)abstract
- The use of 18S rDNA sequences for inferring phylogenies, in particular for higher taxonomic level analysis, has a long tradition in phycology. Similar to ITS2, the 18S rDNA displays a conserved secondary structure that could be used simultaneously with the primary sequence to increase the amount of information used when inferring phylogenetic relationships. Sequence-structure phylogenetics is already established for ITS2 research. Secondary structures no longer simply guide alignments and trees but are used simultaneously by encoding the sequence-structure information into a 12- letter alphabet. We used the knowledge gathered from the extensive body of ITS2 research regarding sequence-structure phylogenetics and applied it to 18S rRNA data; we present THESES db, the Algae 18S rDNA Sequence-Structure Database (http://mbio-serv2.mbioekol.lu.se/THESESdb), which contains sequences and their individual secondary structures for three major groups of algae (Chlorophyta, Bacillariophyta and Rhodophyta). This database was designed to serve as the starting point for future 18S rDNA sequence-structure based phylogenetic analyses that will eventually extend beyond phycology. One hundred phylogenetic trees generated from 18S sequence-only datasets and from parallel 18S sequence-structure datasets were compared for each taxon analyzed in this study (diatoms, green algae and red algae). Half of the comparisons produced trees with different topologies that frequently related to the status of sister genera. Using the lineage information for each species as listed in GenBank, we determined that the sequence-structure approach resolved a genus as monophyletic, while the sequence-only approach failed to do so in comparisons that comprised 3% of the cases examined. The reverse was true for a total of 8.3% of the comparisons that we generated. Future work, both in our labs and among the broader phycological community, will provide additional data to test the accuracy and robustness of a sequence-structure approach at different taxonomic ranks.
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| 33. |
- Sakhnini, Laila I, et al.
(author)
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Improving the Developability of an Antigen Binding Fragment by Aspartate Substitutions
- 2019
-
In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 58:24, s. 2750-2759
-
Journal article (peer-reviewed)abstract
- Aggregation can be a major challenge in the development of antibody-based pharmaceuticals as it can compromise the quality of the product during bioprocessing, formulation, and drug administration. To avoid aggregation, developability assessment is often run in parallel with functional optimization in the early screening phases to flag and deselect problematic molecules. As developability assessment can be demanding with regard to time and resources, there is a high focus on the development of molecule design strategies for engineering molecules with a high developability potential. Previously, Dudgeon et al. [(2012) Proc. Natl. Acad. Sci. U. S. A. 109, 10879-10884] demonstrated how Asp substitutions at specific positions in human variable domains and single-chain variable fragments could decrease the aggregation propensity. Here, we have investigated whether these Asp substitutions would improve the developability potential of a murine antigen binding fragment (Fab). A full combinatorial library consisting of 393 Fab variants with single, double, and triple Asp substitutions was first screened in silico with Rosetta; thereafter, 26 variants with the highest predicted thermodynamic stability were selected for production. All variants were subjected to a set of developability studies. Interestingly, most variants had thermodynamic stability on par with or improved relative to that of the wild type. Twenty-five of the variants exhibited improved nonspecificity. Half of the variants exhibited improved aggregation resistance. Strikingly, while we observed remarkable improvement in the developability potential, the Asp substitutions had no substantial effect on the antigenic binding affinity. Altogether, by combining the insertion of negative charges and the in silico screen based on computational models, we were able to improve the developability of the Fab rapidly.
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| 34. |
- Schuettpelz, Eric, et al.
(author)
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A community-derived classification for extant lycophytes and ferns
- 2016
-
In: Journal of Systematics and Evolution. - : Wiley. - 1674-4918 .- 1759-6831. ; 54:6, s. 563-603
-
Journal article (peer-reviewed)abstract
- Phylogeny has long informed pteridophyte classification. As our ability to infer evolutionary trees has improved, classifications aimed at recognizing natural groups have become increasingly predictive and stable. Here, we provide a modern, comprehensive classification for lycophytes and ferns, down to the genus level, utilizing a community-based approach. We use monophyly as the primary criterion for the recognition of taxa, but also aim to preserve existing taxa and circumscriptions that are both widely accepted and consistent with our understanding of pteridophyte phylogeny. In total, this classification treats an estimated 11 916 species in 337 genera, 51 families, 14 orders, and two classes. This classification is not intended as the final word on lycophyte and fern taxonomy, but rather a summary statement of current hypotheses, derived from the best available data and shaped by those most familiar with the plants in question. We hope that it will serve as a resource for those wanting references to the recent literature on pteridophyte phylogeny and classification, a framework for guiding future investigations, and a stimulus to further discourse.
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| 35. |
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| 36. |
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| 37. |
- Timofeeva, Maria N, et al.
(author)
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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
- 2015
-
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Journal article (peer-reviewed)abstract
- Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
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| 38. |
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| 39. |
- Wagner, Leona, et al.
(author)
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Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease : increased NPY levels and differential degradation of the NPY1-30 fragment
- 2016
-
In: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 137:5, s. 820-837
-
Journal article (peer-reviewed)abstract
- Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. In line with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients. As this antibody-based detection of NPY may provide false positive differences due to the antibody-based detections of only fragments of NPY, the initial finding was validated by investigating the proteolytic stability of NPY in hCSF using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective inhibitors. A comparison between resulting NPY-fragments and detailed epitope analysis verified significant differences of IL-NPY1-36/3-36 and NPY1-30 levels between HD patients and control subjects. Ex vivo degradomics analysis demonstrated that NPY is initially degraded to NPY1-30 by cathepsin D (CTSD) in both HD patients and control subjects. Yet, NPY1-30 is then further differentially hydrolyzed by thimet oligopeptidase (TOP) in HD patients and by neprilysin (NEP) in control subjects. Furthermore, altered hCSF TOP-inhibitor Dynorphin A1-13 (Dyn-A1-13 ) and TOP-substrate Dyn-A1-8 levels indicate an impaired Dyn-A-TOP network in HD patients. Thus, we conclude that elevated IL-NPY-levels in conjunction with TOP- / NEP-activity/protein as well as Dyn-A1-13 -protein levels may serve as a potential biomarker in human CSF of HD. This article is protected by copyright. All rights reserved.
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| 40. |
- Wall Reinius, Sandra, 1974-, et al.
(author)
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Fjällens nyheter
- 2015
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Reports (pop. science, debate, etc.)
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| 41. |
- Wang, He, et al.
(author)
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Increased plasmid copy number is essential for Yersinia T3SS function and virulence
- 2016
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 353:6298, s. 492-495
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Journal article (peer-reviewed)abstract
- Pathogenic bacteria have evolved numerous virulence mechanisms that are essential for establishing infections. The enterobacterium Yersinia uses a type III secretion system (T3SS) encoded by a 70-kilobase, low-copy, IncFII-class virulence plasmid. We report a novel virulence strategy in Y. pseudotuberculosis in which this pathogen up-regulates the plasmid copy number during infection. We found that an increased dose of plasmid-encoded genes is indispensable for virulence and substantially elevates the expression and function of the T3SS. Remarkably, we observed direct, tight coupling between plasmid replication and T3SS function. This regulatory pathway provides a framework for further exploration of the environmental sensing mechanisms of pathogenic bacteria.
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| 42. |
- Wolf, Eva, et al.
(author)
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Non-specific chronic orofacial pain patients' experiences of everyday life situations : a qualitative study
- 2016
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In: Swedish Dental Journal. - : Swedish Dental Association. - 0347-9994. ; 40:2, s. 213-222
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Journal article (peer-reviewed)abstract
- Kronisk ansiktssmärta är ett komplext tillstånd med konsekvenser som påverkar hela livssituationen. Syftet med studien var att med ett kvalitativt angreppssätt analysera upplevelsen av vardagssituationer för patienter med svårförklarlig kronisk ansiktssmärta. Elva kvinnor och tre män (21 till 77 år) valdes strategiskt ut bland de patienter med kronisk ansiktssmärta som remitterats till Orofaciala smärtenheten vid Odontologiska fakulteten, Malmö högskola, Malmö, Sverige. Samtliga utvalda informanter accepterade att delta. Data samlades in genom två tematiska djupintervjuer med varje informant. Intervjuerna spelades in med en digital ljudupptagare och skrevs ut ordagrant. Den text som berörde vardagssituationer identifierades i samtliga intervjuer och analyserades med kvalitativ innehållsanalys. Analysen av informanternas berättelser om vardagssituationer avslöjade en rädsla för konflikter, för den egna svagheten och för det okända. Analysen avslöjade också att informanterna uttryckte självanklagelser och att de undvek situationer som kunde orsaka rädsla. Åtta av de 14 informanterna nämnde inte någon vardagssituation de kände sig tillfreds med. Informanternas upplevelser av vardagssituationer dominerades av negativa känslor. Sammanfattningsvis kan kronisk långvarig svårförklarad ansiktssmärta inte förstås som ett isolerat fenomen utan måste beaktas i relation till den individ som drabbats av tillståndet.
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| 43. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 44. |
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