| 1. |
- Blunden, Jessica, et al.
(författare)
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State of the Climate in 2012
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Tidskriftsartikel (refereegranskat)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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| 2. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 3. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 4. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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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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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 6. |
- Hillier, Ladeana W, et al.
(författare)
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Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
- 2004
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
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Tidskriftsartikel (refereegranskat)abstract
- We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
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| 7. |
- Windhorst, Rogier A., et al.
(författare)
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JWST PEARLS. Prime extragalactic areas for reionization and lensing science : project overview and first results
- 2023
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Ingår i: Astronomical Journal. - : Institute of Physics (IOP). - 0004-6256 .- 1538-3881. ; 165:1
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Tidskriftsartikel (refereegranskat)abstract
- We give an overview and describe the rationale, methods, and first results from NIRCam images of the JWST “Prime Extragalactic Areas for Reionization and Lensing Science” (PEARLS) project. PEARLS uses up to eight NIRCam filters to survey several prime extragalactic survey areas: two fields at the North Ecliptic Pole (NEP); seven gravitationally lensing clusters; two high redshift protoclusters; and the iconic backlit VV 191 galaxy system to map its dust attenuation. PEARLS also includes NIRISS spectra for one of the NEP fields and NIRSpec spectra of two high-redshift quasars. The main goal of PEARLS is to study the epoch of galaxy assembly, active galactic nucleus (AGN) growth, and First Light. Five fields—the JWST NEP Time-Domain Field (TDF), IRAC Dark Field, and three lensing clusters—will be observed in up to four epochs over a year. The cadence and sensitivity of the imaging data are ideally suited to find faint variable objects such as weak AGN, high-redshift supernovae, and cluster caustic transits. Both NEP fields have sightlines through our Galaxy, providing significant numbers of very faint brown dwarfs whose proper motions can be studied. Observations from the first spoke in the NEP TDF are public. This paper presents our first PEARLS observations, their NIRCam data reduction and analysis, our first object catalogs, the 0.9–4.5 μm galaxy counts and Integrated Galaxy Light. We assess the JWST sky brightness in 13 NIRCam filters, yielding our first constraints to diffuse light at 0.9–4.5 μm. PEARLS is designed to be of lasting benefit to the community.
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| 8. |
- Ferrari, Raffaele, et al.
(författare)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 9. |
- Fiedler, Stephanie, et al.
(författare)
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Interactions between atmospheric composition and climate change – progress in understanding and future opportunities from AerChemMIP, PDRMIP, and RFMIP
- 2024
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Ingår i: Geoscientific Model Development. - 1991-959X .- 1991-9603. ; 17:6, s. 2387-2417
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Forskningsöversikt (refereegranskat)abstract
- The climate science community aims to improve our understanding of climate change due to anthropogenic influences on atmospheric composition and the Earth's surface. Yet not all climate interactions are fully understood, and uncertainty in climate model results persists, as assessed in the latest Intergovernmental Panel on Climate Change (IPCC) assessment report. We synthesize current challenges and emphasize opportunities for advancing our understanding of the interactions between atmospheric composition, air quality, and climate change, as well as for quantifying model diversity. Our perspective is based on expert views from three multi-model intercomparison projects (MIPs) – the Precipitation Driver Response MIP (PDRMIP), the Aerosol Chemistry MIP (AerChemMIP), and the Radiative Forcing MIP (RFMIP). While there are many shared interests and specializations across the MIPs, they have their own scientific foci and specific approaches. The partial overlap between the MIPs proved useful for advancing the understanding of the perturbation–response paradigm through multi-model ensembles of Earth system models of varying complexity. We discuss the challenges of gaining insights from Earth system models that face computational and process representation limits and provide guidance from our lessons learned. Promising ideas to overcome some long-standing challenges in the near future are kilometer-scale experiments to better simulate circulation-dependent processes where it is possible and machine learning approaches where they are needed, e.g., for faster and better subgrid-scale parameterizations and pattern recognition in big data. New model constraints can arise from augmented observational products that leverage multiple datasets with machine learning approaches. Future MIPs can develop smart experiment protocols that strive towards an optimal trade-off between the resolution, complexity, and number of simulations and their length and, thereby, help to advance the understanding of climate change and its impacts.
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| 10. |
- Ringqvist, Emma, et al.
(författare)
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Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells
- 2008
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Ingår i: Molecular and biochemical parasitology (Print). - : Elsevier BV. - 0166-6851 .- 1872-9428. ; 159:2, s. 85-91
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Tidskriftsartikel (refereegranskat)abstract
- Giardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine.
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| 11. |
- Sartelli, Massimo, et al.
(författare)
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Ten golden rules for optimal antibiotic use in hospital settings: the WARNING call to action
- 2023
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Ingår i: WORLD JOURNAL OF EMERGENCY SURGERY. - 1749-7922. ; 18:1
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Forskningsöversikt (refereegranskat)abstract
- Antibiotics are recognized widely for their benefits when used appropriately. However, they are often used inappropriately despite the importance of responsible use within good clinical practice. Effective antibiotic treatment is an essential component of universal healthcare, and it is a global responsibility to ensure appropriate use. Currently, pharmaceutical companies have little incentive to develop new antibiotics due to scientific, regulatory, and financial barriers, further emphasizing the importance of appropriate antibiotic use. To address this issue, the Global Alliance for Infections in Surgery established an international multidisciplinary task force of 295 experts from 115 countries with different backgrounds. The task force developed a position statement called WARNING (Worldwide Antimicrobial Resistance National/International Network Group) aimed at raising awareness of antimicrobial resistance and improving antibiotic prescribing practices worldwide. The statement outlined is 10 axioms, or "golden rules," for the appropriate use of antibiotics that all healthcare workers should consistently adhere in clinical practice.
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| 12. |
- Abdel-Khalik, Jonas, et al.
(författare)
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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
- 2021
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Ingår i: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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| 13. |
- Caron, Bénédicte, et al.
(författare)
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IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis : the PROCTRIAL Consensus
- 2022
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 20:11, s. 2169-2627.e1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the PROCTRIAL (Definition and endpoints for ulcerative PROCtitis in clinical TRIALs) initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults.METHODS: Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters.RESULTS: The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity is proposed. Secondary endpoints which should be evaluated include endoscopic remission, histological remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life.CONCLUSION: In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the PROCTRIAL consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.
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| 14. |
- Franke, Andre, et al.
(författare)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Tidskriftsartikel (refereegranskat)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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| 15. |
- Griffiths, William J., et al.
(författare)
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The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson’s Disease and Their Association With Disease State and Clinical Features
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson’s disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.
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| 16. |
- Moslehi, Saba, et al.
(författare)
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Comparison of fractal and grid electrodes for studying the effects of spatial confinement on dissociated retinal neuronal and glial behavior
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the impact of the geometry and material composition of electrodes on the survival and behavior of retinal cells is of importance for both fundamental cell studies and neuromodulation applications. We investigate how dissociated retinal cells from C57BL/6J mice interact with electrodes made of vertically-aligned carbon nanotubes grown on silicon dioxide substrates. We compare electrodes with different degrees of spatial confinement, specifically fractal and grid electrodes featuring connected and disconnected gaps between the electrodes, respectively. For both electrodes, we find that neuron processes predominantly accumulate on the electrode rather than the gap surfaces and that this behavior is strongest for the grid electrodes. However, the ‘closed’ character of the grid electrode gaps inhibits glia from covering the gap surfaces. This lack of glial coverage for the grids is expected to have long-term detrimental effects on neuronal survival and electrical activity. In contrast, the interconnected gaps within the fractal electrodes promote glial coverage. We describe the differing cell responses to the two electrodes and hypothesize that there is an optimal geometry that maximizes the positive response of both neurons and glia when interacting with electrodes.
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| 17. |
- Yutuc, Eylan, et al.
(författare)
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Deep mining of oxysterols and cholestenoic acids in human plasma and cerebrospinal fluid : Quantification using isotope dilution mass spectrometry
- 2021
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Ingår i: Analytica Chimica Acta. - : Elsevier. - 0003-2670 .- 1873-4324. ; 1154
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Tidskriftsartikel (refereegranskat)abstract
- Both plasma and cerebrospinal fluid (CSF) are rich in cholesterol and its metabolites. Here we describe in detail a methodology for the identification and quantification of multiple sterols including oxysterols and sterol-acids found in these fluids. The method is translatable to any laboratory with access to liquid chromatography – tandem mass spectrometry. The method exploits isotope-dilution mass spectrometry for absolute quantification of target metabolites. The method is applicable for semi-quantification of other sterols for which isotope labelled surrogates are not available and approximate quantification of partially identified sterols. Values are reported for non-esterified sterols in the absence of saponification and total sterols following saponification. In this way absolute quantification data is reported for 17 sterols in the NIST SRM 1950 plasma along with semi-quantitative data for 8 additional sterols and approximate quantification for one further sterol. In a pooled (CSF) sample used for internal quality control, absolute quantification was performed on 10 sterols, semi-quantification on 9 sterols and approximate quantification on a further three partially identified sterols. The value of the method is illustrated by confirming the sterol phenotype of a patient suffering from ACOX2 deficiency, a rare disorder of bile acid biosynthesis, and in a plasma sample from a patient suffering from cerebrotendinous xanthomatosis, where cholesterol 27-hydroxylase is deficient.
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| 18. |
- Brunnström, Åsa, et al.
(författare)
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Biosynthesis of 14,15-Hepoxilins in Human L1236 Hodgkin Lymphoma Cells and Eosinophils
- 2011
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Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 46:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- Hepoxilins are epoxy alcohols synthesized through the 12-lipoxygenase (12-LO) pathway in animal cells. The epidermis is the principal source of hepoxilins in humans. Here we report on the formation of novel hepoxilin regioisomers formed by the 15-LO pathway in human cells. The Hodgkin lymphoma cell line L1236 possesses high 15-lipoxygenase-1 (15-LO-1) activity and incubation of L1236 cells with arachidonic acid led to the formation of 11(S)-hydroxy-14(S),15(S)-epoxy 5(Z),8(Z),12(E) eicosatrienoic acid (14,15-HxA(3) 11(S)) and 13(R)-hydroxy-14(S),15(S)-epoxy 5(Z),8(Z),11(Z) eicosatrienoic acid (14,15-HxB(3) 13 (R)). In addition, two hitherto unidentified products were detected and these products were collected and analyzed by positive ion electrospray tandem mass spectrometry. These metabolites were identified as 11(S),15(S)-dihydroxy-14(R)-glutathionyl-5(Z),8(Z),12(E)-eicosatrienoic acid (14,15-HxA(3)-C) and 11(S),15(S)-dihydroxy-14(R)-cysteinyl-glycyl-5(Z),8(Z),12(E)-eicosatrien oic acid (14,15-HxA(3)-D). Incubation of L1236 cells with synthetic 14,15-HxA(3) 11(S) also led to the formation of 14,15-HxA(3)-C and 14,15-HxA(3)-D. Several soluble glutathione transferases, in particular GST M1-1 and GST P1-1, were found to catalyze the conversion of 14,15-HxA(3) to 14,15-HxA(3)-C. L1236 cells produced approximately twice as much eoxins as cysteinyl-containing hepoxilins upon stimulation with arachidonic acid. Human eosinophils, nasal polyps and dendritic cells selectively formed 14,15-HxA(3) 11(S) and 14,15-HxB(3) 13(R) stereoisomers, but not cysteinyl-containing hepoxilins, after stimulation with arachidonic acid. Furthermore, purified recombinant 15-LO-1 alone catalyzed the conversion of arachidonic acid to 14,15-HxA(3) 11(S) and 14,15-HxB(3) 13(R), showing that human 15-LO-1 possesses intrinsic 14,15-hepoxilin synthase activity.
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| 19. |
- Daniilidou, Makrina, et al.
(författare)
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Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities.
- 2023
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Ingår i: Brain communications. - 2632-1297. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.
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| 20. |
- de Kock, Neil
(författare)
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Mass spectrometry based analysis of endogenous sterols and hormones
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bioanalytical applications using supercritical fluid chromatography (SFC) as analytical technique are of increasing interest. In essence, bioanalysis involves measurement of bioactive or endogenous compounds in biological matrices. SFC has emerged as an excellent choice for bioanalytical analysis, attributable to its speed, selectivity and efficiency compared with high performance liquid chromatography. Moreover, coupling of SFC with mass spectrometry (MS) provides the additional benefits of specificity and sensitivity.The aim of this thesis was to exploit these features by developing methods for the analysis of endogenous steroids, cholesterol oxidation products (COPs) and thyroid hormones (THs) by using ultra-performance supercritical fluid chromatography–tandem mass spectrometry (UPSFC–MS/MS) as analytical technique.Endogenous steroids control many physiological processes, including reproduction, maturation, gene expression and neurological functions in humans and animals. In the first study, three steroids were measured in domesticated White Leghorn (WL) chickens and ancestral Red Junglefowl (RJF) birds. Restraining stress caused a significantly larger increase in corticosterone levels in RJF than in WL, indicating a blunted hypothalamic–pituitary–adrenal (HPA) axis activity in domesticated chickens. The second study was a continuation of the first study and corticosterone levels from the F12 generation of an intercross between WL and RJF birds were measured before and after physical restraint stress. The expression levels of the glucocorticoid receptor (GR) in the hypothalamus and several genes in the adrenal glands were correlated with the post-stress levels of corticosterone in plasma. In the third study, the measurement of steroids was extended to assess more endogenous steroids from the four major classes, i.e. estrogens, androgens, progestogens and corticosterone.Endogenous COPs are of interest in pathophysiology. COPs are more readily disposed by cells than cholesterol. Therefore, cholesterol is oxidised to the more polar COPs and are generally more bioactive than cholesterol. Moreover, if their production in cells and tissues and/or their introduction with dietary animal fat are excessive, COPs could indeed contribute to the pathogenesis of various disease processes. Fourteen COPs were included in the fourth study and a novel method for their separation was developed.The last study in this thesis, involved the analysis of five THs. These hormones are vital for growth, developmental and metabolic processes of vertebrate life and play an important role in energy homeostasis. Measurements of circulating thyroid hormone levels are used in thyroid disorder diagnoses or treatment status monitoring. Two rapid methods for the separation of five THs were developed.In summary, the work in this thesis demonstrates the applicability of UPSFC–MS/MS as an analytical technique in bioanalysis of endogenous compounds.
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| 21. |
- Latorre-Leal, María, et al.
(författare)
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CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice
- 2024
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Ingår i: Science advances. - 2375-2548. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer's disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.
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| 22. |
- Nejati, Babak, et al.
(författare)
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Validating the Persian Intuitive Eating Scale-2 Among Breast Cancer Survivors Who Are Overweight/Obese
- 2021
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Ingår i: Evaluation & the Health Professions. - : Sage Publications. - 0163-2787 .- 1552-3918. ; 44:4, s. 385-394
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Tidskriftsartikel (refereegranskat)abstract
- Women with breast cancer are at risk of being overweight/obese which may consequently increase mortality. Intuitive eating is an adaptive eating behavior which might be beneficial for weight outcomes. The present study validated the Persian Intuitive Eating Scale-2 (IES-2) among overweight/obese Iranian females with breast cancer. Women who were overweight/obese with breast cancer (n = 762; mean ± SD age = 55.1 ± 5.7 years) completed the following questionnaires: IES-2, General Self-Efficacy Scale (GSE-6), Hospital Anxiety and Depression Scale (HADS), Short Form-12 (SF-12), Weight Bias Internalization Scale (WBIS), Body Appreciation Scale-2 (BAS-2), and Eating Attitudes Test (EAT-26). Confirmatory factor analysis (CFA) and Rasch analysis were applied to examine the psychometric properties of the IES-2. Associations between IES-2 score and other scale scores were assessed. CFA and Rasch analysis suggested that the Persian IES-2 had robust psychometric properties and all IES-2 items were meaningful in their embedded domains. The four-factor structure of the Persian IES-2 was confirmed. Concurrent validity was supported by the positive correlations between the IES-2 score and scores on the GSE-6, SF-12 mental component, and BAS-2. Negative correlations were found between the IES-2 score and the HADS (anxiety and depression subscales), WBIS, and EAT-26. The present study demonstrated that the Persian IES-2 is a well-designed instrument and is applicable for women who are overweight/obese with breast cancer.
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| 23. |
- Siegel, Corey A., et al.
(författare)
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Development of an index to define overall disease severity in IBD
- 2018
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Ingår i: Gut. - London, United Kingdom : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 67:2, s. 244-254
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC.Methods: Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute.Results: For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities.Conclusions: Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.
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