| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 3. |
- Abend, Sven, et al.
(författare)
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Terrestrial very-long-baseline atom interferometry : Workshop summary
- 2024
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Ingår i: AVS Quantum Science. - : American Institute of Physics (AIP). - 2639-0213. ; 6:2
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Forskningsöversikt (refereegranskat)abstract
- This document presents a summary of the 2023 Terrestrial Very-Long-Baseline Atom Interferometry Workshop hosted by CERN. The workshop brought together experts from around the world to discuss the exciting developments in large-scale atom interferometer (AI) prototypes and their potential for detecting ultralight dark matter and gravitational waves. The primary objective of the workshop was to lay the groundwork for an international TVLBAI proto-collaboration. This collaboration aims to unite researchers from different institutions to strategize and secure funding for terrestrial large-scale AI projects. The ultimate goal is to create a roadmap detailing the design and technology choices for one or more kilometer--scale detectors, which will be operational in the mid-2030s. The key sections of this report present the physics case and technical challenges, together with a comprehensive overview of the discussions at the workshop together with the main conclusions.
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| 4. |
- Eriksson, Mathilda, et al.
(författare)
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Utilization of a right-handed coiled-coil protein from archaebacterium Staphylothermus marinus as a carrier for cisplatin
- 2009
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 29:1, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The nano-sized right-handed coiled-coil (RHCC) protein, originating from the archaebacterium Staphylothermus marinus, is stable at high salt concentrations, high temperatures, high pressures and extremes of pH. Its crystal structure reveals four hydrophobic cavities which can incorporate heavy metals. Nano-sized compounds have been used to carry cytotoxic drugs to tumours, avoiding delivery to healthy tissue, in part due to enhanced permeability in tumour blood vessels (enhanced permeability and retention effect). MATERIALS AND METHODS: The ability of RHCC to carry the platinum-containing chemotherapeutic drug cisplatin to cells, while retaining the cytotoxic potential was tested both in vitro and in vivo. RESULTS: RHCC was able to bind and enter cells in vitro and was not severely toxic or immunogenic in mice. Moreover, RHCC incorporated cisplatin, without inhibiting the cytotoxic potential of the drug against tumour cell lines in vitro or in vivo. CONCLUSION: RHCC can be used as a carrier of cisplatin without abrogating the effect of the drug.
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| 5. |
- Müller, Carsten, et al.
(författare)
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Quantum Monte Carlo Calculation of Correlation Effects on Bond Orders
- 2007
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Ingår i: Theoretical Chemistry accounts. - : Springer Science and Business Media LLC. - 1432-881X .- 1432-2234. ; 117:1, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- We present a computational approach, using quantum Monte Carlo, that provides some insight into the effect of electron correlation on chemical bonding between individual pairs of atoms. Our approach rests upon a recently suggested relation between the bond order and charge fluctuations with respect to atomic domains. Within the present implementation we have taken a compromise between conceptual rigour and computational simplicity. In a first step atomic domains were obtained from Hartree-Fock (HF) densities, using Bader’s definition of atoms in molecules. These domains were used in a second step in quantum Monte Carlo calculations to determine bond orders for pairs of atoms. Correlation effects have been studied by comparison of HF bond orders with those obtained from pure diffusion quantum Monte Carlo calculations. We illustrate this concept for C–O and C–S bonds in different molecular environments. Our results suggest an approximate linear relation between bond order and bond length for these kinds of bonds.
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| 6. |
- Piiper, Albrecht, et al.
(författare)
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Cyclic AMP induces transactivation of the receptors for epidermal growth factor and nerve growth factor, thereby modulating activation of MAP kinase, Akt, and neurite outgrowth in PC12 cells.
- 2002
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Ingår i: J Biol Chem. - 0021-9258. ; 277:46, s. 43623-30
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Tidskriftsartikel (refereegranskat)abstract
- In PC12 cells, a well studied model for neuronal differentiation, an elevation in the intracellular cAMP level increases cell survival, stimulates neurite outgrowth, and causes activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2). Here we show that an increase in the intracellular cAMP concentration induces tyrosine phosphorylation of two receptor tyrosine kinases, i.e. the epidermal growth factor (EGF) receptor and the high affinity receptor for nerve growth factor (NGF), also termed Trk(A). cAMP-induced tyrosine phosphorylation of the EGF receptor is rapid and correlates with ERK1/2 activation. It occurs also in Panc-1, but not in human mesangial cells. cAMP-induced tyrosine phosphorylation of the NGF receptor is slower and correlates with Akt activation. Inhibition of EGF receptor tyrosine phosphorylation, but not of the NGF receptor, reduces cAMP-induced neurite outgrowth. Expression of dominant-negative Akt does not abolish cAMP-induced survival in serum-free media, but increases cAMP-induced ERK1/2 activation and neurite outgrowth. Together, our results demonstrate that cAMP induces dual signaling in PC12 cells: transactivation of the EGF receptor triggering the ERK1/2 pathway and neurite outgrowth; and transactivation of the NGF receptor promoting Akt activation and thereby modulating ERK1/2 activation and neurite outgrowth.
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| 7. |
- Poutanen, Markku, et al.
(författare)
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DynaQlim – Upper Mantle Dynamics and Quaternary Climate in Cratonic Areas
- 2010
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Ingår i: New Frontiers in Integrated Solid Earth Sciences. - Dordrecht : Springer. - 9789048127368 - 9789048127375 ; , s. 349-372
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- The isostatic adjustment of the solid Earth to the glacial loading (GIA, Glacial Isostatic Adjustment) with its temporal signature offers a great opportunity to retrieve information of Earth’s upper mantle to the changing mass of glaciers and ice sheets, which in turn is driven by variations in Quaternary climate. DynaQlim (Upper Mantle Dynamics and Quaternary Climate in Cratonic Areas) has its focus to study the relations between upper mantle dynamics, its composition and physical properties, temperature, rheology, and Quaternary climate. Its regional focus lies on the cratonic areas of northern Canada and Scandinavia.Geodetic methods like repeated precise levelling, tide gauges, high-resolution observations of recent movements, gravity change and monitoring of postglacial faults have given information on the GIA process for more than 100 years. They are accompanied by more recent techniques like GPS observations and the GRACE and GOCE satellite missions which provide additional global and regional constraints on the gravity field. Combining geodetic observations with seismological investigations, studies of the postglacial faults and continuum mechanical modelling of GIA, DynaQlim offers new insights into properties of the lithosphere. Another step toward a better understanding of GIA has been the joint inversion of different types of observational data – preferentially connected with geological relative sea-level evidence of the Earth’s rebound during the last 10,000 years.Due to the changes in the lithospheric stress state large faults ruptured violently at the end of the last glaciation in large earthquakes, up to the magnitudes MW = 7–8. Whether the rebound stress is still able to trigger a significant fraction of intraplate seismic events in these regions is not completely understood due to the complexity and spatial heterogeneity of the regional stress field. Understanding of this mechanism is of societal importance.Glacial ice sheet dynamics are constrained by the coupled process of the deformation of the viscoelastic solid Earth, the ocean and climate variability. Exactly how the climate and oceans reorganize to sustain growth of ice sheets that ground to continents and shallow continental shelves is poorly understood. Incorporation of nonlinear feedback in modelling both ocean heat transport systems and atmospheric CO2 is a major challenge. Climate-related loading cycles and episodes are expected to be important, hence also more short-term features of palaeoclimate should be explicitly treated.Within this Chapter View ChapterIntroductionObservational BasisCurrent Models and Problems to be SolvedClimateChallenges with DynaQlimReferencesReferencesOther actionsExport citationsAbout this BookReprints and Permissions
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| 8. |
- Sandin, Peter, et al.
(författare)
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Diastereoselective self-assembly of clofarabine lipids
- 2014
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Ingår i: New Journal of Chemistry. - 1144-0546 .- 1369-9261. ; 38:11, s. 5247-5253
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Tidskriftsartikel (refereegranskat)abstract
- Clofarabine is a nucleosidic chemotherapeutic approved for the treatment of acute lymphoblastic leukemia, currently undergoing clinical trials for the treatment of solid tumors. Like for many others, lipidic derivatization of this drug improves pharmacokinetics and relieves the heavy side effects. Since the self-assembly pattern can modulate the bioactivity profile, a precise knowledge of the aggregation behavior of these nucleolipids and of the microstructure of the aggregates is central to design formulations that efficiently provide sufficient bioavailability. In this contribution we investigate the self-assembly behavior of two Clofarabine dioxy-ether derivatives, the diastereomers (1-2S and 1-2R). These clofarabine lipid derivatives showed an unexpected diastereoselective self-assembly effect, which we have monitored by observing the time evolution of self-assemblies and their microstructural response to thermal treatment. Dynamic Light Scattering and Circular Dichroism provide an ensemble of results which correlate with the occurrence of a hierarchical association of wormlike aggregates, imaged using Electron Microcopy. A strikingly different behavior for the two diastereomers was observed. This behavior can be crucial for the different bioavailability observed in vivo.
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| 9. |
- Scott, Robert A, et al.
(författare)
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No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels
- 2012
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Ingår i: Diabetes. - Alexandria, VA : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 61:5, s. 1291-1296
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Tidskriftsartikel (refereegranskat)abstract
- Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.
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| 10. |
- Siegel, Sonja, et al.
(författare)
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Coping strategies have a strong impact on quality of life, depression, and embitterment in patients with Cushing's disease
- 2016
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Ingår i: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403. ; 19:6, s. 590-600
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Tidskriftsartikel (refereegranskat)abstract
- Quality of life (QoL) and psychosocial well-being are substantially impaired in patients with Cushing's disease (CD), not only at the acute illness stage but also after therapy; however, the reason for these impairments remains unclear. In this cross-sectional, patient-reported outcome study, we conducted a postal survey on psychosocial impairment and coping strategies in patients after surgical treatment of CD in three large tertiary referral centers. In total, 176 patients with CD completed a compilation of self-assessment inventories pertaining to depression (Hospital Anxiety and Depression Scale, HADS), QoL (Short Form SF-36, Tuebingen CD; Tuebingen CD-25), coping style (Freiburg questionnaire on coping with illness, FKV-LIS), and embitterment (Bern Embitterment Inventory), on average 6.8 +/- 6.66 years after surgery. Regression analyses were performed to identify predictors of psychosocial impairment. At the time of the study, 21.8 % of patients suffered from anxiety, 18.7 % experienced an above-average feeling of embitterment, and 13.1 % suffered from depression. Maladaptive coping styles (FKV-LIS subscales depressive coping and minimizing importance) emerged as robust and strong predictors of psychosocial impairment in all inventories; while age, sex, and hydrocortisone intake failed to explain the variance in these measures. Similar to several studies in non-pituitary patient cohorts (e.g., patients with multiple sclerosis or lower back pain), our results indicate that psychosocial impairment in CD is significantly influenced by how the patient deals with the illness. Therefore, psychological training of positive coping styles could be a helpful complementary therapy in the overall treatment strategy of CD.
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