| 1. |
- Freitag, Daniel F., et al.
(author)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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In: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Journal article (peer-reviewed)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 2. |
- Hollestelle, Antoinette, et al.
(author)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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In: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Journal article (peer-reviewed)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 3. |
- Sánchez-Hernández, Noemí, et al.
(author)
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Targeting proteins to RNA transcription and processing sites within the nucleus
- 2017
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In: International Journal of Biochemistry and Cell Biology. - : Elsevier BV. - 1357-2725 .- 1878-5875. ; 91, s. 194-202
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Journal article (peer-reviewed)abstract
- Studies of the spatial organization of the highly compartmentalized eukaryotic nucleus and dynamics of transcription and RNA processing within it are fundamental for fully understanding how gene expression is regulated in the cell. Although some progress has been made in deciphering the functional consequences of this complex network of interacting molecules in the context of nuclear organization, how proteins and RNA move in the nucleus and how the transcription and RNA processing machineries find their targets are important questions that remain largely unexplored. Here, we review major hallmarks and novel insights regarding the movement of RNA and proteins in the context of nuclear organization as well as the mechanisms by which the proteins involved in RNA processing localize to specific nuclear compartments.
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| 4. |
- Gifford, Danna R., et al.
(author)
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Mutators can drive the evolution of multi-resistance to antibiotics
- 2023
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 19:6
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Journal article (peer-reviewed)abstract
- Antibiotic combination therapies are an approach used to counter the evolution of resistance; their purported benefit is they can stop the successive emergence of independent resistance mutations in the same genome. Here, we show that bacterial populations with ‘mutators’, organisms with defects in DNA repair, readily evolve resistance to combination antibiotic treatment when there is a delay in reaching inhibitory concentrations of antibiotic—under conditions where purely wild-type populations cannot. In populations of Escherichia coli subjected to combination treatment, we detected a diverse array of acquired mutations, including multiple alleles in the canonical targets of resistance for the two drugs, as well as mutations in multi-drug efflux pumps and genes involved in DNA replication and repair. Unexpectedly, mutators not only allowed multi-resistance to evolve under combination treatment where it was favoured, but also under single-drug treatments. Using simulations, we show that the increase in mutation rate of the two canonical resistance targets is sufficient to permit multi-resistance evolution in both single-drug and combination treatments. Under both conditions, the mutator allele swept to fixation through hitch-hiking with single-drug resistance, enabling subsequent resistance mutations to emerge. Ultimately, our results suggest that mutators may hinder the utility of combination therapy when mutators are present. Additionally, by raising the rates of genetic mutation, selection for multi-resistance may have the unwanted side-effect of increasing the potential to evolve resistance to future antibiotic treatments.
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| 7. |
- Kakar, Sanjeev, et al.
(author)
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Technical considerations in the operative management of femoral neck fractures in elderly patients : a multinational survey.
- 2007
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In: The Journal of trauma, injury, infection, and critical care. - : Ovid Technologies (Wolters Kluwer Health). - 1079-6061 .- 0022-5282. ; 63:3, s. 641-646
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To identify current opinions among orthopedic traumatologists relating to technical aspects of internal fixation and arthroplasty for patients with femoral neck fractures. METHODS: We developed and administered a survey to orthopedic surgeons who were members of the Orthopedic Trauma Association and European clinics affiliated with AO International (Davos, Switzerland). Surgeons reported preferences in specific aspects of the surgical technique for internal fixation as well as arthroplasty. Each surgeon received either a mailed package (7-page survey, a personalized cover letter, and a stamped return envelope) or an email with a link to the same survey on the Internet with an identification code. At 6 weeks, 12 weeks, and 18 weeks after the initial mailing, we remailed the questionnaire to all nonresponders. RESULTS: Of the 442 surgeons who were sent the questionnaire, 298 (68%) responded. The typical respondent was a North American aged more than 40 years, in academic practice, supervised residents, had fellowship training in trauma, and worked in a low-volume center. Among surgeons who treated displaced femoral neck fractures with arthroplasty, significant disparities existed in terms of the type of anesthesia (51% preferring general anesthesia), surgical approach (47% used posterior approach), and placement of unipolar implants (50%). Surgeons tended to agree on the use of cement fixation (69%), repairing the capsule (80%), and not using a drain postoperatively (68%). Surgeons who preferentially treated hip fractures with internal fixation tended to have a lack of consensus in terms of what constituted acceptable surgical delays (43% allowing greater than 48 hours) and which screw configuration to use, with more than half using a triangle with base inferior construct. Surgeons tended to agree on the use of closed fracture reduction techniques (69%), three cannulated screws (73%), and did not routinely perform a capsulotomy (80%) or aspirate the fracture hematoma (90%). Within both treatment groups (internal fixation and arthroplasty), surgeons tended to agree on the use of perioperative antibiotics (>92%), thromboprophylaxis (98%), and postoperative weight bearing status (>87%). CONCLUSIONS: A general lack of consensus exists among orthopedic trauma surgeons in the management of displaced femoral neck fractures. With an ever-growing emphasis upon the practice of evidence-based medicine, we have demonstrated several disparities in the technical aspects of fixation and perioperative care likely caused by a general lack of available evidence. We recommend the need for future research and large collaborative efforts.
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| 8. |
- Sinnl, Giulia, et al.
(author)
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Synchronizing ice-core and U/Th timescales in the Last Glacial Maximum using Hulu Cave 14C and new 10Be measurements from Greenland and Antarctica
- 2023
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In: Climate of the Past. - 1814-9324. ; 19:6, s. 1153-1175
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Journal article (peer-reviewed)abstract
- Between 15 and 27kyrb2k (thousands of years before 2000CE) during the last glacial, Greenland experienced a prolonged cold stadial phase, interrupted by two short-lived warm interstadials. Greenland ice-core calcium data show two periods, preceding the interstadials, of anomalously high atmospheric dust loading, the origin of which is not well understood. At approximately the same time as the Greenland dust peaks, the Chinese Hulu Cave speleothems exhibit a climatic signal suggested to be a response to Heinrich Event 2, a period of enhanced ice-rafted debris deposition in the North Atlantic. In the climatic signal of Antarctic ice cores, moreover, a relative warming occurs between 23 and 24.5kyrb2k that is generally interpreted as a counterpart to a cool climate phase in the Northern Hemisphere. Proposed centennial-scale offsets between the polar ice-core timescales and the speleothem timescale hamper the precise reconstruction of the global sequence of these climatic events. Here, we examine two new 10Be datasets from Greenland and Antarctic ice cores to test the agreement between different timescales, by taking advantage of the globally synchronous cosmogenic radionuclide production rates. Evidence of an event similar to the Maunder Solar Minimum is found in the new 10Be datasets, supported by lower-resolution radionuclide data from Greenland and 14C in the Hulu Cave speleothem, representing a good synchronization candidate at around 22kyrb2k. By matching the respective 10Be data, we determine the offset between the Greenland ice-core chronology, GICC05, and the Antarctic chronology for the West Antarctic Ice Sheet Divide ice core (WDC), WD2014, to be 125±40 years. Furthermore, via radionuclide wiggle-matching, we determine the offset between the Hulu speleothem and ice-core timescales to be 375 years for GICC05 (75-625 years at 68% confidence) and 225 years for WD2014 (-25-425 years at 68% confidence). The rather wide uncertainties are intrinsic to the wiggle-matching algorithm and the limitations set by data resolution. The undercounting of annual layers in GICC05 inferred from the offset is hypothesized to have been caused by a combination of underdetected annual layers, especially during periods with low winter precipitation, and misinterpreted unusual patterns in the annual signal during the extremely cold period often referred to as Heinrich Stadial 1.
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| 9. |
- Suñé, Marc, et al.
(author)
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Capillary control of collapse in soft composite columns
- 2021
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In: Physical Review Materials. - : American Physical Society (APS). - 2475-9953. ; 5:5
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Journal article (peer-reviewed)abstract
- Euler buckling is the elastic instability of a column subjected to longitudinal compression forces at its ends. The buckling instability occurs when the compressing load reaches a critical value, and an infinitesimal fluctuation leads to a large amplitude deflection. Since Euler's original study, this process has been extensively examined in homogeneous, isotropic, linear-elastic solids. Here, we examine the nature of the buckling in inhomogeneous soft composite materials. In particular, we consider a soft host with liquid inclusions both large and small relative to the elastocapillarity length, which lead to softening and stiffening, respectively, of a homogeneous composite. However, by imposing a gradient of the inclusion volume fraction or by varying the inclusion size we can deliberately manipulate the spatial structure of the composite properties of a column and thereby control the nature of Euler buckling.
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| 10. |
- Suñé, Marc, et al.
(author)
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Wrinkling composite sheets
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Other publication (other academic/artistic)abstract
- We examine the buckling shape and critical compression of confined inhomogeneous composite sheets lying on a liquid foundation. The buckling modes are controlled by the bending stiffness of the sheet, the density of the substrate, and the size and the spatially dependent elastic coefficients of the sheet. We solve the (linearized) Föppl–von Kármán equations describing the mechanical equilibrium of a sheet when its bending stiffness varies parallel to the direction of confinement. The case of a homogeneous bending stiffness exhibits a degeneracy of wrinkled states for certain sizes of the confined sheet. This degeneracy disappears for spatially dependent elastic coefficients. Medium length sheets buckle similarly to their homogeneous counterparts, whereas the wrinkled states in large length sheets localize the bending energy towards the soft regions of the sheet.
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