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| 2. |
- Aoude, Lauren G, et al.
(författare)
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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:2, s. 408-408
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Tidskriftsartikel (refereegranskat)abstract
- The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
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| 3. |
- Baruch, Zdravko, et al.
(författare)
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Functional acclimation across microgeographic scales in Dodonaea viscosa
- 2018
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Ingår i: AoB Plants. - : Oxford University Press (OUP). - 2041-2851. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Intraspecific plant functional trait variation provides mechanistic insight into persistence and can infer population adaptive capacity. However, most studies explore intraspecific trait variation in systems where geographic and environmental distances co-vary. Such a design reduces the certainty of trait-environment associations, and it is imperative for studies that make trait-environment associations be conducted in systems where environmental distance varies independently of geographic distance. Here we explored trait variation in such a system, and aimed to: (i) quantify trait variation of parent and offspring generations, and associate this variation to parental environments; (ii) determine the traits which best explain population differences; (iii) compare parent and offspring trait-trait relationships. We characterized 15 plant functional traits in eight populations of a shrub with a maximum separation ca. 100 km. Populations differed markedly in aridity and elevation, and environmental distance varied independently of geographic distance. We measured traits in parent populations collected in the field, as well as their offspring reared in greenhouse conditions. Parent traits regularly associated with their environment. These associations were largely lost in the offspring generation, indicating considerable phenotypic plasticity. An ordination of parent traits showed clear structure with strong influence of leaf area, specific leaf area, stomatal traits, isotope delta C-13 and delta N-15 ratios, and N-area, whereas the offspring ordination was less structured. Parent trait-trait correlations were in line with expectations from the leaf economic spectrum. We show considerable trait plasticity in the woody shrub over microgeographic scales (<100 km), indicating it has the adaptive potential within a generation to functionally acclimate to a range of abiotic conditions. Since our study shrub is commonly used for restoration in southern Australia and local populations do not show strong genetic differentiation in functional traits, the potential risks of transferring seed across the broad environmental conditions are not likely to be a significant issue.
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| 4. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 5. |
- Carleo, Ilaria, et al.
(författare)
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The Multiplanet System TOI-421*
- 2020
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 160:3
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations-comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echelle Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution echelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements-and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P-b = 5.19672 +/- 0.00049 days, a mass of M-b = 7.17 +/- 0.66 M-circle plus, and a radius of R-b = R-circle plus, whereas the outer warm Neptune, TOI-421 c, has a period of P-c = 16.06819 +/- 0.00035 days, a mass of M-c = 16.42(-1.04)(+1.06)M(circle plus), a radius of R-c = 5.09(-0.15)(+0.16)R(circle plus), and a density of rho(c) = 0.685(-0.072)(+0.080) cm(-3). With its characteristics, the outer planet (rho(c) = 0.685(-0.0072)(+0.080) cm(-3)) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Ly alpha transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed.
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| 6. |
- Gudmundsdottir, Valborg, et al.
(författare)
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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes : an IMI-DIRECT study
- 2020
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Ingår i: Genome Medicine. - : BioMed Central. - 1756-994X .- 1756-994X. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.
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| 7. |
- Jones, Kristine, et al.
(författare)
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Cost-effectiveness of critical time intervention to reduce homelessness among persons with mental illness
- 2003
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Ingår i: Psychiatric Services. - : American Psychiatric Association Publishing. - 1075-2730 .- 1557-9700. ; 54:6, s. 884-890
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Cost-effective programs are needed to assist homeless persons with severe mental illness in their transition from shelters to community living. The authors investigated the cost-effectiveness of the critical time intervention program, a time-limited adaptation of intensive case management, which has been shown to significantly reduce recurrent homelessness among men with severe mental illness. Methods: Ninety-six study participants recruited from a psychiatric program in a men's public shelter from 1991 to 1993 were randomly assigned to the critical time intervention program or to usual services. Costs and housing outcomes for the two groups were examined over 18 months. Results: Over the study period, the critical time intervention group and the usual services group incurred mean costs of $52,374 and $51,649, respectively, for acute care services, outpatient services, housing and shelter services, criminal justice services, and transfer income. During the same period, the critical time intervention group experienced significantly fewer homeless nights than the usual care group (32 nights versus 90 nights). For each willingness-to-pay value - the additional price society is willing to spend for an additional nonhomeless night - greater than $152, the critical time intervention group exhibited a significantly greater net housing stability benefit, indieating cost-effectiveness, compared with usual care. Conclusions: Although difficult to conduct, studies of the cost-effectiveness of community mental health programs can yield rich information for policy makers and program planners. The critical time intervention program is not only an effective method to reduce recurrent homelessness among persons with severe mental illness but also represents a cost-effective alternative to the status quo.
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| 8. |
- Kaiser, Kristine, et al.
(författare)
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When sounds collide : the effect of anthropogenic noise on a breeding assemblage of frogs in Belize, Central America
- 2011
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Ingår i: Behaviour. - 0005-7959 .- 1568-539X. ; 148:2, s. 215-232
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Tidskriftsartikel (refereegranskat)abstract
- Many organisms depend on acoustic communication for myriad functions, and have evolved behaviours to minimize effects of naturally occurring acoustic interference. However, as habitats are subject to increased alteration, anthropogenic noise becomes unavoidable, and how animals overcome such interference is not well understood. In most ecosystems, only a subset of frog species is associated with disturbed habitats; the ability of these species to overcome exogenous noise suggests that habitat associations may be related to species' response to noise. We tested the hypothesis that frogs associated with largely undisturbed forest habitat would be less likely to increase call output in response to exogenous noise than would those associated with disturbed or open habitat. While this relationship was not significant, we found a slight trend supporting the hypothesis. We then asked whether anthropogenic noise affects chorus tenure at individual- or at chorus-levels. Male frogs exposed to anthropogenic noise decreased both the number of days present at the chorus and the nightly chorus duration relative to controls. Because females generally join choruses late at night to breed, the effects of noise shown here are likely to substantially decrease frog reproductive success; thus, the acoustic environment may play an important role in shaping population dynamics and in amphibian declines.
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| 9. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 10. |
- Yang, Xiaohong R., et al.
(författare)
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Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations
- 2016
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 135:11, s. 1241-1249
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Tidskriftsartikel (refereegranskat)abstract
- The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A− cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A− PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A− PC patients. Further, nine CDKN2A+ and four CDKN2A− PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A− PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A− PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.
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