| 1. |
- Groopman, Emily E., et al.
(author)
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Diagnostic Utility of Exome Sequencing for Kidney Disease
- 2019
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:2, s. 142-151
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Journal article (peer-reviewed)abstract
- BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.
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| 2. |
- Groot, Colin, et al.
(author)
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Differential patterns of gray matter volumes and associated gene expression profiles in cognitively-defined Alzheimer's disease subgroups
- 2021
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In: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 30
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Journal article (peer-reviewed)abstract
- The clinical presentation of Alzheimer's disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences.
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| 3. |
- Lieberman, J, et al.
(author)
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Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection
- 2001
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 98:6, s. 1667-1677
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Journal article (peer-reviewed)abstract
- CD8 T cells play an important role in protection and control of HIV-1 by direct cytolysis of infected cells and by suppression of viral replication by secreted factors. However, although HIV-1–infected individuals have a high frequency of HIV-1–specific CD8 T cells, viral reservoirs persist and progressive immunodeficiency generally ensues in the absence of continuous potent antiviral drugs. Freshly isolated HIV-specific CD8 T cells are often unable to lyse HIV-1–infected cells. Maturation into competent cytotoxic T lymphocytes may be blocked during the initial encounter with antigen because of defects in antigen presentation by interdigitating dendritic cells or HIV-infected macrophages. The molecular basis for impaired function is multifactorial, due to incomplete T-cell signaling and activation (in part related to CD3ζ and CD28 down-modulation), reduced perforin expression, and inefficient trafficking of HIV-specific CD8 T cells to lymphoid sites of infection. CD8 T-cell dysfunction can partially be corrected in vitro with short-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a significant causal or exacerbating role. Functional defects are qualitatively different and more severe with advanced disease, when interferon γ production also becomes compromised.
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| 4. |
- Owen, Michael C., et al.
(author)
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Effects of in vivo conditions on amyloid aggregation
- 2019
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In: Chemical Society Reviews. - : Royal Society of Chemistry (RSC). - 0306-0012 .- 1460-4744. ; 48:14, s. 3946-3996
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Research review (peer-reviewed)abstract
- One of the grand challenges of biophysical chemistry is to understand the principles that govern protein misfolding and aggregation, which is a highly complex process that is sensitive to initial conditions, operates on a huge range of length- and timescales, and has products that range from protein dimers to macroscopic amyloid fibrils. Aberrant aggregation is associated with more than 25 diseases, which include Alzheimer's, Parkinson's, Huntington's, and type II diabetes. Amyloid aggregation has been extensively studied in the test tube, therefore under conditions that are far from physiological relevance. Hence, there is dire need to extend these investigations to in vivo conditions where amyloid formation is affected by a myriad of biochemical interactions. As a hallmark of neurodegenerative diseases, these interactions need to be understood in detail to develop novel therapeutic interventions, as millions of people globally suffer from neurodegenerative disorders and type II diabetes. The aim of this review is to document the progress in the research on amyloid formation from a physicochemical perspective with a special focus on the physiological factors influencing the aggregation of the amyloid-beta peptide, the islet amyloid polypeptide, alpha-synuclein, and the hungingtin protein.
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| 5. |
- Rasmuson, S, et al.
(author)
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Alzheimer's disease and hormones
- 2004
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In: Encyclopedia of Endocrine Diseases.. - : Academic Press, San Diego. - 0124755704
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Book chapter (other academic/artistic)
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| 6. |
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| 7. |
- Sjöberg, Sofia, 1975-
(author)
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The utility gain of leaving professional judgment outside of prediction : Clinical versus mechanical interpretation of GMA and personality
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Other publication (other academic/artistic)abstract
- Purpose – The purpose of this study was to analyze and illustrate the margin utility of using clinical versus mechanical data combination for personnel selection purposes using measures of personality and general mental ability as predictors of job performance.Design/methodology/approach – By utilizing meta-analytic estimates for personality and general mental ability to predict job performance, and for clinical versus mechanical data combination predicting work criteria, utility analysis was applied to estimate the margin utility between data combination approach for different selection scenarios.Findings – The findings indicate that in a selection context, the difference in financial outcome is likely to be extensive between the two data combination methods. The gain in utility of combining data mechanically corresponds to an amount likely to represent the difference between failure and success for many organizations.Implications – This comparison provide professionals with the opportunity to gain insight into the difference in financial outcome of applying data combination method and by that increase the likelihood of acceptance and use of the mechanical approach. It also provides the reader with an example of how to utilize estimates provided by research, how to apply them for data combination purposes, and how to estimate the margin utility in their own selection practice.Originality/value – This is the first study to illustrate the superiority of mechanical data combination compared to clinical for job performance and selection purposes in financial terms.
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| 8. |
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| 9. |
- Tschirren, Barbara, et al.
(author)
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Natural selection acts in opposite ways on correlated hormonal mediators of prenatal maternal effects in a wild bird population
- 2014
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In: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 17:10, s. 1310-1315
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Journal article (peer-reviewed)abstract
- Maternal hormones are important mediators of prenatal maternal effects. Although many experimental studies have demonstrated their potency in shaping offspring phenotypes, we know remarkably little about their adaptive value. Using long-term data on a wild collared flycatcher (Ficedula albicollis) population, we show that natural selection acts in opposite ways on two maternally derived androgens, yolk androstenedione (A4) and yolk testosterone (T). High yolk A4 concentrations are associated with higher fitness, whereas high yolk T concentrations are associated with lower fitness. Natural selection thus favours females that produce eggs with high A4 and low T concentrations. Importantly, however, there exists a positive (non-genetic) correlation between A4 and T, which suggests that females are limited in their ability to reach this adaptive optimum. Thereby, these results provide strong evidence for an adaptive value of differential maternal androgen deposition, and a mechanistic explanation for the maintenance of variation in maternal investment in the wild.
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| 10. |
- Tschirren, Barbara, et al.
(author)
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Polymorphisms at the innate immune receptor TLR2 are associated with Borrelia infection in a wild rodent population
- 2013
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In: Royal Society of London. Proceedings B. Biological Sciences. - : The Royal Society. - 1471-2954. ; 280:1759
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Journal article (peer-reviewed)abstract
- The discovery of the key role of Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding of vertebrate defence against pathogens. Yet, despite their central role in pathogen recognition and defence initiation, there is little information on how variation in TLRs influences disease susceptibility in natural populations. Here, we assessed the extent of naturally occurring polymorphisms at TLR2 in wild bank voles (Myodes glareolus) and tested for associations between TLR2 variants and infection with Borrelia afzelii, a common tick-transmitted pathogen in rodents and one of the causative agents of human Lyme disease. Bank voles in our population had 15 different TLR2 haplotypes (10 different haplotypes at the amino acid level), which grouped in three well-separated clusters. In a large-scale capture-mark-recapture study, we show that voles carrying TLR2 haplotypes of one particular cluster (TLR2(c2)) were almost three times less likely to be Borrelia infected than animals carrying other haplotypes. Moreover, neutrality tests suggested that TLR2 has been under positive selection. This is, to our knowledge, the first demonstration of an association between TLR polymorphism and parasitism in wildlife, and a striking example that genetic variation at innate immune receptors can have a large impact on host resistance.
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