| 1. |
- Ananthaseshan, S., et al.
(författare)
-
Red blood cell distribution width is associated with increased interactions of blood cells with vascular wall
- 2022
-
Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- The mechanism underlying the association between elevated red cell distribution width (RDW) and poor prognosis in variety of diseases is unknown although many researchers consider RDW a marker of inflammation. We hypothesized that RDW directly affects intravascular hemodynamics, interactions between circulating cells and vessel wall, inducing local changes predisposing to atherothrombosis. We applied different human and animal models to verify our hypothesis. Carotid plaques harvested from patients with high RDW had increased expression of genes and proteins associated with accelerated atherosclerosis as compared to subjects with low RDW. In microfluidic channels samples of blood from high RDW subjects showed flow pattern facilitating direct interaction with vessel wall. Flow pattern was also dependent on RDW value in mouse carotid arteries analyzed with Magnetic Resonance Imaging. In different mouse models of elevated RDW accelerated development of atherosclerotic lesions in aortas was observed. Therefore, comprehensive biological, fluid physics and optics studies showed that variation of red blood cells size measured by RDW results in increased interactions between vascular wall and circulating morphotic elements which contribute to vascular pathology.
|
|
| 2. |
- Duffy, J. M. N., et al.
(författare)
-
Top 10 priorities for future infertility research: an international consensus development study
- 2020
-
Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 35:12, s. 2715-2724
-
Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from I I countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda.
|
|
| 3. |
- Ferrari, Raffaele, et al.
(författare)
-
Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
-
Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
-
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.
|
|
| 4. |
- Fresard, Laure, et al.
(författare)
-
Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
-
Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
-
Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
|
|
| 5. |
- MacKenzie, Jordan, et al.
(författare)
-
Turbulent stress measurements of fiber suspensions in a straight pipe with MRV
- 2016
-
Ingår i: Paper Conference and Trade Show, PaperCon 2016. ; , s. 1024-1031
-
Konferensbidrag (refereegranskat)abstract
- The focus of the present work is an experimental study of the behaviour of semi-dilute, opaque fibre suspensions in fully developed cylindrical pipe flows. Measurements of the normal and turbulent shear stress components and the mean flow were acquired using phase-contrast magnetic resonance velocimetry. Two fibre types, namely, pulp fibre and nylon fibre, were considered in this work and are known to differ in elastic modulus. In total, three different mass concentrations and seven Reynolds numbers were tested to investigate the effects of fibre interactions during the transition from the plug flow to fully turbulent flow. It was found that in fully turbulent flows of nylon fibres, the normal, uzuz+, and shear, uzur+ (note that · is the temporal average, u is the fluctuating velocity, z is the axial or streamwise component, and r is the radial direction), turbulent stresses increased with Reynolds number regardless of the crowding number (a concentration measure). For pulp fibre, the turbulent stresses increased with Reynolds number when a fibre plug was present in the flow and were spatially similar in magnitude when no fibre plug was present. Pressure spectra revealed that the stiff, nylon fibre reduced the energy in the inertial-subrange with an increasing Reynolds and crowding number, whereas the less stiff pulp fibre effectively cuts the energy cascade prematurely when the network was fully dispersed.
|
|
| 6. |
- MacKenzie, Jordan, et al.
(författare)
-
Turbulent stress measurements of fibre suspensions in a straight pipe
- 2018
-
Ingår i: Physics of fluids. - : AIP Publishing. - 1070-6631 .- 1089-7666. ; 30:2
-
Tidskriftsartikel (refereegranskat)abstract
- The focus of the present work is an experimental study of the behaviour of semi-dilute, opaque fibre suspensions in fully developed cylindrical pipe flows. Measurements of the normal and turbulent shear stress components and the mean flow were acquired using phase-contrast magnetic resonance velocimetry. Two fibre types, namely, pulp fibre and nylon fibre, were considered in this work and are known to differ in elastic modulus. In total, three different mass concentrations and seven Reynolds numbers were tested to investigate the effects of fibre interactions during the transition from the plug flow to fully turbulent flow. It was found that in fully turbulent flows of nylon fibres, the normal, uzuz+, and shear, uzur+ (note that · is the temporal average, u is the fluctuating velocity, z is the axial or streamwise component, and r is the radial direction), turbulent stresses increased with Reynolds number regardless of the crowding number (a concentration measure). For pulp fibre, the turbulent stresses increased with Reynolds number when a fibre plug was present in the flow and were spatially similar in magnitude when no fibre plug was present. Pressure spectra revealed that the stiff, nylon fibre reduced the energy in the inertial-subrange with an increasing Reynolds and crowding number, whereas the less stiff pulp fibre effectively cuts the energy cascade prematurely when the network was fully dispersed.
|
|
| 7. |
- MacKenzie, Jordan, et al.
(författare)
-
Turbulent stress measurements with phase-contrast magnetic resonance through tilted slices
- 2017
-
Ingår i: Experiments in Fluids. - : Springer Verlag. - 0723-4864 .- 1432-1114. ; 58
-
Tidskriftsartikel (refereegranskat)abstract
- Aiming at turbulent measurements in opaque suspensions, a simplistic methodology for measuring the turbulent stresses with phase-contrast magnetic resonance velocimetry is described. The method relies on flow-compensated and flow-encoding protocols with the flow encoding gradient normal to the slice. The experimental data is compared with direct numerical simulations (DNS), both directly but also, more importantly, after spatial averaging of the DNS data that resembles the measurement and data treatment of the experimental data. The results show that the most important MRI data (streamwise velocity, streamwise variance and Reynolds shear stress) is reliable up to at least r¯=0.75'>r¯=0.75r¯=0.75 without any correction, paving the way for dearly needed turbulence and stress measurements in opaque suspensions.
|
|
| 8. |
- Manzoni, Claudia, et al.
(författare)
-
Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
-
Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
|
|
| 9. |
- Van Deerlin, Vivian M, et al.
(författare)
-
Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
|
|
