| 1. |
- Aad, G, et al.
(author)
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- 2015
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
- Sanchez, Erlan, et al.
(author)
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Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative
- 2024
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In: Alzheimer's and Dementia. - 1552-5260 .- 1552-5279. ; 20:3, s. 1753-1770
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Journal article (peer-reviewed)abstract
- INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40. DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.
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| 4. |
- El Omari, Kamel, et al.
(author)
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Experimental phasing opportunities for macromolecular crystallography at very long wavelengths
- 2023
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In: Communications Chemistry. - : Nature Publishing Group. - 2399-3669. ; 6:1
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Journal article (peer-reviewed)abstract
- Despite recent advances in cryo-electron microscopy and artificial intelligence-based model predictions, a significant fraction of structure determinations by macromolecular crystallography still requires experimental phasing, usually by means of single-wavelength anomalous diffraction (SAD) techniques. Most synchrotron beamlines provide highly brilliant beams of X-rays of between 0.7 and 2 Å wavelength. Use of longer wavelengths to access the absorption edges of biologically important lighter atoms such as calcium, potassium, chlorine, sulfur and phosphorus for native-SAD phasing is attractive but technically highly challenging. The long-wavelength beamline I23 at Diamond Light Source overcomes these limitations and extends the accessible wavelength range to λ = 5.9 Å. Here we report 22 macromolecular structures solved in this extended wavelength range, using anomalous scattering from a range of elements which demonstrate the routine feasibility of lighter atom phasing. We suggest that, in light of its advantages, long-wavelength crystallography is a compelling option for experimental phasing.
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| 5. |
- Lin, Audrey T., et al.
(author)
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The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge
- 2023
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In: Science. - 0036-8075 .- 1095-9203. ; 382:6676, s. 1303-1308
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Journal article (peer-reviewed)abstract
- Ancestral Coast Salish societies in the Pacific Northwest kept long-haired woolly dogs that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton", collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.
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| 6. |
- Northcott, Paul A, et al.
(author)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Journal article (peer-reviewed)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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| 7. |
- Timofeeva, Maria N, et al.
(author)
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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10(-7) and OR = 1.09, P = 7.4 × 10(-8)); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10(-6)). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10(-4)) and DNA mismatch repair genes (P = 6.1 × 10(-4)) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
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| 8. |
- Bollati, Michela, et al.
(author)
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Structure and functionality in flavivirus NS-proteins : perspectives for drug design
- 2010
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In: Antiviral Research. - : Elsevier BV. - 0166-3542 .- 1872-9096. ; 87:2, s. 125-148
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Research review (peer-reviewed)abstract
- Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads.
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| 9. |
- Law, Andrew M. K., et al.
(author)
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ALTEN: A High‐Fidelity Primary Tissue‐Engineering Platform to Assess Cellular Responses Ex Vivo
- 2022
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In: Advanced Science. - : John Wiley & Sons. - 2198-3844. ; 9:21
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Journal article (peer-reviewed)abstract
- To fully investigate cellular responses to stimuli and perturbations within tissues, it is essential to replicate the complex molecular interactions within the local microenvironment of cellular niches. Here, the authors introduce Alginate-based tissue engineering (ALTEN), a biomimetic tissue platform that allows ex vivo analysis of explanted tissue biopsies. This method preserves the original characteristics of the source tissue's cellular milieu, allowing multiple and diverse cell types to be maintained over an extended period of time. As a result, ALTEN enables rapid and faithful characterization of perturbations across specific cell types within a tissue. Importantly, using single-cell genomics, this approach provides integrated cellular responses at the resolution of individual cells. ALTEN is a powerful tool for the analysis of cellular responses upon exposure to cytotoxic agents and immunomodulators. Additionally, ALTEN's scalability using automated microfluidic devices for tissue encapsulation and subsequent transport, to enable centralized high-throughput analysis of samples gathered by large-scale multicenter studies, is shown.
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| 10. |
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