| 41. |
- Liu, Xueping, et al.
(författare)
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Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P=3.96×10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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| 42. |
- May, Sally K., et al.
(författare)
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New Insights into the Rock Art of Anbangbang Gallery, Kakadu National Park
- 2020
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Ingår i: Journal of field archaeology. - : Taylor & Francis Group. - 0093-4690 .- 2042-4582. ; 45:2, s. 120-134
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents findings from a recent study of the Anbangbang Gallery in the Burrungkuy (Nourlangie) site complex of Kakadu National Park, Australia. Using new technologies alongside established methods for rock art documentation, we discuss the complexity and uniqueness of Anbangbang Gallery as an icon of Australian rock art. We have taken a comprehensive approach to our investigations, deliberately linking new technologies and scientific analysis with other archaeological and anthropological research methods. In particular, using evidence from a detailed site recording, oral histories, and pXRF analysis, we explore aspects of the site chronology, the nature of painting activity, and the retouching and repainting of earlier imagery. The findings force us to rethink the existing interpretative narrative for Anbangbang Gallery, the motivations behind previously held beliefs relating to recent rock art, and the implications this has had for ongoing conservation work in the region.
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| 43. |
- Miller, Rachael, et al.
(författare)
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Socio-ecological correlates of neophobia in corvids
- 2022
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822. ; 32:1, s. 4-85
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Tidskriftsartikel (refereegranskat)abstract
- Behavioral responses to novelty, including fear and subsequent avoidance of novel stimuli, i.e., neophobia, determine how animals interact with their environment. Neophobia aids in navigating risk and impacts on adaptability and survival. There is variation within and between individuals and species; however, lack of large-scale, comparative studies critically limits investigation of the socio-ecological drivers of neophobia. In this study, we tested responses to novel objects and food (alongside familiar food) versus a baseline (familiar food alone) in 10 corvid species (241 subjects) across 10 labs worldwide. There were species differences in the latency to touch familiar food in the novel object and novel food conditions relative to the baseline. Four of seven socio-ecological factors influenced object neophobia: (1) use of urban habitat (versus not), (2) territorial pair versus family group sociality, (3) large versus small maximum flock size, and (4) moderate versus specialized caching (whereas range, hunting live animals, and genus did not), while only maximum flock size influenced food neophobia. We found that, overall, individuals were temporally and contextually repeatable (i.e., consistent) in their novelty responses in all conditions, indicating neophobia is a stable behavioral trait. With this study, we have established a network of corvid researchers, demonstrating potential for further collaboration to explore the evolution of cognition in corvids and other bird species. These novel findings enable us, for the first time in corvids, to identify the socio-ecological correlates of neophobia and grant insight into specific elements that drive higher neophobic responses in this avian family group. Video abstract: [Figure presented]
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| 44. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 45. |
- Patricios, Jon S., et al.
(författare)
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Implementation of the 2017 Berlin Concussion in Sport Group Consensus Statement in contact and collision sports: a joint position statement from 11 national and international sports organisations
- 2018
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Ingår i: British Journal of Sports Medicine. - : BMJ PUBLISHING GROUP. - 0306-3674 .- 1473-0480. ; 52:10, s. 635-641
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Tidskriftsartikel (refereegranskat)abstract
- The 2017 Berlin Concussion in Sport Group Consensus Statement provides a global summary of best practice in concussion prevention, diagnosis and management, underpinned by systematic reviews and expert consensus. Due to their different settings and rules, individual sports need to adapt concussion guidelines according to their specific regulatory environment. At the same time, consistent application of the Berlin Consensus Statements themes across sporting codes is likely to facilitate superior and uniform diagnosis and management, improve concussion education and highlight collaborative research opportunities. This document summarises the approaches discussed by medical representatives from the governing bodies of 10 different contact and collision sports in Dublin, Ireland in July 2017. Those sports are: American football, Australian football, basketball, cricket, equestrian sports, football/soccer, ice hockey, rugby league, rugby union and skiing. This document had been endorsed by 11 sport governing bodies/national federations at the time of being published.
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| 46. |
- Sarha, Dhifaf, et al.
(författare)
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161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS
- 2018
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Ingår i: Blood Advances. - : AMER SOC HEMATOLOGY. - 2473-9529 .- 2473-9537. ; 2:12, s. 1459-1469
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Tidskriftsartikel (refereegranskat)abstract
- Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 x CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)-treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE-treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE-treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.
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| 47. |
- Takaro, Tim K., et al.
(författare)
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The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study : assessment of environmental exposures
- 2015
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Ingår i: Journal of Exposure Science and Environmental Epidemiology. - New York : Nature Publishing Group. - 1559-0631 .- 1559-064X. ; 25:6, s. 580-592
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Tidskriftsartikel (refereegranskat)abstract
- The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3-4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set.
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| 48. |
- Trotter, Dinko E. Gonzalez, et al.
(författare)
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In Vivo Imaging of the Programmed Death Ligand 1 by F-18 PET
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 58:11, s. 1852-1857
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Tidskriftsartikel (refereegranskat)abstract
- Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-Z(PD-L1_1) with F-18 and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1-binding Affibody ligand Z(PD-L1_1) was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of F-18-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by gamma-counting biodistribution. Immunohistochemical staining with an antibody specific for anti-PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-Z(PD-L1_1) was labeled, with a radiochemical yield of 15.1% +/- 5.6%, radiochemical purity of 96.7% +/- 2.0%, and specific activity of 14.6 +/- 6.5 GBq/mu mol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD-L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 +/- 0.33) and -negative (% ID/g = 0.32 +/- 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.
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