| 1. |
- Alanio, Cécile, et al.
(författare)
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Bystander hyperactivation of preimmune CD8(+) T cells in chronic HCV patients
- 2015
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Ingår i: eLife. - 2050-084X. ; 2015:4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8(+) T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8(+) T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8(+) T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.
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| 2. |
- Aydemir, Özkan, et al.
(författare)
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Polymorphisms in Intron 1 of HLA-DRA Differentially Associate with Type 1 Diabetes and Celiac Disease and Implicate Involvement of Complement System Genes C4A and C4B
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Ingår i: eLife. - 2050-084X.
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms in genes in the human leukocyte antigen (HLA) class II region comprise the most important inherited risk factors for many autoimmune diseases including type 1 diabetes (T1D) and celiac disease (CD): both diseases are positively associated with the HLA- DR3 haplotype (DRB1*03:01-DQA1*05:01-DQB1*02:01). Studies of two different populations have recently documented that T1D susceptibility in HLA-DR3 homozygous individuals isstratified by a haplotype consisting of three single nucleotide polymorphisms (“tri-SNP”) in intron 1 of the HLA-DRA gene. In this study, we use a large cohort from the longitudinal “The Environmental Determinants of Diabetes in the Young” (TEDDY) study to further refine the tri-SNP association with T1D and with autoantibody-defined T1D endotypes. We found that the tri-SNP association is primarily in subjects whose first-appearing T1D autoantibody is to insulin. In addition, we discovered that the tri-SNP is also associated with celiac disease (CD), and that the particular tri-SNP haplotype (“101”) that is negatively associated with T1D risk is positively associated with risk for CD. The opposite effect of the tri-SNP haplotype on two DR3-associated diseases can enhance and refine current models of disease prediction based on genetic risk. Finally, we investigated possible functional differences between the individuals carrying high and low-risk tri-SNP haplotypes, and found that differences in complement system genes C4A and C4B may underlie the observed divergence in disease risk.
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| 3. |
- Bakochi, Anahita, et al.
(författare)
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Cerebrospinal fluid proteome maps detect pathogen-specific host response patterns in meningitis
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Meningitis is a potentially life-threatening infection characterized by the inflammation of the leptomeningeal membranes. Many different viral and bacterial pathogens can cause meningitis, with differences in mortality rates, risk of developing neurological sequelae and treatment options. Here we constructed a compendium of digital cerebrospinal fluid (CSF) proteome maps to define pathogen-specific host response patterns in meningitis. The results revealed a drastic and pathogen-type specific influx of tissue-, cell- and plasma proteins in the CSF, where in particular a large increase of neutrophil derived proteins in the CSF correlated with acute bacterial meningitis. Additionally, both acute bacterial and viral meningitis result in marked reduction of brain-enriched proteins. Generation of a multi-protein LASSO regression model resulted in an 18-protein panel of cell and tissue associated proteins capable of classifying acute bacterial meningitis and viral meningitis. The same protein panel also enabled classification of tick-borne encephalitis, a subgroup of viral meningitis, with high sensitivity and specificity. The work provides insights into pathogen specific host response patterns in CSF from different disease etiologies to support future classification of pathogen-type based on host response patterns in meningitis.
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| 4. |
- Banerjee, Jennifer J., et al.
(författare)
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Meru couples planar cell polarity with apical-basal polarity during asymmetric cell division
- 2017
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Ingår i: eLife. - 2050-084X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Polarity is a shared feature of most cells. In epithelia, apical-basal polarity often coexists, and sometimes intersects with planar cell polarity (PCP), which orients cells in the epithelial plane. From a limited set of core building blocks (e.g. the Par complexes for apical-basal polarity and the Frizzled/Dishevelled complex for PCP), a diverse array of polarized cells and tissues are generated. This suggests the existence of little-studied tissue-specific factors that rewire the core polarity modules to the appropriate conformation. In Drosophila sensory organ precursors (SOPs), the core PCP components initiate the planar polarization of apical-basal determinants, ensuring asymmetric division into daughter cells of different fates. We show that Meru, a RASSF9/RASSF10 homologue, is expressed specifically in SOPs, recruited to the posterior cortex by Frizzled/Dishevelled, and in turn polarizes the apical-basal polarity factor Bazooka (Par3). Thus, Meru belongs to a class of proteins that act cell/tissue-specifically to remodel the core polarity machinery.
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| 5. |
- Bensch, Hanna M., et al.
(författare)
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Living with relatives offsets the harm caused by pathogens in natural populations
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Living with relatives can be highly beneficial, enhancing reproduction and survival. High relatedness can, however, increase susceptibility to pathogens. Here, we examine whether the benefits of living with relatives offset the harm caused by pathogens, and if this depends on whether species typically live with kin. Using comparative meta-analysis of plants, animals, and a bacterium (nspecies = 56), we show that high within-group relatedness increases mortality when pathogens are present. In contrast, mortality decreased with relatedness when pathogens were rare, particularly in species that live with kin. Furthermore, across groups variation in mortality was lower when relatedness was high, but abundances of pathogens were more variable. The effects of within-group relatedness were only evident when pathogens were experimentally manipulated, suggesting that the harm caused by pathogens is masked by the benefits of living with relatives in nature. These results highlight the importance of kin selection for understanding disease spread in natural populations.
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| 6. |
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| 7. |
- Bhatia, Neha, et al.
(författare)
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Quantitative analysis of auxin sensing in leaf primordia argues against proposed role in regulating leaf dorsoventrality
- 2019
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Ingår i: eLife. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Dorsoventrality in leaves has been shown to depend on the pre-patterned expression of KANADI and HD-ZIPIII genes within the plant shoot apical meristem (SAM). However, it has also been proposed that asymmetric auxin levels within initiating leaves help establish leaf polarity, based in part on observations of the DII auxin sensor. By analyzing and quantifying the expression of the R2D2 auxin sensor, we find that there is no obvious asymmetry in auxin levels during Arabidopsis leaf development. We further show that the mDII control sensor also exhibits an asymmetry in expression in developing leaf primordia early on, while it becomes more symmetric at a later developmental stage as reported previously. Together with other recent findings, our results argue against the importance of auxin asymmetry in establishing leaf polarity.
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| 8. |
- Bice, Annie R., et al.
(författare)
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Homotopic contralesional excitation suppresses spontaneous circuit repair and global network reconnections following ischemic stroke
- 2022
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Ingår i: eLife. - 2050-084X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Understanding circuit-level manipulations that affect the brain’s capacity for plasticity will inform the design of targeted interventions that enhance recovery after stroke. Following stroke, increased contralesional activity (e.g. use of the unaffected limb) can negatively influence recovery, but it is unknown which specific neural connections exert this influence, and to what extent increased contralesional activity affects systems-and molecular-level biomarkers of recovery. Here, we combine optogenetic photostimulation with optical intrinsic signal imaging (OISI) to examine how contralesional excitatory activity affects cortical remodeling after stroke in mice. Following photothrombosis of left primary somatosensory forepaw (S1FP) cortex, mice either recovered spontaneously or received chronic optogenetic excitation of right S1FP over the course of 4 weeks. Contralesional excitation suppressed perilesional S1FP remapping and was associated with abnormal patterns of stimulus-evoked activity in the unaffected limb. This maneuver also prevented the restoration of resting-state functional connectivity (RSFC) within the S1FP network, RSFC in several networks functionally-distinct from somatomotor regions, and resulted in persistent limb-use asymmetry. In stimulated mice, perilesional tissue exhibited transcriptional changes in several genes relevant for recovery. Our results suggest that contralesional excitation impedes local and global circuit reconnection through suppression of cortical activity and several neuroplasticity-related genes after stroke, and highlight the importance of site selection for therapeutic intervention after focal ischemia.
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| 9. |
- Brandariz-Nuñez, Alberto, et al.
(författare)
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Pressure-driven release of viral genome into a host nucleus is a mechanism leading to herpes infection
- 2019
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Ingår i: eLife. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Many viruses previously have been shown to have pressurized genomes inside their viral protein shell, termed the capsid. This pressure results from the tight confinement of negatively charged viral nucleic acids inside the capsid. However, the relevance of capsid pressure to viral infection has not been demonstrated. In this work, we show that the internal DNA pressure of tens of atmospheres inside a herpesvirus capsid powers ejection of the viral genome into a host cell nucleus. To our knowledge, this provides the first demonstration of a pressure-dependent mechanism of viral genome penetration into a host nucleus, leading to infection of eukaryotic cells.
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| 10. |
- Caggiano, Monica Pia, et al.
(författare)
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Cell type boundaries organize plant development
- 2017
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Ingår i: eLife. - 2050-084X.
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Tidskriftsartikel (refereegranskat)abstract
- In plants the dorsoventral boundary of leaves defines an axis of symmetry through thecentre of the organ separating the top (dorsal) and bottom (ventral) tissues. Although thepositioning of this boundary is critical for leaf morphogenesis, how the boundary is established andhow it influences development remains unclear. Using live-imaging and perturbation experimentswe show that leaf orientation, morphology and position are pre-patterned by HD-ZIPIII and KANgene expression in the shoot, leading to a model in which dorsoventral genes coordinate toregulate plant development by localizing auxin response between their expression domains.However we also find that auxin levels feedback on dorsoventral patterning by spatially organizingHD-ZIPIII and KAN expression in the shoot periphery. By demonstrating that the regulation ofthese genes by auxin also governs their response to wounds, our results also provide aparsimonious explanation for the influence of wounds on leaf dorsoventrality.
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